Federal Circuit Affirms Decision Finding Zohydro ER Patents Obvious

On December 27, U.S. Court of Appeals for the Federal Circuit (CAFC) Judge Jimmie Reyna authored an opinion affirming the U.S. District Court for the District of Delaware’s finding that the asserted claims of U.S. Patent Nos. 9,265,760 (‘760) and 9,339,499 (‘499), both titled “Treating Pain in Patients with Hepatic Impairment,” held by Persion Pharmaceuticals LLC,  were invalid due to obviousness. The CAFC found no reversible error in the district court’s decision and therefore affirmed.

Patent Claims for Zohydro ER

The patents themselves are “directed to methods of treating pain in patients with mild or moderate hepatic impairment using extended-release hydrocodone-only formulation.” Hepatic impairment is impaired liver failure, which sometimes alters how some drugs are cleared or metabolized. Hydrocodone is an opioid widely used to treat pain, and is often combined with other active ingredients. Because opioids are primarily metabolized in the liver, patients with hepatic impairment may metabolize hydrocodone slower, increasing the risk of overdose.

The ‘760 and ‘499 patents “cover the formulation for Zohydro ER, Persion’s extended-release hydrocodone-only drug product.” When the previous owner, Pernix, sought approval for the drug from the U.S. Food and Drug Administration (FDA), they were required to conduct a clinical study to determine the effect of the drug on “subjects with mild and moderate hepatic impairment.” Pernix found hepatic impairment did not increase hydrocodone levels in the blood. The patents’ claims were not limited to Zohydro ER and also covered “methods of using any extended-release formulation with hydrocodone” as the only active ingredient.

The claims of the ‘760 and ‘499 patents are separated into two groups: the “non-adjustment” claims and the “pharmacokinetic” claims. The non-adjustment claims refer to a dosage of hydrocodone that is the same for a patient with impaired liver function and one with a healthy liver. Independent claim 1 of the ‘760 patent states, “…the starting dose is not adjusted relative to a patient without hepatic impairment.”

The pharmacokinetic claims recite how the drug moves throughout the body of a hepatic impaired patient versus a healthy patient. Independent claim 12 of the ‘760 patent outlines a method for regulating the dosage of hydrocodone so patients with mild or moderate hepatic impairment are exposed to an average increase of less than a 14% and 30%, respectively. The peak concentration of hydrocodone will also not increase past 9% and 14%.

Devane and Jain Outline Hydrocodone Release

The district court reviewed U.S. Patent Publication No. 2006/0240105 (Devane), titled “Multiparticulate Modified Release Composition,” which is “directed to a controlled-release composition that provides both immediate and extended release of one or more active ingredients.” Hydrocodone is among the active ingredients listed, using the Zohydro ER formulation as an example.

U.S. Patent Publication No. 2010/0010030 (Jain), titled “Extended Release Hydrocodone Acetaminophen and Related Methods and Uses Thereof,” was directed to a drug containing 15mg of hydrocodone and 500mg of acetaminophen, known as Vicodin CR. Jain describes multiple clinical studies—one of which determined the effects of hepatic impairment on the pharmacokinetics of Vicodin CR, including hydrocodone, in the patient.

Lastly, the district court reviewed labels for Vicodin and Lortab, which are immediate-release formulations of hydrocodone and acetaminophen. Although the labels warn patients with impaired liver function, they do not restrict dosage for patients with hepatic impairment.

District Court Proceedings

On March 4, 2016, Persion sued Alvogen Malta Operations Ltd. (Alvogen) alleging that Alvogen infringed on claims 1-4, 11-12, 17, 19 of the ‘760 patent and claim 1 of the ‘499 patent “by filing an Abbreviated New Drug Application (ANDA) seeking to market a generic version of Zohydro ER.”

The district court determined that Alvogen would indirectly infringe on the asserted claims because its product label would “induce doctors and patients to administer Alvogen’s product in an infringing manner.” The district court also concluded that the patents were not invalid due to anticipation by Devane. Persion did not appeal these rulings.

The district court then concluded that the asserted claims were “invalid as obvious over Devane in view of Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels.” The district court found that the specifications in Jain and the Vicodin and Lortab labels would lead a person of ordinary skill to administer an adjusted dose of extended-release hydrocodone to patients with hepatic impairment.

