Endo Pharms. Inc. v. Amneal Pharms. LLC

Controlled-release oxymorphone patents held infringed and valid while abuse-proof oxymorphone patent held infringed but invalid as obvious.

October 15, 2015

GENERICally Speaking

Case Name: Endo Pharms. Inc. v. Amneal Pharms. LLC, Civ. Nos. 12 Civ. 8115 (TPG), 12 Civ. 8060 (TPG), 12 Civ. 8317 (TPG), 12 Civ. 8985 (TPG), 13 Civ. 435 (TPG), 13 Civ. 436 (TPG), 13 Civ. 3288 (TPG), 13 Civ. 4343 (TPG), 13 Civ. 8597 (TPG), 2015 U.S. Dist. LEXIS 114816 (S.D.N.Y. Aug. 14, 2015) (Griesa, J.) 

Drug Product and Patent(s)-in-Suit: Opana® ER (oxymorphone); U.S. Patents Nos. 8,309,122 ("the '122 Patent"), 8,329,216 ("the '216 Patent"), and 8,309,060 ("the '060 patent")

Nature of the Case and Issue(s) Presented: The court held a five-week bench trial for patent infringement. Plaintiffs Endo and Grünenthal argued that defendants, all of which are generic drug manufacturers, infringe on patents covering Endo’s branded painkiller Opana ER by selling or seeking approval to sell generic versions of the drug in either crushable or non-crushable formulations. Defendants argue that their generic products, as described in their ANDAs, do not and will not infringe the patents-in-suit, and that in any event those patents are invalid. Defendants also asserted other statutory and equitable defenses. There were seven groups of defendants in these cases. Plaintiffs sued the defendants separately, but the cases were tried jointly upon mutual consent. The defendants were: Amneal, Teva, Impax, ThoRx, Actavis, Roxane, and Sun.

There were three patents-in-suit. Endo owned the '122 and '216 patents, which claim a controlled release formulation of the painkilling opioid oxymorphone suitable for twelve-hour dosing. Grünenthal owned the ’060 patent, which describes an invention for drug tablets so hard that they are difficult to abuse through crushing and snorting, and which also accommodate other barriers to abuse. The court found that defendants’ generic products infringe or will infringe all but two of the asserted claims of the ’122 and ’216 patents, and that those claims are not invalid. With regard to the ’060 patent, the court found that certain defendants infringed each of the asserted claims, but concluded that those claims were invalid as obvious.

Why Endo Prevailed: Developing oxymorphone into an effective controlled-release formulation presented a number of challenges. There was a relative lack of previous research into orally administered oxymorphone’s pharmacokinetic effects; this lack of pharmacokinetic data made it difficult for Endo’s development team to predict in advance whether oxymorphone would be suitable in a controlled-release form. Moreover, oxymorphone in immediate-release form has an exceptionally low bioavailability of only about 10%. Oxymorphone’s unusually low bioavailability in immediate release form raised doubts that it would work in a controlled release setting, where far less of the tablet is dissolved at any given time.

