Eli Lilly and Company v. Teva Parenteral Medicines, Inc.

Patent in suit was not obvious because a prior-art mouse study did not necessarily translate into the invention’s being carried out in a human, and also because certain prior-art references taught away from the claimed invention.

Spring 2014

Robins Kaplan GENERICally Speaking: A Hatch-Waxman Litigation Bulletin

Case Name: Eli Lilly and Company  v. Teva Parenteral Medicines, Inc., Civ. No. 10-cv-01376-TWP-DKL, 2014 U.S. Dist. LEXIS 43885 (S.D. Ind. Mar. 31, 2014) (Walton-Pratt, J.)

Drug Product and Patent(s)-in-Suit: Alimta® (pemetrexed disodium); U.S. Pat. No. 7,772,209 (“the ’209 patent”)

Nature of the Case and Issue(s) Presented: The ’209 patent is a method-of-use patent that claims the co-administration of pemetrexed disodium with two nutrients—folic acid and vitamin B-12—to prevent side effects from the pemetrexed disodium. Defendants argued that the prior art disclosed co-administration, relying on a mouse study and a Phase I clinical study that modulated the toxicity of pemetrexed by administering folic acid. Defendants argued that these early studies would lead a person of skill in the art (“POSA”) to administer pemetrexed with folic acid. Defendants further argued that the prior art taught that nutritional issues contributed to pemetrexed toxicities and that a POSA would be motivated to combine vitamin B12 with folic acid based on the general knowledge regarding the association of elevated homocysteine with low levels of folic acid and vitamin B12. Defendants also argued that the dosing regimen was obvious in light of ranges disclosed in the prior art. The court was not persuaded by defendants’ arguments. It found that the folic-acid prior art was deficient because those early studies would not correlate to effectiveness in humans, and one reference actually taught away from the invention because it showed that folic acid decreased the effectiveness of pemetrexed. Moreover, the court found that the prior art did not disclose the claimed ranges since there was no confirmed correlation between the use of pemetrexed and folic acid and vitamin B-12. In addition, the court determined that there was evidence of skepticism in the art, failed attempts by others and unexpected properties that could serve as secondary considerations favoring non-obviousness.

Defendants also argued that the asserted claims were invalid for obviousness-type double patenting based on Eli Lilly’s expired ’974 patent. The ’974 patent claims a method of reducing toxicity of a GARFT inhibitor or other antifolate by treating a mammal with folic acid about 1 to 24 hours prior to administration of the antifolate. The court found the asserted claims patentably distinct because the ’974 patent does not disclose pemetrexed or contain any data regarding pemetrexed. Because of pemetrexed’s different toxicity, a POSA would not have selected it.

Defendants finally argued that the asserted claims were invalid under 35 U.S.C. § 112. Defendants asserted the patent failed to meet the written-description requirement, because “an effective amount of pemetrexed” with folic acid and vitamin B-12 pretreatment is insufficient since the specification does not give a particular dose of pemetrexed. The court found that the patent provided sufficient disclosure, since the specification discloses using a pretreatment regimen in combination with an “effective amount” of pemetrexed, not an amount of pemetrexed that would be effective if combined with the vitamin pretreatment. A POSA would be able to determine the effective amount of pemetrexed prior to adding the vitamin pretreatment and would combine it with the vitamin regime. Defendants also argued that the claims were not enabled. The court rejected this argument because the numerous prior-art references available at the time of filing provided data regarding the amount of pemetrexed capable of producing a therapeutic benefit. Thus, undue experimentation was not required to reach the effective amount of pemetrexed.

Why Eli Lilly Prevailed:  Eli Lilly prevailed because the prior art did not teach or suggest the combination of the pemetrexed and vitamin supplements. The prior art references disclosed early testing of pemetrexed and vitamin supplements. The court was not persuaded that a mouse study could provide sufficient teachings, because a POSA would have recognized the difficulty in translating a mouse study to human trials, since mouse models are poor predictors for antifolates’ toxicity. The court also found that the Phase I clinical trial taught away from the claimed invention, since folic acid negatively impacted the efficacy of pemetrexed. Oncologists were not concerned with the pemetrexed toxicities and, while the Phase I clinical trial reported lower toxicities, higher doses of pemetrexed were required. In addition, the court found that the addition of vitamin B-12 would counteract the antifolate and reduce the efficacy of pemetrexed. The court also found secondary considerations favoring non-obviousness, since the FDA was skeptical about the invention and consistently rejected the vitamin supplementation protocol; others had tried and failed with vitamin supplementation; and the results were unexpected since the vitamin supplementation increased the effectiveness of pemetrexed.

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