Safe Harbor for Preclinical Use of Patented Inventions in Drug Research and Development: Merck KGaA v. Integra Lifesciences I, Ltd.
CRS Report for Congress
Safe Harbor for Preclinical Use of Patented
Inventions in Drug Research and Development:
Merck KGaA v. Integra Lifesciences I, Ltd.
October 7, 2005
Brian T. Yeh
American Law Division
Congressional Research Service ˜ The Library of Congress
Safe Harbor for Preclinical Use of Patented Inventions
in Drug Research and Development: Merck KGaA v.
Integra Lifesciences I, Ltd.
In Merck KGaA v. Integra Lifesciences I, Ltd., __ U.S. __, 125 S. Ct. 2372
(2005), the United States Supreme Court unanimously held that the preclinical use
of patented inventions in drug research is exempted from patent infringement claims
by the “safe harbor” provision of the Patent Act, 35 U.S.C. § 271(e)(1). (Merck
KGaA is a German company unaffiliated with the U.S.-based pharmaceutical
company Merck & Co.) This decision potentially may help expedite the
development of new medical treatments and lower the cost of some drugs for
In 2003, the U.S. Court of Appeals for the Federal Circuit had narrowly
construed the safe harbor provision as protecting only clinical research activities that
produce information for submission to the Food and Drug Administration (FDA) in
the regulatory process. In vacating that decision, the U.S. Supreme Court ruled that
the exemption applies to all uses of patented inventions that are “reasonably related”
to the process of developing any information for FDA submission. The Court
explained that, under certain conditions, the safe harbor provision is even
“sufficiently broad” to protect the use of patented compounds in experiments that are
not ultimately submitted to the FDA or drug experiments that are not ultimately the
subject of an FDA submission. Finally, the scope of the exemption is not limited
only to preclinical studies pertaining to a drug’s safety in humans, but also includes
preclinical data regarding a drug’s efficacy, mechanism of action, pharmacokinetics,
However, the Court cautioned that the exemption does not reach all
experimental activity that at some point, however attenuated, may lead to an FDA
approval process. For example, the safe harbor provision does not embrace basic
scientific research performed on a patented compound without the intent to develop
a particular drug or without a reasonable belief that the compound will cause a
particular physiological effect that the researcher desires. In addition, because the
matter was not at issue in the case, the Court expressly declined to decide whether
or to what extent the exemption applies to patented “research tools” that are often
used to facilitate general research in developing compounds for FDA submissions.
In troduction ..................................................1
The Hatch-Waxman Act....................................2
The FDA Drug Approval Process.............................2
The Scope of Safe Harbor.......................................3
Merck KGaA v. Integra Lifesciences I, Ltd..........................4
Facts of the Case..........................................4
The District Court’s Decision in Integra........................6
Integra in the Federal Circuit.................................6
The U.S. Supreme Court’s Decision in Integra.......................7
Basic Research Not Protected................................8
The Standard for “Reasonable Relation”........................8
An Unresolved Question: Patented Research Tools...............9
Safe Harbor for Preclinical Use of Patented
Inventions in Drug Research and
Development: Merck KGaA v. Integra
Lifesciences I, Ltd.
In Merck KGaA v. Integra Lifesciences I, Ltd., __ U.S. __, 125 S. Ct. 2372
(2005), the United States Supreme Court decided, without dissent, that the patent
law’s safe harbor provision exempts from infringement the preclinical use of
patented inventions in drug research. Without this legal immunity, pharmaceutical
companies face patent infringement liability when they conduct preclinical
experiments using rival companies’ patented compounds. The U.S. Court of Appeals
for the Federal Circuit had earlier found that the statutory exemption applied only to
clinical research activity that contributes “relatively directly” to information the Food
and Drug Administration (FDA) considers in approving a drug.1 This narrow
interpretation of the safe harbor provision had raised concerns that the patent law
could significantly restrict the development and introduction of new medical
treatments and generic drugs.
