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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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November 21, 2014

Amgen Claims It All

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Posted by Derek

There's plenty of excitement about PCSK9, the latest LDL-lowering pathway to make it deep into the clinic. You can tell that companies (and investors) have high hopes for it, since it's heading right into a market that's dominated by generic statins. The optimism may well be justified - for example, Sanofi and Regeneron recently presented some impressive data comparing their antibody to Zetia in patients who can't take higher statin doses, and Amgen has shown similar numbers. There are at least five antibodies and one RNAi in development, in a very tight race to the FDA and to the market. To give you an idea, the latest development was Sanofi and Regeneron paying cash to Biomarin for an FDA priority voucher that reduces their review time to six months instead of ten. (No, I didn't know that you could do that, either).

Amgen, though, appears to be trying to own the whole racetrack. They're pushing a patent claim to any antibody to PCSK9, not just their own agent. Update: See below for more on this Here's their press release; they're quite up front about this strategy. But I have doubts about how well that's going to work. Over the years, the judicial trend seems to have been to not go for such broad claims in the biomedical field. There are so many potential antibodies to any given protein, and so many ways of modifying them and dosing them, that I find it hard to imagine a straight patent claim on all that space. It's a lot like claiming "All inhibitors of enzyme X" in small molecules, and we already know that such claims don't stand up. It wouldn't surprise me, in fact, if someone had already tried a broad antibody claim like this and had it shot down (does anyone have an example?)

So I don't think that the PCSK9 struggle is going to be decided by the patent lawyers. It looks to be fought out in the clinic, at the FDA, and especially out there in the real market. And it will be quite something to see.

Update: see the comments section. Amgen doesn't seem to be claiming every single antibody; just those against a particular epitope (although a very useful epitope, obviously). And patent litigation in such situations is complex, with precedents (none of them necessarily exact) going both ways. So this will be quite something to watch. Perhaps Amgen is hoping to paid a cut to go away?

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP

November 4, 2014

Compensating Inventors: Good Idea Or Not?

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Posted by Derek

As an inventor of a new drug here in the US, you are most certainly on the patents that have been filed around it. What do these patents earn for you? Well, in the US, they earn you a hearty handshake (like the one that W. C. Fields used to get when he stopped a bank robber). And this is made clear when you sign up with a company: you assign the rights to your inventions to the company, and if you don't wish to do that, you can go somewhere else and do something else for a living. You may well get a raise or a promotion on the strength of your work (or not!), but the fact of being an inventor on one of the few lucrative pharma patents has no direct effects.

That's not the case in many companies. Germany, for one, is well known to have a patent remuneration system: under German law, those listed as inventors on a patent are entitled to compensation, and that includes a share of the profit that an invention generates. France is somewhat similar, and several other European countries have at least partial compensation as a concept in their patent laws (here's a PDF on the topic). Those variations are complex: in some cases, the invention has to be of "outstanding" value, and in others, the compensation is not automatic, or the inventor has to demonstrate that their salary, etc. was not fair remuneration for the value of the invention to their employer. Germany is pretty clear-cut, though.

And in recent years, China has put in a similar system. Chinese patent law is not for the faint of heart, that's for sure. It's still an evolving system, since a coherent intellectual property regime was not a priority during most of the last century. Large regulatory changes are still taking place, and doubtless will do so in the future. And it's a lively area, because Chinese companies sue each other with great vigor and frequency over IP issues, which can mean a lot of court decisions to keep up with. No, you're going to want to pay some hard-working folks a lot of money if you want to get seriously into Chinese patents. Even then, you will be afflicted by doubts as to how much protection these patents afford you.

In 2010, Chinese patent law changed, and one change was the emphasis on inventor compensation. The law states that the inventor or inventors should be paid "a reasonable rumuneration" based on the use of the patented invention, and it was also stated that this applies to all businesses that have Chinese patents, regardless of the nationalities of the inventors. I'm not sure if it's been completely worked out in the courts what "reasonable" might mean. That link above goes on to mention that other clauses of the law have it that a company should have a set scheme for remuneration in its contacts with its employees, or a standard corporate policy on it. If nothing like that is in place, the inventor is supposed to get no less than 2% of the annual profits. Definitely worth knowing about if you're doing business there.

Discussion of these compensation plans always comes down to a discussion of inventorship. That can be a bit contentious in the US, but such disagreements are nothing compared to the elbow-throwing under the German system (as can be easily imagined). Not too many drug patents ever make money, but the ones that do can make vast amounts, and being an inventor on one of those is very desirable indeed. What happens, I believe, is that a separate bureaucracy develops just to make sure that all questions of inventorship have been settled correctly. Did you make the "inventive step", or were you just carrying out the inventive step of someone else? Did your contribution rise to the level of such an inventive step, to start with? How well did you document that? And so on.

At one time, I thought that the inventor-compensation idea was hard to beat. I still wouldn't mind the money, should I happen to ever get on a patent that makes some. But over time, I've come to wonder about the downsides. Under such a system, there is less incentive for people to throw ideas around in an informal setting. Those lead to disputes about just who said what and when. No, you tend to keep those ideas to yourself until you can get them written down and dated, with your name on them, and I can't help but think that this puts a bit of sand in the gears of discovery. If you're always watching your back, that level of inhibition might be enough to keep you from having as many ideas as you might, in general - it doesn't take much.

Comments (68) + TrackBacks (0) | Category: Patents and IP

October 28, 2014

An Open-Source Cancer Pitch, Deconstructed

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Posted by Derek

I'm confused. Read this and see if you end up the same way. TechCrunch has the story of Isaac Yonemoto, who's crowdsourcing a project around a potential oncology compound. It's a derivative of sibiromycin, a compound I hadn't come across, but it seems that it was first studied in Russia, and then at Maryland. Yonemoto's own work on the compound is in this paper from 2012, which looks reasonable. (Here's more). And the crowdfunding pitch is also reasonable, in lay-audience terms:

The drug candidate 9DS was developed at the University of Maryland. The last work done on the drug showed that it had activity against cancer competitive with leading cancer drugs such as taxol. Moreover, 9DS is also likely to have lower side effects than most chemotherapies, since a related compound, SJG-136, seems to have low side effects in early clinical trials.

Project Marilyn involves: production of more 9DS, and submitting 9DS to a xenograft study ('curing cancer in mice'). This is the next step in drug development and an important one on the way to doing clinical (human) studies. The process we're seeking to fund should take approximately 6 months. If we recieve more funding, we will add stretch goals, such as further preclinical experiments on 9DS, development 9DS analogs, or other exciting anti-cancer ideas.

But here's where things begin to swerve off into different territory. Yonemoto isn't just talking about some preclinical spadework on yet another oncology compound (which is what the project actually is, as far as I can tell). He's pitching it in broader terms:

. . .Some drugs can cost upwards of $100,000 a year, bankrupting patients. This level of expense is simply unacceptable, especially since 1/3 of people will get cancer in their lifetime.

One solution to this problem is to develop unpatented drugs - pharmaceutical companies will have to sell them at a reasonable price. To those who believe that drugs cannot be made without patents we remind them:

When Salk and Sabin cured polio, they didn't patent the vaccine. It's time to develop a patent-free anticancer drug for the 21st century.

The software industry and the open-source movement have shown that patenting is not necessary for innovation. Releasing without a patent means the drugs will be cheaper and it will be easier to build on the work to make improved drugs or drug combinations. Releasing without a patent means expanded access to drugs in countries that can't afford extensive licensing and export agreements.

OK, let's take this one apart, piece by piece, in good old classic blogging style. Yes, some oncology drugs are indeed very expensive. This is more of a problem for insurance companies and governments, since they're paying nearly all of these costs, but the topic of drug prices in oncology has come up around here many times, and will do so again. It's especially worrisome for me that companies are already up close to the what-the-market-will-possibly-bear price with things that are not exactly transformative therapies (what pricing structure will those have?)

But are unpatented drugs the solution? It seems to me that pharmaceutical companies will not "have to sell them at a reasonable price". Rather, unpatented compounds will simply not become drugs. Yonemoto, like so many others who have not actually done drug development, is skipping over the longest, most difficult, and most expensive parts of the process. Readers of the crowdsourcing proposal might be forgiven if they don't pick up on this, but getting a compound to work in some mouse xenograft models does not turn it into a drug. Preparing a compound to go into human trials takes a lot more than that: a reliable scale-up route to the compound itself, toxicology studies, more detailed pharmacokinetic studies, formulation studies. This can't be done by a handful of people: a handful of people don't have the resources and expertise. And that's just setting the stage for the real thing: clinical trials in humans. That crowdsourcing proposal skates over it, big-time, but the truth is that the great majority of money in drug development is spent in the clinic. The amount of money Yonemoto is raising, which is appropriate for the studies he's planning, is a roundoff error in the calculations for a decent clinical campaign.

So who's going to do all that? A drug company. Are they going to take that on with an unpatented compound that they do not own? They are not. Another thing that a lay reader won't get from reading Yonemoto's proposal is that the failure rate for new oncology compounds in the clinic is at least 90%, and probably more like 95. If you are going to spend all that money developing compounds that don't make it, you will need to make some money when one of them finally does. If a compound has no chance of ever doing that, no one's even going to go down that road to start with.

Now we get to the Salk/Sabin patent example. There are plenty of persistent myths about the polio vaccine story (this book review at Technology Review is a good intro to the subject). Jonas Salk created one of the most enduring myths when he famously told Edward R. Murrow in an interview that "There is no patent. Would you patent the sun?". But the idea of patenting his injected, killed-virus vaccine had already been looked into, and lawyers had determined that any application would be invalidated by prior art. (Salk himself, in his late work on a possible HIV vaccine, did indeed file patent applications).

Sabin's oral attenuated-virus vaccine, on the other hand, was indeed deliberately never patented. But this does not shed much light on the patenting of drugs for cancer. The Sabin polio vaccine protected all comers after a single dose. The public health implications of a polio vaccine were obvious and immediate: polio was everywhere, and anyone could get it. But Yonemoto's 9SDS is not in that category: cancer is not a single disease like polio, and is not open to a single cure. Even if a sibiromycin derivative makes it to market (and they've been the subject of research for quite a while now), it will do what almost every other cancer drug does: help some people, to a degree, for a while. The exceptions are rare: patients who have a tumor type that is completely dependent on a particular mechanism, and that doesn't mutate away from that phenotype quickly enough. Most cancer patients aren't that fortunate.

So here's the rough part of cancer drug discovery: cancer, broadly speaking, is indeed a big public health issue. But we're not going to wipe it out the way the polio and smallpox vaccines wiped out their homogeneous diseases. Cancer isn't caused by a human-specific infectious agent that we can eliminate from the world. It crops up over and over again as our cells divide, in thousands of forms, and fighting it is going to take tremendous diagnostic skill and an array of hundreds of different therapies, most of which we haven't discovered yet. And money. Lots of money.

So when Yonemoto says that "The software industry and the open-source movement have shown that patenting is not necessary for innovation", he's comparing apples and iguanas. Drug discovery is not like coding, unfortunately: you're not going to have one person from San Jose pop up and add a chlorine atom to the molecule while another guy pulls an all-nighter in St. Louis and figures out the i.v. formulation for the rat tox experiments. The pitch on Indysci.org, which is really about doing some preliminary experiments, makes it sound like the opening trumpet of a drug discovery revolution and that it's going to lead to "releasing" a drug. That's disingenuous, to say the least. I wish Yonemoto luck, actually, but I think he's going to be running into some very high-density reality pretty soon.

Update: Yonemoto has added this to the comments section, and I appreciate him coming by:

"Thanks Derek! You've basically crystallized all of my insecurities about the future of open-source drugs. But that's okay. I think there are business models wherein you can get this to work, even under the relatively onerous contemporary FDA burden. To answer a few questions. I think sibiromycin is not a bad candidate for several reasons: 1. (I'm not sure I buy this one but) it's a NP derived and NP derived tends to do well. 2. A molecule with a similar mechanism has made it into phase III and phase I/II show only mild hepatotoxicity and water retention, which are prophylactically treatable with common drugs. 3. There is reportedly no bone marrow suppression in these compounds, and importantly it appears to be immune-neutral, which would make PBDs excellent therapies to run alongside immune-recruitment drugs."

Comments (58) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development | Drug Industry History | Infectious Diseases | Patents and IP

August 11, 2014

Is The Current Patent System Distorting Cancer Research?

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Posted by Derek

Via the Economist's "Free Exchange" blog comes this provocative paper (PDF) from the University of Chicago, Harvard, and MIT. Its authors are looking at the effect of patents on the oncology drug market, and they conclude that the current system is probably hurting patients (and the broader economy).

That's a big statement to make, so the first thing to do is dig into the paper and see how it was arrived at. The authors are looking at effective patent terms: how long an invention really has an exclusive market term. That's a big issue in drug development, of course, since the regulatory pathway to approval can be so long that only a few years are left on the patent by the time a drug can be sold.

. . .Since society cares about an invention’s total useful life, but private firms care only about monopoly life, a distortion emerges not just in the level of R&D (as arises in standard models), but also in the composition of R&D: society might value invention A more highly than invention B, but private industry may choose to develop B but not A. Note that, other things equal, commercialization lag lowers both monopoly life and total useful life: both society and private firms prefer inventions to reach the market quickly. But, under a fixed patent term, commercialization lag reduces monopoly life more rapidly than total useful life, hence the distortion away from inventions with both a long total useful life and a long commercialization lag.

The problem with oncology, the paper claims, is that drug firms therefore have an incentive to work on compounds whose clinical trials are shorter, because they have a better chance of a longer effective patent lifetime). Slow-moving cancers, which might be more treatable, are relatively neglected, because there is less likelihood of return from them given the patent timelines.

Cancer drug development tends to be specific to a cancer type (e.g. prostate) and stage of disease (e.g. metastatic). . .providing a natural framework for estimating how expected commercialization lags (as proxied by survival time) and R&D investments vary across different groups of patients. Aggregating survival information from patient-level cancer registry data, we document stark variation in survival times across patients of different cancer types and stages of disease. In order to measure R&D investments on cancer treatments relevant to each cancer type and stage of disease, we use newly-constructed data from a clinical trial registry that has cataloged cancer clinical trials since the 1970s. The key feature of this data which makes it amenable to our analysis is that for each clinical trial, the registry lists each of the specific patient groups eligible to enroll in the trial - thus allowing a match between our measures of expected commercialization lag (as measured by survival time) and R&D activity (as measured by clinical trial investments) across cancer types and stages of disease.

They show that there is much more clinical focus on the severe short-time-course cancers than on the slow-moving localized types, and they ascribe this to distortion caused by patent terms. But as far as I can tell, the authors don't consider some other factors, and as someone who's done drug discovery work in oncology, I'd like to bring these out as well.

There's no doubt that patent lifetimes are a factor, since these allow a company to recoup its development costs - and the costs of all the other failed projects. It's worth remembering that the overall clinical failure rate is still roughly 90%, so there are a lot of costs to be made up whenever sometime actually does work. But imagine that patent terms were suddenly doubled to forty years instead of twenty. This might bring in more investment into slower-moving long-term cancer projects, but I don't think it would be as simple as this paper's model suggests. Overall, a drug company would prefer not to tie up its time, effort, and capital for longer than necessary in the uncertain business of a clinical trial. Even with the prospect of a longer patent term reward at the end of the process, the disincentive for multiyear trials would still be there, because there are so many shorter alternatives in oncology. (That's as opposed to Alzheimer's, where it's long trials or nothing, at least until we understand a lot more about the disease). It's not like the slower-moving cancers are any easier to understand, find targets for, or progress into the clinic: they're all hard.

This is even more the case when you consider that the oncology field has a good number of small companies in it. The barriers to oncology drug development are lower than in some other areas - it's easier to identify patients, and there's a lot of unmet medical need. And those relatively short clinical trial times are another incentive: to do another thought experiment, if you suddenly required all drug companies working on oncology to work only on the slower-moving cancers, there would be far fewer drugs in development, since most of the smaller companies would drop out. They don't have the funds to keep going that long. So while short clinical trials may be a distortion in one direction, they have distorted the market in another, arguably beneficial direction as well, by bringing more companies and more ideas into the field.

I say "beneficial", because some of the drug mechanisms that are being tried on the faster-moving cancers would also be of use on the slower, more localized ones. The genomic, metabolic, and proteomic information learned by studying the faster-moving varieties (and the techniques used to do so) are immediately applicable to the slower-moving ones as well. It's not a zero-sum game.

There's also that unmet-medical-need factor to consider. It's easier for a company, especially a small one, to raise money and justify its spending to investors when it's working against form of cancer with a low survival rate and a relatively fast progression. The belief is that the regulatory barriers to approval are lower for such drugs, and that uptake by physicians would be faster if the drug gets approved. Side effects are also going to be more tolerated for more severe conditions, too, and oncology drugs, as is well known, tend to have some pretty significant ones.

The authors, after considering several alternatives, present evidence that when regulatory agencies allow surrogate endpoints as a factor for drug approval that investment in the longer-term cancers improves. They suggest that research into validated markers of this sort could have the best returns overall, compared to other possibilities (such as just lengthening patent terms, not that that's going to happen in the real world, anyway). And I agree with them there - but I also note that drug companies themselves have been seeking such surrogate endpoints on their own, for the same reasons. (These things speed up all trials, not just the longer ones). Large incentives for good clinical trial markers already exist, but such markers are pretty damned hard to come by, unfortunately.

But as for the main subject of this paper and its explanatory power, I'm not quite convinced. As far as I can see from going through the manuscript, none of the other factors mentioned above have been considered - everything is tied to the effective patent lifetime. And while that's probably real, and a partial surrogate for some of these issues, I have trouble buying it as the only thing that's going on. Now, this may be what economists do: find a correlation that is open to a mathematical treatment and run with it. But I don't see how you can make statements this sweeping without going into more of what (from my perspective) I see as the real world of drug discovery and development.

Comments (13) + TrackBacks (0) | Category: Cancer | Clinical Trials | Patents and IP

July 21, 2014

The Hep C Field Gets Nastier By the Minute

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Posted by Derek

What a mess there is in the hepatitis C world. Gilead is, famously, dominating the market with Sovaldi, whose price has set off all sorts of cost/benefit debates. The companies competing with them are scrambling to claim positions, and the Wall Street Journal says that AbbVie is really pulling out all the stops. Try this strategy on for size:

In a lawsuit filed in February, AbbVie noted it patented the idea of combining two of Gilead's drugs—Sovaldi and an experimental drug called ledipasvir, which Gilead plans to combine into one treatment—and is therefore entitled to monetary damages if Gilead brings the combination pill to market. Legally, AbbVie can't market Sovaldi or ledipasvir because it doesn't have the patents on the underlying compounds. But it is legal for companies to seek and obtain patents describing a particular "method of use" of products that don't belong to them.

Gilead disputes the claims of AbbVie and the other companies. A spokeswoman said Gilead believes it has the sole right to commercialize Sovaldi and products containing Sovaldi's active ingredient, known as sofosbuvir. An AbbVie spokeswoman said the company believes Gilead infringes its patents, and that it stands behind the validity and enforceability of those patents.

You don't see that very often, and it's a good thing. Gilead is, naturally, suing Abbvie over this as well, saying that Abbvie has knowing mispresented to the USPTO that they invented the Gilead therapies. I'm not sure how that's going to play out: Abbvie didn't have to invent the drugs to get a method-of-use patent on them. At the same time, I don't know what sort of enablement Abbvie's patent claims might have behind them, given that these are, well, Gilead's compounds. The company is apparently claiming that a "sophisticated computer model" allows them to make a case that these combinations would be the effective ones, but I really don't know if that's going to cut it (and in fact, I sort of hope it doesn't). But even though I'm not enough of a patent-law guy to say either way, I'm enough of one to say, with great confidence, that this is going to be a very expensive mess to sort out. Gilead's also in court with Merck (and was with Idenix before Merck bought them), and with Roche, and will probably be in court with everyone else before all this is over.

This whole situation reminds me of one of those wildlife documentaries set around a shrinking African watering hole. A lot of lucrative drugs have gone off patent over the last few years, and a lot of them are heading that way soon. So any new therapeutic area with a lot of commercial promise is going to get a lot of attention, and start a lot of fighting. Legal battles aren't cheap on the absolute scale, but on the relative scale of the potential profits, they are. So why not? Claim this, claim that, sue everybody. It might work; you never know. Meanwhile, we have a line forming on the right of ticked-off insurance companies and government health plans, complaining about the Hep C prices, and while they wait they can watch the companies involved throwing buckets of slop on each other and hitting everyone over the head with lawsuits. What a spectacle.

Comments (43) + TrackBacks (0) | Category: Business and Markets | Infectious Diseases | Patents and IP | Why Everyone Loves Us

June 20, 2014

What If Drug Patents Were Written Like Software Patents?

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Posted by Derek

Try this claim on for size and see how it fits:

"A method for treating a human disease state by means of inhibiting an enzyme whose functioning contributes to that disease state, said means comprising the administration of a molecule of molecular weight between 100 and 750 Daltons (composed of carbon, hydrogen, oxygen, nitrogen, and optionally sulfur and/or one or more halogen atoms) that has been determined to interact with the enzyme in such a way as to disturb, inhibit, or alter its function."

Not happening, that one, and it's a good thing. But stuff nearly that vague and idiotic is all over the software patent landscape. Such patents list a superficially impressive amount of detail about how their "invention" is to be implemented, but all too often, that scheme turns out to mean something like "Someone uses a computer to contact a web server" or "Someone turns on their mobile phone". It would be as if we in the drug industry could enable our compounds by citing a few synthetic organic chemistry textbooks - that's how you make 'em, right there!

But the Supreme Court has begun the task of diverting a river through this particular manure-laden stable in a 9-0 decision, Alice Corp. v. CLS. Justice Thomas delivered the opinion:

The patents at issue in this case disclose a computer-implemented scheme for mitigating “settlement risk” (i.e., the risk that only one party to a financial transaction will pay what it owes) by using a third-party intermediary. The question presented is whether these claims are patent eligible under 35 U. S. C. §101, or are instead drawn to a patent-ineligible abstract idea. We hold that the claims at issue are drawn to the abstract idea of intermediated settlement, and that merely requiring generic computer implementation fails to transform that abstract idea into a patent-eligible invention. . .

The opinion starts off by detailing why the patents under question are directed towards an abstract idea, and then goes on to demolish the contention that the method claims turn that into something patentable. All they do, the court says, is instruct someone to go off and use a computer to implement that idea (of an intermediated financial settlement), which in no way makes that idea eligible for a patent. Eventually, there will probably come a case that forces the court to propose a test for what constitutes an abstract idea, but I'll bet that all nine justices hope to be retired by the time that happens. Update: for more on this and other issues associated with this case, see this discussion at Patent Docs.

The opinion cites a number of other recent patent decisions by the court, such as Mayo v. Prometheus and Assoc. Mol. Pathology v. Myriad. One gets the impression that the Supreme Court is engaged in a multiyear, multicase effort to clean up some persistent problems in US patent law, and that this process will continue. More on this decision can be found at SCOTUSblog and The Economist.

Comments (20) + TrackBacks (0) | Category: Patents and IP

May 22, 2014

Oncoceutics' Odd Press Releases (Spam Never Sleeps)

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Posted by Derek

That last entry about Oncoceutics attracted a comment that caught my eye. If you go to the company's web site, and their press release page, there are some oddities. Somehow, the same robo-spammers who infect the comment sections of blogs have worked their way into the text of the company's press releases. Here are some examples (emphasis added):

"There are also claims for ONC201 to be used in combination with other anticancer drugs and to be given orally to generic cialis cheap treat brain cancers. "

"To the extent that statements in this press release are cialis online generic not strictly historical, including statements as to revenue projections, business strategy, outlook, objectives, future milestones, plans, intentions. . ."

"“We are very pleased that the patent cheap viagra canada was issued in less than two years,” said Martin Stogniew, PhD, Chief Development Officer of Oncoceutics."

"“ONC201 is an exciting small molecule that has demonstrated efficacy against therapy-resistant malignancies and has shown to possess therapeutically desirable properties such as oral activity, thermal stability, temporally sustained activity, ability to cross the blood-brain barrier, and Cure Male viagra online cheap Impotence – How to Cure Erectile Dysfunction safety, ” said Wafik El-Deiry, MD, PhD FACP, co-founder and Chief Scientific Advisor of Oncoceutics."

OK, you get the idea, but there are plenty more where those came from. The company might want to clean this stuff up, and figure out how it got into all their press releases in the first place.

Update: the cleaning has taken place! Same-day service. . .

Comments (10) + TrackBacks (0) | Category: Patents and IP

A Horrible, Expensive, and Completely Avoidable Drug Development Mixup

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Posted by Derek

TIC10.jpgC&E News has a story today that is every medicinal chemist's nightmare. We are paid to find and characterize chemical matter, and to develop it (by modifying structures and synthesizing analogs) into something that can be a drug. Key to that whole process is knowing what structure you have in the first place, and now my fellow chemists will see where this is going and begin to cringe.

Shown at left are two rather similar isomeric structures. The top one was characterized at Penn State a few years ago by Wafik El-Deiry's lab as a stimulator of the TRAIL pathway, which could be a useful property against some tumor types (especially glioblastoma). (Article from Nature News here). Their patent, US8673923, was licensed to Oncoceutics, a company formed by El-Deiry, and the compound (now called ONC201) was prepared for clinical trials.

Meanwhile, Kim Janda at Scripps was also interested in TRAIL compounds, and his group resynthesized TIC10. But their freshly prepared material was totally inactive - and let me tell you, this sort of thing happens all too often. The usual story is that the original "hit" wasn't clean, and that its activity was due to metal contamination or colorful gunk, but that wasn't the case here. Janda requested a sample of TIC10 from the National Cancer Institute, and found that (1) it worked in the assays, and (2) it was clean. That discrepancy was resolved when careful characterization, including X-ray crystallography, showed that (3) the original structure had been misassigned.

It's certainly an honest mistake. Organic chemists will look at those two structures and realize that they're both equally plausible, and that you could end up with either one depending on the synthetic route (it's a question of which of two nitrogens gets alkylated first, and with what). It's also clear that telling one from the other is not trivial. They will, of course, have the same molecular weight, and any mass spec differences will be subtle. The same goes for the NMR spectra - they're going to look very similar indeed, and a priori it could be very hard to have any confidence that you'd assigned the right spectrum to the right structure. Janda's lab saw some worrisome correlation patterns in the HMBC spectra, but X-ray was the way to go, clearly - these two molecules have quite different shapes, and the electron density map would nail things down unambiguously.

To confuse everyone even more, the Ang. Chem. paper reports that a commercial supplier (MedKoo Biosciences) has begun offering what they claim is TIC10, but their compound is yet a third isomer, which has no TRAIL activity, either. (It's the "linear" isomer from the patent, but with the 2-methylbenzyl on the nitrogen in the five-membered ring instead).

So Janda's group had found that the published structure was completely dead, and that the newly assigned structure was the real active compound. They then licensed that structure to Sorrento Therapeutics, who are. . .interested in taking it towards clinical trials. Oh boy. This is the clearest example of a blown med-chem structural assignment that I think I've ever seen, and it will be grimly entertaining to see what happens next.

When you go back and look at the El-Deiry/Oncoceutics patent, you find that its claim structure is pretty unambiguous. TIC10 was a known compound, in the NCI collection, so the patent doesn't claim it as chemical matter. Claim 1, accordingly, is written as a method-of-treatment:

"A method of treatment of a subject having brain cancer, comprising: administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and a pharma­ceutically accepted carrier."

And it's illustrated by that top structure shown above - the incorrect one. That is the only chemical structure that appears in the patent, and it does so again and again. All the other claims are written dependent on Claim 1, for treatment of different varieties of tumors, etc. So I don't see any way around it: the El-Deiry patent unambiguously claims the use of one particular compound, and it's the wrong compound. In fact, if you wanted to go to the trouble, you could probably invalidate the whole thing, because it can be shown (and has been) that the chemical structure in Claim 1 does not produce any of the data used to back up the claims. It isn't active at all.

And that makes this statement from the C&E News article a bit hard to comprehend: "Lee Schalop, Oncoceutics’ chief business officer, tells C&EN that the chemical structure is not relevant to Oncoceutics’ underlying invention. Plans for the clinical trials of TIC10 are moving forward." I don't see how. A quick look through the patent databases does not show me anything else that Oncoceutics could have that would mitigate this problem, although I'd be glad to be corrected on this point. Their key patent, or what looks like it to me, has been blown up. What do they own? Anything? But that said, it's not clear what Sorrento owns, either. The C&E News article quotes two disinterested patent attorneys as saying that Sorrento's position isn't very clear, although the company says that its claims have been written with these problems in mind. Could, for example, identifying the active form have been within the abilities of someone skilled in the art? That application doesn't seem to have published yet, so we'll see what they have at that point.

But let's wind up by emphasizing that "skilled in the art" point. As a chemist, you'd expect me to say this, but this whole problem was caused by a lack of input from a skilled medicinal chemist. El-Deiry's lab has plenty of expertise in cancer biology, but when it comes to chemistry, it looks like they just took what was on the label and ran with it. You never do that, though. You never, ever, advance a compound as a serious candidate without at least resynthesizing it, and you never patent a compound without making sure that you're patenting the right thing. What's more, the Oncoceutics patent estate in this area, unless I'm missing some applications that haven't published yet, looks very, very thin.

One compound? You find one compound that works and you figure that it's time to form a company and take it into clinical trials, because one compound equals one drug? I was very surprised, when I saw the patent, that there was no Markush structure and no mention of any analogs whatsoever. No medicinal chemist would look at a single hit out of the NCI collection and say "Well, we're done - let's patent that one single compound and go cure glioblastoma". And no competent medicinal chemist would look at that one hit and say "Yep, LC/MS matches what's on the label - time to declare it our development candidate". There was (to my eyes) a painfully inadequate chemistry follow-through on TCI10, and the price for that is now being paid. Big time.

Comments (31) + TrackBacks (0) | Category: Analytical Chemistry | Cancer | Patents and IP

May 7, 2014

Crap, With the Force of Law Behind It

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Posted by Derek

Patent%20allowance%20rates.pngThere's a piece up at Vox about some changes over the last few years at the US patent office. This will probably not come as good news to those people (and I'm one of them) who think that too much crap makes it through the system as is, but it appears that the PTO is granting more applications than ever.

Vox lays the blame on the policies of David Kappos, appointed by President Obama in 2008. There certainly does seem to be an inflection point in the allowance rate. The two lines reflect the work of some researches at Virginia, who adjust for the number of re-applicant patents. That makes the real allowance rate over ninety per cent for new patents, which just has to be too high. (By the way, Vox really should rethink their tasteful color schemes; two different shades of butterscotch for a chart?)

Most pharma patents get granted already, I'd say. But that's because we're largely patenting new chemical matter, and it's a lot harder to argue about that. Patent quality has always been higher for new drugs than it is in many other areas, as disturbing a thought as that may be. So what else has been let through?

Comments (12) + TrackBacks (0) | Category: Patents and IP

May 6, 2014

CRISPR In the Courts

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Posted by Derek

Here's an article from the Independent on the legal battles that are underway about CRISPR technology. On one level, it can be a somewhat ugly story, but it also shows how much of a discovery the technique has been, that people are willing to fight for the rights to it so vigorously. But it's going to take a lot of straightening out:

On the one side is a consortium of world-class researchers led by French-born Professor Emmanuelle Charpentier who made a key discovery behind the Crispr gene editing technique and has been promised $25m (£16m) by a group of venture capitalists to commercialise her invention for medical use.

On the other side is her former colleague and the co-discoverer of the gene-editing process, Professor Jennifer Doudna of the University of California, Berkeley, who has joined a rival consortium of researchers with $43m in venture capital to advance the Crispr technique into the clinic.

Each group has recruited a formidable panel of senior scientists as advisers. The Charpentier team, called Crispr Therapeutics, includes Nobel Laureate Craig Mello, the co-discoverer of a gene-silencing technique known as RNAi, and Daniel Anderson of the Massachusetts Institute of Technology, who was the first person to show that Crispr can cure a genetic disease in an adult animal.

Meanwhile the Doudna team, known as Editas Medicine, includes the Harvard geneticist George Church, a pioneer in synthetic biology, and Feng Zhang of MIT and the Broad Institute, who successfully managed to get Crispr to work in human cells and was this month awarded the first US patent on the technique – much to the dismay of Professor Charpentier.

Another crack at human gene therapy, that's one of the biggest engines driving all this. I hope that the legal wrangling doesn't slow that down. . .

Comments (11) + TrackBacks (0) | Category: Biological News | Patents and IP

May 1, 2014

Eli Lilly vs. Canada

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Posted by Derek

Eli Lilly has been complaining the U. S. Government for a while about the Canadian regulatory authorities, after they invalidated the company's patents for Strattera and Zyprexa a few years ago. Unfortunately for them, as Ed Silverman reports, the U. S. Trade Representative has refused to put Canada on the list of countries that don't respect intellectual property treaties (and this despite several members of Congress joining in the request). The office has mentioned that the Canadian law is a bit fuzzy, and that the mechanisms to appeal it are not clear, but they're not going anywhere near as far as Lilly wanted. The company is suing the Canadian government under NAFTA provisions, but that's going to take a while to bear results, if it ever does.

So why were the patents invalidated in the first place? They're holding up everywhere else. The Canadian generic drug industry challenged them under what may be a unique provision of Canadian patent law: the "promise" doctrine. If a company files a selection patent, the basis for which is that a particular form of the invention is in fact preferable, then under Canadian law the patent can be invalidated if that "promise" is not borne out by data:

In the mid 2000s one could start to see Canadian patent cases “turning” somewhat. Before this, the general sense was that a mere scintilla of utility was enough to obtain a patent. However, if the patentee made an explicit and unequivocal “Promise” of a certain use or result, recent cases have held the patentee to this result. Eli Lilly’s selection patent for an antipsychotic agent (olanzapine) was first held invalid in 2007 (in preliminary type proceedings) (2007 FC 596). Eli Lilly’s patent promised that its compound was better than the rest. However Eli Lilly had not actually determined its Promise, nor was their Promise soundly predictable (ie. it was a guess).

I'm definitely not a patent attorney, but I don't know of any other jurisdiction that puts the bar up quite that high. My impression is that if a company has demonstrated that it's willing to go to the trouble of filing a selection patent, that this is enough of an indication that it feels that there's something special about its claims. You have to show real advantages versus the prior art (things that are presumably already known), but not against your own initial filing. We'll see how far this gets (and if any other countries are tempted to put in a promise clause of their own, as a handy tool for patent invalidation). India, with its large generic industry, might be a candidate, if they don't have something like this.

Comments (4) + TrackBacks (0) | Category: Patents and IP

April 8, 2014

Can You Patent A Natural Product? Prepare For a Different Answer

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Posted by Derek

So, can you patent naturally occurring substances, or not? That's a rather complicated question, and some recent Supreme Court decisions have recomplicated it in US patent law. Mayo v. Prometheus and Assoc. Mol. Pathology v. Myriad Genetics. The latter, especially, has sent the PTO (and the IP lawyers) back to staring out their respective windows, thinking about what to do next.

The Patent Office has now issued new guidelines for its examiners in light of these rulings, though, and things may be changing. Previous standards for patenting naturally occurring compounds have been tightened up - if I'm reading this correctly, no longer is the process of isolation and purification itself seen as enough of a modification to make a case for patentability. The four "judicial exception" categories, to be used in patentability decisions, are (1) abstract ideas, (2) laws of nature, (3) natural phenomena, and (4) natural products. And examiners are specifically asked to determine if a patent application's claims recite something "significantly different" than these.

Here's the blog of an IP firm that thinks that the USPTO has gone too far:

Now we learn that grant of these and similar patents were mistakes, that 100 years of consistent practice in the field of patents was wrong, that what was invented was no more than products of nature without significant structural difference from the naturally-occurring materials, and that the USPTO will endeavour to avoid such mistakes in future. . .

. . .Whatever workable rule of law is derivable from Prometheus, it is apparent from the opinion of Justice Breyer that it was not the Court’s intention to bring about a radical change in pharmaceutical practice. The opinion gives a warning against undue breadth:

“The Court has recognized, however, that too broad an interpretation of this exclusionary principle could eviscerate patent law. For all inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or abstract ideas.”

The problem (and it's the usual problem with fresh patent law) is that we really don't know what the phrases in the decisions or guidance mean, in practice, until there's been some practice. This is going to be thrashed out application by application, lawsuit by lawsuit, until some new equilibrium is reached. Right now, though, if you're trying to patent something that could be considered an isolated natural product, your life has become much more complicated and uncertain. Here's another IP law firm:

What is the "significantly different" standard? With respect to natural products, the Guidance offers that what is claimed should be "non-naturally occurring and markedly different in structure from the naturally occurring products". Again, it is unclear at this point how different "markedly different" will be. How different it needs to be will be worked out on a case-by-case basis, beginning at the level of the patent examiner at the USPTO.

So how can you protect your IP if it involves subject matter that could be considered a "product of nature" by a US examiner? Since we don't yet really know how different "markedly different" is, one prudent strategy would be to include multiple claims having varying degrees of modifications relative to the naturally occurring thing, to the extent these makes sense commercially and scientifically. The more different your claimed product is from the naturally occurring thing, the more likely it is to be considered patent eligible by the USPTO.

Comments (20) + TrackBacks (0) | Category: Patents and IP

January 22, 2014

A New Book on Scaffold Hopping

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Posted by Derek

I've been sent a copy of Scaffold Hopping in Medicinal Chemistry, a new volume from Wiley, edited by Nathan Brown of the Institute of Cancer Research in London. There are eighteen chapters - five on identifying and characterizing scaffolds to start with, ten on various computational approaches to scaffold-hopping, and three case histories.

One of the things you realize quickly when you starting thinking about (or reading about) that topic is that scaffolds are in the eye of the beholder, and that's what those first chapters are trying to come to grips with. Figuring out the "maximum common substructure" of a large group of analogs, for example, is not an easy problem at all, certainly not by eyeballing, and not through computational means, either (it's not solvable in polynomial time, if we want to get formal about it). One chemist will look at a pile of compounds and say "Oh yeah, the isoxazoles from Project XYZ", while someone who hasn't seen them before might say "Hmm, a bunch of amide heterocycles" or "A bunch of heterobiaryls" or what have you.

Another big question is how far you have to move in order to qualify as having hopped to another scaffold. My own preference is strictly empirical: if you've made a change that would be big enough to make most people draw a new Markush structure compared to your current series, you've scaffold-hopped. Ideally, you've kept the activity at your primary target, but changed it in the counterscreens or changed the ADMET properties. That's not to say that all these changes are going to be beneficial - people try this sort of thing all the time and wipe out the primary activity, or pick up even more clearance or hERG than the original series had. But those are the breaks.

And those are the main reasons that people do this sort of thing: to work out of a patent corner, to fix selectivity, or to get better properties. The appeal is that you might be able to address these without jettisoning everything you learned about the SAR of the previous compounds. If this is a topic of interest, especially from the computational angles, this book is certainly worth a look.

Comments (1) + TrackBacks (0) | Category: Drug Development | Patents and IP | Pharmacokinetics

December 13, 2013

Free Chemical Patent Searching

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Posted by Derek

Here's some good news for open (free) access to chemical information. A company called SureChem was trying to make a business out of chemical patent information, but had to fold. They've donated their database to the EMBL folks, and now we have SureChEMBL. At the moment, that link is taking me to the former SureChem site, but no doubt that's changing shortly.

This will give access to millions of chemical structures in patents, a resource that's been hard to search without laying out some pretty noticeable money. This isn't just the database dump, either - the software has been donated, too, so things will stay up to date:

SureChEMBL takes feeds of full text patents, identifies chemical objects from either the in-line text or from images and adds 2-D chemical structures. This is then loaded into a database and is searchable by chemical structure, so you can do substructure, similarity searching and so forth - all the good things you'd expect from a chemical database. This chemical search functionality is unavailable from the public, published patent documents, and is really essential for anyone seriously using the patent literature. Oh, and the system does this live, so as patents are published, they are processed and added to the system - the delay between publication and structures being available in SureChEMBL is about a day when converted from text, and a few days when converted from image sources.

Chemical Abstracts, Reaxsys, and the others in that business should take note: if they want people to keep paying for their systems, they'll need to keep providing more value for the money. Good news all around.

Comments (11) + TrackBacks (0) | Category: Chemical News | Patents and IP

November 11, 2013

The Past Twenty Years of Drug Development, Via the Literature

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Posted by Derek

Here's a new paper in PlOSOne on drug development over the past 20 years. The authors are using a large database of patents and open literature publications, and trying to draw connections between those two, and between individual drug targets and the number of compounds that have been disclosed against them. Their explanation of patents and publications is a good one:

. . .We have been unable to find any formal description of the information flow between these two document types but it can be briefly described as follows. Drug discovery project teams typically apply for patents to claim and protect the chemical space around their lead series from which clinical development candidates may be chosen. This sets the minimum time between the generation of data and its disclosure to 18 months. In practice, this is usually extended, not only by the time necessary for collating the data and drafting the application but also where strategic choices may be made to file later in the development cycle to maximise the patent term. It is also common to file separate applications for each distinct chemical series the team is progressing.

While some drug discovery operations may eschew non-patent disclosure entirely, it is nevertheless common practice (and has business advantages) for project teams to submit papers to journals that include some of the same structures and data from their patents. While the criteria for inventorship are different than for authorship, there are typically team members in-common between the two types of attribution. Journal publications may or may not identify the lead compound by linking the structure to a code name, depending on how far this may have progressed as a clinical candidate.

The time lag can vary between submitting manuscripts immediately after filing, waiting until the application has published, deferring publication until a project has been discontinued, or the code name may never be publically resolvable to a structure. A recent comparison showed that 6% of compound structures exemplified in patents were also published in journal articles. While the patterns described above will be typical for pharmaceutical and biotechnology companies, the situation in the academic sector differs in a number of respects. Universities and research institutions are publishing increasing numbers of patents for bioactive compounds but their embargo times for publication and/or upload of screening results to open repositories, such as PubChem BioAssay, are generally shorter.

There are also a couple of important factors to keep in mind during the rest of the analysis. The authors point out that their database includes a substantial number of "compounds" which are not small, drug-like molecules (these are antibodies, proteins, large natural products, and so on). (In total, from 1991 to 2010 they have about one million compounds from journal articles and nearly three million from patents). And on the "target" side of the database, there are a significant number of counterscreens included which are not drug targets as such, so it might be better to call the whole thing a compound-to-protein mapping exercise. That said, what did they find?
compounds%20targets%20year%20chart.png
Here's the chart of compounds/target, by year. The peak and decline around 2005 is quite noticeable, and is corroborated by a search through the PCT patent database, which shows a plateau in pharmaceutical patents around this time (which has continued until now, by the way).

Looking at the target side of things, with those warnings above kept in mind, shows a different picture. The journal-publication side of things really has shown an increase over the last ten years, with an apparent inflection point in the early 2000s. What happened? I'd be very surprised if the answer didn't turn out to be genomics. If you want to see the most proximal effect of the human genomics frenzy from around that time, there you have it in the way that curve bends around 2001. Year-on-year, though (see the full paper for that chart), the targets mentioned in journal publications seem to have peaked in 2008 or so, and have either plateaued or actually started to come back down since then. Update: Fixed the second chart, which had been a duplicate of the first).
targets%20source%20year.png
The authors go on to track a number of individual targets by their mentions in patents and journals, and you can certainly see a lot of rise-and-fall stories over the last 20 years. Those actual years should not be over-interpreted, though, because of the delays (mentioned above) in patenting, and the even longer delays, in some cases, for journal publication from inside pharma organizations.

