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Patent Covering Plavix® Drug Not Anticipated and Grant of Preliminary Injunction Upheld

December 08, 2006

Decision icon Decision

Last Month at the Federal Circuit - January 2007

Judges: Lourie (author), Clevenger, Bryson

[Appealed from: S.D.N.Y., Judge Stein]

In Sanofi-Synthelabo v. Apotex, Inc., No. 06-1613 (Fed. Cir. Dec. 8, 2006), the Federal Circuit affirmed the district court’s grant of a preliminary injunction in favor of Sanofi-Synthelabo, Sanofi-Synthelabo, Inc., and Bristol-Myers Squibb (“BMS”) Sanofi Pharmaceuticals Holding Partnership(collectively “Sanofi”).

Sanofi markets Plavix®, a platelet aggregation inhibiting agent used to reduce thrombotic events such as heart attacks and strokes. The active ingredient in Plavix® is clopidogrel sulfate, which is covered by Sanofi’s U.S. Patent No. 4,847,265 (“the ’265 patent”). Apotex Inc. and Apotex Corp.(collectively “Apotex”) filed an ANDA to market a generic version of clopidogrel sulfate, which included a Paragraph IV certification alleging invalidity of the ’265 patent. In response, Sanofi sued Apotex for infringement, and Apotex counterclaimed that the ’265 patent was invalid and unenforceable. The district court granted Sanofi’s motion for a preliminary injunction.

On appeal, Apotex argued that claim 2 of U.S. Patent No. 4,529,596 (“the ’596 patent”) anticipated or rendered obvious claim 3 of the ’265 patent, which covers the active ingredient in Plavix®. The Federal Circuit disagreed, noting that claim 3 of the ’265 patent consists of the following key limitations: (1) the d-enantiomer, (2) the clopidogrel compound, (3) the bisulfate salt, and (4) substantial separation from the levorotatory isomer. The Court held that claim 2 of the ’596 patent did not anticipate claim 3 of the ’265 patent because it failed to describe the dextrorotatory or levorotatory enantiomers or any salt.

The Court also rejected Apotex’s argument that the two missing limitations, i.e., the d-enantiomer and the bisulfate salt, were inherently disclosed in the ’596 patent. The Federal Circuit relied on the district court’s findings that the skilled artisan would not have been led to the bisulfate salt because (1) according to expert testimony, a chemist would believe that the hydrochloride salt, not the bisulfate, is the preferred salt for clopidogrel, in light of Example 1 of the ’596 patent, which taught preparation of the hydrochloride salt; (2) according to expert testimony, salt formation with a new compound is an unpredictable exercise; and (3) a chemist theoretically had at least fifty different pharmaceutically acceptable salts from which he could have chosen for formulation.

The Federal Circuit also rejected Apotex’s argument that In re May, 574 F.2d 1082 (C.C.P.A. 1978), 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), mandated a finding of anticipation. The Federal Circuit distinguished May by noting that the specification of the ’596 patent included “no clear statement in the specification that the bisulfate salt is ‘especially suitable’ for administering compounds of the genus including clopidogrel.” Slip op. at 11. In fact, the Court noted that the specification “discloses a number of potentially acceptable salts and discloses the racemate of clopidogrel in Example 1 only as a hydrochloride salt.” Id. The specification also does not provide “a pattern of preferences,” like the disclosures in Petering and Schaumann, that would limit the genus of claim 2 of the ’596 patent to the narrow class of compounds that includes clopidogrel bisulfate.

The Court then turned its attention to Apotex’s allegation that the ’596 patent rendered claim 3 of the ’265 patent obvious. The Court rejected Apotex’s contention that preparation of clopidogrel bisulfate would have been obvious to the skilled artisan. The Court found persuasive the district court’s finding that “nothing existed in the prior art that would make pursuing the enantiomer of [clopidogrel] an obvious choice, particularly in light of the unpredictability of the pharmaceutical properties of the enantiomers and the potential for enantiomers to racemize in the body.” Id. at 14. Also supporting nonobviousness was the “extensive time and money Sanofi spent developing the racemate before redirecting its efforts toward the enantiomer, and the unpredictability of salt formation, . . . .” Id. In fact, Apotex’s own expert “agreed that salt formation was an unpredictable exercise that would require a chemist ‘to engage in experimentation to determine which salt would in fact be suitable.’” Id.

Moreover, one of the named inventors tested over twenty salts before arriving at the bisulfate, which had the most desirable properties. Id. at 15. The Federal Circuit also found no basis to conclude that the district court erred in considering the unexpected results.

Finally, the Federal Circuit distinguished In re Adamson, 275 F.2d 952 (C.C.P.A. 1960), on two grounds. First, unlike the primary reference in Adamson, which disclosed the racemic mixtures of the isomers and the acid addition salts, the ’596 patent did not disclose the bisulfate salt of the d-enantiomer of clopidogrel. Second, the Adamson court found that it would have been expected by the skilled artisan that “enantiomers would have different pharmacological activity and that the toxicity of the racemate would lie somewhere between that of its isomers.” Slip op. at 16. In contrast, the district court here found that “resolving the racemate was not mere routine experimentation and that it was unexpected that the desirable activity of clopidogrel would be found only in the d-enantiomer.” Id. at 16-17.

The Federal Circuit then considered the remaining elements of the preliminary injunction test. First, the Federal Circuit rejected Apotex’s argument that Sanofi contracted away its right to prove irreparable harm by entering into a settlement agreement to cap damages. The Court also rejected Apotex’s assertion that the district court abused its discretion in concluding that Sanofi would suffer irreversible price erosion, relying on the testimony of Sanofi’s economics expert and a declaration from a Sanofi executive. The Federal Circuit also did not find any error in the district court’s analysis of the remaining evidence that established irreparable harm, including loss of good will, potential reduction in employees, and the discontinuation of clinical trials.

The Federal Circuit also found that the district court did not err in balancing the hardships because Apotex’s harms were “almost entirely preventable” and were the result of its own decision to launch its generic product before a decision. The Federal Circuit also concluded that the fourth factor, the public interest, weighed in favor of Sanofi. The Court found persuasive that the “significant ‘public interest in encouraging investment in drug development and protecting the exclusionary rights conveyed in valid pharmaceutical patents’ tips the scales in favor of Sanofi.” Id. at 24.

Apotex also alleged that the district court erred by precluding Apotex from proffering evidence of unclean hands by counsel for BMS and Sanofi during settlement negotiations. Id. The Federal Circuit rejected Apotex’s allegation, noting that any fraud or perjury committed by BMS or Sanofi during the settlement negotiations was unrelated to the infringement and validity of the ’265 patent. Accordingly, the Court found no abuse of discretion in the grant of the preliminary injunction.