Vacating the appellate court’s decision, the U.S. Supreme Court unanimously
ruled that the exemption protects all uses of patented inventions that are “reasonably
related” to the process of developing any information for FDA submission, which
includes preclinical studies. The Court’s expansive construction of the safe harbor
provision “leaves adequate space for experimentation and failure on the road to
regulatory approval”2 and “provides a wide berth for the use of patented drugs in
activities related to the federal regulatory process.”3
It is normally a violation of the Patent Act to use any patented invention without
prior authorization of the patent owner.4 However, a statutory exception to this
general rule 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
1 Integra Lifesciences I, Ltd. v. Merck KGaA, 331 F.3d 860, 867 (Fed. Cir. 2003) (citation
2 Merck KGaA v. Integra Lifesciences I, Ltd., __ U.S. __, 125 S. Ct. 2372, 2383 (2005).
3 Id. at 2380.
4 35 U.S.C. § 271(a).
invention ... solely for uses reasonably related to the development and submission of
information” to the United States Food and Drug Administration (FDA).5 Thus, a
party that uses a patented invention without the patent owner’s permission is
committing an infringing act, but if the use comes within the scope of the statutory
exception, the party will not be held liable for violating the patent owner’s rights.
The Hatch-Waxman Act. The statutory exception was created by the Drug
Price Competition and Patent Term Restoration Act of 1984,6 commonly known as
the Hatch-Waxman Act. This legislation modified the Patent Act by creating a new
section, 35 U.S.C. § 271(e), that provides “safe harbor” from infringement for
pharmaceutical companies using patented inventions in their drug research and
The Hatch-Waxman Act is widely credited with encouraging and expediting the
creation and availability of generic versions of approved patented drugs. Prior to its
enactment, pharmaceutical companies had to wait until all relevant patents expired
before undertaking the clinical research necessary to obtain FDA approval of generic
equivalents.7 Thus, an established drug’s patent term was de facto extended beyond
its expiration date by the length of the FDA regulatory process for approving the
generic equivalent, which took more than two years.8 The Hatch-Waxman Act
allows generic drug manufacturers to conduct safety and effectiveness tests during
the time the brand name drug’s patent is still in force, often resulting in immediate
introduction of a generic drug into the market upon the pioneer drug’s patent
ex piration. 9
The FDA Drug Approval Process. The Federal Food, Drug, and Cosmetics
Act (FDCA) regulates the manufacture, use, or sale of drugs.10 Under the FDCA, the
FDA must determine that a drug is safe and effective before it can be marketed to
consumers. The FDCA establishes a two-stage approval process for new drugs: an
5 35 U.S.C. § 271(e)(1).
6 P.L. 98-417, 98 Stat. 1585 (1984), codified in 15 U.S.C. §§ 8b-68c, 70b; 21 U.S.C. §§ 301,
7 The statutory exemption is also called the “Bolar Amendment “ or “FDA exemption,”
since it effectively overturns the decision of the U.S. Court of Appeals for the Federal
Circuit in Roche Products, Inc. v. Bolar Pharmaceutical Co., Inc., 733 F.2d 858 (Fed. Cir.
1984), which had found Bolar, a manufacturer of generic drugs, liable for infringing
Roche’s patented drug during the last six months of the term of the patent in its testing and
investigation activities related to FDA drug approval requirements.
8 Roche, 733 F.2d at 860.
9 For more information regarding the Hatch-Waxman Act, see CRS Report RL30756, Patent
Law and Its Application to the Pharmaceutical Industry: An Examination of the Drug Price
Competition and Patent Term Restoration Act of 1984 (“The Hatch-Waxman Act”), by
Wendy H. Schacht and John R. Thomas; and CRS Report RL32377, The Hatch-Waxman
Act: Legislative Changes Affecting Pharmaceutical Patents, by Wendy H. Schacht and John
10 P.L. 75-717 (1938), codified in 21 U.S.C. §§ 301 et seq.
“Investigational New Drug” (IND) application and a “New Drug Application”
The drug manufacturer must file an IND with the FDA after the company has
identified, through preclinical testing on animals and in test tubes, chemical
compounds that appear to have beneficial therapeutic effects. The IND is a request
for authorization to conduct clinical (human) testing, and it must contain information
and data from the preclinical studies that justify the proposed clinical trial.12
Once the FDA approves the IND, the drugmaker can commence clinical studies.
