Hydrocodone bitartrate – USA

Hydrocodone bitartrate – USA

On Dec 27, 2019, Federal Circuit affirmed Delaware court’s decision & found Zohydro® ER patents patents invalid under obviousness.

Persion Pharmaceuticals LLC owns U.S. Patent Nos. 9,265,760 and 9,339,499, both entitled “Treating Pain in Patients with Hepatic Impairment.” The relevant claims of the ’760 and ’499 patents can generally be grouped into two sets: the “non-adjustment” claims and the “pharmacokinetic” claims.

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.

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 Cmax 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 Cmax in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%.

On March 4, 2016, Persion sued 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 ANDA seeking to market a generic version of Zohydro ER. After a bench trial, The district court 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. In addition, the district court determined that the asserted claims of the ’760 and ’499 patents are invalid under 35 U.S.C. § 112(a) for lack of adequate written description support. Please see the previous post “here” for more details.

During appeal, Persion raised four primary challenges to the district court’s obviousness conclusion. First, Persion contends that the district court improperly relied on inherency to conclude that Devane discloses the pharmacokinetic limitations of the asserted claims. Second, Persion argues that the district court improperly relied on pharmacokinetic profiles from drugs other than extended-release single-active-ingredient hydrocodone formulations and from patients other than those with hepatic impairment in reaching its obviousness conclusion. Third, Persion contends that the district court erred by finding the asserted claims obvious before considering the objective indicia factors. Fourth, Persion argues that the district court’s factual findings concerning obviousness are inconsistent with its findings concerning the lack of written description support.

Federal Circuit finally found no error in districts court’s analysis & affirmed its decision while rejecting Persions arguments.

With respect to first point, Federal Circuit said that the district court correclty found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions.

With respect to second point, Federal Circuit said that district court provided several reasons for its conclusion that a person of ordinary skill in the art would have considered other types of drug products in developing a hydrocodone-only extended-release formulation. In particular, the district court found that in light of acetaminophen’s hepatotoxicity, 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 than the combination formulations disclosed in Jain and other references.

With respect to third point, Federal Circuit said that while the district court’s discussion of objective indicia follows its discussion of the asserted prior art, the substance of the 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” relegated to “rebut[ting]” a prima facie case.

With respect to fourth point, Federal Circuit said that Persion’s entire argument with respect to this issue is based on incomplete quotations from the district court’s opinion. The district court stated that “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, with the exception of the single embodiment described in Example 8.” The embodiment described in Example 8 of the common written description of the ’760 and ’499 patents is the Devane formulation, which formed the basis for the district court’s obviousness findings. In contrast to the “essentially limitless number of formulation species” covered by the claims of the ’760 and ’499 patents, the district court found that the prior art provided adequate guidance with respect to the sole formulation described in Example 8: the Devane formulation. Thus, there is no inconsistency between the statement Persion quotes and the district court’s conclusion that a person of ordinary skill in the art would have been motivated to combine Devane with Jain and the Vicodin and Lortab labels to arrive at the claimed invention.

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