The goal of most biopharmaceutical companies is to develop an FDA-approved treatment. But FDA approval takes time, money, and often the use of patented materials for developing, testing, and screening new drugs—which runs the risk of liability for patent infringement. The Hatch Waxman “safe harbor” provision exempts activities that would otherwise infringe a patented invention, as long as those activities are “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” (1). And, according to the United States Supreme Court, a “patented invention … is defined to include all inventions,” not just drug compounds (2). But this safe harbor provision is not without its limits.
The United States Court of Appeals for the Federal Circuit has held that “research tools … may not be covered” by the safe harbor provision (3). These research tools are patented inventions that are “used in the development of … regulatory submissions, but [are] not [themselves] subject to the [regulatory] approval process” (4). How the courts approach the issue of research tools, therefore, has real impacts on the activities of companies looking to develop drugs and patent holders who want to enforce their intellectual property.
The purpose of the Hatch Waxman safe harbor provision
Understanding why the safe harbor provision was created is important to understanding why research tools fall outside its protection. The Hatch Waxman Act was enacted with the goal of correcting two distortions to the term of a patent in the context of pharmaceuticals that are subject to premarket regulatory approval. The safe harbor provision was an important part of Congress’s remedy to this situation.
The first distortion comes at the beginning of a patent’s term, as testing and other regulatory requirements may prevent a patent owner from deriving commercial benefit during the early years of patent protection. This distortion is corrected by providing term extension for patents claiming products that are “subject to a regulatory review period before its commercial marketing or use” (5). Under this statute, a patent’s term can be extended by a period of time that represents a portion of the regulatory review period that occurred after issuance of the patent, thereby giving the patent owner back a portion of the time lost to regulatory approval when they could not yet commercialize their patented invention (6).
The second distortion comes at the end of a patent’s term, when companies looking to develop generic versions of approved pharmaceuticals had to wait for the patent to expire before beginning the regulatory approval process—essentially extending the term of the patent beyond its expiration. The safe harbor provision was designed to remedy this second distortion by “allow[ing] competitors, prior to expiration of a patent, to engage in otherwise infringing activities necessary to obtain regulatory approval” (2). Therefore, a competitor can begin the regulatory approval process—which may involve otherwise infringing activity—even while the patent is in force so that the competing product can come to market without any delay after the patent expires.
Use of research tools is not protected under the safe harbor provision
While cases have emphasized the breadth of the safe harbor provision, the question of research tools has been a trickier subject. In Merck KgaA v. Integra Lifesciences I, Ltd., Merck funded research to develop new integrin antagonists that could be used to reduce tumor growth and used Integra’s patented RGD peptides as a part of that research (7). One of the antagonists showed promise. But when Merck sought to begin clinical trials and the regulatory approval process, Integra sued for patent infringement. The Supreme Court held 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” to the FDA, which “necessarily” included preclinical research like Merck’s. The Supreme Court distinguished this from “basic scientific research” that was not “reasonably related” to developing information for a regulatory submission. Yet the Supreme Court determined that it “need not … express a view about whether, or to what extent, § 271(e)(1) exempts from infringement the use of ‘research tools’ in the development of information for the regulatory process.”
Instead, that question was left to be addressed by the Federal Circuit, which it did in Proveris Scientific Corp. v. Innovasystems, Inc. In that case, Innova made and sold an optical spray analyzer (OSA), which was not itself subject to regulatory approval, but was used by third parties in connection with FDA regulatory submissions to measure parameters of aerosol sprays used in nasal spray drug delivery devices. Proveris sued Innova for infringement of its patent, and Innova invoked the safe harbor provision as a defense. Faced with the question of how to treat a “research tool” like the OSA, the Federal Circuit turned to the two patent term distortions that the Hatch Waxman Act sought to address. Regarding the first distortion, it found that a research tool like the OSA was not a “patented invention” for the purposes of § 271(e)(1). While such research tools may be used in the development of FDA regulatory submissions, they are not actually subject to FDA pre-market approval (and therefore do not lose time for commercialization). And with regard to the second distortion, because research tools are not themselves subject to FDA pre-market approval, there are “no regulatory barriers to market entry upon patent expiration” (4). Innova therefore was not the type of party that the safe harbor provision was intended to protect.
The Federal Circuit seemingly confirmed the holding of Proveris in Momenta Pharms., Inc. v. Teva Pharms. USA Inc. where it stated that “research tools or devices that are not themselves subject to FDA approval may not be covered” by § 271(e)(1) (8). Since then, however, it has been up to the federal district courts to use the framework of Proveris to determine what is and is not a research tool.
District courts grapple with research tools
Most district courts have agreed with Proveris that research tools which are not themselves subject to FDA approval do not fall within the safe harbor provision. In Allele Biotech & Pharms., Inc. v. Pfizer, Inc., the Southern District of California held that Pfizer’s use of Allele’s patented “mNeonGreen product, which is a fluorescent protein used as a biological tag in genetic engineering work” to “research, develop, and test their SARS-CoV-2 vaccine candidates” did not fall under the protection of the safe harbor provision because the tagging technology was not subject to regulatory review (9). And in REGENXBIO Inc. v. Sarepta Therapeutics, Inc., the District of Delaware applied the logic of Proveris to find that Sarepta’s use of patented cultured host cells to make recombinant adeno-associated virus gene therapy products did not fall under the protection of the safe harbor provision because “the cells are not subject to any FDA regulatory approval process” and “Sarepta is not using the patented cultured host cells to obtain FDA approval to introduce generic cultured host cells to compete in the marketplace when the [asserted patent] expires” (10). In contrast, in UCB, Inc. v. Catalent Pharma Sols., Inc., the Eastern District of Kentucky held that Catalent’s use of UCB’s patented lacosamide compound (the active ingredient in UCB’s FDA approved drug, VIMPAT) for “manufacturing and testing services on lacosamide products” in support of a customer’s anticipated FDA submission fell within the safe harbor provision (11).
The Southern District of New York, however, declined to apply Proveris so broadly in Teva Pharms. USA, Inc. v. Sandoz Inc. Teva’s patents covered polypeptide markers “suitable for calibrating chromatographic columns to measure the molecular weight characteristics of glatiramer acetate” (12). Glatiramer acetate is the active ingredient in the drug Copaxone, but the patented polypeptide markers were not themselves drug products or subject to FDA approval. The holding in Proveris suggests that these polypeptide markers would be considered research tools, and Sandoz’s use of them to characterize the active ingredient of their generic drug for an FDA submission should therefore not have fallen within the safe harbor provision. The district court, however, reasoned that the holding of Proveris should be limited to the facts of that case (i.e., where the defendant is actively commercializing the infringing product) and found that the polypeptide markers were not research tools and therefore fell within the safe harbor provision. Other district courts have explicitly disagreed with the reasoning in this case (see 9, 10).
What comes next
The split created by the Teva case has not gone unnoticed. After Sarepta was denied the safe harbor defense in the REGENXBIO case, it filed a motion for interlocutory appeal to the Federal Circuit on the issue of whether Teva’s interpretation of Proveris is actually correct (13). The district court judge denied this request, which would have immediately sent the issue to the Federal Circuit. The judge acknowledged that “there may be room for appellate clarification on the issue,” but Sarepta must wait “for appeal following a final judgment in this case” (14). Trial is currently set to begin on Jan. 29, 2024, and Sarepta should, if it so chooses, be able to appeal this issue sometime in the spring of 2024. A final decision on an appeal could be expected sometime in 2025 or early 2026.
As the issue arises in more cases, it is possible that further decisions might provide more clarity (or complexity) and provide an opportunity for the Federal Circuit (or even the Supreme Court) to revisit the issue of research tools. Until then, Proveris remains the guiding light.