If these studies demonstrate that a new drug is reasonably safe and effective for use,
the drugmaker is required to submit a NDA.13 The NDA must include data from
preclinical and clinical studies. After extensive review of the NDA, the FDA issues
final approval or denial of the application for manufacturing and selling the new drug
to the public.14
The Scope of Safe Harbor
The Patent Act’s safe harbor provision has often been compared to the “fair use”
defense in copyright law, since it immunizes from liability otherwise infringing acts
in order to advance compelling public policy interests. The legislative history of the
Hatch-Waxman Act provides the basis for this analogy: “Just as we have recognized
the doctrine of fair use in copyright, it is appropriate to create a similar mechanism
in the patent law. That is all this bill does.”15 Despite this deceptively simple
language of purpose, the safe harbor provision has been the subject of confusion and
litigation for many years following its enactment. For over two decades, federal
courts struggled to define the breadth and contours of the exemption, particularly
concerning the types and uses of patented invention covered by the safe harbor.
Types Covered. As for the types of covered patented invention, the United
States Supreme Court in Eli Lilly & Co. v. Medtronic, Inc. expansively interpreted
§ 271(e)(1) to include not only drug and veterinary products, but also medical devices
11 21 U.S.C. § 355(i). Generic drug companies may file an abbreviated new drug application
(ANDA) with the FDA. 21 U.S.C. § 355(j). An ANDA must reveal that the generic product
has the same active ingredients as, and is bioequivalent to, a prior approved brand name
drug. Also, in its ANDA, the generic drug manufacturer may rely upon the safety and
efficacy data of the original drug manufacturer.
12 21 U.S.C. § 355(i)(1)(A).
13 21 U.S.C. § 355(b)(1).
14 For more information concerning the FDA drug approval process, see CRS Report
RL32797, Drug Safety and Effectiveness: Issues and Action Options After FDA Approval,
by Susan Thaul, and CRS Report RL30989, The U.S. Drug Approval Process: A Primer, by
Blanchard Randall IV.
15 H.Rept. 98-857 (II) at 30, 98th Cong., 2d Sess. (1984), reprinted in 1984 U.S.C.C.A.N.
that are subject to pre-market approval by the FDA.16 The Eli Lilly Court determined
that “[t]he phrase ‘patented invention’ in § 271(e)(1) is defined to include all
inventions, not drug-related inventions alone.”17 The Court opined that if Congress
had wanted the safe harbor to cover only generic drugs, “there were available such
infinitely more clear and simply ways of expressing that intent.”18 As written, §
271(e)(1) applies to the “entire statutory scheme of regulation,”19 including “medical
devices, food additives, color additives, new drugs, antibiotic drugs, and human
Uses Covered. Concerning the protected uses of a patented invention, a long
disputed issue was what kind of research in the drug development process qualified
for the exemption: basic research, preclinical research, or clinical studies. These
three stages of drug development are described as follows: basic research involves
the testing of thousands of compounds to discover any biological activity relevant to
understanding the cause of a disease; the preclinical stage involves more focused
research on a smaller group of chemical compounds in the hopes of finding the best
candidate for clinical development; and clinical studies are the testing of the drug on
human subjects in preparation for FDA approval.21 Following its interpretive lead
in Eli Lilly, the Supreme Court in Merck KGaA v. Integra Lifesciences I, Ltd.
(“Integra”) ruled that § 271(e)(1) immunizes from infringement both preclinical and
clinical use of patented inventions in the drug research and development process.
Merck KGaA v. Integra Lifesciences I, Ltd.
Facts of the Case. Integra Lifesciences I, Ltd. (“Integra”) is a
pharmaceutical company that owns five patents related to a sequence of three amino
acids, arginine, glycine, and aspartic acid (the “RGD peptide”), which promotes cell22
adhesion by attaching to receptors on cell surface proteins called integrins.
Scientists working for Telios Pharmaceuticals, Inc. discovered that the RGD peptide
had potential use in promoting wound healing and biocompatibility of prosthetic
devices, prompting Telios to obtain patents for the RGD peptide compositions and
methods. However, after failing to develop a viable commercial product, Telios sold
the patents to Integra.23
16 496 U.S. 661 (1990).
