Orexo AB v. Actavis Elizabeth LLC

Case Name: Orexo AB v. Actavis Elizabeth LLC, Fed. Cir. No. 2017-1333, 2018 U.S. App. LEXIS 25531 (Fed. Cir. Sept. 10, 2018) (Circuit Judges Newman, Hughes, and Stoll presiding; Opinion by Newman, J.) (Appeal from D. Del., Robinson, J.) 

Drug Product and Patent(s)-in-Suit: Zubsolv® (buprenorphine and naloxone); U.S. Patent No. 8,940,330 (“the ’330 patent”)

Nature of Case and Issue(s) Presented: The ’330 patent discloses that opioid-based analgesics have become a source of addiction, dependency, and abuse. Treatment for opioid addiction includes a protocol called “substitution therapy,” where partial opioid agonists that have higher binding affinities at opioid receptors but produce lowered dependency than full agonists like heroin, can lead to cessation of addiction by relieving the opioid craving. The ’330 patent claims 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 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.

Orexo appeals the decision of the district court, which held asserted claims 1, 3-6, and 8-10 of the ’330 patent invalid as obvious. The Federal Circuit reversed on the basis that Actavis did not meet its clear-and-convincing burden.

Why Orexo Prevailed: In holding the ’330 patent obvious, the district court relied on the prior-art ’832 patent to show that “the use of citric acid with an interactive mixture would also improve bioavailability.” The ’832 patent is directed to replacing sublingual tablets with oral film, for possible advantage in administration. The Federal Circuit reasoned that there is no suggestion of the different structure of the Zubsolv tablet and its advantage in deterring abuse, and the the “Zubsolv structure is achieved solely upon the hindsight knowledge of the structure and benefits described in the ’330 Patent.”

The district court also relied on the prior-art ’443 application for its disclosure of particles of buprenorphine adhered to carrier particles. But according to the Federal Circuit, the ’443 application does not mention citric acid in its extensive list of carriers, and does not suggest that citric acid carrier particles may provide benefits compared with the prior art. “These benefits were not predicted or suggested in any reference.”

Next, the district court cited the prior-art reference EP ’725 application for its general description of interactive mixtures as pharmaceutical formulations. But this reference “does not mention opioids, does not mention sublingual tablets, does not mention citric acid in its extensive list of carrier particles, and does not suggest the formulation in the ’330 Patent or its unexpected benefits.”

The Federal Circuit found that the product covered by the ’330 patent is admittedly new. “The question is not whether the various references separately taught components of the ’330 Patent formulation, but whether the prior art suggested the selection and combination achieved by the ’330 inventors.” Ultimately the Federal Circuit found that there is no suggestion that the specified elements in the prior art should be selected and combined, and that the designated sublingual formulation would be less subject to abuse than prior formulations for substitution therapy.

Finally, the Federal Circuit took issue with the district court’s analysis of secondary considerations. The district court erred in discounting the enhanced bioavailability in the ’330 patent’s formulation. The district court also discounted Orexo’s evidence that Zubsolv is less susceptible to abuse than Suboxone.