The first step in a patent infringement action is to construe the claims. After the court did so, it next applied the asserted claims, as construed by the court, to the asserted products. The court first addressed the claims of the Endo patents. The first issue concerning those patents was whether defendants’ tablets satisfied the "food effect limitations" of the asserted claims. Relying on the testimony of plaintiffs’ experts, the court found "defendants, by demonstrating to the FDA that their products are bioequivalent to Opana ER and Opana ER CRF, also demonstrated that their products exhibit the same food effects as those branded drugs. The court finds [plaintiffs’ expert] to be persuasive in explaining this inference. The bioequivalence of the products described in defendants’ ANDAs indicates that those products will exhibit the same pharmacokinetic properties as Endo’s branded drug, the effects of which are embodied in relevant claims of ’122 and ’216 Patents." The court also relied on defendants’ package inserts, product labels, dissolution test data, requests for bio-waivers, and approval letters. Finally, the court noted that to require plaintiffs to perform independent clinical testing of each of defendants’ products would put them to a burden beyond a preponderance of the evidence. The second issue concerning the Endo patents was whether defendants’ tablets infringe the asserted method claims. Defendants argued that they do not directly infringe the claims because they simply make and sell tablets and do not actually administer them to patients. "[I]t is not necessary to the completion of the methods that the tablet be taken under fed and fasted conditions. Rather, the methods are completed once the tablets are administered. Once the tablets are administered, the subject will exhibit different pharmacokinetic effects depending on whether he has eaten or fasted." Or put another way, "by instructing subjects to take the tablets at all, defendants assure that patients will complete the methods asserted in the ’122 and ’216 patents." Thus, the court found that a single party performs all the steps in asserted method claims 20 of the ’122 patent and 82 of the ’216 patent. This was not true, however, in asserted method claims 40 and 42 of the ’216 patent: "By writing prescriptions for the tablets, physicians perform the first step of the methods recited in claims 38, 40, and 42 of the ’216 Patent by making tablets available to patients. However, in the majority of cases, it is the patient who performs the second step and administers the tablet at home to treat chronic pain. While there may be isolated settings where physicians physically insert tablets into patients’ mouths, plaintiffs did not provide the court with sufficient evidence to find that this happens with any degree of regularity."

With respect to the infringement issue concerning the ‘’060 patent, Grünenthal presented evidence of infringement against Actavis, Impax, ThoRx and Teva. The court narrowed the infringement inquiry into five issues, and found that Grünenthal proved by a preponderance of the evidence that all of the accused proposed ANDA products: (i) are abuse-proofed; (ii) are "thermoformed;" (iii) have a breaking strength of at least 500 newtons; (iv) have a "viscosity-increasing agent" which "forms a gel" with the extract obtained from the dosage form; and (v) infringe the remainder of the asserted claims.

The court next turned to the issue of whether the ’122 and ’216 patents were obvious. Although oxymorphone was known for use in immediate-release form, it had never been integrated into a controlled-release setting. While certain prior-art references described two controlled-release opioid tablets, MS Contin and OxyContin, both of which used hydrophilic delivery systems, and taught the integration of some opioids in a controlled-release setting, those references were silent in regard to integrating oxymorphone into a controlled-release setting. Moreover, selecting oxymorphone for a controlled-release setting would have been counterintuitive because of its exceptionally low bioavailability. The Oshlack reference taught that bioavailability is a significant, even crucial, factor in evaluating a drug’s suitability for placement in a controlled-release vehicle. The Aungst reference explained that oxymorphone is ideally suited for delivery through the skin since it "is not very effective orally." Finally, the Read reference taught that because drugs like oxymorphone are almost wholly metabolized upon first passing through the liver, the only way to increase the amount of drug that survives to the bloodstream is to use an exceptionally large dose from the beginning, potentially "risking toxicity." The court also found that controlled-release delivery systems were suspected of actually reducing certain drugs’ bioavailability due to a phenomenon known as "saturable first pass metabolism." And during cross-examination of Endo’s expert Dr. Stavchansky, defendants revealed that another low-bioavailability drug, oxybutynin (bioavailability of 6%), had previously been developed into a controlled-release formulation. But in the court’s view, this merely served to underscore, rather than diminish, the fact that low bioavailability drugs were remarkably rare in controlled-release settings. The court dismissed prior-art references on various other grounds: no mention of the use of oxymorphone; reference to oxymorphone based on sheer overinclusion (by listing dozens of molecules and purporting to cover them as part of the invention); lack of disclosure of the dosing interval of the invention; lack of dissolution data. The court then addressed whether the prior art disclosed the dissolution ranges claimed in the ’122 and ’216 patents. The court noted for one thing that each of the prior-art references relied on by defendants disclosed the dissolution profile of a drug with an active ingredient other than oxymorphone. Next, relying on plaintiffs’ expert, the court found that controlled-release systems, including TIMERx, which is incorporated into the inventions of the patents-in-suit, would not be understood by artisans as simply "plug and play." Each controlled release drug is independently formulated and tested. Lastly, the court addressed whether the pharmacokinetic limitations of the patent claims were obvious. The court found that defendants’ expert Dr. Banakar failed to cite any reference for the proposition that the food-effect limitations merely capture natural phenomena, other than opining to that effect. The "multiple peaks" that occur following administration of controlled release oxymorphone are of course the result of the body’s natural processes. But Endo’s patents do not pretend to claim the natural process of enterohepatic recirculation. Rather, the Endo patents claim a dosage form for oxymorphone that provides an analgesic effect over twelve hours and which causes multiple peaks in blood-concentration levels (and ensuing continued analgesic effectiveness) during that same period. The court reasoned that these pharmacokinetic effects are possible only because the dosage form, the invention itself, slows the release of oxymorphone to such a degree that: (i) peak blood concentration of oxymorphone occurs later (within 1–8 hours) than with immediate release oxymorphone (within 1–4 hours); and (ii) the body has multiple opportunities to recirculate the opioid through the bile duct, liver and intestines, producing multiple highpoints in blood-concentration levels. Lastly, the court credited Endo’s evidence establishing commercial success, a long felt but unmet need, and the failure of others.

