Asenapine – USA

On Mar 14, 2019 Federal Circuit vacated & remanded district court’s judgment regarding validity & non-infringement.

Defendants, Sigmapharm, Hikma, Breckenridge, Alembic & Amneal filed ANDA with USFDA seeking to market generic versions of Saphris, a drug product sold by Forest Laboratories, LLC. Saphris is a sublingually administered, atypical antipsychotic containing asenapine maleate. Forest sued for patent infringement, asserting that Defendants proposed generic products would infringe claims 1–2, 4–6, and 9–10 of U.S. Patent No. 5,763,476. Following a bench trial, the district court held Defendants had not established claims 1–2, 4–6, and 9–10 to be invalid and held Forest had not established infringement of claims 4, 9, and 10 as to Alembic and Breckenridge. Defendants then appealed the district court’s construction of claim 1 and its determination that the claims have not been established to be invalid. Forest cross-appealed, arguing that the district court’s finding that Breckenridge and Alembic do not infringe claim 4 was clearly erroneous.

Claims 1 and 4 recite:

1. A pharmaceutical composition comprising as a medicinally active compound: trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole or a pharmaceutically acceptable salt thereof; wherein the composition is a solid composition and disintegrates within 30 seconds in water at 37° C.

4. 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-1H-dibenz[2,3:6,7]oxepino[4,5- c]pyrrole or a pharmaceutically acceptable salt thereof.

I. Construction of Claim 1:

While claim 4 is expressly limited to sublingual or buccal formulations of asenapine, claim 1 is not and instead states that “the composition is a solid composition and disintegrates within 30 seconds in water at 37° C.” The district court nevertheless construed claim 1 to be limited to buccal and sublingual formulations. Appellants argued that the district court erred in construing claim 1 this way. But Federal Circuit saw no error in the district court’s construction.  Federal Circuit said that although claim 1 does not expressly refer to buccal or sublingual administration, the claims “must be read in view of the specification, of which they are a part.” Phillips v. AWH Corp., 415 F.3d 1303, 1315 (Fed. Cir. 2005) (en banc) (quoting Markman v. Westview Instruments, Inc., 52 F.3d 967, 979 (Fed. Cir. 1995)). That construction is further supported by additional language in the specification, which explains the benefits of sublingual and buccal treatment over the prior art. The patent is also expressly titled “Sublingual or Buccal Pharmaceutical Composition.” The specification states that “[p]referred pharmaceutical compositions are solid pharmaceutical compositions which rapidly disintegrate in the mouth of a subject, upon insertion into the buccal pouch or upon placement under the tongue.” This strongly suggests that the language “the composition is a solid composition and disintegrates within 30 seconds in water at 37° C” was meant to limit the claim to buccal and sublingual formulations. Therefore, district court properly construed claim 1 to be limited to buccal and sublingual formulations.

II. Obviousness:

The district court found that Appellants had not established that there was a motivation to combine asenapine maleate into a sublingual or buccal form, and even if there were a motivation to combine, a skilled artisan would not have had a reasonable expectation that it would work. During appeal Appellant argued that an ordinarily skilled artisan would have been motivated to administer asenapine maleate sublingually or buccally to address known compliance concerns. Second, they argued that an ordinarily skilled artisan would have been motivated to administer asenapine maleate sublingually or buccally to obtain more treatment options. Federal Circuit said that the district court already discussed compliance concerns and, citing testimony from Forest’s expert witness Dr. McIntyre, explained that “clinicians with experience in treating schizophrenic patients understand that sublingual dosage forms are more burdensome to schizophrenic patients in that they require the patient to hold the dosage form in the mouth under the tongue for a period of time, and also require that the patient refrain from drinking or swallowing for a period of time.” The court further explained that Appellants’ “own expert clinician, Dr. Hollander, agreed that sublingual administration would not improve patient compliance. Turning to Appellants’ second claimed motivation, Federal Circuit held that the district court did not clearly err in rejecting Appellants’ contention that the benefits of having multiple treatment options available would provide a motivation to combine. The district court did not clearly err, however, in concluding that a generic need for more antipsychotic treatment options did not provide a motivation to combine these particular prior art elements.

