CAFC Affirms District Court Finding that Naloxone Patents are Obvious; Newman Dissents

“Notably, the CAFC mentioned that ‘evidence of copying in the ANDA context is not probative of nonobviousness because a showing of bioequivalence is required for FDA approval.’”

obvious - February 10, the U.S. Court of Appeals for the Federal Circuit (CAFC) affirmed a decision by the U.S. District Court for the District of New Jersey, explaining that the district court did not err in finding several Adapt Pharma patents obvious.

The asserted claims relate to U.S. Patent Nos. 9,468,747; 9,561,177; 9,629,965; and 9,775,838 (collectively, the “patents-in-suit”). 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 the active ingredient in Adapt’s NARCANâ Nasal Spray and is an opioid receptor antagonist, thus helping reverse the effects of opioid overdose. The opinion was authored by Judge Kara Stoll; Judge Pauline Newman dissented.

The Underlying Suit

Teva submitted to the Food and Drug Administration (FDA) Abbreviated New Drug Application (ANDA) No. 209522 seeking approval to manufacture and sell a generic version of NARCAN®; subsequently, Adapt sued Teva for infringement. Before trial, the parties agreed to try validity of the asserted claims of the patents-in-suit.

Thereafter, the district court held a two-week bench trial, where Teva asserted two different combinations of prior art: (1) the Davies combination and (2) the Strang combination. After considering the evidence of record—including testimony from multiple witnesses—the district court found that “the asserted claims would have been obvious in view of the prior art and entered a final judgment of invalidity.”

On appeal, Adapt challenged several of the district court’s factual findings underlying its obviousness determination as clearly erroneous, namely: “(1) its finding that a skilled artisan would have been motivated to combine the prior art references to arrive at the claimed invention; (2) its finding that the prior art, as a whole, does not teach away from the claimed invention; and (3) its findings related to Adapt’s proffered objective indicia of nonobviousness.”

The CAFC addressed each of the stated issues and incorporated specific elements of the combinations of prior art in its analysis.

Motivation to Combine

The district court found that a skilled artisan would have been motivated to: “(1) formulate an intranasal naloxone product that would improve upon the [existing marketed medical device, called the Mucosal Atomization Device Kit]; (2) select the claimed excipients—sodium chloride, BZK, EDTA, and hydrochloric acid for adjusting the pH—and the Aptar Unit Dose device for intranasal delivery; (3) select a 4 mg dose of naloxone; and, accordingly, (4) combine the prior art references themselves.”

On appeal, Adapt argued that the district court failed to articulate a reason why a skilled artisan would have been motivated to fulfill the stated elements. However, the CAFC found the evidence of record supported the district court’s findings of motivation. Among other points, the evidence the district court considered included the known drawbacks to the MAD Kit, the FDA’s encouragement for the development of an intranasal naloxone product, and the teachings of the prior art references themselves.

The CAFC also addressed the dissenting judge’s claims that there was “no suggestion in the prior art to select th[e] specific combination and concentration of components” claimed in the patents-in-suit. The majority pointed out that the asserted references provide exemplary formulations comprising naloxone in combination with one or more of the claimed excipients. It added that while “no single reference discloses naloxone in combination with all of the claimed excipients, . . . Teva’s invalidity case was based on obviousness, not anticipation.

Teaching Away

The district court found that the prior art, as a whole, did not teach away from the claimed invention. At trial, Adapt argued, and the district court rejected, that an asserted reference (the “Wyse” reference) taught away from using BZK as a preservative. However, the asserted reference assessed the compatibility of BZK at a concentration 8.5 times greater than the concentration of BZK claimed in the patents-in-suit. Based on expert testimony, the district court reasoned that a skilled artisan “would not have been dissuaded from using BZK at all in an intranasal naloxone formulation, only from using such high concentrations.

The district court also cited prior art references which taught the use of BZK specifically in intranasal naloxone formulations at concentrations similar to the claimed concentration, without expressing concerns with the stability of these formulations. From this, the CAFC agreed with the district court that “there is no rule that a single reference that teaches away will mandate a finding of nonobviousness.” The majority concluded that the district court, as the fact finder, was entitled to consider the teachings of the prior art as a whole in finding that the prior art did not teach away from the claimed invention.

Objective Indicia of Nonobviousness

The district court rejected Adapt’s arguments that its evidence of unexpected results, copying, skepticism, long-felt need, and failure of others mandate a conclusion of nonobviousness.

In its analysis, the CAFC sided with the district court’s holding that there were no unexpected results. The district court considered the evidence Adapt presented—namely, that the claimed formulations exhibited: (1) an unexpected increase in bioavailability and (2) unexpected stability—and found that this was not evidence of unexpected results probative of nonobviousness. Relying on expert testimony, the CAFC found no clear error in the district court’s finding that a skilled artisan would have expected that using a permeation enhancer such as BZK would increase the relative bioavailability of the formulation compared to a formulation without a permeation enhancer, disclosed in prior art references. The CAFC also agreed with the district court’s finding that the claimed formulations were not unexpectedly stable.

