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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Down With Patents, Eh? | Main | Once More Into the Patent Breech »

April 3, 2006

More On Doing Away With Patents

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Posted by Derek

Many of the folks commenting on that last post know what they're talking about, but not everyone who opines on drug industry patents does. (My fear, as I said yesterday, is that Boldrin and Levine might be in that category). So I thought I'd lay out some of the ground rules that people outside the pharmaceutical world might not be familiar with.

First off: it is not difficult to figure out what is in someone else's pill. Modern instrumental techniques make can make this an about an afternoon's work - a couple of days for a tougher one. And as for the formulation - all the stuff in there other than the active ingredient itself - that's usually easy to reverse-engineer, too. For any practical purpose, without a patent there is no barrier here.

Next, while the process of producing a given drug is often the subject of separate patents, there are still, in most cases, multiple ways to skin the chemical cat. Generic drug companies like Teva and Ranbaxy, among others, are famous for being able to come up with processes that are equivalent (and in some cases superior) to the patented ones. It's rare that there's a barrier to innovation here.

Third, it should be remembered that patents must thoroughly disclose the subject of their claims. Patents on drug substances must provide specific, detailed instructions on how to make the compounds in question and on their physical properties. One "skilled in the art" should be able to step right up and whip up a batch - and in fact, those skilled in the art often do, to get a look at the competition's compounds or to try to improve on them. It can be hard to see which of the claimed compounds is the one that's being developed, true - but by the time it gets into the clinic it's often clear, and by the time it gets to the FDA, all must be revealed.

And finally, please, please take some time to understand the difference between an academic discovery and a finished drug that makes it to market. Talking about how "gosh, most medicines are found through government-funded research anyway, right?" will not convince anyone who's done drug development that you know what you're talking about.

There, that should help clear out some of the underbrush. Workable suggestions for something other than patents on drug substances, anyone?

Comments (35) + TrackBacks (0) | Category:


COMMENTS

1. tom on April 3, 2006 9:43 PM writes...

Disclaimer: other than an interest in IP issues, I've got no qualifications to opine here...

But eliminating patents still seems completely unworkable to me. Establishing a process by which different lengths of patent protection are offered to different drugs might be more realistic -- in that way the government could offer incentives for companies to produce the drugs we most need, rather than the ones the market will (currently) most richly reward.

This would introduce more uncertainty into the process of funding a drug's development, and provide additional encouragement for firms to be the first to race a new class of medication to market, which could raise safety concerns (assuming "me-too"s are given shorter protection). I suspect the safety concerns would be overblown, though, given the money already involved and the depth of the approval process.

I'd be curious to know whether you think such a system could be executed in a way that makes sense.

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2. Palo on April 3, 2006 9:59 PM writes...

Too late to go at at length through your post. I'll take issue with only this for now:

And finally, please, please take some time to understand the difference between an academic discovery and a finished drug that makes it to market. Talking about how "gosh, most medicines are found through government-funded research anyway, right?" will not convince anyone who's done drug development that you know what you're talking about.

That's a bit of a cheap shot. You know full well that when critics claim there is a lot of the research done with federal money it is mostly in response to the "we need to empty your pockets every time you by our pills so we can fund basic research and innovation". Yes, like it or not, your employer claims that a big chunk of money goes to pre-clinical research, and that a lot more goes in red as "cost-opportunity" for the money tied up in years of research that could be invested somewhere else. It is your own industry that makes this claim every time they want the public to really believe that it costs $802 million to bring a pill to the market. So don't you come now with the condescending tone about how insignificant it is that most of the basic research behind the most innovative drugs in the market was actually done with taxpayers money

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3. Derek Lowe on April 3, 2006 10:12 PM writes...

Palo, I didn't mean it as a cheap shot. We don't need to empty everyone's pockets to fund basic research - we spend plenty of cash on the applied stuff, thanks. Academia does the bulk of really basic research; you won't find me arguing with that at all.

Taking a basic research finding (Cox-2, e.g.) and turning it into a drug (Vioxx) is already expensive enough, and that's not even adding in the costs of the ones that don't make it (umpteen other Cox-2 compounds that fell by the wayside) or the ones that have been withdrawn in storms of litigation (Vioxx, again).

It's not insignificant that lots of basic research has been done with taxpayer money - it's very important, and it's something that people in the US should be proud of. But neither, as you surely know, does it translate to marketable drugs without huge piles of further money.

