United States: Unknown Problem Plus Nonobvious Solution Cannot Render Patent For Sublingual Formulation Of Asenapine Obvious

The District Court for the District of Delaware found Forest Labs' patent for sublingual or buccal compositions of asenapine and methods of using such compositions to treat mental disorders, including schizophrenia and mania, infringed and not invalid. Forest Labs., LLC v. Sigmapharm Labs., LLC, et al., Civ. No. 16-cv-914 RGA, (D. Del. June 30, 2017) (Robinson, J.). 

Forest Labs markets Saphris®, an antipsychotic containing asenapine maleate approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Saphris is the only antipsychotic that is administered sublingually. 

Development of the Patented Invention

Asenapine was not initially developed as a sublingual tablet but, instead, as a standard conventional tablet given orally. Early studies published by Organon, the company that first developed asenapine for use in humans, demonstrated that asenapine was safe and clinically effective at relatively low doses. Encouraged by these early studies, Organon continued to perform dose ranging and pharmacokinetic studies with asenapine. Studies were conducted to assess the safety and tolerance of asenapine administered intravenously, and to obtain preliminary data on the bioavailability of orally administered asenapine. The IV studies (which were not published) showed serious adverse side effects such that the investigators concluded IV infusion of asenapine was not well tolerated. After the IV study, Organon scientists focused on an oral tablet formulation. Further tests with the oral tablet formulation also demonstrated serious toxicity side effects not previously shown in the earlier published studies. These further tests of the conventional oral tablet were also not published.  

After brainstorming to develop possible avenues of further research, Organon scientists, including the inventors of the patent-in-suit, postulated using a buccal/sublingual route of administration to solve the problems associated with the cardiotoxic side effects encountered in previous studies focused on IV and oral routes of administration. After further testing, Organon determined that asenapine administered sublingually eliminated the cardiovascular side effects associated with oral and IV administration. Based on this discovery, the inventors filed an application that issued as US Patent No. 5,763,476 (the '476 patent).  

Sigmapharm Laboratories, LLC (Sigmapharm), Breckenridge Pharmaceutical, Inc. (Breckenridge), Hikma Pharmaceuticals, LLC (Hikma), Alembic Pharmaceuticals, Inc. (Alembic) and Amneal Pharmaceuticals, LLC (Amneal), each submitted an abbreviated new drug application (ANDA) in an attempt to market generic versions of asenapine before expiration of the '476 patent. The defendants all conceded infringement of claim 1 of the '476 patent; however, two of the defendants, Sigmapharm and Breckenridge, contested infringement of claim 4. All defendants contended that the '476 patent was invalid for being obvious. 


Claim 4 of the '476 patent is directed to a method for treating: (1) tension, excitation, anxiety, and psychotic and schizophrenic disorders, comprising (2) administering sublingually or buccally an (3) effective amount of asenapine or a pharmaceutically acceptable salt thereof. The issue of infringement of claim 4 boiled down to a single question: whether defendants infringed claim 4 even though their generic asenapine products are indicated only for the treatment of "manic episodes" associated with bipolar I disorder. Forest Labs argued that to the extent there are any differences between the treatment of manic episodes associated with bipolar I disorder with asenapine and the treatment of excitation with asenapine as recited in claim 4, such differences are insubstantial. That is, the treatments are equivalent. Forest Labs relied solely on the testimony of its expert who opined that excitation is the defining feature of manic episodes and, therefore, treating excitation is equivalent to treating manic episodes. The court noted that there was no mention of bipolar I disorder or maniac episodes associated with bipolar I disorder in the '476 patent. Further, while acknowledging that excitation is a symptom of manic episodes, no reference relied upon by Forest Labs' expert literally described excitation as the defining feature of mania. Instead, the references refer to excitation as one of several criteria that must be present to properly diagnose a manic episode of bipolar I disorder. Accordingly, the court found that Forest Labs had not carried its burden to prove direct infringement under the doctrine of equivalents, especially when Alembic's and Breckenridge's proposed labels limit the indication of use to manic and mixed episodes of bipolar I disorder. 

Although there can be no indirect infringement in the absence of a direct infringer, the court addressed Forest's evidence of indirect infringement nonetheless. The court found no intent on the part of Alembic and Breckenridge to induce infringement of the '476 patent. The court's finding was largely based on the fact that after the court issued its claim construction ruling, Alembic and Breckenridge submitted new proposed labels to the FDA for their generic products removing schizophrenia as an indication. The court specifically rejected Forest's off-label infringing use argument to establish intent of inducement. 


The defendants argued that the prior art of record would have motivated persons of ordinary skill in the art to formulate asenapine (a new and promising antipsychotic in 1994) as a rapidly disintegrating composition with a reasonable expectation of success. Defendants' primary invalidity theory was that skilled artisans would have been motivated to develop a sublingual formulation of asenapine because there was a bioavailability concern with conventional, orally administered asenapine. The court rejected this theory and stated that 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. The publically available prior art further showed that Organon was in the process of conducting a large scale Phase II trial with a conventional oral tablet. The court noted that there was nothing in the prior art that would have indicated that the oral tablet had significant side effects, and ultimately concluded that there was no motivation from the record evidence to completely change the route of administration to a sublingual formulation—especially since a sublingual administration had never before been used for an antipsychotic drug. 

The court also found that the objective indicia of nonobviousness weighed in favor of the validity of the '476 patent. Particularly, the court found that the record was full of evidence demonstrating that it was a surprising and unexpected result of the claimed invention that the sublingual route of administration successfully resolved the serious side effects encountered during the development of the invention and as described in the '476 patent. Moreover, prior to the claimed invention, typical antipsychotics used in the treatment of schizophrenia and mania possessed debilitating side effects. The court found that the claimed sublingual administration meet this unsolved need for a much safer treatment of schizophrenia and mania.

Unknown Problem Plus Nonobvious Solution Cannot Render Patent for Sublingual Formulation of Asenapine Obvious

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