In a Hatch-Waxman case involving patents directed to a polymorphic compound for a treatment for polyneuropathic pain, the US Court of Appeals for the Federal Circuit affirmed a district court finding that a patent was not invalid for obviousness and that a patent directed to the method of treating a polyneuropathic pain was indirectly infringed by virtue of product labeling. Grunenthal GMBH, Assertio Therapeutics, Inc. v. Alkem Laboratories LTD, Case Nos. 2017-1153, -2048, -2049, -2050 (Fed. Cir. Mar. 28, 2019) (Reyna J).

The technology at issue relates to a polymorphic compound, tapentadol hydrochloride (tapentadol). A polymorphic compound is one that can present in more than one 3D structure. Tapentadol presents in two forms, Form A and Form B. Grunenthal is the owner of two patents: one directed to the Form A of tapentadol and the other directed to a method of using either form of tapentadol for the treatment of polyneuropathic pain. The patents were licensed to Depomed and listed in the US Food and Drug Administration (FDA) Orange Book for NUCYNTA ER, a tapentadol hydrochloride tablet.

Three generic drug manufacturers, Alkem, Hikma and Actavis, independently filed abbreviated new drug applications (ANDAs) seeking to market generic versions of the tapentadol hydrochloride tablet. Grunenthal and Depomed filed a lawsuit against the three generic drug companies under the Hatch-Waxman Act. After a bench trial, the district court found that Alkem infringed the method patent, but that Actavis and Hikma did not. The court also found that the Form A tapentadol patent was not invalid as obvious, and that the method patent was not invalid due to anticipation or obviousness-type double patenting. Alkem and Hikma each appealed different aspects of the district court’s invalidity rulings, and Grunenthal and Depomed appealed the district court’s findings of non-infringement against Actavis and Hikma.


The Federal Circuit first addressed Grunenthal and Depomed’s cross-appeal of the district court’s finding that Actavis and Hikma did not infringe the patent directed to methods of treating polyneuropathic pain. Depomed’s FDA-approved label of NUCYNTA included as an indication the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN), which is a type of polyneuropathic pain. The proposed labels of Actavis and Hikma’s drugs included an indication for treatment of “chronic pain” but not specifically DPN or polyneuropathic pain. The Court noted that both Actavis and Hikma filed “section viii” statements with their ANDA applications, indicating that they would not seek FDA approval for an indication directed to the treatment of DPN.

Depomed argued that because the Hikma and Actavis labels contained an indication for “severe chronic pain,” the labels would cause at least some users to infringe the method patent because polyneuropathic pain is a common form of “severe chronic pain.” The Federal Circuit disagreed, finding that “even if severe chronic pain includes polyneuropathic pain, it also includes mononeuropathic pain and nociceptive pain. Therefore, the proposed ANDA labels do not specifically encourage the use of tapentadol hydrochloride for the treatment of polyneuropathic pain.” The Court also noted that neither of the accused ANDA labels listed an indication for the management of pain associated with DPN or mentioned any DPN clinical studies as a basis for FDA approval. Accordingly the Court found that Actavis and Hikma were not liable for induced infringement. Further, the Court found no clear error in the district court’s finding that there was no contributory infringement.


Alkem challenged the finding of non-obviousness of the asserted claims of the patent directed to Form A tapentadol based on two prior art references: Byrn and a prior art patent. Byrn taught a “conceptual approach to the characterization of pharmaceutical solids, including a flow chart describing investigative steps to determine whether polymorphs are possible.” However, Byrn did not teach a particular method to definitively test for polymorphism—it simply listed a number of solvents to be used in recrystallizing and other variables that could affect the solids produced by recrystallization with these solvents. The prior art patent disclosed the steps for making Form B of tapentadol. No evidence was presented at trial that the synthesis conditions from the prior art patent would produce any Form A tapentadol.

The Federal Circuit agreed with the district court’s finding that the asserted combination did not render the asserted claims obvious. The Court found that the fact that tapentadol was a polymorphic compound was unknown in the art at the time and that Byrn alone provided insufficient guidance as to what particular solvents, temperatures, agitation rates, etc., were likely to result in Form A. Finally, despite Alkem’s arguments, the Court found there was no evidence presented at trial that the synthesis of tapentadol in the prior art patent results in the Form A version. Therefore, the Court determined that Alkem failed to prove that a skilled artisan would have reasonably expected a polymorph screening of the Form B disclosed in the prior art patent to result in Form A. The Court also noted that a conclusion of obviousness does not follow from merely varying all parameters or trying each of numerous possible choices until one possibly arrives at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices was likely to be successful.

Practice Note: Patents covering polymorphic compounds may become more difficult to invalidate in view of the Federal Circuit’s decision—especially in situations where it is unknown whether a compound is polymorphic at all and there are no concrete steps in the literature to definitively determine that such polymorphism exists.