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Prior Disclosure of a Racemic Mixture of a Compound Does Not Anticipate or Render Obvious a Claim to an Isolated Enantiomer Having Unpredictable Properties

07-1438
December 12, 2008

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Last Month at the Federal Circuit - January 2009

Judges: Newman (author), Lourie, Bryson

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

In Sanofi -Synthelabo v. Apotex, Inc., No. 07-1438 (Fed. Cir. Dec. 12, 2008), the Federal Circuit affirmed the district court’s ruling sustaining the validity of U.S. Patent No. 4,847,265 (“the ’265 patent”) owned by plaintiffs Sanofi -Synthelabo, Sanofi -Synthelabo, Inc., and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership (collectively “Sanofi ”).

The suit relates to Sanofi ’s commercial product Plavix®, which is a platelet aggregation inhibiting agent used to reduce thrombotic events such as heart attacks and strokes. The active ingredient in Plavix®, clopidogrel bisulfate, is claimed in the ’265 patent. Clopidogrel is the common name for the dextrorotatory enantiomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl) (2-chlorophenyl)-acetate (“MATTPCA”). Generally, enantiomers are chemical compounds that have the same chemical structure, but differ in their orientation in three-dimensional space. An equal mixture of enantiomers produces what is called a racemate. The dextrorotatory enantiomer of clopidogrel is unique as it possesses all of the desirable biological properties without any of the negative side effects found in the racemic mixture.

Defendants Apotex, Inc. and Apotex Corp. (collectively “Apotex”) filed an ANDA seeking FDA approval to sell clopidogrel bisulfate. The ANDA included a Paragraph IV certification asserting invalidity of the ’265 patent. In response, Sanofi filed suit for infringement and Apotex counterclaimed, alleging the ’265 patent was invalid. The district court granted a preliminary injunction, enjoining Apotex’s sale of generic clopidogrel bisulfate. The district court later held that the asserted claims of the ’265 patent were not invalid, as the prior disclosure of the racemate of clopidogrel did not anticipate or render claim 3 of the ’265 patent obvious.

On appeal, the Federal Circuit first addressed Apotex’s assertion that claim 3 of the ’265 patent was anticipated by U.S. Patent No. 4,529,596 (“the ’596 patent”) and Canadian Patent No. 1,194,875 (“the ’875 patent”). Claim 3 of the ’265 patent requires (1) the bisulfate salt of (2) the dextrorotatory enantiomer of (3) MATTPCA (4) to be substantially separated from the levorotatory enantiomer. Apotex conceded that the references did not show any separated enantiomers or describe how to separate them, but argued that such detail is not required because persons of ordinary skill would know the existing techniques for separating enantiomers. Relying on In re Ruschig, 343 F.2d 965 (C.C.P.A. 1965), the Court affirmed the district court’s determination that the general statements in the ’596 and ’875 patents were not an anticipatory disclosure of the separated dextrorotatory enantiomer. Specifically, the Court noted that the “knowledge that enantiomers may be separated is not ‘anticipation’ of a specific enantiomer that has not been separated, identified, and characterized.” Slip op. at 14.

Additionally, the Federal Circuit affirmed the district court’s finding that the prior art references did not enable the separation of enantiomers, as they contained no guidance as to how to separate the enantiomers. Apotex argued that the issued patents are entitled to a presumption of enablement, as they carry a presumption of validity. The Court, however, noted that any presumption does not exclude consideration of whether undue experimentation is required, as discussed in In re Wands, 858 F.2d 731 (Fed. Cir. 1988). Noting the known difficulty of separating enantiomers and the unpredictability of their properties, the Court affirmed the holding that the reference patents would not have enabled a person of ordinary skill to obtain clopidogrel substantially separated from the levorotatory enantiomer.

Turning to Apotex’s obviousness argument, the Federal Circuit considered whether claim 3 of the ’265 patent was rendered obvious by the disclosures in the ’596 and ’875 patents. The Court found no clear error in the district court’s finding that one of skill in the art would not have reasonably predicted that the dextrorotatory enantiomer would provide all of the antiplatelet activity but none of the adverse neurotoxicity. The Court also found no clear error in the district court’s extensive findings concerning the difficulty and unpredictability of separating the enantiomers. The Federal Circuit held that these findings undermined Apotex’s hindsight argument that the separation of the enantiomers would have been obvious. Finally, the Court found no clear error in the district court’s conclusion that whether or not separating the enantiomers would have been obvious to try, the wide range of possible outcomes, relative unlikelihood that the resulting compound would exhibit the maximal increase in antiplatelet aggregation activity, and the absence of neurotoxicity makes the compound nonobvious.

The Federal Circuit also rejected Apotex’s argument that the separations would have been obvious based on a regulatory requirement that would have alerted a person to the need to separate enantiomers. The evidence of record indicated that Sanofi began separating the enantiomers in an attempt to address certain side effects of the racemic mixture, and not because of a possible future regulatory requirement. The Court therefore found no clear error in the district court’s findings.

Finally, the Court rejected Apotex’s assertion that, as in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007), claim 3 was obvious as it recited a combination of familiar elements according to known methods, therefore yielding predictable results. Given the extensive evidence of the unpredictable nature of the separation of enantiomers, the Court affirmed that the principles of KSR did not control.