So what's going on with the apparent decline in output? The authors have some ideas, as do (I'm sure) readers of this site. Some of those ideas probably overlap pretty well:

While consideration of all possible causative factors is outside the scope of this work it could be speculated that the dominant causal effect on global output is mergers and acquisition activity (M&A) among pharmaceutical companies. The consequences of this include target portfolio consolidations and the combining of screening collections. This also reduces the number of large units competing in the production of medicinal chemistry IP. A second related factor is less scientists engaged in generating output. Support for the former is provided by the deduction that NME output is directly related to the number of companies and for the latter, a report that US pharmaceutical companies are estimated to have lost 300,000 jobs since 2000. There are other plausible contributory factors where finding corroborative data is difficult but nonetheless deserve comment. Firstly, patent filing and maintenance costs will have risen at approximately the same rate as compound numbers. Therefore part of the decrease could simply be due to companies, quasi-synchronously, reducing their applications to control costs. While this happened for novel sequence filings over the period of 1995–2000, we are neither aware any of data source against which this hypothesis could be explicitly tested for chemical patenting nor any reports that might support it. Similarly, it is difficult to test the hypothesis of resource switching from “R” to “D” as a response to declining NCE approvals. Our data certainly infer the shrinking of “R” but there are no obvious metrics delineating a concomitant expansion of “D”. A third possible factor, a shift in the small-molecule:biologicals ratio in favour of the latter is supported by declared development portfolio changes in recent years but, here again, proving a causative coupling is difficult.

Causality is a real problem in big retrospectives like this. The authors, as you see, are appropriately cautious. (They also mention, as a good example, that a decline in compounds aimed at a particular target can be a signal of both success and of failure). But I'm glad that they've made the effort here. It looks like they're now analyzing the characteristics of the reported compounds with time and by target, and I look forward to seeing the results of that work.

Update: here's a lead author of the paper with more in a blog post.

Comments (22) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Patents and IP | The Scientific Literature

July 8, 2013

Suing Your Grad School, And Your Professor

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Posted by Derek

As anyone who's negotiated with them knows, Harvard plays hardball when it comes to patent rights. But so do the university's students, apparently. C&E News has a report on Mark Charest, a former graduate student in the Myers lab, who is suing the university over patent royalties.

Myers, Charest, and others reported a new synthetic route into the tetracycline antibiotics, and this led to a new company (Tetraphase), which is developing these in the clinic. The dispute is over how the royalties are divided up: Charest, in his legal complaint, claims that the university forced him in 2006 to take a lower share than he considered his due, and he further claims that the university reduced his share even further in 2009.

Note that all of these disputes are over the scraps: Harvard is taking 65% of the royalties right off the top, and no one's going to be reducing that. And I'm not sure how far Charest is going to get with this lawsuit: the article says that an independent panel was called on at one point to review his contributions, so whether he liked the terms he was given or not, they've been scrutinized and he is presumably on record as having agreed to them.

It looks like he's going to claim that this agreement was made under duress and/or under false pretences, though. ChemBark has more details, including statements by Charest in his complaint (link via Paul at ChemBark) that he felt threatened both by Prof. Myers and by Harvard's technology transfer office, and is also alleging fraud (Halvorsen, below, is with Harvard's Office of Technology Development):

74. Dr. Halvorsen threatened that he would award all the inventors an equal 20% share, but that he would allocate 50% of the Inventor Royalties to a wholly separate, undisclosed patent application on which Dr. Charest was not an inventor (the “undisclosed patent application”).
75. Dr. Charest understood Dr. Halvorsen to be threatening him; he wrote to Dr. Halvorsen that “[i]n your previous email you issued the written warning that my portion of the inventor allocation would be reduced if I proceed forward.”
76. Dr. Halvorsen used this separate, undisclosed patent application to force Dr. Charest to take OTD’s offer.
77. The undisclosed patent application, however, was, on information and belief, filed after financial terms were agreed to between Harvard and Tetraphase and added to the license between Harvard and Tetraphase just prior to finalization of their license agreement.
78. Dr. Charest only later learned that this separate, undisclosed patent application was only a ruse to force Dr. Charest to sign OTD’s offer.

No such patent application ever published, the document says. Much of the complaint also focuses on Harvard's decision to give 50% of the inventor royalties to Myers, dividing up the rest between the students and/or postdocs on the patent, and claims that this is a violation of the university's stated policies. So there's no way that this cannot get ugly - it's gotten ugly already. My guess is that Harvard will do whatever it can to get this thrown out (naturally), but if they're unsuccessful in that, that there will be some sort of out-of-court settlement. I really don't see them signing up to have all this dragged though the courts (and the public record) - even if the university did nothing wrong (and I'm agnostic about that), there's still no upside for them.

So for anyone out there whose grad school experience was a bit on the rough side, take heart: at least it didn't end up in court. Updates on this case as it slowly drags itself through the legal system.

Comments (36) + TrackBacks (0) | Category: Graduate School | Patents and IP

June 17, 2013

Pay-to-Delay: Not Necessarily Illegal, But Not Long For The World

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Posted by Derek

The Supreme Court has another ruling that affects the drug industry: FTC v. Actavis took up the question of "pay to delay", the practice of paying generic companies to go away and not challenge a branded drug. Actavis was in the process of bringing a version of Solvay's AndroGel to market, claiming that the Solvay patent was invalid. They won that case, and the FDA approved their generic version, but Solvay turned around and paid them (and Paddock, another generic firm) to not bring any such drug to the market.

The Federal Trade Commission (FTC) filed suit, alleging that re- spondents violated §5 of the Federal Trade Commission Act by unlawfully agreeing to abandon their patent challenges, to refrain from launching their low-cost generic drugs, and to share in Solvay’s monopoly profits. The District Court dismissed the complaint. The Eleventh Circuit concluded that as long as the anticompetitive effects of a settlement fall within the scope of the patent’s exclusionary potential, the settlement is immune from antitrust attack. Noting that the FTC had not alleged that the challenged agreements excluded competition to a greater extent than would the patent, if valid, it affirmed the complaint’s dismissal. It further recognized that if parties to this sort of case do not settle, a court might declare a patent invalid. But since public policy favors the settlement of disputes, it held that courts could not require parties to continue to litigate in order to avoid antitrust liability.

And now the Supreme Court reverses the Eleventh Circuit. The FTC, they hold, should have been given a chance to make its antitrust case. The Court makes a point out of declining to hold such agreements "presumptively unlawful", but gives a guide to breaking them down. There are both patent validity questions and anticompetitive questions involved, they point out, and these are separate issues (and because of that, they might not take forever to litigate, as the Eleventh Circuit decision worried about). Besides, as the justices note, a sudden large payment in such a case could be a reasonable indication of the underlying patent's validity (and chances of holding up to a determined challenge). The Hatch-Waxman Act has a generally pro-competitive bent to it, and that should operate in this situation as well.

I think this is the decision that most people expected (it's certainly the one I did). Pay-to-delay has always had an antitrust-violation smell to it. The Supreme Court has now gone on record as saying that this scent may well be no illusion, and at the very least, the FTC should be able to make a case if it can. I suspect that we're going to see fewer of these deals now - perhaps none at all - because I doubt many of them would hold up.

Comments (3) + TrackBacks (0) | Category: Patents and IP | Regulatory Affairs

June 13, 2013

The Supreme Court Rules on Myriad

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Posted by Derek

Just a little while ago, the Supreme Court issued a unanimous decision (rare these days) in the Myriad Genetics case. I summarized the state of play up until the most recent arguments here, and if you're just getting up to speed on this issue, I'd read that post first. There are a lot of things this case is not about, and there are a lot of headlines that are going to mess things up. I would not be surprised to see "Myriad Wins" and "Myriad Loses" coming up at the same time in a news search.

Here's the actual decision (PDF), and here's the key statement:

A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring.

The earlier appeals court decision was broader, and found that isolated stretches of otherwise natural DNA were, in fact, patent-eligible, because they are not found as such (unwound, de-histoned, cleaved at both ends) in nature. But this ruling dials that back a bit. A cDNA, stripped of introns, etc., is indeed a work of human ingenuity, and is patent-eligible (as indeed, it had been considered to be before this decision). Here's more:

It is important to note what is not implicated by this decision. First, there are no method claims before this Court. Had Myriad created an innovative method of manipulating genes while searching for the BRCA1 and BRCA2 genes, it could possibly have sought a method pat- ent. But the processes used by Myriad to isolate DNA were well understood by geneticists at the time of Myriad’s patents “were well understood, widely used, and fairly uniform insofar as any scientist engaged in the search for a gene would likely have utilized a similar approach,” 702 F. Supp. 2d, at 202–203, and are not at issue in this case.

Similarly, this case does not involve patents on new applications of knowledge about the BRCA1 and BRCA2 genes. Judge Bryson aptly noted that, “[a]s the first party with knowledge of the [BRCA1 and BRCA2] sequences, Myriad was in an excellent position to claim applications of that knowledge. Many of its unchallenged claims are limited to such applications.” 689 F. 3d, at 1349. Nor do we consider the patentability of DNA in which the order of the naturally occurring nucleotides has been altered. Scientific alteration of the genetic code presents a different inquiry, and we express no opinion about the application of §101 to such endeavors. We merely hold that genes and the information they encode are not patent eligible under §101 simply because they have been isolated from the surrounding genetic material.

Unfortunately, many of the news blurbs on this issue are smudging these questions around. I don't actually expect this ruling to have much effect, to be honest, except as a way to help resolve the question of whether stretches of raw DNA are patentable. The glory days of trying to patent such things are long gone, in any case. And since there are many more useful forms which are patentable, any headlines about "No patents for DNA!" are misleading.

Comments (37) + TrackBacks (0) | Category: Patents and IP

June 10, 2013

Deuterated Drugs: An Obvious Idea?

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Posted by Derek

Nature Medicine has an update on the deuterated drug landscape. There are several compounds in the clinic, and the time to the first marketed deuterium-containing drug is surely counting down.

But, as mentioned at the end of that piece, another countdown that also must be ticking away is the one to the first lawsuit. There are several places where one could be fought out. The deuterated-drug landscape was the subject of a vigorous early land rush, and there are surely overlapping claims out there which will have to be sorted out if (when) the money starts to flow from the idea. And there's the whole problem of obviousness, a key patent-killer. The tricky thing is, standards of what is obvious to one skilled in the art change over time. They have to change; the art changes. (I'll risk some more gritted teeth among the readership by breaking into Latin again: Tempora mutantur, nos et mutamur in illis.

We've already seen this with respect to single enantiomers - it's now considered obvious to resolve a racemic mixture, an to expect that the two isomers will have different activities as pharmaceuticals. At what point will it be considered obvious that deuteration can improve the pharmacokinetics? If that does ever happen, it'll take longer, because deuteration is not as simple a process as resolution of a racemate. Itt can be difficlut (and, well, non-obvious) to figure out where to put the deuteriums for maximum effect, and how many need to be added. Adding them is not always so easy, either, which brings up questions of enablement and reduction to practice. You need to teach toward the compounds you want to claim, and for deuteration, that's going to mean getting pretty specific.

There's another consideration that I hadn't been aware of until this weekend. I had the chance to talk with a patent attorney at a social gathering (not everyone's idea of a big Saturday night, admittedly, but I enjoyed the whole affair). He was explaining to me a consequence of the Supreme Court's recent ruling on obviousness, the 2007 KSR v. Teleflex decision. Apparently, one of the major effects of that ruling was the idea that if there are a limited number of known options for an inventor to choose from, that can take the whole thing into the realm of the obvious. The actual language is that when ". . .there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. . .the fact that a combination was obvious to try might show that it was obvious under § 103". You can see the PTO itself trying to come to grips with KSR here, and it seems to be very heavily cited indeed by examiners (and in subsequent court cases).

Naturally, as with legal matters, the big question becomes exactly what a limited number of options might mean. How many, exactly, is that? In the case of a racemate, you have two (only two, always two), and it's certainly reasonable to expect them to be different in vivo. So that would come under the KSR principle, I'd say, and it's not just me. But what if there are a limited number of places that a deuterium can be added to a molecule? At what point does deuterating them become, well, just one of those things that a person skilled in the art would know to try?

Expect a court case on this eventually, when some serious money starts to be made in the area. This is going to be fought out case by case, and it's going to take quite a while.

Comments (30) + TrackBacks (0) | Category: Patents and IP | Pharmacokinetics

April 1, 2013

Novartis Loses the Glivec Patent Fight in India

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Posted by Derek

This story is all over the news today, but it's my impression that most of the stories leave out crucial details. This is not just a big multinational drug company being put in its place by Indian courts, nor is it some crazy ruling with no basis in fact. Here's the story, as best I understand it.

Novartis has never had a patent for imatinib (Glivec/Gleevec) in India. I'm not completely sure why that is, but I would think it's because that back when the compound was being developed was the era when Indian drug patents did not exist. As the country has entered the WTO, it's had to comply with the world's intellectual property framework, and it's safe the say that the dust has not yet settled from this process.

So when Novartis filed for an imatinib patent in India, it was for a different polymorph of the drug, which they hoped would be patentable chemical matter. The Indian patent office disagreed in 2006, saying that this was merely a reformulation of an existing compound (which had been approved in the US back in 2001), and rejected the application. Novartis has been appealing that decision through the Indian court system ever since, and this latest ruling is the last, from the Indian Supreme Court. As the court's decision says:

In the application it claimed that the invented product, the beta crystal form of Imatinib Mesylate, has (i) more beneficial flow properties: (ii) better thermodynamic stability; and (iii) lower hygroscopicity than the alpha crystal form of Imatinib Mesylate. It further claimed that the aforesaid properties makes the invented product “new” (and superior!) as it “stores better and is easier to process”; has “better processability of themethanesulfonic acid addition salt of a compound of formula I”, and has a “further advantage for processing and storing.”

Novartis, for its part, feels that they have been done in by one particular section of Indian patent law, section 3(d). This was put in to prevent companies from "evergreening" their drug patent estates, and it requires proof of enhanced efficacy for new forms of existing compounds in order for them to be patentable. (That's as opposed to the situation in most other patent regimes, where once you've shown that you have a new substance, the uses you already knew about for its earlier form are enough to establish utility, to go along with the novelty). Here's Novartis' take:

Glivec has been awarded patents in nearly 40 other countries, including China, Russia and Taiwan, but the IPAB is denying one for India. The IPAB acknowledges that Glivec satisfies the international requirements for novelty and inventiveness, but it does not find Glivec to meet the requirement under Section 3(d) of the Indian Patents Act of 2005. This act introduced a new efficacy enhancement hurdle for patenting new forms of known compounds. We believe that Section 3(d), the Indian legal paragraph intended as a hurdle for evergreening, should not be applicable to the breakthrough medicine Glivec, which has changed the lives of patients with rare cancers.

The misconception regarding the innovation of Glivec is based on a patent that was granted in 1993 (not in India) for the synthesis of the molecule imatinib. This molecule, without further development, could not safely be administered to patients and represented only the first step in the process to develop Glivec as a viable treatment for cancer. We selected the mesylate salt of imatinib and then developed the beta crystal form of imatinib mesylate to make it suitable for patients to take in a pill form that would deliver consistent, safe and effective levels of medicine.

Novartis claimed that the increased bioavailability qualified as increased efficacy, but the opposing argument was that therapeutically, the two compound forms were never shown to be differentiated. The Indian Supreme Court, in fact, noted in its decision that Novartis had never provided any data on the effect of bioavailability on therapeutic efficacy, with the implication being, I think, that if they had such data they surely would have presented it by now in order to strengthen their case. The court had this to say about the beta-crystalline form:

It is seen above that in the US the drug Gleevec came to the market in 2001. It is beyond doubt that what was marketed then was Imatinib Mesylate and not the subject product, Imatinib Mesylate in beta crystal form. It is also seen above that even while the appellant’s application for grant of patent lay in the “mailbox” awaiting amendments in the law of patent in India, the appellant was granted Exclusive Marketing Rights on November 10,2003, following which Gleevec was marketed in India as well. On its package, the drug was described as “Imatinib Mesylate Tablets 100 mg” and it was further stated that “each film coated tablet contains: 100 mg Imatinib (as Mesylate)”. On the package there is no reference at all to Imatinib Mesylate in beta crystalline form. What appears, therefore, is that what was sold as Gleevec was Imatinib Mesylate and not the subject product, the beta crystalline form of Imatinib Mesylate.

I'm of two minds about that argument. The packaging often does not describe individual polymorphs of compounds - both the original form of imatinib and the beta-crystalline form are properly described as "imatinib mesylate". At the same time, it does appear that the drug has been administered as the earlier form for some time. So the Indian court affirms their section 3(d), which is a high bar, but they do say that it should be one that is clearable in practice:

We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment.”

We'll have to see how this works out in practice. India has a right, of course, to set its patent laws out in this way, but will it always work out like this when a section 3(d) issue comes up again? Or will that only be when it's a multinational company selling an expensive drug? Pricing, in fact, is not supposed to enter into this dispute, although for a while, it looked as if it would. The Indian appellate board, as Spicy IP reports, had originally tried to being in another interesting part of the patent law, section 3(b), which forbids patents for inventions that "offend public order or morality". They had tried the argument that Novartis' pricing offended public morality, but the Indian Supreme Court, to their credit, declined to pursue that line of thought.

So this case is not the end of drug patents in India. It's not supposed to be some mighty victory for the generic drug makers there, either, although I'm sure they're happy with it. (I might note that all the preening in the Indian press about the country being the "pharmacy to the world" would be more justified if any of the drugs being made had actually been discovered in India, through the ingenuity of Indian drug companies, risking Indian capital and shareholders' money. But they weren't).

What it does mean is that Indian drug patent law has gone from being nonexistent a few years ago, to being one of the strictest around. I hope that it's applied uniformly. Novartis has lost what was not a very strong case, to be honest, but the courts in India will hear stronger at some point.

Comments (29) + TrackBacks (0) | Category: Cancer | Patents and IP

February 26, 2013

Standard of Care? Not So Fast, Not in the United Kingdom

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Posted by Derek

Did you know that in the UK, patent law says that using a competitor's compound as a comparison in a clinical trial is an infringement? I sure didn't. The government has realized that this rule is much stricter than most other countries, and is moving to change it in a bid to keep more clinical research in the country. Thanks to FierceBiotech for the heads-up on this.

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October 31, 2012

Oops. We Didn't Mean to Publish That.

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Posted by Derek

Here's an interesting situation, courtesy of Retraction Watch - trying to pull back a paper because it disclosed something that was supposed to be the subject of your patent. Say the authors of the paper in the Korean Journal of Physiology and Pharmacology:

We regret to inform that the published paper included a few parts that disclosed confidential information which should have been protected under patent law. We admit that the request for retraction is due to the indiscretion of the authors, and confirmed that editorial committee of KJPP have not conducted any fault in publishing the paper.

I would think that if you've disclosed, you've disclosed, so this will all come down to timing. Shouldn't matter much whether the paper has been retracted or not. . .

Comments (8) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature

October 30, 2012

JQ1: Giving Up a Fortune?

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Posted by Derek

The Atlantic is out with a list of "Brave Thinkers", and one of them is Jay Bradner at Harvard Medical School. He's on there for JQ1, a small-molecule bromodomain ligand that was reported in 2010. (I note, in passing, that once again nomenclature has come to the opposite of our rescue, since bromodomains have absolutely nothing to do with bromine, in contrast to 98% of all the other words that begin with "bromo-")

These sorts of compounds have been very much in the news recently, as part of the whole multiyear surge in epigenetic research. Drug companies, naturally, are looking to the epigenetic targets that might be amenable to small-molecule intervention, and bromodomains seem to qualify (well, some of them do, anyway).

At any rate, JQ1 is a perfectly reasonable probe compound for bromodomain studies, but it got a lot of press a couple of months ago as a potential male contraceptive. I found all that wildly premature - a compound like this one surely sets off all kinds of effects in vivo, and disruption of spermatogenesis is only one of them. Note (PDF) that it hits a variety of bromodomain subtypes, and we only have the foggiest notion of what most of these are doing in real living systems.

The Atlantic, for its part, makes much of Bradner's publishing JQ1 instead of patenting it:

The monopoly on developing the molecule that Bradner walked away from would likely have been worth a fortune (last year, the median value for U.S.-based biotech companies was $370 million). Now four companies are building on his discovery—which delights Bradner, who this year released four new molecules. “For years, drug discovery has been a dark art performed behind closed doors with the shades pulled,” he says. “I would be greatly satisfied if the example of this research contributed to a change in the culture of drug discovery.”

But as Chemjobber rightly says, the idea that Bradner walked away from a fortune is ridiculous. JQ1 is not a drug, nor is it ever likely to become a drug. It has inspired research programs to find drugs, but they likely won't look much (or anything) like JQ1, and they'll do different things (for one, they'll almost surely be more selective). In fact, chasing after that sort of selectivity is one of the things that Bradner's own research group appears to be doing - and quite rightly - while his employer (Dana-Farber) is filing patent applications on JQ1 derivatives. Quite rightly.

Patents work differently in small-molecule drug research than most people seem to think. (You can argue, in fact, that it's one of the areas where the system works most like it was designed to, as opposed to often-abominable patent efforts in software, interface design, business methods, and the like). People who've never had to work with them have ideas about patents being dark, hidden boxes of secrets, but one of the key things about a patent is disclosure. You have to tell people what your invention is, what it's good for, and how to replicate it, or you don't have a valid patent.

Admittedly, there are patent applications that do not make all of these steps easy - a case in point would be the ones from Exelixis - I wrote here about my onetime attempts to figure out the structures of some of their lead compounds from their patent filings. Not long ago I had a chance to speak with someone who was there at the time, and he was happy to hear that I'd come up short, saying that this had been exactly the plan). But at the same time, all their molecules were in there, along with all the details of how to make them. And the claims of the patents detailed exactly why they were interested in such compounds, and what they planned to do with them as drugs. You could learn a lot about what Exelixis was up to; it was just that finding out the exact structure of the clinical candidate that was tricky. A patent application on JQ1 would have actually ended up disclosing most (or all) of what the publication did.

I'm not criticizing Prof. Bradner and his research group here. He's been doing excellent work in this area, and his papers are a pleasure to read. But the idea that Harvard Medical School and Dana-Farber would walk away from a pharma fortune is laughable.

Comments (33) + TrackBacks (0) | Category: Cancer | Chemical Biology | Drug Development | Patents and IP

September 19, 2012

The American Chemical Society's Lawsuit Problem

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Posted by Derek

Since we've been talking about the ACS around here recently, I wanted to highlight a decision in a long-running court case the society has been involved in, American Chemical Society v. Leadscope. Rich Apodaca has a summary here of the earlier phases of the suit, which is now in its tenth year in the courts. Basically, three employees of Chemical Abstracts left to form their own chemical information company, and ended up with a patent on a particular variety of software that would display structure-activity and structure-property relationships. The ACS felt that this was too similar to the (discontinued) Pathfinder software they'd developed, and sued.

The ACS lost in a jury trial - in fact, they did more than just lose. The jury found that the society had competed unfairly, filing suit maliciously and defaming Leadscope in the process, and they awarded the latter company $26.5 million in damages. The ACS then lost in the Court of Appeals (and the damages were increased). So they took things all the way to the Ohio Supreme Court, and now they've lost there, too. The defamation ruling (and award) was reversed, and will be vacated by the lower court, but the finding of unfair competition stands. It looks like the society still owes $26.5 million. As this post by an IP lawyer shows, they were going all out:

As for the issue of ACS's subjective intent, the Supreme Court found ample support for the jury's finding that ACS had the intent to injure Leadscope and its founders. It noted that ACS's president had closely monitored Leadscope and had even sent out an email to then-Ohio-Governor Robert Taft to abort a visit by the governor to Leadscope's offices. ACS's former information technology director also provided damaging testimony documenting ACS's president's hostility towards Leadscope. In addition, ACS took actions or made statements that interfered with Leadscope's ability to get funding (for example, by dissuading an venture capitalist interested in investing in Leadscope by telling him that there were legal issues with Leadscope's technology) and took actions in the litigation to disrupt Leadscope's ability to get insurance coverage for the dispute.

As detailed here at ChemBark, it's not like there's been a lot of coverage about this (I've never written about it myself). These are things that every member of the ACS should at least be aware of, but it's not like the ACS is going to do that job, for obvious reasons. One of the main venues for such stories would be. . .Chemical and Engineering News, so that's not going to happen. And it's not a story that resonates much with a general newspaper/magazine readership, so what does that leave us with? Well, mentions like that Nature News article to get the word out, and the blogs to go into the details.

That ChemBark post has a whole series of questions that would be very much worth answering. How the the ACS get into this fix in the first place? Was the original suit ill-advised? How much will that $26.5 million affect the society's finances - is that a big deal, or not? How much further money went down the drain in legal fees along the way? Are there any lessons to be learned from all this, or could the same thing start happening again next month?

And beyond those immediate questions, there are the bigger ones that the ACS (and other scientific societies) should be asking. Can a single entity be (A) a publisher of a large stable of high-profile scientific journals, and (B) the curator and disseminator of the (very profitable) primary database of all the reported chemical matter in the world, and (C) the voice of its own membership, who are simultaneously paying money for access to A and B, and (D) the lobbying organization for chemistry in general, as well as (E) a scientific society dedicated to the spread of knowledge? I'm not sure that all these are possible, at the same time, for the same organization. But sites like ChemBark, and this one, and the rest of the chemical blogworld) are the only places that seem to be available to talk about these things.

Comments (33) + TrackBacks (0) | Category: Chemical News | Patents and IP

August 17, 2012

The Myriad Gene Patent Case: Trickier Than You Might Think

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Posted by Derek

All right, there's been another ruling in the Myriad gene patent case, involving genetic testing for the BRCA mutations in breast cancer. There's been a lot of coverage of this, but not all of it gets the details right. And there are a lot of details, so here goes. First off, here is the latest court opinion (PDF), courtesy of the ACLU, which was a party in this case. (That alone should tell you how involved this has become over the years). Allow me to summarize:

Myriad, and others, began offering genetic testing for these mutations in the mid-1990s. The company obtained several patents directed to the gene sequences and methods of assaying them, and informed other players in this field that they were in violation of Myriad intellectual property, specifically the University of Pennsylvania's Genetic Diagnostic Laboratory. Their cease-and-desist letters did not apply to research uses, only to commercial testing for which money was charged. By 1999, the GDL had stopped testing, and Myriad was now the only company in the US carrying out this diagnostic assay.

The plaintiffs in this case are a wide range of people, ranging from the Penn lab and others who wanted to offer BRCA testing, through people who claimed that they had been denied the opportunity to have such a test done through Myriad's exercise of its patents. The lawsuit went through a challenge in district court about whether the plaintiffs had standing to bring suit in the first place, which is an issue that came up again in this appeal, but I'm going to skip over that. It's certainly of potential interest to attorneys in the field, but doesn't get at the scientific and technical end of the case.

To that, then. the district court decision went against Myriad:

The district court held for Plaintiffs, concluding that the fifteen challenged claims were drawn to non-patentable subject matter and thus invalid under § 101. SJ Op., 702 F. Supp. 2d at 220-37. Regarding the composition claims, the court held that isolated DNA molecules fall within the judicially created “products of nature” exception to § 101 because such isolated DNAs are not “markedly different” from native DNAs. Id. at 222, 232 (quoting Diamond v. Chakrabarty, 447 U.S. 303 (1980)). The court relied on the fact that, unlike other biological molecules, DNAs are the “physical embodiment of information,” and that this information is not only preserved in the claimed isolated DNA molecules, but also essential to their utility as molecular tools.

Turning to the method claims, the court held them patent ineligible under this court’s then-definitive machine-or-transformation test. . .The court held that the claims covered “analyzing” or “comparing” DNA sequences by any method, and thus covered mental processes independent of any physical transformations. Id. at 233-35. In so holding, the court distinguished Myriad’s claims from those at issue in Mayo based on the “determining” step in the latter being construed to include the extraction and measurement of metabolite levels from a patient sample. SJ Op., 702 F. Supp. 2d at 234-35 (citing Prometheus Labs., Inc. v. Mayo Collaborative Servs., 628 F.3d 1347, 1350 (Fed. Cir. 2010), rev’d, 132 S. Ct. 1289 (2012)). Alternatively, the court continued, even if the claims could be read to include the transformations associated with isolating and sequencing human DNA, these transformations would constitute no more than preparatory data-gathering steps. Id. at 236 (citing In re Grams, 888 F.2d 835, 840 (Fed. Cir. 1989)). Finally, the court held that the one method claim to “comparing” the growth rate of cells claimed a basic scientific principle and that the transformative steps amounted to only preparatory data gathering.

I didn't even bother going into detail on this decision at the time, because I expected it to be appealed immediately, and so it was. As you'll see from the comments to that post, though, opinions varied widely about the chances for a reversal, but my informal reading was that the more someone knew about patent law, the more they expected the appeals court to reverse.

And that's just what has happened. The problem is, this isn't as wide-ranging a decision as some people (and some headlines) seem to think it is. I'll quote from the latest opinion again:

. . .it is important to state what this appeal is not about. It is not about whether individuals suspected of having an in- creased risk of developing breast cancer are entitled to a second opinion. Nor is it about whether the University of Utah, the owner of the instant patents, or Myriad, the exclusive licensee, has acted improperly in its licensing or enforcement policies with respect to the patents. The question is also not whether is it desirable for one company to hold a patent or license covering a test that may save people’s lives, or for other companies to be excluded from the market encompassed by such a patent—that is the basic right provided by a patent, i.e., to exclude others from practicing the patented subject matter. It is also not whether the claims at issue are novel or nonobvious or too broad. Those questions are not before us. It is solely whether the claims to isolated BRCA DNA, to methods for comparing DNA sequences, and to a process for screening potential cancer therapeutics meet the threshold test for patent-eligible subject matter under 35 U.S.C. § 101 in light of various Supreme Court holdings, particularly including Mayo. The issue is patent eligibility, not patentability.

In other words, this decision is not designed to address the big issues that so many people think that it has. The court goes on to say, as courts at this level often do, that if someone wants to do something about all these things, then the procedure for remedy is clear:

We would further note, in the context of discussing what this case is not about, that patents on life-saving material and processes, involving large amounts of risky investment, would seem to be precisely the types of subject matter that should be subject to the incentives of exclusive rights. But disapproving of patents on medical methods and novel biological molecules are policy questions best left to Congress, and other general questions relating to patentability and use of patents are issues not before us. . .

Still, even if we're talking about patent eligibility and not patentability per se, we still have a tough question here. Myriad says that the isolated DNA molecules that their patent is directed towards are not found in nature as such, that they have to be manipulated and isolated through human ingenuity, and that they (as opposed to native DNA) can be used in their diagnostic applications. They claim that the district court erred in focusing on the informational content of the molecules, and not the actual composition of matter itself. The plaintiffs argue that the isolated DNA molecules have to have a "distinctive name, character, and use", as the law reads, and that they are not "markedly different" enough from the natural substance, especially since (as they hold) the entire point of them is the informational sequence they represent.

The appeals court comes down in favor of Myriad here. A key part of their argument rests on the decision in the Chakrabarty case involving the patenting of genetically engineered bacteria, so if you didn't like that one, you're not going to like this. The court finds that isolated DNA molecules - unwound from their histones, cleaved at both ends, truncated - are "marked different" enough to be eligible for patents:

. . .Accordingly, BRCA1 and BRCA2 in their isolated states are different molecules from DNA that exists in the body; isolated DNA results from human intervention to cleave or synthesize a discrete portion of a native chromosomal DNA, imparting on that isolated DNA a distinctive chemical identity as compared to native DNA.

As the above description indicates, isolated DNA is not just purified DNA. Purification makes pure what was the same material, but was combined, or contaminated, with other materials. Although isolated DNA is removed from its native cellular and chromosomal environment, it has also been manipulated chemically so as to produce a molecule that is markedly different from that which exists in the body. . .

They go on to say that "an isolated DNA molecule is not a purified form of a natural material, but a distinct chemical entity that is obtained by human intervention". As you might imagine, cDNAs are found under this reasoning to be especially far from nature, and these are already held to be patentable. As to the "informational content" argument that carried the day in the lower court, the appeals court has this to say:

. . .We disagree, as it is the distinctive nature of DNA molecules as isolated compositions of matter that determines their patent eligibility rather than their physiological use or benefit. Uses of chemical substances may be relevant to the nonobviousness of these substances or to method claims embodying those uses, but the patent eligibility of an isolated DNA is not negated because it has similar informational properties to a different, more complex natural material. The claimed isolated DNA molecules are distinct from their natural existence as portions of larger entities, and their informational content is irrelevant to that fact. We recognize that biologists may think of molecules in terms of their uses, but genes are in fact materials having a chemical nature and, as such, are best described in patents by their structures rather than by their functions. . .

In other words, this ruling affirms that molecular biology is, in fact, chemistry, if you want to look at it that way. The court goes on to say that if we as a society want to put DNA in a separate category for terms of patent law (because of its unique informational content, etc.), then Congress should get to work on revising the US Code. It's not a matter for the courts to write that in by themselves. The opinion also rejects arguments (made in the dissenting opinion) that make analogies to snipped a leaf off a tree or removing an organ from a human body. These, they say, are not specific, defined substances, but an isolated DNA molecule most certainly is.

There, that's the first part of the opinion. There's another section as to the methods of use, but I think this is enough legal matter for one day around here. And there's plenty of arguing room staked out already!

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June 18, 2012

What Compound Are You Trying to Patent, Again?

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Posted by Derek

I sure hope that Sanofi doesn't really want to own these compounds in this recent patent filing. (Thanks to a reader at another company for sending this along!) But what are the odds of that, given that they went to all the trouble of filing on them?
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The reason I say that is while the compounds are drawn correctly in the experimental section (the part that was done by the chemists), the description and the claims (which were done by the lawyers) have the wrong structure in them. Wrong, as in doesn't match the experimentals, and wrong as in doesn't exist, either. The patent is directed towards indolizine derivatives, but the drawings in the claims are not indolizines, but are rather some sort of charged species whose name I do not exactly have at the tip of my tongue. Not that they're drawn any charges on anything, naturally, even though all those nitrogens have four bonds on them.

Does this invalidate the patent? Probably not, although I am most certainly not a lawyer. The names, as written, still seem to be fine. Does this complicate efforts to defend the chemical matter? You'd have to think so. Does it make people at Sanofi look like they either don't know much chemistry, aren't paying much attention, or both? Absolutely.

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June 11, 2012

China's Compulsory Licensing

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Posted by Derek

The Chinese government recently amended its intellectual property law to allow for compulsory licensing. Similar measures are on the books in many other companies, and it's allowed under international patent law (WIPO) in cases of emergency or threats to public health. India recently did this to Bayer's Nexavar. Thailand has used this provision more than once, and other countries (such as Brazil) have threatened it during negotiations with drug companies.

Pharmalot has more on the story, particularly with respect to Gilead and their dealings with the Chinese government over their HIV therapy Viread. As that piece says, China is particularly well suited (as is India) to follow through on such moves, since both countries have robust pharma manufacturing and generic drug business sectors.

I'm actually surprised that the Chinese government didn't have these provisions in place before, though. It's a useful negotiating tool, and I would expect them to avail themselves of everything available, since they are in such a good position to play hardball. Of course, they also have a huge amount of investment from multinational companies on the other side of such considerations - but they also have that huge market that the companies want access to. My guess is that last factor will, in the end, trump everything. There are many drugs, and many drug companies, but there's only one Chinese market. And the only way to that market is through China's one government, which means that companies (and not just drug companies) will continue to smile through gritted teeth and put up with pretty much anything.

Comments (11) + TrackBacks (0) | Category: Business and Markets | Patents and IP

May 24, 2012

Publishing Without Consent

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Posted by Derek

Here's a note on an ugly situation: when a post-doc publishes a paper without the permission of the principal investigator. Now, this is a fairly rare situation, but still not as rare as you might imagine - the article itself has several citations, and it quotes a journal editor who's seen it happen a number of times.

In most of these cases, there seems to be a more fundamental confusion about ownership of data, with publishing as the sequel. People leave a research group with their piles of results, and decide that since it's theirs, that it's time to get it out into the literature with their name on it. But as the article points out, if work is done under NIH funding, then the results belong to the institution, and the grantee/PI is the person who decides when and where things are published. You may, as a grad student or post-doc, feel that the data you worked so hard to generate are rightfully yours, but most of the time that's just not the case.

In industry we have our own disputes, but this isn't one of them. There's rarely any argument about ownership of data: that's all company property, and you sign documents when you're hired that explicitly spell that out. And publication is rarely as bitter a business as it is in academia (where it's the coin of the realm). We argue about whether a particular project is advanced enough (or dead enough, more likely) to be written up for a journal, but these are secondary questions.

Who gets on the patent is a slightly bigger question, but it's not like you get a cut of the profits based on whether your name is on the list. That's as opposed to Germany, where that's exactly what happens, and I've often wondered if we should try that here. That system leads to some elbow-throwing when it comes to inventorship on a hot project, but it also leads to everyone having a clear idea of the legal requirements to be an inventor. Ownership is, naturally, not in dispute at all. Every invention realized at the company is company property, too (those same documents take care of that back when you're hired on).

So while rogue academic publishing is a known phenomenon, rogue industrial patenting isn't. Well, as far as I know it isn't - anyone have an example of someone who tried to get away with it?

Comments (35) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature

May 3, 2012

A Long-Delayed COX2 Issue Gets Settled - For $450 Million?

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Posted by Derek

Has the last shot been fired, very quietly, in the COX-2 discovery wars? Here's the background, in which some readers of this site have probably participated at various times. Once it was worked out that the nonsteroidal antiinflammatory drugs (aspirin, ibuprofen et al.) were inhibitors of the enzyme cyclooxygenase, it began to seem likely that there were other forms of the enzyme as well. But for a while, no one could put their hands on one. That changed in the early 1990s, when Harvey Herschman at UCLA reported the mouse COX2 gene. The human analog was discovered right on the heels of that one, with priority usually given to Dan Simmons of BYU, with Donald Young of the University of Rochester there at very nearly the same time.

The Rochester story is one that many readers will be familiar with. The university, famously, obtained a patent for compounds that exerted a therapeutic effect through inhibition of COX-2, without specifying what compounds those might be. They did not, in fact, have any, nor did they give any hints about what they'd look like, and this is what sank them in the end when the university lost its case against Searle (and its patent) for not fulfilling the "written description" requirement.

But there was legal action on the BYU end of things, too. Simmons and the university filed suit several years ago, saying that Simmons had entered into a contract with Monsanto in 1991 to discover COX2 inhibitors. The suit claimed that Monsanto had (wrongly) advised Simmons not to file for a patent on his discoveries, and had also reversed course, terminating the deal to concentrate on the company's internal efforts instead once it had obtained what it needed from the Simmons work.

That takes us to the tangled origin of the COX2 chemical matter. The progenitor compound is generally taken to be DuP-697, which was discovered and investigated before the COX-2 enzyme was even characterized. The compound had a strong antiinflammatory profile which was nonetheless different from the NSAIDS, which led to strong suspicions that it was indeed acting through the putative "other cyclooxygenase". And so it proved, once the enzyme was discovered, and a look at its structure versus the marketed drugs shows that it was a robust series of structures indeed.

One big difference between the BYU case and the Rochester case was the Simmons did indeed have a contract, and it was breach-of-contract that formed the basis for the suit. The legal maneuverings have been going on for several years now. But now Pfizer has issued a press release saying that they have reached "an amicable settlement on confidential terms". The only real detail given is that they're going to establish the Dan Simmons Chair at BYU in recognition of his work.

But there may be more to it than that. Pfizer has also reported taking a $450 million charge against earnings related to this whole matter, which certainly makes one think of Latin sayings, among them post hoc, ergo propter hoc and especially quid pro quo. We may not ever get the full details, since part of the deal would presumably include not releasing them. But it looks like a substantial sum has changed hands.

Comments (12) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Patents and IP

March 21, 2012

The Supreme Court Makes Me Smile

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Posted by Derek

I wrote here about the Mayo v. Prometheus case, which dealt with patents on the use of thiopurines for autoimmune therapy. But the patents didn't claim any thiopurine drugs themselves. Or their specific use for autoimmune therapy. Or vehicles to administer them in, or methods for their manufacture, or techniques to package them. Nothing as reasonable as any of that.

No, these patents broke new ground. The problem is, the thiopurines are metabolized rather quickly, and to different degrees in different patients. That can make it tricky to know if someone's getting the right dosage - too much is bad, too little is bad. The Prometheus patents comprise these steps:

1. Telling a doctor to administer the drug to a patient.
2. Telling the doctor to measure the metabolite levels in their blood after dosing.
3. Describing the upper and lower acceptable bounds for these metabolites, and telling the doctor that these indicate a need to raise or lower the dosage.

There! That wasn't so good now, was it? I railed against this ridiculous idea at the time, which is tantamount to trying to patent the entire practice of medicine, step by step. (I know! I'll patent the idea of having a hypothesis, testing it by experiments where I manipulate individual variables, and then revising my hypothesis for the next round based on the results! Step three: profit!)

Fortunately for everyone's sanity, the Supreme Court has put the brakes on this stuff. Here comes the voice of reason:

Because the laws of nature recited by Prometheus’ patent claims—the relationships between concentrations of certain metabolites in the blood and the likelihood that a thiopurine drug dosage will prove ineffective or cause harm—are not themselves patentable, the claimed processes are not patentable unless they have additional features that provide practical assurance that the processes are genuine applications of those laws rather than drafting efforts designed to monopolize the correlations. . .

. . .This Court has repeatedly emphasized a concern that patent law not inhibit future discovery by improperly tying up the use of laws of nature and the like. See, e.g., Benson, 409 U. S., at 67, 68. Rewarding with patents those who discover laws of nature might encourage their discovery. But because those laws and principles are “the basic tools of scientific and technological work,” id., at 67, there is a danger that granting patents that tie up their use will inhibit future innovation, a danger that becomes acute when a patented process is no more than a general instruction to “apply the natural law,” or otherwise forecloses more future invention than the underlying discovery could reasonably justify. . .

Yes, yes, yes. This is Justice Breyer's opinion for the unanimous court (he asked the most questions during the oral arguments), and it's absolutely correct and a great pleasure to read. Let's hope we see no more of this nonsense. (Which means, I guess, that we'll just move on to fresh nonsense instead, but patent law is ever fruitful).

Comments (41) + TrackBacks (0) | Category: Patents and IP

March 5, 2012

Department of Lots of Nerve (Patent Applications Desk)

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Posted by Derek

When you file a patent application, there are plenty of things that the PTO wants you to include. One of the big ones is prior art: you're supposed to disclose all the relevant inventions close to yours that you're aware of, in order to show how your discovery is different. Prior art is naturally to be found in other previous patent filings, and it's also to be found in journal articles and other such public disclosures. If you don't submit relevant prior art that is known to you, your patent application gets into a lot of trouble eventually (and the more worthwhile your invention, the greater the chance becomes of that catching up with you).

