C. Integra Lifesciences I, Ltd. v. Merck KGaA
1. Progress of Integra Lifesciences I, Ltd. v. Merck KGaA
1. Progress of Integra Lifesciences I, Ltd. v. Merck KGaA
Integra is the most recent important case interpreting § 271(e)(1).95 On July 18, 1996, Integra filed a complaint against Merck for patent infringement in the Southern District of California. Integra owns five patents related to a short tri-peptide known as an RGD peptide.96 These peptides are known to bind to αυβ3 receptors on the surface of cells.97 A researcher at Scripps Research Institute (Scripps) discovered that blocking these αυβ3
receptors could have therapeutic uses in inhibiting tumor growth.98 Following this discovery, Merck KGaA (Merck) entered into an agreement with Scripps to fund “the necessary experiments to satisfy the biological bases and regulatory (FDA) requirements for the implementation of clinical trials” using a certain cyclic RGD peptide developed at Scripps, or derivatives thereof.99 A derivative of this peptide was later chosen for clinical development. In its case before the Southern District of California, Integra asserted that the agreement between Merck and Scripps was commercial in nature and that research conducted pursuant to that agreement was an infringement of its patents. After trial, a jury found Merck liable for the infringement of four of Integra's patents.100
Merck appealed to the Federal Circuit from the jury’s verdict of infringement. The company asserted that the district court had erroneously interpreted § 271(e)(l).101 In its review of the lower court’s interpretation of the statute, the Federal Circuit announced that the term “solely” limits the safe harbor exemption from extending beyond uses of patented inventions that are reasonably related to those specified in § 271(e)(1).102 The court further
95 Integra Lifesciences I, Ltd. v. Merck KGaA, 331 F.3d 860 (Fed. Cir. 2003), vacated, 545 U.S. 193 (2005).
96 U.S. Patent No. 5,695,997 (issued Dec. 9, 1997); U.S. Patent No. 4,988,621 (issued Jan. 29, 1991); U.S Patent No. 4,879,237 (issued Nov. 7, 1989); U.S Patent No. 4,792,525 (issued Dec. 20. 1988); U.S Patent No. 4,789,734 (issued Dec. 6, 1988).
97 Integra Lifesciences I, Ltd. v. Merck KGaA, RGD peptides are a short tri-peptide segment of fibronectin (an adhesive protein) having the amino acid sequence Arg-Gly-Asp (in single-letter notation, RGD). The RGD peptide sequence promotes beneficial cell adhesion by interacting with αυβ3 receptors on cell surface proteins called integrins. Id.
98 Id. at 863.
99 Id. Merck KGaA began funding research at Scripps in 1988 when Dr. Cheresh, a researcher at Scripps, identified a monoclonal antibody that had activity as an inhibitor of integrin activity. Id. The collaboration was enlarged in 1995 when Dr. Cheresh discovered that a Merck-provided peptide, having the sequence c(RGDfV), inhibits new blood vessel growth by interaction with a specific integrin. Id. In this collaboration, cyclic RGD peptides were synthesized and studied. Id. It was found that some cyclic RGD peptides have anti-angiogenic properties, of interest for the treatment of a host of diseases, including cancer, macular degeneration, and rheumatoid arthritis. Id. "Angiogenic" refers to the process of generating new blood vessels, a process essential to tumor growth. Id. The purpose of the collaborative research was to (1) assess the potential efficacy of the peptides as therapeutic agents; (2) discover the mechanism of the action of the peptides; and (3) shed light on the histopathology, toxicology, circulation, diffusion, and half-life of the peptides in the blood stream. Id. The ultimate goal of the research was to find a product that would be sufficiently effective in the treatment of angiogenic disease that could be developed and brought to market.
Id. at 873-874.
100 Id. at 863-864.
101 Id.
102 Id. at 866. Section 271(e)(1) allows exemption from infringement for patented inventions "solely for uses reasonably related to the development and submission of information under a Federal law which regulates ...
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explained that the limitation created by the term “solely” was essential because “activities that do not directly produce information for the FDA are already straining the relationship to the central purpose of the safe harbor.”103 The safe harbor's central purpose was explained as an express objective to facilitate the immediate entry of generic drugs into the marketplace.
The court thus held that “[t]he safe harbor does not reach any exploratory research that may rationally form a predicate for future FDA clinical tests.”104
Two rationales support the court’s holding. First, the court noted that the FDA has no interest in the general “hunt” for new drugs.105 Rather, it is concerned with specific drugs for which approval is being sought. Second, the court held that Congress had narrowly tailored the safe harbor in order to ensure only a de minimis impact on patent holders' rights.106 This de minimis impact was protected by limiting safe harbor protection to those activities that are reasonably related to the FDA approval of a drug already on the market.
