July 2013
Combination of Drugs Was Obvious to Try When Synergistic Results Were Predictable
| Judges: Newman (concurring-in-part and dissenting-in-part), Dyk, Prost (author) |
| [Appealed from E.D. Mich., Judge Cohn] |
In Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd., No. 11-1223 (Fed. Cir. June 18, 2013), the Federal Circuit found no error in the district court’s finding that the synergistic effects of two Type II diabetes treatments were predictable, thereby rendering the combination obvious. Accordingly, the Court affirmed the district court’s holding that claim 4 of U.S. Patent No. 6,677,358 (“the ’358 patent”) was invalid. The Court also reversed the district court’s holding that the ’358 patent is unenforceable based on inequitable conduct.
Type II diabetes can be treated with orally administered antidiabetic drugs (“OADs”). Two types of OAD classes at issue in the appeal were insulin secretagogues and insulin sensitizers. Insulin secretagogues work by stimulating insulin release from pancreatic beta cells. Insulin sensitizers reduce insulin resistance by acting on the liver to reduce glucose production and thereby improve insulin sensitivity in muscle and fat tissues. Novo Nordisk A/S and Novo Nordisk Inc. (collectively “Novo”) developed repaglinide, a rapid and short-acting insulin secretagogue. Soon after, Novo conducted a clinical trial (“the Moses Study”) to assess whether the combination of repaglinide and metformin, a well-known insulin sensitizer, would be more effective than repaglinide alone. The study showed that, when given the combination of repaglinide and metformin, the fasting plasma glucose (“FPG”) levels of patients decreased eight times lower than what was typically achieved by metformin alone. This was surprising, because repaglinide on its own actually tended to increase a patient’s FPG levels. Therefore, the scientists concluded that the combination therapy yielded a synergistic effect (instead of an additive effect), because the effect of the combination exceeded the sum of the separately administered effects.
During prosecution of the application that resulted in the ’358 patent, the examiner rejected the application four times, asserting that the combination therapy would have been obvious to try and that the benefit—specifically, an additive effect from taking both drugs—was predictable. In response, Novo submitted the declaration of Dr. Sturis, a Novo scientist, that presented results of an additional study in obese rats (“Sturis Study”) that, when combined with the Moses Study, demonstrated a synergistic effect of repaglinide/metformin combination therapy. Based on this declaration, the PTO issued the ’358 patent.
Novo listed the ’358 patent in the Orange Book entry for repaglinide. In 2005, Caraco Pharmaceutical Laboratories (“Caraco”) filed an ANDA seeking approval to market a generic version. Caraco’s ANDA included a certification that the ’358 patent was invalid or would not be infringed by selling Caraco’s proposed product. In response, Novo sued Caraco, alleging infringement of claim 4 of the ’358 patent. Caraco counterclaimed, asserting, inter alia, that claim 4 would have been obvious and that the ’358 patent is unenforceable. After a bench trial, the district court agreed with Caraco on both of those claims. In so doing, the district court considered Novo’s argument that the degree of synergistic effect was surprising and unexpected, but ultimately found this argument unpersuasive. Thus, the district court held that Caraco had proven the obviousness of claim 4 by clear and convincing evidence.
On appeal, the Federal Circuit first addressed the district court’s obviousness ruling, which Novo challenged on three grounds. First, Novo argued that the district court misallocated the burden of persuasion by forcing Novo to overcome Caraco’s “prima facie” case of obviousness with evidence of unexpected results. Second, Novo argued that even if the burdens were properly allocated, Caraco’s evidence insufficiently supported the district court’s ultimate obviousness findings. Finally, Novo believed that the district court should have deferred to the examiner’s original finding that the Sturis and Moses Studies demonstrated unexpected synergy.
“Nothing in the court’s opinion in this case indicates that it reached a premature conclusion on obviousness. To the contrary, after considering the prima facie evidence ‘[b]ut before reaching the ultimate conclusion on the issue of obviousness,’ the court thoroughly evaluated all evidence of unexpected synergy and commercial success.” Slip op. at 13 (alteration in original).
The Federal Circuit rejected Novo’s contention that the district court misallocated the burden of persuasion, and declined to reverse on this basis. The Federal Circuit concluded that Novo misinterpreted the role of the burden of persuasion in patent infringement litigation. The Court explained that, although the burden of persuasion remains with the challenger during litigation based on the presumption of validity, “the presumption of validity does not relieve the patentee of any responsibility to set forth evidence in opposition to a challenger’s prima facie case which, if left unrebutted, would be sufficient to establish obviousness.” Slip op. at 11. Thus, the patentee has two advantages: (1) only the burden of production shifts to the patentee after the challenger makes a prima facie case, and (2) the burden of persuasion by clear and convincing evidence remains with the challenger throughout the litigation.
