Applicability of Patent Safe Harbor to Conduct Supporting Foreign Regulatory Approvals
Updated: Sep 10, 2021
. . . Some aspects of the safe harbor, however, are not so well charted, especially where the U.S.-based drug and device development activities relate to foreign regulatory approvals. . . .
Since the 1984 addition of Section 271(e)(1) to the U.S. Patent Act, courts have endeavored to map the outer boundaries of its patent “safe harbor.” Section 271(e)(1) exempts certain conduct from liability for patent infringement when carried out “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. . . .” 35 U.S.C. § 271(e)(1). The courts’ decisions demonstrate that Section 271(e)(1) charts not only a “safe” but also an expansive harbor, extending even to conduct in pursuit of medical device approvals from the U.S. Food & Drug Administration (“FDA”). See Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (1990).
Some aspects of the safe harbor, however, are not so well charted, especially where the U.S.-based drug and device development activities relate to foreign regulatory approvals. Court decisions weighing the applicability of the safe harbor against conduct aimed at foreign regulatory approvals were rendered before the Supreme Court’s permissive construction of Section 271(e)(1) in Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005). In the absence of post-Merck cases addressing these issues, the industry is left with little guidance on how the narrow limitations imposed in those early cases on conduct directed to foreign regulatory approvals might be liberalized under Merck’s more permissive reckoning of the safe harbor.
This article explores those issues.
The Early Cases
Overseas Clinical Studies
In 1991, the U.S. District Court for the Northern District of California was one of the first courts to wade into questions about the safe harbor’s application to conduct within the United States directed to clinical studies conducted abroad. That case, Intermedics, Inc. v. Ventritex, Inc., 775 F. Supp. 1269 (N.D. Cal. 1991), involved clinical trials conducted in Germany utilizing implantable defibrillators made and patented in the United States.
The court was receptive to the practice of utilizing foreign clinicians, stressing that “it would be both reasonable and responsible” to do so in order to access “the most experienced and well-respected investigators available, even if some of them practice overseas.” Id. at 1284. The court also found no fault in providing defibrillator test data to German authorities to obtain import approval for the studies, reasoning that the provision of data itself is not an infringing act. Id. at 1281. However, in ruling that the defibrillator shipments in support of the German clinical studies were protected by the safe harbor, the court appeared to buttress its decision on one ominous fact—“all the data generated in those clinical trials in fact have been submitted only to the FDA.” Id. (emphasis in original). On appeal, the Federal Circuit affirmed, emphasizing that point, “There was no evidence that the German data were submitted to any German authorities for any purpose.” Intermedics, Inc. v. Ventritex Co., Inc., 991 F.2d 808, 809 (Fed. Cir. 1993).
A year later, a more precise version of the overseas clinical study issue was presented again to the Northern District of California in Elan Transdermal Ltd. v. Cygnus Therapeutic Systems, No. C-91-1413, 1992 WL 368678 (N.D. Cal. Jun. 23, 1992). In that case, the study’s data clearly had been submitted in parallel to both FDA and overseas regulators. Id. at *8-*9. The court ruled nonetheless that the safe harbor protected the defendant’s activities in support of the multi-purposed clinical study. Id. at *9. In so doing, the Elan court declined to follow an earlier decision in the same district, Scripps Clinic & Research Found. v. Genentech, 666 F. Supp. 1379, 1396 (N.D. Cal. 1987), that had refused to apply the safe harbor to conduct “serving multiple purposes unrelated to meeting FDA requirements.”
The Elan court instead independently parsed the phrases of Section 271(e)(1) and determined that “Section 271(e)(1) exempts otherwise infringing activity that is ‘solely for uses reasonably related’ to FDA approval” rather than solely for “purposes reasonably related to FDA approval.” Elan Transdermal, 1992 WL 368678 at *9 (emphasis in original). Under that construction of the statute, “[a]n alternative potential purpose is irrelevant so long as the ‘use’ itself is reasonably related to FDA approval.” Id.
In 1994, the District Court for the District of New Jersey likewise applied the safe harbor to dual FDA and overseas uses of foreign clinical data but appeared to impose a sequencing limitation on the uses. See NeoRx Corp. v. Immunomedics, Inc., 877 F. Supp. 202, 208 (D.N.J. 1994). The court noted that the defendant’s “16-patient study had first been submitted to the FDA, nearly a year earlier” than its European counterpart submission and expressly ruled that “[w]here data is first submitted to the FDA, subsequent use of the same data is not an infringing act.” Id. (emphasis added). The court’s scrutiny of the clinical studies, however, did not end with the timing of the data submissions but also extended to an examination of each overseas clinician’s individual work.
