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Federal Circuit Affirms As Obvious Suite of Patents Directed to Methods Of Treating Opioid Overdose

(Co-authored by Alexandra Kim)

Introduction

In February of 2022, the Federal Circuit affirmed a New Jersey District Court’s determination that four patents claiming methods of treating opioid overdose by intranasal administration of a naloxone formulation, as well as devices for intranasal administration, were invalid as obvious over two, three-reference, sets of prior art. A panel majority found that all of the individual components of the claimed methods were taught in the prior art and that a person of ordinary skill in the art (POSA) would have been motivated to combine such teachings because there was a strong desire in the prior art to improve upon existing but deficient methods for treating overdose.

In a 15-page dissent, Judge Newman criticized the majority’s logic, asserting that there was no evidence of “teaching or suggestion in the prior art” to make the claimed combination of ingredients for use in the claimed method so as to achieve the described beneficial results. She faulted the majority for relying on “the need for a better product” to provide motivation since “the artisan’s knowledge that the available products are deficient does not render the remedy obvious when it is eventually discovered.”

While the challenger here prevailed, this opinion—both the majority and the dissent—provides valuable guidance (and caution) for assembling multi-reference obviousness challenges.

Background

The patents-in-suit were filed at or near the time when the drug industry was actively seeking improvements to then-available treatments for opioid overdose—a reaction to the rapidly expanding opioid addiction crisis. In April of 2012, three years before the priority date of the patents at issue, the Food and Drug Administration (FDA) held a public meeting to address the need for an improved intranasal treatment that was both FDA-approved and could deliver the same amount of naloxone as an injectable formulation. Naloxone had long been used for treating opioid overdose and was typically administered by intravenous injection or intranasally by using the prior art Mucosal Atomization Device (MAD Kit). Each of these prior art methods, however, suffered disadvantages—only a medical professional could safely inject naloxone, and the MAD Kit required assembly before use and often delivered too much fluid into the nose.

Shortly after the April 2012 meeting, a New Drug Application (NDA) for a 4 mg intranasal naloxone product (under the name NARCAN®) was filed by Lightlake Therapeutics Inc. (the predecessor to co-Plaintiff, Opiant). The NDA was initially set to include a 2 mg intranasal naloxone dosage, but after the FDA raised potential bioavailability concerns, the dosage was increased to 4 mg naloxone. In May 2015, Adapt, Opiant’s partner and co-Plaintiff, filed Patent Application No. 14/659,472 for NARCAN® to which the four patents at issue (U.S. Patent Nos. 9,468,747; 9,561,177; 9,629,965; and 9,775,838) claim priority.

Teva subsequently submitted an Abbreviated New Drug Application (ANDA) seeking approval to manufacture and sell a generic version of Adapt’s NARCAN®, after which Adapt sued Teva for infringement of Adapt’s four patents-in-suit in the New Jersey District Court. Stipulating to infringement, the parties agreed to limit the proceeding to invalidity issues.

District Court Opinion

The New Jersey District Court, finding dependent claim 9 of U.S. Patent No. 9,468,747 (“the ’747 patent”) to be representative, focused on the formulation limitations recited in independent claims 1 and 2:

  1. A method of treatment of opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof … 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.

In a lengthy opinion (which the Federal Circuit noted spanned “nearly 100-page[s]”), the district court found the asserted claims invalid as obvious over two, three-reference, sets of prior art.

Specifically, the district court found that a skilled artisan would have been motivated to combine the teachings in the prior art references because: (1) it was well known that the prior art MAD Kit was not optimized for intranasal administration; (2) a new intranasal formulation was being sought in the industry (referencing the FDA’s statements during the 2012 meeting); and (3) expert testimony revealed that a skilled artisan would have been motivated to combine each of the prior art references. The district court also ruled that the prior art did not teach away from the claimed invention, and that evidence of secondary considerations of nonobviousness did not lead to a finding of nonobviousness. Of note, the district court explained that while the invention (4 mg naloxone formulation and method and device for administering the same) may have been an improvement over the prior art MAD Kit, the invention did not satisfy a significant long-felt need because the basic treatment need was still met by that prior art device.

Majority Opinion of the Federal Circuit

The Federal Circuit reviewed the district court’s legal determinations de novo and its factual findings for clear error, and affirmed the ruling below that the asserted claims were invalid.

First, though there was “no single reference [that] disclose[d] naloxone in combination with all of the claimed excipients,” nor was there an express suggestion in the prior art teachings to select the combination or specific combinations as claimed, the Federal Circuit agreed with the district court’s determination that a skilled artisan would have been “motivated to improve on the MAD Kit because its shortcomings were well-known.” The Federal Circuit was also satisfied that the district court had relied on sufficient evidence in the prior art teachings suggesting that a POSA would have had reason to select each of the particular ingredients for use in the claimed nasal formulation. The Federal Circuit pointed to the district court’s recognition of the “interrelated teachings” of the prior art references to support its determination in this regard. Finally, the Federal Circuit found no clear error in the district court’s finding (crediting Teva’s expert witness) that a skilled artisan would have arrived at the claimed (though not explicitly recited) concentration ranges by “routine optimization.”

Beyond the question of whether a POSA would have had a reason to combine the cited prior art references, Adapt argued strenuously that the prior art taught away from using one of the claimed ingredients—BZK—as a preservative. Though the record contained competing evidence about whether BZK was acceptable for use in an intranasal naloxone formulation, the district court again credited Teva’s expert’s testimony that a POSA would not have been dissuaded from its use, overall. The Federal Circuit found no clear error in the district court’s balancing of evidentiary weight, though, notably the Patent Trial and Appeal Board (PTAB) came to the opposite conclusion regarding teaching away of the same reference in considering the obviousness of these same patents.