17 Id. at 665.
18 Id. at 667.
19 Id. at 666.
20 Id. at 674.
21 James N. Czaban & Nishita Doshi, Supreme Court Applies Broad Interpretation of Bolar
Amendment to Protect Innovative Drug Research From Claims of Patent Infringement, 70
PAT., TRADEMARK, & COPYRIGHT J. (BNA) 1726 (June 24, 2005).
22 Integra, 331 F.3d at 862-63.
23 Id. at 873 (Newman, J., dissenting).
In the mid-1980s, Dr. David Cheresh at the Scripps Research Institute
(“Scripps”), a non-profit corporation that conducts biochemical research, discovered
that blocking integrin receptors using the RGD peptide inhibited angiogenesis, a
process by which new blood vessels sprout from existing vessels. Angiogenesis
plays a critical role in the spread of many diseases, including cancerous tumor
growth, diabetic retinopathy, and rheumatoid arthritis.24
Merck KGaA (“Merck”),25 a German pharmaceutical corporation unaffiliated
with the U.S.-based pharmaceutical company Merck & Co., was interested in
developing this discovery into a drug to control angiogenesis. In 1988, Merck
entered into an agreement with Scripps to provide funding for Dr. Cheresh’s
research, in exchange for Scripps granting Merck an option to license future
discoveries arising from his research.26 In 1994, Dr. Cheresh succeeded in reversing
tumor growth in chicken embryos using a RGD peptide identified as EMD 66203,
which had been provided by Merck. This peptide was covered by Integra’s patent.27
Due to Dr. Cheresh’s breakthrough achievement, Merck and Scripps entered
into a new collaboration agreement in September 1995 to fund the “necessary
experiments to satisfy the biological bases and regulatory (FDA) requirements for the
implementation of clinical trials” with EMD 66203 or a derivative thereof.28 Dr.
Cheresh then proceeded to conduct in vivo and in vitro experiments on EMD 66203
and two derivatives of it, EMD 85189 and EMD 121974, in order to evaluate each
peptide as potential drug candidates. These “tests measured the efficacy, specificity,
and toxicity of the particular peptides as angiogenesis inhibitors, and evaluated their
mechanism of action and pharmacokinetics in animals.”29 Based on these tests, in
November 1996 Merck’s pharmaceutical steering committee selected EMD 85189
for pre-clinical development; in April 1997, Merck switched to EMD 121974 as its
most promising candidate for clinical testing.30 In October 1998, Merck reached an
agreement with the National Cancer Institute (NCI) to sponsor the clinical trials, and
later that year, the NCI filed an IND application with the FDA for EMD 121974.31
24 Id. at 863.
25 See Merck is Not the Same as Merck, available at
[ h t t p : / / www.me r c k.de/ s er vl et / PB/ me nu/ 1014710/ i ndex.ht ml ] .
26 Telios Pharms., Inc. v. Merck KGaA, 1997 U.S. Dist. LEXIS 24187, Case No. 96-CV-
27 Integra, 125 S. Ct. at 2378 n.3.
28 Integra, 331 F.3d at 863.
29 Integra, 125 S. Ct. at 2378. Efficacy means how well a drug can be expected to work in
curing a disease; mechanism of action is how it achieves those results; pharmacokinetics is
the rate at which a drug is absorbed into and eliminated from the bloodstream; and toxicity
is the negative side effects of the drug at different dosages. Brief for Petitioner Merck
KGaA at 12-13, Merck KGaA v. Integra Lifesciences I, Ltd., 125 S. Ct. 2372 (2005) (No.
30 Telios Pharms., 1997 U.S. Dist. LEXIS 24187, at *5.
31 Integra, 331 F.3d at 873 (Newman, J., dissenting).
When Integra became aware of Merck’s agreement with Scripps to conduct
angiogenesis research for commercial purposes, Integra offered Merck the
opportunity to purchase licenses to use its patented RGD peptides. In July 1996, after
Merck had declined the offer, Integra sued Merck, Scripps, and Dr. Cheresh, seeking
monetary damages for Merck’s alleged patent infringement and a declaratory
judgment against Scripps and Dr. Cheresh.32 In defense, Merck asserted that its
actions involving the RGD peptides came within the common-law research
exemption33 and the statutory safe harbor afforded by § 271(e)(1).
