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Aug 1, 2005 (Vol. 25, No. 14)

Safe Harbor Provisions for Preclinical Research

Supreme Court Seeks a New Definition

  • On June 13, 2005, in Merck KGaA v. Integra LifeSciences I, Ltd., the U.S. Supreme Court made clear in a unanimous opinion that broad immunity from patent infringement exists for preclinical research and experimentation reasonably related to the process of developing information required for submission to the FDA.

    This ruling reversed a ruling of the U.S. Court of Appeals for the Federal Circuit, which had held that the safe harbor provisions for non-infringement of 35 U.S.C. 271(e)(1) of the 1984 Hatch-Waxman Act did not extend to drug screening not intended as part of a FDA submission for the later identified drug candidate.

    The Supreme Court held that testing of drug candidates is protected by the safe harbor provision if there is a reasonable basis for believing that the activities will produce the types of information that are relevant to FDA approval.

    The ruling provides a wide berth for the use of patented compositions in activities related to the federal regulatory process, and specifically encompasses experimentation on compositions which are not themselves the subject of an FDA submission.

    The Supreme Court explained that the Federal Circuits interpretation of 271(e)(1) to not include research which is not submitted to the FDA was improperly restrictive and inconsistent with the statutes safe harbor language.

    The safe harbor provisions extend beyond merely research and development of generic drug equivalents to include basic experimental research on new therapeutic drug candidates and other products that require regulatory approval.

    However, the Court was careful to limit its decision to the statutory interpretation issue, and specifically declined to express a view about whether the exemption generally extends to all patented research tools used in the development of information for the regulatory process.

    The Court made clear that basic scientific research performed without an intent to develop a particular drug or a reasonable belief that the composition will cause the sort of physiological effect the researcher intends to induce, is surely not reasonably related to the development and submission of information to the FDA.

    Preclinical activities to determine a compositions efficacy, mechanisms of action, pharmacokinetics and pharmacology, and findings of possible unfavorable and unintended effects would be appropriate to include in a submission to the FDA, and that research is clearly free from patent infringement.

    The case was sent back to the Federal Circuit for a determination of whether Mercks preclinical drug screening activities fall under the protection of the statutes safe harbor, given the Supreme Courts interpretation of the statute. On remand, the Federal Circuit will review the evidence adduced at trial under the standards set forth in the district courts jury instruction, which was consistent with, but less detailed than, the Supreme Courts opinion.

    This opinion is welcome news for companies performing unlicensed research on pharmaceutical candidates. Moreover, the opinion is not limited to patented drug compositions, as the courts have previously construed the safe harbor provisions to include therapeutic biologics (e.g., antibodies) and medical devices requiring FDA approval.

    The decision protects all preclinical therapeutic research reasonably related to the development and submission of information to the FDA.

    However, it remains to be determined if any form of basic research tool activity with an intent to develop a therapeutic composition falls outside this newly expanded safe harbor provision, since the Supreme Court did not specifically address whether any activities related to the preclinical use of patented research tools are protected by the safe harbor.

  • Safe Harbor Development

    Legislators in the mid1980s recognized that the rigors of the FDA premarketing approval process were preventing generic pharmaceutical products from efficiently entering the market despite expiration of the underlying patents.

  • Hatch-Waxman Act

    In 1984, Congress passed the Drug Price Competition and Patent Term Restoration Act, also referred to as the Hatch-Waxman Act, primarily to balance incentives for pharmaceutical firms to make the investment to develop new drug applications (NDAs) through limited patent term extension provisions based on regulatory market delays, with additional provisions for generic drug companies to file abbreviated new drug applications (ANDAs) to bring cheaper versions of drugs to market after patent expiration.

    Section 271(e)(1) provides protection for competitors from pre-commercial sales infringement as long as their activities are reasonably related to the development and submission of data under a Federal Law.

    By its language, however, 271(e)(1) is not limited to entities seeking to produce generic drugs, and could be invoked by any organization seeking to make, use, sell, or offer to sell a patented invention so long as the use is reasonably related to the development and submission of information for FDA approval.

    Determining the extent of the safe harbor protection from patent infringement has been the source of so much legal debate for the last two decades because in the words of the Supreme Court in Eli Lilly v. Medtronic, the hastily drafted 1984 statute is simply not plainly comprehensible in anyones view.

    It was initially understood that 271(e)(1) was implemented to balance the patent term extension provided to patentees for regulatory approval delays under 35 U.S.C. 156. Extensions under 156 can be obtained for new drugs for human use, new Class III medical devices, new food or color additives, new animal drugs, and new veterinary biological products.

    The Federal Circuit extended the safe harbor protections of 271(e)(1) to Class I and/or Class II medical devices, stating that the language of 271(e)(1) makes no distinction among the different FDA classes of medical devices or drugs (Abtox v. Exitron).

    The courts have since determined that the manufacture and the sale of devices to a hospital, which are then used to generate data for the FDA, are exempt from infringement. Additionally, continuing to sell patented devices to hospitals even after the submission of an application for pre-market approval falls under the 271(e)(1) exemption since a company may need further data to satisfy the FDA requirements.