So in light of this, you might find it interesting that some of the large scientific publishers are suing over all this. Why? Well, these lawsuits (filed by Wiley and by the American Institute of Physics) allege that the accused law firms violated copyright by submitting unauthorized copies of journal articles with their patent applications.

As that post at PatentlyO goes on to show, the plaintiffs seem to also be very interested in the internal copies of articles that the law firms are making. But I don't really see how they're going to make either of these stick. I mean, I tend to think that a lot of things are "fair use", but aren't these? This really looks like an act of desperation - the traditional scientific publishing model must be in even worse shape than I thought.

Comments (15) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature

February 24, 2012

Independent Inventions

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Posted by Derek

Alex Tabarrok has an interesting post on the idea of patent protection for "independent invention". This would be for cases when two people or organizations independently arrive at the same thing:

In the minds of the public someone who infringes a patent is like a plagiarist or a thief–the infringer has copied someone else’s work or, even worse, stolen their intellectual property. In reality, patent infringement has very little to do with copying or theft. Here’s how I described what is probably closer to the paradigmatic case of patent infringement in "Launching the Innovation Renaissance":

'Two inventors, Kelly and Pat, work independently, neither aware of the other’s existence. Kelly patents first. Under the present law, if Pat wants to sell or even use his own invention, he must pay Kelly a license fee (!) even though Pat’s idea came from his own head and no other.'

If independent invention were uncommon this type of case wouldn’t be important but independent invention is very common. Classic cases include Newton and Leibniz with the calculus, Alexander Graham Bell, Elisha Gray and Johann Philipp Reis with the telephone, Ohain, Campini, and Whittle with the jet engine and so on. And if independent invention is common with great discoveries and inventions then it is surely much more common with ordinary innovations. As a result, it’s not surprising that most patent cases don’t even allege copying.

He proposes that "independent invention" be an available defense for claims of infringement. I agree in principle, but I worry that it would turn into just another way for people with the legal resources to tie up the system until their opposition gives in.

How would such a system affect drug discovery? Since we tend to spend a lot of time making sure that our molecules really are legally differentiable from the competition, I think that this would be less of an issue for us. But it's certainly true that some cases would arise. I personally have worked on a series of compounds (some years ago) that turned out to be the exact same series that a competitor was working on. The patents applications were filed within a couple of weeks of each other, and there were many compounds that overlapped. There are some areas where an independent invention defense could come in very handy (or be a major pain, depending on your relationship to the sharp end).

Comments (16) + TrackBacks (0) | Category: Patents and IP

February 6, 2012

Academia and Industry, Suing Each Other

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Posted by Derek

This is not the sort of academic-industry interaction I had in mind. There's a gigantic lawsuit underway between Agios and the Abramson Institute at the University of Pennsylvania, alleging intellectual property theft. There are plenty more details at PatentBaristas:

According to the complaint filed in the US District Court Southern District Of New York, the Institute was created by an agreement between The Abramson Family Foundation and the Trustees of the University of Pennsylvania. The Foundation donated over $110 Million Dollars to the Institute with the condition that the money was to be used to explore new and different approaches to cancer treatment.

Dr. Thompson later created a for-profit corporation that he concealed from the Institute. After a name change, that entity became the Defendant Agios Pharmaceuticals, Inc. Dr. Thompson did not disclose to the Institute that at least $261 million had been obtained by Agios for what was described as its “innovative cancer metabolism research platform” – i.e., the description of Dr. Thompson’s work at the Institute. Dr. Thompson did not disclose that Agios was going to sell to Celgene Corporation an exclusive option to develop any drugs resulting from the cancer metabolism research platform.

Such are the accusations. There's more of Thompson's defense in this New York Times article:

Three people with knowledge of Dr. Thompson’s version of events, two of whom would speak only on condition of anonymity because of the litigation, said that the University of Pennsylvania knew about Dr. Thompson’s involvement with Agios and even discussed licensing patents to the company, though no agreement was reached.
“When you start a company like this, you want to try to dominate the field,” said Lewis C. Cantley, another founder of Agios and the director of the cancer center at the Beth Israel Deaconess Medical Center in Boston. “The goal was to get as many patents as possible, and it was frustrating that we weren’t able to get any from Penn.”

Michael J. Cleare, executive director of Penn’s Center for Technology Transfer, declined to discuss whether negotiations had been held but said, “Yes, Penn knew about Agios.”

So, as the lawyers over at PatentBaristas correctly note, this is all going to come down to what happened when. And that's going to be determined during the discovery process - emails, meeting minutes, memos, text messages, whatever can establish who told what to whom. If there's something definitive, the whole case could end up being dismissed (or settled) before anything close to a trial occurs - in fact, that would be my bet. But that's assuming that something definite was transferred at all:

A crucial question, some patent law and technology transfer specialists said, could be whether Dr. Thompson provided patented technology to Agios or merely insights.

“If somebody goes out and forms a company and doesn’t take patented intellectual property — only brings knowledge, know-how, that sort of thing — we wouldn’t make any claims to it,” said Lita Nelsen, director of the technology licensing office at the Massachusetts Institute of Technology.

In its complaint, the Abramson institute does not cite any specific patents. It says Penn did not pursue the matter because Dr. Thompson had told the university that his role in Agios did not involve anything subject to the university’s patent policies. The lawsuit says the institute did not find out about Dr. Thompson’s role in Agios until late 2011.

There will probably be room to argue about what was transferred, which could get expensive. That accusation of not finding out about Agios until 2011, though, can't be right, since he's mentioned all over their press releases and meeting presentations at least two years before that. But no matter how this comes out, this is not the way to build trust. Not quite.

Comments (6) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Patents and IP

December 12, 2011

Don't Dose That Patient Until You Pay Up

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Posted by Derek

Now here is an awful, awful idea, and it's made it all the way to the Supreme Court. Oral arguments were heard last week in Mayo Collaborative Services v. Prometheus Laboratories, and this one really has the potential to screw things up.

Why am I so downbeat? Wait until you hear the basis of this case. Prometheus has a patent whose first claim is as follows:

(1) A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:

(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and

(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8x10^8 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein the level of 6-thioguanine greater than about 400 pmol per 8x10^8 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

There, that sounds like a nice little chunk of medico-legal boilerplate. But look closely: what they're claiming is the process of using a blood test to decide whether or not to administer a drug. Prometheus Labs did not discovery any immune-mediated gastrointestinal diseases. They most certainly did not discover thioguanine, nor did they discover that giving thioguanine is beneficial to people who are deficient in it. No, they make a test kit, and they are claiming the process of checking a patient's blood levels (their test kit's function) in order to make a medical decision. The Mayo Clinic planned to offer a competing test kit, and Prometheus sued, and here we are.

Now, think about a world in which such processes are patentable (here's a column at Ars Technica that's done that already). Prometheus seems to be claiming that the awareness of needing to test for thiopurine levels in order to decide whether to dose a patient is enough to infringe their patent. Doesn't matter if the physician doses anyone or not - just the idea of testing their blood is enough. IP rights have been infringed. Money must change hands. Ka-ching. Imagine every new bit of medical practice broken down into the smallest patentable, monetizable steps. A physician reads about a new finding that might affect clinical practice - but not so fast! Better check to see what the patent rights are. Wouldn't want to get sued for applying the scientific literature without the proper licensing fees. As the AMA's amicus brief has it:

"If claims to exclusive rights over the body’s natural responses to illness and medical treatment are permitted to stand, the result will be a vast thicket of exclusive rights over the use of critical scientific data that must remain widely available if physicians are to provide sound medical care"

If you follow intellectual property issues, you'll have noted the similarity of this case to software and business-method patents, which have been a gigantic tar pit of litigation for some years now. But the tide of tar is not finished rising. The IP lawyers are, as you'd expect, watching this case with great interest, some with thoughts of perpetual employment, and some in a sort of fascinated horror. This problem has been developing for a long time, since the main legal decisions on what constitutes patentable matter actually appear to contradict each other, and perhaps this will be the case that begins the ugly process of sorting all that out. (Or perhaps the Supreme Court will recoil from that task and decide this case on some narrower basis, kicking the issue a few years into the future).

Here's a more technical legal summary of the oral arguments at the Patently-O site. It appears that Justice Breyer will be a key player in the eventual opinion; he spent by far the most amount of time asking questions during the orals. And here (also from Patently-O) is a new law review paper from Case Western on the whole tangled subject of medical diagnostic patents. This post at Patent Baristas has links to the various briefs filed on both sides of the case.

Comments (17) + TrackBacks (0) | Category: Patents and IP

November 28, 2011

Amgen's New Patent: Explanations, Anyone?

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Posted by Derek

Perhaps someone with a better knowledge of the biomolecule patent world can answer this one for me: just how did Amgen suddenly carve out a whole new patent lifetime for Enbrel? This is US patent 8,063,182, and it's hard for me to unravel what the new parts are or how and why this got issued. Merck and others who have been eyeing biosimilars in this area have no doubt already formulated their legal challenges to it. But what's that line of attack going to be?

Update: explanation in the comments. This application was filed in 1995 and had a long, long history at the patent office before finally being granted. Now, of course, the thing runs for 17 years from date of issue. The law has since been changed to keep this exact sort of thing from happening, with a term of 20 years from the application date. But Amgen applied under the old rules, and gets to live by them. I'm still wondering what the difference is between this patent and the others on Enbrel, though. . .

Comments (21) + TrackBacks (0) | Category: Patents and IP

October 18, 2011

A New Book on Chemical Patents

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Posted by Derek

I wanted to mention a book I've received a review copy of recently: Writing Chemistry Patents and Intellectual Property: A Practical Guide. The description is accurate. It'll be most useful for people who don't have access to a lot of well-paid legal talent - or at least would like to get things into shape as much as possible before calling them in and starting the meter running. It goes into detail on what makes a valid application, what patent examiners are trained to look for, and how to draft an application that will stand the best chance of surviving scrutiny. It's not a replacement for a patent attorney - you're still going to need one - but it can keep you from wasting the time of one, or from spending your own money while doing so.

Note added for legal reasons: that's an Amazon affiliate link, meaning that Amazon will (without raising the price to you) rebate a small amount of each purchase you make to me - not just that book, but whatever else you might purchase at the same time. I promise to spend it on the sorts of riotous living that one can fund only through Amazon gift cards.

Comments (4) + TrackBacks (0) | Category: Book Recommendations | Patents and IP

September 30, 2011

Patent Trolling, Money and Fun

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Posted by Derek

Now this is the sort of thing we don't need. Nature News reports on a court case that I missed, Classen Immunotherapies, Inc. v. Biogen IDEC et al.. This is yet another run at the "can you patent natural phenomena?" argument, which seems to be an ever-upwelling spring for patent litigation:

The court upheld a lawsuit filed by Classen Immunotherapies of Baltimore, Maryland, against four biotechnology companies and a medical group, for infringing on a patent that covered the idea of trying to link infant vaccination with later immune disorders. A district court had thrown out the lawsuit, finding that the concept at the heart of the case amounted to an abstract idea that could not be patented. The appeals court found otherwise.

Beyond its complex particulars, the case sets "a troubling precedent", says James Bessen, a lawyer at the Boston University School of Law, Massachusetts, "because you're patenting something that's very broad". (The patents include the act of reading the published scientific literature and using it to create vaccination schedules that minimize immune disorders.)

Oh, I particularly like that last part. I have to congratulate whoever thought of putting it it into a patent application, in sort of the same spirit that one has to congratulate the Mongol hordes on their horsemanship. The facts of the case are a bit more complicated, though, as it always the case in the law. Originally, a district court had indeed ruled (by summary judgment) that the Classen claims were unpatentable, and the CAFC had gone along with that. But the Supreme Court vacated the decision, in light of a 2010 case (Bilski v. Kappos, if you're into this stuff), and remanded it back down to the CAFC. The guidance seems to have been to not make any broad statements about patentability, if possible, and to consider each case narrowly as. On reconsideration, they now find that two of the three claims under dispute are "patent eligible", but they're leaving the door wide open for them to be contested on other grounds:

We conclude that the claimed subject matter of two of the three Classen patents is eligible under §101 to be considered for patenting, although we recognize that the claims may not meet the substantive criteria of patentability as set forth in §102, §103, and §112 of Title 35. However, questions of patent validity are not before us on this appeal. . .

If you want more, there's a detailed look at the decision over at Patent Baristas.

But the broader problem is still with us. Prof. Bessen has just recently published a study of "patent trolls", the organizations that buy up as many (preferably broadly worded) patents as they can, and then go looking for people to sue. That business model (which seems to be more and more popular, damn it all, has always put me in mind of one of the characters in the old Pogo comic strip - when approached with a sure-fire way for him to make money in the advertising business, he responded with a panicked "No, no! I can always rob graves!"

Nature News is incorrect, though, when they imply that the biotech industry has been free of these things up until now. There may have been fewer of the real "non-producing entities", the firms that have nothing but a pile of bought-up patents and some hungry lawyers, but we have had our share of people trying to get rich by enforcing crazily over-broad patents. In the earlier days of this blog, I spent a good amount of time chronicling Ariad's attempt to sue everyone in sight over claims to the Nf-kappa-B pathway that basically covered everything out to the asteroid belt. That one only took about eight full years of lawyering and who knows how much money and effort to be disposed of. And back in the 1990s, I recall that there was some guy with a patent claiming huge swaths of space around the concept of cell-based assays, who was shaking everyone down that he could find.

Some other high-tech areas are infested with this sort of thing. I find that I cannot, for example, listen to any presentation by Nathan Myhrvold - who is otherwise an intelligent and interesting person - without thinking about how he runs Intellectual Ventures, a patent-trolling firm in its purest form. As it happens, the Nature News piece mentions that Myhrvold's minions own hundreds of biotech patents. They claim that they have no plans to litigate in the field, but why on earth would they buy these things up, otherwise? And as a comment to the news article points out, that denial may be disingenuous, because IV's usual procedure is to set up some other entity to do the suing, after first having sold it the rights to the patents at issue. As that extremely interesting NPR story goes on to detail, those other entities tend to be in Marshall, Texas:

The office was in a corridor where all the other doors looked exactly the same —locked, nameplates over the door, no light coming out. It was a corridor of silent, empty offices with names like "Software Rights Archive," and "Bulletproof Technology of Texas."

It turns out a lot of those companies in that corridor, maybe every single one of them, is doing exactly what Oasis Research is doing. They appear to have no employees. They are not coming up with new inventions. The companies are in Marshall, Texas because they are filing lawsuits for patent infringement.

So this is how people make money these days: not by inventing anything themselves, but by buying up other people's work - dubious or valid, it doesn't much matter - and suing people. From empty offices over in ArkLaTex country. And we biopharma people could well find ourselves spending more and more of our own time and money fighting this stuff off, because hey, why not?

Comments (35) + TrackBacks (0) | Category: Patents and IP

September 6, 2011

A Dish Best Served Cold

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Posted by Derek

And the well-known chem-blogger Milkshake knows how to serve it. See his latest post here. It doesn't qiote make up for having one's company bought out, having everyone moved and fired and hosed around, and having to go to court for the severance package that you were promised. . .but you have to take your pleasures where you can.

Comments (37) + TrackBacks (0) | Category: Drug Industry History | Patents and IP

August 1, 2011

Chinese Research: Not Quite the Juggernaut?

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Posted by Derek

A perennial topic around here has been the state of scientific research in China (and other up-and-coming nations). There's no doubt that the number of scientific publications from China has been increasing (be sure to read the comments to that post; there's more to it than I made of it). But many of these papers, on closer inspection, are junk, and are published in junk journals of no impact whatsoever. Mind you, that's not an exclusively Chinese problem - Sturgeon's Law is hard to get away from, and there's a lot of mediocre (and worse than mediocre) stuff coming out of every country's scientific enterprise.

But what about patents? The last couple of years have seen many people predicting that China would soon be leading the world in patent applications as well, which can be the occasion for pride or hand-wringing, depending on your own orientation. But there's a third response: derision. And that's what Anil Gupta and Haiyan Wang provide in the Wall Street Journal. They think that most of these filings are junk:

But more than 95% of the Chinese applications were filed domestically with the State Intellectual Property Office—and the vast majority cover "innovations" that make only tiny changes on existing designs. A better measure is to look at innovations that are recognized outside China—at patent filings or grants to China-origin inventions by the world's leading patent offices, the U.S., the EU and Japan. On this score, China is way behind.

The most compelling evidence is the count of "triadic" patent filings or grants, where an application is filed with or patent granted by all three offices for the same innovation. According to the Organization for Economic Cooperation and Development, in 2008, the most recent year for which data are available, there were only 473 triadic patent filings from China versus 14,399 from the U.S., 14,525 from Europe, and 13,446 from Japan.

Starkly put, in 2010 China accounted for 20% of the world's population, 9% of the world's GDP, 12% of the world's R&D expenditure, but only 1% of the patent filings with or patents granted by any of the leading patent offices outside China. Further, half of the China-origin patents were granted to subsidiaries of foreign multinationals. . .

The authors are perfectly willing to admit that this probably will change with time. But time can make things worse, too: as this editorial in Science last year made clear, the funding of research in China has some real problems. The authors of that piece are professors at two large Chinese universities, and would presumably know what they're talking about. For the biggest grants, they say:

. . .the key is the application guidelines that are issued each year to specify research areas and projects. Their ostensible purpose is to outline “national needs.” But the guidelines are often so narrowly described that they leave little doubt that the “needs” are anything but national; instead, the intended recipients are obvious. Committees appointed by bureaucrats in the funding agencies determine these annual guidelines. For obvious reasons, the chairs of the committees often listen to and usually cooperate with the bureaucrats. “Expert opinions” simply reflect a mutual understanding between a very small group of bureaucrats and their favorite scientists. This top-down approach stifles innovation and makes clear to everyone that the connections with bureaucrats and a few powerful scientists are paramount. . .

Given time, this culture could be changed. Or it could just become more entrenched as the amounts of money become larger and larger and the stakes become higher. China could end up as the biggest scientific and technological powerhouse the world has ever seen - or it could end up never living up to its potential and wasting vast resources on cargo-cult theatrics. It's way too early to say. But if many of those Chinese patents are just being written because someone's figured out that the way to get money and prestige is to file patents - never mind if they're good for anything - then that's not a good sign.

Comments (31) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature | Who Discovers and Why

June 8, 2011

Roche Prevails Over Stanford

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Posted by Derek

The Supreme Court has ruled on the Roche - Stanford case that I blogged about here. In short, the dispute centered on the Bayh-Dole act (on commercializing academic research) and sought to clarify under what circumstances university collaborators signed over the rights to their discoveries. (That makes the case sound quite calm and removed from worldly concerns, but you'll see from that earlier post that it was actually nothing of the sort!)

As I and many others had predicted, Roche prevailed. The justices upheld the ruling (7 to 2) from the Court of Appeals for the Federal Circuit that the Stanford researcher(s) involved had indeed signed over rights to Roche, and that this assignment was compatible with existing law. Here's the decision (PDF). Among the key points:

1. Stanford contended that if an invention had been realized with federal funding (NIH, etc.), that the Bayh-Dole Act automatically assigned it to the university involved. The Court noted that there are, in fact, situations where patent rights are treated this way, but that this language is conspicuously missing from Bayh-Dole. Accordingly, the invention belongs to the inventor, until the inventor assigns the rights to it. And in this case, like it or not, the Stanford post-doc involved signed things over to Cetus (as was). This inventorship business goes for industry as well, of course - one of the key pieces of paper that you sign when you join a drug company assigns the rights to whatever inventions you come up with (on company time, and with its resources) to the company. If you don't sign, you don't have a job. And on the flip side, just being employed is not enough for a company to claim an invention - there has to be an explicit statement to that effect.

Here's Justice Roberts on this point:

Stanford’s contrary construction would permit title to an employee’s inventions to vest in the University even if the invention was conceived before the inventor became an employee, so long as the invention’s reduction to practice was supported by federal funding. It also suggests that the school would obtain title were even one dollar of federal funding applied toward an invention’s conception or reduction to practice. It would be noteworthy enough for Congress to supplant one of the fundamental precepts of patent law and deprive inventors of rights in their own inventions. To do so under such unusual terms would be truly surprising. . .

You might be wondering if this argument bears on the contentions of people who claim that hey, it's all NIH money in the end, so drug companies do nothing but leech off public money, right? Why yes, yes it does. Justice Breyer (joined by Justice Ginsberg) dissents, saying that the intent of Bayh-Dole is to commercialize research, and not having title automatically assign to the university (or other recipient of federal funding) undercuts this substantially. There's a lot of talk in the dissent about the background of the act, about its real intentions, and about how it's supposed to work. And I can see the force of those arguments - but to me, they don't overcome the fact that if Congress wanted Bayh-Dole to work that way, they could have written it that way. And, in fact, they still can, if they decide that this decision illuminates a flaw that they'd like to address. Until then, though, I feel safer with the statutory language that's in there already, and how it compares to other, similar laws.

Comments (3) + TrackBacks (0) | Category: Academia (vs. Industry) | Patents and IP

April 8, 2011

Roche and Stanford: Academia v. Industry?

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Posted by Derek

One morning back in 1989, a guy from Stanford visited the biotech company Cetus and signed a few forms. That action has gradually become the central issue in a nasty patent dispute that's dragged on for years. Roche (who bought Cetus in 1991) and Stanford have been fighting it out through the judicial system, and earlier this year they made their cases before the Supreme Court, who will probably deliver a decision next month. So how did a quick signature

How did This article in Science has a good summary of the details (here's another). What seems to have happened was Thomas Merigan at Stanford sent a postdoc, Mark Holodniy, over to Cetus to learn about their PCR technology. Holodniy signed an agreement to respect Cetus' intellectual property, the standard sort of thing - you'd think. But that's the problem. Ten years later, Stanford (building on work from the Merigan lab and its collaboration with Cetus) received patents on a method to quantify viral RNA in human serum, which turned into a useful assay for monitoring HIV. Roche began to sell kits to do just that in 1996, and starting in 2000, Stanford started pressing them to pay licensing fees to the university.

Roche didn't, so Stanford sued, then Roche claimed that the Stanford patents were invalid, anyway. We'll get back to that question, but the rest of the court cases have turned on a different matter: did what exactly did Holodniy sign away, and was he bound by that agreement, or did that extend to the whole Merigan lab and to Stanford? A district court said that the Bayh-Dole act (which among other things prevents university researchers from cutting patent deals independent of the university), won out, and that Holodniy's Cetus form, which said that he was assigning patent rights to Cetus, was therefore invalid. But the Court of Appeals for the Federal Circuit completely reversed that, and said that Holodniy's agreement (when he was hired) to assign patents to Stanford was just a promise for the future ("I agree to assign. . .", whereas the Cetus agreement took force immediately ("I do hereby assign. . .") and took priority. And thus to the Supreme Court

Academia (and the US Solicitor General) have lined up on Stanford's side, and industry on Roche's, as anyone could have foreseen. If Roche wins, say the former, then no university research group will want to work with industry. If Stanford wins, say the latter, than no corporation will want to work with academia. Here's a hard-core legal summary from the Cornell law school. Their conclusion:

. . .the Supreme Court will decide whether the Bayh-Dole Act precludes an inventor working on a federally funded project from assigning his ownership rights in the invention to a third party. Stanford argues that both the Act and public policy considerations require that research institutions get an exclusive opportunity to patent their employees’ creations. Stanford contends that, if research institutions did not receive this privilege, they would hesitate to pursue costly and time-consuming research projects. Roche, on the other hand, argues that the Bayh-Dole Act did not affect the longstanding rule allowing inventors to assign their ownership rights to third parties. Constitutional and equitable considerations, Roche asserts, caution against Stanford’s interpretation of the Act.

My guess is that Roche will probably win, and that academic/university collaboration will continue anyway, but under even more strictly defined rules. MIT, for example, has already changed its patent assignment forms to the present tense, in a sign that they think that this argument has validity (even though the university has sided with Stanford in this case). One thing that's been lost in all the dust is whether this whole question had to come up. If Stanford's patents were to have been invalidated (another case in itself), then the whole Bayh-Dole argument would have been a moot point. None of the later legal wrangling has addressed this point. As often happens in the courtroom and on the battlefield, the armies end up fighting for larger stakes (and in a different place) than anyone would have predicted at first.

Comments (7) + TrackBacks (0) | Category: Academia (vs. Industry) | Patents and IP

January 20, 2011

Freedom to Operate

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Posted by Derek

A discussion with a colleague the other day brought up a point about drug patents. When you're thinking about the chemical matter you have for your project, one of the things you have to worry about is the patent situation. Are your molecules patentable? For that to be the case, you need novelty and utility. Utility is pretty much a given in this business - you wouldn't be interested in the compounds if they didn't do something - so novelty (prior art) is what we spend time wondering about.

There's usually a way through on that, though. I mean, sure, there are all these generic claims out there in other patent applications that take everything out to the asteroid belt, but you should only get worried about the stuff that the claims are teaching toward and the compounds that have been enabled (that is, actually made). Prior art is crucial, but it's also crucial to only pay attention to what deserves attention. (We last talked about this problem here).

Then there's "freedom to operate". In that case, you're asking not "can I get a patent on this", but "can I do anything with it without infringing someone else's patents". For FTO considerations, you have to look at what IP rights other people have (or are likely to have by the time you'll be ready to go). That can get rather involved, since patents are limited in several dimensions: time (they expire eventually), space (coverage varies country by country), and in "IP space" (what territory the claims stake out). Depending on what comes up, you might decide that you're in the clear. Or you might try to invent yourself out of a tight spot, if you can do that. Or you could pay someone for rights to their IP, or trade them some of yours, if you have something to trade.

But here's where we got to talking: in the drug business, where we're patenting particular chemical matter (and the use of it for particular medical needs), it seems like freedom to operate isn't as big a deal as it is in some other areas. That's partly because it's hard to get sweeping medical claims issued, and it's hard to make them stand up if they do. There have been attempts to stake out whole modes of action ("We claim the method of treating a patient in need of lowering their XYZ levels with any inhibitor of XYZase"), but fortunately, that hasn't taken hold.

So when you're talking chemical matter, does anyone know of drugs (or programs) that have been derailed in development just because of freedom-to-operate concerns? Drug patents get challenged all the time, often by generic companies, but those are patentability issues, trying to overturn the whole filing. But what about FTO? Any examples?

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November 1, 2010

Are Genes Patentable Or Not?

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Posted by Derek

There seems to be some disagreement within the US government on the patentability of human genes. The Department of Justice filed an amicus brief (PDF) in the Myriad Genetics case involving the BRCA genes, saying that it believes that genes are products of nature, and therefore unpatentable.

But this goes opposite to the current practice of the US Patent and Trademark Office, which does indeed grant such patents. No lawyers from the PTO appear on the brief, which may be a significant clue as to how they feel about this. And at any rate, gene patentability is going to be worked out in the courts, rather than by any sort of statement from any particular agency, which takes us back to the Myriad case. . .

Comments (20) + TrackBacks (0) | Category: Biological News | Patents and IP

October 21, 2010

Apotex's Plavix Adventure: Four Years Later

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Posted by Derek

Remember the Plavix Confusion of 2006? That's when Canadian generic company Apotex managed to jump onto the market for a few weeks with its own version of the BMS/Sanofi-Aventis blockbuster. It was always a bit unclear whether they had the right to do that - there was a case that the company had played rough but fair with some tricky language in their agreements with the two pharmas. Still, Apotex racked up over 800 million dollars in sales while everyone was sorting that out.

Well, four years down the road, a judge has ruled that Apotex owes BMS and S-A damages for their adventure: half the sales, plus interest. That's still less than the triple damages that could be obtained in an open-and-shut case of patent infringement, but it's pretty substantial. I wonder how much of the money Apotex still has handy?

Comments (9) + TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP

September 13, 2010

You May Not Be Interested In It - But It's Interested In You

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Posted by Derek

Like any blog owner, I check the traffic on my site. It follows the working day, with peaks during on weekday lunchtimes, in case you're wondering: I can see both the East and West coasts kicking back with sandwiches and some blog time. And I can see when some post has really revved up the readership, or brought in hordes of outside links. (Yep, "Things I Won't Work With" is the champion in that category). I can also see when a topic has failed to do either of the above.

Patent law is the champion there. That's both understandable and sort of a shame, because it is, of course, of huge importance to the drug industry. And it can also be quite interesting, once you get into it a bit. But there's no doubt that it can also make you wish that you'd listened to Momma and gone to truck-driving school like she always wanted. Many chemists just try to avoid dealing with patent questions, or rely on a few rules of thumb that they've picked up over the years, accurately or not.

Well, there's now a book that might do a lot of us a lot of good. I've been looking over The Chemist's Companion Guide to Patent Law, by Chris Miller and Mark Evans, and I think that the field has been needing something like this for a long time. It was published just last month, and one of the authors had Wiley send me a copy. I'm in the process of reading it cover to cover, and it's staying on my reference shelf.

The title is accurate; it's a top-to-bottom look at the major features of patent law as it applies to the business of chemistry. Freedom to operate, patentability (two very different concepts), claim structure, prior art, enablement, obviousness, inventorship, infringement - all the key concepts that, frankly, almost all working chemists turn out to be a bit hazy on when you get down to details. (And law, inevitably, always gets down to the details). It's illustrated with numerous examples from recent cases, structures and all, and with plenty of very realistic hypotheticals. For example:

Imagine that you are a chemist who has been laboring to find a compound that is capable of inhibiting a very important pathway in a human disease state. After many years of hard work and false leads, you find a compound - compound 4 in Figure 7.9 - that appears to possess all of the necessary attributes. However, your information scientist reports that there are prior art references that disclose a total of three different Markush structures, each of which encompasses your compound as shown in Figure 7.9. The prior art references that contain these three genera provide the general methods of making the compounds, and the preparation is enabled for one skilled in the art. A few specific examples have been made that fall within genus 1 (and hence genera 2 and 3 as well) of the prior art, but your exact compound has not been specifically disclosed. The question is now whether compound 4 is anticipated and rendered nonpatentable per se. . .

Sound familiar? For most experienced drug discovery chemists, it sure will. As the authors go on to say, a Markush that has so many variables that it can be expanded to eight wazillion compounds isn't something to really worry about - you're supposed to be able to "at once envisage" the later invention if it's going to wipe out patentability. On the other end, a direct claim of only one compound - yours - is clearly a direct hit. But what about that huge area in between? If you don't know what it means to reference the Petering case in this area, you should.

There's a lot of good stuff in this book. It's not always light reading, but it's the most readable treatment of some very complex patent issues that I've seen. Patent attorneys know everything in it (or they flippin' well should), but if you're a chemist, you probably don't. I've learned quite a few interesting things myself in the few days I've been looking it over. Every industrial chemistry department should have a copy.

Comments (25) + TrackBacks (0) | Category: Patents and IP

June 9, 2010

Running Out of Decent Molecules to Patent?

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Posted by Derek

Yancey Ward, who comments over at Megan McArdle's site at The Atlantic, has started a discussion over there on drug patent issues. There are a couple of things worth talking about here (such as how to handle combination therapies), but I wanted to bring up a particular issue first to see what the readership here makes of it:

". . .It is getting increasingly difficult to patent small molecules because their structures are increasingly found in the ever growing patent literature for completely different targets. I know for a fact that a lot of projects begin on a less than optimal structure for reasons of patentability alone."

How much of a problem is this? I know that sometimes it can be a real roadblock, particularly in areas where particular structural motifs get (over)used. I've been in on some of those projects myself. And "useful chemical space with no prior art" is a large (but finite) resource, which we are using up, as people have realized for years.

But it would be very interesting - although probably impossible - to know how many total projects across the industry have to start from a bad position because of patentability issues. That can be partly a problem of your own screening collection, which is something every company has to guard against. If you have some big, long-running projects that have cranked out a lot of similar-looking chemical matter in certain areas, these things are naturally going to be over-represented in your corporate screening files. If they're really useful structures, the challenge (after a while) becomes how to avoid starting off yet another program from the same general structures, in order to avoid their complex IP and shrinking freedom to operate. The less-trampled your compound collection is, the better off you'll be when something hits from it.

That said, the only projects I've been on that came to a halt because of patentability trouble did so because someone else popped up in the middle of things with coverage of exactly what we were working on. It happens! Other projects have gotten rather complex, as the trends in the active compounds kept pushing us closer to someone else's exemplified chemical matter, but we generally can find a way around that. Now, if we tried to total up the amount of time and money spent in that way, in working around other people's claims, that might truly add up to something alarming. . .

Comments (42) + TrackBacks (0) | Category: Patents and IP

April 9, 2010

Patent Chart Update

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Posted by Derek

I had some correspondence with the people at MassHighTech about their "New England Patent Rankings" chart (which I spoke about here). That's the one that shows Pfizer with only three patents in 2009, which didn't make a whole lot of sense, considering the size of the operation in Groton/New London.

A look through the patent databases (which several readers also confirmed) showed that something was apparently off, since there were numerous Pfizer patents where the inventors all were from Connecticut. But as it turns out, the MassHighTech people say that their consultant looks at the states of the assignees, and filters out any that don't contain CT, VT, ME, NH, MA, or RI. So that means that many Pfizer patents, which are assigned to the company at its global HQ in New York, don't make the cut.

That seems like an odd way to do things, but maybe it's just me. The people at MassHighTech say that they're looking specifically for "New England-based companies" on their list, but in that case, you wonder how even three Pfizer patents made it in.

Comments (5) + TrackBacks (0) | Category: Patents and IP

April 6, 2010

Take These?

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Posted by Derek

A reader sends along a note about this patent application from the University of Rochester. The inventor, David Goldfarb, seems to have used an assay (the subject of a previous application) to screen a library of commercially available compounds for potential life-extending properties in model organisms. Here's some detail on the screen from PubChem.

The abstract of the application makes it sound worse than it is: "A method for altering the lifespan of a eukaryotic organism. The method comprises the steps of providing a lifespan altering compound, and administering an effective amount of the compound to a eukaryotic organism, such that the lifespan of the organism is altered. . ." That sounds like one of those "Oh, get real" applications that the patent databases are cluttered with. But when you get to the claims, you find that a list of compounds is specifically given, with more- and most-preferred ones as you go down. And I don't have a problem with that, as far as it goes - the inventor has an assay, has run a bunch of compounds through it, and finds that some of them have utility that apparently no one else has recognized.

The compounds themselves, though. . .well, here are the specifically claimed ones on the list. I don't necessarily see aliphatic triketones extending my life, but perhaps I'm cynical.

Comments (18) + TrackBacks (0) | Category: Aging and Lifespan | Drug Assays | Patents and IP

March 31, 2010

Only Three Patents? Really?

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Posted by Derek

Here's an interesting list (PDF) of patent activity for life-science firms in the New England area. What I can't quite work out is how the numbers were generated. For example, it's very strange that Pfizer shows up with 3 patents from last year. A quick look through the databases shows more issued patents than that, although many of the ones I'm seeing are probably continuations-in-part of older parents.

But at any rate, if there's any consistent method of evaluating patents that shows Pfizer with fewer patents over the last few years than the likes of Neurogen and Nitromed - and that's what this one shows - then something's quite odd. I've emailed the people at MassHighTech.com to ask what's up.

Update: an email from the magazine says that the patent count is supposed to represent just the ones from the New England area. That does clear out a lot of Pfizer ones which originated from Sandwich, St. Louis, and other exotic ports. But I still can't get the numbers to come out right. I looked through about a quarter of the 2009 US patents assigned to Pfizer, and found five or six out of Groton/New London just in that group. I've emailed the magazine again about this. . .

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March 30, 2010

The Ariad Decision and Written Description

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Posted by Derek

While we're on the subject of patents, PatentBaristas has a good summing-up of the Ariad decision I mentioned here last week. There is indeed a written description requirement for a patent, and it's separate from enablement, and it had better be good.

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Myriad's BRCA Gene Case: Wait For It

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Posted by Derek

I haven't commented so far on the decision yesterday in the Myriad Genetics case involving their breast cancer assay gene patents. This is surely going to be appealed, and we're not going to really know what's up here until the CAFC has a say. And who knows? This is the sort of case that might go even further than that.

That's what the folks at Patently Obvious think, at any rate. They note that this decision is rather far out of the usual range of case law on patentability, and will likely be reversed on appeal. And then?

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March 22, 2010

Ariad Loses on Appeal

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Posted by Derek

And it's an interesting decision. As mentioned here, the company's last stand was on questions of patentability, specifically the written description requirement. Well, the appeals court has ruled this morning, and Ariad's '516 patent does, finally, appear to be invalidated. There's more at Patently Obvious, who seem to be among the first with this story.

From what I can see, the court's decision makes it clear that there really has to be a description sufficient for one skilled in the art to reproduce an invention, and that stating your hypothesis isn't enough to meet this requirement. So in Ariad's case, claiming all sorts of (not yet existing) things to modulate NF-kB function doesn't fly, because they don't actually tell anyone how to do that, just how they wanted to own it if and when someone does. The written description requirement, the court holds, doesn't mean that you have to actually reduce something to practice (although I'd have to say, from my own perspective, that it most certainly would be a good idea to do so if you can), but you have to show how that could be done. "Patents are not awarded for academic theories, no matter how groundbreaking or necessary to the later patentable inventions of others" is a key quote.

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February 17, 2010

Drug Patents in India

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Posted by Derek

The Wall Street Journal has a good article on drug patents in India. Many readers will remember the days when those three words didn't have much chance of appearing together in a sentence, but that all changed in 2005, when the country changed its laws to recognize chemical substances as well as process patents:

When India finally adopted its expanded patent law, it was widely hailed and multinational firms began expanding with gusto. They now sell their latest branded medicines here, expecting the burgeoning middle class and slowly growing health insurance system will pay for them. Pharmaceutical manufacturing has boomed, as has the clinical trial industry.

But little noticed at the time was that the new law sets a higher bar than Europe and the U.S. for approving patents, says D.G. Shah, head of the Indian Pharmaceutical Alliance, a Mumbai-based industry group.

Among the tougher provisions is one that says patents be will granted only when products are more efficacious—a provision the Indian patent office has used to deny several patents, he says.

Improved efficacy, as you might imagine, can turn out to be in the eye of the beholder. Glivec, Tarceva, Viread, and (most recently) Nexavar are drugs that have fallen into this particular pothole. And I have to say, hearing someone from the Indian drug industry lecture about patent quality is a bit hard to take. ((Update: why is that, you ask? Look here for one explanation).

"The U.S. would grant a patent to a piece of toilet paper," says Amar Lulla, chief executive of Cipla, the Indian generics drugmaker. "Just because the U.S. granted a patent, doesn't mean it should be valid."

In its Tuesday decision to dismiss Bayer's appeal, the Delhi High Court made a blistering attack on the company's efforts to block copies of its cancer medicine Nexavar. Calling the appeal "a speculative foray," the court added that "the petitioner, no doubt, is possessed of vast resources and can engage in such pursuits."

Now, I'm not saying that we don't have some poor quality patents. Every country's patent office has allowed junk to issue; the key thing is to try to cut the junk down to a minimum. But I still can't quite figure out what the Indian courts are up to (other than protecting their own generic industry and forcing down the price of drugs, of course). Take a look at this story from the Times of India on the recent Nexavar ruling. I realize that it's hard to tell if it's a news item or an editorial, but have at it anyway.

That article decries "patent linkage", which seems to be the idea that marketing approval for a drug might have something to do with its patent status. Well. . .I sort of thought it was supposed to, when it comes to generic versions. What else is a patent good for, if not for a period of exclusivity? If I'm interpreting this correctly, the Indian courts regard drug patents as granting an exclusive period for a company to market its drug under its own particular brand name - but anyone else can hop right in with the same substance, of course; the patent makes no difference there.

Am I grasping this correctly? If not, I'll be glad to be set straight. And if I am, then what, exactly, is Indian drug patent law supposed to accomplish? And why would any drug-inventing company be so foolish as to rely on it?

Comments (33) + TrackBacks (0) | Category: Business and Markets | Patents and IP

January 28, 2010

Acorda and Ampyra

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Posted by Derek

I had not been following the progress of Acorda's recently approved drug Ampyra for MS. (Well, more specifically, it's to improve gait and walking speed in MS patients). Opinion seems to be rather divided about how successful it'll be. On the one hand, new therapies for multiple sclerosis are certainly needed, but there's also room to argue about just how efficacious Ampyra really is.

I'm not going to fight that one out here, because we'll have the judgment of the market pretty soon. What I find interesting is the structure of this new drug: it's 4-aminopyridine. If there's a more simple, lower molecular weight structure approved within the next few years as an oral drug for anything, I'll be quite surprised.

This brings up several interesting topics relating to drug development and intellectual property. For one thing, this compound has been known for many years as a ligand for neuronal voltage-gated potassium channels, which is the mechanism by which it seems to work for MS patients. Some of these patients have experimented with it themselves over the years; the idea of using it for multiple sclerosis is certainly not new. (Here's a good history, taking things back a good 30 years through many players, with Elan a prominent one).

Secondly, it's not like the compound's chemical structure can be patented as such, either, since it's nowhere near novel. I have no idea of when 4-aminopyridine first makes its appearance in the chemical literature, but it's surely back into the 19th century. Nor is it anything like a rare chemical. For many years it was used as a bird-control poison. (High doses are fatal, but lower ones cause bird seizures that cause the rest of the flock to leave in consternation). We've got some on the shelf in our stockroom; I see in my Aldrich catalog that they're selling the 99% grade for $18/gram. And Aldrich is not exactly the world's low-cost chemical supplier. A railroad car full of the stuff could surely be arranged through someone, although it wouldn't exactly be pharmaceutical grade.

So. . .how then, some might wonder, does Acorda Therapeutics (partnered with Biogen Idec) get to charge several thousand dollars a year for Ampyra? (I don't think the actual price is known yet, but that's the best guess I've seen). One key factor is the bird-repellant aspect. Messing with ion channels in nerves is a tricky business, and 4-aminopyridine can and will cause trouble in humans if it's not dosed carefully. It's also (I believe) cleared pretty quickly, as you'd expect from something with that structure. Ampyra is a time-release formulation, an attempt to get enough of the compound into circulation over a long enough period, but without crossing over the line to too high a concentration, which could set off seizures and worse. Taking 4-aminopyridine from that railroad car and using that instead would be very much not recommended, considering what's waiting out there at inappropriate doses.

And that's Acorda's intellectual property. Plenty of work was done to find a good formulation for the drug, and Acorda spent the time and money to test one for safety and efficacy. They get to reap the fruits of their labors, if fruits there are. And that's what the market will decide for them. . .

Comments (28) + TrackBacks (0) | Category: Patents and IP | The Central Nervous System

November 9, 2009

So, Do I Own This, Or What? Answer: What

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Posted by Derek

The latest issue of Nature Medicine has several short articles on patent issues, and is well worth a look if that's your sort of thing. I enjoyed this from the issue's lead editorial:

"An informal poll we conducted while preparing the focus on patents appearing in this issue (pp 1239–1243) disclosed that about two-thirds of scientists, particularly in Europe, don't know who owns the intellectual rights to the discoveries made in their labs. A similarly high proportion don't know if there are any provisions in their job contracts assigning them any rights over their discovery. And roughly half don't even know whether they are legally entitled to open a company based on their research."

As the piece goes on to explain, these turn out not to be particularly hard questions to answer. They are, in fact, answered in just the way you think they are, which makes me wonder a bit about the people who don't know these things. Let's see, even though you're not a lawyer, and don't know much about these things, and you're signing an agreement with a large entity that's very interested in this subject and can afford to pay for good legal advice about it. . .hmm, I wonder who could possibly have the advantage here?

