Obviousness of a Dosage Regimen: Yeda Research and Development Co., Ltd. v. Mylan Pharmaceuticals Inc. Teva Pharmaceuticals USA, Inc. v. Sandoz Inc.

December 3, 2018

Yeda Research and Development Co., Ltd. (“Yeda”) is the assignee of three “Copaxone patents” that describe and claim COPAXONE® 40mg/mL (glatiramer acetate (“GA”)), a treatment for relapsing-remitting multiple sclerosis (“RRMS”). For analyzing the obviousness of the Copaxone patents, a key limitation of the claims is the administration of a 40mg GA dose in three subcutaneous injections over seven days. The Patent and Trademark Appeal Board (“the Board”) found (and the district court affirmed) that the prior art described all limitations of the claims except for the administration of 40mg GA 3x/week for seven days. However, the Board and the district court concluded that the claimed dosage regimen would have been obvious to a parson of skill in the art (POSITA). Yeda appealed both decisions.

Claim 1 of U.S. 8,232,250 is representative:

1. A method of alleviating a symptom of relapsing- remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient a therapeutically effective regimen of three subcutaneous injections of a 40 mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection, the regimen being sufficient to alleviate the symptom of the patient.

’250 patent col. 16 ll. 35–45.

Yeda Research and Development Co., Ltd. v. Mylan Pharmaceuticals Inc., Nos. 2017-1594, -1596 (Fed. Cir. October 12, 2018) – appeal from the Board

Mylan Pharmaceuticals, Inc. (“Mylan”) filed petitions for inter partes review (“IPR”), challenging all claims of the Copaxone patents on the grounds of obviousness over Pinchasi in view of FDA’s 1996 SBOA, and over Pinchasi, in view of Flechter.

The Board considered multiple prior art references including WO 2007/081975 (“Pinchasi”) that disclose a 40mg GA every other day dosing regimen for the treatment of RRMS. Pinchasi cited to the data from another study to conclude that the increased efficacy observed with 40 mg/day GA in reducing disease activity and a relapse rate indicated that it was well tolerated and could improve the treatment of RRMS patients.  Pinchasi describes that the improvement in efficacy, however, was not accompanied by a corresponding increase of adverse reactions which would be expected upon a doubling of the administered dose. The Board also considered a 2002 study by Flechter that evaluated treatment of RRMS with 20mg of GA administered every other day. Flechter concluded that the alternate-day treatment with GA was safe, well tolerated, and probably as effective as daily GA in reducing a relapse rate and slowing neurologic deterioration. Flechter noted that patient dropout rates decreased when GA was administered every other day as opposed to daily.

The Board also acknowledged that prior to COPAXONE® 40mg/mL, in 1996 FDA approved Teva’s New Drug Application for COPAXONE® 20mg injected daily. The FDA recommended that Teva “evaluate the necessity of daily [GA] injections as opposed to more infrequent intermittent administration of the drug,” because the daily dosing regimen subjected patients to an excessive amount of discomfort, if it is not necessary to maintain efficacy.

The Board first noted that Pinchasi disclosed every limitation of the independent claims of the Copaxone patents, except for the claimed dosing regimen. The Board found that there would have been a motivation to use a 40mg dose, crediting the testimony of Petitioners’ expert, Dr. Green, who noted that Pinchasi demonstrated increased efficacy of 40mg GA compared to 20mg with no significant difference in side effects, and cited a study which concluded that daily administration of 40mg GA was effective, safe, and well tolerated. In reaching this finding, the Board also found that FORTE, a phase III clinical trial comparing 40mg GA and 20mg GA, would not have taught away from using 40mg (as argued by Yeda), because it did not criticize, discredit, or discourage the 40mg GA dose.

The Board next considered whether there was a motivation to modify Pinchasi’s 40mg every other day regimen. The Board noted that the difference between the challenged claims (6 doses over 2 weeks) and Pinchasi (7 doses over 2 weeks) was only one less injection every two weeks. The Board had found motivation to eliminate one injection every other week to increase patient compliance, relying in part on Petitioners’ expert Dr. Green, who testified that decreasing the frequency of injections helps with patient adherence to the treatment regimen, and FDA’s 1996 SBOA, which recommended that the necessity of daily injections, as opposed to less frequent administration, be evaluated. The Board further relied on other prior art references, which showed that the alternate-day dosing of 20 mg was safe, well-tolerated, as effective as daily 20mg, reduced injection reactions, and that patients in the daily-injection group preferred less  frequent dosing. The Board also found Khan 2009 (not prior art) probative of the fact of motivation to investigate dosing regimen of GA with fewer injections to improve patient compliance. The Board then concluded that, in light of the evidence presented, a POSITA would have had a reason to modify Pinchasi’s dosing regimen of 40mg GA every other day to 40mg GA 3x/week, thus rendering the claimed 40mg 3x/week limitation obvious.

