On Sep. 15, 2022, Delaware court found some patents valid and infringed in Aptiom® Hatch-Waxman case.

 

Plaintiffs (Bial- Portela / Sunovion) sued defendant (Alkem) for infringement of five patents as defendant filed ANDA with USFDA to market generic version of APTIOM®. It is orally administered once a day in tablet form to treat epileptic seizures called partial-onset seizures. Plaintiff asserted claim 3 of US 10,675,287; claim 5 of US 10,695,354; claims 7 and 8 of US 10,702,536 (collectively once-daily dosing patents); claim 20 of US 9,763,954 (method of treatment), and claim 17 of US 10,912,781 (formulation) patent.

 

Infringement:

The #954 Patent (Method of Treatment) –

The prime issue was here that whether Alkem’s label contains patients population who are intractable to oxcarbazepine. Court said that nothing in Alkem’ s label teaches, recommends, or encourages using its generic product in patients who are intractable to oxcarbazepine, and nothing in the label suggests that using the product in that patient population specifically would be a “medically desirable activity.” Thus, Alkem’s label does not establish that Alkem intends for its product to be used in this patient population.

The #781 Patent (Formulation) –

Alkem’s generic tablets contain 2.18 wt% microcrystalline cellulose, which the label identifies as a diluent. It is undisputed that microcrystalline cellulose can act as both a diluent and a disintegrant. The parties dispute, however, whether Bial proved at trial that microcrystalline cellulose acts a disintegrant in Alkem’s ANDA product. Court said that microcrystalline cellulose acts a disintegrant in Alkem’s ANDA product. Plaintiff expert (Koleng) testified that pharmaceutical formulators use microcrystalline cellulose as a disintegrant because of its “good wicking properties
and hydrogen bonds between adjacent matchstick-like bundles that break when exposed to water. Alkem did not offer at trial any testimony to rebut Koleng’s testimony about microcrystalline cellulose’s disintegrant properties.

 

Invalidity:

The #287, #354, and #536 Patents (the Once-Daily Patents) –

The benefits of once-daily dosing generally include patient convenience and improved patient adherence to the medication regimen. Court said that prior arts individually or collectively, do not disclose that once-daily dosing of eslicarbazepine acetate is efficacious to treat partial-onset seizures. Moreover, POSA would not have reasonable expectation of success because dosing once-daily has a higher risk of the blood plasma concentration of the active compound falling below the therapeutic level than dosing twice-daily. If anything, the record evidence suggests that an artisan of ordinary skill would doubt that dosing once-daily would be successful. Thus, Alkem did not show by clear and convincing evidence that the claims are invalid as obvious.

The #954 Patent (Method of Treatment) – 

Alkem argued that the patent is invalid under lack of written description. The #954 patent reports that both oxcarbazepine and eslicarbazepine acetate are converted by metabolism to eslicarbazepine (i.e., S-licarbazepine ). The #954 patent implies that eslicarbazepine acetate will have improved effects over oxcarbazepine because, although both drugs metabolize into the same metabolites, eslicarbazepine acetate more favorably metabolizes into S-licarbazepine than oxcarbazepine does. Court said that “there is no study in humans described anywhere in the #954 patent where the human patient or subject of the study was intractable to oxcarbazepine and shown to respond to eslicarbazepine acetate.” Court said that with respect to relative efficacy of S-licarbazepine and R-licarbazepine for the prevention of development of intractable epilepsy, Bial has not shown that such a conclusion is probative of relative efficacy of the metabolites for treatment of intractable epilepsy. Therefore, the patent did not establish that eslicarbazepine acetate would treat patients intractable to oxcarbazepine. Alkem has established by clear and convincing evidence that claim 20 of the #954 patent is invalid under§ 112.

The #781 Patent (Formulation) – 

The #781 patent is directed to “high drug loaded pharmaceutical compositions containing the active drug substance eslicarbazepine acetate, exhibiting an immediate-release dissolution profile with certain excipients and excipient ranges.” “High drug load” refers to the requirement that 80 to 90 wt % of the pharmaceutical composition is eslicarbazepine acetate. Court said that formulation scientist would consider patient compliance and convenience when formulating a pharmaceutical composition. The formulator would have been motivated to make a single tablet containing 1 ,200 mg of eslicarbazepine acetate after reading Almeida 2002 prior art. Further, an artisan of ordinary skill would have been motivated to formulate this composition with eslicarbazepine acetate accounting for 90 wt % because, if excipients accounted for more than 10 wt %, the tablet would be too big to swallow. Thus, Alkem has shown by clear and convincing evidence that the claim is invalid as obvious.