The Federal Circuit reversed the District of Delaware’s decision to invalidate Orexo’s opioid treatment patent as obvious because obviousness was not proved by clear and convincing evidence. Specifically, the Court pointed to the absence of a teaching in the prior art that citric acid could serve as a carrier particle for the drug agonist. The Court also noted that the lower court improperly discounted evidence of objective indicia of nonobviousness. Orexo AB v. Actavis Elizabeth LLC, No. 2017-1333, 2018 WL 4288961, at *1 (Fed. Cir. Sept. 10, 2018) (before Newman, Hughes, and Stoll, J.) (opinion by Newman, J.)

Actavis filed an ANDA application to market a generic version of Zubsolv, a drug approved for the treatment of opioid addiction. Orexo subsequently initiated a Hatch-Waxman litigation asserting Actavis infringed U.S. Patent No. 8,940,330, which is directed to the use of a “substitution therapy” for the treatment of opioid addition. Substitution therapies were known in the art and were used to reduce addiction, dependency, and abuse by using a partial opioid agonist. Those substitution therapies were in turn abused, however, when instead of taking the therapy orally, as was prescribed, drug abusers would dissolve the drug and inject it intravenously. Thus, the prior art had developed a four-to-one ratio of agonist to antagonist that was a viable substitution therapy when taken orally, but resulted in unpleasant symptoms when injected intravenously. The patent at issue sought to improve on this formulation, to further reduce abuse, by “enhancing agonist effectiveness of buprenorphine in the tablet and thus reducing the amount available on dissolving and injecting the product.” It accomplished this by adhering microparticles of buprenorphine, the agonist, to carrier particles of citric acid while also including naloxone, the antagonist, in a 4:1 ratio. In allowing the patent, the Examiner had pointed to the structure of the patent’s drug as the likely cause of its higher bioavailability, stating that “the mere presence of citric acid … is insufficient”.

The district court held the patent claims invalid based on the combination of prior art that disclosed the 4:1 ratio with additional prior art disclosing that citric acid increased bioavailability and how to make such mixtures. The district court rejected several arguments from the patent owner as being directed to unclaimed features. For example, patent owner argued that the prior art would have dissuaded a POSA from using citric acid because it taught that a lowered pH, which would result from using citric acid, would reduce the bioavailability of naloxone and thus compromise the 4:1 ratio. This argument was rejected, however, because the ratio was an unclaimed feature.

The Federal Circuit reversed. It pointed to the fact that Actavis’ expert cited no reference for his reasoning that the prior art disclosed citric acid as a carrier particle. Indeed, the Court noted, Actavis conceded at oral argument that no reference teaches using citric acid as a carrier particle. Thus, 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.”

As Judge Newman explained writing for the majority:

“The question is not whether the various references separately taught components of the [patent] formulation, but whether the prior art suggested the selection and combination achieved by the [patent] inventors. Although the reference [patent] showed that buprenorphine bioavailability in the film formulation is affected by pH, this not a suggestion of the sublingual tablet interactive formula in the [challenged patent] or a teaching of its benefit in deterring abuse. The references show that the field of opioid biopharmacology has received extensive study. The [patent] provides a significant improvement. Despite the extensive study, this improvement over the then-available treatments for addition is not proposed or suggested in the references. There is no suggestion that the specified elements should be selected and combined, and that the designated sublingual formulation would be less subject to abuse than prior formulations for substitution therapy. Although the need to reduce this abuse was known, recognizing a need does not render the solution obvious.”

The Court also found that the district court erred in discounting the unexpected results produced. The Court therefore reversed and remanded for appropriate further proceedings.

Take Away

The proper inquiry in an obviousness analysis is “not whether the various references separately taught components of the [patent] formulation, but whether the prior art suggested the selection and combination achieved by the [patent’s] inventors.”