Yoshiya Nakamura | July 24, 2013
Novo Nordisk A/S v. Caraco Phamaceutical Laboratories, Ltd.
June 18, 2013
Panel: Newman, Dyk and Prost. Opinion by Prost. Dissent by Newman.
A patent claims a combination therapy using two drugs. The patent was issued by overcoming prior art as an examiner recognized an unexpected result proved by an inventor’s declaration. In the district court, defendant presented new evidence challenging the validity of the patent. The evidence showed that one of the claimed drugs was well known to be used in the therapy, and another drug having similar mechanism as the other was also well known to be used in such combination therapy. Relying on the evidence, the district court hold that the patent was obvious because the evidence created a strong prima facie case of obviousness, and it was so strong that the patentee’s evidence showing certain superior effects did not overcome the prima facie obviousness. The majority agreed with the district court holding. Judge Newman dissented.
USP 6,677,358 claimed a therapeutic method for Type II diabetes (the non-insulin dependent diabetes mellitus (NIDDM). This occurs due to the body secretion of insulin at an insufficient level and the body resistance to the effects of insulin.
A claim at issue is:
Claim 4: 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.
Repaglinide is secretagogue which stimulates insulin release from pancreatic cells. This is one of the drugs in the class named sulfonylureas. There are fifteen known secretagogues, but only a handful of these were generally used in treating Type II diabetes. However, this drug has been known as rapid short-acting insulin secretagogue. It can be quickly eliminated from the body.
Metformin is the most widely-used insulin sensitizer, which reduces insulin resistance and improves insulin sensitivity in muscle and fat tissues.
Initially, Novo found that the combined use of repaglinide and metformin was about twice effective than monotherapy using either of the drugs. However, they also found that the combination therapy was eight times more effective in reducing FPG (fasting plasma glucose) levels than metformin alone, even though repaglinide was previously considered to have no effect on FPG due to its short-acting tendencies.
During prosecution, the examiner rejected the claim as obvious to try, by stating that “it was also predictable that the combination would yield, at a minimum an “additive” effect. In order to show a synergistic effect, Novo drew the examiner’s attention to a specific example and finally submitted a declaration demonstrating additional study conducted by Novo’s scientist, in which he calculated a “hypothetical additive effect” of the two drugs and showed that the combination therapy was more effective than the “hypothetical additive effect” of the two drugs. Then, the examiner allowed the claim.
District court decision
Caraco presented evidence, including some prior art and testimony never before the examiner. They indicated that earlier metformin/ other sulfonylurea combinations were generally understood to yield synergy. Based upon this evidence, Caraco argued that artisans would have expected repaglinide to be likewise synergistic when combined with metformin.
In response, Novo provided evidence indicating that repaglinide was known to be a short-acting insulin secretagogue, different from the longer-acting sulfonylureas in Caraco’s prior art. Novo specifically relied on a study which showed that repaglinide in monotherapy had no impact upon patient FPG. Based upon this study, Novo argued that “an artisan would have been very surprised when repaglinide/metformin proved to be eight times more effective in reducing FPG levels than metformin alone.”
The district court concluded that Caraco’s prior art predicted the result in the Novo’ study, by applying the following reasoning:
(1) the closest prior art indicates combination therapy using metformin and a drug from a sulfonylurea class;
(2) the combination therapy 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 CAFC agreed with the district court analysis, by holding:
Caraco set forth a prima facie case that it was obvious to try combination therapy using metformin and repaglinide to treat Type II diabetes…It 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… Combination 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.
The CAFC concluded that it was 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.
Regarding the record in the prosecution of the patent at issue, the CAFC pointed out that the repaglinide/metformin study in the specification showed generally inferior results. Regarding the declaration from Novo’s scientist submitted in the prosecution, the CAFC stated that there was no clear error for the district court to find that the results were expected, given that the conclusions in the declaration mirror the conclusions drawn in Caraco’s new sulfonylurea prior art.
Judge Newman criticized the majority’s conclusion of obviousness, by stating that the finding that “[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” does not mean “obvious to try.” She further commented that the district court held that since these inventors pursued this combination, it was obvious to do so, and this is a misunderstanding of the law, for “[o]bviousness may not be established using hindsight or in view of the teachings or suggestions of the inventor.”
She further pointed out that some other combinations of metformin and a type of sulfonylurea, which does not include repaglinide, “may or may not have a synergistic effect, and that repaglinide is not chemically similar to the sulfonylureas.” She also noted that “[a]ll scientific experiments are conducted with a purpose of inquiry, and all experimenters have a theory of possible outcomes. Such experiments may partake of varying degrees of vision, hope, or expectation on the part of the experimenter, but these are not criteria of patentability.”
An issue of unexpected results is determined on case by case analysis relying largely on facts. In this case, the specific types of drugs were claimed and proved to have quite specific results (eight times in improving FPG levels). However, the CAFC framed underlying facts as the inventors following a general knowledge or guidance for known metformin/other sulfonylurea combinations, and determined that it was obvious to try.
You may agree or disagree since this seems to be a borderline case. As pointed out by Judge Newman, the ordinary course of study in the medicinal field mostly relies on some expectations such as vision or hope, and in most cases, they must have appeared somewhere in the field as the knowledge of artisans including inventors. Even highly-impacting discoveries would be a result of following some expectation or hope for it to happen. In general, nobody invests on something completely unexpected, and this may be true for the study on discovery and commercialization of drugs. The majority opinion set a higher threshold for an unexpected result, by requiring “almost completely” unexpected results, where there seems somewhat a “strong” prima facie case and no commercial success is found.