Similarly, the CAFC saw no clear error in the district court’s findings that Adapt’s evidence of copying and skepticism was non-probative. Notably, the CAFC mentioned that “evidence of copying in the ANDA context is not probative of nonobviousness because a showing of bioequivalence is required for FDA approval.”

However, the CAFC held that the district court incorrectly concluded that there was no long-felt but unmet need for an “easy-to-use intranasal naloxone product.” The CAFC recognized the contradiction in the district court’s analysis and “fail[ed] to see how, on the one hand, the MAD Kit and its known drawbacks can provide a skilled artisan with the motivation to arrive at the claimed invention and, on the other hand, satisfy an unmet need in the prior art.” The CAFC ultimately called the error “harmless” because “[t]his need, even if unmet, was not so long felt that it overcomes the strong case of obviousness.”

Interestingly, the CAFC concluded its opinion by conceding that it was a “close case” and noting that the CAFC is “a court of review, not a court of first resort.” Thus, said the court, its review of the district court’s judgment is “accordingly limited.”

Judge Newman’s Dissent

In her dissent, Judge Newman claimed that the majority’s ruling was contrary to the law of Section 103 and that Adapt’s claimed invention was not obvious.

Judge Newman pointed out that the majority found components of the claimed composition in prior art and simply held that it was obvious to select the specific components and concentrations of the asserted claims from the myriad possible combination of elements. Further, she argued that the prior art makes no reference to the specific claimed combination.

Ultimately, Judge Newman reasoned that “this is a classical example of judicial hindsight, where the invention itself is the only guide to the selections from the prior art. The district court reconstructed the Adapt Pharma method and composition from the teachings of the patents in suit, not from the prior art. My colleagues now adopt the district court’s flawed reasoning.”

In closing, Judge Newman expressed her view that the majority’s holding goes against the public’s interest in a stable patent system: “The majority’s misapplication of law and precedent will simply become a disincentive to the search for improvements in crowded medicinal fields . . . The majority’s new standard will deter research in areas in which the FDA has mentioned the need for improvement.”

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Author: iqoncept
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Join the Discussion

6 comments so far.

  • [Avatar for Pro Say]
    Pro Say
    February 14, 2022 03:28 pm

    “I am not clear where “American innovation” comes into this.”

    Here you go:

    Adapt was robbed . . . while life-saving innovation was further crippled.

    Furthermore, it’s virtually certain that others . . . will rely on this precedential case . . . to further cripple . . . American innovation.

    Which I know you know.

    Abhorrent decisions like these are bad for all of innovation — including American innovation.

  • [Avatar for Greg DeLassus]
    Greg DeLassus
    February 14, 2022 02:56 pm

    “Adapt Pharma’s company headquarters is in Dublin, Ireland, with US headquarters in Radnor, PA.”

    Roger Crystal is a UK citizen. Fintan Keegan is an Irish citizen.

  • [Avatar for B]
    February 14, 2022 01:20 pm

    @ Pro Say

    I 100% agree with you, but Prost and Stoll are both a few sandwiches short. Good God, the motivation Stoll spews is “First, the district court found that a skilled artisan would have been “motivat[ed] to improve on the MAD Kit because its shortcomings were well-known.”

    Stupidest discussion of a “motivation” ever.

    @ Greg “I am not clear where “American innovation” comes into this.”

    Adapt’s HQ is just outside Philly and the inventors are 100% AMERICAN for 2 patents and 75% AMERICAN for the other 2 patents.

    Ergo, it’s not a stretch to assert “American innovation.”

    Just saying

  • [Avatar for Greg DeLassus]
    Greg DeLassus
    February 14, 2022 12:08 pm

    Adapt was robbed… [w]hile life-saving American innovation was further crippled.

    Adapt is an Irish company, and the inventor of this technology is a U.K. citizen. I am not clear where “American innovation” comes into this.

  • [Avatar for Greg DeLassus]
    Greg DeLassus
    February 13, 2022 01:31 am

    The district court here ruled in June 2020 that all challenged claims are obvious, although that judgment was issued under seal and only subsequently became public. The judge had declined to stay the case in favor of a parallel series of IPRs. In August 2020, the PTAB issues final written decisions holding that Teva had failed to prove unpatentability of any of the challenged claims.

    Too bad for Adapt that the PTAB had not gotten their first. Under the recent Intuitive Surgical precedent, Teva would then have been estopped from proceeding with its obviousness argument in the district court.

  • [Avatar for Pro Say]
    Pro Say
    February 12, 2022 03:55 pm

    1. No Motivation to Combine.
    2. Hindsight.
    3. Teaching Away.
    4. Unexpected Results.
    5. Copying.
    6. Skepticism.
    7. Long-Felt Need (untold 10’s of 1,000’s of lost — and now saved — lives weren’t enough to show long-felt need?! How many more grave stones did you need to see? Sickening. Just sicking.).
    8. Failure of Others.

    All eight were shown. All eight.

    A close case. Are you kidding? What alternative universe are you living in?

    Adapt was robbed. Blind.

    While life-saving American innovation was further crippled.

    How do you sleep at night?

    Well; how do you?