In a case closely watched by the biotech and pharmaceutical industries, Merck KGaA v. Integra Lifesciences I, Ltd., the Supreme Court recently held that Section 271(e)(1) of the Patent Act permits researchers to study patented compounds – without the patent holders’ permission – where (a) researchers have a reasonable basis for believing that the patented compounds will be effective, and (b) the results of such research, if successful, would be appropriate to include in an FDA submission (such as an investigational new drug application or a new drug application). 

In so ruling, the Court expanded Section 271(e)(1)’s “safe harbor” to protect not only studies that directly generate information required under the Federal Food, Drug, and Cosmetic Act, but also to investigational research which may neither lead to an FDA application nor be expressly required under law.  In clarifying Section 271(e)(1)’s scope, however, the Court left open important questions about the application of its standard to the case at hand and to the use of inventions other than “patented compounds.”

At issue in Merck v. Integra were five Integra patents covering a specific tripeptide sequence (identified as the “RGD peptide”). During the course of a protracted effort by Integra (and its predecessor) to license the RGD peptide to Merck, a Scripps Research Institute scientist published findings indicating that Integra’s RGD peptide inhibited angiogenesis, the process by which new blood vessels grow out of existing ones. 

Potentially effective in the treatment of tumor growth, diabetic retinopathy, rheumatoid arthritis and psoriasis, Merck promptly sponsored further research by Scripps into the RGD peptide without Integra’s permission. The results were studies into the peptides’ efficacy, specificity, toxicity, mechanism of action and pharmacokinetics as well as the development of two RGD peptide derivatives, one of which was ultimately chosen as a clinical development candidate. Despite sponsoring this extensive research into the RGD peptide, Merck eschewed obtaining a license under Integra’s patent rights.  

Integra eventually filed suit, claiming that Merck’s sponsorship of Scripp’s research activities infringed its patent rights under the RGD peptide. Merck answered by asserting, among other things, that its sponsored research was protected under Section 271(e)(1), which states that:

“It shall not be an act of infringement to make [or] use … a patented invention … solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs …”

The jury sided with Integra, and following an unsuccessful motion with the District Court, Integra appealed to the Federal Circuit. The Appeals Court denied Merck’s Section 271(e)(1) appeal on the grounds that Merck’s sponsored research “did not supply information for submission to the [FDA], but instead identified the best drug candidate to subject to future clinical testing under the FDA process.” The research “was not clinical testing to supply information to the FDA, but only general biomedical research to identify new pharmaceutical compounds.” Merck appealed to the U.S. Supreme Court.

The Supreme Court was careful not to decide whether or not Merck’s activities qualified for Section 271(e)(1)’s safe harbor. Rather, the Court held that the Federal Circuit applied the wrong standard in reviewing Merck’s activities. According to the Court, the central inquiry in applying Section 271(e)(1) is whether or not use of the RGD peptide was “reasonably related to the development and submission of information” to the FDA. The Federal Circuit erred, the Court suggests, by focusing too much on the distinction between pre-clinical and clinical research.  As the Court pointed out, the language of 271(e)(1) does not distinguish between clinical and pre-clinical research.  Furthermore, because the FDA requires both clinical and pre-clinical research during the course of approving a drug, 271(e)(1) must be read to permit both kinds of research.

The Court held that the appropriate standard focuses on the extent to which Merck’s research was “reasonably related” to an FDA filing, which the Court delineated with a two-step test: “As least where a drugmaker has a reasonable basis for believing that a patented compound may … produce a particular physiological effect, and uses the compound in research that, if successful, would be appropriate to include in a submission to the FDA, that use is ‘reasonably related’ to the ‘development and submission of information under … Federal law.’”

In remanding the case for further proceedings, the Court left open a number of questions.  First, the Court’s standard suggests a fairly bright line between when a researcher does and does not have “a reasonable basis for believing that a patented compound” will work.  But what level of confidence does a researcher require to satisfy this standard? Would an educated guess or conjecture suffice? There is a lot at stake in arriving at the correct answer.

Second, although dicta suggest a wide berth allowing uses of patented compounds studies which, “if successful, would be appropriate to include in a submission to the FDA,” it does not discuss treatment of studies that have overlapping applications, such as the development of derivative compounds. Indeed, although the Court exhaustively discusses 271(e)(1)’s “reasonably related” language, it does not discuss the import of the word “solely” in 271(e)(1)’s proscription that the use of patented inventions must be “… solely for uses reasonably related to the development and submission of information” to the FDA.

Finally, the Court’s focus on “patented compounds,” despite 271(e)(1)’s express reference to “patented invention[s],” casts uncertainty as to whether the Court anticipates a separate “reasonably related” standard for inventions that are not compounds. This concern is highlighted in the case of so-called “research tools,” which are used in the discovery and/or development of a compound, but will not be referenced in any FDA application.  Although the Court explicitly states that it “need not – and do[es] not – express a view about whether, or to what extent, §271(e)(1) exempts form infringement the use of ‘research tools’ in the development of information for regulatory purposes,” there is nothing in the text of 271(e)(1) or the Court’s opinion that rationalizes treating research tools any differently than “patented compounds” or any other “patented invention.” Consequently, the decision is less than sanguine news for licensors of research tools who sought a clear statement exempting their use from 271(e)(1)’s ambit.

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Stanton J. Lovenworth is head of IP transactions and technology at Dewey Ballantine LLP.  Email: slovenworth@deweyballantine.com. Riyad A. Omar (associate, intellectual property) and Melissa Cohen (associate, intellectual property) also contributed to this article.