In Leo Pharmaceutical Products, Ltd. v. Rae, the Federal Circuit issued a rare decision reversing an obviousness determination by the USPTO Patent Trial and Appeal Board (PTAB). The patent at issue was a Taclonex® patent, and the court found both that the prior art did not render the claimed combination formulations obvious and that the PTAB had failed to give proper weight to the objective indicia of non-obviousness. This decision reinforces the principle that even under KSR more than general teachings are required to support an “obvious to try” rationale of obviousness.

The Patent At Issue

The patent at issue was Leo’s U.S. 6,753,013, directed to storage stable pharmaceutical compositions comprising both a vitamin D analog (a category A component) and a corticosteroid (a category B component). The ’013 patent is listed in the Orange Book for Taclonex®.

The court identified claim 1 as representative:

1. A pharmaceutical composition for dermal use, said composition comprising:
a first pharmacologically active component A consisting of at least one vitamin D analogue …
a second pharmacologically active component B consisting of at least one corticosteroid,
wherein the difference between the maximum stability pH of said first component A and the maximum stability pH of said second component B is at least 1; and
at least one solvent component C …
wherein said pharmaceutical composition is storage stable and non-aqueous.

As summarized by the court, while it was known prior to the invention that the simultaneous treatment of psoriasis with vitamin D and corticosteroids was advantageous, combination compositions suffered from stability problems because vitamin D analogs are stable at basic pH (e.g., above 8), while corticosteroids are stable at acidic pH (e.g., 4-6). The ’013 patent addressed and solved this problem by identifying suitable solvents (including (POP-15-SE) in which both components are stable.

The PTAB Obviousness Determination

The ’013 patent was challenged in an inter partes reexamination proceeding brought by Galderma R&D. The PTAB upheld the Examiner’s determination that the claims were obvious in view of three prior art references.

Turi is directed to “Topical Steroidal Anti-Inflammatory Preparations Containing Polyoxyproplyene 15 Stearyl Ether.” The reference discloses “pharmaceutical compositions comprising a steroid contained within a solvent, POP-15-SE,” but does not disclose the use of vitamin D. Further, “Turi specifically discloses that the claimed invention does not contain water, gels, or alcohols,” but rather pertains to “topical ointment like compositions and preparations.”

Dikstein discloses “dermatological compositions, including creams, ointments, and lotions, comprising a vitamin D analog and a corticosteroid.” As noted by the court, “[e]very example composition in Dikstein contains almond oil or propylene glycol and several also contain water,” solvents which Leo had shown do not result in good stability. However, “Dikstein does not disclose or recognize the storage stability problems associated with using water, almond oil, or propylene glycol in the combination formulations.”

Serup is directed to “Hydroxy Vitamin D3 Compounds for Treating Skin Atrophy.” Serup discloses “a composition containing a vitamin D analog and a steroid.” However, “Serup does not address any storage stability concerns associated with this combination.” Moreover, “every example composition disclosed in Serup is aqueous, containing either purified or hot water,” and “also contains almond oil, propylene glycol, or alcohol.”

The PTAB determined that the claims were obvious over the combination of Turi and Serup, asserting that “because both Serup and Turi describe compositions with corticosteroids, an artisan would have found the two references reasonably pertinent for the ‘same type of compositions with the same therapeutic purpose,’ and that it would have been obvious to add vitamin D to Turi’s composition ‘to address the well-known side effects of topical steroid treatment.’”

The PTAB determined that the claims were obvious over the combination of Turi and Dikstein, based on the finding that Dikstein “’teaches the benefit of combining a vitamin D analog with a corticosteroid to achieve more complete skin healing.’”

With regard to Leo’s evidence of objective indicia of nonobviousness, the PTAB “acknowledged that the claimed compositions were ‘adequately shown to be more storage stable than compositions formulated with certain ingredients that had been used in the prior art,’” but determined that those results were not “unexpected” because Turi “’provided explicit reason to use POP-15-SE as a solvent.’”

The Federal Circuit Decision

While obviousness is a question of law based on underlying findings of fact, the Federal Circuit noted that the case before it did “not present unresolved issues of fact,” and thus boiled down to a question of law:

[W]hether, in light of the prior art references and objective indicia of nonobviousness, the claimed invention would have been obvious to a person of ordinary skill in the art at a time just before the time of invention.