Finding that three of the clinicians had signed FDA Form 1572 (“Statement of Investigator”) and faithfully followed its referenced clinical protocol, the court ruled that drug shipments from the United States for use in their studies fell within the safe harbor. Id. at 209; 211-12. Shipments to a fourth clinician, however, were found to infringe the patent due to evidence that the clinician did not adhere to the clinical protocol and admitted his belief that the study was conducted for German regulatory approval. Id. at 209. The court explained that “the lack of clear indication that [the clinician’s] work was submitted, or to be submitted, to the FDA argues in favor of a determination that his studies were not reasonably related to FDA submission.” Id. at 209.
Product Samples Shipped to Foreign Regulatory Agencies
Apart from the European clinical studies, the court in NeoRex also considered whether the safe harbor protected shipments of the patented drug from the United States directly to regulatory agencies in the European Union, Hong Kong, and Canada to support approvals in those markets. Id. at 207-08. The defendant asserted that those drug shipments originated from the same manufacturing lot as other samples used for FDA approval and, at most, constituted a de minimis use of the drug. Id. Although acknowledging that “most of the vials were used to generate data for the FDA,” the court, relying on Scripps, concluded that “[u]sing a patented product to seek access to foreign markets is arguably not a de minimis act of patent infringement.” Id. at 208 (citing Scripps, 666 F. Supp. at 1396).
Two years later, the District Court for the District of Massachusetts followed NeoRx and its reliance on Scripps in ruling that the shipment of U.S.-made drug samples “to foreign regulatory authorities was not related to FDA requirements or other federal law and, therefore, was outside the statutory exemption.” Biogen, Inc. v. Schering AG, 954 F. Supp. 391, 397 n.1 (D. Mass. 1996) (citing NeoRx, 877 F. Supp. at 207). The court further distinguished this overseas shipment of drug samples from cases involving the submission of test data to foreign regulatory authorities, noting that the submission of data itself was not an infringing act. See Biogen, 954 F. Supp. at 397 n.1 (citing Intermedics, 775 F. Supp. at 1281 (submission of defibrillator test data for German import approval).
Pre-Clinical Studies Supporting Foreign Regulatory Approvals
In Amgen, Inc. v. Hoechst Marion Roussel, Inc., 3 F. Supp.2d 104 (D. Mass. 1998), the patent owner alleged that “the Defendants are engaged in a world-wide coordinated effort to secure regulatory approval from U.S., Japanese, and European regulators using the same package of data and clinical studies.” Id. at 111. The patentee asserted that “this piggybacking is not what Congress contemplated when establishing the section 271(e)(1) exemption,” especially where some uses of the patented material are directed to non-FDA purposes. Id. Among other things, the patentee argued that the exemption should not apply to uses of the patented biological drug in rabbit pyrogen studies that were appropriate for European regulators but disfavored under FDA guidelines which suggest an alternative in vitro pyrogen study. Id. at 110.
The court refused the patentee’s invitation to “‘read into this statute an unspoken requirement that the disclosure of information obtained during clinical trials to persons other than FDA officials, although not itself an act of infringement, somehow ‘repeals’ the exemption.’” Id. at 111 (quoting Teletronics Pacing Sys., Inc. v. Ventritex, Inc., 982 F.2d 1520, 1524 (Fed. Cir. 1992). The court likewise declined to follow Scripps, reasoning that its analysis incorrectly “conflates the statutory concept of ‘uses’ with the concept of ‘purpose.’” Id. at 107. Consistent with Elan, the court noted that “[t]he phrase ‘solely for uses reasonably related’ is not equivalent to the phrase ‘use is solely for purposes reasonably related.’” Id. And, regarding the rabbit pyrogen testing, the court concluded that even if the tests were neither necessary nor acceptable for FDA review, “they were still reasonably related to the approval process.” Id. at 110. Accordingly, “[u]ses, such as animal testing, human clinical trials, or chemical composition analysis, may be related to FDA approval, and yet be conducted for purposes other than, or in addition to, obtaining FDA approval.” Id. at 107-08 (emphasis in original).
Amgen’s rejection of Scripps’s requirement of a singular focus on FDA approval mirrors a growing number of rulings that apply the safe harbor in contexts where FDA approval is not the sole purpose served in using the patented drug or device. See, e.g., Momenta Pharm., Inc. v. Teva Pharm. USA Inc., 809 F.3d 610 (Fed. Cir. 2015) (promotional purposes); Shaunnessey v. Monteris Medical, Inc., 554 F. Supp.2d 1321, 1328 (M.D. Fla. 2008) (solicitation of funding); Bristol-Meyers Squibb Co. v. Rhone-Poulenc Rorer, Inc., No. 95 Civ. 8833, 2001 WL 1512597 *8 (S.D.N.Y. Nov. 28, 2001) (patent applications). Consistent with Elan, these and other similar cases appear to cast aside the narrow limitations of Intermedics and NeoRx and give some assurance that the safe harbor protections apply generally to clinical work aimed at overseas regulatory approvals that proceeds in parallel with FDA approval. Amgen provides further assurance that the protections of Section 271(e)(1) also accommodate reasonable deviations among the requirements of FDA and overseas approvals.
