DC decision finding Adapt’s naloxone formulations obvious affirmed

Adapt Pharma, Inc. et al. v. Teva Pharmaceuticals USA, Inc. et al.

Docket No. 2020-2106 (https://cafc.uscourts.gov/opinions-orders/20-2106.OPINION.2-10-2022_1906561.pdf)

NEWMAN (D), PROST, STOLL

February 10, 2021

Brief Summary:  DC decision finding Adapt’s naloxone formulations obvious affirmed.

Summary:  Adapt appealed DC final judgment finding US 9,468,747; 9,561,177; 9,629,965; and 9,775,838 related to Adapt’s NARCAN™ intranasal 4 mg naloxone product invalid as obvious.  The patents-in-suit in this paragraph IV ANDA case are six of the patents listed on the FDA’s Orange Book for Adapt’s product.  Representative claim 9 of the ‘747 patent is directed to “[a] method of treatment of opioid overdose” by “nasally administering…an aqueous solution of about 100 [microliter] comprising:  about 4 mg naloxone”, 0.2-1.2 mg “of an isotonicity agent”, 0.005-0.015 mg of “at least one of a preservative, a cationic surfactant, and a permeation enhancer”, 0.1-0.5 mg of a “stabilizing agent”, and “an amount of acid sufficient to achieve a pH of 3.5-5.5.”  Dependent claim 2 requires the isotonicity agent to be NaCl, the preservative benzaolkonium chloride, the stabilizing agent disodium edetate, and the acid is hydrochloric acid.  Teva alleged two combinations of prior art render Adapt’s claims obvious (Davies, Kerr 2009, and Bahal (the Davies combination)) and Strang, Kulkarni, and Djupesland (the Strang combination).  The FC panel reviewed the DC’s legal determinations de novo and its factual findings (what the prior art teaches, the motivation to combine, and secondary considerations) for clear error (Merck, FC 2017; OSI, FC 2019).  Adapt argued the DC clearly erred in finding a motivation to combine, that the prior art does not teach away from the claimed invention, and its findings related to Adapt’s secondary considerations.  The DC found a motivation to “improve upon the MAD kit…because its shortcomings were well-known” (the FDA requested improvements), “select the claimed excipients”, “select a 4 mg dose”, and “combine the prior art references themselves”.  The FC panel explained that the “motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill” (Plantronics, FC 2013).  The FC panel found no clear error with the DC’s analysis of the prior art, based in part of expert testimony, and that “the ‘interrelated teachings’ of the prior art references support the district court’s finding that a skilled artisan would have been motivated to combine the references” (Tyco, FC 2014).  The FC panel “acknowledge[d], as the dissent notes, that [the primary expert] did not expressly provide a reason to combine or modify the prior art” but explained that the DC did not rely solely on that testimony (e.g., “teachings of the prior art or problems known in the field of endeavor at the time of the invention, can provide the requisite support for the court’s motivation finding”).  The FC panel also found no clear error with the DC’s finding of no teaching away because “a reference does not teach away if a skilled artisan, upon reading the reference, would not be ‘discouraged from following the path set out in the reference,’ and would not be ‘led in a direction divergent from the path that was taken by the applicant’”.  It also noted that the DC “correctly observed[] there is no rule that a single reference that teaches away will mandate a finding of nonobviousness” (Medichem, FC 2006).  The FC panel also found the DC properly considered Adapt’s secondary consideration evidence (ZUP, FC 2009 (“‘a strong showing of obviousness may stand ‘even in the face of considerable evidence’ of objective indicia”; Leo Pharm., FC 2013 (“‘part of the whole obviousness analysis, not just an afterthought’ to a forgone legal conclusion”)).  The FC panel disagreed with Adapt that its evidence of an increase in bioavailability and stability was unexpected (Orexo, FC 2018 (“an unexpected increase in bioavailability is a difference in kind that is probative of nonobviousness, not a trivial difference in degree”)).  Regarding Adapt’s evidence of copying (e.g., “Teva, like Mundipharma, changed its formulation to the claimed 4 mg dose”), the FC panel explained that “that ‘evidence of copying in the ANDA context is not probative of nonobviousness because a showing of bioequivalence is required for FDA approval’” (Bayer, FC 2013).  Adapt’s arguments based on industry skepticism were also rejected as “the district court did not ‘g[i]ve this consideration no weight.’”  The FC panel did find the DC erred in its conclusion regarding a long-felt but unmet need for the product but found that error to be harmless as it was “not sufficient to overcome the strong case of obviousness as a matter of law” (Millenium, FC 2017 (particularly regarding Adapt’s argument “that others tried but failed”)).  The FC panel acknowledged “[t]his is a close case” but it affirmed the DC decision. 

Judge Newman dissented because, e.g., “the majority cites no teaching or suggestion” to make Adapt’s invention and the DC “finds the teaching and motivation in the ’747 patent itself”, “a classical example of judicial hindsight, where the invention itself is the only guide to the selections from the prior art” (Plantronics, FC 2013 (“Where, as here, the necessary reasoning is absent, we cannot simply assume that an ordinary artisan would be awakened to modify prior art in such a way as to lead to an obviousness rejection. It is in such circumstances, moreover, that it is especially important to guard against the dangers of hindsight bias.”); In re Van Os, FC 2017 (“existence of the separate elements does not establish the motivation to select and combine them to produce the claimed invention”); Allergan, FC 2015 (teaching away); Leo Pharm., FC 2013 (“important distinction between combining known options into “a finite number of identified, predictable solutions,” KSR, 550 U.S. at 421, and “merely throwing metaphorical darts at a board in hopes of arriving at a successful result.”); In re Stepan, FC 2017 (“To have a reasonable expectation of success, one must be motivated to do more than merely to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result… The selection of specific ingredients from the prior art is not obvious when ‘that same prior art gave no direction as to which of the many possible combination choices were likely to be successful.’”); TQ Delta, Fed. Cir. 2019 (this court cautioned against “allowing the challenger to use the challenged patent as a roadmap to reconstruct the claimed invention using disparate elements from the prior art—i.e., the impermissible ex post reasoning and hindsight bias that KSR warned against.”); Amerigen, FC 2019 (“a ‘general motivation” does “not suffice,” for “[a]ny compound may look obvious once someone has made it and found it to be useful, but working backwards from that compound with the benefit of hindsight, once one is aware of it does not render it obvious’”); Sanofi-Aventis, Fed. Cir. 2019 (“[C]harting a path to the claimed compound by hindsight is not enough to prove obviousness.”))

This entry was posted in Generics / ANDA, Obviousness, Obviousness (Secondary Considerations), Obviousness-Teaching Away. Bookmark the permalink.

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