The requirement of nonobviousness pursuant to section 103 of Title 351 is no stranger to practitioners appearing before the Patent Trial and Appeal Board (“PTAB” or “Board”). The Supreme Court of the United States established the framework for analyzing nonobviousness in Graham v. John Deere Co.,2 identifying various “Graham factors” relevant to nonobviousness analyses.3 When a patent owner is faced with allegations of obviousness in an inter partes review (“IPR”), she can directly counter by arguing, for instance, that the petitioner has mischaracterized the cited prior art; that the references teach away from the claimed invention; that there is no teaching, suggestion, or motivation (“TSM”) for a person of ordinary skill in the art (“POSA”) to combine references;4 or that a POSA would not have had a reasonable expectation of success with respect to a certain combination.
In addition, or in the alternative, the patent owner can demonstrate nonobviousness by providing evidence of secondary considerations (the fourth Graham factor) or—as often done—by showing unexpectedly superior or surprising results achieved by the claimed invention.5 However, in a recent trend, arguments supporting unexpected or surprising results seem to face increased scrutiny, with a higher apparent threshold for achieving success. Evidence that the claimed invention yields an unexpectedly improved property or a property not present in the prior art may not be enough. So when is an unexpected or surprising result “enough” to defeat obviousness? And semantics aside, where is the tipping point between a difference in “degree” versus a difference in “kind”?
UNEXPECTED RESULTS: DEGREE VERSUS KIND
An argument of unexpected and surprising results usually arises during patent prosecution in order to rebut an Examiner’s allegation of prima facie obviousness, and may resurface in post-grant proceedings. An applicant or patent owner may submit (rebuttal) evidence that the claimed invention yields unexpectedly improved properties or possesses properties the prior art lacked.6 The ultimate issue is whether the properties differ to such an extent that the difference is truly unexpected.7 Although the Board has indicated that a discussion of results in terms of “difference in degree” as compared to “differences in kind” as having “very little in a relevant legal sense,”8 such a statement, perhaps confusingly, focuses on a hair-splitting exercise of semantics. Rather, a compelling and successful showing of unexpected results demonstrates a “marked improvement” as to be classified “as a difference in kind, rather than one of degree.”9
Interestingly, 35 U.S.C. § 103 never mentions whether a difference between a claimed invention and the prior art should be a difference “in kind” versus a difference “in degree.”10 Whether a claimed invention has produced unexpected results is a question of fact, and while such unexpected results must be commensurate in scope with the claims,11 the Federal Circuit has never required absolute identity of scope. To be particularly probative, evidence of unexpected results must establish that there is a difference between results obtained and those of the closest prior art, and such a difference would not have been expected by one of ordinary skill in the art.12
In demonstrating unexpectedly improved and surprising results of a claimed invention, a patentee will commonly point to comparative and quantitative data described in the specification, highlighting how such evidence would not have been obvious to a person of ordinary skill in the field of invention. But numeric distinctions may not always save the day. For example, in Galderma Labs., L.P. v. Tolmar, Inc.,13 the Federal Circuit reversed the district court’s finding of validity, explaining that a comparable tolerability of 0.1% versus 0.3% by weight of a pharmaceutical compound—adapalene—used for the treatment of acne did not indicate nonobviousness.14 While the Court acknowledged that it was unexpected that 0.3% of said compound did not result in the estimated and expected side effects, it held that “skilled artisans were capable of adjusting the percentage,” especially when the prior art provided motivation to do so, such that “[r]esults which differ by percentages are differences in degree rather than kind.”15 Judge Newman filed a dissenting opinion, arguing that an “increase by 300% the concentration of the active ingredient adapalene without increasing its known adverse side effects” was in fact a “difference in kind, not in degree.”16
UNEXPECTED RESULTS ARGUMENTS AT THE PATENT TRIAL APPEAL BOARD
Accord Healthcare Inc., v. Daiichi Sankyo Co., IPR2015-00864 and IPR2015-00865
In Accord Healthcare Inc., USA et al. v. Daiichi Sankyo Co., Ltd. et al., IPR2015-00864 and IPR2015-00865, the two patents at issue (respectively U.S. 8,404,703 and U.S. 8,569,325) related to methods for preventing or treating diseases caused by thrombus or embolus, i.e., blood platelet aggregation or blood clotting, by administering an effective amount of prasugrel 17 in combination with aspirin.18 Both prasugrel and aspirin were each known to disrupt platelet aggregation, but via separate and independent mechanisms of action.19 In its Patent Owner Response, Daiichi Sankyo Co. argued that the patents provided unexpected results because a person of ordinary skill in the art would not have believed that the net clinical benefit would increase by adding aspirin to prasugrel as compared to adding aspirin to clopidogrel.20 Various prior art references had disclosed that clopidogrel could be administered optionally with aspirin for blood thinning purposes. Daiichi Sankyo argued that a skilled artisan would have expected that the addition of aspirin to prasugrel would have resulted in a greater bleeding risk relative to the use of clopidogrel and aspirin, and without much gain in efficacy.21
As support, the patent owner relied on results of a phase III clinical trial, with its expert declaring that the combination of prasugrel with aspirin when compared to clopidogrel and aspirin yielded net clinical benefits that were “entirely unexpected . . . as nothing in the prior art would have suggested such a result.”22 The patent owner also argued that the Food and Drug Administration (“FDA”) relied on the favorable results of the clinical trial to approve a drug whose prescribing information requires the use of aspirin with prasugrel.23
Unpersuaded, the Board held that an ordinary artisan would have expected better efficacy (and more bleeding as a result) with the combination of prasugrel and aspirin versus clopidogrel and aspirin, given prasugrel’s faster onset and superior response rate.24 Drawing analogy to Galderma Labs., the Board noted the difference in net clinic benefit was a difference in degree, not kind, because such a difference was not due to new properties resulting from the combination of prasugrel and aspirin.25 Accordingly, the Board did not find the results of the proffered study were “of a ‘kind’ or of a ‘significant degree’ that would have been unexpected by a person of ordinary skill in the art . . . so as to support a finding of nonobviousness of the challenged claims.”26 Ultimately, all other issues considered, the claims of the two patents were found to be unpatentable. Daiichi Sankyo has appealed both PTAB decisions.