These cases, however, do not address the more complicated situation suggested in NeoRx and Biogen—where the U.S.-based manufacture of the patented drug or device supports overseas pre-clinical or clinical work under a foreign regulatory application—in the absence of an Investigational New Drug Application (“IND”) or Investigational Device Exemption Application (“IDE”) on file at FDA. Although not expressly on point, the principles and rationale discussed in the Supreme Court’s Merck v. Integra decision suggest that the safe harbor may shelter such overseas pre-clinical and clinical uses of patented drugs or devices made in the United States.
Merck v. Integra & Overseas Regulatory Approvals
In the 2005 Merck case, Integra Life Sciences (“Integra”) owned patents with claims to the tripeptide sequence ARG-Gly-Asp (“RGP peptide”) and sued Merck and its research partner, Scripps Research Institute (collectively “Merck”), asserting that the companies’ pre-clinical synthesis and screening of multiple RGP peptides infringed the patents. The evidence at trial showed that the focus of Merck’s research was eventually narrowed to three different RGP peptides. Ultimately, Merck submitted an IND for only one of the RGP peptides it had studied.
During the litigation, Integra argued, and the Court of Appeals for the Federal Circuit agreed, that the numerous RGP peptide screening experiments for which no IND had been filed were not “reasonably related to the development and submission of information . . . to FDA.” 35 U.S.C. § 271(e)(1). In short, the Federal Circuit concluded that only research reported to FDA can fall within the protection of the safe harbor. See Integra Lifesciences, Ltd. v. Merck KGaA, 331 F.3d 860, 867-69 (Fed. Cir. 2003).
The Supreme Court reversed the Federal Circuit, ruling that the safe harbor “necessarily includes preclinical studies of patented compounds that are appropriate for submission to the FDA in the regulatory process.” Merck, 545 U.S. at 202 (emphasis added). The Court ruled that the safe harbor is “sufficiently broad” to cover “(1) experimentation on drugs that are not ultimately the subject of an FDA submission or (2) use of patented compounds in experiments that are not ultimately submitted to the FDA.” Id. at 206. In other words, the fact that drug development work proceeds in the absence of an IND or IDE does not necessarily deprive that work from safe harbor protection.
Although Merck was focused on early-stage pre-clinical development work, the Supreme Court made clear that these same principles apply with equal force throughout drug development. The Court explained that “even at late stages in the development of a new drug, scientific testing is a process of trial and error” and that in most situations, “neither the drug maker nor its scientists have any way of knowing whether an initially promising candidate will prove successful over a battery of experiments.” Id. The Court emphasized that “§ 271(e)(1) leaves adequate space for experimentation and failure on the road to regulatory approval.” Id. at 207.
As a practical matter, conducting “late-stage” clinical studies in the United States necessarily requires the prerequisite IND or IDE submission in order to use the drug or device in the clinical setting. However, clinical study of a patented drug or device made in the United States may proceed overseas under authorization of a foreign regulatory application—in the absence of an IND or IDE. The question then becomes whether “§ 271(e)(1) leaves adequate space for experimentation” solely in the context of overseas studies?
The Supreme Court explained, “Congress did not limit § 271(e)(1)’s safe harbor to the development of information for inclusion in a submission to the FDA. . . . Rather, it exempted from infringement all uses of patented compounds ‘reasonably related’ to the process of developing information for submission [to FDA].” Merck, 545 U.S. at 206 (emphasis added). According to Merck, “the process of developing information for FDA submission” involves a broad range of experimental work—including non-clinical experimentation and manufacturing process development, pre-clinical in vitro and in vivo studies, and clinical experimentation. See generally Merck, U.S. 545 at 202-05.
Those activities are “protected under § 271(e)(1) as long as there is a reasonable basis for believing that the experiments will produce ‘the types of information that are relevant to an IND or NDA.’” Merck, 545 U.S. at 208 (quoting Brief for United States as Amicus Curiae 23) (emphasis added). The question raised above as to “whether ‘§ 271(e)(1) leaves adequate space for experimentation’ in the context of overseas studies” therefore turns on whether there is “a reasonable basis for believing that the [overseas] experiments will produce the types of information that are relevant to an IND or NDA.” Id.
