On Remand from the Supreme Court, the U.S. Court of Appeals for the Federal Circuit applied the broad scope of the research exemption to the Integra case and reversed the district court’s judgment of infringement. Integra Lifesciences v. Merck KGaA (02-1052-1065).

Integra Life Sciences has five patents relating to peptides that contain the RGD sequence of amino acids — the contiguous sequence of arginine (R), glycine (G), and aspartic acid (D) within a peptide chain. The inventions are described as demonstrating various cell interactions with the extracellular peptide matrix, including ways of promoting cell attachment, blocking cell attachment, and disrupting cell attachment.

Merck KGaA and Scripps Research Institute were collaborating in research on the inhibition of angiogenesis since the development and growth of undesired blood vessels is a factor in several diseases, including solid tumor cancers, diabetic retinopathy, and rheumatoid arthritis. Integra then sued for infringement.

In the district court, two defenses were presented: first, that the early scientific studies at Scripps on RGD peptides are not subject to patent infringement, based on the common law research exemption; and second, that the ensuing studies were conducted in furtherance of drug development and the projected clinical trials, and are exempt from infringement under the FDA Exemption (or “safe harbor”) established by 35 U.S.C. ‘271(e)(1):

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States 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 or veterinary biological products (emphasis added).

Integra argued that the FDA Exemption must be narrowly construed, explaining that the purpose of ‘271(e)(1) is to shield generic drug producers from patent infringement while they are preparing to enter the market on expiration of the patents on established products — a purpose quite removed from the activities for which Merck and Scripps were now seeking to invoke the Exemption

Merck and Scripps argued that ‘271(e)(1) is not limited to studies of safety for human subjects, and that information about efficacy, pharmacology, pharmacokinetics, and mechanism of action is properly included in the IND application and thus subject to the FDA Exemption.

The jury found infringement and the district court, sustaining the verdict, described the challenged experiments as “insufficiently direct to qualify” for the FDA Exemption.

A split panel of the Federal Circuit affirmed, holding 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.” Integra, 331 F.3d at 866.

In the Supreme Court, the question was as follows:

Whether uses of patented inventions in preclinical research, the results of which are not ultimately included in a submission to the Food and Drug Administration (FDA), are exempted from infringement by 35 U.S.C. ‘271(e)(1).

The Supreme Court explained that ‘271(e)(1) “exempted from infringement all uses of patented compounds ‘reasonably related’ to the process of developing information for submission” to the FDA and that “reasonably related” includes uses in research that are conducted after the biological mechanism and physiological effect of a candidate drug have been recognized, such that if the research is successful it would appropriately be included in a submission to the FDA.

On remand, Integra repeated that ‘271(e)(1) was never intended as a broad authorization to investigators to infringe the patents of others, and that the statute should be strictly construed.

But, the Supreme Court rejected, as a matter of statutory interpretation, Integra’s position that the Scripps experiments that were not included in the IND application are excluded from the FDA Exemption:

There is simply no room in the statute for excluding certain information from the exemption on the basis of the phase of research in which it is developed or the particular submission in which it could be included.

In applying the Supreme Courts directions, the Fed Circuit said:

All of the experiments charged with infringement were conducted for the purposes of determining the optimum candidate angiogenesis inhibitor and proceeding with commercial development of the selected candidate in compliance with regulatory procedures, initially using three structurally related RGD peptides.

Integra also argued that much of this work is properly viewed as “discovery-based research” and is not the “routine FDA-related work” that Integra states is the proper limit of ‘271(e)(1) even on the Court’s view of the statute.

Integra alternatively proposes that each of the Scripps experiments should be classified as either “discovery” or “routine,” and that only those experiments devoid of discovery, and entirely routine, can be subject to the FDA Exemption. But, the Fed Circuit noted that the safe harbor does not depend on a distinction between “discovery” and “routine,” but on whether the threshold biological property and physiological effect had already been recognized as to the candidate drug:

That the experiments contributed to scientific knowledge does not deprive them of the safe-harbor benefit of ‘271(e)(1) when the requirements therefore are met.

Unfortunately, the Federal Circuit did not discuss how a case should be decided based on research tool patents and instead relied on a post-hearing letter in which the parties stated that research tools were not at issue.

Judge Rader, dissenting-in-part and concurring-in-part.

This decision casts a large shadow over patent protection by its overly expansive interpretation of the 35 U.S.C. § 271(e)(1) exemption. In particular, this court today expands the exemption beyond the Supreme Court’s limits on the provision to eliminate protection for research tool inventions. The Supreme Court stated “that § 271(e)(1)’s exemption from infringement extends to all uses of patented inventions that are reasonably related to the development and submission of any information under the [Federal Food, Drug and Cosmetic Act (FDCA)].” Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 202 (2005). Thus, the exemption covers activities that develop information that will ultimately be submitted to the FDA, not patented processes and tools beyond the scope of the “patented compounds” that the Supreme Court placed within the statutory exemption. In this case, two of the patents are research tools that deserve protection. This court should remand with instructions that the district court examine and protect these research tool patents.

A careful examination of the patents shows that two of them have no application at all outside of a laboratory. If the patents in this case are not research tools, then of course this court could quickly construe the claims and show that they claim drugs or other products likely to undergo FDA clearance, not simply laboratory methods. Unfortunately even a cursory analysis of the patents (undertaken in this dissent) shows that two of them have no application outside the laboratory.

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