Asenapine – USA

On Jun 30, 2017 a Delaware court issued opinion in SAPHRIS® (Asenapine) case & upheld validity and partly an infringement of U.S. Patent No. 5,763,476.

This consolidated case arises out of the filing of Abbreviated New Drug Applications ("ANDAs") by defendants Sigmapharm Laboratories, LLC ("Sigmapharm"); Breckenridge Pharmaceutical, Inc. ("Breckenridge"); Hikma Pharmaceuticals, LLC, Hikma Pharmaceuticals, PLC, and West-Ward Pharmaceutical Corporation (collectively, "Hikma"); Alembic Pharmaceuticals Ltd., Alembic Global Holding S.A., and Alembic Pharmaceuticals, Inc. (collectively, "Alembic"); and Amneal Pharmaceuticals, LLC, Amneal Pharmaceuticals of New York, LLC, and Amneal Pharmaceuticals Co. India PVT.LTD (collectively, "Amneal"). All defendants may be collectively referred to as "defendants." Each of the defendants has submitted an ANDA in an attempt to market generic versions of asenapine before the expiration of U.S. Patent No. 5,763,476 ("the '476 patent"), which claims sublingual or buccal compositions of asenapine and methods of using such compositions to treat mental disorders, including schizophrenia. Plaintiffs Forest Laboratories, LLC and Forest Laboratories Holdings, Ltd. (collectively, "Forest" or "plaintiffs") brought patent infringement suits against each of the defendants, which suits were consolidated into the above captioned suit.

In the case tried before the court, 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 focus of the trial (conducted in the fall of 2016) was infringement of claim 4 and the validity of the '476 patent. Based on the invention as disclosed in the specification, asserted claim 4 recites:

"A method for treating tension, excitation, anxiety, and psychotic and schizophrenic disorders, comprising administering sublingually or buccally an effective amount of a pharmaceutical composition comprising trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro- 1Hdibenz[2,3:6,7]oxepino[4,5-c]pyrrole [asenapine] or a pharmaceutically acceptable salt thereof."

Infringement:

As noted, all defendants have conceded infringement of claim 1, as well as dependent claims 2, 5, and 6 of the '476 patent. Only defendants Alembic and Breckenridge challenge infringement of claim 4. Consistent with the parties' dispute, claim 4 contains essentially three relevant limitations: "A method for treating ... [1] excitation ... disorders, comprising [2] administering sublingually or buccally an [3] effective amount of a pharmaceutical composition [asenapine] or a pharmaceutically acceptable salt thereof." Defendants Alembic's and Breckenridge's proposed labels provide literal instructions to carry out elements [2] and [3] of the claim i.e., [2] sublingually administering [3] an effective amount of asenapine maleate to treat the indicated disorder, that is, manic episodes associated with bipolar I disorder. The only issue for the court to decide concerns limitation [1] in the claim, that is, whether defendants infringe claim 4 even though their generic asenapine products are indicated only for the treatment of "manic episodes" associated with bipolar I disorder & not for excitation.

1. Direct infringement under the doctrine of equivalents

The court 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 court explained that 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. Forest argued that the term "excitation" in the claim includes within its literal scope "mania" and, therefore, the claim covers the treatment of the manic component of bipolar disease. To put the point differently, Forest argues 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 recited in claim 4, such differences are insubstantial; i.e., the two treatments are equivalent.

Despite Dr. Mcintyre's efforts to convince the court that those of skill in the art in 1994, as a general proposition, equated the term "excitation" with "mania," the court remains unconvinced. In the first instance, there is no reference of record that literally describes "excitation" as the defining feature of mania. Instead, the references refer to "excitement" (and the words Dr. Mcintyre equates with excitement) as one of several criteria that must be present to properly diagnose a manic episode of bipolar I disorder. In sum, there is no dispute that "excitation" is not itself a disorder. There is also no dispute that "excitation" can be symptomatic of many disorders. The court, however, finds no persuasive objective evidence that those of skill in the art in 1994 considered "excitation" the sine qua non of "mania" such that the two terms would be equated for purposes of treating a patient with asenapine.

