Brimonidine & Timolol – USA

On Dec 22, 2017, The Federal Circuit affirmed Eastern District of Texas' earlier decision that that each of three Allergan patents are valid but reversed the district court's decision of infringement of one patent in Combigan® (Brimonidine & timolol) case.

Allergan holds the approved new drug application for Combigan®, which is used to lower intraocular pressure in glaucoma and ocular hypertension patients. Combigan® is a “fixed combination” ophthalmic solution consisting of 0.2% brimonidine tartrate and 0.68% timolol maleate for twice-daily dosage. Allergan Sales, LLC sued Sandoz under the Hatch-Waxman Act, alleging infringement of U.S. Patent Nos. 7,030,149, 7,320,976, and 8,748,425. In particular, Allergan claims that claim 4 of the ’149 patent, claim 1 of the ’976 patent, and claims 1–8 of the ’425 patent protect Combigan® and its administration. The U.S. District Court for the Eastern District of Texas found the asserted claims not invalid but only claims of the ’425 patent infringed. Sandoz appealed the district court’s no-invalidity and infringement determinations. Allergan cross appealed the finding of non-infringement.

With respect to invalidation, Sandoz argued that the district court erred because the asserted claims merely recite the inherent results of administering an obvious combination. Federal circuit however disagreed & said that each asserted claim, expressly recites an additional efficacy limitation that further restricts the method of administering the composition twice daily: (1) “without loss of efficacy” in claim 4 of the ’149 patent, (2) “a therapeutically effective amount” in claim 1 of the ’976 patent, and (3) “reducing the incidence of one or more adverse events” in claim 1 of the ’425 patent. Those efficacy limitations are not disclosed by any prior art reference in the record. To the contrary, the prior art shows that the combination dosed twice daily produces a loss of efficacy in the afternoon. In light of the foregoing, the district court did not err by finding that Sandoz failed to present clear and convincing evidence to overcome the presumption that the asserted claims are valid.

With respect to infringement, Sandoz argued that the district court erred in finding infringement of claims 1–8 of the ’425 patent. Allergan asserted only literal infringement of those claims. The district court found that the proposed generic contains 0.5% timolol free base and therefore infringed the claims of the ’425 patent. That finding is erroneous for two related reasons. Claims 1–8 are narrowly and specifically drawn, reciting administration of 0.2% brimonidine tartrate and 0.5% timolol free base. Both Combigan® and the proposed generic, however, contain 0.68% timolol maleate, an ophthalmic compound distinct from 0.5% timolol free base. The district court relied on the equivalency of the two compounds in finding literal infringement—that is, 0.5% timolol free base recited in claims 1–8 as chemically equivalent to 0.68% timolol maleate contained in the proposed generic. Because chemical equivalency is not sufficient for literal infringement of these claims, the court clearly erred. Here, Combigan® contains a 0.2% brimonidine tartrate and 0.68% timolol maleate solution, as its FDA-approved label makes clear. But claims 1–8 of the ’425 patent expressly recite 0.5% timolol free base, not 0.68% timolol maleate. Therefore, as a matter of law, Combigan® is not the “drug claimed in” the ’425 patent, and Sandoz’s ANDA does not infringe under § 271(e)(2)(A). In sum, the district court erred by finding that Allergan showed literal infringement of claims 1–8 of the ’425 patent.

Allergan argued on its cross-appeal that the district court erred in finding that Sandoz’s proposed generic does not infringe claim 4 of the ’149 patent and claim 1 of the 976 patent. Allergan again asserted only literal infringement with respect to those claims. Both the claims specifically recite 0.2% brimonidine. But the proposed generic contains 0.2% brimonidine titrate, a distinct pharmaceutical compound that reduces to 0.132% brimonidine—indeed, Allergan’s expert confirmed so. As such, the district court did not err by finding that Allergan failed to show literal infringement of claim 4 of the ’149 patent and claim 1 of the ’976 patent.

Federal circuit finally affirmed that district court’s finding of no invalidity of the asserted claims and non-infringement of the claims of the ’149 and ’976 patents, but reversed the finding of infringement of claim 1 of the ’425 patent.