Buprenorphine & Naloxone - USA

On Sep 10, 2018, Federal Circuit reversed the decision of Delaware court & found patent valid.

Orexo appealed the decision of the District of Delaware, holding claims 1, 3–6, and 8–10 of U.S. Patent No. 8,940,330 (“the ’330 Patent”) invalid on the ground of obviousness in a Hatch-Waxman proceeding against Actavis. The ’330 Patent, entitled “Abuse-Resistant Pharmaceutical Composition for the Treatment of Opioid Dependence,” claims a product having the brand name Zubsolv®, approved by the FDA for treatment of opioid dependence. The ’330 Patent is for a sublingual tablet formulation that is less subject to abuse. The formulation enhances the agonist effectiveness of buprenorphine, permitting a reduced amount of buprenorphine in the tablet and thus reducing the amount available on dissolving and injecting the product. In this formulation, microparticles of buprenorphine are adhered to the surface of carrier particles of citric acid, and the formulation also contains naloxone in the 4:1 ratio. The ’330 Patent explains that the buprenorphine in the microparticles acts with little interference from the naloxone, but if the tablet is dissolved in water for injection into the bloodstream, the naloxone will also be dissolved and will antagonize buprenorphine’s effects.

The district court held the asserted ’330 Patent claims invalid, ruling that a skilled artisan would obviously have selected these components from the prior arts and reformulated them as in the ’330 patent. In response to Orexo’s argument that no reference showed the new formulation in the ’330 patent, stressing the unexpectedly enhanced bioavailability and its benefits, the district court reasoned that a skilled artisan “would not have excluded citric acid” as a carrier and “would have known how to form an interactive mixture using citric acid.” The district court found that the prior art taught “the use of citric acid with an interactive mixture would also improve buprenorphine bioavailability,” and concluded that it would have been obvious to use citric acid as carrier particles.

Federal circuit however, disagreed & said that none of the prior art specifically mentions citric acid as a carrier particles, and does not suggest the formulation in the ’330 Patent or its unexpected benefits. Moreover, at the oral argument of this appeal, Actavis conceded that no reference teaches using citric acid as a carrier particle, or that citric acid should be used as a carrier particle. The product herein is admittedly new & had a 66% improvement in bioavailability. The district court has acknowledged the undisputed testimony of Orexo’s co-founder, Mr. Thomas Lundqvist, and Orexo’s global chief medical officer.  The district court’s finding that “a person of ordinary skill in the art would not have excluded citric acid,” is not a teaching or suggestion to use citric acid. See In re Gordon, 733 F.2d 900, 902 (Fed. Cir. 1984) (“The mere fact that the prior art could be so modified would not have made the modification obvious unless the prior art suggested the desirability of the modification.”). The record does not contain clear and convincing evidence of a teaching or suggestion to use citric acid particles as a carrier for this opioid product in substitution therapy, or that the actual beneficial results would be obtained.

Federal circuit said that here, the objective indicia guide the analysis of obviousness. The district court erred in discounting the enhanced bioavailability as unexpected results in the ’330 Patent’s formulation as “a ‘difference in degree,’ not a difference in ‘kind,’” for the clinical studies reported in the ’330 Patent show 66% improved bioavailability. Particularly in the context of this invention, this is more than a trivial “degree.” The district court also discounted Orexo’s evidence that Zubsolv is less susceptible to abuse than Suboxone. It was established that this novel formulation enables reduced dosage and enhanced efficacy in substitution therapy products, deterring abuse.

Therefore, on the entirety of the record, Actavis did not establish obviousness by clear and convincing evidence & thus the judgment of invalidity is reversed.