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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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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


COMMENTS

1. Nick Henriquez on May 11, 2004 3:45 AM writes...

And so it continues. Much needed revenues are tied up in litigation despite that here is a clear case of prior art.

Where is the advantage in having patent laws if people don't properly implement them? Apart from the clear advantage for lawyers that is.....

There should not even BE an argument or an other side. If we simplify the law and stick to it we can save plenty on lawyer fees. This could be used to boost research or, heck why not, increase shareholder payments.

Permalink to Comment

2. qetzal on May 11, 2004 11:45 AM writes...

I assume the question is whether method of treatment (MoT) patents should be granted in general. I have a hard time seeing the justification.

I believe in the value of patents in general, to encourage innovation as well as public disclosure of innovation. But MoT patents seem an awful lot like to trying to patent something in its natural state. Delmuth didn't invent the fact that inhibiting DP-IV will lower glucose levels. He discovered it.

Now, for the sake of argument, let's assume Delmuth was the first to think of inhibiting DP-IV as a way to treat diabetes. Certainly, he should be free to find some new compounds that are effective in that way, and patent them. He should also be free to find some old compounds, show that they work, and get method of use patents on them.

But patenting the *idea* of inhibiting DPP-IV is like patenting the pathway itself. I don't see that there is sufficient inventiveness involved, and I certainly don't see a practical justification based on the standard net public good arguments for patents.

On the other hand, I can see how you could take the same argument and apply it to method of use patents. So, my general feeling is that MoT patents cross the line, but I can't quite figure out how to define the line clearly!

All personal opinion, of course. I'm not a patent atty, nor do I play one on TV.

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3. SRC on May 11, 2004 1:01 PM writes...

Nick,

Patent law is simple enough; it's reality that's complicated. Every situation grades smoothly into another one, so that there's never a sharp demarcation between what's in and what's out - hence the disputes.

The rules of tennis are simple enough too. If the ball hits on one side of a line it's in, the other side, it's out. The problem is that a blistering serve doesn't just bounce, it skids, leaving a streak that spans the line. In, or out? That's not a bad analogy to many of the disputes in patent law.

I'm speaking generically, here, not to this particular case, for which I don't know the facts. Examiners do blow it, to be sure, but it's rare that an examiner considers a directly on-point reference and then ignores it.

Qetzal,

Typical method of use claims cover a new use of a known compound, which is fair enough (although usually hard to enforce). Delmuth's type of method claim (essentially providing therapy by hitting a target, but without providing any compounds that actually do so) sounds like that of the Univ. of Rochester, whose corresponding claim was recently rejected by a Federal district court.

To your point regarding patenting the idea, it sounds as though there is a strong obviousness argument to be made against Delmuth's claims. (Obviousness in this context does not have its colloquial meaning, which would result in endless arguments; it means someone contributed one piece, and in a written document someone suggested combining that piece with the other critical piece that makes up the invention. Here, Holst's in vitro data plus his suggestion of a treatment for diabetes qualify.)

So my advice to Delmuth would be, cash the checks from Merck and J&J fast.

Permalink to Comment

4. Clay on May 11, 2004 5:13 PM writes...

Hi Derek

Assuming the purpose of patent laws is to encourage innovation (by protecting its value), Demuth's patent might be appropriate. You could argue that he wouldn't have identified the relationship between DP-IV and diabetes if he hadn't believed that the knowledge would be worth something.

Did he? That's where any value lies, it seems. If he didn't, then he's only restating someone else's findings, and that's worth very little, certainly not a patent. I mean, obviously inhibiting a disease pathway will inhibit the disease.

Even if he did make the discovery, it gives him huge power over the development DP-IV inhibitors. Or does it? How much is his discovery worth in comparison with the drug development process? I suppose you could ignore his patent and let a patent court decide how to apportion any profits. I don't know if that's how patent courts work though.

Permalink to Comment

5. Richard on May 14, 2004 10:15 PM writes...

"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."

Ha! C. elegans labs universally understand "GLP-1" to mean the product of the first of the "abnormal germline proliferation" worm genes. This is utterly unrelated to glucagon-like peptide 1, of course.

Permalink to Comment

6. OCB on July 7, 2004 1:38 PM writes...

Delmuth's patent doesn't teach anyone what the inhibitor of DDP-IV looks like, where to go to find one, how to make one. Effectively there is a lack of the written description needed to enable one skilled in the art to practice the claimed invention without undue experimentation. No?

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