On Apr. 19, 2023, Federal Circuit affirmed District Court which found some Apremilast patents valid and invalid.

This is a Hatch-Waxman litigation. Amgen markets apremilast, which is used for treating psoriasis and related conditions, under the brand name Otezla®. US 7,427,638 (composition with stereomerically pure apremilast), US 7,893,101 (crystalline polymorphic forms) and US 10,092,541 (method of treatment using dose titration of apremilast) are listed in Orange Book. Many generic filers including Sandoz / Zydus submitted ANDA to market generic version of apremilast. District court concluded that claims 3 and 6 of the ’638 patent and claims 1 and 15 of the ’101 patent were not invalid as obvious and that claims 2, 19, and 21 of the ’541 patent were invalid as obvious. Sandoz appealed, and Amgen cross-appealed.

US’638: Sandoz argued that the court erred in failing to find a motivation to isolate apremilast from a known racemic mixture. Sandoz also asserted that its expert established that the ’606 application taught that compounds, including the apremilast-containing racemic mixture in Example 12, were preferably administered as substantially stereomerically pure and there was no undue experimentation required in isolating it. Federal Circuit, however, agreed with Amgen and said 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. Also, district court did not err in its finding of strong objective indicia of nonobviousness. The court credited the testimony as establishing that apremilast was much more effective than the apremilast-containing racemic mixture at reducing production of tumor necrosis factor alpha (“TNFα”), a promoter of the inflammatory response linked to clinical problems associated with psoriasis, in murine models.

US’101: Sandoz argued that the district court erred in finding that the ’515 provisional application inherently disclosed crystalline Form B of apremilast and thus provided the necessary support for claims to be entitled to a March 2002 priority date. Sandoz contends that the ’515 provisional application does not explicitly disclose crystalline Form B of apremilast. Amgen asserted that it presented thirteen experiments replicating Example 2 of the ’515 provisional application under a variety of conditions and that Sandoz did not produce any studies or findings showing that Example 2 of the ’515 provisional application failed to produce crystalline Form B of apremilast. Federal Circuit agreed with Amgen 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. District court based its holding on the finding that the ’515 provisional application inherently disclosed crystalline Form B of apremilast. Here, trial evidence credited by the district court, including the experiment-related evidence introduced by Amgen (and the lack of contrary evidence from Sandoz) as well as testimony of Amgen’s expert, establishes that crystalline Form B of apremilast is actually disclosed in the ’515 provisional application.

US’541: Amgen argued that the district court relied on generalized characterizations of a dose-titration schedule and inappropriately analyzed the “gist” of the invention rather than the invention as claimed. Sandoz asserted that a skilled artisan would have been motivated to modify the dosing schedule in Papp, which begins with two days of two 10 mg doses of apremilast, followed by two days of two 20 mg doses of apremilast, and followed by a fifth day of two doses of 30 mg of apremilast to further reduce known side effects and would have had a reasonable expectation of success in doing so. Federal Circuit agreed with Sandoz and said that it was well within a skilled artisan’s ability to titrate an apremilast dose for a patient presenting with psoriasis and that doing so would have been a routine aspect of treating psoriasis. 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. [Genentech, Inc. v. Sandoz Inc., 55 F.4th 1368, 1376–77 (Fed. Cir. 2022)]