Endo Pharms. Sols., Inc. v. Custopharm Inc.

Case Name: Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374, 2018 U.S. App. LEXIS 19265 (Fed. Cir. July 13, 2018) (Circuit Judges Moore, Linn, and Chen presiding; Opinion by Chen, J.) (Appeal from D. Del., Robinson, J.) 

Drug Product and Patent(s)-in-Suit: Aveed® (testosterone undecanoate); U.S. Patents Nos. 7,718,640 (“the ’640 patent”) and 8,338,395 (“the ’395 patent”)

Nature of Case and Issue(s) Presented: Endo holds the NDA to Aveed. Bayer owns the patents-in-suit. Custopharm’s predecessor, Paddock Labs., submitted an ANDA for approval to produce and market generic Aveed. Paddock’s ANDA contained a Paragraph IV Certification against the patents-in-suit. On Nov. 20, 2014, Endo and Bayer sued. Custopharm stipulated to infringement, and Endo and Bayer limited their asserted claims to claim 2 of the ’640 patent and claim 18 of the ’395 patent. After a four-day bench trial on invalidity, the district court concluded that Custopharm had not proven that the claims were invalid as obvious. Custopharm appealed. The Federal Circuit affirmed.

Why Endo Prevailed: The patents-in-suit disclosed three primary elements in the composition and administration of Aveed: (i) 750 mg testosterone undecanoate (“TU”) in (ii) a 40% castor oil and 60% benzyl benzoate vehicle (the benzyl benzoate element only applied to the ’640 patent); and (iii) administered at an initial interval of two injections four weeks apart and maintenance injections at ten week intervals thereafter (this administration element only applied to the ’395 patent). Custopharm contended that the prior art inherently described the vehicle formulation (40% castor oil and 60% benzyl benzoate), and a POSA would have recognized that patients were being overdosed with 1000 mg TU injections at a concentration of 250 mg/ml (for a total of 4 ml injected fluid). Custopharm argued that it would have been obvious to a POSA to reduce the amount of injected fluid to 3 ml while maintaining the same TU concentration for a total of 750 mg TU per injection. This would in turn make the use of a two-phase dosing regimen obvious.

Custopharm’s “overdose” theory relied heavily on the American Association of Clinical Endocrinologists (“MCE”) guidelines, which stated that patients in prior-art clinical studies were being overdosed. The MCE guidelines set the range of normal testosterone levels at 200 to 800 nanograms/deciliter. But the art’s most prevalently applied guidelines in clinical practice—and those referenced by the patents-in-suit, relevant textbooks, etc.—were the FDA Guidelines, which taught a normal range of 300 to 1000 ng/dl. Thus, a POSA would not have thought to lower the dose of TU.

Concerning the vehicle-formulation element, Custopharm argued that it was inherently disclosed in the prior art, which provided a detailed recitation of the TU injection composition’s pharmacokinetic performance, from which a POSA could derive that the vehicle consisted of 40% castor oil and 60% benzyl benzoate. The district court found that this was not enough to establish that the prior art barred the possibility of an alternative vehicle being used in the prior art compositions to meet the rigorous standard of inherency. The Federal Circuit agreed, finding that (i) Custopharm’s opening appeal brief did not argue that the pharmacokinetic performance reported in the prior art could only be attributed to the claimed vehicle formulation; and (ii) the prior art was replete with potential co-solvents such that a POSA would not have necessarily recognized that the benzyl benzoate was being used as a co-solvent for the reported clinical studies.

Finally, Custopharm argued on appeal that once a POSA recognized that patients injected with 1000 mg TU were being overdosed, the specific injection schedule claimed in claim 18 of the ’395 patent would be the result of routine treatment of individual patients and thus obvious. The Federal Circuit dismissed this argument. For one thing, it was predicated on Custopharm’s overdose theory, which was already rejected. Second, the prior art did not clearly contemplate a two-phase dosing regimen with initial loading doses followed by maintenance doses. The prior art did not explicitly teach the use of loading doses. Third, Custopharm’s explanation for why a POSA would have a reasonable expectation of success that changing the injection regimen would result in a long-acting testosterone therapy was lacking.