In Adapt v. Teva, the Federal Circuit affirmed the district court’s findings that methods of administering a naloxone nasal spray formulation were invalid as obvious. The decision, which the Court notes was a “close case,” reminds us how difficult it is to show non-obviousness of pharmaceutical formulations and their use.

The patents at issue relate to a method for treating opioid overdose by intranasal administration of naloxone. Naloxone—the active ingredient in NARCAN®—was historically administered by injection or intranasally using the Mucosal Atomization Device (MAD Kit), but each method had disadvantages. The injection could only be performed by trained medical personnel and the MAD Kit required assembly prior to use and delivered too much fluid into the nose. In the midst of the opioid addiction crisis, the Food and Drug Administration held a public meeting to encourage the industry to develop an intranasal naloxone product that would be comparable to the injectable naloxone products.

The issues on appeal relate to the formulation limitations as recited in 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.

The district court found the claims obvious based on several prior art references, and the Patent Owner appealed. The Federal Circuit affirmed the district court’s obviousness analysis, focusing on three tenets of the obviousness inquiry: 1) motivation to combine, 2) teaching away, and 3) objective indicia of non-obviousness.

Motivation to combine

It is axiomatic that an obviousness finding requires that a person of ordinary skill in the art must have been “motivated to combine or modify the teachings” in the prior art.[1] Here, the Federal Circuit agreed that there was motivation to make improvements to the MAD Kit because its shortcomings were well known.[2]

In addition, the district court found that a person of skill in the art would have been motivated to use each of the claimed excipients since the MAD Kit was not optimized for intranasal administration. It was desirable to make the formulation more acceptable and tolerable in the nose by modifying the tonicity and pH.[3] For example, the claimed sodium chloride excipient is a well-known tonicity agent; likewise, hydrochloric acid is well-known for adjusting the pH.

Even though there was no express suggestion in the prior art to select the specific combination and concentration of components, the Federal Circuit agreed that sufficient motivation existed to support the district court’s finding that arriving at the claimed concentration ranges for each of the “well-known” excipients would have required no more than routine optimization.

Teaching away

The Patent Owner also tried to convince the Court that the prior art’s disclosure of naloxone’s degradation in a 0.125% w/v BZK formulation constituted a “teaching away” from the use of BZK in a naloxone intranasal spray. Patent Owner urged the Court to apply the legal standard that a “reference teaches away if a POSA ‘upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant.’”[4] The Federal Circuit upheld the district court’s findings and applied a corollary, the legal standard urged by Patent Owner: “[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.’”[5]

Here, the Federal Circuit found that there was no clear error in the district court’s finding that the one report of naloxone degradation in a high concentration of BZK would not have discouraged the skilled artisan from using BZK in an intranasal naloxone formulation, especially since BZK has been used with naloxone at lower concentrations similar to those claimed and it is the most commonly used preservative in nasal sprays.[6]

Objective indicia of non-obviousness

The Patent Owner argued that the district court committed legal error by not considering objective indicia of non-obviousness before it found the claims obvious. The Federal Circuit disagreed, finding that the district court properly considered all objective indicia of non-obviousness before arriving at its conclusions. The Federal Circuit addressed the indicia of non-obviousness argued in this case: unexpected results and long-felt but unmet need.

While unexpected superior results are very commonly used indicia of non-obviousness, the court didn’t find that the asserted results were actually unexpected. Expert testimony explained that using BZK “would increase the relative bioavailability of the formulation because BZK was a known permeation enhancer.”[7] As such, the Patent Owner’s results of 56% increase in bioavailability were only a difference in degree, not kind, and so were not unexpected.[8]

The Patent Owner convinced the Court that the district court erred in finding that there was a long-felt need for an easy-to-use intranasal naloxone product. The district court had said that while the product may be an improvement over the MAD Kit, it did not fill a significant long-felt but unmet need because it was known to be safe and effective. But the Federal Circuit reasoned that the district court was taking inconsistent positions. If there was no long-felt but unmet need because the need was met by the MAD Kit, then it doesn’t make sense that the deficiencies in the MAD Kit also provided motivation for a skilled artisan to combine the prior art references to arrive at the claimed invention.[9] Nonetheless, this error was not sufficient to overcome the strong case of obviousness.

All in all, obviousness determinations require the balancing of multiple factors in multiple rationales. With no clear error in the district court’s factual findings and a sufficient factual record, it would not reconsider the evidence on appeal. This was a close case, and since the Federal Circuit is “a court of review, not a court of first resort,” its review is limited. Therefore, it affirmed the district court’s judgment that the claims are invalid.

[1] Adapt Pharma Operations Limited v. Teva Pharmaceuticals USA, Inc., Appeal No. 2020-2106, at 12 (Fed. Cir. Feb. 10, 2022).

[2] 13.

[3] 14.

[4] Id. at 22.

[5] Id., emphasis in original.

[6] Id. at 14.

[7] Id. at 27.

[8] 28.

[9] Id. at 32.