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November 2, 2009

In Which You Get to Hear the Phrase "Hatch-Waxman" Again

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Posted by Derek

There's a constant running battle in the drug industry between the two kinds of pharmaceutical companies: the ones who discover the drugs first, and the ones who sell the drugs cheaply after the patents have expired. It surprises me still how many people I run into (outside my work) who don't make that distinction, or who don't even realize that there is one.

But the generic industry is a very different place. Their research budgets are far smaller than the ones at the discovery companies, since they're only dealing with drugs that everyone knows to already work. Their own research is directed toward satisfying the regulatory requirements that they're making the equivalent substance, and to finding ways to make it as cheaply as possible. And some of them are very good at it - some ingenious syntheses of marketed drugs have come out of the better generic shops. Of course, some real head-shaking hack work has, too, but that you can find everywhere.

The tension between the two types of company is particularly acute when a big-selling drug is nearing its patent expiration. It's very much in the interest of the generic companies to hurry that process along, so often they challenge the existing patents on whatever grounds they can come up with, figuring that the chances of success jutify the legal expenses. Since the 1984 Hatch-Waxman act, there's been an even greater incentive, the so-called "Paragraph IV" challenge. A recent piece in Science now makes the case that this process has gotten out of control.

After four years of a drug's patent life, a generic company can file an Abbreviated New Drug Application (ANDA) and challenge existing patents on the grounds that they're either invalid or that the ANDA doesn't infringe them. (This, for example, is what happened when Teva broke into Merck's Fosamax patent, taking the drug generic about four years early). If the challenge is successful, which can take two or three years to be resolved, the generic company gets an extra bonus of 180 days of exclusivity. The authors of the Science piece say that this process is tipped too far toward the generic side, and it's cutting too deeply into the research-based companies. (As noted here, that's rather ironic, considering the current debate about such provisions for biologic drugs, where some parties have been citing the Hatch-Waxman regime as a wonderful success story in small molecules).

This all took a while to get rolling, but the big successes (such as the Fosamax example) have bred plenty of new activity. There are now five times as many Paragraph IV challenges as there were at the beginning of the decade. Teva, for example, which is one of the big hitters in the generic world, had 160 pending ANDAs in 2007, of which 92 were running under Paragraph IV. Here's a look at some recent litigation in the area, which has certainly enriched various attorneys, no matter what else it's done.

Under Hatch-Waxman, a new drug starts off with five years of "data exclusivity" during which a generic version can't be marketed. The Science authors argue that the losses from Paragraph IV now well outweigh the gains from this provision, and that the term should be extended (which would put it closer to those found in Europe, Canada, and Japan. They also bring up the possibility of selectively extending data exclusivity case-by-case or for certain therapeutic areas, but I have to say, this makes me nervous. There are too many opportunities for gamesmanship in that sort of system, and I think that one goal of a regulatory regime should be to make it resistant to that sort of thing.

But I do support the article's main point, which is that the whole generic industry depends on someone doing to the work to discover new drugs in the first place, and we want to make sure that this engine continues to run. Politically, though, anything like this will be a very hard sell, since it'll be easy to paint it as a Cynical Giveaway to the Rapacious and Hugely Profitable Drug Companies. But speaking as someone working for the RHPDCs, I can tell you that we are indeed having a tougher time coming up with the new products with which to exploit the helpless masses. . .

Comments (23) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Drug Prices | Patents and IP | Regulatory Affairs

October 1, 2009

How To Get Useful Data Out of a Drug Patent

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Posted by Derek

Yesterday's post on citing the patent literature prompts today's. I realize that if you're not used to reading the things, patents can be rather odd and daunting. But there are some rules to follow to let you get useful information out of them. That depends on what you're looking for, though.

If you're searching for preparations of particular chemical compounds, there's an awful lot of that available, although sometimes it's not easy to extract. What you'll probably want to do is skip directly to the experimental section. Ignore the description; ignore the claims - if you want to find out how to make Compound X, you won't find the details you're looking for there.

Problem is, the experimental section will not necessarily be laid out in a user-friendly manner. It doesn't have to be, and in fact, it's sometimes deliberately convoluted. The first thing to make sure of is that you're looking at a real experimental procedure. If it's written in the present tense, and/or with vague details ("A compound of Formula 1 is combined with a base, preferably a tertiary amine, and is heated to between room temperature and 100 degrees C. . ."), then you'd better keep turning pages. This is not what you're looking for. This is a generic or prophetic example, and doesn't necessarily have anything to back it up. Keep going until you hit real amounts of real compounds, and real spectral data. Patent applications, ones that expect to stand up, anyway, have to exemplify the compounds that they're claiming, and that takes real data.

If the patent is written with structures over each each experimental procedure, then your job is a lot easier. Often the preps will be in sequence, one intermediate leading to another, although they don't have to be. Keep paging through until you've found the compound you're after. If the compounds are named in the procedures, a text search for some part of the particular name can save you a lot of time, as can a search for the name of some reagent that you may have seen that the inventors used (from a SciFinder search, for example).

Keep in mind that the particular compound you're looking for may appear as part of a table. Often patents will be written with a detailed general procedure for a particular example, and then there will be a line like "Following this same protocol, the following examples were also prepared. . .", and a table. I know that you'd rather have a detailed individual prep (so would I), but these are still generally pretty reliable. You find this sort of thing for lists of amides or Suzuki coupling products, so it's not too bad.

The amount of spectral data you'll get will vary. Actually, the rule for a patent application is "The more, the better", so a good one will include NMR data, and whatever else they can think of. The minimum is the LC/MS retention time and a few ions, which isn't all that helpful, but satisfies the legal requirements, barely. (Taiwan and a couple of other countries will often balk at that sort of thing, but that doesn't become an issue for a few years).

If you're looking for evidence of new biology or mechanisms of action, that will be a bit trickier. This will show up in the claims, but claim can be structured in a rather Byzantine manner. As with the chemistry, though, if it's something really important, there will be data to back it up. Gels, sequences, purification procedures - all that has to be in there if the company is really serious. If all you can find is a line somewhere about ". . .may also be useful for X Disease" or "as an antagonist of Receptor Y", with no more details, then you can ignore that.

The data for specific compounds will vary quite a bit, too. Everyone likes the sorts of patents that list off the compounds and give you real assay numbers next to them. Unfortunately, many filings take the "A, B, C" approach, where they bin the compounds into a few activity classes. That at least lets you pick the more potent ones out from the lesser ones, but there's an even more egregious practice. That's where there's a description of the assay, ending with a line like "All of the compounds claimed showed activity of at least 10 micromolar under these conditions". That sort of stuff drives me crazy, and I really think it should be legally discouraged. I think that this is gradually disappearing from the world, and speed the day.

If you're looking for the best compound in the whole patent, playing "hunt the clinical candidate", well, that can be a fun game. Sometimes it's clear in the way the claim language narrows down to a handful of "most preferred" compounds. Sometimes you can infer it by going through the experimental section and noting when a bunch of 50-milligram procedures suddenly jump to 25-gram procedures (or more). But if a company really wants to hide their single best compound in a forest of other good ones, it can be done. I once had to dig through a pile of Exelixis kinase patents, looking for structures for their clinical candidates, and after about a week, I concluded that it just couldn't be done. And they're not alone.

Comments (24) + TrackBacks (0) | Category: Patents and IP

September 30, 2009

Ignoring Patents?

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Posted by Derek

There's a letter in the latest Nature from two researchers in Halifax that makes a point which isn't made often enough. Why do so many papers in the literature ignore patent references?

Why are patent citations so conspicuously absent across academic journals, with most even omitting formatting instructions for these in their author guidelines? Patents present novel, rigorously reviewed unpublished work, as well as providing an unmatched resource for detail.

We randomly selected one month (December 2008) and reviewed all citations in the reviews, articles and letters/reports in Nature (1,773 citations) and Science (1,367). These citations included textbooks, http://arXiv.org preprints and abstracts — but no patents.

They go on to point out that searching the patent literature, which traditionally was rather a pain, is much easier now, as is access to the patents themselves. And they have a point. When I was in graduate school in the 1980s, getting a procedure out of a patent was really considered an absolute last resort - it was a special order in the library, and you had this vague feeling that there was some sort of trickiness going on, that none of those syntheses were ever actually supposed to work, anyway.

Not so. While the patent literature is indeed full of junk, the open literature is, too. They're not exactly peer-reviewed, true - but journal papers have a much lower chance of having to stand up in court, so things sort of even out. And as far as organic synthesis is concerned, patents are full of real procedures to make real things (and often enough, with real spectral data to support the claims). Most of the compounds I've made in my career that have seen any light of day at all have done so in patents, and they're real as can be.

I've complained several times when refereeing papers for publication about the lack of relevant patent citations in them. And I'd advise others to do the same - this branch of the scientific literature deserves its due.

Comments (23) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature

August 26, 2009

Thalidomide for Myeloma: Whose Idea Was It?

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Posted by Derek

So, if you're a patient with a rare disease (or a relative of a patient with one), and you have an idea for repurposing an old drug for treatment. . .and you get a company interested, and it actually works. . .works to the point that the company takes in a billion or two dollars a year. . .what then?

Some readers will have guessed that I'm talking about thalidomide and Celgene, and right they are. Beth Jacobsen is the person involved - her husband died of multiple myeloma, but her medical sleuthing had turned up the idea of using thalidomide as a therapy for the disease, and she kept up the pressure to have the idea tried out. Celgene's mentioned her in annual reports, and she's been thanked by name in a publication on the clinical results.

But now she's suing Celgene, saying that they misappropriated her idea. Complicating the issue is the question of whether the late Judah Folkman was really the source of the inspiration, in a phone conversation with Jacobsen (earlier versions of the story have it that way, but the lawsuit apparently tells it differently). Which way did it happen? Is Jacobsen indeed owed compensation? And whether she is or not, will she be able to convince a court? Matt Herper has the story at Forbes.

I'll defer my own comments until I know a bit more about the case, but this is definitely an interesting one. I can add something that might be of relevance, though: a search in PubMed for "thalidomide myeloma" turns up 64 pages of references, almost all of them post-1999. But there is this one, from Italy in 1963. Has the idea been around for that long? Someone who can track down that journal can tell us. . .

Comments (20) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History | Patents and IP

Ariad's Patent Rises From the Grave to Smite the Living

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Posted by Derek

Ariad's trek through the legal system has not yet ended! This story has been running for years now - I think the original lawsuit was filed in 2002. Back in the spring, a decision by the Court of Appeals for the Federal Circuit reversed a Massachusetts District Court ruling in Ariad v. Eli Lilly. That decision invalidated a lot of Ariad's key patent claims regarding the Nf-kB signaling pathway, and some of us thought (well, I did) that this would be the end of the story.

But no, Ariad filed a petition in June (PDF) for a rehearing, and that has now been granted. So this fall, the decision will be revisited. It looks like this time, though, the question will not be decided so much on the science and history of Nf-kB, but on a question of patentability.

There are several requirements to get a patent, of course, novelty and utility being the first big ones. You also have to have a complete written description of the invention, and (if you want your claims to stand up) you're going to want to enable them - that is, actually show that you can do what you say, and prove that you have. For pharmaceuticals, that means you need to make real compounds, show physical data for them sufficient to prove that you've made them, and (if you're claiming their effects) show that they do what you're claiming they can do.

The Ariad v. Eli Lilly decision in April turned on written description. Basically, the court held that the company had not described any molecules that could do the vast numbers of things the claims staked out. There was a 1997 case (also, oddly enough, involving Lilly) that raised the standard in that area, and the famous University of Rochester v. G. D. Searle case (COX-2 inhibitors) was decided by applying the same standard. There's been a lot of controversy about the 1997 ruling, though, with many people complaining that the court sort of superglued a tougher written description requirement onto the existing patent law. Ariad has invited the CAFC to take this opportunity to clear things up. That's probably a good thing, since this issue was going to have to be resolved at some point, but it pains me to see Ariad's ridiculous patent case be the means for this.

Personally, I think that Ariad's claims could be tossed by considering the enablement requirement, rather than just written description. (If you think that they didn't do a sufficient job of describing what they wanted to claim, you should see how they reduced it to practice). Here's a post that agrees with that view, and goes into much more detail. It appears, though, that the courts haven't yet come up with a good way to use enablement to chop humungous patent claims down to size. Perhaps this will eventually happen, and the whole written-description era will come to seem like a detour.

I suppose we'll be returning to this issue something this coming winter. Until then, Ariad's patent walks the earth still.

Comments (6) + TrackBacks (0) | Category: Patents and IP

August 25, 2009

Polymorphs and Salts: India Raises an Eyebrow

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Posted by Derek

As some of you may know, there's a big patent dispute between Novartis and the government of India. The issue is Gleevec (imatinib, sold as Glivec in most of the rest of the world - Novartis must have figured that it would have been pronounced "Gly-veck" over here). The product is sold as a mesylate salt, and in fact, as a particular polymorph of that mesylate salt, and there's the problem.

For those outside the business, most drugs have either acidic or basic groups on them, and you can make a salt of them by combining them with a corresponding base or acid. Basic drugs - amines, mostly - are often sold as hydrochloride, mesylate, citrate, etc. salts, and acidic drugs are often sodium, potassium, calcium, etc. salts. These changes are usually done to make a compound absorb better when it's dosed and/or to make it easier to handle or more stable during manufacturing and storage.

Polymorphs, meanwhile, are different crystalline forms of the same compound. That's something that you don't encounter much outside a chemistry lab. The closest everyday analog is to think of table salt vs. kosher salt vs. sea salt, but those are still the same crystal-packing form when you get right down to it. A real polymorph is quite a different beast; it's as if you could dissolve up regular salt, cool it down in some tricky way, and have it crystallize out as needles or prisms instead of tiny cubes. And those needles or prisms might then, as it happens, refuse to dissolve if you added them to your soup. That's a polymorph, and it's a pretty common occurrence with drug substances. A key step in a real manufacturing process is making sure that you have the best one, and that you can always be sure that it's the one being produced. The wrong one will do things like refuse to dissolve into the bloodstream, which can be most unfortunate.

So Gleevec is a particular polymorph of a particular salt, and Novartis has patents on just that form in many countries. But not India, or not yet. As this post from a lawyer there details, the dispute is (to a large extent) about whether this form of the drug should be compared to another polymorph, to another salt, or to the original free base compound when time comes to judge its novelty and patentability. Another question is whether Novartis's previous patent filings disclose or anticipate the particular salt and polymorph form of the final compound. These arguments are complicated by the fact that India didn't even allow patents on pharmaceutical substances until a few years ago. For more on recent drug company patent disputes there, see this from the WSJ.

So I'd like to throw a question out to the readership: how many examples can people think of where a particular salt or polymorph was a key to getting good efficacy or properties for a drug? I realize that a lot of these stories never see the light of day - I've seen polymorph problems give people fits during development, as have many readers, I'm sure, but most of these things never get published. So I'm not asking for anything from the inside, just the publicly known examples.

Update: if you want a good indicator of how serious the IP issues are around these things, check out this conference. . .

Comments (35) + TrackBacks (0) | Category: Drug Development | Patents and IP

August 5, 2009

How Not To Do It: The Secret Patent Decoder Ring

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Posted by Derek

Patent applications are no fun to write. You have to figure out just what you're trying to cover (and how wide a space around it you want to try to clear), and the lawyers have to whip up language that casts just the right legal spell. The chemists have to write up detailed experimental procedures for all the important compounds and procedures, gather the matching analytical data, and make sure that it all fits together. Just getting the numbers assigned to the compounds right (and keeping them right through all the revisions) is a tedious job in itself. You always have to go through more drafts than you thought. No one enjoys it.

So maybe it's not surprising that things sometimes, well, slip a little. But how about when they slip a lot? Take this morning's example from Merck (a company that pitchforks out patent applications by the pile). Their WO2009091856 just published recently, directed at bicyclic beta-lactamase inhibitors. And everything looks normal for quite a while - 120 pages or so, in fact. Then the text suddenly snaps into bold face, and an authorial voice makes itself heard:

It appears that the data in Table 3 were generated in the same manner using the same enzymes as in Table 2 (Table 2 is unchanged from the provisional filing. I plan to DELETE the entries in Table 3 for Ex. 2,6,7 and 8 because this data duplicates the data in Table 2. . .Also, the entries in Table 2 for Ex.8 are both "1.6", not "16" as shown in Table 3. Please clarify these differences. . .

Is the data shown for Ex 1A data generated in a separate run, or is it supposed to be the same as for Ex. 1?. . .You don't want to include synergy data for these compouds (sic). It would be helpful to include it, at least for some of the examples (could put in a separate table). Recommend we include it for Ex. 14, since this is a likely backup candidate.

Now that's not supposed to be in there! What you're reading are the comments of someone in Merck's legal department - the sorts of comments that every patent draft collects as it's written, the sorts of comments that are supposed to be excised before you send in the application. Not this time! So if you were wondering which compound in this application represents the real candidate, and which ones are the backups to it, well, wonder no more. That query about including synergy data, for example, is an attempt to make it harder to figure out the most preferred compound itself - in vain, as it turns out. Oh, and those corrections that the comments say should be made? They weren't. So you'll want to fill in the correct numbers yourself.

That sort of thing goes on all the time in patent writing. You have to disclose your best compound - and in fact, you have to "teach toward" it in the claims. But you don't have to spray-paint it orange, and there's no sense in making things easy for your competition to figure out. A careful analysis of a patent application's claim structure will narrow down what a patent's authors are really interested in protecting, but there's often still some doubt about which exact compound is the winner. There can be other clues. Sometimes it'll be the compound with the most extensive biological characterization, or sometimes, if you look through all the experimental procedures, you'll notice that everything's being done on 50-milligram scale until one prep jumps to twenty grams. Bingo! Careful preparation of an application can scrub most of this stuff out. But all is for naught if your legal team's strategy comments are included in the Special Bonus Director's Cut version of the application.

Oh well, bonus dormitat Homerus. Anyone who's interested in beta-lactamase inhibitors (which, I should add, I'm not) now has more data to work with. The patent analysts at Thomson-Reuters are the people who caught this mistake (a colleague forwarded their writeup on to me). As they note, the wayward legal paragraphs also mention the possibility of comparing compounds to "MK-8712". That MK designation is Merck's usual method of showing a compound that's been recommended for the clinic, but this is the first that anyone seems to have heard about this one. But we can be pretty sure of something: someone in Merck's legal department has had a very bad day of it within the past couple of weeks. . .

Comments (15) + TrackBacks (0) | Category: How Not to Do It | Patents and IP

June 18, 2009

Professors Patent Pathways and Possibly Profit? Please.

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Posted by Derek

Nature Biotechnology has a good wrap-up of the Ariad patent case, and it includes some insights into the whole "patent the pathway and profit" mindset. That was the heart of Ariad's strategy: they licensed a patent on NF-kappaB from Harvard, MIT, and the Whitehead institute, and promptly went wild threatening to sue everyone that came within a mile of its already ridiculously vast) claims.

I particularly like this description of the legal process involved:

. . .Despite the earlier jury verdict in Ariad's favor, "the federal circuit [court] treated these claims, you know, almost derisively. They just smacked them," says Minnesota patent attorney Warren Woessner, former chair of the biotech committee of the American Intellectual Property Law Association. Woessner had predicted Ariad's defeat. "They won in a jury trial—big deal. They got some Nobel prizewinners up there to say how wonderful this was, and the jury folded like a cheap lawn chair. That's not uncommon. But the [appeals judges] just demolished this."

Indeed. But the strategy isn't dead yet, unfortunately:

Companies asserting broad claims "are not going to get much sympathy" from the federal circuit, agrees (Duke's Arti) Rai. "And if they're trying to assert them against a defendant who is as willing to fight as Eli Lilly is, they're ultimately going to lose."

Many universities, however, emboldened by Ariad's 2006 district court victory, have been pressing for such broad claims. "Every professor that discovers a mechanism of action now wants you to claim it," says Woessner, who advises universities. "And it can be hard to dissuade them from that." The take-home lesson from the Ariad case, says Woessner, is that filing such broad claims, without specifying compounds, hoping that some will stand, is a risky patent strategy. "Don't try to get broad functional claims, like the Ariad claims, or the Rochester claims," he says, without describing specific pathway modulators.

Ah, but coming up with specific pathway modulators is often the job of. . .(drumroll) a drug company. One that's full of medicinal chemists who know how to try to optimize these things. Unless an academic group gets lucky in screening a smaller commercial compound collection, they're not likely to be able to show such enabling compounds. And since most academic researchers don't have access to anything like the industry's high-throughput screening technology, let alone the industry's files of plausible-looking molecules, the chances aren't good. Heck, they aren't all that good for us over here, and we have all those things. To get the full flavor, you really need to see some big HTS campaigns rummage expensively through a whopping compound collection and still come up with only 3-hydroxy-diddleysquat. . .

Comments (23) + TrackBacks (0) | Category: Patents and IP

June 4, 2009

Perpetual Patents: A Nasty Thought Occurs

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Posted by Derek

A colleague of mine read the "Perpetual Patent" item below, and had a thought of his own. "If I were the head of a company that just discovered something like Lipitor", he said, using the example that the Xconomy piece used as well, "I'm probably going to fire all the early stage research people. Who needs 'em? We've got a never-ending patent on a huge drug".

And you know, I hate to say it, but I can't completely rule that one out myself. Not every management team would do this, but some would indeed transform the place from "Company That Looks For New Drugs" to "Company That Found One And Will Now Live Off It For As Long As Possible". After all, the R&D part of the operation is, most of the time, a huge drag on the bottom line. You only keep it around because you need it to come up with something that'll bring in the revenue eventually. So what happens if you decide that your current level of revenue is pretty good - and would look even better if you got rid of that big cost center?

Comments (18) + TrackBacks (0) | Category: Business and Markets | Patents and IP | The Dark Side

Perpetual Patent Motion Machine

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Posted by Derek

Over at Xconomy, there’s a provocative piece entitled “Diamonds Are Forever: Why Not Drug Patents?”. You have to give the author (Carl Weissman) credit for not playing to the crowd, I guess. So what’s his reasoning?

I can own a tangible good forever, I can own a trademark virtually forever, I can own a copyright for my entire life plus 70 years. But property which is more intrinsically a part of me - my idea, my invention, the product of my intellect - I am only allowed to own that for 20 years after I reveal it to the patent office.

Rationally, it seems obvious that all property - whether tangible or intellectual - should be subject to the same rules and laws of ownership. If you can own a gemstone forever, you should be able to own an invention forever. In fact, if a society wishes to impose differential standards for ownership rights to different types of property, wouldn’t it make more sense that preferential treatment be given to those items which are the product of your talent, your creativity, your self, over those things which you earn or purchase based upon that product of your efforts? The logical extension of this argument, in any free society, is that you should be able to own all property, whether purchased or invented, physical or ethereal, for as long as you wish. Patents, trademarks, copyrights, title - all should be perpetual.

Of course, since patents and copyright aren’t perpetual, someone must, along the way, have made a case for why they shouldn’t be. I’m going to stick with patents in this post, since copyright isn’t nearly as relevant to the drug business, but I refer you to this discussion and the links therein for some reasons why copyright is probably too lengthy in the US already. (A quick note: no creative work has gone into the public domain in this country since 1978. This is a state of affairs we can blame partly on a cartoon mouse, which also benefits some guys in capes).

The idea behind a patent system is that you will disclose your idea, in enough detail that others can follow it and build on it. In return, you will get a licensed monopoly on it for a set period of time, after which it becomes available to all, to profit from as best they can. We can argue about how well this ideal is realized – how full the disclosures are, how long the rights should last (and how long they really do). But I think that the basic idea is a sound one.

But Weissman just brushes it off, as far as I can see. His piece addresses some of the possible objections, but mostly by assertion. He points out that me-too drug efforts manage to populate therapeutic spaces (such as with the statins), and says that this shows that no monopolies would be created by perpetual drug patent rights. But any analysis of the drug landscape has to take into account that it came about under the current patent system. Everyone knows that Lipitor, for example, is going to expire eventually, and that their own drugs will, too. And everyone has planned accordingly. It’s not possible to draw conclusions about a perpetual patent regime by bringing up examples from the current one, since it’s so different. It’s only possible to draw these conclusions from the inner recesses of one’s own body – the brain, of course I mean.

His next point is drug pricing:

”With a perpetual patent, drug companies would be free to think longer term about pricing (without the artificial addition of patent lifetime in the equation). They would set prices lower in order to discourage new competitors from entering their market. This would enable the innovator to retain greater market share, and generate higher long term sales. The likely result is pricing near, if not lower, than current generic pricing.”

I’m not necessarily buying this one, either, since I think that drug companies will, like anyone else, try to maximize profits. And I think that the ability of (somewhat) lower prices to discourage competition is low, compared to the lure of more immediate higher profits. But really, drug pricing isn’t my biggest concern with this whole idea. That comes up here:

”In fact, with perpetual patents, the public good is better served because the incentive to discover and develop drugs is maximized. Secure in the knowledge that they will own the products of their own discovery and development efforts, drug companies will be able to assess the true risk vs. reward of any development programs free of artificial time limits imposed upon their ownership of those products.

Now here’s where I really part company with this idea, once and for all. I see where he gets this idea – patent rights are the incentive for discovery, so stronger patent rights are an incentive for even more discovery, right? But that first sentence is almost totally wrong; let me see if I can spell out why. No, what keeps us discovering new drugs is the fact that our patents are going to expire.

There, that wasn’t hard. But it’s true. The time limits we work under are one of the things that keeps everyone moving. We work hard before filing, because we’re afraid that someone else will scoop us. And we work hard after filing, because the clock has begun to tick. Every patent is a wasting asset, which is what seems to be driving Weissman crazy. And sometimes it drives me crazy, too, but I think his solution is even crazier.

I’m not arguing for shortening patent terms, either, just in case someone gets that idea. There’s a range where companies have the best chances to realize the return on their ideas and their labor, and I’m not sure that we’ve quite found it. But I know for sure that the patent lifespan needed is somewhere between zero and infinity. And I know that the argument for infinity does not convince. Just because a time limit is artificial doesn't mean it's wrong, or that there should be no time limit at all.

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May 28, 2009

Deuterated Drugs: The PTO Says OK, So Far

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Posted by Derek

As a follow-up to the deuterated-drugs idea, I note (courtesy of a co-worker) that Concert Pharmaceuticals has press-released their first issued patents on deuterated analogs of existing drugs.

So apparently the novelty and utility requirements have passed the first major sniff tests. I don't know if the case to be made for these (rimonabant and mosapride) is different than the others that Concert has on their IP assembly line, but I doubt it. If these issued, you'd figure that the others probably will, too. I can't imagine that the rimonabant patent's going to be worth all that much, though, since that drug has failed for reasons that I can't see being addressed by a deuterium analog.

As mentioned here before, though, the IP space here seems to be rather crowded, at least when you look at the number of applications. It's presumably quite a traffic jam at the patent offices - and it'll presumably be some time before that gets sorted out. And that's just at this stage of the game: if any of the companies in this space start to hit it big, it wouldn't surprise me to see lawsuits, requests for re-examination and the like.

Comments (14) + TrackBacks (0) | Category: Drug Development | Patents and IP

April 9, 2009

Ariad's Patent: Let Us Now Dance In Circles

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Posted by Derek

It's been some time since I've written about Ariad and their NF-kB patent. This has been a very long story, full of legal twists and turns, but I believe that it's finally come to an end.

Back in 2002, Ariad was issued an extremely broad patent on the uses of agents that affected the NF-kappaB pathway. And since it's basically impossible to talk about inflammation without talking about NF-kB at some point, the company believed that it had the legal means to claim that many other companies were infringing their intellectual property. Among the first to be sued was Eli Lilly - here was my reaction at the time. Short form: I was not pleased. I found it potentially catastrophic that one could lay claim to fundamental biochemical pathways and then assert that this naturally gave you a piece of the action for any compound that affected them. Update: it's worth noting that even as late as last month, Ariad's boilerplate at the bottom of their press releases included basically that process as part of their corporate strategy.

Well, the case finally was argued before a court in 2006, and to my surprise and disgust, a jury found for Ariad. Part of that surprise was a financial one, since (as I noted at the time) I'd gone short Ariad stock in anticipation of a more sensible verdict. (Note that I have no position in their stock or options now. They've significantly underperformed the market since 2006, which is no mean feat).

Every time I wrote about the company I would get beaten up on various message boards by its fans. I was a tool of Eli Lilly, Amgen (another of Ariad's legal opponents), or just of the Monied Interests in general. I was a shill, a moron, you name it. The glee was especially pronounced after that court case in 2006. A separate bench trial took place afterwards on whether the Ariad patent was enforceable at all, partly on the issues of its subject matter and possible inequitable conduct, but Ariad won that round as well.

The case then went to the Court of Appeals for the Federal Circuit, which is where all tough patent cases are going to end up eventually (a very small number go on from there to the Supreme Court). And last week the CAFC ruled: Ariad's key patent claims, they find, are in fact invalid. Lilly was right. The jury was wrong, and so was the verdict in the bench trial:

"Ariad claims methods comprising the single step of reducing NF-κB activity. Lilly argues that the asserted claims are not supported by written description because the specification of the ’516 patent fails to adequately disclose how the claimed reduction of NF-κB activity is achieved. The parties agree that the specification of the ’516 patent hypothesizes three classes of molecules potentially capable of reducing NF-κB activity: specific inhibitors, dominantly interfering molecules, and decoy molecules. Lilly contends that this disclosure amounts to little more than a research plan, and does not satisfy the patentee’s quid pro quo as described in Rochester. Ariad responds that Lilly’s arguments fail as a matter of law because Ariad did not actually claim the molecules. According to Ariad, because there is no term in the asserted claims that corresponds to the molecules, it is entitled to claim the methods without describing the molecules. Ariad’s legal assertion, however, is flawed.

I've been waiting to hear someone say that since 2002. I have never been able to figure out how the company could lay claim to such huge swaths of cellular biology with no real enablement, no demonstration that they could actually do what they were asserting the rights to. Well, in the end, they can't:

"Regardless of whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods, and Ariad admits that the specification suggests only the use of the three classes of molecules to achieve NF-κB reduction. Thus, to satisfy the written description requirement for the asserted claims, the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-κB activity. . .

. . .The ’516 patent discloses no working or even prophetic examples of methods that reduce NF-κB activity, and no completed syntheses of any of the molecules prophesized to be capable of reducing NF-κB activity. The state of the art at the time of filing was primitive and uncertain, leaving Ariad with an insufficient supply of prior art knowledge with which to fill the gaping holes in its disclosure. . .

Ariad sought and obtained the broad claims we now hold to be invalid. For its own reasons, Ariad maintained the breadth of these claims through claim construction and into trial. As Judge Rader observed, the situation presented in this case should not often occur, because “[i]n simple terms, a court would properly interpret the claim[s] as limited.” Univ. of Rochester v. G.D. Searle & Co., 375 F.3d 1303, 1312 (Fed. Cir. 2004) (dissenting from denial of petition for rehearing en banc). Nonetheless, as it stands, Ariad chose to assert claims that are broad far beyond the scope of the disclosure provided in the specification of the ’516 patent. Cf. Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 1380 (Fed. Cir. 2007) (“The motto, ‘beware of what one asks for,’ might be applicable here.”)."

On the other hand, the CAFC did not side with Lilly in their arguments about inequitable conduct or inherent anticipation of the patent's claims, finding that there was no clear evidence of intent to deceive on Ariad's part. But since they find that the key claims of the patent are invalid anyway due to lack of written description, it hardly matters. Ariad's patent is dead. And this ruling should deter anyone from trying another idiotic IP power grab like this in the future. Good news, and it only took seven years of constant legal wrangling to emerge. . .

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March 3, 2009

How Good (or Bad?) Are Patent Procedures, Anyway?

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Posted by Derek

All the comments on the Lundbeck / Dr. Reddy's imbroglio got me to thinking: how good are patent procedures, anyway? I said in that earlier post that I didn't think that they were that much different from procedures in the open literature, but I'd like to throw the issue open for comment.

You might think that patent procedures would be better, actually. There are potential legal implications to bad patent writeups that don't apply to lousy procedures published in a journal. You're supposed to teach how to make the new chemical matter (or how to do the new process) that you're claiming, and if your patent's details really are insufficient to fulfill that requirement, you have a problem. Patents have been invalidated over such disputes. If you thought your invention worth the trouble of patenting, you'd presumably be motivated to provide sufficient detail to make sure the patent is granted, and that it holds up if challenged.

That said, not all that many patents get seriously challenged over such issues. It takes lot of time and a lot of money, and the number of cases where it's worth the trouble are limited. And a patent has to be pretty lousy (or pretty deceptive) to truly fail to teach what its procedures outline. I guess what I'm asking about is the wide middle ground - the various procedures that aren't necessarily make-or-break for the validity of the patent, but are in there as parts of synthetic schemes. What's your success rate following these? And is it better or worse than your success rate trying to reproduce things out of, say, The Journal of Organic Chemistry?

Comments (21) + TrackBacks (0) | Category: Life in the Drug Labs | Patents and IP

September 24, 2008

Ariad's Patent: A Court Rules

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Posted by Derek

Over the years on this blog, I’ve written quite a few times about Ariad Pharmaceuticals and their quest to assert some rather sweeping patent rights. For background, see here and search for "Ariad" - there's a lot to read, in you're in the mood. The short version is that the company is the licensee of a patent which was issued with extremely broad claims around the NF-kappaB pathway in cells. Dozens and dozens of claims – the thing just drones on and on about compounds, methods, techniques that affect, inhibit, modulate, fill-in-your-verb anything that regulates, changes, modulates, etc. anything to do with NF-kappaB.

My problem with that is I think that claiming such broad swaths of biochemical mechanism is counterproductive. It’s bad for drug research, bad for patent law, and bad for the enterprise of science in general. For example, the company had no compounds to actually enable a lot of these claims when the patent was issued. A lot of other people did, though, because that pathway is tied up with all sorts of cellular processes, especially those dealing with inflammation and immune response. So Ariad immediately went after other companies with profitable drugs whose mechanism of action went, at least partly, through their newfound patent rights. I find it perverse that a company, rather than patenting their drug, could be able to patent the idea of how a yet-to-be-found drug might work, or retroactively, having had no role in the process at all, claim the rights to other drugs that had already been developed and marketed by someone else.

Of course, all this ended up in litigation, which has gone on for years now. There are all sorts of issues – you have the separate court cases with Lilly and Amgen, for one, and then there’s the question of whether Ariad’s patent is valid at all. I’ve chronicled some of the twists and turns – Lilly, for example, lost the first round in court (to my, and no doubt their, disbelief).

But the latest news is much more to my liking. Here’s the background: Amgen struck first in 2006, fearing a lawsuit by Ariad over the use of Enbrel – hey, it goes through NF-kappaB, so it’s fair game, right? Amgen asked for a declaration that all 203 claims of the Ariad patent were invalid. Ariad wanted that dismissed, naturally. But in September of 2006, the court turned them down, saying that Amgen did indeed have grounds to sue, since internal Ariad presentation documents specifically mentioned targeting Enbrel (and another Amgen product, Kineret) as part of their business strategy. (The court also took a moment to point out that had these documents not turned up, Ariad would have gotten its desired dismissal right there).

Ariad followed up by saying that they’d done no work related to whether the Amgen drugs infringed its patent, but they were going to do so now, by gosh, and in April 2007 they added a counterclaim that Amgen had indeed infringed 22 of the claims. (They later revised that down to nine). By January of this year, they’d dropped the Kineret part of the case and cut the list of claims down to seven.

But court found, in a summary judgment, that Amgen had indeed not infringed the Ariad patent. The use of Enbrel, they ruled, falls outside the scope of Ariad’s claims – mainly because all of Ariad’s claims related to reducing NF-kappaB activity inside the cell, and Enbrel acts on TNF-alpha exclusively outside the cell and never enters cells at all. Ariad has no case for infringement.

But there was another ruling, which I found quite interesting, and want to go into in detail. During this litigation, Amgen had proposed a broad covenant with Ariad not to sue them, and Ariad responded that sure, they’d sign that – but only covering Enbrel and Kineret. They reserved the right to sue at some future date about something else, you see.

Amgen rejected this idea, but Ariad went ahead and publicly declared that they’d abide unilaterally by their proposal – and then they turned around and asked the court to butt out of the original Amgen motion to invalidate all 203 claims of their patent, on the grounds that their covenant deprived the court of jurisdiction to consider the request. After all, they said, the only issues here were Enbrel and Kineret, and they’d promised not to sue Amgen over those, anyway! (Now you see why Ariad would go to the trouble of entering into a covenant with, basically, themselves).

Amgen didn’t go for that at all, saying that they were trying, once and for all, to settle the issue of whether Ariad could sue them on any ground related to the original patent – neglecting, as far as I can tell, to append the phrase delenda est Cartago to their filing. They disparaged Ariad’s maneuver as a last-ditch attempt to avoid arguing about invalidity and unenforceability, and said that they had no interest in leaving Ariad’s patent issues open and being sued later on at Ariad’s convenience. I’m paraphrasing here from the court documents, but not by very much, I have to tell you. There’s a distinctly irritated tone to most of the filings in this case.

The court went for Ariad on part of this, saying that Amgen’s potential pipeline of drugs and Ariad’s possible lawsuits didn’t amount to a real controversy – not compared to the other two products, which after all had been specifically mentioned in Ariad’s internal documents. Amgen’s attempts to go on with its invalidity claims were no longer on the table. But, as the latest document goes on to say, “The court reaches the opposite conclusion with regard to Amgen’s declaratory judgment claim of unenforceability”. The court held that it did indeed have jurisdiction to hear that part of the case.

Amgen’s line of argument was inequitable conduct – that when Ariad’s patent was filed, that the parties involved had not met the “candor and good faith” requirement to disclose all known information related to patentability. They claimed this both for the initial filing and for the PTO’s re-examination of the patent, but it’s the latter that was an issue in this latest ruling. Ariad had filed declarations by two expert witnesses, Inder Verma and Thomas Kadesch, during that process. Amgen claims that Verma’s statement is misleading, and that Ariad didn’t point that that he’d published articles that appear to contradict his own statements. And as for Kadesch, he was deposed by Amgen in the course of another trial that they were involved in (vs. Roche), and they claim that he recanted testimony that he’d given for Ariad in the Lilly trial, which was used by Ariad in their dealings with the PTO. (Amgen apparently had to pry the Kadesch’s reversal documents out of Roche with a subpoena).

Ariad did finally get around to submitting all these details to the PTO, but only during the course of 2007 and 2008, after the Amgen legal wrangling was underway. And Amgen claims that they dumped most of the really hot stuff in with a pile of other things, so as not to call attention to any of it.

As it turns out, the court found that Ariad had behaved properly with respect to the Kadesch documents – but the Verma stuff was another matter. In his statement for Ariad, Verma said several times that the actions of glucocorticoids through NF-kappaB were poorly understood, not known, etc. But his own articles concluded that glucocorticoids repressed NF-kappaB-mediated transcription, making those statements hard to reconcile.

If this was indeed evidence of inequitable conduct, the case all turned on the criteria worked out in a previous case (Rohm and Haas) on whether Ariad had voluntarily submitted this later evidence to the PTO. The court found that there was no evidence for that, that Ariad had only disclosed these documents under threat of Amgen’s litigation, and that Amgen’s motion for (partial) summary judgment on equitable conduct was thus granted.

So not only does Ariad have a ruling that interprets its claims in a way it doesn't like (and lets Amgen off the hook, besides), it also has one that raises significant concerns about inequitable conduct, and calls the entire enforceability of its patent into question. Not a good day for them - but a good day for common sense.

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July 31, 2008

Rember for Alzheimer's: Methylene Blue's Comeback

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Posted by Derek

Today we take up the extremely interesting story of Rember, hailed in this week’s press as a potential wonder drug for Alzheimer’s. There are a lot of unusual features to this one.

To take the most obvious first, the Phase II data seem to have been impressive. It’s hard to show decent efficacy in an Alzheimer’s trial – you can ask Wyeth and Elan about that, although it’s a sore subject with them. But Rember, according to reports (this is the best I've seen), was significantly more effective than the current standard of care (Aricept/donezepil, a cholinesterase inhibitor). In light of some of the more breathless news stories, though, it’s worth keeping in mind that this was efficacy in slowing the rate of decline – not stopping it, and certainly not reversing it. Especially in the later stages of the disease, it’s extremely hard to imagine reversing the sort of damage that Alzheimer’s does to the brain (and yes, I know about the TNF-alpha reports – that subject is coming in a post next week). If Rember is twice as effective as Aricept, that's great - except Aricept's efficacy has never been all that impressive.

But that's still something, considering how the drug is supposed to work. Its target is different than the usual Alzheimer’s therapy. Accumulation of amyloid protein has long been suspected as the cause of the disease, but there have always been partisans for another pathology, the neurofibrillary tangles associated with tau protein. Arguments have been going on for years – decades – about which of these has more to do with the underlying cause(s) of Alzheimer’s. Rember is the first clinical shot (that I’m aware of) at targeting tau. If the first attempt manages to show such interesting results, it’s a strong argument that tau must be important. (Other people are working in this area, too, of course, but my impression is that it's nowhere near as many as work on amyloid).

That’s food for thought, considering the amount of time and effort that’s been expending on amyloid. It may be that both pathologies are worth targeting, or it may even be that these results with Rember are a fluke. But it’s also possible that tau is really the place to be, in which case the amyloid hypothesis will take its place in the medical histories as a gigantic dead end. I’m not quite ready to bet that way myself, but it’s definitely not something that can be ruled out. I wouldn’t put all my money on amyloid either, at this point. (Boy, am I glad I'm not still working in Alzheimer's: this sort of stuff is wonderful to watch from the outside, but from the inside it's hard to deal with).

Now, what about the drug itself? It’s coming from a small company called TauRx, whose unimpressive web site just went up recently. The underlying science (and the clinical data) all come from Dr. Claude Wischik of the University of Aberdeen, who has so far not published anything on the drug. The presentation this week has, by far, been the most that anyone’s seen of it (papers are said to be in the works).

And Rember itself is. . .well, it’s methylene blue. Now there’s an interesting development. Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it’s turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer’s urine greenish/blue, generally to their great alarm: a storied med school prank from the old days). What on earth is it doing for tau protein?

According to TauRx, the problem is that the aggregation of tau protein is autocatalytic: once it gets going, it's a cascade. They believe that methylene blue disrupts the aggregation, and even helps to dissociate existing aggregates. Once they're out in their monomeric forms, the helical tau fragments are degraded normally again, and the whole tau backup starts to clear out.

Now for another issue: there's been some commentary to the effect that Rember can't possibly make anyone any money, because it's a known compound. Au contraire. While we evil pharmaceutical folks would much rather have proprietary chemical matter, there are plenty of other inventive steps worth a patent. For one thing, I suspect that formulation will be a challenge here (and that Medpage story seems to bear this out). I doubt if methylene blue crosses the blood-brain barrier so wonderfully, and I also believe that it's cleared pretty well (thus that green urine). So TauRx had to dose three times a day, and their highest dose didn't seem to work, probably because of absorption issues. (That's also going to lead to gastrointestinal trouble). So formulating this ancient stuff so it'll actually work well could be a real challenge: t.i.d with diarrhea is not the ideal dosing profile for an Alzheimer's therapy, to put it mildly.

