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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: Twitter: Dereklowe

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February 13, 2006

Heart-Warming Stories of Success

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Posted by Derek

One of the things about the Rishton article that set off some of my colleagues at work is the section where he discusses small-company successes. They've got a point, because the list is a bit off. Among the companies that he mentions as being very productive are Neurogen. I have a problem with that choice, partly because I've known people who've worked and interviewed there. I'll give them credit for surviving as long as they have, but the reason that's worth congratulating is that the company has, to my knowledge, never made a dime.

They've been at it for ten or fifteen years now, and have never brought a compound to market. Now, I can't be too hard on them, because they're working in the CNS field, which is a well-known Boulevard of Broken Dreams in drug development. But still, their success rate (measured where it really counts) is zero. The sort of success they've had is in getting other companies to invest money in them, which many have done over the years. That's nothing to sneeze at, but it may not be something that we should all emulate, either.

Another company on his list is Sepracor, and you'd have to consider them a special case, wouldn't you? After all, I don't think that we can all make a living by ripping off(or more charitably, piggybacking on) other people's patents - can we? That's what got them to where they are today. Their current success story, Lunesta (eszopiclone) is the S enantiomer (the left-handed form) of an older Aventis drug, zopiclone (note the generic name: S-zopiclone, get it?) I understand and agree with Rishton's point about working on druglike molecules, but somehow I don't think this is quite what he had in mind. . .

Comments (13) + TrackBacks (0) | Category: Drug Development


1. Palo on February 13, 2006 11:59 PM writes...

I thought the whole thesis of Rishton had to do with pipeline problems as a consequence of bad R&D strategies. Neurogen not making money yet does not take anything away from his main points, provided that Neurogen pipeline is promising for a cost-efficient small company. They do have a novel insomnia compound in trials, I think.
I don't know Sepracor's pipeline and originality. I agree with derek on his distaste for their me-too drug strategy, although I truly don't see the S-enantiomer as a more egregious rip-off than other me-toos. If anything, they were smarter in their rip-off.

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2. Petros on February 14, 2006 3:04 AM writes...

I didn't have time to read all the article yesterday bur articles of this type often choose imperfect examples of companies success to prove the point the author is trying to make.

I'd concur with the comments about Sepracor, whose success has relied on patent examiners not deeming it obvious that a single enantiomer is more active than the previousl patented racemate. But the sustained success of Plavix also hangs on such an arguement in a case that is in court this year.

Examination of Sepracor's patents suggested its strategy was to file before doing any significant work, since many filings consisted of pairs of patents referring to (+) and (-) enentaiomers with identifical claims and dislcosures about from the compound descriptor and no evidence as to whether one enantiomer was actually more potent.

This approach used to be called Improved Chemical Entities (ICE) but the company started to get touchy about the ICE hanld and dropped using this name a few years ago.

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3. Pankaj on February 14, 2006 7:22 AM writes...

Not all "me-too" drugs are bad science. In fact, for industry outside of US, this strategy has meant development of process chemistry by leaps and bounds. A case in point is that of India. Due to the process patent laws in pre-GATT India, the local process optimization chemistry expertise has improved a lot. The Indian chemists are very good at taking a long multi-step process and optimizing it down to a more economical and faster route.

Second, however incremental it might be, a "me-too" drug is an improvement afterall (in most cases). Just because it is "easier" route towards commercial success, is it allright to deride it?

Of course, there are exceptions........

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4. Derek Lowe on February 14, 2006 7:58 AM writes...

I don't mind the me-too aspect (note the category by that name at the top of the list there to the right). But Sepracor cuts it about as close as it's possible to cut it. At least the structures of the various statins and ACE inhibitors are all different, giving them some real differences in the patient population.

The closest thing to the chiral-switch strategy is taking the active metabolite of your drug and calling that the second generation, with Claritin/Clarinex being the most glaring example. And Sepracor had their hand in that one, too.

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5. tom bartlett on February 14, 2006 8:48 AM writes...

I share everyone's feelings about Sepracor, BUT what REALLY gots under my skin are "gene patents" you see out there. By what stretch of imagination can you patenet a gene?

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6. RKN on February 14, 2006 9:37 AM writes...

By what stretch of imagination can you patenet a gene?

  I wondered the same thing. I found these reasons in favor of gene patents at the human genome project web site.

  Of all the arguments against, I found this one the most curious:

"Patent holders are being allowed to patent a part of nature --a basic constituent of life; this allows one organism to own all or part of another organism."