The District Court’s Decision in Integra. At the conclusion of trial, the
U.S. District Court for the Southern District of California dismissed Integra’s claim
for declaratory judgment and held that the common-law research exemption protected34
Merck’s pre-1995 use of the RGD peptides. However, the court found that a
question of fact remained as to whether Merck’s post-1995 actions fell within the
scope of the § 271(e)(1) safe harbor. The district court instructed the jury that, for
Merck to prevail on the safe harbor defense, it must prove by a preponderance of the
evidence that it was objectively reasonable for the company to believe that “there was
a decent prospect” that the experiments “would contribute, relatively directly,” to the
generation of information likely to be relevant to the drug approval regulatory
The jury found Merck liable for infringing Integra’s patents and that Merck had
failed to show that § 271(e)(1) protected its post-1995 research activities. The jury
awarded damages of $15 million in royalties. In response to post-trial motions, the
district court dismissed Integra’s suit against Scripps and Dr. Cheresh, but affirmed
the jury’s monetary award, explaining that there was substantial evidence to show
that the connection between the experiments and FDA review was “insufficiently
direct to qualify for the [§ 271(e)(1) exemption].”36
Integra in the Federal Circuit. In June 2003, a divided panel of the Court
of Appeals for the Federal Circuit affirmed the district court’s determination as to
liability but reversed the court’s refusal to modify the damages award.37 The panel
majority found that safe harbor does not “reach any exploratory research that may
32 Id. at 863.
33 The common-law research exemption is a limited, judge-made exception to the patentee’s
right to exclude. Its historic foundations arise from Whittemore v. Cutter, 29 Fed. Cas.
1120, 1121 (C.C.D. Mass. 1813), in which Justice Story stated, “it could never have been
the intention of the legislature to punish a man, who constructed such a machine merely for
philosophical experiments...” Courts have recognized the use of this exemption for research
that has no commercial purpose. Integra, 331 F.3d at 874-75 (Newman, J., dissenting).
34 Integra, 125 S. Ct. at 2379.
36 Id. at 2380.
37 On remand, the District Court reduced the award to $6.375 million, on the calculated basis
of $1.5 million per year as a reasonable royalty between the infringement period August
rationally form only a predicate for future FDA clinical tests.”38 In confining the §
271(e)(1) exemption to research activities that contribute “relatively directly” to
information “reasonably related” to clinical testing for the FDA, the appellate court
In this case, the Scripps work sponsored by Merck was not clinical testing to
supply information to the FDA, but only general biomedical research to identify
new pharmaceutical compounds. The FDA has no interest in the hunt for drugs
that may or may not later undergo clinical testing for FDA approval.39
Furthermore, the court expressed concern that construing the safe harbor provision
more expansively “would effectively vitiate the exclusive rights of patentees owning
biotechnology tool patents,” since patented research tools are often used in general
research to identify candidate drugs and experiments on those drugs.40
On January 7, 2005, the U.S. Supreme Court granted certiorari to review the
court of appeals’ interpretation of the safe harbor provision.41
The U.S. Supreme Court’s Decision in Integra
The question presented to the Supreme Court was “whether uses of patented
inventions in preclinical research, the results of which are not ultimately included in
a submission to the Food and Drug Administration (FDA), are exempted from42
infringement by 35 U.S.C. § 271(e)(1).” In a unanimous opinion written by Justice
Scalia, the Court vacated the judgment of the Federal Circuit and held that the §
271(e)(1) safe harbor protected the preclinical use of patented compounds “as long
as there is a reasonable basis for believing that the experiments will produce ‘the43
types of information that are relevant to an IND or NDA’” submission to the FDA.
The Court explained:
[W]e think it apparent from the statutory text 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 under the FDCA. ... This
necessarily includes preclinical studies of patented compounds that are
appropriate for submission to the FDA in the regulatory process. There 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 particular44
submission in which it could be included.
