Novo Nordisk v. Caraco Pharm. Labs., No. 2011-1223 (Fed. Cir.)
In its third trip to the Federal Circuit, the court on Tuesday affirmed a decision holding claim 4 of Novo's U.S. Patent No. 6,677,358 invalid as obvious. Claim 4 of the '358 patent, listed in the Orange Book for PRANDIN (repaglinide) tablets, is directed to "[a] method for treating non-insulin dependent diabetes mellitus (NIDDM) comprising administering to a patient in need of such treatment repaglinide in combination with metformin." This is the same case in which the Supreme Court decided last year that a "delisting counterclaim" may be used to force amendment of an Orange Book use code.
The Federal Circuit's opinion on Tuesday was authored by Judge Prost and joined by Judge Dyk. Judge Newman dissented in a pointed opinion. The court also unanimously reversed the district court's finding that the '358 patent is unenforceable due to inequitable conduct.
The case revolved around the three bases that Novo advanced for reversal of the district court's finding of obviousness--two of which (incorrect burden shifting to the patentee and lack of deferral to fact-finding by the USPTO) were quickly dispatched by the court. But on the third basis for reversal--that Caraco's evidence insufficiently supported the district court's ultimate obviousness finding, the judges divided sharply on their interpretation of the record.
The majority based its affirmance of obviousness on the district court's reasoning that:
1. the closest prior art [to the repaglinide/metformin combination] was combination therapy using metformin and a sulfonylurea;
2. combination therapy using metformin and one of the sulfonylurea class of secretagogues was well known in the art to produce beneficial and even synergistic results in controlling glucose levels in Type II diabetes patients; [and]
3. repaglinide was known as an insulin secretagogue having a similar mechanism of action to the sulfonylurea class of secretagogues.
These findings outweighed Novo's evidence, both before the USPTO and during litigation, that the combination of repaglinide and metformin is, unexpectedly, eight times more effective in reducing fasting plasma glucose ("FPG") levels than metformin alone and despite repaglinide having no impact on FPG.
The majority explained away the allegedly unexpected effect of repaglinide/metformin on FPG by noting that "[r]epaglinide and sulfonylureas are both insulin secretagogues, and they therefore have a 'similar mechanism of action'" and that "the prior art taught that metformin could be combined with certain sulfonylureas which were, like repaglinide, short-acting secretagogues." In particular, the court noted that prior art proffered by Caraco "report[ed] that metformin/sulfonylurea combinations yielded an 'apparent synergistic effect' and 'appear[ed] to have a synergistic effect'."
The court further picked apart Novo's evidence of unexpected results by noting that (1) the same study that found the reduction in FPG (the "Moses Study"), also showed that the near-term and long-term benefits of repaglinide/metformin "were generally inferior to the results found by prior art studies involving metformin combined with sulfonylureas"; (2) Novo's expert, Dr. Sturis, felt that the Moses Study had not mathematically or scientifically proven the existence of synergy; (3) Dr Sturis' own repaglinide/metformin study only "strongly suggest[ed]" synergy; (4) Novo's final study (Pfeiffer), showing a 35% improvement in insulin sensitivity in repaglinide/metformin combination therapy over metformin alone, had questionable reliability due to its small sample size, or results that were "explained away" by Pfeiffer in a contemporaneous report as predictable in view of the prior art; and (5) certain other tests on drug-naïve patients either did not "consistently" show a synergistic effect on FPG or did not "show statistically better results than the drugs used in monotherapy."
On these bases, the court concluded that "it is reasonable that an artisan seeking to combine a known insulin sensitizer (like metformin) with a new insulin secretagogue (like repaglinide) would base his expectations upon prior art sensitizer/secretagogue combinations." In fact, the Court found that it was "not erroneous . . . to conclud that the prior art predicted the results" of the combination of repaglinide and metformin on FPG.
Judge Newman begged to differ from her colleagues' "erroneous view of the evidence and incorrect application of the law of obviousness." In her view, the panel majority's generalization that "earlier metformin/sulfonylurea combinations were generally understood to yield synergy," was inaccurate. Rather, only some sulfonylureas formed synergistic combinations, but "synergism was not a general property of the combinations." According to Judge Newman, "it was well-known that not all insulin stimulants form synergistic combinations with metformin."
Focusing on the district court's selection of the combination of metformin-glyburide to invalidate the '358 patent, Judge Newman noted the substantial differences between repaglinide and glyburide, including the substantial structural differences between the two and the fact that the latter is a long-lasting insulin secretagogue while repaglinide is a short-lasting secretagogue. In order to provide a more equal comparison from which to draw reasonable expectations, Judge Newman suggested that "a more reasonable analysis would consider metformin in combination with nateglinide, which is structurally similar to repaglinide, or a shorter-acting sulfonylurea such as glipizide." That is, "the 'closest prior art' is the reference having the most 'in common' with the claimed invention, not the reference that happens to describe the most impressive results."
Reacting to the majority's dissection of Novo's evidence of unexpected results, Judge Newman reminded the majority that, "[t]o be patentable, a compound need not excel over prior art compounds in all common properties." Rather, one must look to whether the claimed combination "would produce results superior to the additive effect of the components separately." On a record where it was not shown that glyburide was an effective synergist in combination with metformin, Judge Newman could not conclude that repaglinide would be expected to be an effective synergist. Ultimately, for Judge Newman, "[t]he synergy demonstrated by Novo for the metformin-repaglinide combination therapy was not predicted or predictable, and was not obvious."