By Kevin E. Noonan —

In a crowded pharmaceutical art, the deficiencies thereof being so patent that the FDA encouraged industry to address and correct them, concerning a formulation developed to address the opioid crisis raging earlier in this century (see "Empire of Pain"), when is a resulting formulation obvious over that prior art and in view of the objective indicia of nonobviousness?  This was the question facing the Federal Circuit in Adapt Pharma Operations Ltd. v. Teva Pharmaceuticals USA, Inc., the panel majority affirming a District Court decision that the claimed invention was indeed obvious.

The suit arose over Teva's submission of an ANDA for a generic version of Adapt's Narcan® product having a Paragraph IV certification over the Adapt's Orange Book Listed patents.  Adapt asserted U.S. Patent Nos. 9,468,747; 9,561,177; 9,629,965; and 9,775,838 in this litigation, which are directed to methods for treating opioid addiction by intranasal administration of naloxone (using a revised formulation of Adapt's Narcan® medication for preventing opioid overdoses).  The use of naloxone was well-known in the art at the time the patents-in-suit were filed, and there were several alternative pharmaceutical products used for this purpose.  In addition to intravenous Narcan® administration, the art also recognized intranasal administration routes using an FDA-approved atomization device (termed MAD in the opinion).  In addition, the opinion notes that Narcan® doses of 2 mg, 8 mg, and 16 mg were known in the art to be effectively administered intranasally.  These administration routes and methods had the disadvantage of being amenable for use only to trained medical personnel (for the intravenous injection route) and for requiring assembly of the MAD device which even then could deliver too much fluid in the nose.

The trial was limited to a subset of the claims of the asserted patents, specifically "claims 7 and 9 of the '747 patent; claim 4 of the '177 patent; claims 21, 24, and 25 of the '965 patent; and claims 2, 24, 33, and 38 of the '838 patent."  The District Court considered dependent claim 9 of the '747 patent to be representative, but the Federal Circuit, understanding the issues on appeal to relate to claims 1 and 2, reproduced these claims in the opinion:

1.  A method of treatment of opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride using a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 μL comprising:
    about 4 mg naloxone hydrochloride or a hydrate thereof;
    between about 0.2 mg and about 1.2 mg of an isotonicity agent;
    between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer;
    between about 0.1 mg and about 0.5 mg of a stabilizing agent; and
    an amount of an acid sufficient to achieve a pH of 3.5-5.5.

2.  The method as recited in claim 1 wherein: the isotonicity agent is NaCl;
the preservative is benzalkonium chloride; the stabilizing agent is disodium edetate; and the acid is hydrochloric acid.

(where italicized limitations are relevant to the outcome).

The District Court found that the asserted claims were invalid as being obvious over the disclosures of either of two sets of prior art references:  PCT Pub. No. WO 2000/62757 in view of U.S. Patent No. 5,866,154 and a scientific reference (designated Kerr 2009) directed to a clinical trial of intranasal versus intramuscular naloxone treatment for heroin overdose (termed "the Davies combination"); or PCT Pub. No. WO 2012/15317 in view of a first scientific review of nasal drug delivery devices and a second scientific review article on nasal spray formulations (termed the "Strang combination").  According to the Federal Circuit opinion, the '757 PCT application sets forth detailed drawings and disclosure of spray applicators for intranasal administration and particularly naloxone, wherein administration "can be carried out by an unskilled person, rapidly and with a good chance of successfully reviving a patient suffering from opioid over-dosage."  Naloxone formulations for use with the disclosed applicators can include isotonic salt solutions (specifically 0.9% NaCl) and have a "slightly acidic" pH (with pH 6.5 being exemplary).  The reference disclosed that such formulations could also include preservatives including benzalkonium chloride (BZK).  The Kerr 2009 reference disclosed specifically that intranasal of naloxone was beneficial, inter alia to reduce the risk of needlesticks in intravenous administration, and provided a comparison between administering 2 mg/mL naloxone intranasally with intramuscular naloxone injections.  The '154 patent provided evidence that including EDTA enabled naloxone formulations to be sterilized without significant degradation.

The second set of references considered by the District Court, the Strang combination, included various naloxone formulations for intranasal administration in the '317 PCT application, including 4 mg/mL concentrations of the drug in aqueous saline solution and a pH of 5.5, administered in small (100 µL) volumes.  This reference was considered in combination with a first review article regarding drug formulations for nasal naloxone administration and the effects of various excipients, including benzalkonium chloride as a preservative, EDTA as a chelating agent, and sodium chloride as a tonicity agent, having an optimal pH of between 4.5 and 6.5; and a second review article disclosing various delivery devices.  In particular, the latter article advised that drugs like naloxone are advantageously administered using single- or double-dose devices.

The parties having stipulated to infringement, the District Court entered judgment that the asserted claims were invalid and this appeal followed.

The Federal Circuit affirmed, in an opinion by Judge Stoll joined by Judge Prost; Judge Newman dissented.  Adapt based its appeal on three of the District Court's factual findings:

(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.

