By Kevin E. Noonan --
Earlier this month, the Federal Circuit affirmed a District Court judgment of obviousness in ANDA litigation under the Hatch Waxman Act having a long provenance of earlier litigation, in Senju Pharmaceutical Co., Ltd. v. Lupin Ltd. The case involved patentee Senju Pharmaceutical's (joined by Kyorin Pharmaceutical Co. and Allergan, Inc.) suit against Lupin Ltd., Lupin Pharmaceuticals, and Hi-Tech Pharmacal in response to a Paragraph IV certification against Senju's patented ocular antimicrobial agent containing the drug gatifloxacin as claimed in re-examined U.S. Patent No. 6,333,045 and marketed under the brand name Zymar®. The patent claimed an ophthalmic formulation of the drug containing 0.01% (w/v) disodium edetate (EDTA) that improved delivery of the drug across the cornea of the eye.
In earlier litigation against Apotex (before the same U.S. District Court judge on the same patent), the generic formulation was found to infringe but the asserted claims were found invalid for obviousness. Thereafter, the patentee submitted a request for ex parte reexamination containing all of the art cited at trial. This resulted in cancellation of all but one of the claims asserted against Apotex and a reexamination certificate containing additional claims having limitations that overcame the grounds of obviousness found by the District Court.
Senju and co-plaintiffs filed the lawsuit that is the subject of this appeal against Lupin, asserting the re-examined claims against generic formulations comprising 0.5% w/v gatifloxacin and 0/3% w/v gatifloxacin. The District Court, keeping in mind its earlier obviousness determination (according to Senju) again invalidated the re-examined claims as being obvious while finding that if valid Lupin's generic formulation would infringe the re-examined claims.
The Federal Circuit affirmed, in an opinion by Judge Plager joined by Judge Moore, with Judge Newman dissenting. The opinion exhaustively set forth the arguments from both sides, the Court setting forth these arguments but little regarding the District Court's grounds for finding the claims obvious; claims 6 and 12 are as follows:
6. A method for raising corneal permeability of an aqueous pharmaceutical Gatifloxacin eye drop solution comprising Gatifloxacin or its salt, having a pH of from about 5 to about 6 containing from about 0.3 to about 0.8 w/v% Gatifloxacin or its salt, which comprises incorporating about 0.01 w/v% disodium edetate into [eye drops containing Gatifloxacin or its salt] said Gatifloxacin eye drop solution.
12. An aqueous liquid pharmaceutical eye drop solution which comprises from about 0.3 to about 0.8 w/v% Gatifloxacin or its salt, about 0.01 w/v% disodium edetate, and wherein the aqueous liquid pharmaceutical solution has a pH of from about pH 5 to pH 6.
(following the convention that the italicized portions of the claims were added during reexamination and the bracketed portions deleted).
The majority found Senju's arguments to be unavailing, specifically that the District Court had improperly included her earlier judgment concerning obviousness and thus lowered Lupin's burden for satisfying the clear and convincing evidence standard for invalidating the claims, and further not considering the limiting amendments made during reexamination. The opinion identified two primary arguments on the merits put forth by Senju: (1) the District Court erred by finding that the prior art taught using 0.01 w/v% EDTA in an ophthalmic formulation would work to increase corneal permeability; and (2) the District Court erred by finding appellants' proffer of evidence of unexpected results unavailing. Regarding the first argument, the Court considered the four prior art references asserted by Lupin (which were the same asserted by Apotex in the earlier litigation): "U.S. Patent Nos. 4,551,456 ("the '456 patent"), 4,780,465 ("the '465 patent"), and 4,980,470 ("the '470 patent"), and Grass 1985 [Effects of Calcium Chelating Agents on Corneal Permeability, 26 Investigative Ophthalmology & Visual Science 110 (1985)]." These references taught other examples of topical administration of quinolones (including norfloxacin and lomefloxacin) for treating bacterial infections in the eye, in formulations containing EDTA as a "conventional excipient" at 0.01 w/v% concentrations. One of the references, the '470 patent, taught that gatifloxacin was "an improvement over the prior art quinolones in that it exhibits a broader antibacterial activity, higher selective toxicity and safe oral and parenteral administration." And the Grace reference taught using EDTA to improve corneal permeability, albeit at concentrations much (~50-fold) higher than the 0.01 w/v% specified in the '045 patent's claims. However, the lower concentration (and its efficacy with regard to increased corneal permeability) was disclosed in additional references not earlier considered (including two additional Glass references, which showed concentrations of 0.1, 0.05, and 0.01 w/v% EDTA in quinolone formulations, and the Rojanasakul reference which showed enhanced corneal permeability even at EDTA concentrations of 0.00037 w/v%).
