In the first decision of its kind that we have seen, the Federal Circuit has upheld a decision by the Patent Trial and Appeals Board (“PTAB”) that the concentration of a new chemical entity in a solution for treating toenail fungus would have been obvious – a matter of “routine optimization” – even though no one had previously used this molecule for toenail fungus, the prior art disclosed a wide range of suitable concentrations for industrial applications, and two separate dose ranging studies, involving “various treatment regimens” and 4 separate concentrations were required to arrive at the patented concentration. See Anacor Pharm. v. Flatwing Pharm., 2020 U.S. App. LEXIS 27399 (Fed. Cir. Aug. 27, 2020). According to FDA’s summary review for the drug,
“Tavaborole solution was evaluated in a double-blind dose-ranging Phase 2 study, two open label cohort Phase 2 studies, where one dosing regimen cohort is fully enrolled before the next cohort is enrolled, and two identical vehicle-controlled Phase 3 studies. The Phase 2 studies evaluated dose levels of 1 %, 2.5%, 5%, and 7.5% and various treatment regimens from once daily for 30 days followed by three times weekly for 150 days to once daily treatment for 360 days.”
The drug in this case, tavaborole, was a new chemical entity belonging to a chemical class known as “oxaboroles.” The primary reference, Austin (WO1995/033754), had previously proposed tavaborole as an industrial biocide based on a study showing antifungal activity against five different fungi, including the most common fungus responsible for toenail infections, Candida albicans. As for concentration, Austin did not discuss tavaborole specifically, but he did state generally that oxaboroles could be formulated:
“preferably from 1 to 50%, especially from 5 to 30% and more especially from 10 to 20% by weight relative to the total weight of the biocide composition.”
A secondary reference, Samour (U.S. Patent 6,224,887), described toenail solutions based on econazole (among other antifungal agents). According to Samour,
“the amount of active [antifungal] agent is generally about 1 to 50%, preferably about 2 to 35%, more preferably, from about 2 to 30%, especially preferably from about 5 to 20%, by weight of the composition.”
Samour’s examples taught the effect of changing the concentration of econazole “for a single dose application,” tested the efficacy of 1%, 2%, 5%, 10%, and 20% econazole concentrations, and disclosed lacquer formulations containing 5% econazole. A lacquer, according to Samour, “when applied to nails form strongly adherent, water-resistant, clear films.”
The particular claim on appeal was claim 2 of U.S. Patent No. 9,572,823, which recited (along with independent claim 2 from which it depends):
1. A method of delivering a compound, in a human, from a dorsal layer of a nail plate to a nail bed to treat onychomycosis caused by Trichophyton rubrum or Trichophyton mentagrophytes, the method comprising: contacting the dorsal layer of the nail plate with a pharmaceutical composition comprising a compound that penetrates the nail plate, the compound being 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole or a pharmaceutically acceptable salt thereof, thereby treating onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes.
2. The method of claim 1, wherein the pharmaceutical composition is in the form of a topical solution comprising 5% w/w of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, and wherein the pharmaceutical composition further comprises ethanol and propylene glycol.
In defense of claim 2, Anacor focused entirely on the 5% limitation, and offered testimony from two technical experts explaining why the 5% concentration would not have been obvious. It’s first expert, Dr. Reider, concluded that a person of ordinary skill in the art would have been inclined to use a higher concentration because he or she:
“would … have expected tavaborole to bind keratin and become entrapped within the keratin network of the nail rather than treat the underlying infection.”
Anacor’s second expert, Dr. Lane, analyzed the Samour reference, which used econazole, and concluded that:
“based on Example 9 [of the Samour reference], when read in the context of the entire reference, a person of ordinary skill in the art would have used more than 5% w/w of an antifungal agent.”
The PTAB, however, gave greatest weight to the testimony of Flatwing’s expert, that low molecular weight is the most important factor in predicting whether a molecule will penetrate the nail plate. According to the PTAB decision (Case IPR2018-00171 (PTAB June 5, 2019)):
“Although other factors such as lipophilicity, keratin binding, and potency of the compound may influence transungual drug delivery, we are persuaded by the well-supported testimony of Dr. Murthy that low molecular weight is the most important factor in predicting whether a molecule will penetrate the nail plate, and that the remaining factors described by Patent Owner’s declarant, Dr. Lane, are of less importance, particularly with a low molecular weight and low MIC molecule such as tavaborole.”
Having lost at the PTAB, Anacor was at a huge disadvantage on its appeal to the Federal Circuit. Under longstanding precedent, the Federal Circuit is obliged to accept the PTAB’s factual conclusions “if a reasonable mind might accept the evidence as adequate to support the finding.”
Nevertheless, we were most disturbed by the Federal Circuit’s blind acceptance of the proposition that a person of ordinary skill would have arrived at a 5% concentration as a matter of “routine optimization” starting from the Austin reference. The only “routine optimization” case cited by the Federal Circuit on this issue, In re Aller, 220 F.2d 454 (CCPA 1955), was concerned with bench chemistry. In that case the applicant was trying to claim an identical chemical reaction described in the prior art, at a slightly lower temperature and slightly higher sulfuric acid concentration. The amount of experimentation was small, and the number of potential variables limited. And, most important, the “routine optimization” in In re Aller could be performed by a single bench chemist in the course of several days if not one day. Unlike tavaborole, the person of ordinary skill was not required to conduct two separate clinical studies, involving “various treatment regimens,” and 4 separate concentrations, to arrive at the claimed invention.
It appears that Anacor did not even advance this argument. As the Federal Circuit concluded:
"there is no dispute that a skilled artisan would have appreciated that concentration is a result-effective variable, Reply Br. 2, such that one could optimize nail penetration by routine experimentation within a predictable range of concentrations."
We sincerely hope that cases like this do not become the norm, and that the PTAB and Federal Circuit will better respect the enormous work required to bring a drug to market in future cases. Anacor took a significant risk developing tavaborole from an industrial fungicide to a toenail fungus, and deserves more than NCE exclusivity to reward its efforts.
