Unexpected result for combination therapy using two known drugs

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.

Summary:

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.

地裁は、2つの公知の薬物(repaglinideとmetformin)の併用による糖尿病治療方法の特許に関して予期せぬ効果は立証されなかったため無効であると判断した。連邦巡回区控訴裁判所(CAFC)はその特許無効判決を支持した。Metforminは同治療用として周知であり、repaglinideはmetforminとは異なる経路に作用するものとして糖尿病治療に利用されていた。先ず特許庁では、その併用は加算的な効果しかないとして審査官に拒絶されたが、出願人が追加実験データを提出することにより相乗効果が認められ特許になった。その後、侵害被疑者は地裁で新たな証拠を出した。それによるとrepaglinideと同じクラス(sulfonylureas)に属する同様の機能を有する化合物をmetforminと併用する療法が知られていた。他方、特許権者は、repaglinideはその文献に記載のsulfonylurea化合物とは異なること、特にmetforminとrepaglinideの併用はmetforminの単独使用と比較して空腹時血漿グルコースレベルを8倍も改善するという証拠を出した。しかしながら,地裁は侵害被疑者の証拠を採用し、特許無効の判決を出した。CAFCは、repaglinideとsulfonylurea類の併用が周知であり、ある種の相乗効果も報告されている点を強調し、地裁に同意し、特許権者の主張を退けた。特許権者の証拠によるとrepaglinide単独の特性から見て予想外な併用効果があることも示唆されるがCAFCは類似の併用療法が周知であるという全体的な方向性を見て、特許権者の具体的な反論を認めなかった。本件は、公知の薬物の併用はそれと類似の併用例が知られていると強い自明性の仮定が働き、特許権者はそれを克服するために相当に高いレベルの反証が要求されることを示す判決である。本件では、クレーム治療方法の商業的成功の証拠は不十分であるとして認められなかった。

なお、判事の一人(Newman)は、反対意見を述べている。化学的実験というものはある程度の予測、希望を持ってなされるものであり、そのような状況があるということで直ちに「自明な試み」として特許しないのはいかにも不合理であるといった趣旨である。特にrepaglinide自体は先行技術の化合物とは異なるにもかかわらず、repaglinideによる併用効果の発見は特許権者が公知の併用療法をさらに追求した結果にすぎないと示唆したことは、後知恵による判断であると非難した。

Details:

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.

(emphasis added)

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.

PTO procedure

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.

CAFC decision

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.

Dissent

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.”

Comments:

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.

Full Opinion

Patent At Issue

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