I haven't noticed drug companies specifically talking about the expenses of pre-clinical work as opposed to the clinical expenditures, which is where the long green gets laid out.

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4. Palo on April 3, 2006 10:51 PM writes...

Derek, about half of the mythical $802 million it takes to develop a drug goes, according to industry's estimates into 'capital-opportunity". Some other day we can discuss just how misleading that is. But if that is the case, the long years of basic research (longer, typically done clinical) take a huge chunk of that money that "could be invested somewhere else". So again, basic research done at the taxpayer's expense doesn't simply help, it is essential. That is why pharma executives often testify in Congress in favor of heavily funding NIH, and that is why one of the main lobbyists for California's Stem Cell Research funding was big pharma.

I know the difference between funding basic research and investing in bringing the molecule to the market. I know the costs of clinical are huge (although probably considerably less than your CEO claims). We all know all that.

The main point by Boldrin and Levine still stands: is the patent system as it is now the best, the most efficient? They make a compelling case that is is not. Your dismissal as "they don't know what they are talking about" is hollow as you provide no refutation, except for a minor point on orphan drugs. You simply state they don't know and pull an authority stunt pretending to undermine serious criticism.

Yes, drug discovery is expensive. Yes, some sort of protection should exist to promote innovation. The truth as many of us see it is that your industry spends a lot more in marketing unnecessary drugs than in the R&D so close to your heart. A lot of us think that the patenting system as it is rewards wasteful (for society) spending in legalistic and marketing tricks to extend patents. The case for an industry that is more interested in hiring drug reps and ad agencies than scientist is strong, and you will not brush it away with simply stating that you know and we don't

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5. Palo on April 3, 2006 11:01 PM writes...

It's late, I'm tired, a bit pissed off, and I made an unacceptable amount of typos. It could be used against me as it was against Boldrin and Levine.

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6. wcw on April 4, 2006 1:32 AM writes...

Wow -- after my first comment that discussion went places I didn't expect. To refresh: I think patents *in general* are broken (one click, people) and need fixing, but that pharma is a special case, for the same reasons that health spending works best under socialized (Germany, France) systems.

So, say you hate patents. What can pharma do? Trade secrets, as noted, do nothing. It would seem simple to me: give patent-like protection to the people who jump through the FDA hoops, or socialize the whole damned thing. It's no good being allowed to make a generic if the FDA won't let you sell it for twelve or eighteen years, mm? Moreover, I don't see how wonder-drug chemists would do worse work is their checks were cut by the Feds rather than by Merck.

In the end, it's all execution. I have as little regard for Fed bureaucrats as other have for Pfizer's, so the I'm agnostic on the latter alternative. On the former, try to remember: Pharma is a big industry, but it remains a fraction of economic activity. Patent affects everything.

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7. Derek Lowe on April 4, 2006 7:49 AM writes...

Palo, I'll start another post on the topic of opportunity costs and basic research, and we'll see where that goes. It's a topic that I've covered before: see here and here, among others.

If I'm not mistaken, you're from academia - am I right? Most of the passionate drugs-are-paid-for-by-federal-money arguments I've come across come from there. Believe me, most folks in industry haven't heard that one, and when they do, the response is incredulous laughter.

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8. Antineoplastic on April 4, 2006 8:34 AM writes...

Said wcw "To refresh: I think patents *in general* are broken (one click, people) and need fixing, but that pharma is a special case, for the same reasons that health spending works best under socialized (Germany, France) systems."

Are you serious?

Rationing health care and cutting people off once they reach a predetermined age is much worse than our imperfect system.

Not to mention the fact that as a researcher, I easily put in 70 hours a week, equal to two French workers. Although I would love the 5-6 weeks of vacation per year, I feel that my work would stagnate and I would never find enough to do while away from my bench.

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9. JSinger on April 4, 2006 11:02 AM writes...

The main point by Boldrin and Levine still stands: is the patent system as it is now the best, the most efficient? They make a compelling case that is is not.

I think that's an entirely reasonable point, and one with which most of us would agree, albeit with different ideas for improvement.

It has nothing to do, though, with Boldrin and Levine's argument, which is that patents should be abolished entirely, so we can return to the glorious days of travelling medicine shows.

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10. qetzal on April 4, 2006 12:36 PM writes...

