Adapt Pharma Operations Ltd. v. Teva Pharms. USA, Inc.

NarcanĀ® (naloxone)

February 10, 2022

GENERICally Speaking

Case Name: Adapt Pharma Operations Ltd. v. Teva Pharms. USA, Inc., Case No. 2020-2106, 25 F.4th 1354 (Fed. Cir. Feb. 10, 2022) (Circuit Judges Newman, Prost, and Stoll presiding; Opinion by Stoll, J.; Dissenting Opinion by Newman, J.) (Appeal from D.N.J., Martinotti, J.) 

Drug Product and Patent(s)-in-Suit: Narcan® (naloxone); U.S. Patents Nos. 9,468,747 (“the ’747 patent”), 9,561,177 (“the ’177 patent”), 9,629,965 (“the ’965 patent”), and 9,775,838 (“the ’838 patent”)

Nature of the Case and Issue(s) Presented: The patents-in-suit claim methods of treating opioid overdose by intranasal administration of a naloxone formulation, as well as devices for intranasal administration. Naloxone is an opioid receptor antagonist that blocks opioids from reaching the opioid receptors, thus helping reverse the effects of opioid overdose. The use of naloxone to treat opioid overdose was not a new concept at the time of the invention. It was also known in the prior art to administer naloxone intranasally. But administering naloxone was not without disadvantages. On April 12, 2012, FDA held a public meeting to “promote and encourage the industry to develop an intranasal naloxone product that could be FDA-approved.” On May 24, 2012, Lightlake Therapeutics, Inc.—plaintiff’s predecessor—met with the FDA to discuss a potential INDA for a intranasal naloxone formulation. Lightlake ultimately submitted an NDA for a 4 mg intranasal naloxone product, approved under the name Narcan. On March 16, 2015, Adapt filed U.S. Patent Application No. 14/659,472, from which each of the patents-in-suit claims priority. Teva filed its ANDA seeking to make and sell a generic version of naloxone. Adapt sued, Teva stipulated to infringement, and after a two-week bench trial, the district court determined that the asserted claims would have been obvious in view of the prior art. Finding no error, the Federal Circuit affirmed.

Why Adapt Prevailed: Adapt argues on appeal that the district court erred in its finding: (i) that a POSA would have been motivated to combine the prior-art references to arrive at the claimed invention; (ii) that the prior art, as a whole, did not teach away from the claimed invention; and (iii) related to Adapt’s proffered objective indicia of non-obviousness. The Federal Circuit addressed each.

Motivation to combine. The district court found correctly that a POSA would have been motivated to improve upon the prior art because its shortcomings were well known. The FDA discussed its interest in improving on the prior art and encouraged the industry to “develop an intranasal naloxone product that could be FDA approved. Thus, several years before the priority date of the patents-in-suit, the FDA explicitly provided a motivation to formulate an intranasal naloxone product by identifying a need or problem known in the [industry] ... at the time of the invention.” The prior art and credited expert-witness testimony corroborated this motivation as well as the motivation to use sodium chloride, hydrochloric acid, BZK, and EDTA in an intranasal naloxone formulation. Additionally, recognizing that the Aptar UnitDose Device was an already-FDA-approved medical device specifically recommended in the prior art for use with drugs that were administered sporadically (like intranasal naloxone), the district court also correctly found that a POSA would have “been motivated to select the Aptar UnitDose device when developing an improved intranasal naloxone product” as a way of administering intranasal naloxone in lieu of using the prior-art device. And at the FDA’s 2012 meeting, “[t]he FDA specifically mentioned that it was curious about the bioavailability of an intranasal naloxone product as compared to the existing intravenous or intramuscular products” so a POSA would have been motivated to try a formulation with an intranasal dose of 3 mg to 4 mg naloxone. Finally, a POSA would have been motivated to combine the prior-art references to arrive at an improved intranasal naloxone product as they were “clearly within a common field of endeavor.”

Teaching away. At trial, Adapt argued that the Wyse reference taught away from using BZK as a preservative. The district court found otherwise, and Adapt argued on appeal that the district court used the wrong standard. Wyse described a screening study conducted on various excipients for use in intranasal naloxone formulations. Wyse observed that “the use of [BZK], a common nasal product preservative, resulted in an additional degradant in formulations 7, 9, 14, and 14A.” Although Wyse concluded that BZK was not acceptable for use in an intranasal naloxone formulation, Teva’s expert testified that a POSA would not have been dissuaded from using BZK at all in an intranasal naloxone formulation, only from using such high concentrations. 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.” The district court specifically credited Teva’s expert’s testimony and therefore did not err.

Objective indicia of non-obviousness. It was not unexpected that Narcan had a 56% increase in bioavailability compared to the prior-art formulation because the prior art included citric acid and benzyl alcohol but does not BZK, a known “permeation enhancer that causes a drug to permeate more readily across a membrane.” It was not unexpected that Narcan exhibited better stability in light of the fact that it included BZK, which the Wyse prior-art reference suggested should not be used in intranasal naloxone formulations, because the formulation in Wyse used a much higher concentration of BZK than is claimed in the patents-in-suit. The district court dismissed Adapt’s copying arguments because “evidence of copying in the ANDA context is not probative of non-obviousness because a showing of bioequivalence is required for FDA approval.” There was no industry skepticism concerning the 4 mg naloxone dose given the FDA’s statements (i) recommending that Lightlake consider a higher dose of naloxone than its contemplated 2 mg dose and (ii) that it would be “acceptable” if a higher dose of naloxone were needed to achieve bioavailability similar to that of the approved intramuscular product. And, finally, there was evidence in the record of long-felt need, which the district court erred in ignoring, but the Federal Circuit concluded that such evidence was not sufficient to overcome the strong case of obviousness.

In her dissenting opinion, Judge Newman notes that the claimed method is reported by the FDA to deliver 56% more naloxone into the bloodstream compared with the closest prior art, and that “Narcan became ‘the first and only’ FDA-approved naloxone intranasal spray,” and it ‘captured over 95% of the retail market.’” In her opinion, the court’s ruling is “contrary to the law of Section 103, for there was no teaching or suggestion in the prior art to make this combination of ingredients for use in the claimed method to achieve the described beneficial results.”

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