Mylan Labs, Ltd v. Aventis Pharma S.A., IPR2016-00712
In Mylan Labs, Ltd v. Aventis Pharma S.A., IPR2016-00712, the patent at issue (U.S. 8,927,592) was directed to use of cabazitaxel in the treatment of prostate cancer.27 Because cancer cells may develop resistance to docetaxel, a known chemotherapy medication, administering cabazitaxel 28 helps treat prostate cancer in patients with advanced forms (i.e., metastatic castration resistant prostate cancer (“mCRPC”)) that have progressed despite previous treatment regimens.29 In its petition, Mylan argued that the critical features of the claimed invention were disclosed in the prior art—alleging that the claimed method administered a known drug, in a known dosage range, in a known combination, with known activity against a known indication to patients.30 The patent owner, Aventis Pharma, responded that it was unexpected that cabazitaxel therapy would “prolong overall survival” of docetaxel-refractory mCRPC patients with reduced side effects, as shown in a clinical trial study.31
The Board stated the evidence of unexpected results was “neutral in this case.”32 While the results of the clinical study were “unexpected enough” to result in the fast-track approval by the FDA for docetaxel-refractory mCRPC patients, the Board also noted that the claimed method was disclosed in the prior art.33 For instance, one reference expressly disclosed that results in docetaxel-refractory patients were sufficient to permit moving directly to clinical studies that compared cabazitaxel with other therapies in mCRPC patients.34 Further, any statistically significant increase in overall patient population survival discussed by the patent owner was not an actual claim limitation in any of the patent claims.35 Therefore, “on balance,” the unexpected results evidence did not support the patent owner’s nonobviousness argument here.36 In the end, the Board found the petitioner had shown by a preponderance of the evidence that the asserted claims were unpatentable. Aventis Pharma has appealed the PTAB’s decision.
Argentum Pharmaceuticals LLC v. Cipla Ltd., IPR2017-00807
In Argentum Pharmaceuticals LLC v. Cipla Ltd., IPR2017-00807, the patent at issue (U.S. 8,168,620) covers a combination nasal spray formulation with two active ingredients: azelastine hydrochloride (“azelastine”) and fluticasone propionate (“fluticasone”).37 This is embodied in patent owner Cipla’s commercial product, Dymista®. In its petition, Argentum argued that a prior art reference discloses the combination of azelastine and fluticasone in a nasal spray for treatment of allergic rhinitis.38 Argentum noted that the patent owner submitted a declaration during prosecution that claimed Dymista® was unexpectedly superior to azelastine monotherapy and to fluticasone monotherapy, but argued such an analysis was flawed because the relevant comparator should be concurrent use of azelastine with fluticasone—not each monotherapy in isolation.39 Moreover, studies show Dymista® is not superior to the concurrent use of azelastine and fluticasone.40
In response, the Cipla indicated the “closest prior art for all clinical purposes” is studies of co-administration of an antihistamine and a steroid.41 Cipla then highlighted three factors: faster onset, reduced side effects, and improved clinical efficacy.42 The patent owner pointed to an onset of action within 30 minutes as compared to 3 hours for azelastine or 12 hours for fluticasone, reduced side effects of bitter taste or headache despite expectations of increased incidences, and two to three times the therapeutic effect of the claimed invention.43 Cipla argued all three factors are unexpected differences in kind instead of degree.44
In a subsequent reply, Argentum reemphasized that evidence of unexpected results must stem from a comparison to the closest prior art, which in this case, is a co-administration or conjunctive use of azelastine and fluticasone—not individual monotherapies.45 Argentum argued against each of Cipla’s three factors, stating that Dymista®’s efficacy is the same as conjunctive use, that the onset of action is expected and the same as azelastine, and that Dymista® had worse side effects than azelastine or fluticasone.46 The Board has not yet made a decision in this IPR; oral arguments have been set for May 16, 2018.47
The current case precedent regarding unexpected results, and in view of final written decisions issued by the PTAB, provide some helpful guiding points. When arguing a claimed invention poses unexpected results that have differences in kind (or significant differences in degree) compared to the prior art or expected results, the more concrete and detailed facts that can be provided, the better. Further, it is important, when drafting a patent application or later arguing for nonobviousness in a post-grant proceeding, to consider whether the prior art has hinted at or provided motivation to experiment within a certain range. If a range has been disclosed, as was the case in Galderma Labs, it may be more difficult to show unexpected results are a difference in kind, and therefore more important to make a clear and substantial showing of improvements. Also, if a patent specification provides for unexpected results, consideration should be given as to whether these features should be recited in the claims themselves. While arguing unexpected results continues to be a common strategy to show secondary indicia of nonobviousness, as the cases cited herein point out, it can be a rigorous, fact-intensive exercise.