In considering the question of secondary indicia of nonobviousness, the Federal Circuit again expressed confidence in the length of the record, noting that the district court’s consideration of evidence on this question “spanned twenty pages.” Walking through the district court’s evidence of unexpected results, copying, industry skepticism, and long-felt but unmet need, the Federal Circuit acknowledged Adapt’s arguments but ultimately found sufficient evidence to support the district court’s invalidity conclusion. Though disagreeing with the district court’s finding regarding long-felt but unmet need, the Federal Circuit deemed such error harmless in the context of the weight of the remaining evidence contributing to a “strong case of obviousness.”

Tellingly, the majority conceded that “[t]his is a close case” but reminded the parties that the Federal Circuit is a court of limited review and that in view of the weight of the evidence presented in favor of obviousness, it found no reason to disturb the district court’s ultimate conclusion that the asserted claims were invalid as being obvious.

Judge Newman’s Dissent

In a lengthy dissent, Judge Newman took aim at what she perceived to be a complete absence of evidence specifically in support of a finding that the prior art provided a motivation or reason to combine the various references assembled by the defendant. In Judge Newman’s opinion, while the prior art indicated the “existence of the separate components,” there was no “direction as to which of the many possible combination choices were likely to be successful.” In other words, while the claimed components were separately known, while Teva’s expert testified that the claimed invention was obvious to him, and while the record was replete with various evidence of different kinds, there was simply no evidence that the prior art itself contained teaching or suggestion to combine the references in question to make the claimed invention. Instead, Judge Newman found that the majority’s opinion was “a classical example of judicial hindsight, where the invention itself is the only guide to the selections from the prior art.” As noted above, she was particularly critical of the majority’s reliance on evidence of “the known need for a better product” as providing the “motivation” element of obviousness. After all, “[a] motivation to improve a product does not render the successful improvement obvious.” In her view, an invention is not obvious simply because there are deficiencies in the prior art and the field is looking for ways to improve that product. The practical effect of such logic, of course, would be that every improvement would be obvious.

Takeaways

  • This decision emphasizes just how difficult it is to overturn a finding of obviousness on appeal. Even in admittedly “close call” cases, so long as the challenger’s obviousness theories are buttressed by supporting evidence (the more the better), the Federal Circuit is highly reluctant to disturb a finding of invalidity. Even where the district court may have erred on certain findings (in this case, on the question of long-felt but unmet need), a significant amount of evidence on other factors (“nearly 100-page” opinion, analysis of secondary considerations “span[ning] over twenty pages”) can outweigh such error. Although Judge Newman tried to point out that a mountain of evidence does not necessarily mean that a challenger has presented sufficient relevant evidence, the majority here did not agree.
  • This decision highlights a few key points to keep in mind when bringing (or defending against) a multi-reference obviousness challenge:
    • Context matters: In this case, it was undisputed that no single reference disclosed or suggested all of the claimed limitations, but that each element could be found across multiple prior art references. When considering why a POSA would combine such references, the district court (affirmed by the majority) was persuaded by the context of the problem to be solved—the known drawbacks of the MAD Kit, the desire for an improved treatment in the midst of a public health crisis, the FDA discussions occurring around this topic, and the “interrelated teachings” of the several relied-upon references that discussed common features, benefits, and improvements of various naloxone formulations which the court credited and relied upon in finding a reason to combine the same.
    • Expert testimony should be specific, well-developed, and buttressed, if possible, by other evidence of record: Though the majority gave it significant weight, Judge Newman was very critical of the testimony offered by Teva’s expert, quoting it in her dissent on several occasions to highlight that evidence of “general motivation” is insufficient to combat hindsight. Characterizing such testimony as “Teva’s only support for its argument of obviousness,” Judge Newman found that Teva’s expert identified no teaching or motivation in the prior art to make the claimed selection of elements. Though the district court found such expert “highly credible and convincing” and the Federal Circuit noted that expert testimony is not required on every element of obviousness, it certainly appeared that Teva’s expert would have drawn less critique from the dissent and put Teva on even more solid ground had he explicitly linked his opinion on reason to combine with the additional evidence of record (drawbacks of the MAD Kit, guidance from the FDA, “interrelated teachings” of the prior art, etc.).
    • Teaching away assessed in the context of the prior art of record and knowledge of a POSA: It is notable that the district court/Federal Circuit and PTAB arrived at different results with respect to the teaching away of reference, Wyse, which indicated that the BZK preservative would not be acceptable in the claimed intranasal naloxone formulation “due to increase observed degradation.” In its Final Written Decision (IPR 2019-00688 in which the ’747 patent was challenged by Nalox-1 Pharmaceuticals), the PTAB narrowed in on Wyse as “the only reference of record that compares naloxone formulations having different excipient combinations, and provides stability data for intranasal naloxone formulations.” Based on this, the PTAB agreed with the “teaching away” sentiment expressed in Wyse to uphold the patentability of the claims at issue. By contrast, recognizing that there was no requirement that a single reference that teaches away mandates a finding of nonobviousness, the Federal Circuit found that the district court had properly analyzed Wyse as not teaching away due to the context of the other prior art of record (which did not express “any concerns” with the stability of formulations involving BZK and naloxone) and based on the knowledge of a POSA (as evidenced by expert testimony). Depending upon which forum a particular challenge is being brought, placing “teaching away” references in the context of other, less problematic, prior art can help neutralize such evidence, while, on the other hand, emphasizing such teachings as the only or most relevant teaching on the issue can help combat validity challenges.