Tavaborole – USA

On Aug. 27, 2020, Federal Circuit affirmed PTAB’s decision which found antifungal MoU/composition patents invalid as obvious.

Flatwing pharmaceuticals filed IPRs on US 9,549,938, US 9,566,289, US 9,566,290, and US 9,572,823 patents. These patents are listed in orange book for KERYDIN® (Tavaborole) topical solution, which is marketed by Anacor pharmaceuticals. KERYDIN® is indicated for the treatment of onychomycosis, or fungal infection, of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. Claim 2 of the ’823 patent is representative and it is dependent upon claim 1.

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 [tavaborole] 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 [tavaborole], and wherein the pharmaceutical composition further comprises ethanol and propylene glycol.

The Board issued final written decisions concluding that the challenged claims would have been obvious over a combination of WO1995/033754 (Austin),US 2002/0165121 (Brehove), and US 6,224,887 (Samour). Austin discloses tavaborole as fungicides which shows antifungal activity against several fungi. Brehove discloses topical compositions of organoboron compounds and results showing nail penetration and antifungal activity for compositions of organoboron compounds formulated in petroleum jelly or mineral oil at 10% or 25% concentration. Samour discloses topical formulations of other antifungal compounds, such as econazole, at concentrations of 5% by weight. The Board found that Austin, Brehove, and Samour each teach antifungal compositions at concentration ranges that overlap 5%, that a skilled artisan would have been able to make the claimed composition of tavaborole using known techniques, and that formulation of tavaborole, even as a boron-containing compound, would not have been unpredictable.

Court’s analysis:

During appeal, Anacor argued that the Board erred in determining that the claimed composition would have been obvious as the product of routine optimization. Specifically, Anacor argued that it would not have been obvious to formulate the claimed composition, as organoborons are quite reactive compounds. Second, Samour teaches away from a 5%-econazole composition in favor of a 10%-econazole composition.

Federal Circuit with respect to teaching away argument said that Samour discloses several small experiments to determine the effect of econazole concentration on nail penetration. The results indicate that 10%-econazole compositions provide greater nail penetration than the 5%-econazole compositions, but the effect is modest overall and depends on other variables, such as excipients. Samour ultimately claims compositions with concentrations of 1 to 10% econazole. Court said that Samour’s teachings barely even suggest a “preference for an alternative” approach—let alone discourage a skilled artisan from pursuing a 5%-antifungal composition, as is required for a reference to teach away.

With respect to special technical challenges in formulating organoborons compounds, court found Anacor’s arguments unpersuasive. Flatwing’s expert said that the claimed composition could have been made according to well-known formulation techniques, and tavaborole’s potential reactivity as an organoboron compound would not have been an important consideration.  Moreover, the inventors evidently did not consider formulating organoborons a great challenge, as the specification does not offer any guidance beyond citation of well-known guides to pharmaceutical formulation.  Furthermore, there is no dispute that a skilled artisan would have appreciated that concentration is a result-effective variable, such that one could optimize nail penetration by routine experimentation within a predictable range of concentrations. Therefore, the selection of 5% as the concentration of a tavaborole composition would have been obvious to a skilled artisan.

Thus, the Board did not err in determining that creating a tavaborole topical composition would have been obvious.