Stephen G. Adrian | September 27, 2013
Leo Pharmaceutical Products v. Rea
August 12, 2013
Panel of Rader, O’Malley and Reyna; opinion by Rader
The Court of Appeals for the Federal Circuit recently provided excellent guidance for responding to obviousness rejections which at first blush seem strong. In Leo Pharmaceutical Products Ltd. v. Rea, decided August 12, 2013, it reversed the Board of Patent Appeals and Interferences because the Board incorrectly weighed the objective indicia of non-obviousness.
The appeal arises from an inter partes reexamination of U.S. Patent No. 6,753,013 (the ‘013 patent). Claim 1 is directed to a pharmaceutical composition for dermal use which included a vitamin D analog, a corticosteroid and a solvent. During the inter partes reexamination proceeding, claim 1 had been amended to include the phrase “wherein said pharmaceutical composition is storage stable and non-aqueous,” which proved to be pivotal in securing the favorable decision for Leo Pharmaceutical Products, Ltd.
According to the ‘013 patent, a storage stable combination of vitamin D and corticosteroids in a single formulation did not exist in the prior art. Previous formulations were not storage stable because vitamin D analogs require a basic environment of higher pH value whereas corticosteroids are most stable in acidic environments with a lower pH value. After discovering the stability problem and testing different formulations, Leo found that aqueous, alcohol based solvents such as almond oil, propylene glycol and water did not solve the problem, whereas a new set of solvents, including polyoxypropylene 15 stearyl ether (POP-15-SE), allowed the vitamin D analog and the corticosteroid to coexist stably.
The Board relied upon the Examiner’s findings to affirm the rejection of all the claims based on a combination of three prior art references to Turi, Dikstein and Serup. Turi discloses a pharmaceutical composition including a steroid and a solvent of POP-15-SE, but did not teach use of vitamin D. Turi specifically teaches that its composition does not contain water, gels or alcohol. Dikstein discloses a dermatological composition comprising a vitamin D analog and a corticosteroid, in which each disclosed example contains almond oil or propylene glycol, with several also including water. Serup also discloses a composition containing a vitamin D analog and a steroid. Serup describes the benefits of using vitamin D to treat steroid-induced atrophy, but does not address any storage stability concerns. Every example in Serup is aqueous and also contains almond oil, propylene glycol or alcohol.
The Board took numerous positions in arguing that the combination of prior art would render the claimed invention obvious. These positions are similar to those taken frequently by Examiners during a typical prosecution, namely:
– The reason for combining the references was “for the [Turi’s] solvent advantages and to ‘obtain a more effective preparation without the potential of causing skin atrophy.’”
– An artisan would have found the two references reasonably pertinent for the “same type of compositions with the same therapeutic purpose.”
– Adding vitamin D to Turi “would have been obvious to address the well-known side effects of topical steroid treatment.”
– Because Serup discloses selecting ingredients that are “compatible” and “not deleterious,” an artisan would have been familiar with selecting components by routinely “picking and choosing” from a list to achieve a compatible and non-deleterious preparation.
– The prior art “teaches the benefit of combining a vitamin D analog with a corticosteroid to achieve a more complete skin healing.”
– The “unexpected results” claimed by Leo Pharmaceuticals were not unexpected results because Turi “provided explicit reasons to use POP-15-SE as a solvent.”
– Even though Turi did not teach POP-15-SE as a solvent to allow “vitamin D and corticosteroid to coexist,” “the reason for utilizing the solvent does not have to be the same reason [the solvent] was employed by the inventors.”
How was it possible for Leo Pharmaceuticals to prevail before the CAFC, particularly in view of the higher “substantial evidence” standard of review? In Judge Rader’s words, “the Board erred by collapsing the obviousness analysis into a hindsight-guided combination of elements. This record, however, 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.” The ‘013 patent was not simply a combination of elements found in the prior art, but was an invention which resulted from a recognition of a storage stability problem and a solution to that problem which was not solved for more than a decade.
The CAFC found that the prior art either discouraged combining vitamin D analogs and corticosteroids in a single formulation, or attempted the combination without recognizing or solving the storage stability problems associated with the combination. Leo Pharmaceuticals had presented research articles during the reexamination showing the possible advantages of a vitamin D treatment with topical corticosteroids, but nonetheless researchers recommended a regimen of applying the two drugs separately. Leo Pharmaceuticals also presented experiments showing that the combinations of vitamin D and steroids disclosed in each of Dikstein and Serup did not exhibit storage stable properties. Furthermore, because neither Dikstein nor Serup recognized or disclosed the stability problem, there would be no reason for one of ordinary skill to attempt to improve upon either Dikstein or Serup by using Turi.
The Board’s conclusion that the references would be combined to solve the well-known side effects of steroid treatment is only straightforward in hindsight. The CAFC noted that Turi had been available for twenty-two years, yet there was no evidence that anyone sought to improve Turi with vitamin D. Even after Serup became available in 1994, no one, including Serup, sought to improve Turi by adding vitamin D. In addition, the CAFC found that the substantial evidence did not support the finding that the vitamin D analog would have been plucked from the compositions of Serup or Dikstein and incorporated into Turi. Turi’s guidance to exclude water, alcohol and propylene glycol actually taught away from the Board’s combination as both Serup and Dikstein employed these solvents.
Even though the prior art taught different solvents, the Board attempted to explain that Turi provided a reason to exclude water and propylene glycol, which would make POP-15-SE a logical non-aqueous choice for improving Serup and Dikstein. The CAFC was not persuaded, noting that both Serup and Dikstein had emphasized that their compositions had provided surprising results. “With surprisingly successful results, an ordinary artisan would not have been motivated to change the solvents Serup or Dikstein relied upon and use the different solvent disclosed in Turi.” The CAFC concluded: “Thus, in the face of such divergent compositions with express disclaimers of the other’s contents, the record showing that Turi, Serup, and Dikstein describe compositions for the same therapeutic purpose does not rise to the level of motivation to combine. Without more …the Board erred by using hindsight to determine that the addition of Serup’s or Dikstein’s vitamin D analog to Turi’s formulation would have been obvious.”
The CAFC also responded to the Board’s position that one of ordinary skill would have been capable of selecting the correct formulation from available alternatives. The CAFC found that the breadth of choices and numerous combinations indicate that the prior art would not have rendered the invention obvious to try. “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 or ordinary skill in the art to make the claimed invention.”
The CAFC was not yet through in its reasoning, and then turned to the objective indicia of non-obviousness. The Board had concluded that the strong case of obviousness outweighed any experimental evidence and testimony about the advantages of the claimed composition. The CAFC responded that “the objective indicia of nonobviousness highlight that the Board’s analysis regarding the combination of Serup or Dikstein with Turi was colored by hindsight.” Here, the CAFC emphasized that during an inter partes reexamination, the Board should review evidence of obviousness, including objective indicia, submitted by two adversarial parties. As such, the objective indicia must be given its proper weight and place in the obviousness analysis and not be treated as an afterthought. “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 obvious over Turi in combination with Dikstein or Serup.”
When addressing obviousness rejections that appear strong, the teachings of the prior art can be used to rebut reasons advanced by the Examiner in formulating the rejection. One should look for reasons why one of ordinary skill would not combine the prior art “in a hindsight-guided combination of elements.” Objective evidence of non-obviousness is effective as long as the evidence is commensurate in scope with the claims (as seen here, by a showing that the prior art compositions are not “storage stable and non-aqueous.”)