The Federal Circuit, like the District Court, also rejected Senju's argument that two additional references, the Mitra reference and the Kompella reference, supported their non-obviousness argument by teaching away from the combination of other references. The opinion further rejected Senju's argument that, because the references were published "at least eight years" prior to their earliest filing date their claims should not be considered obvious over these references (apparently taking the position that if their invention was obvious at its filing date the references would have motivated the skilled worker to combine them prior to that date). (The Court held that this argument had been waived for not being timely advanced by Senju at trial.) The Court also held that the enhanced corneal permeability limitation was not affirmatively recited in the composition of matter claims (claims 12-16) and thus any evidence of this property was "not relevant" to the asserted non-obviousness of these claims. And absent this limitation inclusion of EDTA was merely one of several "conventional ingredients" the inclusion of which in the claimed formulations was not sufficient to render them non-obvious.
Similarly, the Federal Circuit affirmed the obviousness of claim 6, the sole method claim on the basis that the Mitra and Kompella references did not teach away from the combination of references and this combination (of all the other references of record) supported the District Court's obviousness determination. Curiously the opinion states that "[w]hile both references find success at higher EDTA concentrations, they do not provide any indication that lower EDTA concentrations would not also work," which seems to put the evidentiary shoe on the wrong foot, particularly because Senju argued that the District Court did not properly consider these references. (In her dissent, Judge Newman states in this regard: "[a] reference need not foresee a later-discovered invention and warn against it, to teach away from the discovery," citing Spectralytics, Inc. v. Cordis Corp., 649 F.3d 1336, 1343 (Fed. Cir. 2011).) The opinion also discredits Senju's argument that the art did not show that EDTA was effective at concentrations of 0.01 w/v% based on teachings in the art of concentrations of this component of the claimed formulation that were 30-50-fold higher. The opinion cites with approval disclosure in the cited art that any amount of EDTA increased corneal permeability, even amounts showing no statistically significant increase over control. Finally, the opinion appears to defer to the District Court's crediting of Lupin's witnesses over Senju's (not heretofore mentioned in the opinion) to support its decision affirming the obviousness determination below.
The Federal Circuit approved of the District Court's disregard for evidence of unexpected results put forward by Senju, on the grounds that the results were "a product of routine optimization that would have been obvious to one of skill in the art," again deferring to the credibility determinations of the District Court (and despite the same evidence having been considered sufficient to overcome an obviousness rejection during the re-examination, i.e., under a much lower evidentiary burden). In view of the higher burden at trial, the following statement in the opinion seems somewhat baffling:
We further conclude that the district court properly applied a presumption of validity, considering both the evidence of obviousness and the evidence of unexpected results, to find that appellees set forth clear and convincing evidence of invalidity in this case. See Sciele Pharma Inc., 684 F.3d at 1260. We agree that it was not clear error for the district court to conclude that the unexpected results evidence that Senju relied upon during reexamination,  did not withstand scrutiny by Lupin's experts and the district court. Ultimately, the district court properly concluded that the theories presented during reexamination proved too weak when challenged in a judicial forum to rise to the level of unexpected results sufficient to rebut a strong case of obviousness. See Proctor & Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009).
Judge Newman dissented, based on her perception that neither the District Court nor the panel majority showed proper deference to the presumption of validity for the re-examined claims and her belief that both judicial bodies misinterpreted the teachings of the cited art.
She states her understanding of the law of obviousness: "[o]bviousness is a matter of foresight, not hindsight. A determination of obviousness requires some reason or suggestion, in the prior art or in common sense, that the claimed subject matter is likely to be effective for its intended purpose," citing KSR Int'l Corp. v. Teleflex Inc., 550 U.S. 398, 420–22 (2007), and that here the evidence of record was that the art taught away from the method claimed in claim 6 as issued in the reexamination certificate. She also cites Daubert v. Merrell Dow Pharm., Inc., for the proposition that a court must not give unsupported expert testimony greater weight than the experimental data set forth in the cited art. 509 U.S. 579, 589 (1993). She asserts that "[t]he published contemporaneous statements of scientists interpreting their experiments warrant more weight than unsupported opinions appearing for the first time in litigation" and that the District Court improperly dismissed Senju's expert's testimony because he did not use "statistical analysis" to show the significance of the data supporting non-obviousness in the '045 patent specification. This failure was not enough for either the District Court or the panel majority to disregard this expert's opinion, according to Judge Newman, because "[w]ith the exception of Lupin's expert witnesses, those skilled in the art interpreted Senju's experiments as demonstrating unexpected results."
Senju Pharmaceutical Co., Ltd. v. Lupin Ltd. (Fed. Cir. 2015)
Panel: Circuit Judges Newman, Plager, and Moore
Opinion by Circuit Judge Plager; dissenting opinion by Circuit Judge Newman