   This might not be a big concern in every case. If a researcher wanted to experiment with a patented gene, might they not simply create a single nucleotide mutant of the patented gene in an organism, one that preserves the function of the gene product, and in that way clear patent infringement? Similar to what happened in the Diamond vs Chakrabarty case, also mentioned at the site.

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7. jxh on February 14, 2006 10:52 AM writes...

At least as far as metabolites are concerned, it's becoming somewhat more difficult to obtain patent protection. Actually, it would be more appropriate to say it is more difficult to "maintain" patent protection for metabolites.

The Federal Circuit (generally the final decision-maker regarding patent matters) recently decided Smithkline Beecham v. Apotex. Smithkline originally had a patent on an anhydrous molecule. Later they obtained a patent for the hemihydrate version, which we know as Paxil. Apotex, wanting to bring their product to market, needed to invalidate the claims covering the hemihydrate.

They were successful. Simply put, a person can't get a patent if their invention was already known before they filed their application - this is known as anticipation. Here, the court said that you can't make the anhydrate without making at least *some* hemihydrate; thus, the court said, following the procedure disclosed in the anhydrate patent inevitably creates some hemihydrate, and thus anticipates the claims of the hemihydrate patent. This renders the hemihydrate claims invalid.

This decision is at odds with prior cases. Formerly, there would've had to have been some recognition that following the procedure to make the anhydrate would necessarily produce the hemihydrate, but there was no such recognition at the time they came up with that process.

So what happens now? Tough to say - theoretically, any patent claim to a metabolite now can be knocked out if you can simply show that production of the metabolite is a natural result flowing from following some known procedure, even if nobody was previously aware of this.

As one Federal Circuit judge noted, this calls into question "the patentability of antibiotics, hormones, antibodies, and myriad other previously unknown or unisolated products." It will be interesting to see where this goes.

An interesting aside - for years, the Fed. Circuit judges usually had strong science backgrounds. Recently, though, its appointments have been more and more political. in fact, the judge who decided Smithkline, while certainly very intelligent, does not have a background in any science. In order for an attorney or agent to be admitted to practice before the Patent and Trademark Office, a science degree is generally necessary. My suggestion is to have a similar requirement for the judges of the Federal Circuit.

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8. Chris C. on February 14, 2006 5:53 PM writes...

He has another article in Drug Discovery Today from 2003 which I think is equally provocative and probably more practically useful. I highly recommend it.

Rishton's article in Drug Discovery Today:

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9. Chris C. on February 14, 2006 6:06 PM writes...

What are "warheads"? Are these highly reactive groups that covalently bond to a protein?

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10. Theodore Price on February 14, 2006 8:58 PM writes...

Per the 2 comments above, I also think gene patenting seems to be unwarranted and completely unjustifiable. I also know several people that hold patents (through their universities) on genes important for CNS research and target development. I am curious, does this create a real hinderance for drug discovery if the patent is held by a public university (through NIH funds)? I'm sure it does if it is held by a pharma or biotech company. For instance if a pharma company holds a patent on an important (or potenitally) GPCR does that then stop another company from developing a high throughput screen against that GPCR? Can this be circumvented by cloning the cDNA from another species (say canine vs human) and re-patenting? I'd love to know...

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11. LNT on February 15, 2006 9:18 AM writes...

The gene patent is actually a patent on the DNA sequence, not the protein product. Therefore a company CAN do research on a patented GPCR provided that they do not use the cDNA sequence in order to obtain the protein. There are various biotech companies that provide methods of obtaining protein products without ever going through the DNA sequence. (thereby circumventing gene patents)

I also believe that an multinational company can use the patented cDNA sequence "offshore" without violating US patent laws. Therefore, a pharmaceutical company can get around a gene patent by doing the "infringing" work in a country that doesn't allow gene patenting. (If I remember right, Ireland is a common place to do this)

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12. Tacker on November 24, 2006 9:02 AM writes...

This decision is at odds with prior cases. Formerly, there would've had to have been some recognition that following the procedure to make the anhydrate would necessarily produce the hemihydrate, but there was no such recognition at the time they came up with that process.

Permalink to Comment

13. Ken Dryden on December 5, 2006 5:49 AM writes...

The court said that you can't make the anhydrate without making at least *some* hemihydrate; thus, the court said, following the procedure disclosed in the anhydrate patent inevitably creates some hemihydrate, and thus anticipates the claims of the hemihydrate patent.

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