For the first time, on March 28, 2019, the Federal Circuit addressed obviousness of polymorph claims based on a known approach to polymorph screening, finding no reasonable expectation of success.

In the case, Plaintiffs Grünenthal and Assertio Therapeutics, Inc. asserted U.S. Patent Nos. 7,994,364 and 8,536,130[1] against Defendants Alkem Laboratories Ltd., Hikma Pharmaceuticals International Ltd., Hikma Pharmaceuticals USA Inc., and Actavis Elizabeth, LLC. Both patents were listed in the Orange Book for NUCYNTA® ER, a tapentadol hydrochloride tablet used to treat pain.

Prior Art “Form B” Plus Byrn (1995) Did Not Provide a Reasonable Expectation of Success

The ‘364 patent is directed to the Form A polymorph of tapentadol hydrochloride. At trial, Alkem argued that prior art disclosure of crystalline Form B tapentadol hydrochloride, along with known approaches to polymorph screening rendered the claimed Form A obvious. To support a reasonable expectation of success, Alkem relied on a 1995 article by Stephen Byrn which disclosed a decision tree outlining a typical polymorph screen. The Federal Circuit affirmed the district court’s finding that there was no reasonable expectation of success.

The Federal Circuit treated Byrn as highlighting the variables involved in a polymorph screen, including the choice of solvent and variations in temperature, concentration, agitation and pH, and called its disclosure “insufficient guidance in discussing the wide array of conditions that could affect recrystallization and, therefore, the crystal structure of a resulting compound.”

Prior Art Reproduction Results Supported Unpredictability

The Federal Circuit also cited Alkem’s prior art reproduction to reject Alkem’s argument that, because claimed Form A is the most stable form, “any polymorph screening of a sample of tapentadol hydrochloride would result in Form A, either in whole or in part.” Alkem had attempted to show inherent anticipation by the prior art and, although its experts found Form A, they had not performed all steps of the prior art process. Plaintiffs’ experts performed all steps and found no Form A. Even though Alkem did not appeal the district court’s rejection of its anticipation argument, the Federal Circuit nonetheless reasoned that different results from the parties’ respective experts highlight the effects of the variables at play.

Following Grunenthal, Polymorph Challenges Become More Difficult

In view of Grunenthal, ANDA filers should expect that already difficult obviousness challenges to polymorph patents will be even more difficult. While the Federal Circuit rejected a per se rule—“Our decision today does not rule out the possibility that polymorph patents could be found obvious”—Grunenthal leaves little room to argue based on Byrn that the results of routine polymorph screens are expected. Grunenthal also highlights the dangers of relying on prior art reproductions that deviate from the prior art and underscores the need to craft a holistic invalidity strategy. Separately, given Grunenthal, ANDA filers have even more incentive to utilize non-infringing polymorphic forms where possible.