    Selling devices for further clinical trials after FDA approval has been obtained, however, would not fall under the safe harbor exemption since the information obtained would no longer be necessary to satisfy FDA requirements.

    One lower court has held that the safe harbor statute reaches all the way up the chain to research that involves identifying analogs. In Bristol-Myers Squibb v. Rhone-Poulenc Rorer, the court for the Southern District of New York held that the safe harbor immunizes early-stage research to develop analogs.

    The defendant was infringing the patents-in-suit, covering certain intermediates (taxane derivatives), to research and develop analogs of taxol. While the research group was identifying 23 analogs per week and conducting therapeutic screening tests, the Rhone court, however, simply held that the safe harbor applies to the intermediates.

    On the other hand, the court for the Western District of Wisconsin held that the protection of 271(e)(1) does not extend to protect the use of a research tool not regulated by the FDA in Infigen v. ACT. Infigen was the assignee of patents claiming a process for activating bovine oocytes for use in cloning cattle and claiming a bovine embryo culture medium used to grow and develop bovine embryos.

    Both Infigen and ACT were interested in the development of transgenic cattle that would produce a pharmaceutical drug in their milk, and the commercialization of such a drug would require FDA approval.

    The court stated that the safe harbor exemption did not apply to the product or methods claimed by the Infigen patents since the patent claims were not eligible for FDA-based patent term extension under 156.

    While the 156 distinction has been deemed moot by more recent holdings of a broader safe harbor exemption, the question now remains whether such activity is still reasonably related to submission of information to FDA, or is an infringement of a research tool patent.

    Despite the Supreme Courts recent ruling in Merck v. Integra, there is still insufficient clarification of whether the use of a patented research tool to develop therapeutic agents regulated by FDA is protected by the safe harbor exemption. The Court specifically declined to address the topic in Merck.

    Research tools were defined by the 1998 NIH Working Group on Research Tools as embracing the full range of resources that scientists use in the laboratory, including cell lines, monoclonal antibodies, reagents, animal models, growth factors, combinatorial chemistry libraries, drugs and drug targets, clones and cloning tools (such as PCR), methods, laboratory equipment and machines, databases, and computer software.

    When the Federal Circuit applies the facts surrounding the preclinical drug discovery research conducted on behalf of Merck under the guidelines established by the Supreme Court in Merck v. Integra, observers hope for further clarification as to which patented research tools are eligible for the safe harbor protections from infringement liability.

  • Research at Issue

    The technology at issue in the remanded Merck case is the RGD-peptide sequence to promote adhesion to av3 receptors on endothelial cells to inhibit angiogenesis, the process for generating new blood vessels. Inhibiting angiogenesis has therapeutic applications in treating cancer among many other neovasculature-related diseases.

    Scientists Erkki Ruoslahti, M.D., Ph.D., and Michael Piersbacher, M.D., at the Burnham Institute were apparently the first to discover the cell surface binding action of the RGD-peptide, which led to the filing of patents in 1983 and 1985.

    In 1987, the Burnham Institute and investors established Telios Pharmaceuticals to commercially exploit these patents. Telios declared bankruptcy in January of 1995, at which time the patents were sold to Integra.

    Beginning in 1988, without a license to the referenced patents, Merck provided funding for David Cheresh, Ph.D., at the Scripps Research Institute for his research with inhibiting angiogenesis by blocking av3 integrin proteins. In 1994, Dr. Cherish was able to demonstrate in vivo (in a chicken CAM assay) that a compound using a cyclic RGD peptide could block the receptor and blood vessel growth.

    The promising results led to a new agreement in 1995 between Merck, Scripps, and Dr. Cheresh to develop more preclinical data for submission of a new drug application. The research involved testing of the RDG peptide containing molecules for therapeutic potential, as well as their use as positive controls in other organic mimetic drug screening assays.

  • Tool Infringement Still Subject to Debate

    The Federal Circuit attempted to narrow the scope of safe harbor protections afforded to research tool patent infringers in Integra v. Merck, and was rebuked by the Supreme Court.

    The Federal Circuit had posited that the FDA has no interest in the hunt for drugs that may or may not later undergo clinical testing for FDA approval, and that expansion of 271(e)(1) to include the Scripps-Merck activities would effectively vitiate the exclusive rights of patentees owning biotechnology tool patents.

    The Supreme Court did not agree to such limitations on the safe harbor provisions and has remanded the case for reconsideration.

    Yet the Supreme Court failed to explicitly take this opportunity to clarify that the use of research tool patents in all preclinical drug identification falls within the safe harbor. Nonetheless, the Court paradoxically indicated that Scripps use of the patented RGD peptide as a positive control while screening for other potential drugs was not such a research tool application, and therefore, would be entitled to safe harbor protection.

    In this light, it appears that almost any conceivable form of experimentation performed with a patented research tool for the purposes of developing a human therapy would be non-infringing.

    It remains to be determined by future lower courts application of the newly defined standard, if any form of basic research tool activity at all, performed with an intent to develop a therapeutic composition, falls outside this newly expanded safe harbor provision.



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