The court therefore concluded that Merck’s activities, which were not related to a drug already on the market, did not fall under the safe harbor.107
The Federal Circuit held that general research activities used to screen potential drug candidates were not protected by the safe harbor of § 271(e)(1).108 The court also argued that if the safe harbor exemption was expanded to include Merck’s activities, it would
“effectively vitiate the exclusive rights of patentees owning biotechnology tool patents.”109
[E]xpansion of section 271(e)(1) to include [new drug development] activities would effectively vitiate the exclusive rights of patentees owning biotechnology tool patents. After all, patented tools often facilitate general research to identify candidate drugs, as well as downstream safety-related experiments on those new drugs. Because the downstream clinical testing for FDA approval falls within the safe harbor, these patented tools would only supply some commercial benefit to the inventor when applied to general research. Thus, exaggerating section 271(e)(1) out of context would swallow the whole benefit of the Patent Act for some categories of biotechnological inventions. Needless to say, the 1984 Act was meant to reverse the effects of Roche under limited circumstances, not to deprive entire categories of
drugs or veterinary biological products." 35 U.S.C. § 271(e)(1).
103 Integra, 331 F.3d at 866.
104 Id. at 866-867.
105 Id. at 866. In using the word "hunt" the court elaborated upon its meaning by saying that "the FDA does not require information about drugs other than the compound featured in an Investigational New Drug application."
106 Id. at 867.
107 Id.
108 Integra, 331 F.3d at 867-868.
109 Id. (explaining that patented tools facilitate general research in identifying and testing the safety of new drugs).
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inventions of patent protection.110
By stating that the “downstream clinical testing ... falls within the safe harbor,” the Federal Circuit implied that use of patented research tools is eligible for § 271(e)(1) protection, provided that the research tools are used pursuant to a testing phase of a new drug approval process. Integra directly affirmed and narrowed the scope of the “reasonably related” test111 set forth in Intermedics,112 and, for the first time, directly commented on the status of research tools with respect to the safe harbor. The court explained that many patents cover tools that are used to facilitate general research to identify candidate drugs and to test the safety of those newly identified drugs. The court acknowledged that such tools fall within the safe harbor when used for clinical testing required for FDA approval, yet argued that they would hold little commercial benefit to the patent holder if they fell within the safe harbor when used to support general research. The court then held that if § 271(e)(1) was
“exaggerated,” it “would swallow the whole benefit of the Patent Act for some categories of biotechnological inventions.”113
In 2005, the Supreme Court rejected the Federal Circuit’s holding and construed the provision more broadly, but impliedly affirmed the Federal Circuit's stance on symmetry.114 The Court sided with the Federal Circuit's analysis of Eli Lilly as decided in AbTox, that the plain language trumps any symmetry.115 The Court held that the exception was not limited to tests that generate safety and effectiveness data; rather, it included “any” tests (including basic research on biological mechanisms) that might generate data submitted to the FDA.
Addressing the Court’s conclusion116 that the § 271(e)(1) exemption was largely limited to bioequivalency studies, the Supreme Court added, “[t]here 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”.117 Rather, the safe harbor includes within its scope “(1) experimentation on drugs that are not ultimately the subject of an FDA submission or (2) use of patented compounds in
110 Id. (emphasis added). Congress added § 271(e)(1) after the main quid pro quo (term extension and changes to the FDCA to make ANDA approval available to generic manufacturers) to take care of the de facto term extension.
111 Intermedics, Inc. v. Ventritex, Inc., 775 F. Supp. 1269, 1280 (N.D. Cal. 1991), aff'd, 991 F.2d 808 (Fed. Cir.
1993) (discussing the reasonably related test).
112 Stephen A. Becker, I PATENT APPLICATIONS HANDBOOK § 3:19 (2005 ed.). “[T]he Federal Circuit held that the exemption is limited to uses reasonably related only to the development and submission of information for FDA safety and effectiveness approval process.” Id. (emphasis added)
113 Id.
114 Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (Congress extended § 271(e)(1) protection to "all uses . . . ‘reasonably related’ to [the development of] information f o r submission under a federal law regulating ... drugs").