Regarding a non-prior art reference, Khan 2009, relied upon by the Board in the obviousness determination, the district court pointed out that the question was whether the Board could rely on non-prior art evidence in considering the knowledge, motivations, and expectations of a POSITA regarding the prior art.

The Federal Circuit (“the Court”) agreed that the Board properly relied on evidence other than just prior art in this case. The Board had recognized that non-prior art evidence of what was known “cannot be applied, independently, as teachings separately combinable” with other prior art, but “can be relied on for their proper supporting roles, e.g., indicating the level of ordinary skill in the art, what certain terms would mean to one with ordinary skill in the art, and how one with ordinary skill in the art would have understood a prior art disclosure.” The Court concluded that Khan 2009 was probative of the fact that those skilled in the art were motivated to investigate dosing regimen of GA with fewer injections to improve patient compliance.

On appeal, Yeda disputed the Board’s conclusion of obviousness by also arguing that the Board disregarded certain uncertainties associated with the fact that GA’s pharmacokinetic and pharmacodynamic (“pk/pd”) profile, mechanism of action, optimal dose, and active species were all unknown. Yeda cited to In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063 (Fed. Cir. 2012).

The Court clarified that in Cyclobenzaprine, “we held that bioequivalence alone could not establish obviousness because . . . ‘skilled artisans could not predict whether any particular PK profile, including a bioequivalent one, would produce a therapeutically effective formulation.” 676 F.3d at 1070.  However, in Cyclobenzaprine, “there were no prior art clinical studies to suggest what would be a therapeutically effective formulation. We do not read Cyclobenzaprine as establishing a rigid rule categorically precluding obviousness determinations without pk/pd data. Here, however, the Board committed no such error; the record is replete with prior art that would have taught or suggested a therapeutically effective formulation to a POSITA. The Board pointed to clinical studies that taught the effectiveness of 20mg daily (Copaxone® 20mg), 20mg every other day (Flechter, Khan 2008, Caon), and 40mg daily (Cohen, FORTE), and the Pinchasi application, which suggested that 40mg every other day would be therapeutically effective.

The Board’s finding that the uncertainty around GA’s mechanism of action would motivate a

POSITA to stick to dosing regimen with existing clinical support, such as 20mg and 40mg, is supported by substantial evidence from Dr. Green (Petitioner’s expert).” The Court concluded that because the expectation of success need only to be reasonable, not absolute, there was no error in these findings.

The Court found no hindsight in the Board’s analysis. “Here, far from a ‘sea of prior art,’ the references before the Board presented a finite and known pool of dose and frequency options easily traversed to show obviousness. The dosages in the prior art that had clinical support for being effective and safe consisted of only two: 20mg and 40mg. The prior art disclosed both daily and every other day administration, and the Board found a motivation for both less frequent

injections and a thrice-weekly regimen specifically.”  The Court found no clear error in the Board’s finding that the “[p]otent and promising activity in the prior art” would have encouraged a POSITA “to traverse the experimental options to produce this invention,” given the small field of prior art references with clinical support.

In light of the foregoing, the Court concluded that substantial evidence supported the Board’s reliance on the clinical data and its conclusion that a POSITA would have been motivated to combine Pinchasi’s 40mg every other day dose with a less frequent dosing regimen, such as 3x/week, and would have had a reasonable expectation of success in therapeutic effectiveness and patient compliance. Accordingly, the Court affirmed the Board’s finding that the 40mg GA 3x/week regimen was obvious in light of the prior art.

In a companion case that consolidated five district court cases (ANDA related litigation), Teva Pharmaceuticals USA, Inc. v. Sandoz Inc., No. 17-1575 (Fed. Cir. Oct. 12, 2018), collectively “Teva” and Yeda appealed the decision of the District Court for the District of Delaware invalidating all asserted claims of the patents directed to COPAXONE® 40mg/mL.  The Court of Appeals for the Federal Circuit affirmed.

