Persion Pharm. LLC v. Alvogen Malta Operations Ltd.

• Decision Date: 27 December 2019
• Docket Number: 2018-2361
• Citation: 945 F.3d 1184
• Parties: PERSION PHARMACEUTICALS LLC, Plaintiff-Appellant v. ALVOGEN MALTA OPERATIONS LTD., Defendant-Appellee
• Court: U.S. Court of Appeals — Federal Circuit

945 F.3d 1184

PERSION PHARMACEUTICALS LLC, Plaintiff-Appellant

v.ALVOGEN MALTA OPERATIONS LTD., Defendant-Appellee

2018-2361

United States Court of Appeals, Federal Circuit.

Decided: December 27, 2019

Dominick A. Conde, Venable LLP, New York, NY, argued for plaintiff-appellant. Also represented by Christopher P. Borello, Joshua Daniel Calabro, Zachary Garrett.

Chad A. Landmon, Axinn Veltrop Harkrider, LLP, Hartford, CT, argued for defendant-appellee. Also represented by Matthew Becker, Thomas K. Hedemann, David Keeler Ludwig, Edward M. Mathias ; Christopher Michael Gallo, Washington, DC.

Before O'Malley, Reyna, and Chen, Circuit Judges.

Reyna, Circuit Judge.

Persion Pharmaceuticals LLC appeals from a decision of the U.S. District Court for the District of Delaware finding the asserted claims of U.S. Patent Nos. 9,265,760 and 9,339,499 invalid as obvious and lacking adequate written description. Because we find no reversible error in the district court's obviousness determination, we affirm on that basis and do not reach the written description issue.

BACKGROUND

I. The Asserted Patents

Persion Pharmaceuticals LLC ("Persion")¹ owns U.S. Patent Nos. 9,265,760 ("the ’760 patent") and 9,339,499 ("the ’499 patent"), both entitled "Treating Pain in Patients with Hepatic Impairment

." Both patents share a common written description² and priority date and are directed to methods of treating pain in patients with mild or moderate hepatic impairment using extended-release hydrocodone-only formulations. Hepatic impairment is compromised liver functionality.

Hydrocodone

is an opioid that is widely used to treat pain and has been FDA approved since 1943. It is marketed in both extended-release and immediate-release formulations and is often combined with other active ingredients. Like many opioids, hydrocodone is primarily metabolized in the human liver. If liver function is impaired, metabolism of opioids is slowed. Thus, the same dose of hydrocodone may pose a higher risk of overdose in a patient with hepatic impairment than in a healthy patient due to potential build-up of the drug in the patient's bloodstream.

The ’760 and ’499 patents cover the formulation for Zohydro ER, Persion's extended-release hydrocodone-only drug product. When Zohydro ER's prior owner sought approval to market the drug from the U.S. Food and Drug Administration ("FDA"), the FDA required the owner to conduct a clinical study to determine the potential effect of the drug on patients with hepatic impairment

. The study showed that use of Zohydro ER did not result in substantially higher concentrations of hydrocodone in the bloodstream of subjects with mild and moderate hepatic impairment than in subjects without hepatic impairment.

Following this study, the researchers filed patent applications directed to their discovery, which later issued as the ’760 and ’499 patents. Example 8 of the patents describes the Zohydro ER clinical study and its results. Id. col. 22 l. 52–col. 23 l. 48. However, the patent claims are not limited to the use of the Zohydro ER formulation but instead cover methods of using any extended-release formulation with "hydrocodone

bitartrate as the only active ingredient" to treat pain in patients with mild or moderate hepatic impairment.³ ’760 patent col. 24 ll. 1–5, col. 25 ll. 13–17, ’499 patent col. 24 ll. 1–5, col. 26 ll. 9–13.

The relevant claims of the ’760 and ’499 patents can generally be grouped into two sets: the "non-adjustment" claims and the "pharmacokinetic" claims. The non-adjustment claims are directed to administering a starting dose of hydrocodone

to a patient having mild or moderate hepatic impairment without adjusting the dose relative to a patient with a healthy liver. Independent claim 1 of the ’760 patent is representative of the non-adjustment claims, and recites:

1. A method of treating pain in a patient having mild or moderate hepatic impairment

, the method comprising:

administering to the patient having mild or moderate hepatic impairment a starting dose of an oral dosage unit having hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate, and wherein the starting dose is not adjusted relative to a patient without hepatic impairment.

’760 patent col. 23 l. 66–col. 24 l. 7.