And for another, there's always mechanism of action. I deeply dislike patent claims that try to grab hold of an entire area, but there's so much prior art in tau that no one could try it. But use of a specific compound (or group of compounds) for a specific therapy: oh, yes indeed. It's a complicated area, and the law varies between Europe and the US, but it definitely can be done. The people who say that this can't be patented should check out the issued patents US7335505 or US6953794. Or patent applications US20070191352, WO2007110627, WO2007110629, and WO2007110630. There you go; that wasn't hard. Mind you, there might be some prior art for using such compounds as cognition-improving agents: I'd start here if I were in the business of looking into that sort of thing.

Finally, is methylene blue (or some derivative thereof) actually going to be a reasonable drug? There's that dosing problem, for one thing, but the long history in humans is encouraging (and is a key part of TauRx's hopes not to spend so much money on toxicity testing in the clinic - talks with the FDA should be starting soon). There have been contradictory reports (plus, minus) on the effects of the compound on the brain in general, though, so they may have to do more work than they're planning on. All in all, a fascinating story.

Comments (116) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Patents and IP | Regulatory Affairs

July 24, 2008

Confident

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Posted by Derek

I’m going to expand on one of the points brought up yesterday, about the reported drug industry executive who was confident that his company’s Alzheimer’s therapy was ready to go out and make billions of dollars. It was that word “confident” that set me off, I think.

Because that’s not a word that you hear much of in this industry. The strongest form that you’ll come across is something like “fairly confident”, which is how you feel when you send in a compound that’s a minor change off something that’s already active, or how you feel about screening a target that’s a close homologue of something you already have plenty of ligands for. You can be pretty sure in those cases that something’s going to hit – but you’ll note that both of those are pretty far upstream in the drug discovery process. As you move toward animals, that confidence begins to look pretty ragged, and depending on the disease, it can just flat-out evaporate.

Despite all our efforts to avoid the expensive little beasts, there is still no way to be sure about how your compound is going to act in an animal until you’ve put it into an animal. That goes for predicting its peak blood levels, its half-life, its metabolites, and the duration and degree of its efficacy. You can have your compounds all ranked in order of how you think they’ll perform, and that list will, every time, be reordered after a first round of animal testing.

And when you go further, you really have no idea. As I’ve said here before, if you don’t cross your fingers when you take a compound into two-week toxicity testing, you haven’t been doing this stuff very long. Despite all efforts to avoid this expensive step, two-week (and four-week and longer) tox testing in animals will always, always tell you things you didn’t know. (Most of the time it’ll tell you things you didn’t particularly want to hear). No one worth their salary will ever use the adjective “confident” before the first multiweek tox data come in.

So much for animals: how about people? Well, despite all our efforts, there are still surprises in Phase I dosing, the tip-toe clinical stage where you look for blood levels in healthy volunteers. The animal pharmacokinetic data tell you where to start the doses in humans, but you can still get ambushed. I worked on a receptor agonist project once where the human blood levels came back at just about 10% of what we’d predicted, so back to the drawing board we went. No, I’ve never heard anyone describe themselves as “confident” before Phase I.

And that’s an easy step compared to Phase II, where for the first time you put your drug into sick patients. The failure rate in Phase II is just abominable, and stands as an indictment of just how little we understand about the biochemistry of human disease and how to modify it. When you consider a central nervous system disease like Alzheimer's, the source of the "confident" quote that started this digression, the failure rate is over 90%. Our understanding of the causes and progression of Alzheimer's is very poor. That's as opposed to a more well-worked-out condition like, say, hypertension, where our understanding is merely quite inadequate.

But if you make it through that fine sieve, you move on to Phase III, a larger and more real-world look at the patient population. If your Phase II trial was designed to provide a robust test, rather than just to make you and your investors feel good, you can hope that your Phase III will work out. But the whole time it's going on, the prudent drug developer will remember that the biggest, most well-funded, and most competent research organizations in the world have all taken huge cratering dives in Phase III. You know a lot more about your compound by this stage, so these disasters don't happen as often - but that means that when they do, they rise right up out of the floor in front of you. No, you can feel better by Phase III, but "confident" is pushing it.

How about when your drug goes to the FDA? Try asking any drug company executive if they'd like to go on record as being "confident" of regulatory approval. And when your drug actually goes to market? Is anyone really confident about those projections from the people in marketing? Pfizer sure talked a good game about Exubera, remember. Don't forget, too, that nasty side effects can always be waiting out there in the larger patient population. Even after your drug goes out and starts earning a living, it can be completely torpedoed at any time. Baycol, Vioxx, Avandia - you can name more.

So that's the story: you can never kick back and relax in this business. For all the perception that some people have of the drug industry as a sure-fire money machine, it sure doesn't look that way from inside. Anyone who describes themselves as "confident" about their new experimental medication is trying to fool their listeners. Or themselves. Maybe both.

Comments (11) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Patents and IP

July 23, 2008

Patents Stopping an Alzheimer's Wonder Drug?

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Posted by Derek

A longtime reader sent along a very interesting example that’s being used in a new book. The Gridlock Economy by Columbia economist Michael Heller is getting some good press, including this interview over at the Wall Street Journal>’s Law Blog. Heller’s thesis is:

“When too many owners control a single resource, cooperation breaks down, wealth disappears and everybody loses.” That is, the gridlock created by too much private ownership is wreaking havoc on our economy and lives. It’s keeping badly needed runways from being built, stifling high-tech innovation, and “costing lives” by keeping groundbreaking drugs from hitting the market.

It’s that last example that caught the eye of my correspondent, and I wanted more details. Fortunately, Heller went on the in the interview to talk about that very case, and I’m going to just quote him on it:

”Here’s a life or death example that’s happening right now: A drug company executive tells me he may have a better Alzheimer’s treatment. But to get FDA approval and bring it to market, he has to license dozens and dozens of patents relevant to testing for safety and side effects. So negotiations fail and the Alzheimer’s drug sits on a shelf, even though my informant is confident it could save countless lives and earn billions of dollars.”

Now, here’s the problem: I’ve actually worked on Alzheimer’s disease myself, and this story does not ring true. I don’t know if Heller’s “informant” is talking about animal testing or clinical trials in humans, but the same points hold in both cases. For one thing, I’m not aware of any patents that have to be licensed to do the standard testing for safety and side effects. There could conceivably be a couple for faster or more convenient tests, but I don’t even know of those. Otherwise, safety testing, in both animals and humans, is (to the best of my knowledge) done pretty much outside the realm of patent considerations. That “dozens and dozens of patents” line seems wildly off to me. I have never heard of a drug (for any disease) that has not advanced due to patent considerations related to safety testing.

Update - and that's partly for a very good legal reason: the safe harbor provisions of the 1984 Hatch-Waxman Act, as reaffirmed in the 2005 Merck v. Integra decision by the Supreme Court. There is specific protection from infringement in the use of a patented compound for purposes of submitting regulatory filings. And the language of the ruling makes it look like it's intended to cover all sorts of patented technologies as well.

Second, it’s important to remember that efficacy testing comes after safety, at least when you get to humans. So this contact of Heller’s is talking about a drug that has not been evaluated in humans for either quality, but he’s still “confident it could save countless lives and earn billions of dollars”. Right – for Alzheimer’s, where you have to worry about human brain levels, where we’re still arguing about what even causes the whole disease, where the clinical trials take years because the deterioration is so slow. Professor Heller is being had.

And let’s stipulate that there are, somehow, enough convincing data to make a reasonable observer confident that said drug would go on to earn billions of dollars. (There is never enough information to completely convince anyone of that in this industry before a drug hits the market, but let’s pretend that there is). In that case, those mysterious patent negotiations would not fail. Some sort of agreement would be reached, with money like that on the table.

The problem with Heller using this example is that there are indeed a lot of problems and potential problems with intellectual property in the drug industry. (I’ve talked about a few of them here). It’s a big, important, complicated, topic – and for all I know, it gets a good treatment in Heller’s book. (I’ll read it and find out). But this cartoon of an example is going to confuse anyone outside the field, and irritate anyone inside it.

Comments (24) + TrackBacks (0) | Category: Alzheimer's Disease | Patents and IP

June 27, 2008

Unknown - But You Can Buy It

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Posted by Derek

I sketched out a rather small molecule the other day, a perfectly reasonable looking thing, which nonetheless had absolutely no references in Chemical Abstracts. (I’d certainly like to be able to put up a drawing of the structure, but it’s something that I have a work-related interest in, so it has to stay under wraps). But it’s something with only a dozen or so heavy atoms, most of them flat and aromatic – you’d certainly expect something to have been made like it, but apparently not.

This has happened to me many times over the years. Now, you can obviously get into unknown territory immediately if you start looking for bizarre compounds: I don’t happen to have SciFinder access here on the train this morning, but I’m willing to bet that (for example) three-membered rings with one carbon, one boron, and one silicon are pretty wide open for some brave weirdo to explore. Enjoy!

But you don’t have to go that crazy to leave the paved roads behind. Many reasonable low-molecular-weight areas are only very lightly explored. You can get out of the universe of known compounds very quickly, for example, by searching for spirocycles, particularly with an oxygen or nitrogen or two scattered into the rings. Most of these would surely be interesting scaffolds for drug discovery libraries, if there were reasonable chemistry to explore them with. Even some perfectly normal looking substitution patterns of monocyclic compounds haven’t been looked into – I dreamed up a series of oxazole derivatives not long ago that no one’s ever made, and there’s nothing odd about them at all.

As you’d expect, there’s a commercial niche here. Novelty is a key requirement for patentability, so seeing no references turn up around your interesting structure is good news from an IP standpoint. (It may be bad news from a laboratory standpoint, though, because sometimes these things are unknown for a reason). But not always: there are companies that pride themselves on being able to supply such unknown scaffolds and libraries. bicyclo.gifThe perfectly reasonable-looking diazabicyclo compound shown here, for example, has no references in SciFinder, but can be purchased on a multigram scale. (There are about fifty derivatives of that bare scaffold known in the literature, which makes it pretty much uncleared ground compared to the absolutely pulverized IP landscape around, say, piperazine). Next time you're searching for such things, refine your answer set to give only those compounds with no references, and take a look at how many of them are commercially available anyway. . .

Comments (10) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature

December 18, 2007

Hearing Footsteps

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Posted by Derek

The next few years don’t necessarily look good for several large drug companies, just because of the patents that will be expiring. King of them all is Lipitor, of course, the world’s biggest selling drug which will then become the drug industry’s single largest lost revenue stream. But if you dig back through the newspaper archives, you’ll find the “Big Patent Expirations Looming” story showing up year after year. It’s basically true every time.

And that illustrates a point that a lot of people from outside the drug industry forget when discussing our rapacious business models, obscene profits, and so on: more than almost any other industry, we’re built on a pile of wasting assets. And not just any old nonspecific wasting assets – our valuable drugs are ticking away with a specific timetable, at which time they turn generic and most of the revenue stream goes flooosh. There might as well be a big LED clock strapped to the things, counting backwards – but unlike a bad movie, there’s no sweating hero trying to figure out whether to cut the red wire or not. Put down those needlenose pliers, Buck or Jock or whatever your heroic name is, because nothing will help.

Nothing, that is, except having some other drugs coming down the chute to replace the ones that are blowing up. Oh, I know, I know, patent evergreening and so on. I agree that it’s a problem, but that stuff doesn’t work most of the time. And when it does, you can maybe wring a year or two out of the system. But the bells toll for all our drugs in the end, and we have to deal with that fact by cranking out new stuff as fast as we can.

In recent years, that hasn’t been fast enough. I worked for a company back in the early 1990s that had a big-selling drug which was headed for the patent cliff. Everyone knew it, everyone knew when it would happen, and everyone knew what we had to do about it: get more stuff into the pipeline to replace it. The company expanded its research department and built a whole new drug discovery building complex to put us all in. To no avail. The day came, and nothing significant had been found in the intervening years. The company’s earnings hopped into a handy handbasket and went to the usual destination, the stock fell off a cliff, and all sorts of people who’d been loading up on the shares during the glory years felt all kinds of pain.

This story has been repeated several times around the industry. We all know about the declining productivity story – it was one of the first things I blogged about back in 2002. But the back side of that story is the frantic activities to try to make it go away. Some of them aren’t too glorious – cherry-flavored line extensions, patent gimmickry – but a lot of the work is serious stuff. We know that our discovery and clinical success rates are too low, and we’re pouring all kinds of money into trying to fix them. So far, the successes haven’t been anything to jump around about, but the efforts continue.

There’s an exception: the biotechs. The FDA has been trying to get its regulatory head around the issue of biogeneric equivalency, but it isn’t easy (more on this in a separate post some time). What this means is that the likes of Amgen, Biogen, Genentech Genzyme et al. have had far fewer worries about some of their products expiring on them. If the FDA can’t certify that a generic version of a protein drug is the same as the original, and can’t agree on how to even do that in the first place, then no generic will appear. There are several companies that would like to do it, but they’ve been moving more slowly than they’d like to, since the regulatory environment is so unclear. Things are moving a bit more quickly in Europe, but the pace is still glacial compared to the situation over here in the traditional small-molecule world.

And that’s not doing the biotech industry any good. I realize that this sounds perverse, especially to the people at the companies involved. What do I mean, that it’s a bad thing that their drugs rake in billions year after year? What’s not to like? Well, what’s not to like is that this kind of thing slows down the need to come up with new products and new approaches. I know that the big biotechs are spending lots of money on research, but we’ll never know what things would have been like if the dogs had been at their heels more. Organizations get lazy in all kinds of almost imperceptible ways when there’s no reason to move quickly.

Having those incentives doesn’t mean that things will work out for you, of course – see that story a couple of paragraphs above. But I think it works out better for everyone if research organizations are kept on their toes, competing with each other, and competing with those big red digital countdowns. It’s no fun, but it’s the best way.

Comments (8) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Patents and IP

September 19, 2007

Fixing the Patent System?

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Posted by Derek

For a good long time now, a massive piece of patent legislation has been working its way through Congress. It's cleared the House and is on its way to the Senate, so the number of twists and turns it can take is still substantial. And there's no telling if the President will sign it, since the administration has expressed its worries about the bill as it stands. In its current form, this law would change things around quite a bit.

For one thing, it would finally make the US a first-to-file country, like basically everywhere else in the world. The first-to-invent regime is one of the reasons that chemists throughout the country are harangued to get their lab notebooks witnessed promptly, because if it came down to a notebook-and-calendar fight, the company with the earlier witness date would likely win. First-to-file eliminates that particular worry (while not obviating the need for witness signatures), but could replace them with others. You hear a lot about how this will benefit larger players at the expense of smaller ones, since it makes the trouble and expense of filing a patent the determining factor. I think that this is exaggerated a bit, though. The trouble and expense of proving that you were the first to invent is pretty significant, too. (Admittedly, some of the parts of this bill look to make filing a patent even more expensive than it is now).

But there are many other provisions in this bill, ones which have managed to split the high-tech part of the US economy into camps.. Software companies are mostly lining up for the new legislation, while biotech and pharma are coming down against it. The arguing ground is a set of new rules about how easily patents can be obtained, and how easily they can be challenged after they’re granted.

In short, the computer sector feels victimized by people who get some useful step or technology patented and camp out on it, shaking everyone down for fees. (The real problem, as far as I can see, is that patent quality is just awful in this area, and all kinds of junk gets granted). At any rate, software and hardware companies would like to see fewer such things get patented, and are looking forward to some new tools to get them invalidated in a more timely fashion.

But over here in the drug industry, we’re jumpy about that sort of thing. Many companies in this area feel that their patents are being challenged enough already, thanks very much, and would rather not give the generic companies more new tools to tie things up in court. I think that the overall quality of patents is much higher in the pharma business, which helps to explain the difference of opinion. We generally have fewer, tougher patents protecting our important stuff over here, as compared to more (and weaker) ones in the software world.

It’s not so simple a breakdown, though. The flow can reverse in either industry. We do have some cases of smaller outfits getting some IP that they try to beat everyone up with – Ariad’s NF-kB patent, which I haven’t written about in a while, is a good example. And it’s not like the computer giants don’t ever get their patents challenged, either. Both industries are playing the percentages – this change won’t suddenly remake the whole landscape for either of them.

Overall, even though I’m a drug-industry guy, I think I come down on the side of making patent challenges a bit easier. After all, most of our patents in the industry stand up anyway – we shouldn’t have as much to fear. And I think that it’s easier to do harm by rent-seeking on a patent of dubious validity than it is to do harm by uselessly challenging an existing one. When you get down to it, the argument is about who you fear more: the patent office, for allowing junk to issue, or the courts, for making incorrect rulings when they’re challenged.

It’s a tough call, but I think the patent office is a bit more disgraceful. Frankly, I think if so many bad patents weren’t being granted, we wouldn’t be having this discussion at all. But before I sound like I’m beating up on the PTO, I should note that their funding and staffing has not come close to keeping up with their duties over the years. There are a lot of decent examiners there working under ridiculous conditions, so it’s not surprising that we find ourselves in the shape we’re in.

For more on this bill, I refer you to excellent posts (for example, here and here) at PatentBaristas and at Patently Obvious – those guys are lawyers, while I’m merely a client.

Comments (13) + TrackBacks (0) | Category: Patents and IP

September 18, 2007

Ugly, But Useful

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Posted by Derek

vianilin.gifI also mentioned recently that I’d come across a good example of an academic compound with interesting activity but no chance of being a drug. Try this one out, from Organic Letters. Yes, there aren’t many other compounds that do what this one does (inhibit the production of TNF-alpha). And no, it’s not going to be a drug – well, at least the odds are very, very long against it.

Why so negative? Several reasons. For one thing, this molecule is extremely greasy. This is not a killer in and of itself, but it’s inviting trouble, for the reasons noted here. The second problem is that this thing looks like it’s going to have some trouble dissolving. That’s trouble both from both the thermodynamic (eventual amount in solution) and kinetic (speed of dissolution) senses. That greasiness will be the problem with the former, since a lot of this molecule’s surface area gives water molecules no incentives to join in on anything. And all those aryl rings (along with the symmetric structure) are asking for trouble with the latter. Those features make the structure look like it’ll form a very good, very happy crystal, with its aromatic rings stacked onto each other like ornamental bricks. “Brick” is the very word that comes to mind, actually.

But solubility is only the beginning. The real problem is that catechol functionality in the center of the molecule, which is just waiting to turn into a quinone. In medicinal chemistry, no one wants quinones; no one likes them. They’re just too reactive. It would not surprise me for a minute to learn that this group, though, is the reason for the compound’s activity. It’s probably reacting with some functional group on the surface of the target protein and gumming up the works that way. It’ll do that to others, too, if it gets the chance. There are all sorts of weird little quinones in the literature that hit proteins that nothing else will touch, but none of them are going anywhere.

No, it’s safe to say that any experienced drug-company chemist would draw a red X through this one on sight. Plenty of reasonable-looking compounds turn up with unanticipated problems, so we don’t need to go looking for trouble. That’s not to say that it can’t be a research tool (although I’d be careful interpreting the data from complex systems – there’s no telling how many other things that quinone is going to react with).

But all this brings up another thing that we were talking about around here – how much do drug companies owe academia for working out fundamental biochemistry and molecular biology? What if someone uses this very compound, for example, as a research tool and discovers something about its target that could be used to develop an actual drug? What do we call that?

Well, we call that “science”, as far as I can see. Everything is built on top of something else. In a case like this, the discoverers of this current compound, even if they’ve patented it, do not have a claim on what discoveries might come from it later on. An even stronger case was decided in that direction – the University of Rochester’s discovery of the COX-2 enzyme, the patent for which led to their attempt to claim revenue from Celebrex. The judge ruled, absolutely correctly in my opinion, that the discovery of a drug target is not the discovery of a drug, and that the effort and inventiveness needed for that second step is more than enough for it to stand on its own.

There’s a “research exemption” for patents, giving legal room to use the disclosed inventions and compounds to make further inventions. I think that’s an extremely important concept. It lets academic labs study patented industrial compounds for their own purposes, and it even lets companies do that to each other. How would we compare our internal compounds to the competing ones if we couldn’t use them? (There’s more than one research exemption, though, and the traditional common-law one took a big hit a few years ago in Madey v. Duke, which worries me).

I strongly oppose broad patent claims for uses and pathways, because I think that these cut into legitimate research. Patents should cover things that are novel and useful. They should completely disclose the substance of their invention. And in return for the period of exclusive rights, anyone else who wants to should be able to get to work on what will replace them. A patent is not a license to kick back; it’s a reminder to keep moving.

Comments (35) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | Patents and IP

September 17, 2007

Arsenic, Patents, and the World

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Posted by Derek

As I was mentioning the other day, the latest issue of Nature Medicine has the details on a story that doesn’t, on the face of it, do the industry any credit. About twenty years ago, there were reports out of China that a solublized form of arsenic was very effective in treating acute promyelocytic leukemia, a rare (and fatal) form of the disease. Arsenic had been used as a folk remedy for such conditions, as it has been for many others (often with much less justification!), but its most common compounds (like arsenic trioxide) are tremendously insoluble. The Chinese authors had found a way to make that one go into solution where it could be dosed, but didn’t disclose it in their publication.

That left the door open to someone else, namely a small company called PolaRx. They found a way to do the same thing with the oxide (as far as anyone can tell), and got a patent on its use in oncology. Over years, mergers, and reshuffles, the patent finally ended up in the hands of Cephalon, who now market the soluble arsenic trioxide. However, a course of treatment costs about $50,000, which means that for many patients around the world, the drug is totally out of reach.

Even across the entire world, there aren’t that many patients for this therapy, so the price would tend to be high no matter what. It’s worth remembering that production costs are not a major factor in the pricing of most drugs. We’re not indifferent in this business to how much it costs us to make something, far from it, but we try to keep that a small part of the price. So what does set the price? What sets the price is what sets most prices in this world: what the market will bear. A drug that only treats a small number of patients every year is going to cost a lot of money, no matter what it’s made out of. A company will not market a compound unless they can use its profits to help defray the costs of all the things that don’t make it to market at all.

Cephalon is charging what their market will bear, which is their right, but their market is the health insurance organizations of the industrialized world. That’s another thing to remember – drug companies aren’t selling direct to patients most of the time. They’re selling to insurance companies, and first-world health insurance will put up with a lot of things that no one else can or will. There’s a lot of room to talk (and to complain) about this (I think it distorts pricing signals something fierce), but all the complaints have to start with the realization that this is how things are now set up. Cephalon, for its part, says that it’s open to compassionate use of its drug – that is, providing it to people in need who absolutely cannot afford it. With any luck articles like the Nature Medicine one will help to get the word out about that, and we’ll see how well they follow through.

It’s tempting to blame the patent system for this whole situation – after all, the only reason the company can charge these prices is that they’re the only ones who can sell it, right? But perversely, this might actually show the need for more use of patents rather than less. As another piece in Nature has helpfully reminded people, patents not only grant a period of exclusivity. In return for that, you have to tell people how to replicate your invention.

The alternative, in countries that don’t follow this system, is usually secrecy, and I can’t help but think that this is why the original Chinese work didn’t disclose all the details. A strong patent system eliminates a lot of trade-secret grey areas: someone owns a discovery (for a predetermined period of time), no one owns it, or everyone owns it. There’s none of this “someone owns it until someone else finds out about it” stuff.

But my guess is that the Chinese lab, being used to a trade-secret (or government-secret) culture, reflexively held back their important details. If they wanted to make sure that no one could patent anything, they would have (or at least should have) put all the information out into the public domain, where it would have been prior art against anyone attempting to file on it. (But see below - would that have helped get it through clinical trials, or not?) It’s worth noting that if a patent had been filed back in the early 1990s, the drug would not only have come to the world’s markets faster, the patent would also be much closer to expiration by now, opening up its production. The US researcher who formed PolaRx and filed the patent, Raymond Warrell (now chairman of Genta), stands up for it in the Nature Medicine article, and like it or not, he has a point, too, saying that the patent stimulated interest in the compound: "Without the patent, it would have remained a curious Chinese drug, not available to anyone else." I should note that there may well be room to argue about the validity of the patent, from prior-art concerns, but no one (as far as I know) has seen fit to challenge it.

But I can say for sure that without intellectual property protection in the US and Europe, no drug company would have touched the compound. Without industrial input, the drug would have either never reached the market at all (arsenic trials were a hard sell at the FDA), or would have likely come on more slowly. (That ticking patent clock does keep an organization moving, I can tell you). And now its success in the market has other companies working on improved versions of the therapy. This is how our world works, and (for better or worse) there's no requirement that it be aesthetically appealing.

Comments (8) + TrackBacks (0) | Category: Cancer | Drug Development | Odd Elements in Drugs | Patents and IP | Why Everyone Loves Us

May 7, 2007

Nonsense. On Stilts. Playing a Trumpet.

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Posted by Derek

A comment in the last post pointed me to an op-ed in today's New York Times by Suketu Mehta. It's on India and intellectual property, specifically the idea of patenting yoga techniques. Mehta finds this both laughable and troubling, while noting that most of the applicants are overseas Indians themselves. I'm no yoga expert (maybe Michael Blowhard can, uh, enlighten us on the issue), but as it goes on, Mehta's piece gets off some remarkably cloth-headed observations on drug patents:

"Western pharmaceutical companies make billions on drugs that are often first discovered in developing countries — but herbal remedies like bitter gourd or turmeric, which are known to be effective against everything from diabetes to piles, earn nothing for the country whose sages first isolated their virtues. The Indian government estimates that worldwide, 2000 patents are issued a year based on traditional Indian medicines.

Drugs and hatha yoga have the same aim: to help us lead healthier lives. India has given the world yoga for free. No wonder so many in the country feel that the world should return the favor by making lifesaving drugs available at reduced prices, or at least letting Indian companies make cheap generics. If padmasana — a k a the lotus position — belongs to all mankind, so should the formula for Gleevec. . ."

There's more where that came from, and if you wish you can drink from this fount of wisdom yourself. Rinse thoroughly. OK, where to start? The whole piece is a panoramic view of the fallacy that chewing a leaf (or finding out what leaves the natives chew) is equivalent to discovering a drug. That skips over some rather intricate and expensive steps - isolating the active fractions of the original medicine, determining what compounds are in there and what their structures are, figuring out what they do and how they do it, improving them to make them less toxic and more efficacious, and figuring out how to dose them. Then there's the little matter of scores of millions of dollars to be spent on clinical trials.

Perhaps I could start by asking for a list of those patents - granted patents, mind you, not applications - that apparently issued in complete ignorance of all that well-established prior art? Sure, I'm game. Anyone who has the 2006 list of the two thousand patents ripping off traditional Indian medicine, send it along. If no one has last year's roundup yet, I'll take the list from 2005 - another two thousand! How many are there in reality, do you think? How many of them come from real drug companies?

If not that, I'd be glad to hear about those drugs that were "often" first discovered in developing countries. How often is that, exactly? While there are examples, I'm rather hard pressed to come up with many recent ones. Despite what you might think from the editorial, Gleevec is not one of them, unless Switzerland is your idea of a developing country. Besides, we're skipping all those steps again if we decide that Madagascar gets all the credit for, say, vincristine. As for bitter gourd and turmeric, even if those ancient sages had filed for proto-patents of some sort, wouldn't their terms have, y'know, expired by now? Patents aren't forever, although you wouldn't know this from reading this stuff.

That brings us up to that "yoga is free, and Gleevec should be, too" argument. Again, I hardly know which handle to grasp. There's always the very basic argument, which I will advance in a small, weary voice, that if Gleevec and other medications were given away for free that it might be difficult to persuade people to spend hundreds of millions of dollars developing them.

But enough logic! Let's Mehta up some similar arguments and see how they fly: because the idea of pasta was given to the world for free, no Italian restaurant should be able to charge money for it. Not bad. . .how about, because my daughter gives me a drawing for free to put on my wall, no one should ever charge anything to see a painting? Here we go - what about those darn Sumerians and their writing? How can the publishing industry show its face, when cuneiform was released straight into the public domain? Oh, I like this, it's a lot easier than science - which I think is the point, right there. . .

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Brazil Raises The Pirate Flag

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Posted by Derek

Back in 2005, the government of Brazil threatened to break the patent on Abbott's HIV medication Kaletra if the price didn't come down (see here and here). But after a lot of arm-wrestling, a deal was reached. Now it's Merck's turn, with their efavirenz, and this time things went all the way: on Friday, Brazil's president issued a compulsory license to produce the drug outside Merck's patent.

My problem with this, other than the obvious problem I have with expropriation of someone else's property, is that Brazil is trying to have things both ways. The government spends much of its time talking about how the country is an emerging power, with the 12th-largest economy in the world, huge natural resources, its own successful aircraft industry and space program, and so on. But when it comes time to pay for HIV medications, which are important both medically and politically, suddenly they're a poor third-world country being exploited by the evil multinational drugmakers. A look back at the second blog link above, with its quotes from Brazil's Minister of Health on how nationalizing drug patents would help the country's industry, shows that this issue probably has more to do with the first worldview than the second one.

During the Kaletra dispute, I asked a question:

I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?

And now Merck is basically asking Brazil the same thing:

"Research and development-based pharmaceutical companies like Merck simply cannot sustain a situation in which the developed countries alone are expected to bear the cost for essential drugs in both least-developed countries and emerging markets. As such, we believe it is essential to price our medicines according to a country's level of development and HIV burden, thereby ensuring equitable access as well as our ability to invest in future innovative medicines. As the world's 12th largest economy, Brazil has a greater capacity to pay for HIV medicines than countries that are poorer or harder hit by the disease.

This decision by the Government of Brazil will have a negative impact on Brazil's reputation as an industrialized country seeking to attract inward investment, and thus its ability to build world-class research and development."

It should have, anyway. Look, intellectual property law is not pretty, and doesn't give anyone a warm feeling. It's not meant to. But the alternative Jolly-Roger world is even worse, and anything that takes us toward that is a bad move.

Comments (44) + TrackBacks (0) | Category: Drug Prices | Infectious Diseases | Patents and IP

May 2, 2007

Obvious Ain't Obvious No More

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Posted by Derek

The Supreme Court doesn't take too many patent cases, but when they rule on one, it's news. This week they handed down a decision in KSR v. Teleflex, and most pharma/biotech readers can be forgiven if their immediate reaction is "Who they?"

But you'll hear about them, all right. This case turned on the definition of obviousness, which is Section 103(a) for lovers of patent law. The standard, ever since the Graham decision many years ago, has been that a patent claim can't be rejected on obviousness grounds unless there's some "TSM" (teaching, suggestion, or motivation) in the prior art, something that would have lead a person of ordinary skill in the art to take that step. (Update - not quite. I've conflated the original Graham stuff with later decisions - see below). That's the sort of thinking behind this earlier post, for example, and it's the way we've all thought about drug patents.

You see where this is headed. The Supreme Court has (by a 9-0 vote) redefined this criterion. (Interested fanatics can get the full decision here). Here's a key section that gets across the spirit of the thing:

". . .Helpful insights, however, need not become rigid and mandatory formulas. If it is so applied, the TSM test is incompatible with this Court’s precedents. The diversity of inventive pursuits and of modern technology counsels against confining the obviousness analysis by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasizing the importance of published articles and the explicit content of issued patents. In many fields there may be little discussion of obvious techniques or combinations, and market demand, rather than scientific literature, may often drive design trends. Granting patent protection to advances that would occur in the ordinary course without real innovation retards progress and may, for patents combining previously known elements, deprive prior inventions of their value or utility."

In other words, the Graham tests are history. (Update - not so fast! TSM was a construct of the CAFC, the Court of Appeals for the Federal Circuit, in an attempt to come up with an mechanism to apply the Graham decision). What replaces them? There's language in the ruling about "predictable" combinations of the prior art as opposed to "real innovation", but in the end, this is going to have to be thrashed out by years of lawsuits. If this had been a legislative act instead of a judicial ruling, it would be called the "Intellectual Property Lawyer's Perpetual Employment Act of 2007". Here's a post on the ruling from PatentBaristas (who also have an excellent roundup of other takes here).

What will this mean for pharma? Eventually (and this will take a while), it looks to me like it's going to be harder to do the sort of patent-extending moves with formulations, enantiomers, and such that we've seen so much of. Some of these are surely going to end up on the wrong side of the new obviousness line, when it gets drawn. That's going to be the biggest effect, I'd say, and overall, I'm not going to be sorry to see some of that stuff go.

I know that this ruling is going to be seen as a blow to the drug companies, and financially, that's what it's going to be. But in the long run, I think we're better off without incentives to dink and tweak existing drugs to extend their patent lives. It's profitable, and given our success rate in the clinic, we could use the money. But without the temptation to do this kind of thing, which is basically a moral hazard, we'll be forced to work on more substantial things. If some of these modifications really are an advance, then presumably they'll fall on the protected side of the patentability line, so we won't miss out on the really good stuff. The now-with-the-great-taste-of-fish innovations, though, I think we're better off without. It's not going to be easy to give them up, but hey, it's not an easy industry.

Comments (4) + TrackBacks (0) | Category: Patents and IP

February 13, 2007

Crichton, Patents, and Genes

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Posted by Derek

Today's New York Times has a passionate op-ed by Michael Crichton on the subject of gene patents. Now, as my previous posts will demonstrate, I'm no fan of over-patenting. And the whole topic of gene (and protein) patents is a very interesting and important one.

Unfortunately, though, it's also very complex, and Crichton's piece manages to complete reduce the subject to tinkling fragments. The op-ed is so vigorously argued that its readers will probably come away feeling as if they've been informed, but I'm afraid that they're going to end up knowing less than when they started. I hate to be this blunt about it, but Crichton's done his cause a great disservice by spreading ignorance and confusion.

The official position of the Patent Office is that products of nature are not patentable. But. . .an isolated or purified one, in a form not found naturally, can be. Single genes, ripped out of their context in genomic DNA and expressed as a pure form, are considered to be new chemical substances, and thus can indeed be patented. We can argue about whether this is a proper interpretation or whether it's a good idea, but to ignore the point completely (as Crichton's piece does) isn't going to help anyone understand the problem.

You'd also never guess from reading Crichton that the subject of utility is of great importance in patent law. There's a profound difference between a patent on a gene, and a patent on a use for a gene. (That may sound trivial, but only if you've never been involved in writing or analyzing any patents). Ten years ago, the US Patent Office was getting swamped by gene applications with very little thought to their use (other than some pro forma statements, but they raised their standardsper se shouldn't be allowed, you'd still have the use issue to deal with. The word "utility" does not appear in today's op-ed.

You'd also never know that the whole subject is being contested, very seriously and expensively, in court cases all over the world. The Metabolite case, which the Supreme Court recently dodged, is the one with the highest recent profile, and there will be more. It's not like the topic hasn't created controversy.

If you want a thoughtful analysis of the problems of gene patenting, start with this analysis (PDF) from the Congressional Research Service. Reading and understanding it will put you way ahead of the readers of the New York Times and, it seems, way ahead of Michael Crichton.

Comments (26) + TrackBacks (0) | Category: Patents and IP | Press Coverage

November 21, 2006

The Paper Mountain

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Posted by Derek

Another thing a large research site has, and in mighty impressive quantities, is paper. Something's got to be done with it, but not all laboratory paper is created equal.

Of course, a lot of the mass represents hard copies of files that exist in digital form. Non-proprietary stuff (journal articles that are no longer needed, etc.) will go into big recycling bins to be handled by guys who really have some long days ahead of them. A serious office move (and this is about as serious as it gets) is a good chance to toss ancient literature folders whose contents have become outdated. I just heaved out a pile of that stuff the other day, since I don't thing that 1991 reviews of Alzheimer's pathology are going to come back into fashion. I also had a bunch of miscellaneous hard copies of the Journal of Organic Chemistry from the early 1990s stuffed into a file cabinet - out they went. They were joined by old copies of C&E News, local phone books, 3-ring binder contents of short courses whose contents I don't expect to ever need, and a pile of chemical company and lab equipment catalogs.

Pages with proprietary data on them are a different matter. They're to be tossed in a special shredder box, to be picked up later by some other guys who are also going to earn their money. There are trailer-size portable shredder operations that you can hire for occasions like this. Compound lists, graphs of in vivo activity, photocopies of notebook procedures, handouts from project meetings - all that stuff is headed down this path. Different people save different amounts of this material. I save all the computer files, but heave most of the paper when a project finishes up, so I don't have as much in this category.

Things like printed NMR spectra used to be in a special category, because back in the days of expensive digital storage the hard copy was all you had. I guarded my NMR spectra pile fiercely in grad school, since I was going to need that data to get out of there. And in my first years in the industry, digital archiving was spotty. Now that gigabytes are carried around on key chains, all spectral data are automatically archived, so hard copies are just a convenience.

At the top of the paper mountain are lab notebooks. We switched over to an electronic notebook system a few years ago, but it didn't relieve us of the obligation of keeping a hard copy. Printouts are to be taped into the good ol' notebooks, and signed and witnesses just like the handwritten pages of yore. That's a legal requirement, and scientists at research sites across this great nation are regularly harangued about keeping up to date on it. It does little good. Researchers are just not wired to get things countersigned on a regular basis.

That can lead to some real problems for US patents in particular. We're still a "first to invent" country, while the rest of the world is mostly "first to file". And if you get in an argument about the date of an invention, well, lab notebooks are probably where you're going to end up. An invention that isn't signed and witnessed until a year or so later isn't going to help much in that situation. Admittedly, it's rare that things get to that point, but when they do it means that serious money is at stake.

So no one's throwing away any notebooks, that's for sure. And we're all getting them up to date, signed off on, etc. Companies keep track of every extant lab notebook - they're all numbered, and completed ones no longer in immediate use are kept under lock and key. Nothing's going to be allowed to slide.

Comments (4) + TrackBacks (0) | Category: Closing Time | Closing Time | Drug Industry History | Patents and IP

October 16, 2006

Show What You Know

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Posted by Derek

Reader Steve C. analyses patents for a living, and he's been taking an interest in the Ariad / Lilly litigation. He was kind enough to send along some analysis that he's been working on (on behalf of some paying clients, as opposed to me). After looking through the court documents, he thinks that Lilly has a very good chance of prevailing, and I thought I'd share some of his reasoning, with his permission. I should disclose (again) that I am short Ariad stock, because I expect them to lose their patent, and that I think that they (and others who attempt to claim such things) deserve to lose.

As is the manner of lawyers everywhere, both sides advance a number of arguments, hoping that one of them will stick. In Lilly's case, they claim (among other things) that the claims of Ariad's patent are invalid because they were obtained through inequitable conduct, and that they include non-statutory subject matter. That last part is the argument that I've been making here over the last few years - that Ariad's patent on regulating NF-kB every way under the sun is an attempt to own a naturally occurring process. But Steve, while agreeing with that in light of the Searle/Rochester COX-2 decision, says that Ariad may have even bigger problems

The inequitable conduct argument is one that I hadn't paid attention to before. Applicants for a patent have a duty of candor - you're supposed to inform the examiner of everything that you know of that has a bearing on your application and claims, whether it helps your case or hurts it. Concealing potentially damaging material is grounds for having your patent revoked or declared unenforceable. Lilly argues that figure 43 of Ariad's '516 patent is labeled as the nucleotide and amino acid sequence of a protein that would reduce NF-kB activity, but that it's actually a partial sequence, short some 56 amino acids. They further claim that this shortened peptide wouldn't work, and (crucially) that Ariad knew all about this, but didn't disclose it. As it turns out, this protein was a key piece of evidence during the (lengthy) examination of Ariad's application at the PTO, so losing it would be trouble.

And that leads to an even bigger problem. During the near-endless Ariad patent prosecution, US law changed to become more like international patent law. The term of a US patent used to be 17 years from date of issue, but since 1995 it's been 20 years from date of filing. Ariad had been working this case for sixteen years (no, that's not a typo), and was grandfathered in under the old law. But if they refiled, everything would have suddenly changed (and their patent would have already expired as of last January!)

Lilly is arguing that Ariad was doing everything they could to hide any problems severe enough to cause a refiling. Specifically, they charge that Ariad hid the problems with figure 43, which were crucial to the validity of their claims. They hammer on the fact that the protein in that figure is more or less the only thing in the whole patent that actually is capable of inhibiting NF-kB - without it, there's no enablement, just a bunch of talk about inhibiting and modulating NF-kB with no way shown of actually ever doing it. Ariad, for their part, claims that the whole thing was unintentional, that the examiner had all the information needed to check the figure, and that the difference was so subtle that even Lilly's expert witness didn't pick up on it.

Steve thinks, though, that this could be a killer issue for the whole bench trial. His view is that Ariad's trying to have it both ways: saying that the examiner had all the information needed makes it sound like it's a serious problem that had been dealt with, but then they claim that it was such a small matter that Lilly's witness didn't notice it. Those two defenses can't be simultaneously valid. The extreme importance of the issue makes Lilly's job easier, since they don't have to show as much intent on Ariad's part.

I have no word on when the judge's decision might be coming, but I'll be watching closely. The research world will be better off, I think, when patents like this are no longer an option or a temptation.

Comments (2) + TrackBacks (0) | Category: Patents and IP

September 7, 2006

Inherently Obvious - It's Obviously Inherent

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Posted by Derek

Note: This is part 2 of tonight's Ariad-fest. Part 1 is below.

The Ariad reexamination itself makes for entertaining reading, if you have a sufficiently geeky worldview, which I do. I was incorrect in my first look at this the other night, when I thought that the rejections were largely on means-plus-function grounds. All of the claim rejections are based on 35 U.S.C. 102, which is good ol' prior art, and 35 U.S.C. 103, which is obviousness. If something has been publicly described, you can't patent it. The bulk of the document is a case-by-case recitation of the various publications which anticipated the patent's claims or rendered them obvious.

By my count, there are fifty-three of them cited. Since the patent's claims are written in the pounding, repetitive, unbalanced-washing-machine style favored by many attorneys, most of these citations turn around and invalidate great swaths of them, over and over. Not only are there the expected papers from the primary literature, but various textbooks and reference handbooks (the PDR, Goodman and Gilman) make an appearance as well.

The actions and literature descriptions of the mechanisms of cyclosporin, glucocorticoids, various antibiotics, and many other substances are adduced. My favorite section is on pages 46-49, on the effect of substances such as resveratrol, found in grapes and in red wine. (More on resveratrol here and here). The examiner cites the King James Bible as invalidating prior art, along with several more conventional citations, and points out that:

"In short, any time someone, over the last several hundred or thousand years, drank even a moderate amount of red wine with food containing significant fats (e.g., the typical French diet) they were reducing NF-kB acitivity (and concomitant NF-kB mediated gene expression) that had been induced by the fat content in the food."

And as the official Manual of Patent Examining Procedure makes clear, something old doesn't become patentable just because you've finally discovered the scientific reason for its effects. If the use or property you're trying to claim is inherent in the prior art, it's unpatentable. As long as the inherent characteristic necessarily flows from the prior art, and is not just one of many other possibilities, the claim can be rejected. Once this happens, the burden of proof is on the applicant to show that there's a difference that isn't obvious. That will be Ariad's only recourse at the USPTO, which is why they're also going outside and petitioning the US District Court.