I second JSinger's comments.

Is the patent system as it is now the best, the most efficient? Probably not.

Do Boldrin and Levine make a compelling case? In general, I don't know; I've only read the pharma chapter. But at least in that specific case, they clearly do not.

As I noted in the previous thread, they do not adequately address how regulatory requirements affect development costs. It costs far more for an innovator to identify a new drug and prove that it's safe and effective, versus a generic firm that only needs to show bioequivalence to the innovator's product. I think that's pretty much indisputable, no matter what you believe about the "real" cost to develop a new drug.

Patents are currently the only mechanism that allows an innovator to recoup those extra costs. If you abolish drug patents without addressing that inequality, private firms will NOT continue to innovate.

Boldrin and Levine argue that drug development can be made more efficient if we abolish patents. Perhaps they believe the above problem can be readily addressed (e.g. by socializing drug development). Maybe they're right. But their chapter on pharmaceuticals doesn't come close to making that case.

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11. Palo on April 4, 2006 12:46 PM writes...

If I'm not mistaken, you're from academia - am I right? Most of the passionate drugs-are-paid-for-by-federal-money arguments I've come across come from there. Believe me, most folks in industry haven't heard that one, and when they do, the response is incredulous laughter.

Derek,
We can dance around this topic and each of us can dance to the tune we choose. Yes, am from academia, I'm a trained chemist, a practicing molecular biologist and an intruder into science and technology politics. My stand, and that of others, on this topic is good or bad on the basis of my arguments, and not on the label you want to stick on me to make your arguments easier. The laughter of your colleagues is inconsequential to me and to this discussion, as they provide not a single idea or argument.

Again, the only reason we critics point out that most basic research is done by the public is because pharma keeps playing the scare card "if don't make this great profits you don't get innovative drugs". You seem to share the view that Academia does the bulk of basic research, where most of real innovation comes from. You rightly talk about the great costs of development and clinical trials. The conclusion could then be: innovation comes from Academia, pharma adds the big money muscle required to bring it to the market. Well, that is precisely the argument and potential alternative that some critics envision: leave drug discovery to Academia, let private business compete in development. The historical perspective Boldrin and Levine provide goes in that direction.

Besides, you keep downplaying as insignificant the costs of pre-clinical as compared to clinical, without factual basis. The study by DiMassi et. al, claims that $335 million of the $802 million it takes to bring a new drug to the market are pre-clinical, while the clinical phase takes $465 million. Not that far apart. Again, this is a the pharma-friendly, pharma-funded Study. This is what your bosses claim. Your dismissal of pre-clinical costs to downplay the contribution of federal-funded research is simply self-serving.

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12. Novice Chemist on April 4, 2006 1:14 PM writes...

Here's what I dislike about the 'academia does/can do drug development' argument: what's drug development? Where does academia contribute the most? Is it (in order of 'idea' to 'pill'):

A. Biological target identification?
B. Assay development?
C. Finding hits?
D. Hit-to-lead development?

I'm going to guess (out of near ignorance) that most of academia's contribution is in A through C in descending likelihood. I'm guessing that pharma does a far better job (as it should) of D.

What's an important contribution? Hard to say. Palo, can you draw a 'timeline' of your own and suggest where you think academia makes its contribution? Derek, could you do the same?

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13. Bruce Hamilton on April 4, 2006 1:37 PM writes...

I haven't read the original tome, and also post from a country whose government drug purchasing agency favours subsidising only those drugs from the cheapest supplier globally, with no acknowledgement of original research costs/activities.

I assume that the vast majority of the cost of novel pharmaceuticals is the "do no harm" imperative, followed by the efficacy confirmation.

The problem with abolishing patents is that they protect prior investment in the IP, and many other methods are less robust - music, film royalties anyone?. The IP owners are screwed by the marketing/production firms that attribute excessive costs to bringing items to the consumer, as royalties tend to be related to "after costs" values. Lawyers tend to get rich also.

Some patent activities currently have longer lives ( including pharmaceuticals ), and lifetime seems to be one method of providing incentives for desirable research.

Maybe another method would be to have multi-staged patents, that more closely match the phases of drug development regulatory requirements.

Make it easier to patent the overall IP, but with a finite short time to perform each of the next stages, which then gradually narrow down the final claims, and the commercial product is protected for an agreed period.

