Brivaracetam – USA

Brivaracetam – USA

On Aug. 16, 2023, Delaware district court found Brivaracetam compound patent valid and infringed.

 

This is an Hatch-Waxman litigation related to Briviact® product, marketed by UCB. USFDA approved Briviact® for the treatment of partial-onset seizures in epilepsy patients one month of age or older. UCB sells Briviact® in 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg tablets, a 50 mg/5 mL single-dose intravenous solution, and a 10 mg/mL oral solution. Defendants (Annora pharma / Apotex / MSN Pharma) filed ANDAs with the FDA to market generic version. UCB alleged that Defendants’ ANDA submissions constitute infringement of claim 5 of U.S. Patent No. 6,911 ,461 which claims compound brivaracetam. Defendants did not dispute at trial that they infringe claim 5 but asserted in their defense that claim 5 is invalid as obvious under § 103.

 

Court analysis:

Brivaracetam is an analogue of the compound levetiracetam, a predecessor compound patented by UCB in 1987. Brivaracetam and levetiracetam share the same chemical formula in all but one respect: Brivaracetam has a propyl group at the 4-position of the so-called pyrrolidine ring. Defendants argued that the #461 patent is invalid because it would have been obvious to a skilled artisan to select levetiracetam as a lead compound and to modify levetiracetam by increasing its lipophilicity with the addition of a propyl group to the 4-position of its pyrrolidine ring.

 

Court said that as a result of UCB’s concession that an artisan of ordinary skill would have chosen levetiracetam as a
lead compound for development of new anti-seizure drugs is also a concession that an artisan would have been motivated to modify levetiracetam to develop new antiseizure drugs. Therefore, the sole issue is to decide whether it would have been obvious to POSA to modify levetiracetam by increasing its lipophilicity with the addition of a propyl group to the 4-position of its pyrrolidine ring.

 

Court said that Defendants failed to establish a direct relationship between lipophilicity and antiepileptic Activity. It’s possible for a more lipophilic compound to have increased permeability for other cells in the body; if the compound enters those cells, the compound is prevented from going into the brain and thus brain permeability is decreased. . Defendants also did not establish by clear and convincing evidence a motivation to increase Levetiracetam ‘s lipophilicity. A skilled artisan would not have been motivated to improve levetiracetam’ s brain uptake, because levetiracetam was already a successful central nervous system drug and increasing brain uptake would risk increasing its side effect. Defendants failed to establish that a skilled artisan as of the priority date would have been motivated to use lipophilicity as a guiding principle for structural modification of levetiracetam.

 

Court said that none of the prior art would have provided a skilled artisan with experimental data about what would happen to anticonvulsant activity if positions on the pyrrolidine ring of piracetam analogues alone were
substituted. A skilled artisan would have understood that the LBS was sensitive to small structural changes, thereby making it difficult to predict the impact of adding a 4-propyl group to levetiracetam on LBS affinity and audiogenic mouse activity. Defendants also failed to establish that a skilled artisan would have prioritized the 4-position on the pyrrolidine ring for modification relative to the other available positions based on the prior art. Although a skilled artisan seeking to enhance the lipophilicity of a compound might have considered adding a straight-chain alkyl, Defendants failed to establish clearly and convincingly that a skilled artisan seeking to enhance the lipophilicity of levetiracetam would have prioritized adding a straight-chain alkyl to it. A skilled artisan adding a 4-n-propyl group to a compound would consider both resulting diastereomers, which “is another level of complexity” regarding the impact “on biologic interactions.” It therefore follows that a skilled artisan would not have reasonably expected a propyl substitution at the 4-position of levetiracetam to improve antiepileptic activity.

 

With respect to secondary considerations, court held that expert testimony did not establish by a preponderance of the evidence that brivaracetam’s results were unexpected and there was long-felt unmet need. However, UCB established by a preponderance of the evidence that others tried but failed to develop antiepileptic drugs that achieve approval by FDA and there was a mild amount of industry praise for brivaracetam to support a finding of nonobviouness.

 

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