From my perspective, they're not going to have an easy time of it. The rejection of the NF-kB claims seems pretty comprehensive, and it's hard for me to think of arguments that would refute enough of the examiner's contentions to matter. Left unspoken in the office action is the clear inference that the original patent should never have been granted in the first place, which is what I thought back in 2002. Looking back, that post seems downright psychic, if I do say so myself.

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Move On, Move On - Nothing To See Here. . .

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Posted by Derek

I seem to have set off all kinds of interest with that Ariad patent item from the other day (thanks to the folks from the Dow Jones news wire for citing me as a source, by the way). I'm not sure when the reexamination actually showed up on the USPTO site, but I was alerted to it this week by an email from a regular reader.

And that when-did-people-know question is an interesting one. Some of the fans of Ariad's stock have been claiming that this is all old stuff, that the company has already disclosed this information, no news here, already priced in, etc. Ariad's management seems to be taking roughly the same tack, according to Peter Loftus at Dow Jones:

"An Ariad spokeswoman referred inquiries to comments made by company executives on a conference call in August. "This action is a routine and expected step in the re-examination procedure and does not represent the final ruling," Ariad Chief Executive Harvey Berger said on the call, according to a transcript. "The PTO action invites a response from the patentees which will be filed in due course." He also said the patent remains valid and enforceable during the re-examination process."

Berger is right that this isn't the final ruling, of course. I believe that Ariad has one shot at an appeal through the Patent Office, though, before this becomes final. Since early June, they've also tried to stop the whole thing through legal action (a request to enjoin the PTO from continuing the reexamination, and a request for summary judgment on their complaint) in the U.S. District Court (Eastern Virginia). A hearing was set for September 1, and a dollar or so spent this evening on the PACER document retrieval system tells me that the motion was argued on that day, but no court order has been recorded yet.

So, are Ariad's fans correct that all this is old news? If you go back to Ariad's most recent 10-Q form, you find the whole painful topic glossed over a bit on page 23:

As a result of the PTO orders described above, Lilly's ex parte request has been merged into a single action with the ex parte request filed on December 2, 2005 (the "Merged Requests"). The Merged Requests question the patentability of certain claims of the '516 Patent by newly cited references which (i) either inherently or expressly disclose the use of a variety of prior art compounds as reducing NF-?B activity and resulting gene expression, or (ii) are directed to the use of oligonucleotides having an NF-?B binding site for reduction of NF-?B activity. The PTO issued a first office action affirming the Merged Requests on August 2, 2006.

And that's that. You have to go to the PTO to find out that "affirming the merged requests" means "agreeing with them wholeheartedly, to the tune of throwing out most of the patent's claims, including all the ones that were used as the basis for the lawsuit". (See the next post for the details). Despite this oblique acknowledgement of the PTO's decision, the rest of the 10-Q form carries on as if nothing had happened. Referring to the uncertainty surrounding the patent, the quarterly report cites:

. . .The timing and ultimate outcome of Plaintiff's motion for summary judgment enjoining the PTO from proceeding with the reexamination of the Merged Requests, and the consequent reexamination of the Merged Requests by the PTO if the motion is denied . . ."

And says that:

Although we have prevailed at trial in the Lilly litigation, the damages we have been awarded by the jury may be eliminated or limited by an adverse finding upon appeal or in the event that the claims of the '516 Patent are invalidated by the PTO.

Emphasis added in both cases. Now, I'm sure that legally Ariad is within its rights to talk this way, because the reexamination process isn't finished until they've had a right to reply and the PTO has issued its final action. But you wouldn't know from reading this that large sections of their patent had already been ripped out by the seams, and that the task before Ariad now was to make this go away rather than to keep it from happening in the first place.

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September 5, 2006

Ariad's Patent Eviscerated

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Posted by Derek

A correspondent has alerted me that the US Patent Office's re-examination of Ariad's huge NF-kB patent is complete. And 160 of its 203 claims have been rejected. This includes, I believe, all of the ones that Ariad used to make its recent case against Eli Lilly (#s 80, 95, 144, and 145). For example, it appears that only six of the first fifty claims are still standing.

You can find all the details here at the USPTO's PAIR site. (That 66-page "Re-exam Non-Final Action" is where the good stuff is). It appears that most of the claims have been dismissed due to over-broad functional language. There's a statement in there that most of the claims are "purely functional":

"With respect to claim 1 it is noted that the sole method step is function i.e. reducing NF-kB activity. Accordingly, the claims would encompass any in vitro or in vivo, natural (indirect) or man-made (direct) means of reducing NF-kB activity. Indeed, most of the method steps recited in the Baltimore patent are purely functional. . ."

This is an argument over the "means-plus-function" section of US patent law, 35 U.S.C. section 112, paragraph 6 if you want to get right down to it, which has been the subject of many a lawsuit. Here's a good discussion of the topic, and here's the Patent Office's take on it for its examiners, if you want to feel a throbbing sensation in your temples. Basically, I think the problem is that the patent is claiming a function (inhibition of NF-kB signaling) without specifying the means by which it is to be carried out.

And there's that nasty problem of prior art. The examiner notes a paper from the Journal of Biological Chemistry (265, 8339) which "teaches the reduction of NF-kB activity in induced cells". This reference, the office action goes on to state, expressly anticipates a large swath of the patent's claims right there. It makes for interesting reading, this re-exam, and I certainly don't have time to dig into all 66 pages of it tonight. But it'll be interesting to hear what Ariad (and its stock boosters) have to say in the morning. There's nothing on their web site tonight. . .

Update, September 6: Still nothing from the company on this - wouldn't an office action on a key piece of intellectual property qualify as a material event? One that affects ongoing litigation? Dated August 2, yet?

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September 4, 2006

Plavix Plot Twists

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Posted by Derek

The mighty Plavix battle has taken another unexpected twist. In the last installment, Canadian generic company Apotex had snookered (a completely accurate description) Bristol-Meyers Squibb and Sanofi/Aventis into an ill-advised agreement that ended up destroying the drug's patent protection. Apotex had begun gleefully shipping their generic, while the two larger companies sought relief in court from what appears to have been largely a problem of their own making.

To my surprise, that relief has been granted. Last week, a judge issued an injunction against further sales by Apotex in the U.S. until the patent infringement trial is completed. That's not even going to begin until early next year, and you can be sure that BMS and S-A are going to drag it out as much as possible. No legal bills can compare with the hit they've taken over generic Plavix. Sanofi-Aventis, for example, has lowered its profit forecast to a 2% increase over last year, instead of 12%, claiming that Apotex has clogged up all the distribution channels with their generic. I'm a little sceptical of the size of that effect - it's not unheard of for companies to unload other types of bad news under a convenient banner, given the chance - but there's no doubt that it's been a nasty experience.

Apotex may have just had its moment of glory, at least as far as Plavix is concerned. I'm sure that they made money during this adventure, so if they were going to lose the patent case anyway, they're still ahead. No doubt they'd have been even happier to go on selling it, but they'll take what they can get.

Meanwhile, the Federal Trade Commission is making threatening noises about investigating other pay-the-generic-to-go-away deals. The courts have ruled that such deals are legal if they don't push past the patent expiration of the drug, so I'm not sure what the FTC is going to be able to do. But they're clearly unhappy about the situation. For my part, I'd as soon see the generic companies go ahead and challenge the patent-holding ones, as long as the decisions are made in a competent legal venue. By which I mean, not like the one that upheld Ariad's patent. Keeping everyone on their toes is a good thing, as long as it's done fairly.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP

August 24, 2006

Respect! Honor! Recognition! All For $149.95!

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Posted by Derek

Turns out that I had another patent issued the other day. The way I usually find out about these things isn't through a note from the US Patent and Trademark Office - they have enough to do already. And it's not via a note from my company, although they do eventually mark the event in a way that's dear to my heart and which shows up in my paycheck. No, the quickest notification is via junk mail from the patent plaque companies.

If you're not in an industry that does a lot of patenting, you might not have run across these people. What they do is offer (for a price, naturally) a wall plaque to show off your patent. These come in all sorts of designs and combinations - just Google the phrase "patent plaques" and you'll get all the options you could ever need. It's a competitive business, and the real go-getters use the latest updates to the patent databases as their mailing lists.

What I find interesting is the language that the brochures use. They seem aimed at people with self-esteem issues. The words "respect" and "recognition" occur frequently, as do "accomplishment" and "achievement". Einstein and Edison come up more often than they do in normal conversation. The more expensive options (better-looking wood, more three-dimensional etching in the metal, what have you) are pitched to some hypothetical audience of demanding achievers who would clearly settle for nothing less. The general tone of the copy is similar to the ads you find in airline in-flight magazines, set relentlessly to a level that's designed to flatter the intended audience and play to their fantasies.

Many of the pitches thus seem to be aimed at individual inventors who have been issued their first patent and want to let everyone know about it. I'm sure that's a big part of the market, and the rest of it is probably taken up by large companies who get a discount on their orders for their employees. I have a stack of the things myself, given to me by the companies I've worked for. I don't mind having them, but they're not on my wall, and I'd never order one on my own - not least because you can't get anything out of these outfits for less than about $70 for the El Cheapo Maximo model. The Deluxe Edisonian Hyperventilator plaques can go up past $300, by which time you're looking at rich Corinthian leather and who knows what else. I await the future LCD-screen option that displays a moving model of the invention.

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August 10, 2006

The Great Plavix Disaster

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Posted by Derek

I've been remiss in not covering the Plavix situation, which is quite a story. The huge-selling anticoagulant is marketed in the US by Bristol-Meyers Squibb and in the rest of the world by Sanofi-Aventis. It's been the target of the Canadian generic firm Apotex, who've maintained that key parts of its patent coverage are invalid. They won the right from the FDA back in January to sell their generic form - but keep in mind that the FDA is not concerned with patent law, only the drug's manufacturing standards and identity with the original version.

The company was in the middle of their patent suit with BMS and S-A, and were holding back to see how that would go. In March, though, a deal was cut: Apotex agreed to wait until 2011, the lifetime of the (unchallenged) patent, and in return they got paid by the larger firms and received a guarantee that they wouldn't be undercut until then.

Paying generic firms to go away is not unheard of, but companies can put themselves at risk when such deals are made too blatantly. This one fell apart, big-time, last month. Not only was it rejected by various state attorneys-general, but a criminal investigation was launched into the whole matter.

The ceiling tiles really began to rain down at that point. There was a clause in the agreement that if the deal didn't go through, Apotex could start selling its generic version with five days notice, and that's exactly what they've started doing as of earlier this week. The generic isn't all that much cheaper, but it's enough to torpedo the branded version.

What's more, it appears that BMS and Sanofi-Aventis limited their potential recourse. Under the usual rules, they'd be able to sue and obtain triple damages if they won, but they seem to have waived that right, along with several others. This would seem to be an indicator of just how much they wanted to keep the generic off the market, and how hard a bargain Apotex drove. It's enough to make you wonder if Apotex factored in, up front, the chance of the whole thing being rejected and decided to give their rivals enough rope with which to hang themselves.

Update: as pointed out in the comments, the CEO of Apotex is making it sound like that was exactly the plan. Perhaps he's laying it on a bit thick, but he's in a position to, isn't he?

Shares of both Bristol-Meyers Squibb and Sanofi-Aventis took a fine hammering, as you can well imagine, since Plavix represents about 30% of BMS's profits. (Here's a read-'em-and-weep chart). Apotex is privately held, which is a shame in a way, because it would have been something to see what the trading in their stock would have been like. Sanofi may try to obtain an injunction to stop the generic sales, but no one seems to think that it will be granted - partly because of all those Apotex-favoring terms that the companies agreed to originally.

It's difficult to see how this could have worked out more horribly for the two big companies here: their best-selling drug is under attack five years early, they've signed away their rights to do much about it, the analysts are downgrading their stock and the financial rating agencies are looking at lowering their credit ratings, and the criminal investigation is rolling right along. Short of a meteor strike or a plague of frogs, I'm not sure what else could go wrong. And the worst part is, they brought it on themselves. Their patent position should have been stronger in the first place to protect a compound of this importance, and they shouldn't have pushed the envelope so much with their go-away payments to Apotex. It didn't have to be this way. Did it?

Comments (36) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Patents and IP | The Dark Side

July 18, 2006

Getting and Spending

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Posted by Derek

Well, we're now into earnings report season in the drug industry. Not that we notice much in the labs, mind you, but the stockholders do sit up and pay attention. Profits seem to be up, which prompted a colleague of mine to wonder today when the first New York Times story will appear noting this with worry and disapproval. They have some people that I enjoy reading, but a tone does tend to creep in that suggests that any profitable industry must necessarily be extorting The Masses.

Well, I can cheer them up. The thing about drug industry profits is, they're pretty much all based on wasting assets. The drug business is an endless treadmill. Most businesses have this problem to some extent, but it's very explicit in our case. When your big patent runs out, the music stops very abruptly these days, so you'd better have something to replace it.

But you know, I'm not complaining about that. Patents should have defined lifespans, although we can argue about how to set them. Knowing that they're going to go away, though, keeps us moving. (For similar reasons, I wish that copyright hadn't been extended a few years ago). If we had big whopping patent terms, the temptation to just sit around and roll in the money would be too great. The pace of discovery would slow. I see it as the function of government to discourage that kind of inertia, although not by just yanking all the cash away, which position I realize also has some support.

Nope, it's the middle ground for me: enough time to make good money, but not so much time that everyone becomes too lazy. Here's the question, though: stipulating that that's what we want, are the current patent terms too short, too long, or on target?

Comments (24) + TrackBacks (0) | Category: Business and Markets | Patents and IP

May 4, 2006

Ariad Wins a Round

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Posted by Derek

Well, you'll no doubt have heard that Ariad won its case against Eli Lilly today. The jury found that Ariad's patent was valid, that Lilly had infringed it, and that Ariad was owed royalties, retroactively and in the future. This isn't the sort of case (or the sort of universe) where the jurors would get interviewed by Larry King and Oprah, but I would very much like to know what this jury knew, or believed that they knew, about intellectual property and cell biology. Ah well, at times like this, my wife reminds me that I thought that O.J. Simpson would be convicted, too.

I'll not rant; my position on this has been as clear as I can make it for some time. I hope that Ariad and its shareholders enjoy their victory while they can. Said shareholders should realize, though, that it's very unlikely that one dime will be coming to the company until several other legal proceedings finish up. First off, Lilly will appeal this verdict. Then there's the reexamination of Ariad's patent that Lilly requested. And there's another Lilly trial - a bench trial this time, no jury - on whether Ariad's patent is enforceable. And let's not forget Amgen's recently filed suit in Delaware.

I find it very unlikely that all of these will go Ariad's way, since at least three of them will be judged by people who know what they're talking about. In the meantime, I haven't covered the short position I spoke about the other day, even though I'm about $1500 to the bad right now. The stock didn't take off like a skyrocket today, and I think that the legal uncertainty around today's verdict will keep it from doing so over the next few months. I have time and collateral. Who knows, as things go on I might short some more, and I'll post it if I do. Court of Appeals for the Federal Circuit, over to you.

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May 3, 2006

Full Disclosure

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Posted by Derek

Since I made a big point out of this in a comment to the last Ariad post, I wanted to update things. The jury is out - literally - on the case versus Lilly right now, and I notice the stock creeping up a bit today.

So, I am now short Ariad stock, 1000 shares at 5.56. This isn't a recommendation that anyone else should run out and do the same, but I thought it was important that I mention it since I've written about the company. I'll post again on the topic after the verdict comes in (which will be when I close out this position, one way or another, I should think).

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April 25, 2006

A Shot Across the Bow

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Posted by Derek

The Ariad-Lilly suit that I spoke about here earlier this month is continuing along, with no news to report. But there is an interesting development: Amgen, surely one of the companies contacted by Ariad about infringement of their NF-kB patent, has decided to play offense. They've filed suit against Ariad in the US District Court in Delaware, seeking a declaratory judgement that Ariad's patent is invalid and that Amgen hasn't infringed any part of it. Interestingly, there's no press release about this to be had from Amgen. Ariad is the source of all the information on this - it's much more of a material event for them, so they're under greater regulatory pressure to disclose the news.

Such rulings can be sought when one party feels what the law terms a "reasonable apprehension" of legal action by another, and I'm sure that Ariad's letter would be enough to meet that requirement.

Meanwhile, according to the U.S. Patent Office's "Official Gazette", there's been a re-examination request filed for Ariad's original patent, as of last December. The applicant is listed as Bawa Biotechnology Consulting, which would be Raj Bawa's firm. They're well-known for doing biotech freedom-to-operate and infringement work, and I would assume that they're being paid by Lilly. Or maybe Amgen. Heck, maybe even someone else - there are enough people mad at Ariad that it's hard to narrow the list down.

My opinion hasn't changed: I think that Ariad deserves to lose this case, and that they will. If their patent goes down in flames, taking all others of its sort with it, that'll be even better.

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April 11, 2006

Ariad's Day in Court

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Posted by Derek

It's been a while since I wrote about Ariad and their suit against Eli Lilly, but the time has come again. Back in 2002, the company was granted (after sixteen years of prosecution) a patent with broad claims around the transcription factor NF-kappaB. I mentioned that one the other day as a good example of a protein that's involved in more things than human beings can keep track of, so you can imagine where these claims could take you.

In Ariad's case, they're planning on taking them to the bank. As I wrote at the time:

Ariad had a lawsuit fueled and on the pad, and as soon as their patent was issued, they launched. In fact, the Business Wire press release about the lawsuit went out before the one about the patent, which shows you where Ariad's priorities are. They claim that two of Lilly's biggest products, Evista for osteoporosis and Xigris for sepsis, both work through NF-kB (and there's little doubt that they do, at least partially.) Therefore they're demanding royalties, and pronto. Lilly had ignored Ariad's previous requests for a licensing deal, according to the Wall St. Journal, which moved them up to the exalted position of First Target. The other fifty companies can presumably expect the same treatment if they don't get on Ariad's good side.

And back in 2003, when the suit finally seemed to be cleared to go to trial, I wrote that it might get there during 2004, which shows you how much I overestimate our legal system. Or perhaps how I underestimate Lilly's legal team, which I'm sure has kept things spinning out as expensively as possible. After all, Ariad lost over fifty million dollars last year - perhaps Lilly were hoping they'd go out of business before things went to court.

Actually, that's not likely, since Ariad is merely the licensee. The assignees on the orginal patent are Harvard, MIT, and the Whitehead Institute, none of which will be going to be going out of business any time soon. I would very much like to know how much of their money is going into this fight, as opposed to Ariad's (more on this in a minute).

So here we go; arguments started this week. The implications, as I said back in those older posts, are potentially very large. Patenting big swaths of important biochemical pathway space has the potential to turn drug development into even more of an expensive nightmare than it already is. As this thorough overview in Science mentions, there are over 200 drugs that could plausibly be said to work (at least partially) through NF-kB signaling, from aspirin on up. You can add all sorts of development candidates for arthritis, cancer, diabetes and many other indications to that list. That article includes this interesting note:

Ariad's chances of winning, at first glance, appear small. "It's probably somewhat less than 20%," says Philip Nadeau, a biotech analyst at investment bank Cowen & Co., which counts Ariad among its clients. "These broad patents in general seem to be tough to defend when brought to court." But among the inventors on the NF-B patent are David Baltimore, now president of the California Institute of Technology in Pasadena, fellow Nobel laureate Phillip Sharp of MIT, and well-known Harvard molecular biologist Thomas Maniatis. Their very presence on the patent, and possibly in court, could be decisive. "You've got very prominent scientists who are the inventors," notes Rochelle Seide, a patent attorney with Arent Fox in New York. "That sells very well before a jury." (These inventors have not commented publicly on the patent or lawsuit and declined to do so for this story.)

And that's going to be interesting. Ariad would presumably like to have these luminaries in court, testifying on its behalf. Will they? These people surely know what the implications of an Ariad victory will be for industrial (and even academic) research. Do they really want this suit to succeed? I wish I knew.

A separate question is whether the institutions involved want it to succeed, and those answers might well be different. They all stand to gain some revenue from Lilly if Ariad wins - although, let's be honest, what's another few million or so to Harvard? Presumably there's even more money in the offing if Ariad starts to lean on everyone else, though. And since it's these sorts of institutions that discover more of these fundamental pathways, they might not be averse to a system that lets them profit from them - let the lesser outfits take their chances, eh? Pecunia non olet?

Lilly's defense seems as if it'll be that (first) their drugs were in development long before NFkB was even discovered, and (second) that, as in the Rochester/COX-2 ruling, that the identification of a biochemical pathway does not equal finding a drug that affects it. Those are both good arguments, and (like other observers) I expect Lilly to win. Of course, no matter what happens, there's going to be an appeal, so it could be years before we hear the last of this. (The Metabolite case that's been before the Supreme Court could well have a bearing on this, too. I'll have more on that in another post; I've been neglecting that one).

But along the way, it'll be interesting to see how the issue is reported. My fear is that the whole thing might end up being framed as a battle between disinterested, truth-seeking academic researchers and rapacious pharma drug peddlers. Let's hope not - there's only so much that my stomach can take.

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April 4, 2006

Once More Into the Patent Breech

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Posted by Derek

Man, is everyone going at it hammer and tongs in the comments sections to the last two posts. There are a lot of good issues being raised, along with some interesting invective. But (as several people have noted), we're conflating several issues here.

On the subject of me-too drugs, I've already said a lot of what I have to say on the subject, and it can be found in that category over on the right. Looking over the comments, I tend to agree with SRC's take on the subject, although I'm pretty sure that my blood pressure doesn't go up as high as his does. A point that he makes, that many of these drugs are the sign of roughly simultaneous development (rather than sequential) is something a lot of people don't think about.

That said, there are some sequential me-toos, of varying degrees of utility. I've gone on about Clarinex/Claritin and Nexium/Prilosec here before, because I think that those are the two most egregious within-the-same-company examples. See this post on Sepracor for some others - come to think of it, they're involved in the Clarinex example, too, much to Schering-Plough's sorrow. It's fine with me if insurance companies decide that they don't want to pay for these things without a clear demonstration of medical need. If the market isn't big enough, companies won't develop such drugs. I'm in favor of as many pricing signals being sent as possible, all up and down the business.

Then there's the whole "how much does the federal research budget subsidize Big Pharma?" question. I'm going to have to pull that one out and deal with it - again - but not tonight. I continue to think that if you haven't been through the process, it can be difficult to realize just how long, twisty, and expensive the path between a great initial paper in Nature and a great drug on the market really is.

But these two issues have become thoroughly tangled up with the "can patents be improved" question. There have been some good suggestions scattered throughout the comments: longer granted terms for unmet medical needs, for example. If you try to apply these things too slickly, you open the way into terrible arguments, but for conditions where there isn't an existing therapy, the case should be clear. But isn't this exactly what the Orphan Drug Act is supposed to already do for us? There may not be as much uncaptured benefit here as we're thinking.

I wonder if there could be a (presumably shorter) fixed patent term that only starts once a compound comes to market, to deal with those long-gestation-period drugs that companies worry about getting involved with. You could also imagine adding onto a patent's term if the company agrees to do further studies (data to be made completely available,) which discover further utility (especially against competitor compounds?) But there's lots of arguing room in any scheme like that, too. And I could easily imagine companies carefully timing their investigations in order to stretch the patent out in the most lucrative way possible. (There was a similar suggestion in there for time limits to various milestones, tied to patent terms).

Coming up with incentives that can't be easily gamed isn't trivial, and it's a problem that's much larger than the patent debate.

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April 2, 2006

Down With Patents, Eh?

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Posted by Derek

I see that Against Intellectual Monopoly by Michele Boldrin and David Levine is about to be released. This is a provocative work, parts of which have appeared in articles over the last couple of years. The first few chapters are available online (still with some typos, I've noticed).

What makes this a bomb-throwing sort of book, from the perspective of a drug company researcher like me, is that the authors recommend abolishing the patent system as we know it. They have a chapter (PDF) on the drug industry specifically, as you'd expect. Looking it over, I find it a peculiar mix of compelling argument and things that make me hold my head and moan. For instance, the authors, in all their discussion of the German and Italian drug industries, don't seem to take into account the way these industries have been able to make money over here.

I'm open to the idea that there might be other ways to encourage innovation than the patent system we have now. But Boldrin and Levine seem to have bought into the whole it's-the-government-that-finds-drugs idea, which never fails to drive me insane. (See this category for more on the same topic here).

Here's just one example of a hold-my-head section:

Much of the case for drug patents rests on the high cost of bringing drugs to market. Most studies have been sponsored by the pharmaceutical industry and are so quite suspect. The Consumer Project on Technology examined the cost of clinical trials for orphan drugs – good data are available for these drugs because they are eligible for special government benefits. A pharmaceutical industry sponsored study estimated the average cost of clinical trials for a drug at about $24.5 million 1995 dollars. However, for orphan drugs where better data are available, the average cost of clinical trials was only about $6.5 million 1995 dollars – yet there is no reason to believe that these clinical trials are in any way atypical.

There aren't? How about the fact that they're often first-in-class therapies, and thus can have a lower efficacy standard (better than nothing!) to meet? Or the fact that they're orphan drugs, meaning that there's a limited patient population available to start with? There are cardiovascular drugs that have been through trials in more patients than the total market size of some orphan therapies. No, there are some deficiencies here.

For a worried take on Boldrin and Levine's work, see Arnold Kling, and for its application to the drug industry, this post at Samizdata. Here's some more discussion on the same topic.

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January 26, 2006

Ah, It's Fine. Just Send the Darn Thing Out Already.

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Posted by Derek

Since I was mentioning the other day how little I enjoy reading (or writing) patents, I thought I'd pass along this item from Greg Aharonian's PatNews mailing list. There are plenty of other people, it seems, whose attentions wander while doing IP work. Take, for example, the luckless 3 inventors from the New York area who filed application US 20030004652, which published about three weeks ago.

They've got a (putatively new) system to monitor animal behavior during drug testing. The abstract starts off by describing:

A  system  and method used to assess animal behavior includes a module having sensors that collects a variety of physical and biological data from a test subject. Interpretation of the data is provided to assess the  test subject's behavior, neurology, biochemistry and physiology. The module  is  useful in observing the effects of a drug on the test animal and providing information on the drug's signature.

OK, fine. I'm pretty sure I've seen things like this before, but who knows, maybe they have something inventive in there. So, you're asking, what are the wonderful features of this new invention? As you'll see, the folks who drafted (and edited) the abstract were asking themselves the same question during the document's preparation. Verbatim, it continues with the following, whose unsteady grammar is the least of its problems:

Another advantage is module's portability that allows it to be used in standard laboratory cages.  (NOT SURE ABOUT THIS PORTABILITY) This portability allows the animal to be tested in its own habitat, that can reduce any erroneous data due to stressing the animal when removed to a test cage.

Proofreading, guys, proofreading. You're going to have a tough time with the novelty and enablement requirements if you tell the patent office what you really think, you know.

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January 24, 2006

The Examiner Finally Snaps

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Posted by Derek

PCT (Patent Cooperation Treaty) applications are published with an "International Search Report" appendix document. This is done by one of the larger patent offices from the countries in the PCT, and is a preliminary assessment of the patentability of the claims in the application. The searchers try to identify other documents in the patent or open literature that might bear on their novelty or scope.

It would be difficult to pay me sufficiently to do this for a living. I've been involved in many in-house patentability and claim-writing discussions, and they can be agonizingly tedious and frustrating. That's why I've never been able to understand how some pharmaceutical applications are written. They start off with chemical claims whose first generic structure seems to take in the vast reaches of interstellar space. Then the next fifty or sixty claims narrow this down in gratingly tiny steps to oh, about the edge of the Kuiper belt. Then comes a recitation of six hundred and seventy-eight specific names of compounds that are specifically claimed, and on and on.

I have trouble imagining how anyone can go to such pains, and I have trouble imagining why they bother. After all, if you don't enable these claims (patent-speak for "show that you actually made something that fits that description"), they're not worth all that much if it comes down to a fight. And I've seen many claims that couldn't be fully enabled short of putting five hundred people to work on them full-time for about ten years.

For those of you with access to patent images, try the generic structure in US6214850 on for size. It's very concise, as these things go, but rapidly expands like some sort of mutant fungus. For a wordier example, try WO2002042272. This jewel has 139 pages of claims in it, and the number of R-groups that show up in its laughable generic structures goes up into the hundreds.

The whole purpose seems to be to confuse and irritate anyone who tries to read the claims - and to be fair, that's very likely just that the purpose is, since that makes it harder for someone else to figure out what the real subject of these hay-bale-sized applications actually is. But the poor souls at the search agencies are paid to do that, and every so often they lose it. I just came across a search report which starts out with this cri de coeur:

"In these claims, the numerous variables and their voluminous, complex meanings and their seemingly endless permutations, makes it virtually impossible to determine the full scope and complete meaning of the claimed subject matter. . .it is impossible to carry out a meaningful search on same."

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July 20, 2005

Arr, Me Hearties!

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Posted by Derek

Reader SP sends along this speculation:

"Something that comes up every now and then when discussing IP issues and freedom to operate is to dream about having a ship or island that's in international waters and free from all international patent laws.  Obviously you can't sell things made on the ship in any country that are covered by composition of matter, but any patented processes could be performed there, and people who wanted to use patented matter could go there for treatment. . ."

He passes along a link to this blog, which is discussing this news item. There's an outfit called SeaCode that plans to anchor a ship just outside US waters off Los Angeles, stock it full of coders, and crank out software at outsourcing prices (while staying in the same time zone as Silicon Valley.)

And the thing is, something similar to SP's idea already goes on. Multinational US companies, for example, run assays in Europe if they're blocked by a US patent. And there's Panlabs, part of MDS Pharma Services. They run all sorts of assays for you, hundreds of the things, and some of them are clearly covered by other people's patents in some of their customer service zones. But they have that taken care of by being all over the place, including some spots that many assay patents don't necessarily reach (Taipei, to pick a big example, where their main assay lab is.)

The difference between this sort of thing and SeaCode is that the assay companies aren't primarily driven by labor costs. Larger companies use them because they don't keep all these screens running all the time, and it's a convenient one-stop way to profile interesting compounds. (Including, of course, some assays that you probably just can't run.) But they're not particularly cheap, although when you work out the cost of establishing a new assay of your own, they don't look as bad. . .

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July 18, 2005

The Leash of the Law

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Posted by Derek

One of the many interesting points that came up in the comments to my Brazil posts was from a reader who wondered how easy it was for someone to get the structure (and synthetic route) for a marketed medicine. In other words, what are the barriers to ripping off someone's patent?

And as some of my industry readers correctly told him, those barriers are few indeed. The structure of an FDA-approved drug is a matter of public record, and is included in the required package insert with every prescription. And the patents are required to tell you how to make it. In fact, in almost every case, the only reason that a patented drug isn't copied is patent law itself. That gets right to the concept of what a patent is: in return for a defined period of monopoly, the patent holder agrees to disclose all the relevant facts about the invention.

For a drug industry patent, that means that the generic structure of the claimed compounds is in there, as well as at least the names and some physical properties of all the specifically exemplified compounds. (Chemical names are systematic enough to determine the structure, but most patents have the structural drawings, anyway.) General chemical routes are laid out, along with specific examples that get right down to the bench-level details. A chemical matter patent, in order to be valid, has to teach a reader of ordinary skill in the art how to make the claimed compounds. If it doesn't, it shouldn't have been granted, and can be invalidated. (This isn't merely an academic point - part of the reason that Bayer got ciprofloxacin (Cipro) from out of a SmithKline patent claim was that the routes shown couldn't make the compound.)

Now, there's still a bit of wiggle room. You don't have to list biological activities of all the compounds that you exemplify, although it does build a stronger case. If you're claiming a particular biological activity, you have to show how you assayed for it, but often you'll see the detailed assay procedure along with a note to the effect that "the compounds of this invention were tested according to this protocol and showed inhibition constants of between 0.01 and 10 micromolar."

That satisfies the legal requirements, but it doesn't satisfy the reader very much, which is the whole idea. There's a constant guessing game when your competitors aren't on the market yet and haven't disclosed much about their clinical trials. Ten nanomolar to 10 micromolar is a wide range of activity, from the very interesting to the surely useless, and there's often no way of finding out which compounds were the best.

You can narrow things down by some detective work, though. Looking over the specific examples in the patent(s) can tell you what chemical classes they spent the most time on, and what regions of the molecule seemed to be most important. If your competitor has gone to the trouble of filing a process patent (covering a specific route to make certain compounds, as well as the compounds themselves), then you can be pretty sure that they're interested in that class. And looking at the specific examples in the patents will sometimes show an interesting pattern: ten, twenty, fifty compounds are all shown being prepared in 20-milligram amounts, followed by one that's made on a ten-gram scale. Aha!

Now, in the absence of a process patent, you're still not guaranteed that the method shown in the original patent is the one that they're using to make it on large scale. Actually, you're more like guaranteed that it's not. Ten grams is one thing, but a thousand-kilo route is quite another. A patent is required to disclose the best mode to realize the invention that you know of at the time of filing, and that's generally before the process chemists have had time to work on the synthetic route. (Patent cases have hinged on the timing of those steps.)

But a good process group can usually take the structure and the patent route and work something out, for a tiny fraction of the time and effort it took to find the compound the first time and get it tested and approved. And if it weren't illegal, that's exactly what people would do. And then who would go to the trouble of being first?

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July 6, 2005

Brazil Pulls Out the Pin

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Posted by Derek

Just how much should an anti-HIV drug cost? What if you're selling it in a place where most of the patients can't afford it? These questions have been fought out in Africa and other parts of the developing world over the last few years (and the stagnating world, too, unfortunately.) Now Brazil may be making good on a threat of outright patent confiscation.

The Brazilian government is unhappy with the price of Abbott's combination therapy, Kaletra (PDF), which they already pay just over $100 million per year for. Mind you, that's the lowest price in the world outside Africa. Online pharmacies claim that the average US retail for Kaletra tablets is about $4.06 each, and they offer it at about $3.60. Brazil's paying $1.17, and they're saying that they'll issue a compulsory license if the price doesn't come down to 68 cents.

They've threatened to do this before, but have never come this close to following through. The worry for Abbott is that once the Brazilian generic companies start making the stuff, it'll end up all over the rest of the world at a base of $0.68/tablet. And where do you think demand for it will be strongest? In the countries where it's already the most expensive, which Abbott is counting on for their profits.

Opinions vary a bit, as you'd figure. You can find no shortage of activists cheering the Brazilians on. To wit, from the AP article linked above:

"We are the hostages of these companies, and compulsory licensing is a defense against the abuse of monopolies," said Jorge Beloqui, the leader of a Sao Paulo-based AIDS support group.
Beloqui, a university math professor, has taken 30,000 anti-AIDS pills provided free by the government since 1991. If Brazil breaks the patent, he says, activists will pressure Brazilian politicians to go a step further and let its generic drug makers produce much more of Abbott's drug so it can be shipped around the world to needy patients.
"These medicines are essential to the world, and I think Brazil should sell them," he said.

Actually, Prof. Beloqui is the hostage of a retrovirus, but his comments seem pretty representative of the "stick it to The Man!" point of view. Well, speaking for The Man (to crib a line from Tom Wolfe), I have to say that Brazil seems to be playing to the galleries here. There are accusations that the country is spending less on anti-HIV medications than it did five years ago, and they turned down $40 million in US money not so long ago. There's another problem, too. Brazil is acting according to WTO language about breaking patents in case of a public health crisis. But you have to wonder

Allowing Brazil to use the "public health crisis" justification creates a dangerous and perverse incentive for governments of the developing world: if you as a government are responsible and work hard to uphold a fiscally manageable public health program, then you will be punished by having to pay for expensive drugs, but if you fail or simply ignore the problem and cry "crisis," then you will be rewarded with permission to trample on intellectual property rights.

I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?

Comments (43) + TrackBacks (0) | Category: Drug Prices | Infectious Diseases | Patents and IP

June 29, 2005

Vaccines and Human Folly

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Posted by Derek

Things seem to have taken a bit of a turn for the worse around here. Let me take a day to set the record straight on a few things.

I believe that vaccinations have been a tremendous boon to human health. Here in the developed world, we've forgotten what the infectious diseases are like that we vaccinate against: try the table at this site to remind yourself. We can argue about rare side effects, but we need to avoid remedies worse than what we're trying to cure.

The classic example is Japan in the 1970s. They had two deaths from the pertussis vaccine, a tragedy by any definition, which led to a 1975 halt in Japan's vaccination program. And that contributed to an even larger tragedy from 1977 to 1979: a pertussis epidemic that killed 41 people. Pertussis, in case you didn't know, is whooping cough, a funny name for something that kills children and doesn't have to.

Japanese scientists took the lead in developing even safer pertussis vaccines, which was sound research in a good cause, and I'm happy to talk about that, too. What I am not happy about are pages upon pages of increasingly vituperative insinuations that vaccines are poisoning millions of people, giving them cancer and fatal diseases, and that pharmaceutical companies and the medical establishment are standing around snickering while it all happens. Readers of the comment sections of the recent posts here will recognize what I'm talking about.

These accusations are, of course, untrue, and their entertainment value is beginning to erode. I am not interested in debating them, any more than I am interested in debating the details of Scientology or the supposed activities of noctural alien proctologists. Now, it is anyone's right to stuff their own head with whatever debris they choose, and it's even their right to urge others to do the same. But you don't get unlimited room to do it here. I strongly urge anyone who feels irresistible impulses to post thirteen-page comments in this vein to get their own blog and generate their own traffic.

I'm talking about etiquette, not censorship. I will continue, naturally, to let anyone post comments that disagree with my own opinions. But gigantic screeds are another thing entirely. If you have some of those to get off your chest, feel free to post a brief overview and a link. Send people to your own site, and enjoy the visitors.

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June 14, 2005

The Research Exemption Lives!

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Posted by Derek

The Supreme Court has ruled on the Merck/Integra case that I wrote about here last month, and reversed the most recent lower court ruling. And I'm glad to see it. This all turns on a 1984 change in the patent law, called 271(e)(1) for short, which says, broadly, that it's not an act of patent infringement to make or use a patented invention during its patent term "solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs. . ."

Justice Scalia wrote the unanimous opinion, a PDF of which which is available from this list of recent decisions. It covers the issues thoroughly and concisely, and if you're really into this stuff you'll want to read the original. But here's a summary, if you're not up for 17 pages of opinion (which isn't as bad as it sounds, considering the Supreme Court's traditional paper margins):

The Court found it apparent that 271(3) was designed to exempt all uses of patented inventions that were reasonably related to the development and submission of any data under the Federal Food, Drug and Cosmetic Act (the FDCA, which established the FDA.) Said Scalia, "There is simply no room in the statute for excluding certain information from the exemption. . ."

Integra argued that "the only preclinical data the FDA is interested in is that which pertains to the safety of the drug in humans," and that broader studies on mechanism of action, PK, etc. weren't meant to be exempt under 271(e). But Scalia noted that the FDA requires summaries of all these studies when an Investigational New Drug application is filed, and that these are necessary to assess the whole risk/benefit question of whether a human clinical trial should be allowed.

Integra's counterargument to that is that Merck's experiments are disqualified from the exemption, because they weren't conducted under the FDA's Good Laboratory Practices (GLP) protocols, and thus weren't intended for regulatory use. But the Court cited the law as showing that GLP studies are only required for safety assessments, and that earlier work (on mechanism, efficacy, PK, etc.) doesn't have to be run under GLP. (And they want to see non-GLP safety studies, too, if you have them, along with an explanation for why they weren't run under the protocols.)

The Court of Appeals for the Federal Circuit, when they ruled for Integra, found that the Merck/Scripps experiments "did not supply information for the FDA, but instead identified the best drug candidate to subject to further clinical testing. . .The FDA has not interest in the hunt for drugs that may or may not later undergo clinical testing for FDA approval. . .Thus, the Scripps work sponsored by Merck was not solely for uses reasonably related to clinical testing for the FDA."

The Court rejected this line of argument, which, as Scalia writes:

". . .disregards the reality that, even at late stages in the development of a new drug, scientific testing is a process of trial and error. In the vast majority of cases, neither the drugmaker nor its scientists have any way or knowing whether an initially promising candidate will prove successful over a battery of experiments. That is the reason they conduct the experiments. . . We decline to read the "reasonable relation" requirement so narrowly as to render 271(e)(1)'s stated protection of activities leading to FDA approval for all drugs illusory.

. . .the use of a patented compound in experiments that are not themselves included in a "submission of information" to the FDA does not, standing alone, render the use infringing."

Scalia and the court are completely right here, as far as I'm concerned. Drug companies constantly make each other's patented compounds for comparisons against their own, and if 271(e)(1) was interpreted as the CAFC had it, we'd be constantly second-guessing ourselves about whether we'd infringed or not. It would slow down the development of new drugs, without a doubt, and in some cases it would bring preclinical programs to an immediate halt while licensing issues were thrashed out. Which they might never be - why should a company give a competitor a license to try to beat its patented compound? Better to go tell them to grit their teeth and wait for the patent to expire.

But that's not going to happen. We're back to the "research exemption" as we've understood it, and that's a good thing.

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May 2, 2005

Merck and Integra Go the Distance

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Posted by Derek

As many readers will have recognized, I was speaking yesterday about the suit between Merck KGaA and Integra. This one has been going on for nearly ten years now, and is a bit of a mess, but here comes the short version:

In the early 1980s, researchers at the Burnham Institute in La Jolla discovered the so-called "RGD peptides", named for the single-letter amino acid sequences they share. These bind to cell-surface receptors called integrins, which are important in a variety of processes that involve cell adhesion. Blood clotting, wound healing, bone growth, and the invasiveness of some cancer cells all have integrin components. The Burnham group formed a company, Telios, and licensed their patents to it. (Later on, Integra bought the rights from Telios, which is where they enter the picture.)

Merck (Darmstadt) and several other companies also became interested in integrins. In the mid-1980s, Merck collaborated with a group at Scripps (also, as fate would have it, in La Jolla), who showed the potential of blocking some integrin subtypes as a method for inhibiting angiogenesis in tumors. (Yep, anti-angiogenic therapies have been in the works for that long.)

Burnham sued, claiming that use of three key RGD peptides by Merck and Scripps violated their patents. (Licensing discussions had fallen though.) Merck fought back by claiming that their work came under a "safe harbor" provision of patent law, by which companies can do research needed for FDA approval of a drug even if that work actually infringes other patents. A District Court jury awarded Integra $5 million in 2000, later reduced, and Merck appealed. The Federal Circuit Court didn't buy Merck's reasoning, either, and ruled that the safe harbor language wasn't meant to extend that far back into early drug discovery and lead identification. (A longer discussion of that ruling can be found here.)

Merck appealed again, and the Supreme Court agreed to hear the case. That's unusual; most patent disuputes don't make it past the Federal Circuit. But the court seems to think that the safe harbor language is both ill-defined and important enough to deserve their attention, and I think that they're right. Merck (and several other drug firms who've filed friend-of-the-court briefs) argue that if the safe harbor provision is defined that narrowly, then big swaths of drug research are going to have to either come to a halt while patents are hashed out, or it'll just up and move to some country that doesn't respect the IP.

Meanwhile, Integra (and other companies who've lined up with them) say that if the law were interpreted according to Merck, then there would be no incentive to companies to search for and patent new research tools. After all, if you could claim the FDA exemption for anything that might end up leading to a drug - that is, anything that might lead to someone making some money - then what's the point?