Teva argued that the district court impermissibly relied on hindsight and an improper “obvious to try” analysis, and analyzed the obviousness of individual claim elements, rather than the invention as a whole. Teva also maintained that the district court’s decision was at odds with the  decision in In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation,

676 F.3d 1063 (Fed. Cir. 2012).

The Court again explained two categories of impermissible “obvious to try” analyses that run afoul of KSR and § 103: “when what was ‘obvious to try’ was (a) to vary all parameters or try every available option until one succeeds, where the prior art gave no indication of critical parameters and no direction as to which of many possibilities is likely to be successful; or (b) to explore a new technology or general approach in a seemingly promising field of experimentation, where the prior art gave only general guidance as to the particular form or method of achieving the claimed invention.” The Court distinguished the present case and said that it fell into neither of the two impermissible categories. “Here, the prior art focused on two critical variables, dose size and injection frequency, and provided clear direction as to choices likely to be successful in reducing adverse side effects and increasing patient adherence.”  The Court pointed out that only two GA dose sizes had been shown to be effective, safe, and well-tolerated (20mg and 40mg).  The Court agreed with the district court that cited prior art that encouraged to pursue a less frequent than daily dosing regimen. The district court properly relied on certain references that were not statutory prior art, as probative references that persons of skill in the art were interested in pursuing less frequent dosing regimens. “Given this motivation, a POSITA had only a limited number of permutations of dose and frequency to explore that were not already disclosed in the prior art.”

Teva further argued that the district court narrowed the universe of possible GA regimens and used hindsight. The Court disagreed because “the district court had ample evidence besides hindsight and the disclosures” on which to find a thrice-weekly dosing regimen of 40mg GA to be obvious to try. The Court explained that although the universe of potential GA doses was theoretically unlimited, the universe of dosages in the prior art that had clinical support for being effective and safe consisted of only two doses: 20mg and 40mg. “This is not a situation where the prior art gave no direction in how to reach a successful result; the prior art clearly indicated that less frequent doses should be explored” and that higher doses could increase efficacy while not affecting adverse reactions.  “We recognize that the prior art did not conclusively teach that a regimen of 40mg GA 3x/week would be effective. However, ‘[c]onclusive proof of efficacy is not necessary to show obviousness. All that is required is a reasonable expectation of success.’”

Teva also argued that prior to the invention, higher doses of GA were not necessarily known to be more effective, GA’s pharmacokinetic and pharmacodynamic (“pk/pd”) profile was and remains unknown, GA’s mechanism of action was still unknown, and the cause of patient’s reactions to injections of GA was unknown. Teva argued that the unpredictable nature of GA categorically precluded the obvious-to-try analysis employed by the district court.

The Court replied that “[w]e do not read Cyclobenzaprine as establishing a rigid rule categorically precluding obviousness findings without pk/pd data. Further, Cyclobenzaprine is distinguishable in that, there, the obviousness proof relied entirely on the bioequivalence of certain pharmacokinetic profiles. Bioequivalence is not argued here; instead, obviousness is proven through human clinical studies establishing the safety, efficacy, and tolerability of GA at

doses and dose frequencies similar to the claimed regimen. In this case, the evidence shows that pk/pd data was largely irrelevant to the invention. Numerous clinical studies in the prior art describe GA and its effects on the human body. Although the precise mechanism of GA is not known, it is known to be immunomodulating—i.e., it changes the immune system—and is not necessarily measurable in the bloodstream and its levels are not indicative of efficacy.

Testimony was given at trial that pharmacokinetic studies for drugs like GA are less appropriate than for small molecule drugs, such as those at issue in Cyclobenzaprine. GA was also known to be “forgiving,” in that occasional missed doses would not reduce efficacy, and that fact gave POSITAs further confidence in eliminating one dose every two weeks. Higher doses were clinically shown to be at least as effective as lower doses.”

The Court held that the existence of the studies showed a motivation to provide less frequent dose regimens and the 40mg GA 3x/week regimen was obvious in light of the prior art despite the argued lack of expectations of success, hindsight, and failure to follow the minimum effective dose principle. The Court found no clear error in the conclusion that a POSITA would have been motivated to combine the 40mg GA dose, which had proven efficacy, with a 3x/week frequency, which was desirable because the prior art indicated that less frequent administration increased patient adherence while maintaining efficacy.

***

Applicants should search not only for prior knowledge before the priority date, but monitor more recent developments and publications that could be used as probative evidence, e.g., to show motivation to try, a reasonable expectation of success, the level of a skilled artisan, the meaning of terms to one with ordinary skill in the art, and how one with ordinary skill in the art would have understood a prior art disclosure.