Asenapine - USA

On Jul. 21, 2020, Delaware Court on remand found Asenapine sublingual composition patent not obvious.

Forest Laboratories / Allergan (Plaintiffs) owns NDA for Saphris® (Asenapine maleate) sublingual tablet. Plaintiffs sued five generic manufacturers, Sigmapharm, Hikma, Breckenridge, Alembic and Amneal (Defendants) for infringement of U.S. Patent No. 5,763,476. US’476 patent claims sublingual and buccal compositions of asenapine and their methods of use. At trial, Defendants argued, amongst other things, that the ’476 patent was invalid for obviousness because there was a motivation to develop sublingual and buccal forms of asenapine based on compliance concerns with the orally administered forms in schizophrenic patients. After trial in 2016, District Court held that the ’476 patent was not invalid for obviousness. Defendants appealed. During appeal, Federal Circuit remanded case back to District Court because summarizing testimony regarding motivation to combine prior arts based on compliance issue was not a clear finding. Federal Circuit observed that  review would be aided by an express finding regarding whether compliance concerns regarding patients with swallowing difficulties would provide a motivation to combine.

Back to district court, there were 2 issues: (1) “the limited question of whether compliance concerns with patients who have trouble swallowing would provide a motivation to combine”; and (2) “its impact on the obviousness analysis.”

District court with respect to first issue said that there was no motivation to combine the prior art references. Because none of these references discuss schizophrenic or bipolar patients experiencing compliance problems or difficulty swallowing. Instead, one of the references discusses geriatric and pediatric patients “in particular” as the type of patients that raises compliance concerns. In addition, none of the references identify asenapine in particular or antipsychotics in general as suitable for a sublingual or buccal route of administration.  In addition, a general understanding that a certain dosage form may improve patient compliance is not enough, by itself, to show that a POSA would have been motivated to develop a specific drug or a drug for a specific illness using that dosage form.

With respect to reasonable expectation of success, court said that even if a skilled artisan was motivated to solve compliance problems for schizophrenic or bipolar patients using orally administered tablets, there was no reasonable expectation that sublingual and buccal routes of administration would lead to success. The testimony in the record from clinical experts establishes that sublingual and buccal dosage forms are more difficult to use for patients with schizophrenia and bipolar disorders. Plaintiff’s clinical expert, Dr. McIntryre, testified that sublingual formulations require an atypical set of instructions that must be carefully followed, including refraining from food and water for a certain period of time and holding the dosage form in the mouth under the tongue for a period of time. In addition, Defendants’ own prior art references do not provide a reasonable expectation of success. Instead, some references cast doubt on using sublingual dosage form. Court thus held that there was neither a motivation based on compliance concerns to combine the drug compound asenapine with sublingual and buccal dosage forms nor a reasonable expectation of success.

With respect to second issue, court said that there is no impact of findings on compliance concerns to the overall obviousness analysis. Court found several factors weighed in favor of nonobviousness such as  solution to the unrecognized problem of cardiotoxicity & long-felt need. Thus, court held that Defendants have not established by clear and convincing evidence that the ’476 patent was obvious.