About this Author
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: Twitter: Dereklowe

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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 29, 2011

XMRV: Over With and Done?

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Posted by Derek

Here's an excellent post-mortem on the whole XMRV chronic-fatigue controversy, which I think almost everyone can agree is now at an end. The latest results are from a large blinded effort to detect the virus across a variety of patient sample (and across a number of labs) - and it's negative. The paper that started all the furor has been partially retracted. As far as I can see, the story is over.

But Judy Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) in Nevada, whose work started all this off, is still a believer. And so, as you might imagine, are many patients:

Mikovits has become something of a savior in the community of people with CFS (also known as myalgic encephalomyelitis, or ME), who for decades have endured charges that the disease is psychosomatic. The 2009 Science paper shouted out that CFS may well have a clear biological cause, and, in turn, raised hopes of effective treatments and even a cure. The new findings give her “great pause,” yet she suspects they're but a speed bump. “I haven't changed my thinking at all,” she says. And she worries that the Blood Working Group conclusions will confuse people with CFS, some of whom got wind of the results early in the blogosphere and contacted her in a panic. “I had 15 suicidal patients call me last week,” she says.

In scientific circles, Mikovits has developed a less flattering reputation. Critics have accused her and her backers of stubbornly wedding themselves to a thesis and moving the goalposts with each study that challenges their conclusions. Even disease advocates who welcome the attention XMRV has brought to CFS believe the time has come to put this line of research to rest. “It's hard to say that this has not received a fair appraisal,” says Kimberly McCleary, president of the CFIDS Association of America, a patient group in Charlotte, North Carolina.

At the worst extreme, you get things like this. Note that that post's comment section filled up with people doubting, very vocally, that any such thing was going on, and sometime hinting at big conspiracies to keep the truth from being heard. I'll be a bit disappointed if some more of that doesn't attach to this post as well.

But while I can see why patients in this area are frustrated beyond words, and desperately hoping for something to help them, they're going to have to deal with what every scientist deals with: the indifference of the universe to what we want it to provide. Blind alleys there are beyond counting, wasted effort there is beyond measuring, in trying to understand a disease. We're used to, as humans, seeing agency and design when something seems so well hidden and so complex - in this case, malevolent design. But just as I reject the intelligent design hypothesis to explain what looks benevolent, I reject it for what sometimes looks like an evil practical joke: the perverse difficulties of biomedical research.

Comments (31) + TrackBacks (0) | Category: Infectious Diseases

Ah, Remember Those Days? How Will We Remember These?

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Posted by Derek

If you want to know what it was like during the height of the genomics frenzy, here's a quote for you, from an old Adam Feuerstein post. Return with me to the year 2000:

During his presentation Wednesday, Mark Levin, the very enthusiastic CEO of Millennium Pharmaceuticals (MLNM), remarked that his company's gene-to-patient technology would turbo-charge drug-development productivity to levels never before seen in the industry. Just how productive? Well, he predicted that by 2005, Millennium would be pushing one or two new drugs every year onto the market, while keeping the pipeline brimming with at least five experimental drugs entering human clinical trials every year.

Note that I'm not trying to make fun of Millennium, or of Mark Levin (still helping to found new companies at Third Rock Ventures). A lot of people were talking the same way back then - although, to be sure, Feuerstein notes that many people in the audience had trouble believing this one, too. But there's no doubt that a wild kind of optimism was in the air then. (Here's another Levin interview from that era).

That's as opposed to the wild kind of pessimism that's in the air these days. Here's hoping that it turns out to be as strange, in retrospect, as this earlier craziness. And yes, I know that the current reasons for pessimism are, in fact, rather bonier and more resilient than the glowing clouds of the genomics era were. But it's still possible to overdo it. Right?

Comments (22) + TrackBacks (0) | Category: Drug Industry History

September 28, 2011

Andy Grove's Idea For Opening Up Clinical Trials

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Posted by Derek

The last time I talked here at length about Andy Grove, ex-Intel CEO, I was rather hard on him, not that I imagine that I ruined his afternoon much. And in the same vein, I recently gave his name to the fallacy that runs like this: other high-tech R&D sector X is doing better than the pharmaceutical business is. Therefore the drug industry should do what those other businesses do, and things will be better. In Grove's original case, X was naturally "chip designers like Intel", and those two links above will tell you what I think of that analogy. (Hint: not too much).

But Grove has an editorial in Science with a concrete suggestion about how things could be done differently in clinical research. Specifically, he's looking at the ways that large outfits like Amazon manage their customer databases, and wonders about applying that to clinical trial management. Here's the key section:

Drug safety would continue to be ensured by the U.S. Food and Drug Administration. While safety-focused Phase I trials would continue under their jurisdiction, establishing efficacy would no longer be under their purview. Once safety is proven, patients could access the medicine in question through qualified physicians. Patients' responses to a drug would be stored in a database, along with their medical histories. Patient identity would be protected by biometric identifiers, and the database would be open to qualified medical researchers as a “commons.” The response of any patient or group of patients to a drug or treatment would be tracked and compared to those of others in the database who were treated in a different manner or not at all. These comparisons would provide insights into the factors that determine real-life efficacy: how individuals or subgroups respond to the drug. This would liberate drugs from the tyranny of the averages that characterize trial information today.

Now, that is not a crazy idea, but I think it still needs some work. The first issue that comes to mind is heterogeneity of the resulting data. One of the tricky parts of Phase II (and especially Phase III) trials is trying to make sure that all the patients, scattered as they often are across various trial sites, are really being treated and evaluated in exactly the same way. Grove's plan sort of swerves around that issue, in not-a-bug-but-a-feature style. I worry, though, that rather than getting away from his "tyranny of averages", that this might end up swamping things that could be meaningful clinical signals, losing them in a noisy pile of averaged-out errors. The easier the dosing protocols, and the more straighforward the clinical workup, the better it'll go for this method.

That leads right in to the second question: who decides which patients get tested? That's another major issue for any clinical program (and is, in fact, one of the biggest differences between Phase II and Phase III, as you open up the patient population). There are all sorts of errors to make here. On one end of the scale, you can be too restrictive, which will lead the regulatory agencies to wonder if your drug will have any benefit out in the real world (or to just approve you for the same narrow slice you tested in). If you make that error in Phase II, then you'll go on to waste your money in Phase III when your drug has to come out of the climate-controlled clinical greenhouse. But on the other end, you can ruin your chances for statistical significance by going too broad too soon. Monitoring and enforcing such things in a wide-open plan like Grove's proposal could be tough. (But that may not be what he has in mind. From the sound of it, wide-open is the key part of the whole thing, and as long as a complete medical history and record is kept of each patient, then let a thousand flowers bloom).

A few other questions: what, under these conditions, constitutes an endpoint for a trial? That is, when do you say "Great! Enough good data!" and go to the FDA for approval? On the other side, when do you decide that you've seen enough because things aren't working - how would a drug drop out of this process? And how would drugs be made available for the whole process, anyway? Wouldn't this favor the big companies even more, since they'd be able to distribute their clinical candidates to a wider population? (And wouldn't there be even more opportunities for unethical behavior, in trying to crowd out competitor compounds in some manner?)

Even after all those objections, I can still see some merit in this idea. But the details of it, which slide by very quickly in Grove's article, are the real problems. Aren't they always?

Comments (46) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs