Safe Harbor § 271(e)(1)

35 U.S.C. § 271(e)(1) provides: '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 (other than a new animal drug or veterinary biological product as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Act of March 4, 1913) 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.' ORIGIN: Hatch-Waxman Act (1984); designed to allow generic manufacturers to conduct bioequivalence testing during the brand's patent term so generics can launch immediately when the patent expires; BROAD INTERPRETATION (Merck KGaA v. Integra Lifesciences I, Ltd., S.Ct. 2005): the safe harbor applies to all research activities 'reasonably related' to FDA approval — not just the final studies that are directly submitted to the FDA; activities that are 'reasonably related' include early-stage research that may be used to develop a drug candidate eventually submitted to FDA, even if the specific compound studied is never actually submitted; the Supreme Court unanimously reversed the Federal Circuit's narrow interpretation; WHAT IS COVERED: (1) preclinical testing of compounds being evaluated for potential FDA submission; (2) clinical trials conducted for FDA approval; (3) bioequivalence studies (ANDA process); (4) pharmacokinetic studies; (5) process chemistry research for manufacturing of drug candidates.

Despite Merck's broad reading, important activities remain outside the safe harbor: NOT COVERED: (1) PURELY COMMERCIAL RESEARCH: if the purpose is to develop commercial products or tools — not to gather data for FDA submission — the safe harbor does not apply; research into manufacturing processes used after FDA approval for commercial manufacturing (not for FDA submission) is not covered; (2) RESEARCH TOOLS: the safe harbor does NOT cover the use of patented research tools (diagnostic reagents, cell lines, assay equipment) that are used in FDA-related research but are not themselves the subject of the FDA submission; Merck clarified that using a patented tool in research related to FDA submission does not exempt the TOOL from infringement liability; (3) EXCEEDING FDA PURPOSES: quantities manufactured substantially exceeding what is needed for FDA submissions are not covered; stockpiling product for commercial launch while ostensibly doing FDA research crosses the line; (4) NON-PHARMACEUTICAL FIELDS: the safe harbor applies to drugs, biologics, and medical devices regulated under specific federal laws; it does not apply to patents outside the pharmaceutical/biotech/device space (e.g., general electronics patents, software patents); (5) MEDICAL DEVICES: § 271(e)(1) applies to medical devices regulated under the FDCA — FDA device approval (PMA, 510(k)) qualifies, but only if the research is reasonably related to the submission; using a patented device for general clinical research does not qualify.

Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (S.Ct. 2005) is the landmark Supreme Court decision on the scope of § 271(e)(1): FACTS: Merck KGaA (now Merck & Co.) licensed peptide compounds from Scripps Research Institute without paying royalties to Integra, which owned patents on RGD peptides; Merck used the compounds in preclinical studies (in vitro and animal studies) to identify drug candidates; some of the research involved patented compounds that were never actually submitted to FDA; FEDERAL CIRCUIT: had held the safe harbor was limited to activities that would generate information directly included in an FDA submission; preclinical studies that screened out compounds (and thus were never submitted) did not qualify; SUPREME COURT: reversed unanimously; the safe harbor extends to all activities with a 'reasonable basis for believing that a patented compound may work, through a particular biological process, to produce a particular physiological effect'; the statute requires that activities be 'reasonably related to FDA submissions' — not that they ACTUALLY generate data in the submission; this covers exploratory, early-stage research where the compound is being evaluated for potential FDA submission even if ultimately not submitted; IMPACT: broadly expanded the safe harbor to cover most pharmaceutical and biotech drug discovery research; generic manufacturers, pharmaceutical companies, and research institutions all benefit; reduced the scope of patent enforcement during the drug development pipeline; RESIDUAL UNCERTAINTY: basic research with no realistic prospect of FDA submission (pure academic research with no drug development goal) may not qualify — but courts have interpreted 'reasonably related' broadly.

The § 271(e)(1) safe harbor was specifically designed for the ANDA bioequivalence testing context — and its application to biologics is similar: ANDA CONTEXT (generics): generic drug companies conduct bioequivalence studies during the brand's patent term to have their ANDA ready for submission; the bioequivalence testing (comparing generic to brand) uses the patented drug product; § 271(e)(1) exempts this use; without the safe harbor, generics could not submit ANDAs until the brand's patents expired — effectively extending the brand's monopoly beyond the patent term; BPCIA CONTEXT (biosimilars): the Biologics Price Competition and Innovation Act (2010) extended the § 271(e)(1) safe harbor to the biosimilar approval pathway (aBLA filings); biosimilar applicants may engage in testing and manufacturing research using the reference product (which may be covered by patents) under the safe harbor; SAFE HARBOR + PARAGRAPH IV INTERACTION: filing a Paragraph IV certification is ARTIFICIAL infringement under § 271(e)(2) — the filing is the act of infringement, not any actual research; the § 271(e)(1) safe harbor exempts RESEARCH activities; the § 271(e)(2) artificial infringement applies to the FILING; these are separate doctrines; STOCKPILING EXCEPTION: the safe harbor was never meant to cover stockpiling commercial quantities; Eli Lilly & Co. v. Medtronic (S.Ct. 1990): the safe harbor applies to medical devices regulated under FDCA; Proveris Scientific v. Innovasystems (Fed. Cir. 2008): the safe harbor does not apply if the activity goes beyond reasonable FDA-related research.

The § 271(e)(1) safe harbor is commonly called the 'Bolar amendment' after the case that prompted Congress to enact it: ROCHE PRODUCTS v. BOLAR PHARMACEUTICAL (Fed. Cir. 1984): Bolar Pharmaceutical, a generic drug manufacturer, conducted bioequivalence testing of a sleeping pill (Roche's Dalmane) before Roche's patents expired — specifically to file an ANDA immediately upon expiration; the Federal Circuit held this constituted patent infringement — the experimental use exception did not apply to commercial use for regulatory purposes; without Congressional action, generic drug companies would have been unable to conduct FDA-required testing during patent term, delaying generic entry for months or years after patent expiration; CONGRESSIONAL RESPONSE: the Hatch-Waxman Act (1984) enacted § 271(e)(1) as a direct response to Bolar, explicitly exempting such activities from infringement; EXPERIMENTAL USE EXCEPTION vs. § 271(e)(1): the common law experimental use exception is extremely narrow (Madey v. Duke University, Fed. Cir. 2002) — it covers only research done 'for amusement, to satisfy idle curiosity, or for strictly philosophical inquiry'; even university research for commercial purposes is NOT covered; § 271(e)(1) is the statutory response that covers commercial FDA-related research; practitioners cannot rely on the common law exception for pharmaceutical research — only § 271(e)(1) provides meaningful protection; INTERNATIONAL EQUIVALENTS: most jurisdictions have an equivalent: EU's Bolar provision (Directive 2004/27/EC); the EU provision covers 'studies and trials' for regulatory approval purposes; scope varies by member state.