The pharmacokinetic claims recite pharmacokinetic parameters either as absolute values or in relation to values in a healthy patient. Independent claim 12 of the ’760 patent is representative of the pharmacokinetic claims, and recites:

12. A method of treating pain in a patient having mild or moderate hepatic impairment

, the method comprising:

administering to the patient having mild or moderate hepatic impairment an oral dosage unit having hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate,

wherein the dosage unit provides a release profile of hydrocodone that:

(1) does not increase average hydrocodone AUC0–inf in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%;

(2) does not increase average hydrocodone AUC0–inf in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 30%;

(3) does not increase average hydrocodone C_max in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 9%; and

(4) does not increase average hydrocodone C_max in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%.

’760 patent col. 25 ll. 11–35.

II. Prior Art

A. Devane

U.S. Patent Publication No. 2006/0240105 ("Devane") is entitled "Multiparticulate Modified Release Composition" and was published on October 26, 2006. Devane is directed to a controlled-release composition that provides both immediate and extended release of one or more active ingredients. J.A. 3616 (Devane, ¶¶ 26–27). Devane teaches that one active ingredient that can be used with these compositions is hydrocodone

. J.A. 3615 (Devane, ¶ 17); J.A. 3620 (Devane, ¶ 70). As an example, Devane discloses the Zohydro ER formulation and describes an in vivo study in which the formulation is used to treat pain. J.A. 3625–26 (Devane, ¶¶ 103–06); J.A. 6, 490; Appellee's Br. 4.

B. Jain

U.S. Patent Publication No. 2010/0010030 ("Jain") is entitled "Extended Release Hydrocodone

Acetaminophen and Related Methods and Uses Thereof" and was published on January 14, 2010. Jain is directed to methods of treating pain using an extended-release formulation containing about 15 milligrams of hydrocodone and about 500 milligrams of acetaminophen. J.A. 3631 (Jain, Abstract). This formulation is known as Vicodin CR. J.A. 3647 (Jain, ¶ 34). Jain describes several clinical studies involving Vicodin CR, including a study conducted to determine the effects of hepatic insufficiency on the pharmacokinetics of Vicodin CR. J.A. 3649 (Jain, ¶ 64). The results of the study demonstrated that pharmacokinetic parameters for hydrocodone "were similar in normal subjects and subjects with mild and moderate hepatic impairment." Id. The results further demonstrated that the pharmacokinetic parameters for acetaminophen "were similar in normal subjects and subjects with mild hepatic impairment, and 34 to 42% higher in subjects with moderate hepatic impairment." Id.

C. Vicodin

and Lortab Labels

Vicodin

and Lortab are both immediate-release formulations of hydrocodone and acetaminophen that are used to treat pain. J.A. 3121, 3230. The 2011 labels for these products provide safety information and instructions for use. J.A. 3121, 3230–33. Although both labels state that these drugs "should be used with caution in ... those [patients] with severe impairment of hepatic ... function," neither label includes any precautions or dosage restrictions for patients with mild or moderate hepatic impairment. J.A. 3121, 3231.

III. District Court Proceedings

On March 4, 2016, Persion sued Alvogen Malta Operations Ltd. ("Alvogen") for infringement of claims 1–4, 11–12, 17, and 19 of the ’760 patent. After the ’499 patent issued, Persion filed an amended complaint additionally asserting infringement of claim 1 of that patent. Persion alleged that Alvogen infringed these claims by filing an Abbreviated New Drug Application ("ANDA") seeking to market a generic version of Zohydro ER.⁴

After a bench trial, the district court concluded that Alvogen would indirectly infringe the asserted claims because its product label would induce doctors and patients to administer Alvogen's product in an infringing manner. Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd. , 323 F. Supp. 3d 566, 579 (D. Del. 2018). The district court also concluded that the asserted claims are not invalid as anticipated by Devane. Id. at 594. These rulings are not at issue on appeal.

The district court next determined that the asserted claims are 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. Id. at 595–96, 610. Specifically, the district court found that in light of the teachings of Jain and the Vicodin and Lortab labels, a person of ordinary skill in the art would have been motivated to administer the extended-release hydrocodone bitartrate formulation disclosed in Devane to patients with mild or moderate hepatic impairment at an unadjusted dose and would have had a reasonable expectation of success in so doing. Id. at 609–10, 615. The district court further found that the pharmacokinetic limitations in the pharmacokinetic claims are "inherent in any obviousness combination that contains the Devane formulation" because the recited pharmacokinetic parameters were "necessarily...