Orexo AB v. Actavis Elizabeth LLC

Case Name: Orexo AB v. Actavis Elizabeth LLC, 14-cv-829-SLR, 2016 U.S. Dist. LEXIS 157683 (D. Del. Nov. 15, 2016) (Robinson, J.)

Drug Product and Patents-in-Suit: Zubsolv® (buprenorphine / naloxone sublingual tablet); U.S. Patents Nos. 8,454,996 (“the ’996 patent”) and 8,940,330 (“the ’330 patent”)

Nature of the Case and Issue(s) Presented: Buprenorphine is an opioid agonist used to treat patients that are addicted to opioids. But if solubilized and injected, buprenorphine itself can be abused. To solve this problem, buprenorphine was combined with naloxone, a compound that reverses the effects of opioid analgesics. Naloxone also has poor transmucosal bioavailability. Thus, when combined with naloxone in a sublingual tablet, buprenorphine can be administered with a lower risk of abuse. While this process has been known since 2004, Orexo subsequently developed a more abuse resistant sublingual tablet containing buprenorphine and naloxone. This tablet, and the method of administering the tablet, was claimed by the patents-in-suit.

Actavis filed an ANDA seeking to market a generic version of Orexo’s tablet. Orexo sued Actavis for patent infringement. After a bench trial and post-trial briefing, the court concluded that the method patent, the ’996 patent, was valid and infringed, and that the product patent, the ’330 patent, was invalid as obvious.

Why Orexo Prevailed: The parties agreed that the ’996 patent called for the use of an “interactive mixture”—particles of an active ingredient adhered to carrier particles by interactive forces. The dispute focused on whether one of ordinary skill would know to use interactive mixtures in sublingual tablets prior to the priority date of the ’996 patent. The court agreed with Orexo and held that one of ordinary skill would not have known to combine interactive mixtures and sublingual tablets at the time of invention. This was the case even though each concept was independently known in the art at the time. The court reasoned that there was no motivation to combine references describing sublingual tablets with the art relating to interactive mixtures. The art before the court related to multiple competing, and incompatible, groups of formulations. Thus, it was inventive for Orexo to combine the disparate concepts in its patented method.

The Court also found sufficient evidence that Actavis infringed the ’996 patent. Orexo’s expert testified that his laboratory manufactured pre-compression blends of Actavis’ product by following the instructions in Actavis’ ANDA to determine if an interactive mixture were present. Although there were some errors in the process, even Actavis’ expert agreed that the manufactured product would be accepted. That product was then analyzed using a scanning electron microscope, which revealed an interactive mixture. Further, Actavis’ development documents revealed that the formulation consisted of a uniform blend. Orexo’s expert indicated that blend uniformity was suggestive of the presence of an interactive mixture. Finally, Orexo’s expert also performed Raman imaging of Actavis’ final product. The results were consistent with the presence of an interactive mixture.

Turning to the ’330 patent, the court determined that patent was obvious in light of the prior art. Prior to the development of Orexo’s tablet, a buprenorphine/naloxone tablet called Suboxone was administered sublingually. Orexo improved on Suboxone by adding citric acid using an interactive mixture, in order to increase the bioavailability of the tablet. The prior art, however, expressly taught that combining citric acid with buprenorphine increased the absorption of buprenorphine. Further, the prior art also taught that using citric acid to form an interactive mixture improved the bioavailability of the compound. A person of ordinary skill, the court reasoned, would have been motivated to combine these references to improve the bioavailability of buprenorphine.