Case Name: Avanir Pharms., Inc. v. Actavis South Atlantic LLC, Case No. 1:11-cv-0704-LPS, 2014 U.S. Dist. LEXIS 67111 (D. Del. May 5, 2014) (Stark, J.)
Drug Product and Patent(s)-in-Suit: Nuedexta® (dextromethorphan/quinidine); U.S. Pats. Nos. RE38,115 (“the ’115 patent”), 7,659,282 (“the ’282 patent”), and 8,227,484 (“the ’484 patent”)
Nature of the Case and Issue(s) Presented: The ’115 patent relates to formulations containing dextromethorphan and quinidine for the treatment of chronic or intractable pain. The ’282 and ’484 patents relate to the use of dextromethorphan and quinidine for the treatment of a neurological disorder known as pseudobulbar affect (“PBA”). Defendants stipulated that their proposed products infringe claims 1-9 of the ’282 patent and claims 1-9, 12, 13, 15, and 17 of the ’484 patent. After a six-day bench trial, the court found that: (i) plaintiffs have not proven by a preponderance of the evidence that defendants infringe claims 18-21 of the ’115 patent, (ii) defendants have failed to prove by clear and convincing evidence that claims 1-9 of the ’282 patent are invalid; (iii) defendants have failed to prove by clear and convincing evidence that claims 1-9, 12, 13, 15, and 17 of the ’484 patent are invalid; and (iv) defendants have failed to prove by clear and convincing evidence that claims 18-21 of the ’115 patent are invalid.
Why Avanir Prevailed: Concerning whether defendants’ ANDA products infringed the ’115 patent, the dispute focused on whether Nuedexta contains a combined unit dosage of dextromethorphan and quinidine that is “therapeutically effective in substantially reducing chronic or intractable pain, without unacceptable side effects.” Nuedexta has been approved by the FDA only to treat PBA. Its package insert provides no statement on treating pain, and none of the Nuedexta clinical studies establish that Nuedexta is “therapeutically effective” in substantially reducing chronic pain. Avanir’s reliance on patient interviews, which are undocumented and lack objective measures of efficacy, provided little evidence in support of its infringement theory. Moreover, studies measuring the response to Nuedexta among normal subjects experiencing pain are only minimally relevant to whether Nuedexta can effectively treat patients with chronic or intractable pain without causing unacceptable side effects. Therefore, defendants’ ANDA products do not infringe the asserted claims of the ’115 patent.
Concerning whether the prior art renders the ’484 and ’282 patents obvious, defendants argued that the only difference between the prior art and the asserted claims is the dose ranges of quinidine. This, however, ignores the subject matter of the claims as a whole, including the amounts of dextromethorphan and the claimed weight to weight ratios of dextromethorphan and quinidine. Defendants also argued that a person or ordinary skill would have been motivated to modify the dose of quinidine because of safety concerns and industry practice. The court disagreed. Defendants’ evidence for cardiotoxicity pertained only to the far higher antiarrhythmic dose levels of quinidine and the other side effects were associated with dextromethorphan rather than quinidine. In any event, any remaining safety concerns about quinidine taught a person of ordinary skill either to obtain only the lowest efficacious dose or to discontinue use of quinidine altogether. The court found that there would also be no reasonable expectation of success when lowering the dose of quinidine because as a general matter, central nervous system drug development is “challenging and unpredictable, especially in relation to treatment PBA, a disease for which the mechanism for treatment remains unknown.” Next, the court addressed secondary considerations of non-obviousness. The court concluded that a nexus existed between Nuedexta’s commercial success and the claimed invention. It also found that Avanir presented evidence of unexpected safety benefits and unexpected efficacy in the treatment of PBA.
Finally, since defendants failed to proffer any evidence that a person of ordinary skill would have found the claimed invention of the ’115 patent obvious in light of the “therapeutically effective” limitation, the court concluded that defendants had not shown, by clear and convincing evidence, that the asserted claims of the ’115 patent are obvious.