In some contexts, such a reasonable belief may be plausible.
International Conventions & “Types of Information Relevant to” FDA Review
Under certain circumstances, “FDA will accept as support for an IND or application for marketing approval . . . a well-designed and well-conducted foreign clinical study not conducted under an IND. . . .” 21 C.F.R. § 312.120(a)(1). The acceptance of foreign clinical studies is conditioned upon the studies having been “conducted in accordance with good clinical practice (GCP).” Id. at §312.120(a)(1)(i) (defining “good clinical practice”). In some instances, foreign clinical data may comprise the totality of the clinical data required for marketing approval. FDA regulations expressly contemplate that a new drug application “based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved” when certain conditions are met. See 21 C.F.R. § 314.106(b) (emphasis added).
According to FDA regulations, therefore, FDA may accept non-US clinical studies in support of an IND or NDA (in whole or in part), depending on the studies’ compliance with GCP. The likelihood of FDA accepting foreign clinical data increases when the studies are conducted in countries that participate in The International Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”).
The ICH has been actively harmonizing the GCP requirements among its member nations for several decades. Japan, for example, first adopted the ICH GCP guidelines in 1997. See Ministry of Health, Labor and Welfare Ministerial Ordinance No. 28 (March 27, 1997) (effective April 1, 1997). As another example, the European Medicines Agency was established in 1995 and coordinates the authorization procedures for the national regulatory authorities of the European Union, which have adopted the ICH GCP guidelines.
Recent FDA guidance gives the following report on the scope and function of the ICH GCP harmonization:
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
The objective of this ICH GCP guidance is to provide a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry (March 2018) at 1.
Conducting clinical studies in ICH member countries that have implemented ICH’s harmonized GCP, therefore, adds substantial weight to the basis for believing that the clinical studies will comply with FDA’s GCP requirements. In other words, if the clinical trials comply with the ICH member country’s regulatory requirements (which they must), then it would seem reasonable to believe that the clinical trials will be conducted under harmonized standards, permitting their use in an IND or NDA.
Keep in mind, however, that Merck does not require that the foreign clinical studies actually be accepted or acceptable by FDA in support of an IND or NDA. Rather, Merck requires only “a reasonable basis for believing that the experiments will produce the types of information that are relevant to an IND or NDA.” Merck, 545 U.S. at 208 (emphasis added). Even if FDA were to ultimately reject the foreign clinical data in support of an IND or NDA, there may still be a reasonable basis to believe that the data would be relevant to FDA’s review.
According to FDA regulation, “Although FDA will not accept as support for an IND or [NDA] a study that does not meet [GCP], FDA will examine data from such a study.” 21 C.F.R. § 312.120(a)(2) (emphasis added). See also Merck, 545 U.S. at 204-05 (noting that even preclinical testing “not conducted in conformity with the FDA’s good laboratory practices regulations” may still be relevant to FDA review); Amgen, 3 F. Supp.2d at 109-10 (rabbit pyrogen studies that fell within the safe harbor despite non-conformity with FDA testing requirements). Moreover, even in situations where the overall study results are not included in an IND or NDA, the study sponsors must still report any adverse events or other risk evidence arising from the studies. Under 21 C.F.R. § 312.32(c)(1)(C)(ii), “[t]he sponsors must report any findings from epidemiological studies, pooled analysis of multiple studies, or clinical studies . . . whether or not conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug.” (Emphasis added.)
The expanding global pharmaceutical and medical device markets, the ever-increasing expense of FDA approvals, and the convenience of working with local regulatory agencies often combine to induce drug and device makers to choose first-launch markets outside of the United States. Ordinarily, there is little concern for U.S. patent risk when the development work is conducted entirely outside of the United States. Despite Merck’s apparent framework for applying the patent safe harbor where some aspect of the foreign regulatory work touches the United States, the early cases discussed above have not been expressly overruled and require caution. In varying degrees, each of the early cases demanded some evidentiary linkage between the overseas activity and the pursuit of FDA approval. Amgen and Elan appear to reflect both settled law and the safest course of action—the parallel quest for FDA and overseas approvals.
Although Merck does not condition safe harbor protection on an active IND or IDE submission, the assumption underlying the decision is that the work must target actual drug development in the direction of FDA approval. See Merck, 545 U.S. at 207 (requiring “reasonable basis for believing that a patented compound may work, . . . to produce a particular physiological effect, and . . . if successful, would be appropriate to include in a submission to the FDA”). Drug makers with an established track record of developing drugs for both the U.S. and overseas markets, whether alone or through licensees, are likely best positioned to demonstrate that an overseas first launch does not preclude clinical and other experimental work that produces information appropriate for eventual FDA submission.