Oral arguments took place on April 20th. I'm going to bet that the decision will split hairs in such a way as to not shake things up too drastically (as the court did in the Festo patent law case), but I'm glad I'm not betting with the kind of money that Merck and Integra are.

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May 1, 2005

Between Friends. Sort of.

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Posted by Derek

There's a patent issue that I've been meaning to write about for a week or so. All I have time to do tonight is set the stage for it.

Let's say that Company A has an interesting compound, a clinical candidate that's moving along and showing interesting activity. It's out there in the patent literature, and they've spoken about it enough to release its structure. Naturally, the competition is interested. Can Company B make themselves a batch of the compound to see how good it really is?

Well, I hope that the answer remains "yes", because we do that sort of thing all the time. We're always sizing up the competition, and they're doing to same to us. It's not unheard of for scientists with friends at other companies to get calls from them saying "How come you people say that your compound does so-and-so? It sure doesn't for us, you losers!"

What if Company B wants to use Company A's compound to do a little bit more for them, though. . .like, say, serve as a crucial ligand in a screen of their own compound library? And what if Company B uses those results to eventually discovers a fine drug candidate of their own, one which, arguably, they wouldn't have found at all without the use of Company A's chemical matter? Is there a problem here, or not?

Well, the Supreme Court has ended up with a case that bears on just these sorts of questions, so later on this year we can expect to all be enlightened, enraged, or just plain baffled. More on this tomorrow. . .

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March 15, 2005

Back For More

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Posted by Derek

Well, I'm back from my undisclosed location, ready to see what's been going on at work the past couple of days. I passed the site on the highway on the way home this evening, so I know that it's at least still there. The side of the building containing my lab was still intact, which is always a good sign.

What passes for normal blogging around here will resume shortly. For now, I wanted to point out this article from Matthew Herper at Forbes, who asks the inflammatory question: "Are Drug Patents Too Short?" His point, a valid one, is that clinical trials have tended to get longer, larger, and more expensive, while patent lifetimes aren't changing. And once a drug is off patent, no company is likely to spend the money to study it with much intensity.

The thing is, a patent extension for drug companies has, as Herper well knows, zero chance of being enacted. There are arguments for and against the idea, but we wouldn't even get that far. The inflatable bats and cream pies would come out immediately, and we'd set in dealing with this issue in the time-honored fashion. . .

The other solution is to make the clinical trials shorter and less painful, which is what the whole biomarker idea is aiming to do. So far, though, there's not much to point at in that field, but these are early days.

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February 16, 2005

Dysfunctional Disclosure

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Posted by Derek

I spent the last part of the day wrestling with a competitor's patent application, trying to decode the darn thing, so I won't be sitting here looking at this monitor for very long tonight. There's a "best mode" requirement in patent law, where you're supposed to disclose the best way you know of to realize your invention, but there's no requirement that you have to make it easy to find. Plenty of drug companies bury their gems in truckloads of patent gravel.

I have to say, after looking through a lot of recent applications, that I think that the amount of disclosure needed to show utility should be increased. You see patents claiming structures of (this kind, insert vague generic structure that claims things out to Neptune), as inhibitors of (reverse whateverase, ya-ya kinase, etc.) for the treatment of what ails you. Fine by me. But shouldn't you have to put in some real numbers from your "reverse whateverase" assay (or, uh, whatever?)

Some people do, and good for them. And many other companies get around disclosing too much by assigning little plus-mark symbols for levels of activity, and then giving a table of compounds with one, two, or three plus marks next to each compound. That's just very slightly better than nothing, but it's an open book compared to the bozos who spend the last twenty pages of their applications describing, in horrible detail, every step of every assay they can think of - and then mention, offhandedly, that the compounds of this invention were tested in these assays and were found to be, you know, active and stuff. Should the patent offices of the world really let people get away with that one?

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February 3, 2005

Elbow Room

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Posted by Derek

I mentioned going through the scientific literature yesterday - it's only when you start on a deep search that you realize what huge swaths of chemical space are covered by patent claims. Of course, just about every word in that sentence needs some clarification.

"Chemical space", the universe of possible structures, is of course gigantic. Even if you confine yourself to the basic elements of organic chemistry - carbon, hydrogen, nitrogen, oxygen and sulfur - you still end up with insane numbers, with ten-to-the-sixtieth-power being one of the orders of magnitude being tossed around. Clearly, in a number that size you could lose all the chemical compounds prepared so far in human history and never see them again.

Plenty of those compounds are found (only) in the patent literature. But chemical patents typically claim much, much more territory than they ever exemplify. I spoke about this last spring.) As I mentioned then, those huge claims don't mean all that much when it comes to spraying down the area against competitor patents. If you want to know more, heaps more, about patentability in these situations, try this section of the US Patent Office's Manual of Patent Examining Procedure. It's an illustration in prose of what the phrase "grind to a halt" is supposed to convey, but I regret to admit that I've read the whole thing.

Back to the outer reaches of chemical space: I'd be in violation of my medicinal chemistry club pledge if I didn't point out that big swaths of it are a priorialmost certainly useless for drug discovery. Molecules can be too big, too polar, too greasy, or too rock-like to ever be of any medicinal use. That much everyone agrees on, but when you start to apply numerical cutoffs to those ideas, the arguing starts. More on this next week.

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February 1, 2005

Merck Takes Another One

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Posted by Derek

A lot of people at Merck must be wondering just exactly what they're being paid back for. If you'd sat down a couple of years ago and tried to come up with a doomsday timeline for Merck, you couldn't have done much better than what's actually happened. The latest is Friday's ruling (PDF) that Merck's patent for a weekly dosing formulation of their osteoporosis drug Fosamax is invalid. That's their second-biggest selling drug - the biggest, Zocor, is coming off patent next year, don't you know.

Teva, a generic powerhouse, already has an application in to sell Fosamax (alendronate) in 2008, when the original chemical matter patent expires. But the biggest-selling form of the drug is the weekly dose, and Merck had (so they thought) wrapped up patent protection on that one until 2018. They'd won a round in the District Court in 2003, which found that Teva's application infringed on the Merck formulation patent. But Teva appealed, and the Court of Appeals for the Federal Circuit, to Merck's dismay, reversed the District Court ruling.

That doesn't leave Merck too much room, as I understand it. The Supreme Court doesn't take many patent cases - the last one, I think, was the Festo appeal, and that dealt with more fundamental questions of patent law. This, unfortunately for Merck, just looks like another patent fight, and as such I'd be surprised if the Supreme Court agrees to hear it.

One of the grounds for reversal is an obviousness argument against Merck's patent, based on a 1996 article in a trade publication on the desirability of a weekly dose of alendronate. The other reversal argument comes down to the interpretation of a single word in the original patent claims. Merck claimed a method for treating osteoporosis by administering "about 70 mg" of the compound once weekly, and a method for preventing it by administering "about 35 mg" of the compound weekly. Based on other language in the patent, the District Court believed that this "about" language was an attempt to take into account the different salt forms and formulations of alendronic acid, in order to deliver the exact 35 or 70 mg of sodium alendronate. Teva's application was for 35 and 70 mg dosages, and they were held to infringe.

The CAFC, noting that Merck had acted "as its own lexicographer", pointed out that this would mean that "about 35 mg" now was being held to mean the same thing as "exactly 35 mg.", Noting the weirdness of this, they sharply yanked the definition back to the more commonly accepted one. Teva is now in the clear, and Merck (who probably hoped to throw the largest shadow they could with that adjective) finds themselves in trouble.

There's a testy dissent to the ruling (also in that PDF file above), which the majority opinion describes as ". . .pursuing a philosophical argument as to the deference which should be given to the trial court. Claim construction being a legal matter it is reviewed de novo and this is still the law notwithstanding the desire of some members of this court to consider creating an exception to that rule." Perhaps Howard Bashman has some background on this intra-judicial elbow-throwing. The Patent Law Blog has some comments, too, along with a more technical discussion of the case than I've given here.

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January 10, 2005

Success Has A Thousand Fathers

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Posted by Derek

Over at Uncertain Principles, Chad Orzel's commentators got into a discussion of how you list people in a large multi-author publication. My system is that the first author and the last author are the people who did most of the work and/or were in charge. It's worth amoment to think about the gap that can open up between those two descriptions. Between those bookend names, I've opted for alphabetical order when I've written or helped write papers, because the alternative is an institutional-sized easy-open pressurized Can O' Worms.

Assigning credit in a scientific project is an awful job. Multiple people will be sure that they thought of an idea first and that everyone else just borrowed it from them. Some people will be livid at how others on the team got by without seeming to ever contribute anything, while they carried the whole project on their backs. Meanwhile, some of that latter group will be furious at the first ones, who from their perspective got to do the easy stuff that generated all the cheap and flashy results while they labored in the salt mine.

Sometimes these things can be resolved by enough tedious effort, but most of the time they can't. And it's almost always not worth the effort - at least for a journal article. Now, for a patent, things are very different, as one of Chad's commentators rightly points out. Everyone listed on a patent has to be able to state clearly what their contribution to the invention was. If you can prove that a patent has people on it that did not contribute (or left out people who did), you can get the thing invalidated. That's not easy, but it has happened, and the mere threat is enough to make everyone take inventorship pretty seriously.

My quick-and-dirty test for inventorship has been to tell people to ignore the whole draft of the patent application except the claims. Go straight to those, and find something there that you thought of, and be ready to point to it. Ideally, you should check to make sure no one else is going to point to the same thing. Best are the things that you thought of first and were also the first to do. No one can take that away from you.

Next best are the things that you thought of first and handed off to someone else to accomplish - if they didn't add anything to your idea, you're probably an inventor and they certainly aren't. Being the first one to try someone else's idea in the lab doesn't mean much in inventorship terms, and quite rightly. Now, if the person you handed things off to added something meaningful, you may both be inventors, which is were things can become interesting. Sometimes the original idea has been mutated so thoroughly that the final claim is really the work of the second person, with nothing recognizable from the first one.

I tell people who work for me that if they want to be on the patents coming from our lab, they'd better have some ideas of their own to show when patent-writing time comes. Naturally, I try to fulfill my end of that deal by letting people work on their own stuff as much as possible. The only way we can end up in trouble is if we pick a total-loss part of the molecule to work on and end up with nothing worth including in the patents. You want to keep a sharp eye out for that situation, and be ready to steer yourself (and your lab) out of it.

Comments (1) | Category: Patents and IP | The Scientific Literature

December 13, 2004

Fixing the Drug Industry?

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Posted by Derek

I had a post ready to go tonight, but we'll roll that one over to tomorrow. I'd suggest that if you're interested in patents and their place in the drug industry (and hey, who isn't, right? Uh, right?) that you trot over to the new Becker/Posner blog for a discussion of the topic. (Permalinks are here and here.)

Both of them have an excellent understanding of the issues involved, commensurate with their reputations. Gary Becker leads off by examining several possible reforms, but has some reservations:

"To be sure, a patent system creates a tension between the effect that prices well above costs of production have in reducing the use of drugs by sick persons, and the effect of high prices in helping companies recoup their large R&D spending. This tension is the cause of the increasing attacks on drug companies as more blockbuster drugs have been introduced during the past couple of decades. So an important public policy question is whether we can do better than the present patent system? I believe we can improve how the system operates in many ways, but some suggestions are likely to make matters worse rather than better."

Richard Posner's suggestion is to actually shorten patent terms a bit. His reasoning:

"Against this it may be argued that the fact that the drug companies apparently do not have excess profits show they need every bit of patent protection they have. Not necessarily. Competition for a profit opportunity may transform expected profits into costs. Suppose the drug companies believe that the invention of some new drug will yield the successful inventor a $1 billion net profit. The prospect will induce heavy expenditures on being first (the aggregate expenditures may actually exceed $1 billion). The result is that none of the companies, or the industry as a whole, may have abnormal profits. Now suppose that as a result of a shortening of the patent term, the prospect for the successful inventor is for making only an $800 million profit. Less will be spent on the patent race. Yet consumers as a whole may be better off, because the investment saved may have greater value elsewhere in the economy. The entire patent “prize” goes to the firm that crosses the finish line first, and so a firm might spend a huge amount of money to beat its nearest rival by one day even though the value to the public of having the invention one day earlier might be negligible. This danger is greater, the bigger the prize. Shortening the patent term would reduce this potential waste by reducing the revenue from a patent; it would also reduce the transaction costs of licensing, because more inventions would be in the public domain."

My worry about this idea is that the prices of drugs discovered under this system would rise to make up the difference in the patent term, making the "prize" about the same size as before. Complaints about price-gouging would only increase, and I fear that we'd end up in worse shape than before.

I like a couple of Becker's suggestions better: he would like to consider the idea of offering prize money instead of patent protection for diseases with the greatest impact on public health (here's a detailed proposal, on which more later), and he's also in favor (PDF) of loosening the FDA's efficacy requirements and turning drugs out on to the market after proving safety.

Steve Postrel of SMU tried to persuade me of that last idea a couple of years ago, and I wasn't having any. But I'm slowly coming around to it, although my original objections are still somewhat in force - namely, that it could be an open invitation to snake-oil salesmen (which would only pollute the whole industry's reputation - I know, like it's so clean right now), and that any such regulatory change would have to be coupled with some kind of tort reform. Even with all the FDA-mandated testing we have now, the trial lawyers flense the flesh from our bones when anything goes wrong. See Exhibit A, over there in Rahway.

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November 15, 2004

Keep It To Yourself

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Posted by Derek

I've mentioned how patentability can be ruined by any sort of prior publication, but - since we're talking about the law, after all - there's always room to argue about what a "publication" might be. That's been clarified a bit by the recent In re Klopfenstein decision, available herein all its legal glory as a Word document.

Carol Klopfenstein and John Brent filed an application in 2000 for a method to lower cholesterol and increase HDL by including soy cotyledon fiber in food. They appear to have had an improved method for producing and using the substance. No problem there - patents are filed all the time for methods like that - but it turned out that their invention had been the subject of a poster presented at the American Association of Cereal Chemists meeting in 1998. The poster had no printed handouts to go along with it, and was displayed for about three days. Unlike many such poster sessions at meetings, it wasn't catalogued or indexed in any publication. Later that year, the same poster was displayed for an afternoon at Kansas State.

And on that basis, the PTO turned down their application, saying that this was a public presentation. Klopfenstein and Brent appealed the examiner's decision, but it was no dice. Said the court:

"The factors relevant to the facts of this case are: the length of time the display was exhibited, the expertise of the target audience, the existence (or lack thereof) of reasonable expectations that the material displayed would not be copied, and the simplicity or ease with which the material displayed could have been copied. . .Upon reviewing the above factors, it becomes clear that the (poster) was sufficiently publicly accessible to count as a "printed publication". . .The reference itself was shown for an extended period of time to members of the public having ordinary skill in the art of the invention behind the '950 patent application. Those members of the public were not precluded from taking notes or even photographs of the reference. And the reference itself was presented in such a way that copying of the information it contained would have been a relatively simple undertaking for those to whom it was exposed-particularly given the amount of time they had to copy the information and the lack of any restrictions. . ."

This doesn't surprise me, because in the drug industry there's no way that we would show a poster on anything before the patent application had been filed. We err on the side of caution. But if you're an inventor and wants to live dangerously, there are still ways to be a disclosure daredevil: for example, if this poster had only been displayed for an afternoon, it might well not have counted. A disclaimer that they didn't want the information on it copied would have done the trick, although I have to say I've never seen one of those in a poster session. And if the key data had been buried inside the presentation in a way that was difficult to comprehend and copy (and man, have I ever seen some posters that fit that description), that might have slipped by, too. But it was out there too long, too openly, and with no reason for anyone not to copy it.

That hasn't stopped some law firms from issuing ominous-sounding releases about how the courts are trampling on the patent rights of individuals. But that's ridiculous. Here's a free clue: if you want to patent something, you should avoid writing it on a big piece of posterboard and showing it off to anyone who walks by.

I do have one question, though, which I haven't seen answered in any of the accounts of this case that I've read: how was the AACR poster brought to the attention of the Patent and Trademark Office if there was no record of it? I'm sure there's a good explanation; I just don't know what it might be.

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November 14, 2004

I'll Have the Lot

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Posted by Derek

Thanks to the Patnews mailing list, I was made aware of an alarming patent application from Genentech (WO2004060270, for intellectual property aficianados following along at home.) It's pretty unremarkable, if you just look at the front page. Two inventors, and a bland one-sentence abstract: "The present invention is directed to compositions of matter useful for the diagnosis and treatment of tumor in mammals and to methods of using those compositions of matter for the same."

Generic as can be - that sentence would do, if you were pressed for time, for any of several hundred patent applications that come out every year. Walking around the patent landscape, you'd never stop to pick that one up. But just try it. . .hmmm, seems to be buried in the ground a bit. Dig around, and it's larger than you think. . .you're going to need a shovel to get this thing out. As you go on, this nondescript little pebble turns out to be a bump on the anchor of an entire buried aircraft carrier, and a fleet of diesel-powered backhoes aren't going to be enough to unearth it.

This is just how you feel if you're foolish enough to try to download this thing. My company subscribes to a service called Micropatent, which for a fee gives you access to just about every application and issued patent you could want. Check-mark this one and they cheerfully inform you that it's five thousand and fifty-four pages long. Better make sure that the printer is still under a service contract.

It turns out that this behemoth contains over four thousand gene sequences, presumably the compositions of matter that they're talking about. Now, this would have (almost) made sense eight or ten years ago, in the land-rush era of genomic sequencing. People were flooding patent offices with all kinds of flimsy applications as soon as they got an open reading frame. But a few years ago, the various authorities began to tighten up on this sort of thing.

They wanted to see a lot more enablement of the claims that were coming in - no longer could you say: "I claim gene sequence ATCGAAGTA, etc., and all the diagnostic methods for whatever diseases turn out to be associated with it and any treatments that make someday make use of it and whatever else might end up turning a buck, that too." But that looks like just what Genentech is saying here. The patent has a priority date of October 2002, long after this kind of nonsense was supposed to have packed up.

What's going on? It's no afternoon's work, putting together a five-thousand-page application, and prosecuting it is going to get pretty expensive for a practical joke. I have to presume that they have a reason, but it's hard to see what it might be. The only thing I can think of is that they want to spray down all of these sequences as prior art.

Perhaps Genentech has an idea that there are some useful things in this haystack, but no way to be sure which ones they are. They know, appearances aside, that it's not 1994 any more, and they won't be able to get real patent rights for such a fishing expedition. So if they can't own them, well, here's the way to make sure that no one else can, either. Publish 'em openly, and they're non-patentable. The only problem is that no journal would accept a paper with a title like "Forty-Five Hundred Gene Sequences That Might Be Of Use Someday", with five thousand pages of supplementary material. Heck, they wouldn't have even taken that in 1994.

But the patent office will take it. They'll take most anything if you pay the filing fee, and the application will publish in a year or two no matter how hideous it is. It'll be interesting to watch the prosecution of this one. It's hard to imagine that Genentech is seriously going to take thing thing on and let it nationalize. Nope, my bet is that they're just going to drop it. The mission has already been accomplished.

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November 11, 2004

Alexander Would Have Understood

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Posted by Derek

You'd think that by now most reasonably simple chemical structures would have been explored, but it's funny how many untouched areas still exist. I was looking at one the other day, which I certainly can't specify, but it surprised me that such a small "drug-like" template hadn't been worked on. I expected to see a message like "1097 substances, displaying 1-25" displayed in SciFinder - the chemists in the audience will know the kind of search results I mean.

It's things like this that keep us in business, from a patent perspective. But patentable chemical space isn't a renewable resource. There are already large areas where it's basically impossible to get coverage - try for some reasonable indoles, piperazines, or imidazoles, for example. You'll have to get fairly baroque in the side chains before you'll find any uncleared territory.

We use up big chunks of intellectual-property real estate every year. Even when a patent expires, it's prior art forever, and that goes for publications of all kinds. (A recent court case established that even rather obscure and limited poster presentations are public disclosures sufficient to make their contents unpatentable.) When will we run out of frontier? And what will we do then?

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October 22, 2004

Hey, I Could Patent That. . .

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Posted by Derek

I'll finish up the week with something a bit out of my usual range. I talk about patents and intellectual property around here from time to time, and it's easy for me to think of pharmaceutical patents as the centerpiece of the whole system. They're important, but it's good to be reminded that there are a lot of other things that people feel are worth claiming.

A lot of other things. . .via Greg Aharonian's patent mailing list, I present for your perusal US Patent 6,805,663, freshly issued as of October 19th. If you have a TIFF viewer plugin for your browser (or are using a Mac with a recent version of QuickTime), you can see the images for this patent. I'm not sure if this direct link will work, but it's worth trying for the front page drawing to see if you can figure out what it's for. Believe me, you can't. (UPDATE: that link doesn't work very well, but courtesy of the deviants at Fark.com, here's a link to a PDF of the patent drawings. But you still won't be able to guess what's going on.)

Give up? Here's the full text, which should make everything clear. Why, it's a "Method of Shared Erotic Experience and Facilities For Same," of course. The claims and specifications make this the first patent I've encountered that I would be uncomfortable reading aloud in public.

The inventors appear to be a husband-and-wife team from California, and they must be a fun couple indeed. What I find particularly interesting is their description of the prior art. They actually cite 10 relevant patents, which means that there's a whole world of intellectual property I'd never dreamed of. Here's hoping that none of us have inadvertently infringed any of these.

Actually, there could be a pharma angle to all this. Note that the facility theyre describing includes some sort of concession stand. Perhaps this is a marketing opportunity in the vicious promotional fight between Viagra, Levitra, and Cialis! I can imagine blue- or purple-painted domes, with a helpful MD distributing free samples. . .but then, I have a pretty good imagination. But not as good as the folks who came up with this patent.

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August 25, 2004

Will the Uncommon Work for the Common Good?

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Posted by Derek

Yochai Benkler of the Yale Law School has an interesting policy article in a recent issue of Science. It's on the "Problems of Patents", and he's wondering about the application of open-source methods to scientific research. He has two proposals, one of which I'll talk about today.

In some sort of ideal world (which for some folks also means Back In The Good Old Days of (X) Years Ago), science would be pretty much open-source already. Everyone would be able to find out what everyone else was working on, and comment on it or contribute to it as they saw fit. In chemistry and biology, the closest things we have now, as Benkler notes, are things like the Public Library of Science (open-source publishing) and the genomics tool Ensembl. Moving over to physics and math, you have the ArXiv preprint server, which is further down this path than anything that exists in this end of the world.

Note, of course, that these are all academic projects. Benkler points out that university research departments, for all the fuss about Bayh-Dole patenting, still get the huge majority of their money from granting agencies. He proposes, then, that universities adopt some sort of Open Research License for their technologies, which would let a university use and sublicense them (with no exclusivity) for research and education. (Commercial use would be another thing entirely.) This would take us back, in a way, to the environment of the "research exemption" that was widely thought to be part of patent law until recently (a subject that I keep intending to write about, but am always turned away from by pounding headaches.)

As Benkler correctly notes, though, this would mean that universities would lose their chance for the big payoff should they discover some sort of key research tool. A good example of this would be the Cohen/Boyer recombinant DNA patent, licensed out 467 times by Stanford for hundreds of millions of dollars. And an example of a failed attempt to go for the golden gusto would be the University of Rochester's reach for a chunk of the revenues from COX-2 inhibitors, despite never having made one. (That's a slightly unfair summary of the case, I know, but not as far from reality as Rochester would wish it to be.)

That's another one I should talk about in detail some time, because the decision didn't rule out future claims of that sort - it just said that you have to be slicker about it than the University of Rochester was. As long as there's a chance to hit the winning patent lottery ticket, it's going to be hard to persuade universities to forgo their chance at it. Benkler's take is that the offsetting gains for universities, under the Open Research License, would be "reduced research impediments and improved public perception of universities as public interest organizations, not private businesses." To compensate them for the loss of the chance at the big payoff, he suggests "minor increases in public funding of university science."

Laudable. But will that really do it? As far as I can tell, most universities are pretty convinced already that they're just about the finest public interest organizations going. I'm not sure that much need for good publicity, rightly or not. And Benkler's right that a relatively small increase in funding would give universities, on average, what they would make, on average, from chasing patent licensing money. But show me a university that's willing to admit that it's just "average."

The problem gets even tougher as you get to the research departments that really aren'taverage, because they're simultaneously the ones with technologies that would be most useful to the broader research community and the ones with the best chance of hitting on something big. I'll be surprised - pleasantly, but still very surprised - if the big heavy research lifters of the world agree to any such thing.

Comments (4) + TrackBacks (0) | Category: Academia (vs. Industry) | Patents and IP

August 24, 2004

Living by the IP Sword

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Posted by Derek

Back when I was in graduate school, we didn't have these here fancy automated literature searches here. So I had to find out in the old-fashioned way that the molecule I was working on had just been synthesized (first) by someone else: by picking up the library's latest issue of the Journal of the American Chemical Society (in its old grey-covered era) and coming across it in the table of contents.

Not a fun moment. I gave a muffled shout and started paging frantically to the article. And yep, there was another research group's total synthesis all right. The only consolation was that they weren't doing it the way that I was, and my route was better. Allegedly. After this, my attitude was "The world does not need another synthesis of rosaramicin. But I do."

Now that I'm in industry, I don't fear the open literature so much. I fear the patent literature. Whenever a drug company starts serious work on a chemical series, it puts out a sieve of automated searches for the core structure and all its close relatives. If you're ripping off someone else's known structure, which we all do from time to time, then you really spend a lot of time looking over your shoulder. These searches usually run once a week, and you want to see a comforting "0 results" come up, which tells you that you're still in the clear. Sometimes you're in the middle of the road, though, with the high-beam headlights bearing down on you. Most people with pharma experience have had a chemical series (or a whole project) yanked out from under them because it turns out that someone else was already working on it.

I can think of at least one case where it turns out that my group and a group at another company had stumbled across the exact same chemical series, and we were both working away at it at exactly the same time. Neither of us knew it at the time, of course, but when the patent applications published, everything became clear. We'd filed our applications with a few weeks of each other. And neither project was taking off from a known compound in the field; we'd apparently each discovered our leads through random screening. Makes you wonder about how much overlap there is between company screening collections. . .

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July 18, 2004

Back for More

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Posted by Derek

I've spaded through the heap of e-mail at home and at work, and I'm ready to get going again. My lab is on another new project, which means that I need to clear my desk of the piles of notes and papers from the last one. Some of those will go into the permanent files, while others will go into the handy recycling box. Rather more of the latter, actually.

Here comes another class of molecules that I've never worked on before, but to judge from the torrent of hits that I get from literature searches, they've had plenty of admirers. It's the exact situation I spoke about recently: we've got to carve out some patent space and hope that it overlaps with the space of active compounds. There are whole classes of structures that we're probably not even going to bother looking at, because it's clear that we can't own a position there.

Really significant effort goes into such contortions. I can't imagine what a pharmaceutical world without chemical intellectual property would feel like, but it sure would be less complex for people like me. Mere anarchy would sure enough be loosed: just make whatever you want to, and go where the assays tell you. But I can't imagine how you'd make it pay, either, which is why we're in the world we're in.

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July 6, 2004

Lighting Out for the Frontier

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Posted by Derek

Next week I'll be on vacation, and this week I find myself flogging the chemistry databases. We're looking at a new series of compounds with some interesting activity, and they're easy to make. That's the problem.

They're so easy to make that everyone has made them. That means trouble, because there's so much prior art (and so many potentially interfering claims) that we'd have a difficult time getting a patent position. There are quite a few popular structural classes with this problem: piperazines, indoles, and imidazoles have been trampled flat, for example, and try getting (for example) a claim in some of the benzofuran compound space that Lilly has staked out. Not fun.

So we're looking to change the inner parts of the structure in some non-obvious way and thus stake out a position with some elbow room in it. It's not easy - for one thing, things are to the point that some of the obvious paths to elbow room have already been worn out a little. And you don't want to come up with new ones that are going to take fourteen steps to make, either. That's because it's unclear whether the interesting activity that got us here will persist once we start chopping and rearranging.

Often it doesn't. You feel like a real idiot - even if you aren't - when you spend a lot of time on a series like that and none of the compounds are active. And you feel as if you've wasted our time, because you have. "Fail quickly" is one of the basic mottos of medicinal chemistry.

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June 3, 2004

Doublets, Triplets, Whateverlets

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Posted by Derek

Another day spent rooting around in the archives, trying to appease the rapacious Taiwanese patent office. One more day should about do it, and not a moment too soon. I'm now unearthing NMR spectral data for compounds, and translating those to print is not enjoyable.

For those outside the field, an NMR spectrum of a typical organic molecule is a rather complex linear plot of multiple lines and peaks. After staring at it a while, it gets rendered into text as something like "1.63, t, 3H; 2.34, s, 3H; 3.1 - 3.39, m, 4H. . ." In plain text, that's "At 1.63 and 2.34, there are a triplet signals that represent three protons each, and between 3.1 and 3.39 there's a messy multiplet that adds up to four protons' worth. . ."

If you really want to get into it, you list the coupling constants, the spacings between the individual peaks of those triplets and etc. No thanks. A typical spectrum will go on for a reasonable paragraph in this way, and the Taiwanese would like nothing better than several pages of this sort of thing, or so they maintain. What they'll is get as much as I can stand.

I'll try to lead off next week with a discussion of today's news about everyone's pal, Elliot Spitzer, and his suit against GSK. It's a wide-ranging topic, and there wasn't enough time to wrestle it to the ground today.

Comments (2) + TrackBacks (0) | Category: Analytical Chemistry | Patents and IP

June 2, 2004

This Isn't the Kind of Office Action You're Thinking Of

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Posted by Derek

I've had enough staring at the computer monitor for one day, so this will be short. I've been dealing with an "office action" from Taiwan's patent office. They're reviewing an application on which I'm the lead inventor, so this one lands on my desk. Taiwan isn't a member of the Patent Cooperation Treaty; you have to file a separate application. And they have their own standards, which they lose few chances to demonstrate.

According to their examiner, we need to provide more biological data and more chemical characterization data for the compounds in the patent, which is not particularly enjoyable since these compounds were all made three or four years ago. Everyone in the drug industry is supposed to have data handling systems that make such queries light and breezy, but just try putting them to the test. It's all there, but you have to know which rock it's hiding under. And the numbering of the compounds in the patent is totally different from any of the numbering schemes used in our record keeping, and so on. You know the sort of thing.

The data provided have been perfectly acceptable to the patent offices in Europe and the US so far, but that cuts no ice in Taipei. I'm just glad that the other non-PCT countries don't engage in this sort of thing. Separate office actions, one after the other, from the likes of Peru, Pakistan, Thailand and Venezuela would probably push me over the edge. Like Taiwan, though, they have their own special application paperwork, which is enough of a racket as it is.

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May 19, 2004

All the Myriad Ways

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Posted by Derek

Closely related to the patenting of biochemical pathways is the patenting of genes. I'm not completely thrilled with that, either, but it still makes a bit more sense to me. With these patents, you own the gene and uses for it, but you don't get to claim everything else downstream of it (like the protein it codes for!) In the first genomic gold rush, the USPTO was swamped with gene applications, and granted quite a few of them without too much in the way of defined utility. Since then, they've tightened up, and you're really supposed to spell out what a gene is good for in order to patent it. Generally, that means using the gene as the basis for a diagnostic test.

In that vein, Myriad Genetics holds lucrative patents on the BRCA1 and BRCA2 breast-cancer susceptibility genes (background here), on which it makes plenty of diagnostic revenue. But it's been losing protection in Europe. Earlier this year, they lost their European patent for BRCA2, and now their BRCA1 patent is history, too.

In general, it's harder to get and hold on to such patents with the European Patent Office, but these decisions seem to have been taken on good old prior-art grounds rather than any finer points. It turns out that a British cancer charity research foundation had applied for BRCA2 before Myriad, which would seem to indicate that the latter's patent never should have even been granted. As for BRCA1, New Scientist reports that the Myriad amended their claims for it in 1995, correcting a few base pairs months after their first filing, during which time the sequence was published in the open literature. Whoops! Can't get a patent after that happens.

Myriad seems to have pretty much given up on the European market for these patents some time ago, what with all the legal trouble. But you have to assume that they're going to continue to pump the US market for all it's worth. Meanwhile, Canada (well, Ontario at least) is just ignoring these patents, according to the New York Times.

A question now is whether Myriad's claims are going to hold up over here. If this were a high-level question about the patentability of genes, the arguing could go on for a long time. But if we're just talking prior art, then it just comes down to some relatively simple issues: are their filing dates just as hosed up here, or not? And even if they are, is there anyone motivated enough to challenge them?

Comments (14) + TrackBacks (0) | Category: Cancer | Patents and IP

May 16, 2004

Owning the Road

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Posted by Derek

I mentioned method-of-treatment patents last week, and it's time for me to come back to the topic. These aren't what people think of as "use patents" - the sort of thing you'd apply for when you discover a new use for a known compound. No, method-of-treatment patents seek to own an entire biochemical pathway, and to collect a fee from every drug that might use it.

A fine example of the breed is attempt by a small biotech, Ariad, to exert rights to the NF-kappa-B signaling pathway. (I wrote about this on my old Lagniappe site more than once, and the legal maneuverings are still far from complete.) Ariad is the sole licensee to a patent obtained by the discoverers of this protein, a patent that enumerates, in horrible detail, its two hundred and threeclaims to everything having to do in any way with anything that so much as touches NF-kappa-B and any of its myriad signaling pathways. You have to see it to believe it. The claims are a relentless paving machine, spreading hot asphalt on everything in sight and spraying lane markers for the toll booths. Here's a PDF of Ariad's side of the story, if you'd like it.

Ariad's fired legal shots at several dozen companies, but their lawsuit with Eli Lilly will be the real test. Lilly's sepsis drug, Xigris, works through NF-kB, as does damn near everything else that has to do with inflammation. And their osteoporosis drug, Evista, works through it too, as does damn near everything else that involves signaling through the estrogen receptor. Bristol-Meyers Squibb has already rolled over and paid Ariad, which I have to say seems rather spineless of them, but most other companies have either stalled or told Ariad to take a hike. Needless to say, everyone will be watching the Lilly case with great interest.

I don't know if the case will be fundamental enough to answer the real question, though: should such patents even exist? Not every patent office will grant this sort of thing, although the US PTO sure will. I know what I think: there just seems to be something wrong about being able to set up a turnstile and coin box on a fundamental biochemical pathway.

Now, I know that people patent enzymes, and I know that companies have all sorts of proprietary cells and enzyme systems that they sell. Hey, look at PCR. But what gets me about patents like Ariad's is that they seem to cast too large a shadow. We own the pathway, because we found it first. Does your drug touch it? Too bad - pay up. Didn't know that it did? Not our problem. Not its primary mode of action? Not our problem. You say that you did all the work on your drug yourself and you don't see why you should pay us? Time to read those two hundred and three claims more closely, bub.

The parallels between this and the University of Rochester's fight over COX-2 inhibitors are interesting. Rochester lost the latest round, because the court held that their claim to inhibitors of COX-2 wasn't valid. They hadn't made one, and had no idea of how to make one, but they claimed any inhibitor from anywhere because it touched the magic enzyme. No dice. Will this reasoning gut Ariad's claims?

As you can probably tell, I damn well hope so. I know that there are other companies playing the same game, but I wish none of us were. We're going to cut our own throats by trying to cut everybody else's, if we're not careful. I'm a big fan of patent protection, but I have my limits. I'd like robust protection, sure, but for real objects that do real things. (And yes, this means that I hold business-method patents in contempt, too.) However, I know from my last time writing on this subject that not everyone agrees with me on this, so I'm bracing for a round of comments and e-mail. Good luck convincing me, though.

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May 10, 2004

Why Own the Car, When You Can Own the Road?

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Posted by Derek

I've written before about method-of-treatment patents, and now the subject makes today's front page of the Wall Street Journal. They've picked a pure example of the breed. Hans-Ulrich Demuth at the University of Halle in Germany filed for a patent in 1996 on the use of inhibitors of dipeptidyl peptidase IV in the treatment of diabetes. The patent was granted in the U.S. in late 2001 (as US6303661, and no, for those outside the field, that's not an odd delay at all, for better or worse.)

Like many peptidases, DPP-IV is a wrecking ball of an enzyme. It breaks down (among other things) an important signaling protein called GLP-1 (that stands for glucagon-like-peptide 1, which shows you how fuzzy a lot of biochemical nomenclature can be.) And GLP-1 is important in maintaining glycemic control - type II diabetic patients could sure use more of it than they have. If you could find a GLP-1 mimic, you'd have a very interesting drug. That's an unlikely hope for a small molecule, though, so other bounce-shot approaches have been tried. GLP-1 itself has been tweaked in attempts to make it more stable, and people have tried various smaller proteins as well.

There are more. People have tried to cause more GLP-1 to be secreted, without tremendous amounts of success, and then there's the DPP-IV inhibitor approach, which would cause it not to be broken down so quickly. Whatever works! Several companies have taken a whack at this route, because the inhibition of protease enzymes, while still nowhere near a sure thing, has a reasonably good track record in drug development. Novartis is the company in the lead, with a compound well into clinical trials.

Demuth, naturally enough, wants a piece of the action. His first patent claim is for: "A method for lowering elevated blood glucose levels in mammals resulting from food intake comprising administering at least one oral administration of a therapeutically effective amount of at least one inhibitor of Dipeptidyl Peptidase IV (DP IV) or of DP IV-like enzyme activity."

Well, that covers the bases, you'd think. But there's a Prof. Jens Holst in the picture as well, from the University of Copenhagen. His group published a paper a few months before Delmuth's patent was filed, in which they showed the effect of a DPP-IV inhibitor in vitro, and suggested it as an adjunct therapy for diabetes. That's a complication, because if anyone spells out your idea in print, you can't get a patent on it later. (This applies to your own statements, too, which is another reason why we in the drug industry only publish on projects that either well along in the clinic or already dead.)

But Delmuth's patent issued, Holst or no Holst, and he cited the prior work in it. That makes breaking his patent harder, because (presumably) the patent examiner took Holst's work into account and decided to allow the claim anyway. Anyone who wants to say that the earlier publication is invalidating prior art is going to have to prove that the examiner blew it - which certainly isn't unheard of, but is still a harder path to take.

Merck and J&J have already either paid Delmuth or indicated that they're going to. BMS isn't saying what they'll do. Novartis, on the other hand, has so far flatly refused to pay anything. A spokesman told the Journal that they're considering doing some sort of deal, though. You can bet that it's going to be based strictly on the numbers: on one side, figure out how much the drug is likely to make, and find out what sort of cut Delmuth wants. Then factor in how likely it is that you'll actually get to the market. On the other side, how much would it cost in time and legal fees to break his patent? Factor in how likely you think you'll be to win, and you've got the whole equation.

Now, I haven't studied this closely, but that's not going to stop me from having an opinion. (When, since the dawn of time, has that every stopped anyone?) Holst's paper looks like a reasonable candidate for prior art to me, frankly. (He seems to think so, too - he and Delmuth have had some testy exchanges in print.) You'd want to look over the prosecution history of Delmuth's patent, to see if there was any back-and-forthing about it during the examination period. It seems clear to me that the higher the expectations Novartis has for their inhibitor, the less likely they'll be to settle.

But all this suggests the next question, coming up for discussion here within the next few days: should such patents even be granted? Highly paid people are prepared to argue either side of the issue! Heck, I'm even prepared to take one side of it myself.

Comments (6) + TrackBacks (0) | Category: Diabetes and Obesity | Patents and IP

April 5, 2004

Oblivious to One Skilled in the Art

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Posted by Derek

I've noticed that discussions of patent law really wilt my traffic something fierce, so I thought I'd go ahead and get another one out of my system now. Perhaps the effect isn't additive. (It'll serve me right if turns out to be nonlinear the other way).

One of the things that hits you when you start worrying about patenting chemical compounds is that there sure have been a lot of them patented. The number of compounds exemplified is pretty large all by itself, but it's just a roundoff error compared to the number that have been claimed. I've seen patent specifications that I swear would run well into the millions if every claimed variation were rung.

They aren't, of course. There's no way that they could be. The extra space is just breathing room, to try to keep the competition from coming too close to the good stuff. It's also to protect some of it for you if you happen to come across something else that's good after you file, but that's a two-edged sword - if you find it too much later, you've got a patent with years of its lifetime already expired, for one thing.

It's important to remember that these drug patents aren't just randomly distributed around the world of chemical structures, either. There are plenty of things that no one is going to be interested in patenting, because they're too reactive or toxic. And there are other structures that just lend themselves to drug discovery: piperidines, piperazines, biphenyls, imidazoles, and tricyclics are just a few that come immediately to mind. The patent space around those things has been trampled, plowed, clear-cut and strip-mined.

These things are all prior art for new patent applications to worry about. Exemplified, reduced-to-practice compounds are bulletproof prior art: if it's been described in the literature, you can't own it. You can claim a new way to make it, or a new use for it, but you can't claim the chemical matter. Section 103 of the patent code says that an invention has to be nonobvious, and you don't get much more obvious than something that's already there. But what about all those claims, those huge, inflated claim structures that reach well into the Kuiper Belt? Are all those off limits?

We'd be in big trouble if that were the case. After all, the problem gets worse each year, nonlinearly worse as the pace of research (and the pace of patenting) picks up. But there's a way to sneak into those putatively fenced-off reserves. If you turn to the MPEP, the patent examiner's manual, you find that "the fact that a claimed species or subgenus is encompassed by a prior art claim is not sufficient by itself to establish a prima facie case of obviousness." Good news, indeed.

For a patent examiner to reject a claim on the grounds of obviousness, the manual says that "it is essential that Office personnel find some motivation or suggestion to make the claimed invention in light of the prior art teachings. . .regardless of the type of disclosure, the prior art must provide some motivation to one of ordinary skill in the art to make the claimed invention. . ." And that's the key. Those massive edifices of claim language eventually have to get down to earth. As the claims roll on, page after page, they start narrowing down. A preferred embodiment of the invention is. . .a still more preferred embodiment. . .a particularly preferred embodiment. . .eventually you get down to what they really, really want to protect.

And legally, what they're doing is teaching you the invention. The claims teach toward the true invention, and the rest of the patent is supposed to teach you how to carry it out (including the "best mode" requirement I mentioned yesterday.) If you're claiming something that's way out in the fringes of the first forest of claims, then the rest of the patent is clearly going to teach away from it. And that means that you can get it for yourself.

There are complications. This is patent law; of course there are complications. It'll hurt your case if you're going for the same use as the original compounds. Your best chance there is to show that your compounds perform in some unexpected way, which the original patent claims clearly didn't anticipate. A less common way to break out of this situation is to show that the original patent's methods wouldn't even be able to produce some of the distant structures - if they don't teach how to make the structures, they can't have 'em.

So that's how it's done. That's not to say that patenting isn't getting harder all the time, because it is (after all, there are all those truly exemplified compounds piling up.) But at least it isn't getting impossible. Nothing a lot of time, effort, money, and legal resources can't attack, anyway.

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April 4, 2004

Obvious to One Skilled in the Art

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Posted by Derek

Not much time to post tonight. Things have been fairly busy in the research world, with the added burden of some patent filings and some evaluations of other filings from the competition. These only confirm to me that there is no way that I could possibly keep bread on my table as a patent lawyer.