115 Id. at 2382-84.
116 Integra Lifesciences I, Ltd. v. Merck KGaA, 331 F.3d 860 (Fed. Cir. 2003).
117 Id.
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experiments that are not ultimately submitted to the FDA”.118
While preclinical work need not directly generate information for inclusion in an FDA submission, the Supreme Court held that use of another’s patented invention must still be
‘reasonably related’ to the development and submission of information to the FDA for § 271(e)(1) to apply. According to the Court, a reasonable relationship exists, and the safe harbor applies, “[a]t least where a drug maker has a reasonable basis for believing that a patented compound may work, through a particular biological process, to produce a particular physiological effect, and uses the compound in research that, if successful, would be appropriate to include in a submission to the FDA”.119 The Court’s requirement that the experimentalist at least have a notion of the biological mechanism underlying the drug’s effect appears to be an effort to exclude basic research from the scope of the safe harbor.120
The Supreme Court explicitly refrained, however, from addressing whether its expansive reading of § 271(e)(1) might permit drug researchers freedom to use not just patented compounds in their work, but patented research tools as well. Because Integra had not argued that its patented RGD peptides were research tools, the Supreme Court explicitly did 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”.121 The Supreme Court vacated the Federal Circuit’s decision and remanded the case to the appeals court for fresh review of the evidentiary record in view of the correct, newly enunciated legal standard.
Moreover, the Supreme Court did not comment on the scope of “patented invention” in
§ 271(e)(1).122 The Court explicitly declined to address the application of the regulatory approval exception to patented research tools, and did not address the scope of the experimental use exception. In a footnote, the Court opined, “We ... do not . . . express a view about whether, or to what extent, [section] 271(e)(1) exempts from infringement the use of ‘research tools’ in the development of information for the regulatory process.”123
The Supreme Court agreed with the Federal Circuit that “basic scientific research on a particular compound, performed without the intent to develop a particular drug or a
118 Id. at 206.
119 Id. at 207.
120 Id. Basic scientific research on a particular compound, performed without the intent to develop a particular drug or a reasonable belief that the compound 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.
121 Id. at 205.
122 Id. at 2382-83.
123 Id. at 2382 n.7. In the Supreme Court’s defense, however, Integra did not argue that the patents in issue covered research tools or that Merck used them as research tools. Id. at 2382-84. Thus, the court did not comment on the applicability of § 271(e)(1) to research tools.
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reasonable belief that the compound will cause the sort of physiological effect the researcher intends to induce” is surely not “reasonably related” in the meaning of § 271(e)(1). Although the scope of “reasonably related” is unresolved after Integra, one may infer that as the holding relates to research tools, anything goes to research tools may be used by pioneer or generic drug companies, license free, provided the end goal leads to development of information that could be submitted under an IND, NDA, or ANDA, regardless of the timing or whether the information is ever submitted to the FDA.124 Thus, the holding did little to clarify the research tool problem. It only further confused the issues as they relate to research tools.
In 2007, the U.S. Court of Appeals for the Federal Circuit has issued an opinion on remand from the Supreme Court’s decision125, Integra argued that at least some of Dr Cheresh’s preclinical work on the cyclic peptides was directed to generating information that was never submitted to the FDA, and thus fell outside the safe harbor. The majority rejected this argument, and others raised by Integra, as inconsistent with the Supreme Court’s broad interpretation of § 271(e)(1), according to which “all uses of patented compounds reasonably related to the process of developing information for submission to the FDA”
would be exempted from infringement.126
As explained in the majority opinion, whether a use is ‘reasonably related’ to developing information for submission to the FDA is established at the time of the experiment, and does not depend on the success or failure of the experimentation or actual submission of the experimental results.127 Even work on compounds “not ultimately proposed for clinical trials” is protected “when there was a reasonable basis for identifying the compounds as working through a particular biological process to produce a particular physiological effect”.128 The majority also explained that the experiments must reasonably be expected to produce information relevant to a submission to the FDA for the safe harbor to apply.129 If these requirements are satisfied, § 271(e)(1) “applies to experiments conducted to determine the optimum candidate drug, including experiments with rejected candidates”.130 Applying these standards, the majority of the judges on the appellate panel inquired whether the Merck defendants had a reasonable basis for believing the cyclic RGD peptides would work in a particular way to yield a particular effect, and also considered 16 different categories of experiments conducted by Dr. Cheresh using the peptides to determine if each was designed to yield the type of information that would be relevant for
124 Id. at 2382-2383.
125 Integra Lifesciences I, Ltd v. Merck KGaA, 496 F.3d 1334 (Fed. Cir. 2007).
126 Id. at 1338.
127 Id. at 1341.
128 Id.
129 Id. at 1340.
130 Id. at 1341.
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inclusion in an IND submitted to the FDA.131
2. Analysis of Disputed Patent Claims in Integra v. Merck and Rader’s