That would also encourage researchers to consider multiple specialist partners to bring products to market, rather than one large corporation.

IP is never appreciated in consumer societies, it's always seen as unwarranted cost, to be bypassed by consumers if at all legally possible.

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14. Palo on April 4, 2006 1:37 PM writes...

To obtain a patent, an invention must be:
1- novel, original
2- not obvious
3- useful

Since in the last decade or so, the great majority of drugs developed by Pharma are me-too drugs, it turns out that current patenting system as it applies to pharmaceutical compounds granted monopoly rights to drugs that are, overwhelmingly:

1- barely novel, definitely not original
2- very obvious from the chemical structure
3- not necessary

It is not too hard to see that the patent system sucks, and it sucks to a tremendous cost to society, that ends up paying higher prices to cover for the development and marketing of products that it does not need.

The reflexive response from pharma supporters to this problem is, generally speaking, divided in two:

1) There's no problem. Me-too drugs are great, critics don't know what they are talking about.
2) Yes, the system is not great but there's no alternative

I won't argue with 1) because we talk a different language. As for 2), I'll take some time to put together all the many different solutions that people proposed, and they are many.

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15. Buddha on April 4, 2006 1:39 PM writes...

With reference to the academic discovery of the COX-2 receptor, I believe the Rochester group that discovered it attempted to sue Merck for royalties. They lost. It seems the courts did not believe their contributions led to the direct discovery of Vioxx. Was it important? No question however it is completely seperate from the drug discovery process.

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16. Palo on April 4, 2006 1:40 PM writes...

Novice chemist, I mostly of agree with your timeline.

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17. Atom pusher on April 4, 2006 2:43 PM writes...

With regard to the pre-clinical timeline, one should also consider (E.) lead-to-candidate development. This is a tremendous amount of work such as: full physiochemical characterization, in vitro assays (such as CYP IC50's, hERG, AMES) and in vivo assays (rat PK, dog PK, accute and chronic tox) keeping in mind the stringent requirements of GLP.

Does this sort of research go on in government or academic labs? I haven't seen it in my limited experience.

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18. nalcy on April 4, 2006 3:02 PM writes...

From the outside-- it seems to me that equating the basic research done by academia with the actual discovery of drugs is not so different from imagining that once you've identified bernoulli's principal, you'll know how to build an airplane.

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19. Buddha on April 4, 2006 3:46 PM writes...

Palo,
Do you have any idea how what you call me-too drugs come about? Do you think companies wait until a drug is on the market before they initiate a drug discovery program? What typically happens is that there is fierce competition within a certain therapeutic area with many companies filing numerous patents around theier respective chemical series'. If a company observes another company patenting in the same therapeutic area does the company throw in the towel. Ofcouse not. Each company pushes forward at varying speeds and what you end up with is potentially several drugs coming out within several years of eachother from different companies. Will they all act the same in humans. Probably not. Will some have better side effect profiles than others. Probably yes. Where is the malicious intent of the pharma company? As for the Nexium drum you keep beating, do you think the shareholders and analysts believe a $5 billion/year drug was a waste of time?

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20. JSinger on April 4, 2006 3:48 PM writes...

With regard to the pre-clinical timeline, one should also consider (E.) lead-to-candidate development.

Precisely! That's the biggest flaw in Palo's conflation of "pre-clinical research" with "basic research". That $335 million is being spent on formulation chemistry, large syntheses, PK/PD and tox studies -- for compounds with a %90+ failure rate! Not on producing JBC papers!

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21. t. rev on April 4, 2006 3:51 PM writes...

Or (speaking as a mathematician) imagining that discovering and developing the theory of Turing machines makes coding Microsoft Windows a trivial exercise.


(Yes, yes, Linux, whatever. Wait thirty years and maybe people will be able to do (legal!) drug development in their basement as a hobby, but we aren't there yet.)

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22. Morten on April 4, 2006 4:08 PM writes...

I'm not quite up to speed on the American health insurance concepts but can't you simply change to a company that only subsidices the cheapest drug in a class? So that no matter if your doctor prescribes Clarinex or Claritin you only get insurance money for the cheapest of the two? That would seem to make "me-too" drugs work for the consumer instead.
And of course a me-too drug is cheaper to develop than anything completely novel - for one thing the target has been proved to be drugable without (terribly) adverse effects. The only way to stop pharmas from developing me-too drugs is to extend patents to be a protection of treating a particular condition through a particular molecular target (leaving any drug where you can't exactly prove the mechanism of action out in the cold). Removing patents will simply replace me-too drugs with exactly-the-same-compound drugs.

