Persion Pharms. LLC v. Alvogen Malta Operations Ltd.

The Federal Circuit affirmed the district court’s obviousness determination, holding that the district court correctly applied the law of inherency and did not clearly err in its factual findings relating to obviousness and objective indicia.

December 27, 2019

Robins Kaplan GENERICally Speaking: A Hatch-Waxman Litigation Bulletin

Case Name: Persion Pharms. LLC v. Alvogen Malta Operations Ltd., 2018-2361, 945 F.3d 1184 (Fed. Cir. Dec. 27, 2019) (Judges O’Malley, Reyna, and Chen presiding; Opinion by Reyna, J.) (Appeal from D. Del., Bryson, J.) 

Drug Product and Patent(s)-in-Suit:  Zohydro® ER (hydrocodone bitartrate); U.S. Patents Nos. 9,265,760 (“the ’760 patent”) and 9,339,499 (“the ’499 patent”)

Nature of the Case and Issue(s) Presented: Zohydro ER is Persion’s extended-release hydrocodone-only drug product. Hydrocodone is an opioid painkiller. Persion sued Alvogen for infringement of various claims of the patents-in-suit based on the filing of Alvogen’s ANDA for extended-release hydrocodone. After a bench trial, the district court found that Alvogen indirectly infringed the asserted claims and that the claims were not anticipated. But the district court found the claims invalid as obvious. The sole issue on appeal was the district court’s obviousness finding, which the Federal Circuit affirmed.

Why Alvogen Prevailed: The patents-in-suit shared a specification and priority date, and were directed to methods of treating pain in patients with hepatic impairment (i.e. impaired liver function) using extended-release hydrocodone-only formulations. The claims were not limited to the specific Zohydro ER formulation, but were directed broadly to the use of hydrocodone bitartrate as the only active ingredient. The court grouped the asserted claims into two categories: (i) the “non-adjustment” claims, which were directed to administering hydrocodone to a patient with hepatic impairment without adjusting the dose relative to a healthy patient; and (ii) the “pharmacokinetic” claims, which recited pharmacokinetic parameters with specific values or with values in relation to a healthy patient.

Alvogen argued that the patents-in-suit were obvious in view of Devane, Jain, and the Vicodin and Lortab drug labels, all of which were prior art. Devane was directed to a controlled-release composition that could be used with hydrocodone and further disclosed, as an example, the Zohydro ER formulation and its use in an in vivo study to treat pain. Jain was directed to methods of using an extended release formulation of hydrocodone and acetaminophen (Vicodin CR) to treat pain, and described a clinical study used to determine the effects of hepatic insufficiency on the pharmacokinetics of Vicodin CR. The study demonstrated that the pharmacokinetics for hydrocodone were similar in healthy patients and those with mild or moderate hepatic impairment. Vicodin and Lortab were both immediate-release formulations of hydrocodone and acetaminophen. Those labels provided safety information that cautioned use in patients with severe—but not mild or moderate—impairment.

The district court determined that a POSA would have been motivated to administer extended release hydrocodone bitartrate to patients with mild to moderate hepatic impairment at an unadjusted dose in light of Devane, and the Vicodin and Lortab label and would have had a reasonable expectation of success. Additionally, the district court determined that the pharmacokinetic limitations were “inherent in any obviousness combination that contains the Devane formulation.” The district court also found that the objective indicia did not weigh in favor of finding non-obviousness.

Persion argued on appeal that the district court: (i) improperly relied on inherency; (ii) improperly relied on pharmacokinetic profiles of drugs other than extended-release single-active-ingredient hydrocodone formulations and healthy patients; (iii) erred by finding obviousness before considering objective indicia of non-obviousness; and (iv) made inconsistent findings as between its obvious and written description analyses.

On inherency, Persion argued that Devane did not teach the administration of a hydrocodone-only formulation to patients with hepatic impairment, and therefore did not teach the claimed pharmacokinetic values for hepatically impaired patients. But Persion’s argument was contrary to the Federal Circuit’s “recognition that ‘inherency may supply a missing claim limitation in an obviousness analysis’ where the limitation at issue is ‘the result of the combination of prior art elements.” Here, the district court found that Devane, Jain, the state of the art, and the Vicodin and Lortab labels taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. Also, the district court found a POSA would have been motivated to administer an unadjusted dose of the Devane formulation (which was undisputedly identical to the Zohydro ER formulation) to a patient with mild to moderate hepatic impairment. A finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable significance to the asserted claims was not legal error.

Next, Persion argued that pharmacokinetic data for drug products with more than one active ingredient and from patient groups without hepatic impairment was irrelevant to obviousness. Persion reasoned that those data would not allow a POSA to predict the dose of a hydrocodone-only drug product for a patient with hepatic impairment, or that a POSA could administer the same dose a healthy patient and an impaired patient with a reasonable expectation of success. The Federal circuit found no clear error in the district court’s analysis.

On the issue of objective indicia, relying on In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063, 1075 (Fed. Cir. 2012), Persion argued that the district court erred by finding obviousness prior to addressing objective indicia, which clouded its analysis. The Federal Circuit explained that unlike in In re Cyclobenzaprine, the district court considered Persion’s evidence of objective indicia and other evidence regarding obviousness together, and in effect, considered the totality of the obviousness evidence before reaching its conclusion. Persion further argued that the district court did not give proper weight to the objective indicia. But the Federal Circuit found that the district court specifically addressed the objective indicia and found that it did not warrant a finding of non-obviousness. For example, Persion argued that the district court did not give proper weight to another pharmaceutical company’s failure to develop a drug that did not require dose adjustment for hepatically impaired patients. The district court found this evidence unpersuasive in light of others’ success in making a hydrocodone product that did not require dose adjustment. Similarly, Persion argued that the district court improperly dismissed the inventors’ testimony concerning unexpected results. The Federal Circuit, however, found that the district court considered that evidence, and found no clear error in the district court’s discounting of that evidence in light of the inventors’ failure to account for the teachings in Jain.

Finally, on the issue of inconsistency, the Federal Circuit rejected Persion’s argument, explaining that it entirely relied on incomplete quotations form the district court’s opinion. The Federal Circuit held that in context there was no inconsistency in the district court’s findings and therefore declined to reverse.

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