In Adapt v. Teva, the Federal Circuit upheld the district court’s findings that the methods of administering a nasal spray formulation of naloxone were invalid as obvious. The decision, which the Court said was a “closed case,” reminds us of how difficult it is to demonstrate the non-obviousness of pharmaceutical formulations and their use.
The patents at issue relate to a method of treating an opioid overdose by intranasal administration of naloxone. Naloxone, the active ingredient in NARCAN®, was once administered by injection or intranasally using the Mucosal Atomization Device (MAD Kit), but each method had drawbacks. The injection could only be performed by trained medical personnel and the MAD kit required assembly before use and delivered too much fluid into the nose. Amid the opioid addiction crisis, the Food and Drug Administration held a public meeting to encourage industry to develop an intranasal naloxone product that would be comparable to injectable naloxone products.
The issues on appeal relate to the limitations of formulation as set out in claims 1 and 2:
1. A method of treating an opioid overdose or a symptom thereof, comprising nasal administration to a patient in need thereof…a pharmaceutical composition which is an aqueous solution of about 100 μL comprising : approximately 4 mg of naloxone hydrochloride or one of its hydrates; 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 to 5.5.
2. Process according to claim 1, in which: 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 ruled the claims obvious based on several prior art references, and the patentee appealed. The Federal Circuit upheld the District Court’s analysis of the evidence, focusing on three principles of evidence inquiry: 1) motivation to combine, 2) teaching, and 3) objective indicia. of non-obviousness.
Motivation to combine
Of course, a finding of obviousness requires that a person of ordinary skill in the art has been “motivated to combine or modify the teachings” of the prior art. Here, the Federal Circuit agreed that there was motivation to make improvements to the MAD kit because its shortcomings were well known.
Additionally, the district court found that a person skilled 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 palatable and tolerable to the nose by changing the tone and pH. For example, the claimed excipient sodium chloride is a well-known tonic agent; similarly, hydrochloric acid is well known for adjusting 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 there was sufficient motivation to support the district court’s conclusion that which to arrive at the claimed concentration ranges for each of the “well-known components” excipients would have required only routine optimization.
The patentee also attempted to persuade the court that the prior art’s disclosure of the degradation of naloxone in a 0.125% w/v formulation of BZK constituted a “denunciation” of the use of BZK in a intranasal naloxone spray. The patent proprietor urged the Court to apply the legal standard that a “reference teaches if a POSA” upon reading the reference, would be discouraged from following the path indicated in the reference, or would be led in a direction diverging from the path which was taken by the applicant.’ » The Federal Circuit upheld the district court’s findings and applied a corollary, the legal standard advocated by the patent owner: “[A] reference does not teach whether a person skilled in the art, on reading the reference, do not would be “deterred from going the route indicated in the reference”, and would be do not be ‘led in a direction diverging from the path taken by the applicant.’ »
Here, the Federal Circuit found that there was no obvious error in the district court’s conclusion that the mere report of naloxone degradation in a high concentration of BZK would not have deterred the craftsman. qualified to use BZK in an intranasal formulation of naloxone, 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.
Objective clues of non-obviousness
The patent proprietor argued that the District Court erred in law by failing to consider objective indicia of non-obviousness before concluding that the claims were obvious. The Federal Circuit disagreed, finding that the district court properly considered all objective indicia of non-obviousness before reaching its conclusions. The Federal Circuit has considered the indicia of non-obviousness invoked in this case: unexpected results and long-felt but unmet needs.
Although unexpected superior results are very commonly used indicia of non-obviousness, the court did not find that the asserted results were actually unexpected. Expert testimony explained that the use of BZK “would increase the relative bioavailability of the formulation because BZK was a known permeation enhancer.” Thus, the patentee’s results of a 56% increase in bioavailability were only a difference in degree, not kind, and therefore not unexpected.
The patentee persuaded 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 said that while the product may be an improvement over the MAD kit, it did not meet a significant long-felt but unmet need, as it was known to be safe and effective. But the Federal Circuit found 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, it doesn’t make sense that the shortcomings of the MAD kit also motivated a skilled craftsman to combine the part numbers of the prior art to arrive at the claimed invention. However, this error was not sufficient to overcome the strong case of evidence.
Overall, determinations of obviousness require the balancing of multiple factors across multiple rationales. Absent a manifest error in the factual findings of the district court and a sufficient factual record, it would not reconsider the evidence on appeal. This was a closed case, and since the Federal Circuit is “a court of review, not a trial court,” its review is limited. Accordingly, he upheld the district court’s judgment that the claims were invalid.