But a suggestion for the improvement of drug development that I liked was setting up a kind of bounty system where the next patent (or couple of patents) obtained to treat a specific condition gets an extended protection period. The reason why some people laugh at efforts to develop drugs that won't earn I'm not quite up to speed on the American health insurance concepts but can't you simply change to a company that only subsidices the cheapest drug in a class? So that no matter if your doctor prescribes Clarinex or Claritin you only get insurance money for the cheapest of the two? That would seem to make "me-too" drugs work for the consumer instead.
And of course a me-too drug is cheaper to develop than anything completely novel - for one thing the target has been proved to be drugable without (terribly) adverse effects. The only way to stop pharmas from developing me-too drugs is to extend patents to be a protection of treating a particular condition through a particular molecular target (leaving any drug where you can't exactly prove the mechanism of action out in the cold). Removing patents will simply replace me-too drugs with exactly-the-same-compound drugs.

But a suggestion for the improvement of drug development that I liked was setting up a kind of bounty system where the next patent (or couple of patents) obtained to treat a specific condition gets an extended protection period. The reason why some people laugh at efforts to develop drugs that won't earn more than 1 billion $ a year is that the number of years it can earn that much are very limited...

I see the point of those against the massive marketing machines of big pharma. There are definitely some marketing execs in that are overpaid (and evil) - that's why we laugh at CEOs getting shackled =)
I'm from Denmark where ads for prescription drugs are banned (so are ads for cigarettes but not nicotine gum).

I don't like capitalism and democracy is quite overrated, but they are better than the alternatives. And to all you Americans - Denmark has free education systems (university included), health care, and an extensive welfare system (mostly unemployment benefits - it's not much especially if you don't have a private unemployment insurance and that requires that you keep a job for a year) but our political system is a constitutional monarchy. Not what you popularly call a socialist country (i.e. Cuba or North Korea, or to some extent China). It's fairly easy to fire people as long as you have a reason e.g. down-sizing or gross neglect of duties. Unemployment figures are currently 5%.

Whew, this got long. For Palo: How exactly would drug development work in a world without patents? I considered open-source but I wouldn't want to run buggy code on my nieces and nephews...

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23. SRC on April 4, 2006 5:24 PM writes...

1 -barely novel, definitely not original

2- very obvious from the chemical structure

3- [utility] not necessary

To answer each point in turn:

1. From a patentability perspective novelty/originality (you seem to draw a distinction between these, which makes no sense - how could something be novel, but not original, or vice versa? - but never mind) is a threshold phenomenon, rather like pregnancy. Something either is, or is not, novel. Novelty means (since, surprisingly, most people appear unaware of its definition) "has not been done before."

2. Obviousness cannot generally be inferred from structure. I give you your choice of beverage: methanol, ethanol, or propanol. Or the choice of exposure to benzene or toluene. Predicting the chemistry of structurally-similar compounds can be humbling, never mind the biology. (Consider the rather different biological properties of the enantiomers of thalidomide.)

As regards patents and chemical structure, let's face it, everything is structurally obvious in view of something else, depending on the level of abstraction to which you're willing to go. Is addition of a methylene group obvious? See the alcohols above. (And bear in mind that "obvious to try" is not the patent standard. I'll leave it as an exercise to figure out why.) How about adding a methyl group? Replacing a methyl group with a primary amine? Acetylating that amine? You see the point. Through relatively smooth conceptual gradations, each "obvious" in view of the adjacent ones, it is possible to make anything. The key to obviousness is whether the new compound behaves as would be expected, or provides an unexpected benefit.

3. You also obviously (no pun intended) do not understand what the word "utility" means. It means "useful." Its antonym is "useless." A me-too drug most certainly has utility; it is useful in the treatment of disease. You probably meant "greater utility than the comparison drug." Suppose the me-too has longer half-life but causes greater GI upset, but only in some people. Is that better, or worse? The problem is that you're considering the value of a drug as a scalar, when it is in fact a tensor.

Again, let the market decide which drugs are worth purchasing, and which are not.

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24. Palo on April 4, 2006 5:35 PM writes...

