There is room for controversy about who should be acknowledged as the discoverer of COX-2 and its structure and physiological role. Professor Philip Neederman in St Louis, USA has been credited with having first hypothesized that there are two COX enzymes. Professor Daniel Simmons of Brigham Young University, Utah claims to have discovered COX-2 in 1989 and published his team’s findings in April 19911. However, Dr Donald A. Young at the University of Rochester (the team involved in the present dispute) claimed to have built on the work of the Simmons team and to have described in successive US patent applications dating back to 22nd September 1992:
- That there are two COX (PGHS) genes, one of which was constitutively expressed and is called COX-1 and the other of which is responsive to regulatory control and is called COX-2.
- That COX-2 is a unique isoform of cyclooxygenase which in contrast to COX-1 is dramatically up-regulated by growth factors, tissue injury and proinflammatory cytokines, and plays a major role in peripheral inflammation.
- The cDNA and predicted amino acid sequence of COX-2.
Based on these discoveries the Rochester team produced cell lines stably expressing COX-2, which could be used to provide a simple in vitro screen for new drugs that would inhibit inflammation and which were predicted to be free from side effects.
Compounds that acted as COX-2 inhibitors were in existence as of September 1992 although they had, according to the University, not been specifically disclosed for human use2. For example, EP-A-0317332 (Taisho Pharma) described and claimed sulfonanilide compounds that showed anti-inflammatory, antipyretic and analgesic effects combined with a decrease in gastrointestinal side effects. Amongst these was a compound NS-398 which has been widely used in experimental work e.g. in the rat, but which has not been developed for clinical use. The activity of this compound was acknowledged by the Rochester team in their US patent 6048850 (the patent in issue) which states: "The fact that induced cyclooxygenase activity is blocked by NS-398, a specific inhibitor of PGHS-2, confirms that induction of PGHS-2 is responsible for increased prostaglandin production in cytokine-treated astrocytes".
The Rochester inventors did not consider that what they had invented was merely a research tool, and they wished to "reach-through" to claim the clinically useful compounds that resulted from their discoveries. The main claim of their patent read:
"A method for selectively inhibiting PGHS-2 [COX-2] activity in a human host, comprising administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene in a human host in need of such treatment."
The patent was granted on 11th April 2000, and legal proceedings against Searle and Pfizer were started on that day. On the following day the University announced in a press release that they had been awarded a pioneering patent for the use of the entire class of COX-2 inhibitors that included the blockbuster drugs Celebrex and Vioxx, and that over the 17-year life of the patent the royalty payments could yield the University billions of dollars, making it the most lucrative pharmaceutical patent in history.
The hopes of the University received a potentially fatal setback following an application by the defendants for summary judgment on the grounds of lack of written description and non-enablement because the patent disclosed no selective COX-2 inhibitor and finding such compounds required further empirical research.
In its opinion3 the US District Court accepted the defendant’s arguments. It explained that although the University may have laid the groundwork for the later invention of COX-2 inhibitors, they had not taken the last critical step of isolating such a compound or developing a process by which a skilled person would be directly lead to such a compound, and that even if the inventors were reasonably certain that the necessary compound existed and could eventually be found, there was no showing in the patent that they knew this to be a fact. The Court summarised its conclusions as regards written description4 in the following passage:
"In effect, then, the ‘850 patent claims a method that cannot be practiced until one discovers a compound that was not in the possession of, or known to, the inventors themselves. Putting the claimed method into practice awaited someone actually discovering a necessary component of the invention. In some ways, this is reminiscent of the search for the so-called "philosopher’s stone," eagerly sought after by medieval alchemists, which supposedly would transmute lead into gold. While the Court does not mean to suggest that the inventors’ significant work in this field is on a par with alchemy, the fact remains that without the compound called for in the patent, the inventors could no more be said to have possessed the complete invention claimed by the ‘850 patent than the alchemists possessed a method of turning base metals into gold."
The court’s interest, if not fascination, with the history of the philosopher’s stone is further demonstrated by the following footnoted passage:
"A patent for the philosopher’s stone was actually issued during the reign of Edward III. "The invention we now regard as a superstition, but the application was referred by the King to a commission, which reported favorably upon it, and the patent issued apparently upon what we now regard as sound doctrine, that the invention was new and useful." McKeever v. United States, 14 Ct.Cl. 396 (1878). It is not apparent whether the patentee claimed actually to possess the stone, or whether he simply described it in terms of its function, in the hope that he would be entitled to royalties should it ever be discovered."