2. Indirect infringement

In the absence of direct infringement, there can be no liability for indirect infringement. Nevertheless, the court will address Forest's evidence relating to inducement for completeness. Alembic's and Breckenridge's original ANDA submissions (like the other defendants at bar) contained proposed labels that included all of the Saphris approved indications - schizophrenia and manic and mixed episodes associated with bipolar I disorder. Subsequent to the court's claim construction order, Alembic and Breckenridge submitted new labels to the FDA that proposed removing schizophrenia as an indication. According to Forest, the proposed labels also provide sufficient instructions for doctors and patients to administer the generic asenapine products sublingually, and to use an "effective amount" of asenapine to treat schizophrenia, as required by claim 4. More specifically, defendants' proposed labels include a section titled "Dosage Forms and Strengths," which indicates that their asenapine sublingual tablets are available in 5 mg and 10 mg doses. The recommended dosing for schizophrenia and bipolar mania are similar. The Saphris label indicates that the starting dose for schizophrenia is 5 mg sublingually twice daily, with a recommended dose of 5 to 10 mg sublingually twice daily and a maximum dose of 10 mg sublingually twice daily.

Despite these essentially undisputed facts, the Federal Circuit has held that even the "knowledge of off-label infringing uses" will not establish inducement. The facts at bar are unusual, 17 but not more compelling than the facts reviewed by the Federal Circuit in Takeda. The court concludes that the evidence proferred by Forest in this regard is 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.

Invalidity due to Obviousness

Defendants rely on the teachings of three different prior art combinations to demonstrate that the subject matter of claim 1 of the '476 patent is obvious: (1) Sitsen (PTX 37) 19 in view of the '516 patent (PTX 28); (2) Van der Berg '434 patent (PTX 133) in view of the '516 patent; or (3) Van der Berg '434 patent in view of the '423 application (PTX 30), each combined with the knowledge of the ordinarily skilled artisan. Defendants argue that the prior art identified above would have motivated persons of skill in the art to formulate asenapine ("a new and promising antipsychotic in 1994," D.I 288 at 26) as a rapidly disintegrating composition (consistent with the improved composition platforms disclosed in the '516 patent and '423 application) with a reasonable expectation of success.

The court discerns no motivation from the record evidence to use a sublingual formulation-a formulation that had never before been used for an antipsychotic drug. Courts have recognized that solving an unrecognized problem in the art can itself be an nonobvious patentable invention, even where the solution is obvious once the problem is known. Eibel Process Co. v. Minn. & Ontario Paper Co., 261 U.S. 45, 68 (1923). The record at bar demonstrates that it was unknown in the art that oral or IV administration of asenapine could cause severe cardiotoxic side effects. 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. Accordingly, the use of a sublingual formulation was not obvious.

Invalidity due to Lack of Written Description

Defendants allege that the claims of the '476 patent lack adequate written description because the specification does not adequately describe asenapine free base. The evidence adduced at trial demonstrates 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 does the '476 patent explicitly describe asenapine in its free base form, it indicates that "[t]he invention therefore relates to a sublingual or buccal pharmaceutical composition comprising [asenapine free base. The fact that there is no explicit example of a sublingual or buccal composition containing asenapine free base or use of such a composition is not dispositive. Under controlling precedent, explicit examples are not needed to provide adequate written description support. Ariad, 598 F .3d at 1352; Fa/ko-Gunter, 448 F .3d at 1366.

Invalidity due to Lack of Enablement

Defendants' non-enablement contention rests on the allegation that a single embodiment (a composition comprising asenapine free base) out of many is not enabled. This argument is legally insufficient. See In re Angstadt, 537 F.2d 498, 502- 503 (C.C.P.A. 1976) (holding that patent applicants are not required to enable every species encompassed by their claims). Defendants have failed to establish, by clear and convincing evidence, that the asserted claims are not enabled.

Objective indicia

The record at bar demonstrates that it continues 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. Based on the IV study, even the inventors of the '476 patent believed that sublingual administration would also result in a negative outcome. (D.I. 311 at 269:24-270:18) And there is nothing in the prior art suggesting that sublingual administration could be used to resolve this type of side effect.

Given the problems with typical antipsychotics and the two atypical antipsychotics available as of 1994, skilled artisans recognized the need for additional antipsychotic drugs that had minimal EPS symptoms as well as a favorable weight gain, metabolic, and prolactin profile. Asenapine met the criteria for Long-felt need.

CONCLUSION: For the reasons stated, Forest has not carried its burden to prove, by a preponderance of the evidence, that defendants Alembic and Breckenridge infringe claim 4 of the '476 patent. Defendants have failed to carry their burden to prove, by clear and convincing evidence, that claims 1 and 4 of the '476 patent are invalid by reason of obviousness, lack of written description, or lack of enablement.