SRC,
if you are going to take shots on me, at least have the decency of quoting what I write, not what you wish I said. The "utility" bit in your "3- [utility] not necessary" was added by you. I simply said "not necessary". So your claim that I don't understand the word "utility" is a malicious shot.

I'll discuss the rest later when I have more time

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25. Milo on April 4, 2006 6:48 PM writes...

I have only two small things to contribute, so here goes:

1) I think it is silly that you can make a handful of compounds, say 15, and create a patent that has lots more than 15 compounds. I think the law should clearly state (and enforce) the idea that you have to make exactly what you patent. I don't like the idea of saying, "well we made this, so we are claiming all these related structures." If you claim the salt, then make the salt!

2) From what I can tell, each patent application, once sent to the PTO gets reviewed for a tiny bit of time (I seem to recall 6 hours). In this time, the reviewer has to become aware of prior art, read the application and absorb/understand it all. Some of the patents I read are 150+ pages, packed to the gills with awful legalese. How can the examiner honestly make a good descision on whether the invention is novel/non-obvious/useful in such a short period of time?

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26. Anonymous on April 4, 2006 7:32 PM writes...

Morten said:

But a suggestion for the improvement of drug development that I liked was setting up a kind of bounty system where the next patent (or couple of patents) obtained to treat a specific condition gets an extended protection period.

This already occurs to some degree with the Orphan Drug Act of 1983 where novel drugs being developed for diseases/conditions affecting fewer than 200,000 individuals in the US are eligible for tax credits, special grants and contracts, and extended patient protection.

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27. SRC on April 4, 2006 7:44 PM writes...

So your claim that I don't understand the word "utility" is a malicious shot.

You're right, I did inadvertently put words in your mouth, for which I apologize. It's the word "useful" you don't understand, not "utility."

My mistake. Sorry.

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28. Palo on April 4, 2006 9:20 PM writes...

Thanks for the clarification SRC.

With respect to your post, you clearly missed my point. I know me-too drugs are “technically� novel, not obvious and useful, that's why they get a patent. The problem is precisely that. A system that cannot distinguish between true innovation and me-too drugs is highly distorted.

1. From a patentability perspective novelty/originality (you seem to draw a distinction between these, which makes no sense

I tried to finely distinguish between technically "novel" (the wording in patents) from truly original. It seems I failed.

2. Obviousness cannot generally be inferred from structure.

But then, you answer the point yourself: "As regards patents and chemical structure, let's face it, everything is structurally obvious in view of something else". You know that once you have your pharmacologically active three-ring structure, you can play enough with all the secondary modification and you will eventually get a molecule that closely resembles the original activity. Not surprisingly, it's done too often and it works too often. How is that not a somewhat obvious process? (again, not in the legal way)

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29. weirdo on April 4, 2006 9:51 PM writes...

"You know that once you have your pharmacologically active three-ring structure, you can play enough with all the secondary modification and you will eventually get a molecule that closely resembles the original activity. Not surprisingly, it's done too often and it works too often. How is that not a somewhat obvious process?"

When someone who has absolutely no idea how to discover a drug makes comments like that, it's hard to take them seriously.

Let's take your (admittedly false) premise to it's logical conclusion: with a biological target and a screening hit, isn't it obvious just about anybody can find a drug? So why patent any of them?

That's basically what you're saying, isn't it -- the scientists in Big Pharma are just too plain stupid to do anything truly innovative. Nature papers and JPET articles are innovation. Finding drugs that treat patients, well, that's just grunt work, and not worth the time of a serious (innovative) scientist.

Sheesh.

Oh, and those pesky me-toos? Go back to taking diphenhydramine, then. Yup, those "non-sedating" anti-histamines just weren't worth the time and money required to discover them. Oh, here's a better example -- don't take Allegra, take Seldane. But then don't get too upset if your heart stops beating.

By the way, any answer to that question to you about your statement that over half of all blockbusters were actually discovered on the Federal dime? "Because Marcia Angell said so" doesn't quite cut it.

We've simply got to get past this "Us vs. Them" BS. Academic researchers by and large have NO CONCEPT of drug discovery and so dismiss it out of hand. Your average industrial drug researcher never read a paper from an academic lab that helped him/her make a better molecule for Project X, so think academicians are a waste of time (and their tax dollars). The truth is somewhere in between, and the sooner we get there, the better off we'll all be.