Additionally, the district court determined that the asserted claims of the ‘760 and ‘499 patents lacked an adequate written description under 35 U.S.C § 112(a). The written descriptions of the patents were “not limited to that single disclosed formulation.” The district court concluded that because the pharmacokinetic data for the Devane formulation provides no guidance as to whether other formulations would satisfy their claims, the asserted claims of the ‘760 and ‘499 patent were not adequately supported by written description. Persion appealed this decision, bringing it to the CAFC.

Persion’s Four-Part Appeal

Persion appealed on four grounds. First, it said that the district court improperly concluded that Devane disclosed the pharmacokinetic limitations of the asserted claims by reliance on inherency. Second, it said the district court reached an erroneous obviousness conclusion by relying on drugs other than “extended-release single-active-ingredient hydrocodone formulations.” Third, Persion argued that the district court failed to consider the objective indicia factors before finding the claims obvious. Lastly, Persion argued that the findings of obviousness were inconsistent with the findings concerning lack of a physical description.

In inherency as it pertains to obviousness, the recitation of a new function inherently possessed by a prior art “does not distinguish a claim drawn to those things from the prior art.” The CAFC also noted that an obvious formulation cannot become non-obvious by claiming the concentrations in a patient. If the alternate were true, “any formulation—no matter how obvious—[would] become patentable merely by testing and claiming an inherent property[,]” as stated in Santarus, Inc. v. Par Pharm., Inc.

Persion contended that the district court erred in applying the inherency doctrine because Devane does not cover administering a hydrocodone-only formulation to patients with hepatic impairment. Persion further argued that a single reference must contain all limitations. The CAFC disagreed, stating that prior recognition of inherency could contain a “combination of prior art elements[,]” in this case, Devane in combination with Jain, and the labels of Vicodin and Lortab. Together, they inherently taught the pharmacokinetic parameters claimed by Persion. The CAFC determined that, in this context, the district court did not err in its decision.

Persion also argued that the district court erred in its obviousness findings because it relied on pharmacokinetic formulations and patient groups not covered by the patent claims. They asserted that the prior art studies on immediate-release formulations with healthy patients would not allow a person of ordinary skill in the art to predict the correct dosage of extended-release hydrocodone in hepatic impaired patients. The CAFC found the district court did not err in its analysis because “a person of skill in the art would have expected that an acetaminophen-free hydrocodone formulation, such as the one disclosed in Devane, would have been even safer for patients with hepatic impairment[.]” This led the CAFC to conclude that the district court had not made an erroneous decision.

Persion said that the district court prematurely found obviousness because it did not consider the asserted indicia of nonobviousness first. The Federal Circuit disagreed, stating that “the substance of the [district] court’s analysis makes clear that it properly considered the totality of the obviousness evidence in reaching its conclusion and did not treat the objective indicia as a mere ‘afterthought’.”

Persion further challenged the district court’s weighing of objective indicia, arguing that they did not give proper weight to Cephalon, Inc.’s failure to produce a drug that would not require dose adjustment. The district court however, had weighed this evidence and determined that it did not support nonobviousness because other manufacturers had succeeded in making a hydrocodone-based drug that did not require dose adjustment.

Finally, Persion argued that the district court’s obviousness decision had to be reversed because it conflicted with the findings regarding the patents’ written descriptions. Persion pointed to the district court’s statement, “there was nothing in the state of the art as of July 2012 that would have provided guidance as to which of the broadly claimed formulations would work and which would not[.]” The Federal Circuit noted that this was only a partial quotation, excluding the phrase “with the exception of the single embodiment described in Example 8.” Example 8 of the common written description of the ‘760 and ‘499 patents covered the Devane formulation, which formed the basis for the district court’s obviousness findings. Consequently, the CAFC found no inconsistencies in the district court’s conclusion.

Alvogen was represented by Chad Landmon, Matt Becker, Thomas Hedemann, David Ludwig, Ted Mathias and Chris Gallo of Axinn Veltrop & Harkrider, LLP and Persion was represented by Dominick Conde of Venable.