The Cited Prior Art 

The Federal Circuit made the following points when reviewing the PTAB’s finding that the prior art rendered the claimed subject matter obvious.

“an invention can often be the recognition of a problem itself”

The ’013 patent … is not simply a combination of elements found in the prior art. The inventors … recognized and solved a problem with the storage stability of certain formulations—a problem that the prior art did not recognize and a problem that was not solved for over a decade.

“By brushing aside the storage stability issue, the Board erred by collapsing the obviousness analysis into a hindsight-guided combination of elements.”

“This record … discloses several reasons that a person of ordinary skill in the art would not have been motivated to try, let alone make, the claimed invention of the ’013 patent.” For example, the cited references disclose “divergent compositions with express disclaimers of the other’s contents.” Thus, “the record showing that Turi, Serup, and Dikstein describe compositions for the same therapeutic purpose does not rise to the level of a motivation to combine.”

“[W]here the prior art, at best gives only general guidance as to the particular form of the claimed invention or how to achieve it, relying on an obvious-to-try theory to support an obviousness finding is impermissible.”

“The problem was not known, the possible approaches to solving the problem were not known or finite, and the solution was not predictable. Therefore, the claimed invention would not have been obvious to try to one of ordinary skill in the art.”

“[E]ven if it was obvious to experiment with these options, ‘there is nothing to indicate that a skilled artisan would have had a reasonable expectation that such an experiment would succeed in being therapeutically effective.’ … There is no indication in the prior art which of these possible formulations would be the most promising to try. … Without a reasonable expectation of success or clues pointing to the most promising combinations, an artisan could have spent years experimenting without success.”

The elapsed time between the prior art and the ’013 patent’s filing date evinces that the ’013 patent’s claimed invention was not obvious to try.

If these discoveries and advances were routine and relatively easy, the record would undoubtedly have shown that some ordinary artisan would have achieved this invention within months of Dikstein or Serup. Instead this invention does not appear for more than a decade.

The court concluded:

In light of the lack of expectation of a successful result, the failure of the prior art to provide direction, and the substantial number of intervening years between the publication of the prior art and the ’013 patent’s filing date, this invention is not simply a case of “‘picking and choosing’ from a list in order to achieve a compatible and non-deleterious preparation” as the Board suggests. … Because the problem was not known, the possible approaches to solving the problem were not known or finite, and the solution was not predictable, it would not have been obvious for a person of ordinary skill to make the claimed invention.

The Objective Indicia of Non-Obviousness

The Federal Circuit disapproved of the PTAB’s treatment of the objective indicia of non-obviousness as an “afterthought.”

Objective indicia of nonobviousness play a critical role in the obviousness analysis. They are “not just a cumulative or confirmatory part of the obviousness calculus but constitute[] independent evidence of nonobviousness.”

The Federal Circuit found that “substantial evidence does not support the Board’s conclusion” that Leo’s evidence of “unexpected results” “were not surprising or unexpected” Instead, the court found that Leo’s “test results are a strong indication that the ’013 patent’s combination of known elements yields more than just predictable results.”

The Federal Circuit also commented on Leo’s evidence of commercial success (its Taclonex® ointment is the first FDA-approved drug to combine vitamin D and corticosteroids into a single topical formulation) and satisfaction of a long-felt but unsolved need (as evidenced by the delay between the discussion of combination therapies in 1986 and the invention in 2000).

Viewed through the lens of the objective indicia, as opposed to the hindsight lens used by the Board, the ’013 patent would not have been not obvious over Turi in combination with Dikstein or Serup. Therefore, this court reverses the Board’s obviousness determination.

Road Map For A Successful Appeal?

Reviewing this decision, it is evident that Leo created a good record for a successful appeal. In addition to challenging the ability of the references to suggest the claimed invention, Leo had presented evidence of unexpected results, commercial success, and satisfaction of a long-felt, unmet need. Perhaps most important was Leo’s ability to focus the issues presented as questions of law. This let the court apply a de novo standard of review to the PTAB decision instead of the very deferential “substantial evidence” standard of review it applies to PTAB factual findings.