Breaking Up Is Hard to Do: Validity Upheld Based on Expert Separation Testimony

By on April 27, 2023
Posted In Patents

The US Court of Appeals for the Federal Circuit affirmed a district court decision finding that two patents covering enantiomerically pure compositions of the psoriasis drug Otezla® (apremilast) were valid and one patent covering a dosage titration schedule was invalid as obvious. Amgen Inc. v. Sandoz Inc. Case No. 22-1147 (Fed. Cir. Apr. 19, 2023) (Lourie, Cunningham, Stark, JJ.)

Amgen markets apremilast, a phosphodiesterase-4 inhibitor that is used for treating psoriasis and related conditions, under the brand name Otezla®. Amgen has three patents covering Otezla®. Two of the patents are directed to orally administered pharmaceutical compositions of enantiomerically pure apremilast (composition patents), and one of the patents covers a dosage titration schedule for enantiomerically pure apremilast that ranges from a starting dose of 10 mg to a dose of 60 mg by the sixth day (dosage patent). Sandoz submitted an Abbreviated New Drug Application (ANDA) seeking approval from the US Food and Drug Administration (FDA) to market a generic version of apremilast. Amgen filed suit against Sandoz for infringement of its three patents covering Otezla®.

Sandoz asserted that the composition patents were invalid based on prior art that had an example (Example 12) that described a 50%:50% racemic mixture of apremilast but did not disclose the purified apremilast (+) enantiomer recited in the claims. The prior art did state that apremilast could be isolated from this racemic mixture using chiral chromatography, a well-known technique. The district court rejected Sandoz’s argument, finding that there was insufficient evidence to conclude that a skilled artisan would have had reason to believe that the desirable properties of Example 12 derived in whole or in part from the apremilast enantiomer (i.e., the (+) enantiomer). The district court also concluded that Sandoz had not demonstrated that a skilled artisan would have had a reasonable expectation of success in resolving Example 12 into its individual enantiomeric components. Furthermore, the district court looked to objective indicia of non-obviousness, finding that apremilast unexpectedly provided substantial improvement over previously known phosphodiesterase inhibitors in terms of both efficacy and tolerability, and a nexus existed between the unexpected potency and the asserted claims.

Sandoz also argued that the dosage patent was invalid based on prior art that taught various dosage schedules and amounts for 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 (such as apremilast) that was known in the art to require dose titration to ameliorate side effects. The district court therefore found that the dosage patent was invalid. Sandoz appealed with respect to the composition patents, and Amgen appealed with respect to the dosage patent.

The Federal Circuit affirmed the district court’s decision with respect to the composition patents, finding that Sandoz had not proven that a skilled artisan would have had sufficient motivation to purify apremilast’s (+) enantiomer from the racemic mixture disclosed in Example 12. Sandoz had argued that motivation existed because the FDA had, for many years, urged manufacturers to synthesize new drugs as single enantiomers and because apremilast was an analogue of thalidomide, an enantiomeric drug with proven toxicity and teratogenicity. The Court rejected these arguments, relying on Amgen’s expert testimony that separating enantiomers is a difficult process, particularly when, as was the case here, the prior art did not disclose a suitable solvent system to use for the separation process. The Court also affirmed the district court’s conclusion that a skilled artisan would not have had a reasonable expectation of success in resolving Example 12’s mixture into its enantiomeric components given its difficult and unpredictable nature. The Court noted that Sandoz’s own expert conceded that chiral chromatography was not a viable method for separating the Example 12 enantiomers, which directly contradicted the assertions made in Sandoz’s cited art.

The Federal Circuit also affirmed the district court’s findings that there were strong secondary indicia of nonobviousness, especially with respect to the unexpected potency of the apremilast (+) enantiomer. While stating that there was “no specific fold-difference that defines what may, or may not, support a finding of non-obviousness,” the Court found that a “20-fold difference, when an otherwise two-fold difference would have been expected by the skilled artisan” was sufficient to affirm the district court’s determination of nonobviousness.

The Federal Circuit also affirmed the district court’s conclusion that the dosage patent was invalid, explaining that varying a dose in response to the occurrence of side effects is a well-known standard medical practice, supporting a finding of obviousness.

Alexandra Cavazos, PhD
Alexandra Cavazos, PhD, focuses her practice on patent prosecution and intellectual property in the life sciences, using her expertise in biochemistry and molecular biology to help companies maximize the value of their US and international IP portfolios. Alexandra also has significant Hatch-Waxman litigation experience in the small molecule space, as well as PTAB litigation experience relating to large molecules. Read Alexandra Cavazos's full bio.