On April 11, 2000, United States Patent No. 6,048,850, entitled "Method of inhibiting prostaglandin synthesis in a human host" issued to inventors Donald A. Young, Michael K. O'Banion, and Virginia D. Winn, of the University of Rochester. On April 12, 2000, a press release appeared on the internet which noted the relationship of this patent to the antiinflammatory drug Celebrex (celecoxib, marketed jointly by Searle/Pharmacia and Pfizer as a COX-2 inhibitor) and stated in part "The patent awarded yesterday entitles the University of Rochester to royalties on the sale of all cox-2 inhibitors." The release further stated: "Over the 17-year life of the patent, royalty payments could yield the University royalties in the billions of dollars, making it the most lucrative pharmaceutical patent in history." n2 Later on April 12 a press release from Pharmacia appeared, which said in part "We are disappointed to hear of this development from the media, rather than being contacted directly by the University of Rochester. Uncertainty in the market about such an important and beneficial pharmaceutical agent is not in anyone's best interest -- particularly arthritis patients." On April 13, 2000, The Wall Street Journal reported the University of Rochester would begin negotiations with Pharmacia by insisting on receiving 10% of Celebrex's total sales, which amounted to $ 1.4 billion in 1999, and that Rochester's suit is part of an increasingly aggressive effort by universities to receive their cut of pharmaceutical ventures, which often are funded by the federal government agencies, such as the National Institutes of Health ("NIH") n3 In its April 17 issue, Chemical & Engineering News ("C&EN") reported that "clashes over patent rights may hinder major drug producers' sales of some of the fastest growing and biggest selling pharmaceutical products." n4 The Rochester/ Pharmacia "interaction" has many dimensions, some of which are explored below.
BACKGROUND
It is estimated that 25% of patients using non-steroidal anti-inflammatory drugs ("NSAIDs") experience some kind of side effect and about 5% develop serious health consequence (massive GI bleed, acute renal failure, etc.). The improvements in NSAIDs, as manifested by COX-2 inhibitors, are most directly related to these 25% who suffer problems with conventional NSAIDs. n5
In 1971, Dr. John Vane discovered that NSAIDs such as aspirin n6 exert their actions primarily by inhibiting the production of prostaglandins and in 1982 won a Nobel Prize for the work. Vane and his colleagues showed NSAIDs inhibited the enzyme, cyclooxygenase (COX), which is the rate limiting enzyme in the production of prostaglandins from arachidonic acid that is found in all cell membranes. n7 Cyclooxygenase (also known as PGH synthase) was purified in 1976 and cloned in 1988.
In the 1980's, Philip Needleman showed that COX enzyme was increased in inflamed tissue. In 1990, Needleman and co-workers postulated a second COX enzyme. In 1991 the second COX isoform was cloned. This represented what is now known as COX-2. COX-1 (the "good" COX) is now known to be present in most tissues as the housekeeper enzyme. COX-2 (the "bad" COX) is inducible by inflammation. It is not present at baseline conditions, but increases in response to inflammation such as by arthritis. Both COX-1 and COX-2 have the same affinity to convert arachidonic acid to prostaglandin. COX-1 maintains normal gastric mucosa and influences kidney function. The inhibition of COX-1 is therefore undesirable. The inhibition of COX-2, on the other hand, is a desirable effect. n8
There have been issues with definitions. For example, there is an issue of specific versus preferential COX-2 inhibitors. Further, enzyme assays do not predict in-vivo selectivity. In-vivo selectivity should be measured at therapeutic concentrations and proof of objective specificity in humans is required.
Celebrex is 375 fold more selective for COX-2 compared to COX-1. It does not inhibit COX-1 at therapeutic doses in contrast to standard NSAID's which have been measured.
The drug Celebrex received regulatory approval in December 1998 n9 Earlier, in March 1998, the FDA described the status of COX-2 inhibitors in the following way: n10
Prostaglandins are formed by the action of the enzyme cyclooxygenase (COX) on arachidonic acid. Prostaglandins play an important role in gastric, mucosal, renal, and platelet function. Prostaglandins are also important contributors to the signs and symptoms of inflammation. Recently two forms of COX have been identified, COX-1 and COX-2. COX-1 is found in a number of tissues and is believed responsible for the homeostatic and protective actions of prostaglandins listed above. It is hypothesized that inhibition of COX-1 results in many of the adverse events associated with the use of NSAIDs (citing to Peter E. Lipsky, October 22, 1996).
