Oxymorphone - USA

On May 16, 2018, Federal Circuit affirmed district court & found two opioid patents owned by Endo Pharmaceuticals valid and infringed by ANDA filers in Opana® ER Hatch-Waxman litigation.

Endo holds the approved new drug application for OPANA®ER, a controlled release formulation of the painkiller opioid oxymorphone. Endo Pharmaceuticals Inc. and Grünenthal GmbH sued generic drug manufacturers under the Hatch-Waxman Act in the U.S. District Court for the Southern District of New York, alleging infringement of U.S. Patent Nos. 8,309,122 B2 and 8,329,216 B2. These patents relate to a controlled release formulation of the painkiller opioid oxymorphone. The asserted claims of the two patents generally recite the following categories of limitations: (1) A “dissolution” or “release rate” limitation, which describes the release of oxymorphone at a specified rate and is measured using the “USP Paddle Method at 50 rpm in 500 ml media.” (2) A pharmacokinetic limitation, which describes how OPANA®ER tablets affect the human body once ingested like analgesic effect, food effect etc. The generic drug manufacturers argued that the asserted patents’ claims were invalid or not infringed. The district court rejected those arguments and found all asserted claims of the ’122 and ’216 patents not invalid, and all but two asserted claims infringed. Specifically, the court found that the asserted claims of the two patents are not invalid for obviousness; that the asserted claims with the dissolution limitations are not invalid for lack of written description; and that the asserted claims reciting the multiple peaks limitations are not invalid for indefiniteness. The court also found that Endo carried its burden to show that defendants infringe or will infringe all but two of the asserted claims of the ’122 and ’216 patents. ANDA filers appealed.

Obviousness:

Appellants first argued that the district court erred in concluding that the asserted claims are not invalid as obvious. Court said that the prior art references in the record strongly discourage a controlled release formulation of opioids with low bioavailability, such as oxymorphone, and, more critically, do not suggest the dissolution and pharmacokinetic limitations recited in the asserted claims of the ’122 and ’216 patents. Expert testimony showed that a skilled artisan would not have been motivated to select oxymorphone for use in a controlled release setting because of its “exceptionally low bioavailability.” The court also observed that “[t]he notion that low-bioavailability drugs were considered unsuitable for extended-release formulation is reinforced by the fact that, until Endo’s development of OPANA®ER, there were remarkably few such examples.” Appellants argued further that the district court erred by giving patentable weight to the pharmacokinetic limitations inherent to the formulations disclosed by the prior art. The district court found that none of the prior art references in the record discloses the analgesic effectiveness of oxymorphone over a twelve-hour period; the claimed food effect limitations; the multiple peaks in blood concentration levels exhibited by controlled release oxymorphone over a twelve-hour period; or the detectable level limitations of the Endo patents. The district court also relied on secondary considerations, which “strongly indicate[d]” the non-obviousness of the invention. Endo’s expert on commercial success established that OPANA®ER achieved tremendous sales growth since its launch. The expert also demonstrated a clear nexus between the asserted claims of the two patents and the market success of OPANA®ER. Endo’s expert on long-felt need separately testified that the medical community had long sought to effectively combat chronic pain, but the numerous immediate release opioids on the market had a short duration of effectiveness and often involved inconvenient routes of administration. Federal circuit held that on balance, Appellants failed to carry their burden to show, by clear and convincing evidence, that claims reciting the dissolution and pharmacokinetic limitations are fairly suggested by any prior art of record or combination thereof. The district court therefore did not err by concluding that the asserted claims of the ’122 and ’216 patents are not invalid as obvious.

Written Description:

Appellants next argued that the district court erred by concluding that the asserted claims of the ’122 and ’216 patents that recite the dissolution limitations are not invalid for lack of written description in the specification. Specifically, Appellants argued that the asserted claims reciting the dissolution limitations claim a much broader range of release rates (15–50% of the drug after one hour, 45–80% after four hours, and more than 80% after ten hours), but the specification discloses much narrower ranges of release rates (27.8–32.3% at one hour, 58.1–66.9% at four hours, and 85.3–95.8% at ten hours) for formulations having 12 hours of analgesic efficacy. Court held that the specification clearly explains that an analgesically effective dosage could contain as low as about 5 mg to as high as about 80 mg of oxymorphone hydrochloride. Accordingly, Endo is entitled to claim not just the narrower range based on a 20 mg dosage, but a broader range based on 5 mg to 80 mg dosage—and that is exactly what it did in the claims reciting the dissolution limitations. The district court therefore did not err by concluding that the asserted claims of the ’122 and ’216 patents that recite the dissolution limitations are not invalid for inadequate written description.

Indefiniteness:

Appellants next argued that the district court erred in concluding that the asserted claims that recite the multiple peaks limitations are not invalid for indefiniteness. Specifically, Appellants argued that claims 1, 71, and 78 of the ’216 patent are invalid for indefiniteness because the claims recite the term “peaks,” contending that the patents contain no explanation of how peaks should be measured or what constitutes peaks. Court said that upon looking at the charts in the specification, a skilled artisan would recognize a peak as occurring where blood concentration of oxymorphone reaches a high-point before declining. In fact, the court’s definition of the term peaks is no different from that offered by Appellants’ own expert at trial. In sum, the district court did not err by concluding that the asserted claims that recite the multiple peaks limitations are not invalid for indefiniteness.

Infringement:

Appellants also argued that the district court erred in finding that Endo showed infringement of all but two asserted claims of the ’122 and ’216 patents. Appellants argued that the district court erred in finding infringement because the ANDA products do not infringe the “food effect” limitations. But the court found that “[d]efendants’ package inserts expressly state that their products satisfy the AUC and Cmax limitations of the ’122 and ’216 patents.” There is no basis to disregard the information contained on the package inserts, which are representations made to the FDA to establish that the proposed generics possess the same characteristics, including the food effect limitations, present in Endo’s approved products. Thus, the court did not clearly err by finding infringement of all but two of the asserted claims of the patents.