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30. Palo on April 4, 2006 10:00 PM writes...

Wow, it seems all the virtuous worshippers of the Church of Pharma came out to vote today. It just feels like being gay in Ohio during a presidential election.
Oh Lord, our CEO, forgive the sinners who question pharma’s tactics and motivations. Forgive the heresy of those who question how innovative the Church is by spreading blasphemous stories about NIH contributions. Amen.

Just how blasphemous am I?

Atom pusher writes...

With regard to the pre-clinical timeline, one should also consider (E.) lead-to-candidate development. […] Does this sort of research go on in government or academic labs? I haven't seen it in my limited experience.

You obviously haven’t heard of AZT and other AIDS therapies, or of Taxol, all completely developed by the NIH with federal funding
You still miss the point. The fact that not all pre-clinical work is done by Academia, a large part of the discovery is. That is a huge chunk of money invested by the taxpayer that pharma doesn’t have to spend, but it claims it does. And like it or not, discovery is where the true innovation resides. Post-discovery and clinical phases are mostly brut force. (I know, heresy!)

Similarly, Jsinger says,

Precisely! That's the biggest flaw in Palo's conflation of "pre-clinical research" with "basic research". That $335 million is being spent on formulation chemistry, large syntheses, PK/PD and tox studies -- for compounds with a %90+ failure rate! Not on producing JBC papers!

Not true. You have your facts wrong. Let’s split the discovery phase (what Academia mostly contributes to) from the rest, as you demand. When you do that, according to, once again, Joe DiMasi, unsuspected pharma cheerleader, about 34% of the $802 million it takes to bring a pill to the market goes to the discovery phase. That is about $272 million. Discover, or basic research as you write, is by far the most expensive part of pre-clinical

Nalcy and t.rev make some bogus analogies:

it seems to me that equating the basic research done by academia with the actual discovery of drugs is not so different from imagining that once you've identified bernoulli's principal, you'll know how to build an airplane.

This clearly shows a lack of understanding of the role the 28billion dollar annual NIH budget plays in drug discovery. A closer analogy to what the NIH means to drug discovery would be for government to fund all the research in airflow dynamics modelling, all the development of light solid materials, all the aircraft design, and then have the company that does the assembly and testing claim they invented the air travel..

Buddha , you explanation of how me-too drugs come about is of no consequence. Whether a me-too drug comes after patent filing or after successful product launch by the competition, it is still a repetitive non-original copycat.

Where is the malicious intent of the pharma company?
. Buddha, it is not a question of malice or even of intent. It is a matter of public policy. Are copycats good for society or not?

As for the Nexium drum you keep beating, do you think the shareholders and analysts believe a $5 billion/year drug was a waste of time?
.

Of course not. They are indeed quite happy with pushing a needless pill if it means aft profits. You are completely missing the point. I don’t complain in the name of the shareholders, I complain in the name of the patients that pay a lot more for a drug (which obviously makes your shareholders happy).

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31. Palo on April 4, 2006 10:10 PM writes...

That's basically what you're saying, isn't it -- the scientists in Big Pharma are just too plain stupid to do anything truly innovative

It has nothing to do with stupidity. It has to do with the funding allocations that pharma CEO take to maximize profits. It is cheaper and more profitable to go after a me-too drug than to invest in real innovation. That's why pharma leaves basic research to the NIH, because it is cheaper.

Let's take your (admittedly false) premise to it's logical conclusion: with a biological target and a screening hit, isn't it obvious just about anybody can find a drug? So why patent any of them?

The problem is that what you call my premise is actually yours. We are not talking about "screening hits", we are talking about proven, successful drugs. Those are the ones copied by me-too drugs, not simply "screening hits".

It seems it is customary to some pharma simpathizers to draw straw men and fight them hard. Good job weirdo

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32. Jim Hu on April 5, 2006 1:15 AM writes...

I'm missing something basic here. I don't understand why these threads (and Boldrin and Levine) spend so much energy on the copycats. Isn't the question whether the truly innovative stuff would be more or less available if patents were abolished?

I thought part of the reason for the copycats is that they're cheaper on average to bring to market than things that are riskier. So, suppose me-too drugs are indistinguishable from the things they're copying...and as a result of changes in patent law we, as a society, remove the incentives for that kind of drug development (let's just assume for the sake of argument that we have some objective way to decide what is or is not a copycat). Wouldn't that make the average cost of bringing a new drug to market go up?