The Federal Circuit found nothing in the district court’s opinion to indicate that it reached a premature conclusion on obviousness. To the contrary, after considering the prima facie evidence but before reaching the ultimate conclusion on the issue of obviousness, the district court thoroughly evaluated all evidence of unexpected synergy and commercial success. It then concluded that, in view of all of this evidence, Caraco had shown by clear and convincing evidence that the combination was obvious. The Court also found that the district court did not invalidate claim 4 due to Novo’s failure to prove unexpected results, as Novo alleged. Rather, the district court found that Caraco had established by clear and convincing evidence that the results of the claimed combination therapy were expected and explainable in light of the state of the art as of the critical date.
The Federal Circuit then reviewed the district court’s findings and concluded that it was not erroneous for the district court to conclude that the prior art predicted the results found in the Moses and Sturis Studies. Specifically, the Federal Circuit considered the following findings: (1) the closest prior art was combination therapy using metformin and a sulfonylurea, which is another type of insulin secretagogue; (2) that prior art combination therapy was well known to produce beneficial and even synergistic results; and (3) repaglinide was known to be an insulin secretagogue having a similar mechanism of action to the sulfonylurea class of secretagogues, including some short-acting sulfonylurea secretagogues.
The Court next turned to Novo’s third challenge to the district court’s obviousness determination—that the district court should have deferred to the PTO’s findings that the Moses and Sturis Studies demonstrated synergy. In support of this argument, Novo relied on the recent holding in Kappos v. Hyatt, 132 S. Ct. 1690, 1696 (2012). There, the Supreme Court held that, in cases involving district court review of PTO rejections under 35 U.S.C. § 145, new evidence may be considered and that district courts should not defer to PTO factual findings that are contradicted by the new evidence. The Federal Circuit found that Hyatt had no relevance because, here, there was no challenge to a PTO rejection under § 145. Moreover, the Court explained that initial determinations by the PTO in determining whether to grant the application are entitled to no deference in district court infringement proceedings. For these reasons, the Federal Circuit affirmed the district court’s obviousness finding.
Next, the Federal Circuit addressed the inequitable conduct determination. Caraco argued that the Sturis declaration and certain representations made by Novo’s prosecution counsel, Dr. Bork, constituted inequitable conduct. In particular, Caraco challenged Dr. Sturis’s failure to tell the PTO that certain of his reported test results had not been part of his original test protocol. Caraco also challenged Dr. Bork’s assertion during prosecution that Dr. Sturis’s data provided clear evidence of synergy and his failure to disclose certain e-mails that refuted that statement. Because the district court’s decision issued before the Federal Circuit issued its en banc decision in Therasense, Inc. v. Becton, Dickinson & Co., 649 F.3d 1276 (Fed. Cir. 2011) (en banc), the district court had held the ’358 patent unenforceable under either the pre-Therasense or post-Therasense test for materiality and intent. On appeal, Novo argued that the underlying facts were not material under the post-Therasense but-for standard. The Federal Circuit agreed.
Dr. Sturis was accused of failing to notify the PTO that the original test plan did not include his data calculations at 120 minutes. The Federal Circuit found it to be a nonmaterial omission because it did not qualify as “but-for” material. The Court explained that this was not a case in which adverse results were hidden in favor of more positive data, nor did the omission undermine the opinion stated in the declaration. The Court also found that Dr. Bork’s statements during prosecution were not material. Important in this determination was that Dr. Bork referred to Dr. Sturis’s test results as “evidence” rather than “proof.” Therefore, the Federal Circuit reversed the district court’s materiality and inequitable conduct findings with regard to both Dr. Sturis and Dr. Bork. The Court did not reach the issue of intent.
Judge Newman, dissenting-in-part, agreed with the majority that neither Dr. Sturis nor Dr. Bork engaged in inequitable conduct, and concurred in the judgment reversing the district court’s ruling in that respect. However, in Judge Newman’s view, Novo’s discovery of the synergistic combination of metformin and repaglinide meets the criteria of patentability, and was incorrectly held to be unpatentable on the ground of obviousness under 35 U.S.C. § 103. Judge Newman noted that “[t]he question is not whether it would have been obvious to look for synergistic combinations; the question is whether it was obvious that the combination of metformin and repaglinide would exhibit synergism and that the combination would be 800% more effective than the additive effect of the components separately.” Newman Concurrence-in-Part and Dissent-in-Part at 2. Judge Newman was persuaded by the evidence that the PTO granted the ’358 patent based on the synergistic effect that the inventors discovered and established, and that this activity was not suggested in the prior art, was not predictable, and was not obvious.