38 Integra, 331 F.3d at 867.
39 Id. at 866-67.
40 Id. at 868.
41 Integra, 125 S. Ct. 823 (2005).
42 Integra, 125 S. Ct. at 2376.
43 Id. at 2383-84 (citation omitted).
44 Id. at 2380 (emphasis in original) (citations omitted).
The Court rejected Integra’s argument that the scope of the safe harbor is limited
only to preclinical studies pertaining to the safety of a drug in humans.45 Since the
FDA requires an IND to be filed before human trials can begin, IND applications
must include summaries of a drug’s efficacy, pharmacokinetics, pharmacology, and
toxicological effects in animals.46 This data would necessarily have to be developed
in preclinical studies — information that is “reasonably related” to an FDA
submission and thus covered by § 271(e)(1).47
The Court further disagreed with Integra’s claim that Merck’s preclinical
research is disqualified from safe harbor protection because the experiments were not
conducted in conformity with the FDA’s “good laboratory practices” (GLP)
regulations. Two reasons supported the Court’s reasoning: first, the FDA’s GLP
regulations concerning preclinical studies apply only to experiments on drugs “to
determine their safety,” and not to studies of a drug’s efficacy, mechanism of action,
pharmacology, or pharmacokinetics; second, even non-GLP compliant safety-related
studies are suitable for submission in an IND, when such studies are accompanied by
a reason for the noncompliance.48
Basic Research Not Protected. The Court placed an outer limit to the safe
harbor provision by endorsing the Federal Circuit’s conclusion that the exemption
does not reach all experimental activity that at some point, however attenuated, may
lead to an FDA approval process.49 For example, safe harbor does not embrace basic
scientific research performed on a patented compound without the intent to develop
a particular drug or without a reasonable belief that the compound will cause a50
particular physiological effect that the researcher desires. Thus, the boundary line
between unprotected basic research and protected preclinical research is reached
when a scientist discovers that a patented compound produces a “particular”
physiological effect through a “particular” biological process.51
The Standard for “Reasonable Relation”. In denying safe harbor
protection for Merck’s preclinical activities, the Federal Circuit had relied upon the
fact that the “Scripps-Merck experiments did not supply information for submission
to the [FDA], but instead identified the best drug candidate to subject to future
clinical testing under the FDA processes.”52 The Supreme Court dismissed the
appellate court’s narrow interpretation of the “reasonably related” requirement in §
scientific testing is a process of trial and error,” and that “neither the drugmaker nor
45 Id. at 2381 (“We do not understand the FDA’s interest in information gathered in
preclinical studies to be so constrained.”)
46 21 C.F.R. § 312.23(a)(5).
47 Integra, 125 S. Ct. at 2381.
48 Id. at 2382 (citations omitted).
51 Id. at 2383.
52 Integra, 331 F.3d at 865-66.
its scientists have any way of knowing whether an initially promising candidate will
prove successful over a battery of experiments.”53 Thus, under certain conditions,
the Court noted that the safe harbor provision is “sufficiently broad” to protect the
use of patented compounds in experiments that are not ultimately submitted to the
FDA or drug experiments that are not ultimately the subject of an FDA submission.54
The Court announced a standard for construing § 271(e)(1)’s reasonable relation
requirement in a way that “leaves adequate space for experimentation and failure on
the road to regulatory approval”:
At least where a drugmaker 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, that use
is “reasonably related” to the “development and submission of information under
... Federal law.”55
An Unresolved Question: Patented Research Tools. Research tools
are defined as “tools that scientists use in the laboratory, including cell lines,
monoclonal antibodies, reagents, animal models, growth factors, combinatorial
chemistry and DNA libraries, clones and cloning tools (such as PCR), methods,
laboratory equipment and machines.”56 Smaller biotechnology companies and
universities that invent research tools are concerned that a broader construction of
§ 271(e)(1) encompassing these tools will deprive them of licensing fees that they57
collect from larger pharmaceutical firms. Moreover, some companies rely on such
fees for their financial existence, since many of these research tools have little58
commercial value beyond usage in drug research. The Federal Circuit in Integra
had specifically identified this potential negative consequence for patented research
tools, in its support for a more limited safe harbor:
[T]he context of this safe harbor originally keyed its use to facilitating expedited
approval of patented pioneer drugs already on the market. Extending § 271(e)(1)
