In its third look at the Novo Nordisk A/S patent related to Prandin®, in Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories Ltd., the Federal Circuit affirmed the district court’s finding that claim 4 of U.S. Patent No. 6,677,358 is invalid as obvious, but reversed the district court’s finding that the patent is unenforceable due to inequitable conduct. This decision illustrates both the difficulty of sustaining a patent based on unexpected results and the difficulty of invalidating a patent based on inequitable conduct.

The Patent at Issue

The patent at issue in this case is U.S. Patent No. 6,677,358, which is listed in the FDA’s Orange Book for Novo Nordisk’s Prandin® repaglinide product. Claim 4 recites 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.”

As summarized by the Federal Circuit, “Type II diabetes can be treated with orally administered antidiabetic drugs (“OADs”) in the form of monotherapy (a single OAD) or combination therapy (more than one OAD).” The drug repaglinide is an insulin secretagogue that works by stimulating insulin release from pancreatic beta cells, while the drug metformin is an insulin sensitizer that reduces insulin resistance by acting on the liver to reduce glucose production and thereby improve insulin sensitivity in muscle and fat tissues. The patent at issue arose from Novo Nordisk’s discovery that combination therapy with both repaglinide and metformin achieved better results than monotherapy with either drug.

The District Court Decision

Caraco filed an Abbreviated New Drug Application in 2005, seeking FDA approval to market a generic version of Prandin®. Caraco’s ANDA included a Paragraph IV certification asserting that the ’358 patent was invalid or would not be infringed by its product. In response, Novo Nordisk brought suit under the Hatch-Waxman patent litigation framework, asserting claim 4 of the ’358 patent. Caraco filed a counterclaim asserting invalidity and unenforceability. The district court conducted a bench trial, and held claim 4 invalid as obvious and that the patent was not enforceable because of inequitable conduct. Novo Nordisk appealed.


The parties did not dispute the district court’s finding that Caraco had presented a prima facie case that “it was obvious to try combination therapy using metformin and repaglinide to treat Type II diabetes.” In particular, “[i]t was apparently well-known in the art that two drugs having different mechanisms for attacking diabetes may be more effective than one, and so drugs were often tested in combination therapy after demonstrating effectiveness in monotherapy.” Moreover, “[c]ombination therapy using insulin sensitizers and insulin secretagogues was common at the time, and metformin was the most widely-used insulin sensitizer as of the ’358 patent’s filing date.” Thus, the issue before the court was whether the combination therapy achieved surprising and unexpected results, such as “synergistic” results.” The district court found that it did not.

On appeal, Novo Nordisk lodged three main challenges to the district court decision, but the Federal Circuit was not persuaded by any of them.

First, Novo Nordisk asserted that “the district court misallocated the burden of persuasion in this case by forcing Novo to ‘overcome’ Caraco’s ‘prima facie’ case of obviousness with evidence of unexpected results.”

However, the Federal Circuit found that the district court properly had applied the presumption of validity by requiring Caraco to come forward with evidence of invalidity in the first instance. Only after finding “that Caraco’s prima facie evidence, if unrebutted, would be sufficient to establish that the repaglinide/metformin combination was obvious to try, and that a person of ordinary skill in the art would have reasonably expected the combination would yield success in the form of beneficial, and even synergistic, results” did the district court “consider whether Novo’s countervailing secondary consideration evidence of unexpected synergy (i.e., its “attempt to prove unexpected results”) was sufficient to ‘overcome’ Caraco’s prima facie case. Further, after evaluating “all evidence of unexpected synergy and commercial success,” the district court “concluded that … Caraco had shown by clear and convincing evidence that the combination was obvious.”

Second, Novo argued that “even if the burdens were properly allocated in this case, Caraco’s evidence insufficiently supported the court’s ultimate obviousness findings.”

The Federal Circuit disagreed. Novo Nordisk’s position was based on unexpected results vis-à-vis “repaglinide’s known efficacy in monotherapy.” In contrast, the district court’s analysis followed a three-step reasoning:
(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.
The Federal Circuit found no error in the district court’s analysis:

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.

Third, Novo urged that “the district court should have deferred to the examiner’s original finding that the Sturis and Moses studies demonstrated unexpected synergy.”

This argument was based on the recent Supreme Court decision in Kappos v. Hyatt, which the Federal Circuit found “has no relevance here.” As explained by the court, “the initial determinations by the PTO in determining to grant the application are entitled to no deference as they would be in an appeal to this court under 28 U.S.C. § 1295(4)(A) or (absent new evidence) in a district court proceeding under 35 U.S.C. § 145. Rather, we treat the issued patent as having a presumption of validity that must be overcome by clear and convincing evidence. No decision of the Supreme Court or this court has ever suggested that there is an added burden to overcome PTO findings in district court infringement proceedings. … Neither are we persuaded that the presence or absence of PTO findings on particular issues affects the basic presumption of validity.”

Having rejected Novo Nordisk’s challenges to the district court decision, the Federal Circuit affirmed the district court’s finding of obviousness.

Inequitable Conduct

Caraco’s inequitable conduct charges stemmed from statements and omissions in two expert declarations that had been submitted to the USPTO during prosecution of the ‘358 patent as evidence of unexpected results and the synergistic effect of the combination therapy. The district court found that the statements and omissions were “but for” material under the Federal Circuit’s en banc decision in Therasense because the USPTO examiner had relied upon the declarations when deciding to withdraw the obviousness rejections. The Federal Circuit disagreed.

Although the court found that some of the statements and omissions at issue were “troubling,” it could “not see how [the] omissions qualify as ‘but for’ material.” The court emphasized:

This is not a case where a declarant hid adverse test results from the PTO in favor of more promising data selected post hoc.… Nor is this a case where the declarant’s omission expressly undermined his stated opinion. To the contrary, even after taking the omitted test protocol into account, the court specifically found that Dr. Sturis’s conclusions on synergy had not been shown to be false.

Having found that the materiality prong of the inequitable conduct test was not satisfied, the Federal Circuit reversed the finding of inequitable conduct.

Speaking of Therasense, is the USPTO ever going to revise its guidance on the Duty of Disclosure to take this case into consideration?

The Back Story

Please see this article for a discussion of the Supreme Court decision which held that 21 USC § 355(j)(5)(C)(ii)(I) provided Caraco with a mechanism for challenging the use code that Novo Nordisk had provided in its Orange Book listing for Prandin®.

Please see this article for a discussion of the Federal Circuit decision which revised the district court’s injunction requiring Novo Nordisk to replace the original use code with specific language.