By Kevin E. Noonan —
Denial of an ANDA validity challenge by generic pharmaceutical company Apotex of Sanofi-Synthelabo's Orange Book-listed patent for Plavix® was affirmed by the Federal Circuit last week. The decision, by Judge Newman, joined by Judges Lourie and Bryson, was unremarkable and should remain so, unless the Supreme Court were to grant certiorari and work more of its particular brand of mischief on U.S. patent law.
Sanofi-Synthelabo, Sanofi-Synthelabo, Inc., and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership (collectively, Sanofi) brought suit under 35 U.S.C. § 271(e)(4) in response to a Paragraph IV certification submitted to the Food and Drug Administration by Apotex, Inc. and Apotex Corp., alleging that Sanofi's U.S. Patent No. 4,847,265 was invalid for anticipation and obviousness over Sanofi's U.S. Patent No. 4,529,596 and Canadian Patent No. 1,194,875. The active pharmaceutical agent of Plavix®, clopidogrel bisulfite, is recited in claim 3 of the '265 patent:
3. Hydrogen sulfate of the dextro-rotatory isomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate substantially separated from the levo-rotatory isomer.
At trial, the District Court heard evidence that Sanofi synthesized many hundreds of derivatives of the basic structure of clopidogrel, thienopyridines, and that the first compound approved for use in humans, ticlopidine, was associated with serious side effects. The unsatisfactory nature of this first thienopyridine drug led to Sanofi producing a second series of compounds, which were the basis for the prior art U.S. and Canadian patents asserted by Apotex as anticipating and/or rendering obvious the claims of the '265 patent. These patents disclosed 21 specific examples, including a racemic mixture of clopidogrel termed PCR 4099, or by an acronym for its chemical name MATTPCA. In addition, the evidence indicated that the hydrochloride salt of these compounds was similarly unsuitable for use in humans, due to severe side effects. Finally, the Court heard testimony from both Sanofi and Apotex that separating enantiomers was both difficult and unpredictable, both in terms of whether the enantiomers could be separated and the properties of each of the enantiomers if they were successfully separated; indeed, the Federal Circuit opinion characterized the way actually used to separate the Plavix® enantiomer from the racemic mixture to be a "lucky combination" of chemical reagents. For chiral thienopyridines other than PCR 4099 that had been separated into their component enantiomers, there was no evidence of any advantage over the original racemic mixture: although one enantiomer was more biologically active, it was also more neurotoxic, a common side effect of these drugs.
Evidence heard by the District Court established that the Plavix® enantiomer displayed absolute stereoselectivity, i.e., all of the desired biological activity was found in the Plavix® enantiomer, while all of the neurotoxic side effects were found in its enantiomeric twin. The Court characterized this distribution of properties to be rare, unexpected, and unpredictable.
In considering Apotex's anticipation defense, the District Court parsed claim 3 of the '265 patent into the following 4 elements: 1) the bisulfate salt; of 2) the "d" enantiomer; of the compound 3) methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenyl) acetate (MATTPCA); that was 4) "substantially" separated from the "l" enantiomer. Apotex argued that Sanofi's prior patents disclosed not only the racemic mixture, but that the separated enantiomers were encompassed by the invention. Apotex argued that disclosure of the racemate, plus the knowledge of the skilled worker of methods for separating enantiomers, anticipated claim 3 of the '265 patent.
The District Court, and the Federal Circuit, disagreed, on the grounds that an anticipating reference must be enabling. Moreover, according to Judge Newman's opinion, an anticipating reference requires "the specific description as well as enablement of the subject matter at issue," and that the art must disclose the elements "arranged as in the claim," citing the Federal Circuit's recent decision in Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir. 2008). As stated in In re Arkley, 455 F.2d 586, 587 (C.C.P.A. 1972), cited in Net MoneyIN:
[The] reference must clearly and unequivocally disclose the claimed [invention] or direct those skilled in the art to the [invention] without any need for picking, choosing, and combining various disclosures not directly related to each other by the teachings of the cited reference.
Apotex cited In re Petering, 301 F.2d 676 (C.C.P.A. 1962), and In re Schaumann, 572 F.2d 312 (C.C.P.A. 1978) in support of its argument, but the Federal Circuit found that these cases required an enabling reference disclosing a genus to disclose "specific preferences" not disclosed by the art cited here. Judge Newman asserted to the contrary In re May, 574 F.2d 1082, 1090 (C.C.P.A. 1978), which is explicit (according to the CAFC) that "the novelty of an optical isomer is not negated by the prior art disclosure of its racemate."
The Federal Circuit expressly held that knowledge that enantiomers may be separated is not anticipation of a specific enantiomer that has not been separated, identified, and characterized in the cited prior art. The Federal Circuit agreed with the District Court that separation of these enantiomers was not enabled because such separation would constitute undue experimentation. Judge Newman cited Forest Laboratories, Inc. v. Ivax Pharmaceuticals, Inc., 501 F.3d 1263, 1268-69 (Fed. Cir. 2007), that "this court recognized the known difficulty of separating enantiomers and the unpredictability of their properties, and held that a reference that stated that a compound has enantiomers did not enable the separation of those enantiomers, where the reference did not teach how to obtain the enantiomer." The Federal Circuit rejected Apotex's argument that the cited '596 patent should be presumed to be enabled, under the Court's Amgen Inc. v. Hoechst Marion Roussel, Inc. decision, stating that the presumption could, and here was, overcome by the particular facts and circumstances of this case.