Some of my co-workers might find that a bit odd, since I have the reputation at work of knowing a bit more than usual about the subject, for a medicinal chemist. But that just means that I know enough about it to be an irritant to the attorneys. I can't shake, while thinking about the legal issues, a feeling that all that mental effort could surely be put to some better use.

As no doubt it could, but only with some other species. As with any other field, there is no way to write the rules in such a manner that no one can get around them. Writing a patent is a deadly mixture of drudgery and, well, trickery. You're required to disclose the best mode for realizing your invention, and you'd better do it, too. But you're not required to mount a flashing neon sign pointing to it. And you have to exemplify the things that are at the heart of your claims, to reduce them to practice, as the lingo has it. But there's nothing that says that you can't exemplify lots of other things, too, during which you feel like a cuttlefish spewing ink.

Nope, it's not something I can do for long stretches. I enjoy brief visits into Lawyer Country, but I make sure that I have my return ticket in my pocket at all times. No doubt they'd find it easier if they didn't have to deal with us lab types so much, too. I won't ask; they'd tell me.

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February 2, 2004

How to Be an Inventor

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Posted by Derek

While I'm talking about inventorship on patents, I should note that there's a factor that doesn't get the attention it deserves: luck. Well, not the public attention, anyway. But talk to any group of researchers about who gets on which patent, or whose lab produced the most active compounds in any given project, and the word will inevitably come up.>/p>

There's something to that talk. We really don't know how to make active drugs on demand. Otherwise, I can assure you, we'd be making a heck of a lot more of them than we are. There are too many variables, and too many things we just don't understand. In that sense, every drug that's made it to market has been the beneficiary of plenty of luck indeed. At the research stage, you never know who's going to produce the anointed clinical candidate.


And as for who gets on the patent, well, if we don't know what compounds are going to be good ones when the project starts, then it's hard to say what the final patent claims are going to look like, either. People divide up the structure and work on different areas, some of which are going to take off and most of which aren't. When you begin work on a project, you really have no idea where the winds are going to take you.


I'm making it sound like inventorship is all a matter of chance, but that's only partly true. To be listed on a drug patent, you have to have made a distinct non-obvious contribution to the claimed invention, which in our case is usually a new series of compounds. Some idea of yours has to be one of the things that's being claimed. A good mental test is to imagine a lawyer asking you what your part of the invention is. If you can't immediately point to something specific, you're very likely not an inventor.


With that in mind, you can see which way things are headed as a project comes closer to maturity, and judge for yourself if you're likely to be included on the patent(s). Researchers who are alert to this sort of thing often adjust their work accordingly, to have something to point to come patent time. This means that it's harder, especially in some organizations, for lab associates to be listed as inventors. If someone is serving as merely the proverbial pair of hands, they're not going to be on there.


And they shouldn't be. Even if you make the wonder drug that saves the whole project, you're not an inventor if you're just doing what someone else thought up and told you to do. I've always tried to make sure that people who report to me understand the legal requirements of inventorship, and I give them room to think of (and work on) their own ideas. You get better research done that way, too, I might add.


An extra patent note - Gregory Hlatky responds to yesterday's post by pointing out that although we US researchers don't get a cut of the profits from our patents, we don't have to pay the fees associated with filing them, either. He's right that these can be quite substantial, epecially for the ones that you're filing all over the world. I take his point. But I regard those fees as a cost of doing business, like buying reagents (which I'm glad I'm not paying for out of my own pocket, either.) Of course, in the end, we employees are (quite properly) paying for all of these, since that money, derived from business profits, could otherwise be used to increase everyone's salary, among other things. The same argument applies, of course, to the money that would be spent giving inventors a cut of said profits, but I think it could be money well spent.

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January 29, 2004

From Each According To Their Creativity, To Each According To Their Difficulty?

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Posted by Derek

Alex Tabarrok over at Marginal Revolution is proposing an interesting idea: He's suggesting that the lifetime of a patent be adjusted for the R&D costs that went into the ideas behind it. Things that took little effort would have a short term until expiration, while those who went through expensive slogs would have a better chance to recoup costs.


That's an idea that had never occurred to me, by which you can tell that I'm not an economist. And I can see the appeal - but I can also see the potential for abuse. For a while in graduate school, I shared an apartment with a fairly doctrinaire libertarian. We had quite a few discussions, as you can imagine, but I found that they often fell into the same low-energy state. He would point out the benefits of some scheme, and I would agree in the abstract. But I'd then imagine how it would have worked out in the northeast Arkansas county I'd grown up in. Theory and practice tended, in my view, to diverge.


As I think they would here, too. What I think this would do is create a powerful incentive to hocus one's R&D figures. In the drug industry, each extra year of patent protection can well be worth hundreds of millions of dollars in revenue, which is an incentive indeed (with hot fudge and extra sprinkles on it.) It's not like our drugs come cheaply to us now, but I can see that for an anticipated blockbuster, ways would be found to ensure that the patent racked up the longest possible life. You already see that happening at the back end of patent terms, as the constant battles with generic companies illustrate. Every possible reason is trotted out for why a given patent is invalid, and every possible means to preserve or extend the patent's term is invoked in response.


Frankly, we have enough trouble working out how much things cost in this industry already. I mean, we can see how much money we're spending, but assigning specific amounts to specific projects is harder than it looks. The number of people working on a project fluctuates constantly, for example, and many of them have other simultaneous responsibilities. Many supplies are bought in bulk and shared between projects, and all the analytical work is done on large capital-budget machines that are used constantly for everything. I've seen all sort of schemes to track costs by project, but all of them have a voodoo component.


Another problem is that the big money-making drug is only one part of a large patent, which would typically exemplify dozens or hundreds of separate compounds. Naturally enough, some of these took a lot more effort to discover, make, and test than others. If keeping track of costs per project is tough, costing things out by compound would be insane. Then there's the problem of multiple patents protecting the same drug. You'll see a composition of matter patent, a method-of-medical-treatment patent, several patents on specific formulations. . .when a generic company comes after you, these things are used as firewalls and are fought out as separate issues. And these would all have different R&D cost structures, although I've no idea how you'd figure some of them out, and thus presumably different patent lifetimes.


No, I think that passage of such a law would turn out to be the Cost Accountant and Patent Lawyer Full Employment Act of 200x. As I said, I can see the theoretical appeal. But in practice, I think that this attempt to reward the costs of innovation would only create more expensive makework, none of which would have anything to do with research itself. We've got too steady a supply of such as it is.

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January 15, 2004

And Now for Something Completely Different

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Posted by Derek

Here's something new to finish off the week. As even casual observers know, patents are extremely important in the drug industry. We spend whacking amounts of time writing them, reading them, and worrying about the ones that other companies have filed. And it should also be clear, to the same laid-back observers, that a good number of patents are. . .well. . .not what they could be. Many are a bit. . .overstated, or perhaps a bit under-enabled. Estimates vary. Some people think it's 90% of all patents. Others more conservatively estimate that only half of them are nonsense.


It's taken a team effort for things to come to this. Patent applicants have to write crummy applications; the patent office then does its part by granting way too many of them. And that leads up to this latest bolt of inspiration, whose examination by the PTO I would pay to witness. Prepare yourselves for US application 200400055535: "Process of Reincarnation."


Uh-huh. Allow me to quote from the Summary of the Invention. Heck, let's do the whole thing; it won't take long:


"[0001] This invention resulted from my combining Einstein's Theory of Relativity and Newton's Second Law of Physics." (sic)


"[0002] Reincarnation is defined in Webster's Third New Inernational (sic) Dictionary as "rebith" (sic). Thus my invention is a process of rebirth or in other words immortality."


There we go. Actually, I could have saved myself some time by just putting (sic) after the whole damn thing. You can guess what the single claim consists of. It's the shortest patent application I've ever seen, which is only one of its many distinctive qualities. But - and I'd hate to break this to the applicant in person - I don't think it has a chance.


You see, the, er, inventor didn't cite all the Buddhist and Hindu prior art. It's the sure sign of an intellectual-property amateur. If he'd just worked in a couple of references to the Tibetan Book of the Dead, say, I think he could have been out the door in a matter of weeks with his issued patent. But as it is, it'll probably take months for approval. Details, details.

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December 10, 2002

Don't Wait - Patent Today!

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Posted by Derek

GlaxoSmithKline won an interesting patent fight in Canada the other day. This has been going for quite a while, as you'll be able to tell when I mention that involves AZT. Canadian generic companies Aponex and Novopharm had been trying to show that Glaxo's patent was invalid - and Glaxo had been trying to recover the money that they claimed they didn't make because of low-priced competition from those two.

The two generic companies argued that Glaxo's patent shouldn't have been issued for human treatment of AIDS, because at the time the compound had been tested only in mice. I'm relieved to say that this argument was rejected. Unless you've read the patent literature, you have no idea how many patents claim human therapy on the basis of even less data than that.

The generic companies claimed that Glaxo "had no way of reasonably foreseeing at that stage that its drug would ultimately work for humans." Well, fine - but who has such a way? I mean, what other sorts of data would you have by the time you file for a patent? There's always a timing decision to make on when you file, but I've never heard of anyone hesitating when they have proof of principle in an animal model. Would you wait until the compound had already gone into man? That takes years, of course, and you'd be working without a net the whole time - just one publication or patent filing and your work would be pulled out from under you. I think not.

At the same time, the judge in the case held that claims had to be in accord with the knowledge available at the time the patent was written. You can't just write all sorts of speculation in and hope to hit on a lucky chance. The fighting will come when two sides disagree over whether something was a reasonably sure extrapolation or sheer guesswork.

As an aside, Glaxo and Novopharm are no strangers in court - they fought a protracted battle (through most of the 1990s) over some Xantac (ranitidine) patents, which I'll post about some time. It's a very interesting one, and is a key case to study regarding the issue of disclosing the best mode of an invention (versus keeping it as a trade secret.) Actually, generic drug makers aren't strangers to anyone in court; they basically live there.

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November 4, 2002

Generic Prilosec - the Sequel

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Posted by Derek

The sequel to the Prilosec (omeprazole) patent case (see the October 13 post) is an interesting one. The only company to prevail against AstraZeneca's patents on their tablet coating was a small one, Schwarz Pharma. At the time, I said "Now it'll depend on whether Schwarz can actually get the stuff on the market." One problem was that the other two companies, Andrx and Genpharm (part of Germany's Merck KGaA) had won the right to be first on the market with generic omeprazole. (They're appealing the original decision, and the exclusivity lasts for six months after the appeals court ruling, whenever the heck that might be.)

But rather than put all their chips on that outcome, the three companies have now teamed up, in a move too sensible for me to have foreseen, This "come, let us reason together" spirit was surely quite profitable for Schwarz, although I don't think anyone's seen the terms of the deal. Time is most definitely money in this case, which accounts for the speed of the negotiations. AstraZeneca's trying to get as many people off of Prilosec and on to Nexium as they can, and on the other, there's that six-month clock that'll start ticking. I believe that AZN is ready to get into the generic Prilosec business itself, if need be. Let's see how fast the competition is in getting the pills turned out. . .

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It'll Be a While

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Posted by Derek

Merck has won the first round in its legal fight to protect their Fosamax (alendronate) patents (see my September 3 post.) On Monday, a U.S. District court found for Merck in the lawsuit filed by Teva. I haven't seen the decision, so I'm not sure if the ruling directly addressed Merck's method-of-treatment claims for the entire class of compounds. I assume that it did, though.

There are more cases pending in other jurisdictions, though - some of these involve Merck's claims to Fosamax protection (in some dosage forms) out to 2018. Teva's already said that they'll appeal this week's decision, so it could be a while before anyone figures out what's going on. Time is on Merck's side, of course, but at the same time, the long time horizon of the patents that they're defending makes them a more worthwhile target to break.

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October 23, 2002

The Latest Mudfight

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Posted by Derek

Today's court battle is between Pfizer and two rival drug teams. On Tuesday, Pfizer was issued a US patent relating to Viagra, and that same day they filed lawsuits against Eli Lilly and Icos (one the one hand) along with Bayer and GlaxoSmithKline on the other. Both are developing rivals to Viagra (Cialis and Levitra, respectively.) Both work on exactly the same enzyme, phosphodiesterase-5, and it's the PDE-5 action that Pfizer used as the ground for the suits.

The patent has claims for some chemical matter, and several specific compounds. Their ace, though, is near the end of the list: they claim the treatment of erectile disfunction by administering a PDE-5 inhibitor. Any inhibitor. You can make a compound that hits that enzyme, says Pfizer, but if you treat erectile disfunction with it then you can expect to hear from their lawyers.

This is a pure "method of treatment" patent, and regular readers will know that I don't have a very high opinion of those, on principle. The interesting thing is, Pfizer may not have that high an opinion of their chances here. They've already lost to Lilly and Icos in the UK over just this same issue, and the European Patent Office followed suit last year, citing that decision. The argument was that this mode of action was already known before the patent was applied for, and that'll surely be the defense that Lilly/Icos and Bayer/GSK will use here.

So why is Pfizer even trying? Easy: they'll be trying to tie things up so thoroughly that their competitors will be delayed in getting their drugs to market. When you consider that their legal bills will be perhaps a few weeks worth of Viagra profits (at most,) then it looks pretty cost-effective to make the attempt.

And lest anyone think that I'm just picking on Pfizer, I should add that plenty of other companies in the industry have patents that could allow them to do the same thing in such a situation. And most, probably all, of them would. After all, it makes financial sense. But I have to say, I'd like to live in a world, and work in an industry, where it didn't.

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October 1, 2002

Overpatenting?

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Posted by Derek

There's an article in the latest New Republic on innovation in the drug industry. As far as I'm concerned, it draws good conclusions from faulty premises (which, admittedly, is a lot better than drawing bad ones from a good starting point!)

The author, Nicholas Thompson, says that

shares in the pharmaceuticals index, meanwhile, are down 25 percent. And the industry deserves it. For years it has squeezed consumers the world over, endlessly arguing that it needs its huge profits in order to invest in new, lifesaving innovations. But while that might once have been true, lately the industry hasn't been innovating at its past rate--and that's probably the main reason investors have started to back off.

Well, that last part rather goes without saying. But, talk of "deserving it" aside, his reasons why this has happened are a little too glib:

The cliché of the moment is that pharmaceuticalcompanies have picked the low-hanging fruit, developing drugs that interact with the limited number of enzymes and molecules that we already understand and have thoroughly modeled.

Sounds like he's been reading this site. Some things get to be truisms because they're true.

But people have always mourned the loss of the low-hanging fruit--and then smart and innovative folks built taller ladders. The tools and computational abilities available to drug companies today dwarf those that companies employed to develop the blockbusters that fueled the 1990s boom. Scientists now have access to the human genome and a vastly increased understanding of everything from gene expression to organ physiology as well as extraordinarily powerful computing and modeling capabilities. In many ways, discovery should be easier and cheaper now than ever before.

You'd think so, wouldn't you? Problem is, all that knowledge has also bred more complications. Look at gene expression: we can now look at thousands and thousands of genes going up and down when we administer our drug candidates. What percentage of that do we actually understand? You'd be hard pressed to get a knowledgable answer that gets out of the single digits. As for computational ability, the big news the other day was that we finally (after decades of trying) predicted a protein's structure from knowing its amino acid sequence. Another few hundred thousand of those and we'll be in business. Then we can start figuring out how they interact with each other, and then we can start figuring out how to make drugs that do the same. It'll be a great day when we do - but that day isn't here.

And the very successes of the industry over the last 25 years have led to the bar being raised. Some things that were huge blockbusters back then wouldn't stand a chance today - too many side effects, for example. Racemic compounds (Prozac, to pick an example from the article) don't stand much of a regulatory chance today; the FDA wants single enantiomers. (Ironically, the active enantiomer of Prozac actually has a worse window for tox effects - the same compound might not have made it at all today.)

Thompson goes on to decry the amount of money put into marketing, and I can't argue with him much there (tomorrow I'll try to talk about the new government guidelines issued today.) But I think he's fallen into a post hoc, ergo propter hoc fallacy: in many cases, the marketing has been cranked up because the drug pipeline is thin. The money spent on marketing isn't necessarily what thinned it out.

Where he strikes gold is when he starts talking about the patenting of "upstream" products: assays, research tools, biological pathways, and methods of treatment. He goes over some examples familiar to readers of this blog (Ariad!) and correctly points out that this sort of thing is fast becoming a crippling influence. Actually, I think it's been a lesser contributor to the productivity decline so far, but it's set to pile on top of what's already a tough situation. Then we really be up the creek.

His solution? Right on target, to my thinking:

The best thing for the pharmaceutical industry would probably be to maintain its strong protection over downstream products while opening access for upstream products.

Preach it, and speed the day! I've been working on some pieces addressing this issue (guess I won't be selling them to TNR, dang it all.) We haven't heard the last about this issue - at least, not if I have anything to do about it.

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September 25, 2002

Different Opinions About A Difference That Makes No Difference

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Posted by Derek

Since Monday's posting was about the terrible consequences of changing one amino acid, I thought I'd stick with that theme. Today's outcome isn't life-and-death, fortunately for everyone involved.

But it does involve the patent rights to a $500 million/year antibody, so it's not without interest. Particularly if you think that another company has blatantly ripped off your patent, after doing a licensing deal with you that was supposed to preclude that sort of thing. The patent holder is Celltech, a UK company with a technique for generating humanized monoclonal antibodies in mice.

Antibodies are very useful, of course, but getting good ones isn't easy. There's no way to make them other than from a living organism (cell cultures, usually.) Ideally, you'd want to generate them in the same species that they're to be used in. Otherwise, you run a high risk of setting off an immune response in the treatment animal - instead of the antibody doing its thing and alerting the host's immune system to something else, it gets recognized as a foreign object all by itself. Whatever immune signal it's trying to send gets lost in the ensuing confusion, which can range from local irritation all the way up to anaphylactic shock. A humanized antibody has a generally human immunogluobulin structure with some specifically mouse-generated immunoreactive sections in it. These can pass, for the most part. It's a very useful technology, but rather tricky and sometimes hard to generalize.

Medimmune developed Synagis (palivizumab) as a treatment for respiratory syncytial virus (RSV,) which can be severe in infants. It's pretty much the only thing out there for it. No vaccine exists, for example: the first attempts to develop one in the 1960s backfired tragically when it turned out that treated children actually had a worse outcome if they were exposed to the real virus later on. (Here is a thorough report on Synagis and RSV, courtesy of Biopharma.com.)

Celltech claims that Medimmune's antibody, though, is equivalent to something they've already patented. It's a point worth arguing: of the over 1300 amino acids in the antibody's chain, there's one that differs between Celltech's patent and Medimmune's drug. (Specifically, it's a threonine for serine, which is a mighty small change indeed: just one methyl in the side chain. That makes the Dutch mutation I spoke of yesterday seem like a total makeover.)

I can hear the groans now from the cognoscenti who can tell what's coming next: yes, this is going to turn on the Doctrine of Equivalents and the Festo decision. I wrote about this at length back on June 5, but I'd caution you if you go back to read that post.

Gary Pulsinelli of Tennessee's law school (yep, just down the hall from Glenn Reynolds, I gather) wrote to point out that I'd thoroughly smeared together the issues of infringement and patentability. That I did! My own background biased me into thinking in terms of battling patents, and that led me astray. It's important to keep in mind, for example, that something can be found not to infringe someone else's patent, but at the same time not be patentable on its own.

The Festo case was all about infringement. Here's a distilled version:
1. Festo (of Long Island) starts selling a nifty mechanical cylinder device.
2. SMC (of Japan) starts selling a nifty (and hauntingly familiar) mechanical cylinder device.
3. Festo sues SMC for patent infringement. They claim that the doctrine of equivalents prevents SMC from making a minor modification and calling it theirs.
4. SMC claims that Festo doesn't get to invoke the doctrine, because they made changes to the relevant claims while the patent was going through the approval process. That's "prosecution history estoppel," which has been the counterweight to overly broad doctrine of equivalents interpretations. If a claim gets narrowed during the pre-approval prosecution of a patent application, you can't go back (for example) and try to get D of E protection based on the original broader claim. After all, the Patent Office presumably narrowed the claim because they thought the broader one wasn't patentable in the first place.
5. Festo wins in the District Court, and the decision is kicked upstairs on appeal, to no one's surprise. It bounces around the Appeals Court for a while, with another big patent case (Warner-Jenkinson) complicating the issues in the meantime.
6. To everyone's surprise, the Federal Circuit eventually reverses the decision and takes the hardest line yet on using the doctrine of equivalents. Saying that the case-by-case approach had led to a mess, the court decides to draw the line so everyone can see it: Just about any changes made to a claim during the prosecution of the patent, the court now says, trigger prosecution history estoppel. Their take-home is something like "write your claims better from the start, and we wouldn't have these problems." The decision applies to a huge number of patents that were written and prosecuted while the parties still had a stronger doctrine of equivalents in mind. Confusion reigns.
7. Festo appeals to the Supreme Court. They don't hear many patent cases, but this is the biggest one since Warner-Jenkinson. Heavy amicus curiae briefs are filed in support of both upholding and reversing the Circuit Court's decision.
8. The Supreme Court largely reverses the lower court. The doctrine of equivalents is given new life, and the court attempts to clarify the no-man's-land between it and prosecution history estoppel by setting some new criteria. All interested parties in the intellectual property world settle down to figuring out the new landscape, and waiting for the first major court cases that'll hammer out the details.

That leaves out a lot of tricky stuff (such as the details of those new criteria ,) but I think it gets the main points across. Celltech, as you might guess, filed a brief urging that the lower-court decision be junked. If you weaken the doctrine of equivalents, they said in essence, you're going to open up everyone in biotech to what MedImmune is doing to us. Meanwhile, MedImmune claimed that this sort of time-wasting litigation was just what the lower court was trying to prevent by drawing its clear, bright line. If Celltech wanted to claim this protein, then they should have claimed it, was their point of view - it's time to stop hiding in the bushes, waiting to whack people in the head with the doctrine of equivalents if they think they can lay claim to something valuable.

The rest of the biotech industry was split along roughly these lines, with the likes of Chiron siding with the original doctrine of equivalents, and Genentech (among others) wanting the limitations imposed by the Circuit Court to stand. I like the first approach better. While I take the point that there's a lot of deliberately broad or vague claim language out there, I think that's the lesser evil compared to what this case is showing us.

If single amino acid changes are enough to break a patent, then what isn't? Instead of wasting time on post-patent litigation, we'd all be wasting our time writing incredibly precise and intricate claims (and doing a lot more running in circles trying to come up with data to enable them.) Celltech should win this one, and I hope they do.

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September 19, 2002

More Fun With Patent Expirations

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Posted by Derek

Sometimes I think I should write some sort of script to insert that headline automatically. Not that I want the site to become "Patent Wrangling News," but that's where the action seems to be these days. (If you don't have the new drugs, then fight over the old ones, I guess.)

There's one of these that I haven't talked about yet that could be coming to a decision soon - AstraZeneca versus a host of generic companies, fighting over Prilosec (omeprazole.) (The Wall Street Journal also covered this issue in its "Heard on the Street" column on September 10.)

"Who cares?" might be the first reaction. Omeprazole's off-patent anyway, right? That's why AZN's been trying to convince everyone to take Nexium instead - for the millions who shouldn't take a lower-cost drug that works just fine. All that's true (or my firmly held opinion, in the last clause,) but this case could turn around and affect Nexium as well.

While omeprazole, as a chemical substance, is no longer covered by a patent, there are some formulation patents are the subject of litigation. That's because just taking the compound by itself won't do anyone much good, because it's unstable to stomach acid. AstraZeneca claims (in a patent that won't expire until 2007) to have invented a proprietary coating technology that allows the pill to make it to the small intestine.

The thing is, acid-resistant (enteric) coatings are no big deal in the drug industry, which is just the point that Andrx and several other companies are trying to make. They say that they have an equivalent coating which nonetheless doesn't infringe AZN's patent. "Equivalent" is a key word here, because if the generic behave differently, then it's not really a generic, is it? Andrx would have a new formulation on their hands, and would have to do more extensive testing to get FDA approval. Meanwhile, AstraZeneca is making their coating technique sound like it's the most complicated thing next to an interstellar warp drive, and about as easy to discover.

There's also a manufacturing patent on the same sort of technology. While AZN claims that several generic companies are infringing the first patent, Andrx is the lone defendant in the manufacturing fight. Needless to say, if Andrx wins on the first point but loses on the second, they'll still be stuck. You can't make money off a drug if you can't legally manufacture it. This has all been going on since late last year, and rulings are expected Real Soon Now.

Reversals for AstraZeneca could lead to trouble for Nexium, because the same formulation is used for that one, too (as you'd expect.) Nexium is, as the world should know, merely one pure optical isomer from the racemic mixture that is Prilosec. AZN's position is that the two substances are as different as asphalt and chocolate mousse, and that their separate patents on the optically pure form are as solid as can be. But if the first Nexium firewall (the formulation) is breached, the generic companies may attack the chemical substance itself.

What are the chances? This issue is being fought out in several cases. In Europe, the EPO seems to have clearly stated (as much as that phrase can apply in patent law) that a known racemate doesn't necessarily affect the novelty of the two optical isomers it contains.

But novelty is only one component of patentability. Showing a inventive step can be tricky, because it's widely assumed that one isomer is going to have more biological activity than the other one. It's been held that "an enhanced effect cannot be adduced as evidence of inventive step if it emerges from obvious tests." Now we start arguing about what "obvious" is, and it's just another day in the life of an intellectual property lawyer. Challenges in the US, where single optical isomers have been patented frequently, might well take this "lack of inventive step" tack.

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September 3, 2002

The Patent Expiration Fun Continues

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Posted by Derek

Meanwhile, Merck has a patent fight of its own going on. Their osteoporosis drug Fosamax (alendronate) is being targeted by Teva and Barr, but Merck (not surprisingly) has been filing suits against both of them over the last few months. The Barr lawsuits are in New York, Teva's is in Delaware, and we might see some decision on them in the next couple of months.

Merck doesn't seem to be arguing the point about composition-of-matter. What they're claiming is that they have patents covering the entire methods of treatment for bone resorption. These patents have expiration dates all the way out to 2018, which is a date that they can live with. After then, they say, you can do anything you want with alendronate. It's not clear what other sorts of compounds might fall under these treatment claims, but I haven't heard of any other companies that feel that they have a stake in this fight.

This is yet another test of the whole method-of-treatment patent idea. It's complicated in this case, because there are nine Merck patents involved, and they have all sorts of claims among them: chemical matter, processes for preparation, medical treatment, and who knows what else. I've looked into them a bit, but my head starts to pound a bit after about five or six patents in a row. Gets me right up around the eyebrows. . .but I digress.

There are plenty of compound-specific claims, of the sort that read "A method for treating diseases involving bone resorption, which comprises administering to a patient in need thereof a therapeutically effective dose of a compound of claim #. . ." Many of these don't seem to be for alendronate-type compounds, since this is the sort of claim that usually refers back to some novel chemical matter (which is the real subject of the particular patent.) But a closer reading would, I'm sure, find some that refer to alendronate itself, because these cases would have been decided already if there weren't some meat on the bones. [Note added 9/4: I edited this paragraph from its original version last night, which made even less sense.]

Barr and Teva say, as you'd expect them to, that the Merck patents are invalid and/or unenforceable. Unraveling all this won't be fun, and no doubt whatever verdict comes down will be immediately appealed. "Where it will all end, knows God" as the old New Yorker parody of Time magazine had it.

These sorts of court battles are routine, and it's easy to see why. While they go on, the status quo is preserved. The challenging generic company has its hands tied. As long as the drug brings in more money than you pay in legal fees, then you're ahead of the game.

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September 2, 2002

A Last-Ditch Effort - Or Is It?

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Posted by Derek

There's a rather weird legal fight going on between Glaxo SmithKline and the rest of the world. Like everyone else, GSK is fighting to hold on to profitable drugs that are losing patent protection. A lot of. . .creative. . .arguments are being deployed in these efforts, and I can't figure out if this is one of them or not.

The drug is Augmentin, which is actually two drugs in one. (For those readers old enough to remember it, you can now cue up the voice-over to the old Certs ad.) The antibiotic ingredient is plain old amoxicillin, a beta-lactam warhorse that's been generic for a long time now. Unfortunately, plenty of bacteria can chew right through amoxicillin and others of that era. I mean that literally: they use an enzyme called beta-lactamase to break open the four-membered ring at the core of all the penicillins.

That's where the second ingredient comes in, clavulinic acid (actually, its potassium salt.) It's a natural product that has a roughly similar structure, similar enough to fit into the active site of the beta-lactamase enzyme and gum up the works. Using the enzyme inhibitor leaves the amoxicillin free to do its work, and the combination is quite effective.

Well, amoxicillin you can order by the drum. But clavulinic acid is another matter. It's not economical to synthesize, not from the ground up (and neither are the beta-lactam antibiotics themselves, for that matter.) All these compounds are made (at least partially) by fermentation, which is just short of being a black art. You have to find strains of organisms (fungi for the 'cillins, bacteria for clavulinate) that produce unusually high amounts of the material, and you have to make them do it reproducibly. That means keeping them happy, but not so happy that they decide to give up the hard biochemical work of synthesizing your compound. And you have to find a good way to purify your stuff from the reeking fermentation broth - ideally in a continuous-feed mode so you don't have to run batch after batch. It's not trivial.

Perhaps you can guess where this is heading. GSK claims that they spent a lot of time and money developing a particular bacterial strain that produced clavulinic acid better than anything else known. And they're now claiming that some of these bacteria walked out of their facilities and are being used by their competitors (specifically Novartis as well as the generic companies Ranbaxy and Teva.) They seem to have a particular employee in mind, and a particular transaction history for the theft.

Problem is, that all happened starting in 1988. You wonder why GSK sat back for this long if they knew all this. . .and there are generic Augmentin formulations in Europe which don't figure into the suit. How'd they make their clavulinic acid? You do have to wonder if this isn't a desperation move.

On the other hand, this sort of theft isn't unknown. About twelve years ago, a New Jersey drug company had a former employee walk out with some of their engineered bacteria, which he later tried to sell to at least one small biotech outfit. They went to the Feds. The employee was caught on tape, thinking that he was selling the material to a Middle Eastern government, when he was really selling it to the FBI on two camera angles.

So GSK could be on to something, too. It'll be fun to watch.

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August 15, 2002

Great Moments in Legal Reasoning

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Posted by Derek

I can't resist passing on this argument, made unsuccessfully by Schering-Plough. It's a tactic that's been tried before, and has never worked. But desperate times demand such measures, I suppose, although - well, you be the judge.

SGP's Clarinex is, as I've mentioned, extremely similar to their Claritin. It's an active metabolite, so if you've taken Claritin, you've taken Clarinex. That's the whole point, according to Schering. If you allow other companies to sell Claritin as a generic, then when people take it, their bodies will turn that into Clarinex.

Which is, of course, a patented, proprietary substance. Which these patients are breaking the law by producing - led into this illegal act by the actions of a generic drug maker. Shocking!

This didn't fly. For this and other reasons I'll go into next week, Schering ended up on the losing side (by a summary judgment) and generic Claritin (loratadine) moved much closer to the market.

[Disclosure added on 8/16: notwithstanding the tone of the above, I actually own some SGP stock, back from the days when it was a good performer.]

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July 2, 2002

Now, Where Was I?

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Posted by Derek

Well, I'm back from vacation, not quite as worn out as I'd feared. But I haven't been keeping up with the news, unless my son's frequent updates on the extinct status of Tyrannosaurs counts (they're still extinct, worse luck, in case you're wondering.)

I'll get oriented in the scientific world tomorrow at work, but it'll be a short week in generalm as mentioned in the previous post. I've had more interesting e-mails on the Ariad patent business, which move me to clear up something:

I don't have the list of roughly fifty companies that Ariad seems to have contacted. That info was from the Wall St. Journal story from last week, which is still one of the more complete write-ups. There's an AP story that several newspapers picked up, but it doesn't really give the flavor of the thing, and Ariad's Business Wire press releases aren't the most wonderful source, either.

If Ariad's really serious, I think we can assume that every company that works in cancer, inflammation, or autoimmune diseases has been contacted. That should give you fifty companies with no problem at all. It would be very interesting to know if anyone has actually agreed to terms with them, but my guess is that no one has. It's too early for anyone to have reacted to the issuance of their patent, and if anyone had licensed with them earlier, I feel sure that Ariad would have press-released the deal until hell wouldn't have it.

The other thing I'd like to make clear is that I have no position, long or short, in Ariad stock. Judging from the trading volume and the choppy look of their daily charts, not many other people do, either. Nor do I have any position in their options, not that there must be too many open contracts there, either. If I do take any positions, I'll state them publicly.

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June 26, 2002

A Race to the Bottom

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Posted by Derek

I've already spoken of my disdain for "method of treatment" patents, the claiming of entire biochemical pathways for their medical use. It's something that you never used to see, even though US patent law has long allowed it. But in recent years, an increasing number of these applications have shown up, and they're starting to become issued patents. One of them issued on Tuesday. It's a big one, and it's going to cause a massive legal tangle.

I want to distinguish such patents from the standard "use patents" that companies file on a compound class when they discover a new use. I've no problem with that at all, since it relates to specific chemical entities and what they're good for. A patent claim that "3-aminothingamabobs are useful for the inhibition of whateverase enzyme" is fine with me, as is one that says that "3-aminothingamabobs are useful for the treatment of diabetes." Such patents will have to enable the claims, by backing them up with data showing that the compounds really do inhibit the enzyme, or really do lower blood sugar.

But the kinds of claims that are sending us toward a huge intellectual-property train wreck read like this: "Treatment of disease through inhibition of whateverase enzyme." Note that this claim doesn't address any chemical matter at all - it's similar to a business-method patent of the kind that have been driving technology companies crazy. In effect, this claim says "If you come up with a drug that works through this pathway, you infringe our patent. It doesn't matter if you were looking for something that worked that way or not. It doesn't matter if your compound has six other modes of action. And it doesn't matter if you even knew how it worked when you developed it."

Such patents have come to the drug industry's attention over the last few years, and there have been some local legal skirmishes. But this latest one could start the all-out battle. It covers the use of a cell signaling protein called NF-kappaB (NF-kB, with that "k" more properly in a Greek font.) That one's involved in regulation of genes that are extremely important in inflammation, cell death, and cancerous states. The list of diseases that have an NF-kB component is therefore impressive: cancers of various types, atherosclerosis, osteoporosis, arthritis and sundry other autoimmune diseases, septic shock, and so on. Here's a diagram of its main functions that will be impressively incomprehensible without some cell biology background, and here's a more extended review of the field if you're up for it.

I've no idea of how many academic research groups are working on this, but it's a heap. And in industry? How many drug companies have compounds that hit NF-kB? Well, that figure has been more exactly determined for us by the sole licensee of the new patent, Ariad Pharmaceuticals. They have sent letters to over 50 companies whose marketed or developmental compounds appear to work (at least partially) through that pathway. And they want money from all of them. Right now.

This patent's history goes back to 1986 - the earliest filing in its history is from January of that year, although the issued patent, for reasons that make my head hurt to go into, has an official filing date of 1995. That's an awful long time for an application to be kicking around the patent office; the file wrapper dealing with its prosecution history must be something to see. And I can guarantee that plenty of people are going to ask to see it, starting with the legal department at Eli Lilly.

Ariad had a lawsuit fueled and on the pad, and as soon as their patent was issued, they launched. In fact, the Business Wire press release about the lawsuit went out before the one about the patent, which shows you where Ariad's priorities are. They claim that two of Lilly's biggest products, Evista for osteoporosis and Xigris for sepsis, both work through NF-kB (and there's little doubt that they do, at least partially.) Therefore they're demanding royalties, and pronto. Lilly had ignored Ariad's previous requests for a licensing deal, according to the Wall St. Journal, which moved them up to the exalted position of First Target. The other fifty companies can presumably expect the same treatment if they don't get on Ariad's good side.

Is this going to work? I fervantly hope not, but it's anyone's guess. Almost all my colleagues that I spoke to today said "Oh, come on" to the idea that anyone could legitimately patent all the NF-kB pathways, but the patent runs to a relentless 203 issued claims. It was written carefully and comprehensively. My informal survey group didn't think much of Ariad's chances in court, either. But the company points out, correctly, that they'd be foolish to go ahead without some informed legal opinion saying that they can win.

Ariad's CEO, Harvey Berger, has this to say on their web page:

"We are focusing in 2002 on realizing the value of our intellectual property portfolio,
especially our patents related to NF-kB. . . We are the exclusive licensee
of this pioneering technology and are committed to creating value for the distinguished
team of inventors including two Nobel laureates, their institutions - The Whitehead
Institute, M.I.T., and Harvard University - and our stockholders. Our share of the potential
revenues generated from such efforts should ultimately help underwrite the cost of
developing and commercializing our promising portfolio of breakthrough medicines."

I'd like to furnish my own translation of this statement: "We are focusing in 2002 on shaking down every company we can find, by whacking them over their heads with our mighty patent. This IP windfall could provide us with the huge sums needed to get some of our own ideas to work. But for now, we're going to enjoy stripping the cash from people who have actually been able to develop useful drugs."

Well, as far as I'm aware, I don't know anyone at Ariad. I'm sure that there are some good people there, and I'm sure that some of them are working hard on good ideas. But for now, their company is devoted to a strategy that I think can only hinder medical progress and lead the pharmaceutical industry into a destructive, wasteful, patent war. Ariad should be ashamed, and MIT, Harvard and the Whitehead Institute, the assignees of the patent, should be ashamed to let them go out and do the dirty work for them. Because if they win this, everyone's going to follow suit. They'll have to. And I'm not sure I'm going to be able to stand working in an industry that looks like what that will lead to.

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May 20, 2002

Hands Off

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Posted by Derek

There's another aspect to pharmaceutical patenting that you really only find in the US, among major countries: "method of treatment" patents. I don't care for them, myself, but before I explain why, it'll help to see what the usual patents cover.

The traditional drug patent is for composition of matter - you've made some new chemical compound, and you're claiming it as your own. If your new compound is too close to someone else's claims, they can come after you (via the "doctrine of equivalents,") but generally that's not a problem. If it's really new, it's yours if you want it. A footnote for the future: as chemistry advances, we keep having to push into new territory to find patentable material, and some day it's going to be a real problem. For now, finding new stuff is often just an inconvenience, but ask me in twenty years, and I might word things more strongly.

What if you've found something useful, but someone else already owns it? Then you can get a "use patent" - you claim this compound (or class of compounds) for the particular use. If the compound itself - the composition of matter - belongs to someone, then the two of you are in a standoff. They own the compound, but they can't use it. You can use it, but you don't own it. That's the time to have your people contact their people, and hammer something out.

Similarly, if the compound you've found is something that was already known in the literature (or from an expired patent,) then no one can claim composition of matter, and a use patent is the best you can do. It sure beats nothing.

Now for method of treatment claims. These claim the use of some compound (any compound!) that works by some mechanism you've discovered, to treat some disease. That sounds innocuous, but it can spray down a whole field of research. If I'm the first person to discover that blocking the whateverase enzyme is good for treating allergies, say, then I write a patent claiming whatever compounds I've discovered to do it (composition of matter,) the use of those compounds to inhibit whateverase, and the treatment of allergies by using anything that blocks it.That last one is the medical treatment claim. It means that if you go find a compound (a totally different compound,) that does the same thing, then you can patent it until you turn blue. But you can't use it. I've got the medical treatment patented.

The European patent office won't allow those claims, at least not in so many words. They hold that such claims are an unlawful restraint on medical practitioners. There's a tricky technique known as a "Swiss Claim," where you write things up like this: "We claim the process of producing compounds such as Structure I, which are useful for the treatment of allergies through inhibition of whateverase." You didn't claim the treatment per se;you claimed a process of making a compound. But you worked in the whole purpose of making the compounds, and if you've written things in a convoluted enough form, it can be very hard to disentangle the two. A good Swiss claim is virtually a guarantee of a prolonged court fight.

I'd prefer to see the whole business disappear. Medical treatment claims have become more and more popular in recent years, and they're driving everyone in the drug industry nuts. It's turned into a mutually-assured-destruction game: "So, you claim all that stuff! Hah! I claim all this!" If we keep this up, we're going to end up with a medical landscape made up of Balkanized patches, with barbed wire and wasteland in between.

But what to do about it? As these things show up, researchers that wouldn't have thought about writing such claims feel forced to keep up. As long as they're possible, they'll be used. It may take a few years, but I think that we could be heading for some interesting situations if some of the sealed-off treatments look like they could turn into blockbusters.

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May 19, 2002

Not As Bad As It Looks

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Posted by Derek

The patent whose illustration I reproduced here the other day is a weird one; I can't take away from that. But in many respects, it's a well-written and reasonable patent, and the way the law is written, I don't see any reason why it shouldn't have been granted.

Some of the key things a patent should show are novelty, disclosure of the best mode of carrying out the invention, and comparison with the prior art. Now, I haven't carried out an exhaustive survey of the butt-kicking literature, but the inventor seems to have taken some time to do all of these. You can contrast that with some of the loser patents that are being granted in what are supposedly more exalted fields. For example, pharmaceuticals. . .

Take a look at those requirements again. Novelty is the easy one, in some ways. These days, you just go on for a paragraph or two about how unprecedented your invention is, contrasting it with the most hapless previous examples you can come up with. Best mode disclosure is a bit more tricky. There's a legal quagmire between this requirement and your right to keep a trade secret, and some truly nasty patent battles have been fought in that swamp. Most of the time, though, you can disclose best mode without too much problem, since the process is still being refined as you write the patent. This lets you show the best way you currently know how to do things, and allows you to reserve later tricky refinements as trade secrets. (When it gets nasty is when there's evidence that these two eras overlapped.)

That brings us to prior art, and here's where the stink of dead fish becomes pronounced. As Greg Aharonian never ceases to point out, technology patents in general do an awful job disclosing prior art. In some cases, the reason for this is pure laziness or stupidity. More oftenm though, the motives are baser. If you just ignore prior art that might invalidate your patent, you can get the thing granted more easily. Then it's an uphill fight for someone who wants to invalidate it - after all, you've got the law on your side until someone proves otherwise. It's doable, but you've raised a barrier that someone will have to think about.

In recent years, there's been a variation on this technique. There are patents that actually disclose what, to an outside observer, would appear to be invalidating prior art - and the patent office grants the thing anyway. This disclosure usually consists of dropping the references into a list, and not dwelling on them in the text. The patent examiners are so overworked that they let a lot of this stuff through.

And if you want to invalidate one of these winners, good luck. Because now the very thing you want to use to show the patent shouldn't have been granted is. . .in the patent. And, legally, has been assumed to have been considered, and found insufficient to deny the application. You're stuck with arguing that the examiner made a mistake, which is generally a losing position.

You've got a better chance of getting one of these through if your examiner is not only overworked, but incompetent. I have it on good authority that some companies will submit the identical application in multiple copies (which is illegal,) waiting to see which examiners get assigned to the cases. Then they'll pick the one that they know from experience is the least demanding or skillful, and withdraw the other applications. I'm proud to say that that one wouldn't have occurred to me.

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May 15, 2002

Eliminate the Middleman

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Posted by Derek

There's been a lot of talk recently about problems with the US and European Patent offices. And there are some serious issues to talk about, too.

Maybe tomorrow I'll talk about them! But for now, I pass along US 6,293,874, issued last September, titled "User-Operated Amusement Apparatus for Kicking the User's Buttocks." Have trouble believing this one? The full patent's here.

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