Targets Versus Drugs

Summary

• The '850 patent filed by the University of Rochester had several claims, with several key ones coming down to a method of treating human patients with a compound that was a selective inhibitor of COX-2.
• After being granted that patent, the University of Rochester filed suit against Pfizer for marketing two COX-2 inhibitors, which Rochester claimed violated their patent.
• In order to be useful, a drug has to be able to be dosed in a human patient, last long enough to have a beneficial effect, and not by itself (or through its breakdown products) cause so many harmful side effects that it's not worth taking.
• It also has to be produced on large scale, under very tight tolerances, and be stable enough so that it can be stored and shipped without alteration.
• But the main point is that a target, a mechanism is most certainly not a drug.

There was a comment on the blog the other day about how there are people in academia who feel that the discovery of a new target or pathway is basically finding a new drug, and that the rest is "technicalities". I've encountered that view of the world before (Donald Light/Rebecca Warburton, Marcia Angell, and similarly, Arnold Relman), so it's not just some aberration, but it's just amazingly wrong. People keep pointing this out, including people who've worked in the industry and people who haven't, but to no avail.

So, here's an example that illustrates the difference. If you pick one of the most famous drugs in the world (aspirin, first reported in 1899), it can come as a surprise to people outside the field how long it took to find out how it worked. It wasn't until 1971 that John Vane at the University of London figured out that it (and the other non-steroidal anti-inflammatory drugs) worked by inhibiting the cyclooxygenase enzyme (COX), which is responsible for producing the signaling molecules (prostaglandins) that produce the downstream effects. Aspirin does other things as well, but that's the big mechanism that everyone had been searching for. During the 1980s, extensive work on this enzyme and its genetic background led to the discovery in 1991 (at Brigham Young, by Dan Simmons and his group) of a second subtype of the enzyme (COX-2).

And that set off quite a chase. Because it looked like if you could inhibit COX-2 and not COX-1, you might be able to get the pain-relieving antiinflammatory effects of aspirin without the gastrointestinal side effects of bleeding, irritation, etc. The idea of an "aspirin 2.0" was immensely appealing, and a great deal of work went into finding such compounds. In 1992, a team from the University of Rochester filed a patent application for an assay to distinguish whether new compounds were binding selectively to COX-2, and this eventually issued as US5,837,479 in 1998. A division of that also issued in 2000 as US6,048,850, the "850 patent", as it came to be referred to. Then, the fireworks display really started.

Immediately after being granted that patent (that very day, actually), the University of Rochester filed suit against Pfizer (PFE) for marketing two COX-2 inhibitors, which Rochester claimed violated their patent. The G. D. Searle company (part of Monsanto) had discovered Celebrex (celecoxib) and the related drug Bextra (valdecoxib), and Pfizer had taken them over largely to get the rights to the drugs. You'll also remember Vioxx (rofecoxib), another drug in this class from Merck (MRK), which was not party to this case - and these companies were by no means the only ones that had been working on selective COX-2 chemical matter. This wasn't the only lawsuit, either. Brigham Young, mentioned above, had licensed the Simmons discovery to Monsanto, whose drug research arm was also taken over by Pfizer, and had sued Pfizer over royalties (eventually settling with the company for a payment of $450 million).

Pfizer's response to the Rochester suit was to ask for summary judgment - basically, saying that the facts of the law were so plain that there was no use in even going to trial. Issued patents start off as presumed valid, of course, but that motion was granted by the District Court of the Western District of New York, whereupon Rochester immediately appealed that decision. It ended up, as these cases do, at the Court of Appeals for the Federal Circuit, which upheld the summary judgment in 2004. And here's where we talk about targets versus drugs.

The '850 patent had several claims, with several key ones coming down to a method of treating human patients with a compound that was a selective inhibitor of COX-2. That's what Rochester claimed that Pfizer was infringing by selling such a compound to human patients. Pfizer, meanwhile, claimed that the patent was invalid from the start because it didn't meet some key requirements. A patent has to have a complete written description of the invention, and Rochester felt that they'd done that, but Pfizer held that you can't just say you own the method of treating someone by giving a selective compound without describing what that selective compound is - that description is inadequate. A written description has to be in enough clear and complete detail that another person "skilled in the art" can reproduce the invention, you have to go on to describe how the invention is used, and you also have to have disclosed the "best mode" of doing so.

In other words, Rochester was claiming that the important parts were the discovery of COX-2 and, especially, the discovery of the assay for selective COX-2 compounds. The compounds themselves? A mere technicality - anyone of ordinary skill in the art can come up with compounds and drugs. The Court of Appeals disagreed. The pointed out that those three requirements just mentioned have been found (over and over) to be independent of each other. If you want to claim a chemical compound (a drug, in this case), you have to show what it is and how to make it and use it, not just specify what it does. This means that you can't say that your invention is giving someone such a drug and then claim every drug of that kind that someone else finds. The court noted that nothing in Rochester's patent indicated that they had any such COX-2 compounds or knew what they might be. As the court said:

Even with the three-dimensional structures of enzymes such as COX-1 and COX-2 in hand, it may even now not be within the ordinary skill in the art to predict what compounds might bind to and inhibit them, let alone have been within the purview of one of ordinary skill in the art in the 1993-1995 period in which the applications that led to the ′850 patent were filed. Rochester and its experts do not offer any persuasive evidence to the contrary.

And although this was not an issue in this case, I would also like add that even having a compound in hand from such a selectivity assay does not necessarily give you a drug. In order to be useful, a drug has to be able to be dosed in a human patient, last long enough to have a beneficial effect, and not by itself (or through its breakdown products) cause so many harmful side effects that it's not worth taking. It also has to be produced on large scale, under very tight tolerances, and be stable enough so that it can be stored and shipped without alteration. A rather large amount of time, effort, and money goes into figuring out these things.

But the main point is that a target, a mechanism is most certainly not a drug. This is true scientifically, and thanks to Univ. of Rochester v. Searle, it's true legally as well.

Postscript: Of course, the history of the COX-2 inhibitors was rocky. Merck's Vioxx was taken off the market due to cardiovascular side effects, followed by Bextra, and Pfizer ended up paying a $2.3 billion fine for its marketing of the latter. Celebrex is still sold, however - extensive reviews of its effects in human patients have not shown excess cardiac liabilities. The University of Rochester did not, as far as I know, offer to help share in the losses incurred by the withdrawals.

Disclosure: None.

Editor's Note: The summary bullets for this article were chosen by Seeking Alpha editors.

Comments

[Winston Van]

For sure