In contrast, COX-2 is not found in the normal resting condition but is found in response to inflammatory stimuli and is responsible for the enhanced production of arachidonic acid metabolites at sites of inflammation. Thus, it has been hypothesized that inhibition of COX-2 results in anti-inflammatory and analgesic effects. It is hoped that an anti-inflammatory agent that selectively inhibits COX-2, but does not inhibit COX-1 would be able to treat the signs and symptoms of inflammation without causing the type of adverse events associated with the use of NSAIDs. This hypothesis is, however, not yet established and the manufacturers developing COX-2 selective agents have been asked to support such advantages with clinical data before making such claims.
WHAT IS US 6,048,850 ABOUT?
The Wall Street Journal article stated that SCIENTISTS involved in discovering the mechanisms said the patent is flawed but that a [patent] LAWYER said the patent was as broad as the university contends. [emphasis added] On the one hand, a patent can disclose an incorrect scientific explanation and still yield valid claims. On the other hand, the claims of a patent can be broad AND invalid.
Claim 1 of the '850 reads as follows n11: A method for selectively inhibiting PGHS-2 activity in a human host, comprising administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product to a human host in need of such treatment. [The term PGHS stands for prostaglandin H synthase.]
The beginning of the "summary of the invention" of the '850 states n12: The invention relates to the gene encoding the mammalian prostaglandin H synthase-2 and its product. The invention is based, in part, on the discovery that there are two PGHS genes; one constituitively [sic] expressed and termed herein PGHS-1, and a second which is responsive to regulatory control and termed herein PGHS-2. More specifically, the invention relates to the diagnosis of an aberrant PGHS-2 gene or gene product; the identification, production, and use of compounds which modulate PGHS-2 gene expression or the activity of the PGHS-2 gene product including but not limited to nucleic acid encoding PGHS-2 and homologues, analogues, and deletions thereof, as well as antisense, ribozyme, triple helix, antibody, and polypeptide molecules and small inorganic molecules; and pharmaceutical formulations and routes of administration for such compounds. The invention also relates to the identification of naturally occurring cells and the creation of cells that express PGHS-1 or PGHS-2 exclusively and the use of such cells in drug screening.
One notes that the term "selectively inhibiting" of claim 1 does not appear in the summary of the invention. Further, the concept "selective inhibition" does not appear to be defined in the specification. Text pertinent to "selective inhibition" which appears elsewhere in the specification is the following:
Thus, the present invention also provides a method to evaluate the relative inhibitory activity of a compound to selectively inhibit PGHS-2 versus PGHS-1, and thus to specifically inhibit the elevated prostaglandin synthesis that occurs in inflamed mammalian tissues, preferably human tissues, or in other physiological or pathological conditions in a mammalian host, preferably a human host, in which the PGHS-2 is elevated and the constitutive PGHS-1 is not.
The compound can be evaluated for its ability to selectively inhibit PGHS-1 or PGHS-2 by performing a second assay employing the above-described steps, but substituting the PGHS-1-expressing transgenic cell line for the PGHS-2-expressing cell line of the invention.
Both of these texts are more about a method to MEASURE "selective inhibition" than a method to CAUSE selective inhibition, as is claimed in claim 1. In its press release, Searle/Pharmacia "maintains the patent fails to describe or teach, with any particularity, how to put the invention into practice." n13
WHAT DOES "SELECTIVE INHIBITION" MEAN?
An issue that may arise in an analysis of invalidity of the '850 patent under 35 USC 102(b) pertains to the meaning of the text "selective inhibition" in the claims of the '850. Previously, there had been scientific debate over the concepts "preferential" and "specific" inhibition. A preferential inhibitor might inhibit COX-2 more than COX-1, but a specific inhibitor (at therapeutic doses) might inhibit COX-2 and not COX-1. The prior art may contain NSAIDs which are inherently preferential inhibitors. The question would become: is a "selective" inhibitor preferential or specific?