Also, suppose Palo, Boldrin, and Levine are correct that the Federal contribution to research is vastly undervalued in the discussion of the cost of drug development. I can see that as arguable depending on where you draw the lines around what counts as drug development. It doesn't follow that stuff developed in academic/nonindustry labs would be efficiently brought to market without protection of the costs sunk into the later development and testing. The vast majority of that NIH-funded research doesn't make the later phases cheaper or faster.

I think the patent system does have rent-seeking issues and other problems...many patents are overly broad, I'm not crazy about patenting targets, much less genes, and so on. I also think that the problem of suppressing some desired activities at the same time that one encourages others is real. But I'm not sure that it follows that we'd be better off with no patents at all for pharma, which seems to be Boldrin and Levine's argument. Despite going through all the posts, I can't tell if Palo goes that far or not (if I missed it, sorry, it's late).

I would like to hear more about Boldrin and Levine's claims with respect to Swiss pharma...I don't know enough to evaluate how they portray it.

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33. Will on April 6, 2006 2:11 AM writes...

Palo,

I'm certainly not a pharma worshipper, but I do believe in the value of patents. The issues with me-too drugs would still be present in a no patent system. The marketing problems would still be present in a no patent system. I would be willing to bet that the marketing problems would be even worse in a no patent system. Just think, instead of all the commercials we see talking about how Bud Light is better than Miller Light, we would have commercials about how drug X is better than drug Y, when they are both identical. This would create even more confusion and it would be even easier for drug companies to "buy off" doctors.

I agree the patent system has a lot of problems with it. I also think me-too drugs don't add much real value. But no one knows what company is going to find the compound that cures alzheimers, cancer, or diabetes. The more drug companies with money to develop new products the better chance we have that new cures will be found.

I think it would be better to get the FDA drug approval process reformed so that more drugs are approved (costs are lower)and then giving doctors, pharmacists, and consumers more control(responsibility) over what drugs they choose to use.

Healthcare as we know it in the US is going to fall to pieces in my generation (im 22). Luckily by that time a lot of the blockbuster/wonder drugs/whatever of today will be generic by then.

-Will

PS: I've been a lurker forever at this blog. Ever since the Science article that referenced it. Your website is in my favorites Derek, keep up the great work!

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34. Sebastian Holsclaw on April 6, 2006 10:20 AM writes...

Palo, I don't understand why you are so concerned about patents for the "useless" me-too drugs. The patent isn't causing problems for research because according to you the me-too drug is useless. The patent isn't allowing drug companies to squeeze money out of consumers because they can just use the first product (which will be cheaper now that it has more competition). So, why do you worry so much about it? The only way a patent impacts one of these areas is if it doesn't in fact describe something useless.

In the previous thread, but still regarding the uselessness of me-toos, PS suggested that the problem was "people dont buy me-toos, their insurance companies do (and indirectly all of us via higher insurance premiums)."

This doesn't make sense to me. Insurance companies have a huge incentive to keep costs down—and if you have ever worked with them you know they don’t take it lying down. It is very common for insurance companies to insist that you not use more expensive brands until you show side effects from a generic drug or cheaper active patent drug. In fact it is so common that there are regular complaints about insurance companies getting between people and their doctors. The storyline in the patent cases is about a majority of poor innocent doctors being unable to make informed decisions in the face of brilliant marketing. The storyline in the insurance discussion revolves around super-informed doctors having their judgment questioned by insurance companies.

That is a bit of a digression, but whatever you think about insurance companies, you should realize that they look out for themselves. The idea that innocent insurance companies are getting tricked into paying for useless products just doesn’t stand up.

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35. TWAndrews on April 6, 2006 8:39 PM writes...

,i>Here's what I dislike about the 'academia does/can do drug development' argument: what's drug development? Where does academia contribute the most? Is it (in order of 'idea' to 'pill'):

A. Biological target identification?
B. Assay development?
C. Finding hits?
D. Hit-to-lead development?

Academia's focus has been almost exclusively on A, with efforts now being made in B. The NIH roadmap establishes a number of chemical screening centers (most of which are only getting started), so in the future there will be some very minor dabbling in C.

But while academia is good at finding (and ok at validating) targets, I don't konw of a single molecule which has been discovered in an academic lab.

Can anyone point me to an example?

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