With regard to the motivation to combine question, the majority expressly disagreed with Adapt's argument that the District Court erred in 'fail[ing] to articulate a reason why a skilled artisan would have been motivated to combine the prior art references to arrive at the claimed invention."  According to the opinion, the District Court's reasoning, that the skilled worker would have been motivated to "(1) formulate an intranasal naloxone product that would improve upon the MAD Kit; (2) select the claimed excipients—sodium chloride, BZK, EDTA, and hydrochloric acid for adjusting the pH—and [a prior art] device for intranasal delivery; (3) select a 4 mg dose of naloxone; and, accordingly, (4) combine the prior art references themselves" was supported by substantial evidence (the Federal Circuit noted that "the district court issued a nearly 100-page, comprehensive opinion setting forth its findings of fact and conclusions of law . . . , as well as making specific credibility determinations as to each of the witnesses that testified").  That motivation was based on the shortcomings of the prior art being sufficiently "well-known" that the FDA had encouraged industry to develop improved intranasal delivery methods (which had prompted co-plaintiff Opiant's predecessor Lightlake to develop the invention encompassed in the patents-in-suit).  These deficiencies were further supported by the prior art references Teva asserted against Adapt's patents and by expert testimony at trial.  The appropriate motivation extended, in the majority's view, to the components of the claimed formulation, based on testimony from both parties' experts and specific reference in the cited art to each claimed excipient and formuation conditions (i.e., pH).  Similarly, the majority found support in the art and evidence for the 4 mg dose.  Taken together, the majority found substantial evidence that the skilled worker would have been properly and sufficiently motivated to combine these features and elements (as part of the "interrelated teachings") to arrive at the invention claimed in the patents-in-suit, considering the Davies or Strang combination of references.

Next, the majority addressed Adapt's argument that the prior art, as a whole, taught away from the claimed invention, in particular a reference that taught against BZK as a preservative.  This reference was not relied upon otherwise and, the majority noted, was published after the earliest priority date of the patents-in-suit.  Expert testimony countered this argument at trial based on the higher (8.5-fold) BZK concentration taught in the reference, which testimony the District Court credited.  This was not error, according to the majority, and agreed the teachings of a single reference would not satisfy the teaching away standard, which depends on the rubric that an obviousness determination is made over the prior art "as a whole," citing Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (emphasis in opinion), further asserting that "[t]he district court, sitting 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."

Adapt's final argument, regarding the objective indicia of nonobviousness was no more availing.  Adapt's argument on the order in which the District Court made its determinations (finding the claims to be obvious before considering evidence for the objective indicia) was not supported by In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat. Litig., 676 F.3d 1063, 1075–76, 1079 (Fed. Cir. 2012), in the majority's view.  That decision had been predicated on the District Court not considering all the evidence relating to the obviousness question, whereas here the District Court had not so err (indeed, the majority cited KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), for the principle that the order in which the obviousness analysis is performed is not controlling).  The majority then considered the District Court's findings on unexpected results, copying by others, industry skepticism, and long-felt but unmet need, and failure of others (again, noting the extensiveness, over twenty pages, of the District Court's analysis in its opinion).  The majority agreed with the District Court's holding that the evidence adduced at trial did not support Adapt's contentions that the District Court had erred in not finding these objective indicia to have overcome its holding that the asserted claims were obvious (although the majority did criticize the District Court's performance of the analysis regarding long-felt need, being focused "almost entirely" of the prior art MAD kit, but said it was harmless error).

While admitting that this was a "close case," the majority concluded that the District Court's opinion was supported by substantial evidence and affirmed on that basis.

Judge Newman dissented, based in large part on her assessment of the objective indicia and in particular the long-felt but unmet need and failure of others to satisfy it.  In the Judge's opinion, the prior art contained no teaching nor suggestion for the claimed invention, all the components of which were separately known.  And Judge Newman was not convinced by the evidence that there was a sufficient motivation to combine these several elements; in the Judge's view this is "a classical example of judicial hindsight, where the invention itself is the only guide to the selections from the prior art."  The majority's error was, in the Judge's view, in taking the "existence of the separate components [to] suffice[] to find obviousness of this specific [claimed] combination" when the prior art "gave no direction as to which of the many possible combination choices were likely to be successful," citing Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013).  Judge Newman also considered the majority to have provided the motivation to combine the references from "the known need for a better product" and that this was error, saying that "[t]he artisan's knowledge that the available products are deficient does not render the remedy obvious when it is eventually discovered" and that "[a] motivation to improve a product does not render the successful improvement obvious."  In addition, the prior art teachings "against" using BZK were persuasive to Judge Newman as a teaching away.  Finally, unlike the majority Judge Newman found procedural error in the District Court's assessment of the objective indicia of nonobviousness after determining the claims were obvious, and that on the merits these considerations should have led the Court to a conclusion that the claims were nonobvious.

Adapt Pharma Operations Ltd. v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2022)
Panel: Circuit Judges Newman, Prost, and Stoll
Opinion by Circuit Judge Stoll; dissenting opinion by Circuit Judge Newman