Selective inhibition of the "bad" COX-2 enzyme, while preserving the functional activity of the "good" COX-1 enzyme necessary for normal production of gastroprotective and other prostaglandins, is the strategic goal in this theory. A convenient method to determine the [RELATIVE] selectivity is to examine the IC50 COX-2 to IC50 COX-1 ratio. The IC50 is the concentration of the drug that inhibits COX enzyme activity by 50%. If the number is 0.01 or less, the agent can be said to have COX-2 specificity. When epidemiological results are compared with COX-2/COX-1 activity ratios, there is a clear relationship between the gastrointestinal side effects and the ratios. For example, piroxicam has a high COX-2/COX-1 cyclooxygenase inhibition ratio (>28), meaning low COX-2 specificity. The risk for developing ulcers is high for piroxicam. Etodolac, with a lower cyclooxygenase inhibition ratio of 0.8, is more COX-2 selective than other older NSAIDs, and has a low gastrointestinal complication risk associated with its use. The traditional NSAIDs, even those with lower ratios, will still have adverse effects because the concentrations needed to completely inhibit COX-2 will also significantly inhibit COX-1 n14
IN PASSING
On April 25, 2000, the Supreme Court reversed the decision of the Federal Circuit n15 in Nelson v. Adams USA. The Supreme Court found that defendant Nelson was never afforded an opportunity to respond, and Justice Ginsburg, in whimsical footnote 2, mentioned text from Lewis Carroll's "Alice in Wonderland." Nevertheless, the ultimate outcome of the case may be dictated by issue preclusion (collateral estoppel). Time magazine got into the intellectual property business with an article on April 10, 2000 which provoked two responsive letters on May 1, 2000, one by Evan Soule concerning Joseph Newman and one by Randell Mills concerning his discovery of the hydrino ["fractional quantum level hydrogen atom"]. The latter is mentioned in U.S. Patent 6,024,935 [which has a large reference list of "cold fusion" articles] and was presented at a meeting of the American Chemical Society [35th Western Regional Meeting, held Oct. 6-8, 1999 in Ontario, California; see also www.blacklightpower.com] This discussion reminds one of the article in Science on May 21, 1999 by David Voss on "new physics" finding a home at the Patent Office. n16 A question remains. Which is more disruptive to business: patents which cover products or processes that don't exist or work because they rely on improperly understood chemistry/physics OR patents which are, improperly, asserted to cover products or processes that do work? Perhaps U.S. 6,049,811, which discloses a method to draft patent applications, can help. Separately, there has been some discussion of the denial of Napster's summary judgment motion (for a "safe harbor" defense under the Digital Millennium Copyright Act) in A&M Records v. Napster (ND Calif.) and the interactions of Napster with the band Metallica. Beyond Napster, one has the distributed information systems of Freenet (Ian Clarke), Gnutella, Yo!nk, and Gnarly! which may pose even trickier problems. The New York Times quoted Clarke: "If this whole thing catches on, I think that people will look back in 20 to 40 years and look at the idea that you can own information in the same way as gold or real estate in the same way we look at witch burning today." (NYT, pp. A1, A23 May 10, 2000, with the A23 headline: "Concept of Copyright Fights for Internet Survival.") With Napster compromising with Metallica and Clarke more anticensorship than anti-copyright, one suspects that copyright will evolve, rather than die, within the internet world.
ENDNOTES
n2 The Campus Times of the University of Rochester reported on April 18, 2000: The University of Rochester received what may become the most lucrative patent in U.S. history for a class of drugs known as cox-2 inhibitors. The U.S. Patent and Trademark Office issued the patent on April 11. The money the university could receive over the 17-year life of the patent would accumulate into the billions, according to the Rochester Democrat and Chronicle. (Available NorthernLight).
n3 "Pharmacia Is Sued After University Gets Drug Patent," Gardiner Harris and Thomas M. Burton, The Wall Street Journal, p. A6 (April 13, 2000).
