Grunenthal Gmbh et al. v. Alkem Labs. Ltd., Hikma Pharm., Actavis et al.

Docket No. 2017-1153, -2048-50

March 28, 2019

Brief summary: DC decisions of nonobviousness of Grunenthal’s polymorph claims, no induced or contributory infringement due to section viii carve-out, and specific utility of the claimed polymorph affirmed.

Summary: Alkem and Hikma appealed the DC’s judgment that Grunenthal’s US 7,994,364, an Orange Book patent for the tapentadol HCl product NUCYNTA extended release (ER) (an opioid agonist) is not invalid for obviousness or lack of utility. Grunenthal cross-appealed DC finding of no infringement of another OB patent (US 8,536,130) by Hikma and Actavis (the DC also found Alkem does infringe the ‘130 patent). Assertio Therapeutics, formerly Depomed, is the exclusive licensee of both patents. The ‘364 patent is specifically directed to the Form A polymorph of tapentadol HCl (there is also a Form B) by “various X-ray powder diffraction patterns (XRPD)” and methods of treating pain and/or urinary incontinence. The ‘130 patent is directed to methods for using “tapentadol or “a pharmaceutically acceptable salt thereof” to treat “polyneuropathic pain”.

The FC panel first considered whether Hikma induced infringed the ‘130 patent. The FC panel explained that NUCYNTA ER is “indicated for the management of…neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults”, not explicitly “polyneuropathic pain”, but also that “DPN is a type of polyneuropathic pain” and that this indication was not on the original label. Both Hikma and Actavis filed “Section viii” statements with their ANDAs, telling the “FDA that they will not seek FDA approval for an indication directed to the treatment of DPN.” The FC panel reviewed the DC’s infringement decision as “a question of fact…for clear error” (AstraZeneca, FC 2010 (“clearly erroneous when ‘the reviewing court is left with the definite and firm conviction that a mistake has been made”, “specific intent could be inferred” since it knew “its lable posed infringement problems”)). “In this case,” the FC panel wrote, “the question of induced infringement turns on whether Hikma and Actavis have the specific intent, based on the contents of their proposed labels, to encourage physicians to use their proposed ANDA products to treat polyneuropathic pain” (Takeda, FC 2015 (“whether the label encourages, recommends, or promotes infringement”)). The FC panel concluded that “[t]hey do not” induce infringement (e.g., “even if sever chronic pain includes polyneuropathic pain, it also includes mononeuropathic pain and nociceptive pain”, the “‘Section viii’ statements…specifically carv[e] out the neuropathic pain indication”, and “AstraZeneca is inapposite to our facts”). The FC panel also credited the DC’s conclusion of no contributory infringement because there are “substantial noninfringing uses for the accused product” (§ 271(c); Toshiba, FC 2012; Eli Lilly, FC 2011 (“must be in accordance with the use for which the product is indicated”; “unauthorized activity does not avoid infringement by a product that is authorized to be sold solely for the infringing use”)).

To succeed in its obviousness arguments, Alkem needed “to prove a reasonable expectation of success in arriving at Form A or, relatedly, it would have been obvious to try to find a polymorph of Form B”. The FC panel disagreed since the “polymorphism of tapentadol hydrochloride was unknown at the time of filing the ‘364 patent” (it was described in Grunenthal’s US 6,248,737) and the prior art (the Byrn reference) “presents a flow chart that outlines a number of variables that may be adjusted during the recrystallization process to determine whether polymorphism occurs in a compound” but “does not provide guidelines regarding which temperature, concentration, agitation, or pH levels are likely to result in polymorphs of particular compounds”, and therefore found no clear error with the DC’s “crediting Dr. Bernstein’s testimony or concluding that Byrn provides insufficient guidance” (no known or expected polymorphism, no evidence that ‘737 patent synthesis “results in any Form A”, and no guidance as to what conditions “were likely to result in Form A” (no inherent anticipation by the ‘737 patent)) (Pfizer, FC 2007 (“a POSA would have narrowed the list of 53 anions ‘to a few’”); AstraZeneca, FC 2015 (4/5 “sterilization techniques would result in a sterile…product that met the purity limitations”); Cubist, FC 2015 (claimed purity levels “could be achieved” using known techniques); all three of these cases finding obviousness and being “inapposite to the facts at hand” in this case; “Our decision today does not rule out the possibility that polymorph patents could be found obvious.”) The FC panel also found that “it would not have been obvious to try to produce Form A” (e.g., “Byrn identified many variables…as opposed to a ‘finite number,’ as contemplated in KSR” (US 2007) and only gave “‘general guidance,’ without providing ‘detailed enabling methodology’” (In re Kubin, FC 2009)).

Hikma also argued that the ‘364 patent lacks specific utility (In re Fisher, FC 2005) because “Form A…has the same pharmacological activity as Form B but is more stable under ambient conditions” but the FC panel found these arguments to be “without merit” since “the ‘364 patent concretely discloses the practical benefit of Form A…as an analgesic” and “[i]t is sufficient that Form A is shown to be stable at room temperature and useful for pain relief” (Rasmussen, FC 2005 (testing is not always required); Fujikawa, FC 1996 (“All that is required is that the tests be reasonably indicative of the desired [pharmacological] response.”))

This entry was posted in Anticipation (35 USC 102), Contributory Infringement, Generics / ANDA, Inducement to Infringe, Inherency, Obviousness, Utility. Bookmark the permalink.

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