Forest Labs., LLC v. Sigmapharm Labs., LLC

Case Name: Forest Labs., LLC v. Sigmapharm Labs., LLC, Civ. No. 16-cv-914-RGA, 2017 U.S. Dist. LEXIS 101653 (D. Del. June 30, 2017) (Robinson, J.)

Drug Product and U.S. Patent: Saphris® (asenapine); U.S. Patent No. 5,763,476 (“the ’476 patent”)

Nature of the Case and Issue(s) Presented: Defendants submitted ANDAs to market generic asenapine before the expiration of the ’476 patent, which claims sublingual or buccal compositions of asenapine and methods of using such compositions to treat mental disorders, including schizophrenia. Forest filed suit. Each of the defendants conceded infringement of claim 1 of the ’476 patent and two of the four defendants (Amneal and Hikma) conceded infringement of claim 4. Therefore, the trial focused on the infringement of claim 4 and the validity of the ’476 patent. The court found that Forest had not carried its burden to prove that defendants Alembic and Breckenridge infringed claim 4 of the ’476 patent, and that Defendants had failed to carry their burden to prove, by clear and convincing evidence, that claims 1 and 4 of the ’476 patent were invalid by reason of obviousness, lack of written description, or lack of enablement.

Why Alembic and Breckenridge Prevailed: The court first addressed an issue concerning claim construction. Defendants argued that an amendment made during prosecution broadened claim 1 to cover any composition—administered sublingually or not—that disintegrates within 30 seconds. The court disagreed, finding that the statements made during prosecution demonstrate that the inventors limited the claims to sublingual or buccal compositions (and specifically excluded per-oral administration) to avoid the cardiotoxic effects observed upon oral administration.

Next, the court addressed Alembic and Breckenridge’s non-infringement arguments. Claim 4 contains essentially three relevant limitations: a method for treating (i) excitation … disorders, comprising (ii) administering sublingually or buccally an (iii) effective amount of a pharmaceutical composition [asenapine] or a pharmaceutically acceptable salt thereof. Alembic’s and Breckenridge’s proposed labels provided literal instructions to carry out elements (ii) and (iii) of the claim. Defendants’ labels provided instructions and a chart reciting effective doses to treat bipolar mania, as well as provide instructions and a chart reciting effective doses to treat manic episodes. Consequently, the only issue for the court to decide concerns limitation (i), i.e., whether defendants infringed claim 4 even though their generic asenapine products were indicated only for the treatment of “manic episodes” associated with bipolar I disorder. The court previously construed the phrase “tension, excitation, anxiety, and psychotic and schizophrenic disorders” as not literally including the treatment of bipolar disorder, including manic or mixed episodes associated with bipolar I disorder. The word “bipolar” was not used or described in the specification and, indeed, the use of asenapine to treat bipolar disorder was claimed in a later patent application. The court did not review its claim construction again, but did address Forest’s argument that the term “excitation” in the claim included within its literal scope “mania” and, therefore, the claim covered the treatment of the manic component of bipolar disease. The court found that there was no reference of record that literally described “excitation” as the defining feature of mania; therefore, it could not be disputed that “excitation” was not itself a disorder. Moreover, in the absence of direct infringement, there could be no liability for indirect infringement. Nevertheless, the court considered Forest’s indirect infringement arguments and found that the evidence proffered by Forest was insufficient to establish a specific intent on the part of Alembic or on the part of Breckenridge to induce infringement of claim 4 of the ’476 patent.

Finally, the court addressed defendants’ invalidity arguments. Concerning the court’s obviousness analysis, there was no dispute that by March 1994, asenapine had been described as having “CNS-depressant activity.” It was further undisputed that by March 1994, rapidly disintegrating solid oral formulations were being developed as an alternative for conventional oral tablets that had to be swallowed. The evidence at trial demonstrated that skilled artisans reviewing the publically reported clinical studies would have understood that orally administered asenapine was safe, bioavailable, and clinically effective even at relatively low doses. The art further showed that another manufacturer was in the process of conducting large-scale Phase II trials in Scandinavia with the conventional oral tablet, and that there were no safety concerns or clinically meaningful adverse advents as a consequence of those trials. But there was nothing in the prior art that would have indicated that the oral tablet had problems, such that skilled artisans would have been motivated to invest the resources necessary to completely change the route of administration. Therefore, there was no motivation from the record evidence to use a sublingual formulation for an antipsychotic drug. The court further found that the record demonstrated that it was unknown in the art that oral or IV administration of asenapine could cause severe cardiotoxic side effects. And further, the sublingual solution to the cardiotoxicity problem was not predictable or expected. There were numerous other formulations that could have been experimented with to try to solve the problem, but no reasonable expectation that any of them would have. The court rejected defendants’ arguments to the contrary.

With respect to secondary considerations of non-obviousness, the court found that the record demonstrated that it continued to be a surprising and unexpected result of the claimed invention that the sublingual route of administration successfully resolved the serious cardiotoxic event reported in the ’476 patent. That asenapine, administered sublingually, was ultimately used in multiple Phase III clinical trials and was determined by the FDA to not only be efficacious but safe, was itself surprising and unexpected. Moreover, since the approval of Saphris, there had not been any reported events of asystole or the need for the FDA to add additional warnings to the Saphris label, further confirming the surprising and unexpected nature of the claimed invention. Additionally, prior to 1994, typical antipsychotics were the primary therapeutic options for treating schizophrenia and mania. But these typical antipsychotics possessed debilitating side effects, and a significant number of patients did not respond to treatment. Thus, skilled artisans recognized the need for additional antipsychotic drugs that had minimal side effects, and asenapine met this criteria. The asserted claims were therefore not obvious.

The court likewise dispensed with defendants’ 112 defenses. Defendants argued that the claims of the ’476 patent lack adequate written description because the specification does not adequately describe asenapine free base. But the court found that evidence adduced at trial demonstrated that a skilled artisan would understand that the inventors of the ’476 patent were in possession of compositions comprising asenapine free base and methods of using these compositions to treat the claimed conditions. Not only did the ’476 patent explicitly describe asenapine in its free base form, the specification further stated that these compositions comprising asenapine free base “are useful in treating mammals, including humans, suffering from diseases which are susceptible to treatment by [asenapine free base],” including “mental disorders, such as tension, excitation, anxiety, psychosis and schizophrenia.” Defendants’s non-enablement argument was premised on the fact that a single embodiment (a composition comprising asenapine free base) out of many was not enabled. The court dismissed this argument as legally insufficient.