n4 "Patent Rights to Major Drugs at Risk," Ann Thayer, Chemical & Engineering News, pp. 9-10 (April 17, 2000). The headline confuses the Rochester/Pharmacia issue (wherein Searle/Pharmacia's patent rights as to specific drugs are NOT at risk, but the scope of Rochester's rights are to be determined) with the Bristol-Myers Squibb Taxol issue (wherein BMS's patent rights are at issue).
n5 See for example JAMA. 1999; 282:1921-1928, which reports 26% of patients using naproxen experienced gastroduodenal ulcers compared to 4-6% for celecoxib. Also, "Getting a Grip on Pain," Newsweek, December 14, 1998: Other experts worry that people for whom traditional NSAIDs are perfectly safe will start demanding the costly new Cox-2 inhibitors, creating a needless drain on the health-care system. Some 96 percent of high-does NSAID users don't develop ulcers, notes Dr. Thomas Schnitzer of Northwestern University. "If you're an elderly person with a history of gastrointestinal problems, the new drugs make sense," he says. "If you're a 30-year-old athlete with a sprained ankle, why should an insurer spend $ 4 to $ 5 a pill to get you the same relief you get safely for a few cents?"
n6 Aspirin is a "natural product"; it is the active ingredient in willow bark and other plant extracts, observed, since antiquity, to have analgesic and antipyretic properties.
n7 J. R. Vane et al., Annu. Rev. Pharmacol. Toxicol. 1998, 38, 97-120; see also article by Vane at www.rheumaclub.com.
n8 Some relevant publications include P. E. Lipsky; P. C. Isakson; Outcome of specific COX-2 inhibition in rheumatoid arthritis, J. Rheumatol., 1997 Jul, 24 Suppl 49; 9-14; B. Cryer; M. Feldman; Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am. J. Med., 1998 May, 104:5, 413-21; J. R. Vane; Y. S. Bakhle; R. M. Botting; Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol., 1998, 38, 97-120; L. S. Simon; F. L. Lanza; P. E. Lipsky; Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum. 1998, 41, 1591-602.
n9 Curiously, shortly AFTER approval, a scientific paper was published which raised issues with Celebrex. According to a report from the group of Dr. Ganet A. FitzGerald in the Proceedings of the National Academy of Science, 1999, 96:272-277, the drug may increase the risk of heart attack, stroke and blood clotting disorders. Many older people who may want to take COX-2 inhibitors for conditions like arthritis could be at risk for developing heart and blood vessel problems from the drug. Dr. Saul Bloomfield said that taking COX-2 inhibitors might be a matter of exchanging a gastrointestinal risk from one painkiller to a cardiovascular risk for another. See also Wall St. Jour., April 20, 1999. On April 27, 2000, there was a Reuters release "Merck's Vioxx seen facing FDA scrutiny on heart attacks." [Vioxx (rofecoxib) is a different COX-2 inhibitor.] On April 28, 2000, PR Newswire reported results of a study in which Pharmacia found even at very high doses, Celebrex showed no increases in stroke or heart attack with or without aspirin. [See Hoover's Online]
n10 From a "warning letter" sent by Minnie Baylor-Henry of DDMAC of FDA to Howard Pien of SKB, dated March 13, 1998, available on the internet at www.fda.gov/warn/warn1998/htm. This letter arose, in part, because of SKB's claims that Relafen is COX-2 selective.
n11 Because this is a "method" claim, the nominal direct infringer would be the patient or the doctor, and the manufacturer would be considered an indirect infringer.
n12 As taken from the USPTO database. Note the text interrelates kDa with "kilodation," rather than kiloDalton.
n13 In an article in wired news (www.wired.com), Roger Williams, a patent lawyer at Searle, was quoted as saying the patent was overly broad and lacked enablement (because it did not teach how to select compounds to practice the invention.)
n14 Dr. Steven R. Erickson, ACPE Program 424-000-99-007-H01, available www.powerpak.com/CE/COX2. Erickson's factual statements and terminology of "specific" and "selective" are used in the paragraph concluding with this endnote; other interpretations are possible. Also, see www.uspharmacist.com/NewLook/CE.
n15 175 F.3d 1343 (CAFC 1999)
n16 Science, 1999, 284, 1252 but see also Intellectual Property Today, pp.22-23 (July 1999) criticizing the position of Voss.