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FDA “Safe Harbor” Provision Applied to Experiments Not Ultimately Submitted to the FDA

July 27, 2007

Decision icon Decision

Last Month at the Federal Circuit - August 2007

Judges: Newman (author), Rader (dissenting-in-part and concurring-in-part), Prost

[Appealed from: Sup. Ct.]

In Integra Lifesciences I, Ltd. v. Merck KGaA, Nos. 02-1052, -1065 (Fed. Cir. July 27, 2007), the Federal Circuit reversed the district court’s judgment of infringement, holding that no reasonable jury could find other than that the accused activities were within the FDA Exemption under 35 U.S.C. § 271(e)(1) and rendering JMOL in favor of Merck KGaA (“Merck”).

The subject patents, owned by Integra Lifesciences Corporation (“Integra”), involved peptides that contained an RGD sequence of amino acids, i.e., a contiguous sequence of arginine (R), glycine (G), and aspartic acid (D), within a peptide chain. The peptides modulate cell interactions with the extracellular peptide matrix, and thus they can promote, block, or disrupt cell attachment, a process that is important for angiogenesis (the development of blood vessels).

Merck and Scripps Research Institute (“Scripps”) collaborated in research on the inhibition of angiogenesis that was conducted by Dr. David Cheresh and others at Scripps. In 1994, while evaluating a cyclic RGD peptide provided by Merck, Dr. Cheresh discovered that the compound was effective in inhibiting angiogenesis. It meant that RGD peptides could have a potential to treat such conditions as solid tumor cancers, rheumatoid arthritis, and diabetic retinopathy, all of which are characterized by the development and growth of undesired blood vessels. As a result, Merck and Scripps entered into a sponsorship agreement, ultimately planning to file an Investigative New Drug (“IND”) application to seek FDA approval for clinical trial with human subjects.

During the collaboration with Merck, Dr. Cheresh and other Scripps scientists conducted in vitro and in vivo experiments that focused on the efficacy, mechanism of action, pharmacology, pharmacokinetics, and safety of three structurally related RGD peptides. The researchers ultimately selected one peptide, EMD 121974, as the optimum drug candidate and in 1998 proceeded to clinical trials using that particular compound.

Integra filed a patent infringement suit against Merck, Scripps, and Dr. Cheresh, alleging that the use of the patented compounds in preclinical testing constituted patent infringement. In its defense, Merck argued that the accused experiments qualified for the FDA “Safe Harbor” Exemption under 35 U.S.C. § 271(e)(1), as the studies were conducted in furtherance of drug development and the projected clinical trials. Nonetheless, the jury found infringement, and the district court sustained the jury verdict, holding that the safe harbor provision did not apply to Merck’s use of the RGD peptides. A split panel of the Federal Circuit affirmed the district court’s ruling. It held that “the Scripps work sponsored by Merck was not clinical testing to supply information to the FDA, but only general biomedical research to identify new pharmaceutical compounds.”

The Supreme Court, however, granted certiorari. The Court limited its review to the infringement status of experiments using the two RGD peptides that were not selected for clinical trials as well as studies using EMD 121974 that were not submitted to the FDA. Interpreting the scope of § 271(e)(1), the Court ruled that “the FDA Exemption includes experimentation on products that are not ultimately the subject of an FDA submission, provided that the particular biological process and physiological effect had been identified and the work was reasonably related to that appropriate for inclusion in an IND application.” Slip op. at 10. Therefore, the Supreme Court vacated and remanded the Federal Circuit’s ruling.

On remand, the Federal Circuit’s focus was to apply the Supreme Court’s statutory interpretation of § 271(e)(1). Integra argued that Scripps’s experiments on the two RGD peptides other than EMD 121974 were not within the “safe harbor” FDA provision because the two peptides were not included in the IND application. The Federal Circuit, following the Supreme Court’s statutory interpretation, rejected Integra’s argument. Studies of compounds that are not ultimately used in the clinical trials are within the FDA Exemption, the Federal Circuit stated, “when there was a reasonable basis for identifying the compounds as working through a particular biological process to produce a particular physiological effect.” Id. at 11. Thus, the Court concluded that the FDA Exemption applied to Scripps’s experiments aimed at selecting the optimum candidate drug, including the experiments with the two RGD peptides other than EMD 121974.

Integra also contended that at the IND application stage, the FDA Exemption applies only to experiments designed to show that the candidate drug is safe for administration to humans. The Federal Circuit emphasized that the Supreme Court rejected this position, stating that, besides safety, the FDA requires that applicants include information in an IND about the drug’s efficacy, structure, toxicology, mode of action, side effects, its administration, formulation, and like information. The Federal Circuit pointed to the testimony at trial of Merck’s and Scripps’s witnesses that the experiments, including the animal tests, all yielded information concerning efficacy, pharmacology, pharmacokinetics, and mechanism of action of the studied RGD compounds. The Supreme Court recognized that such data were relevant to FDA approval, and that qualified the experiments for the FDA Exemption. According to the Supreme Court, the absence of FDA certification as to all three RGD peptides did not defeat the “safe harbor” provision.

As the Federal Circuit was reviewing the jury verdict for support by “substantial evidence,” it refused to ignore the evidence that did not support the verdict. Instead, the Court gave credence to the evidence favoring the nonmoving party as well as “that ‘evidence supporting the moving party that is uncontradicted and unimpeached.’” Id. at 19 (citation omitted). Thus, the Federal Circuit pointed out that at trial, Integra did not present evidence to contradict Merck’s evidence that all of the accused experiments were conducted after it had been discovered that an RGD peptide inhibited angiogenesis and thus shrank tumors in an animal model. Neither did Integra dispute the relevance of the experiments to efficacy, mechanism of action, pharmacology, and pharmacokinetics, i.e., subjects that are relevant to an IND submission to the FDA. Thus, after reviewing the entirety of record, the Federal Circuit pointed out the absence of substantial evidence to support the jury verdict of infringement. The Court, therefore, rendered JMOL in favor of Merck.

In a dissenting-in-part and concurring-in-part opinion, Judge Rader insisted that the Federal Circuit expanded the FDA Exemption beyond the Supreme Court’s limits on the provision and thus eliminated protection for research tool inventions. Judge Rader wrote that the Federal Circuit should have first construed the patent claims. According to him, two of the patents at issue apply only to laboratory methods without any possibility of submission to the FDA; therefore, the two patents are directed to research tools. Since the Supreme Court did not extend the FDA “safe harbor” provision to encompass research tools, Judge Rader dissented with respect to two of the litigated patents, while concurring with the majority as to the remaining patents.