The Court further held that the patent was non-enabling because it provided little guidance about selecting a particular compound or narrowing the range of candidates, with the result that a suitable compound could not be found without undue experimentation. Although the need for trial and error experimentation was not per se decisive, there had to be reasonable detail to enable members of the public to understand and carry out the invention and tossing out the mere germ of an idea was not enough5. Searle had started a screening program in August 1992, and by May 1993 had screened some 600 compounds and identified a number of selective COX-2 inhibitors, but the Court held that this merely demonstrated that considerable research was necessary to turn the claimed invention into reality. Although not cited in the judgment, a significant paper by Kunin et al6 foreshadowed the conclusion reached by the Court and expresses a firm view at a senior level within the USPTO that reach-through claims should not be allowed.
What might be said in support of the University on appeal? A major weakness in their position is that the reference in claim 1 to "a human host" is essential to distinguish their method from previous proposals such as the NS-398 compound. Even if an appellate Court could be persuaded that the task of finding some compounds that are active in the sense that they selectively inhibit COX-2 was within routine skill once COX-2 had been isolated and its structure and physiological role had become known, it might reasonably refuse to say that the further task of identifying the subclass of active compounds that were safe to administer to humans was also routine. On the other hand, the discovery of COX-2 was a scientific breakthrough, not alchemy. The prediction that useful inhibitors would follow quickly upon the discovery of the enzyme proved true. It could reasonably be argued that subsequent events demonstrate the incorrectness of the Court’s view concerning non-enablement. The commercially successful compounds Celebrex and Vioxx appeared in the late 1990’s, which, in the timescale of the pharmaceutical industry, was rapid and it is therefore disingenuous to say that the necessary skills were lacking There is the further argument that the written description requirement should not be applied so strictly that the reward for discovering COX-2 inhibitors goes in its entirety to the discoverers of the active compounds and is not shared with the academic scientists whose breakthrough enabled those compounds to be discovered. Such arguments are unlikely to appeal to the CAFC in the existing state of US case law, but if the case were taken up by the Supreme Court7 might a less onerous view of what patent law should demand of researchers in academic institutions give rise to a different result?
Footnotes
1 Xie et al., Proc. Nat’l. Acad. Sci. USA, 1991, 2692-2696 (April 1991), see also the deposited sequence at AAA58433.
2 The early development of COX-2 inhibitors is extensively discussed in the UK case Monsanto v Merck [2000] RPC 77 (HC), [2000] RPC 709 (CA) which concerns inter alia non-enablement of a patent claiming a Markush group of compounds, some of whose members had been experimentally demonstrated not to be selective COX-2 inhibitors as alleged in the specification.
3 Unites States District Court, Western District of New York, 00-CV-616L, Larimer J. 5th March 2003, downloadable from
http://www.nywd.uscourts.gov/decision/20030305_00cv6161_larimer.pdf.4 For the written description requirement in biotechnology patents see: Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998); Fiers, 984 F.2d at 1171; Enzo Biochem, Inc. v. Gen-Probe Inc., 285 F.3d 1013 (Fed. Cir. 2002), rehearing 296 F.3d 1316. Cases found non-persuasive because the patent specification contained enough information to lead a skilled person to the claimed compound included: Union Oil Co. v. Atlantic Richfield Co., 208 F.3d 989 (Fed. Cir. 2000), cert. denied, 531 U.S. 1183 (2001); In re Herscher, 591 F.2d 693 (C.C.P.A. 1979), and In re Edwards, 568 F.2d 1349 (C.C.P.A. 1978).
5 See, inter alia: W.L. Gore & Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 1557 (Fed. Cir. 1983); Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1365 (Fed. Cir.), cert. denied, 522 U.S. 963 (1997); In re Wands, 858 F.2d 731, 736-40 (Fed. Cir. 1988); Enzo Biochem, Inc. v. Calgene, Inc. ("Calgene"), 188 F.3d 1362, 1371 (Fed. Cir. 1999); Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927 F.2d 1200, 1213 (Fed. Cir.).
6 Stephen G. Kunin, Deputy Commissioner for Patent Examination Policy at the USPTO, Mark Nagumo, Administrative Patent Judge in the Board of Patent Appeals and Interferences, Brian Stanton, Technology Center 1600 Practice Specialist , Linda S. Therkorn, Patent Examination Policy Advisor, Office of the Deputy Commissioner for Patent Examination Policy, Stephen Walsh, Associate Solicitor, Office of General Counsel at the USPTO, American University Law Review, 51, 609-638, 2002. The article can be downloaded from
7 Review of CAFC decisions by the Supreme Court is rare. However, there may be an argument that the Court should review this case because the question whether and in what circumstances reach-through claims are allowable affects the balance of risks and rewards as between academic and industrial research over an important range of technologies.