The next defense raised by Defendants concerned the on-sale bar pursuant to 35 U.S.C. § 102. The court rejected this argument because it had found that the evidence did not demonstrate that the invention was ready for patenting more than a year before the applications were filed and was not the subject of an offer for sale. The invention could not be reduced to practice until the inventors were "certain" that it would provide the claimed analgesic effect. While preliminary reports indicated Opana ER’s analgesic effectiveness, those results were not sufficiently trustworthy until the study data had been fully scrutinized. In June of 2000, Endo entered into a "Development and Clinical Supply Agreement" with drug manufacturer Novartis Consumer Health Inc. That transaction, the court reasoned, was clearly experimental in nature.

The defendants’ final defense concerning the Endo patents related to Section 112. But the court found that the claims gave adequate notice of the metes and bounds of the invention. The specification provided that the studies described in the patents were performed using "standard FDA procedures such as those employed in producing results for use in a new drug application." Moreover, each of the features recited in the patent claims, such as an "oral controlled release oxymorphone formulation" of "about 5 mg to about 80 mg of oxymorphone" found adequate, even abundant, support in the specification. The patent specifications are replete with examples of dosage forms satisfying each of the claimed limitations, and gave detailed descriptions of the in vitro and in vivo testing methods employed in developing the tablets.

The invalidity of the ’060 patent based on obvious was the next issue addressed by the court. The prior art was replete with examples acknowledging the abuse of narcotics, including opioids and oxymorphone, through crushing and other means. Thus, there was a motivation to solve that problem. In particular, the prior art surrounding the branded drug Concerta taught the use of exceptional hardness to deter drug abuse. Four pieces of prior art in 2002 indicated that Concerta was known to be hard, and also known to deter abuse through crushing. While Concerta’s active ingredient was a stimulant, an ordinarily skilled artisan would readily understand it to teach the abuse-deterring value of hardness for other active ingredients, including opioids. Thus, the court was persuaded that there was a motivation in the art to solve the crushing of opioids by making tablets of exceptional hardness. Turning to the disclosure of the asserted claims, the court found that the prior art disclosed: (i) an abuse-proofed thermoformed dosage form; comprising (ii) one or more active ingredients with abuse potential and (iii) at least one synthetic or natural polymer with a weight of at least 0.5 million according to rheological measurements; and more specifically the polymer polyethylene oxide; and (iv) which exhibits a breaking strength of 500N; and (v) the six additional barriers to abuse recited in Claim 9 of the ’060 patent. The final step the court considered related to the secondary consideration of non-obviousness associated with the ’060 patent. The commercial success of the invention indicated its non-obviousness, and that success was directly related to the asserted claims, because each of the license agreements involved developing abuse-deterrent dosage forms, and abuse-deterrence was the primary feature of the asserted claims of the ’060 patent. But there did not appear to have been a long-felt need for the invention because there was at most only a few years separating the rise of OxyContin abuse and Grünenthal’s invention. The court also found Grünenthal’s evidence of skepticism and industry acclaim unpersuasive. "In the court’s view, th[at] evidence is too anecdotal to be useful."

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