Finally, Appellants argued that the district court erred in treating the claimed invention as providing a solution to an unrecognized problem in the art. District court found that the Organon scientists discovered a “previously unknown” problem and developed the claimed sublingual dosage forms as a solution to that problem. Specifically, it found that during early clinical studies Organon discovered intravenous and oral administration of asenapine resulted in severe cardiotoxic events. As a result, those studies were terminated prior to completion. The district court found, however, that during subsequent testing on beagles, while there was “a clear trend of increased heart effects with an oral tablet,” “no such trend was observed with the sublingual forms.” The district court found that while Organon became aware of these problems, “[t]here was nothing in the prior art that would have indicated that the oral tablet had problems.” The district court further held that the solution Organon developed to address the cardiotoxic effect was also non-obvious. Therefore, Federal Circuit saw no clear error in the district court’s consideration of the unknown nature of the problem solved by the inventors and the factors that would teach away from their solution.

Federal Circuit however, in light of the district court’s failure to make an express finding as to whether compliance concerns for patients with trouble swallowing would provide a motivation to combine, remanded this issue to the district court to address it further.

Long-Felt Need: Appellants pointed to evidence that the claimed invention did not satisfy a long-felt but unmet need. Specifically, they argued there were a variety of antipsychotic drugs available at the time of the invention, there is evidence that physicians did not switch treatment preferences for patients with schizophrenia when Saphris entered the market, and there is evidence that Saphris did not have better efficacy or compliance than other antipsychotics available in 1994. They further argued that Saphris itself has many side effects and a high discontinuation rate. Federal Circuit said that in reviewing the district court’s fact findings, we do not ask whether evidence could have supported the opposing view, only whether the district court clearly erred. Here it did not. Although there were a variety of existing antipsychotics, they had debilitating negative side effects, which evidence indicates are reduced in Saphris. Thus, the district court did not clearly err in finding it weighs in favor of non-obviousness.

Unexpected Results: Here, the district court found it was “surprising and unexpected” that the claimed “sublingual route of administration successfully resolved the serious cardiotoxic event reported in the ’476 patent.” However, as the district court found, there was nothing in the prior art that indicated cardiotoxic problems existed with other routes of administration. At the time of the claimed invention, a person of ordinary skill could not have been surprised that the sublingual route of administration did not result in cardiotoxic effects because the person of ordinary skill would not have been aware that other routes of administration do result in cardiotoxic effects. The district court, therefore, erred in its analysis of unexpected results.

III. Written Description:

Appellants argued that the specification fails to describe asenapine free base in a rapidly disintegrating, sublingual, or buccal solid composition. The district court’s finding that the specification contains sufficient written description support for claims 1 and 4 was not clearly erroneous. Appellants’ expert witness Dr. Gould acknowledged asenapine free base was known in the art. The specification repeatedly refers to pharmaceutical compositions containing asenapine free base.

IV. Infringement of Claim 4:

The district court found Breckenridge and Alembic do not infringe claim 4 directly, indirectly, or under the doctrine of equivalents. Breckenridge and Alembic’s proposed generic products are indicated for the treatment of “manic episodes” associated with bipolar I disorder. Claim 4 is directed to “a method for treating tension, excitation, anxiety, and psychotic and schizophrenic disorders.” The court construed claim 4 to not cover the treatment of bipolar disorders. The claim language and the specification indicate that “excitation” refers to a symptom rather than a “disorder. Moreover, experts for both parties agree that there is no such thing as an “excitation disorder,” further indicating the claim covers treatment of the symptom “excitation” rather than treatment of an “excitation disorder.” Although excitation may be a symptom of bipolar I disorder, the district court nevertheless carved bipolar I disorder out of its construction because it concluded that the “language of the ’476 patent is directed to ‘diseases’ and ‘disorders,’ not to symptoms of such.” This misreads the plain language of the claims and specification. Because the district court erred in treating “excitation” as being limited to “excitation disorders,” Federal Circuit vacated its finding of non-infringement and construed “excitation” to refer to a symptom and remanded to the district court to assess infringement in light of this construction.

CONCLUSION:

Federal Circuit thus vacated the district court’s judgment that Claims 1 and 4 are not invalid and remanded for it to consider the limited question of whether compliance concerns with patients who have trouble swallowing would provide a motivation to combine and its impact on the obviousness analysis. Federal Circuit also vacated district court’s judgment of non-infringement of claims 4, 9, and 10 as to Breckenridge and Alembic and remanded for the court to consider whether Breckenridge and Alembic infringe under revised construction.