Turning to Apotex's obviousness defense, Judge Newman assessed how the District Court applied the Graham v. John Deere Co. factors in view of the Supreme Court's recent decision in KSR Int'l Co. v. Teleflex Inc. Initially, the opinion defined the basis for doing this analysis for a chemical compound on the principle that a chemical compound and its properties are inseparable when assessing obviousness, citing In re Sullivan and In re Papesch. The District Court had assumed that Apotex had made out a prima facie case of obviousness, but found that "the unpredictable and unusual properties of the dextrorotatory enantiomer and the therapeutic advantages thereby provided, weighed in favor of nonobviousness, and that Apotex had not met its burden of establishing otherwise." The bases for this determination were, inter alia, the absolute stereospecificity of the Plavix® enantiomer, which experts for both Sanofi and Apotex testified were both unpredictable and rare, and that it was even more rare that all of the biological activity would be in one enantiomer and all the neurotoxicity would be in the other.
Apotex's argument was substantially that the recognition in the art that enantiomers exist, and known methods for isolating them, were sufficient to overcome Sanofi's argument of unexpected results of the claimed enantiomer. In this regard, the argument echoes the Patent Office position in Ex parte Kubin (as well as In re Deuel) that the obviousness of a method for isolating a nucleic acid sequence can make the nucleic acid itself obvious. Here, the Federal Circuit rejected this argument:
Apotex argues that the district court applied an incorrect inquiry, and that the correct inquiry is not whether the results obtained with the separated enantiomer were unexpected, but whether it would have been obvious to separate and test the enantiomers, based on the general knowledge that enantiomers can exhibit different properties.
A more intriguing argument by Apotex was that recognition in the art that enantiomers existed provided sufficient motivation to separate them, using known methods, and that routine methods could be used to identify the properties of the separated enantiomers. In this calculus, the very properties relied upon by Sanofi and the Court to establish that the Plavix® enantiomer is non-obvious can be considered inherent, albeit unrecognized, properties that (under Papesch) are inseparable from their chemical structure (which was recognized in the art). Especially considering that obviousness references do not have the same enablement requirements as anticipatory references do, there is some (but here insufficient) force to this argument.
For both the District Court and the Federal Circuit, testimony from Sanofi's expert that enantiomeric separation was difficult and unpredictable was persuasive. The District Court described the separation as a "paradigm of trial and error," and found that:
neither the chemists at Sanofi nor a person of ordinary skill in the art could have reasonably expected that the separate enantiomers of PCR 4099 could be obtained at the time that Sanofi was contemplating whether to investigate them and, if obtained, they could not have predicted by what method and configuration.
Judge Newman's opinion expressly contrasted the Forest Labs case and Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293 (Fed. Cir. 2007), noting that in Forest Labs
"the (+) enantiomer of citalopram would not have been obvious in light
of the known racemate, when it was shown that the therapeutic
properties of the (+) enantiomer were unexpected." In the Lupin
case, on the other hand, "this court held that the ramipril isomer's
potency was 'precisely what one would expect, as compared to a mixture
containing other, inert or near-inert stereoisomers.'" Although Apotex
argued that the CAFC should come to the same decision it came to in the
Lupin case, Judge Newman opined that "the evidence was directly
contrary to that position. The district court entered extensive
findings in this case on the unexpected and unpredictable properties of
clopidogrel, and there was no contrary evidence suggesting, based on
the prior art, that the stereoselective properties were 'precisely what
one would expect,'" as required for the Lupin case to be controlling.
In addition to the issue of the non-obviousness of the Plavix® enantiomer per se, the Federal Circuit also addressed the non-obviousness of the bisulfite salt as recited in claim 3 of the '265 patent. The Court noted that the cited U.S. and Canadian prior art patents disclosed the HCl salt, and that there were 80 possible alternative candidate candidates, with 53 of these being FDA approved. The Court noted that it was unpredictable whether a particular salt with a particular drug would form a "pharmaceutically-suitable crystalline salt." Moreover:
The district court distinguished the facts of this case from those of Pfizer v. Apotex (480 F.3d 1348), where there was evidence that based on the prior art a person of ordinary skill would have narrowed the possible salts to only a few including the claimed besylate, whereas here Sanofi presented evidence that the prior art taught away from the use of sulfuric acid with an enantiomer, for strong acids could encourage re-racemization.
The Federal Circuit's decision in this case is both unremarkable and entirely consistent with its own and Supreme Court precedent. Particularly with regard to chemical obviousness of separated enantiomers in view of the KSR decision, here the Federal Circuit has consistently relied on evidence of unexpected results of the separated enantiomer coupled with difficulties in achieving enantiomeric separation. The Federal Circuit has avoided per se rules or mechanical or rigid application of any rubrics other than the Graham factors, based on a case-by-case determination of the facts disclosed in the prior art and underlying the claimed invention.
Nevertheless, Plavix® is a "blockbuster" drug, garnering $3 billion in revenue in 2007, and moreover is an example of a pharmaceutical company obtaining a "later-filed" patent to increase patent protection specifically directed to its commercial product. These factors increase the political pressures surrounding this case, from a diverse cross-section of the public that opposes "high" drug prices and "lengthened" terms of patent protection for human drugs. Plavix® has already been the target of efforts in countries like Thailand to exercise national preogatives granted under the Doha Declaration to void drug patent rights (see "EU trade Commissioner Sends Warning Letter to Thailand"). The next and final step for Apotex to challenge Sanofi's patent protection for Plavix® would be for the Supreme Court to grant certiorari. If the legal issues were paramount, this might be considered unlikely. But in view of the serious political pressures around this patent and this drug, and the Supreme Court's recent sensitivity to political considerations in patent law, there is a real possibility that the Supreme Court will decide to review this Federal Circuit decision.
Sanofi-Synthelabo v. Apotex, Inc. (Fed. Cir. 2008)
Panel: Circuit Judges Newman, Lourie, and Bryson
Opinion by Circuit Judge Newman
January 3-7, 2009 – 
Patent Docs 