Addressing the issue of whether a biologically-active enantiomer of a patented drug is invalid over the prior art, the U.S. Court of Appeals for the Federal Circuit affirmed a district court decision that upheld the validity of Forest Laboratories’ U.S. Reissue Patent 34,712, which covers (+)-citalopram, the active ingredient in Lexapro®. The majority panel further upheld an injunction of both the Abbreviated New Drug Application (ANDA) filer, Ivax Pharmaceuticals, as well its drug supplier, Cipla, Ltd. Forest Labs., Inc. v. Ivax Pharms., Inc., Case No. 07-1059 (Fed. Cir., Sept. 5, 2007) (Lourie, J.; Schall, J., dissenting-in-part).
Ivax filed an ANDA for approval to market generic tablets of escitalopram oxalate (EO). EO, the oxalate salt form of escitalopram, functions as an antidepressant by virtue of being a selective serotonin reuptake inhibitor and is the active ingredient in Forest’s Lexapro branded drug. The ANDA included a Paragraph IV certification that the claims of Forest’s United States Reissue Patent 34,712 (the ’712 patent) patent are invalid and/or not infringed. The ’712 patent relates to a substantially pure (+)-enantiomer of citalopram, referred to as escitalopram, and acid salts thereof. Forest filed suit against Ivax and later added Cipla, which is the intended supplier of EO for Ivax and contributed information for the filing of the ANDA. The parties stipulated infringement and, after a bench trial, the district court concluded that Ivax had failed to establish invalidity on the grounds of, inter alia, anticipation and obviousness.
Stereoisomers are molecules that have the same atomic composition, but different spatial arrangements. Enantiomers are a pair stereoisomers, referred to as "(+)" and "(-)," that are non-superimposable mirror images of each other and often have distinct physical properties. A racemate (or racemic mixture) is an equal mixture of two enantiomers.
On appeal, the Court agreed with Forest that the ’712 patent was not anticipated by a pharmacology paper (the "Smith reference") that described effects of various enantiomers of particular drugs, not including (+)-citalopram, on serotonin uptake. The Court noted that, while the Smith reference mentioned racemic citalopram in passing, it incorrectly predicted that the (-)-enantiomer for citalopram should be a far more potent serotonin reuptake inhibitor compared to the claimed (+)-enantiomer. The Court conceded that the paper effectively disclosed the (+)-enantiomer of citalopram by discussing the racemate, but concluded that it did not anticipate due to its lack of enablement on how to obtain the (+)-enantiomer. The Court disposed of the issue of obviousness in one paragraph, noting that Ivax and Cipla failed to address any of the evidence favorable to Forest, which included the failure of the inventors and others to resolve citalopram without undue experimentation and the testimony of Forest’s experts. The Court found this evidence was sufficient to support the conclusion that the claimed subject matter would not have been obvious to one of ordinary skill in the art. Finally, the Court rejected the argument that Cipla should not be subject to the injunction by virtue of being outside the artificial act of infringement created by 35 U.S.C. § 271(e)(2)(A). Characterizing the relationship between Ivax and Cipla as "undoubtedly a cooperative venture," in which "Cipla was to manufacture and sell infringing [escitalopram oxalate] products to Ivax for resale in the United States," the majority panel concluded it was appropriate for the injunction to extend to Cipla. However, the Court agreed with Ivax and Cipla that the injunction was overly broad. Noting that 35 U.S.C. § 271(e)(4)(B) limits injunctive relief to "an approved drug," the Court limited the scope of the injunction significantly to cover only the drug approved by the U.S. Food and Drug Administration.
In dissent, Judge Schall argued that under Merck KGaA v. Integra Lifesciences I, Ltd., the work performed by Cipla falls within the 35 U.S.C. § 271(e)(1)’s exemption from infringement and is exempted from both the suit and the injunction.
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