Case Name: Amgen Inc. v. Sandoz Inc., Nos. 2022-1147, 2022-1149, 2022-1150, 2022-1151, 2023 WL 2994166 (Fed. Cir. Apr. 19, 2023) (Circuit Judges Lourie, Cunningham, and Stark presiding; Opinion by Lourie, J.) (Appeal from D.N.J., Shipp, J.)

Drug Product and Patent(s)-in-Suit: Otezla® (apremilast); U.S. Patents Nos. 7,427,638 (“the ’638 patent”), 7,893,101 (“the ’101 patent”), 10,092,541 (“the ’541 patent”)

Nature of the Case and Issue(s) Presented: Amgen markets apremilast, a phosphodiesterase-4 (“PDE4”) inhibitor, which is used for treating psoriasis and related conditions, under the brand name Otezla. The patents-in-suit cover Otezla. Sandoz submitted an ANDA seeking approval to market generic apremilast. Celgene, the original plaintiff who later assigned its rights to Amgen, brought suit alleging infringement of the ’638 and ’101 patents. When the ’541 patent issued, Celgene asserted infringement of that patent as well.

The ’638 patent claims pharmaceutical compositions comprising stereomerically pure apremilast, including oral formulations, as well as dosing forms. The district court held that the ’638 patent was not invalid as obvious. The ’101 patent claims solid forms (e.g., crystalline polymorphic forms) of apremilast and claims priority from several earlier-filed applications, including the ’515 provisional application, which was filed on March 20, 2002. The district court held that Sandoz failed to argue that art prior to March 2002 rendered the claims of the ’101 patent invalid as obvious. Finally, the ’541 patent claims methods for the treatment of diseases ameliorated by inhibition of phosphodiesterases using dose titration of apremilast. The district court found that it would have been within the ability of a skilled artisan to titrate apremilast for a patient presenting with psoriasis and that doing so would have been a routine aspect of treating psoriasis with a drug like apremilast that was known in the art to require dose titration to ameliorate side effects. Thus, the district court held the asserted claims of the ’541 patent invalid as obvious. Sandoz appealed and Amgen cross-appealed. The Federal Circuit affirmed.

Why Amgen Prevailed: Sandoz raises two issues on appeal (i) concerning the ’639 patent, Sandoz contends that the district court erred in failing to find a motivation to isolate apremilast from a known racemic mixture and also for failing to find a reasonable expectation of success in separating the mixture; and (ii) concerning the ’101 patent, Sandoz argues that the district court erred in holding that the ’515 provisional application inherently disclosed the crystalline Form B of apremilast, and thus provided the necessary written description support to entitle claims 1 and 15 of the '101 patent to a March 2002 priority date. In its cross appeal, Amgen asserts that the district court erred in holding that the dose-titration schedule in the asserted claims of the ’541 patent would have been obvious.

The ’638 patent. The Federal Circuit found “no clear error in the district court’s holding that Sandoz did not meet its burden of establishing that the prior art gave a skilled artisan reason or motivation to resolve the Example 12 racemic mixture into its enantiomers, to conclude that a skilled artisan would have had reason to believe that the desirable properties of the Example 12 racemic mixture derived in whole or in part from the apremilast isomer, or that a skilled artisan would have had a reasonable expectation of success in resolving the mixture of Example 12.” The district court correctly credited the experts’ testimony “that resolving a racemic mixture is a difficult process based on trial-and-error experimentation and that using chiral chromatography to resolve the Example 12 racemic mixture into its enantiomers would require a skilled artisan to find an appropriate solvent system for the chiral column, of which there were many possible options at the time the invention was made.” Sandoz’s own expert conceded that the formation of chiral salts was not a viable method for separating the Example 12 enantiomers contrary to the statement in the specification. The Federal Circuit also credited the district court’s findings of unexpected results, long-felt need, and others’ failure to develop other PDE4 inhibitors, objective indicia of non-obviousness.

The ’101 patent. The Federal Circuit found that the district court did not clearly err in finding that claims 1 and 15 of the ’101 patent were entitled to the March 2002 priority date (i.e., the filing date of the ’515 provisional application). Amgen provided the results of over a dozen experiments following the procedure in Example 2 of the ’515 provisional application, all of which resulted in crystalline Form B of apremilast. On the other hand, Sandoz did not produce the results of any experiments showing that Example 2 of the ’515 provisional application did not produce crystalline Form B of apremilast. Relying on Federal Circuit case law, the district court also correctly found that the ’515 provisional application inherently disclosed crystalline Form B of apremilast. Because Sandoz failed to show that any prior art before March 2002 rendered the ’101 patent claims invalid for obviousness, the district court’s holding was affirmed.

The ’541 patent. The district court properly credited expert testimony establishing that the twice-daily fixed apremilast dosing schedule, initiating treatment at 10 mg and increasing toward a 30 mg twice-daily target dose in 10 mg increments, was rendered obvious by the prior art. The Federal Circuit has previously held that varying a dose in response to the occurrence of side effects is a well-known, standard medical practice that may well lead to a finding of obviousness.