to embrace all aspects of new drug development activities would ignore its
language and context with respect to the [Hatch-Waxman Act] in an attempt to
53 Integra, 125 S. Ct. at 2383.
54 Id. at 2382. The legislative history of § 271(e)(1) supports this reasoning: “A party which
develops [information for the FDA regulatory process], but decides not to submit an
application for approval, is protected [by the safe harbor] as long as the development was
done to determine whether or not an application for approval would be sought.” H.Rept. 98-
55 Integra, 125 S. Ct. at 2383 (citing § 271(e)(1)).
56 Integra, 331 F.3d at 874 n.4 (citing Sharing Biomedical Research Resources: Principles
and Guidelines for Recipients of NIH Research Grants and Contracts, 64 Fed. Reg. 72090,
57 David Savage & Denise Gellene, High Court Boosts Drug Research; Justices Say
Companies Are Free to Use Patented Compounds in Developing Medicines. Analysts Say
Ruling May Hurt Some Biotech Firms, L.A. TIMES, June 14, 2005, at C1.
exonerate infringing uses only potentially related to information for FDA
approval. Moreover, such an extension would not confine the scope of §
271(e)(1) to de minimis encroachment on the rights of the patentee. For
example, expansion of § 271(e)(1) to include the Scripps-Merck activities would
effectively vitiate the exclusive rights of patentees owning biotechnology tool
patents. Thus, exaggerating § 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 [Hatch-Waxman Act] was [not] meant ... to deprive entire59
categories of inventions of patent protection.
In its amicus curiae brief submitted to the Supreme Court, the U.S. Government
suggests that § 271(e)(1) does not apply to patented research tools.60 The
Government’s brief explains that the safe harbor section, by its own terms, applies
only to “a patented invention.” The Patent Act defines the term “invention” to mean61
any “invention or discovery,” “unless the context otherwise indicates.” The brief
asserts that the context of § 271(e)(1) indicates that Congress may not have intended
to include patented research tools within the scope of the safe harbor exemption.
Since most research tools are used to study or develop other compounds for
submission to the FDA regulatory approval process, rather than being themselves the
subject of FDA regulatory review, it is plausible to conclude that research tools are62
not “patented inventions” within the meaning of the statute.
In Integra, the Supreme Court expressly declined to decide whether or to what
extent the exemption applies to patented research tools since the matter was not at
issue in the case. The Court explained that Integra had never argued that the RGD
peptides were used by Merck/Scripps as research tools, “and it is apparent from the63
record that they were not.” Thus, without a definitive judicial determination from
the Court, the use of patented research tools in drug research and development may
or may not fall under the § 271(e)(1) exemption from infringement. Such uncertainty
over the patent rights of makers of research tools could serve as a source of continued
confusion and litigation in this area.
The original legislative intent behind the Hatch-Waxman Act that created §
271(e)(1) was to facilitate the introduction of a generic drug upon the patent
expiration of the brand name drug. However, as the Supreme Court explained in the
Eli Lilly case that broadened § 271(e)(1) beyond generic drugs to the entire statutory
scheme of FDA regulation:”[I]t is not the law that a statute can have no effects which64
are not explicitly mentioned in its legislative history.”
59 Integra, 331 F.3d at 867.
60 Brief for United States as Amicus Curiae, at 29, Merck KGaA v. Integra Lifesciences I,
Ltd., 125 S. Ct. 2372 (2005) (No. 03-1237).
61 35 U.S.C. § 100(a) (emphasis added).
62 Brief for United States as Amicus Curiae, at 29.
63 Integra, 125 S. Ct. at 2382 n.7.
64 Eli Lilly, 496 U.S. at 669 n.2 (quoting Pittston Coal Group v. Sebben, 488 U.S. 105, 115
The consequences of the Supreme Court’s decision in Integra are significant.
Some observers argue that if the Federal Circuit’s opinion had not been vacated, its
narrow interpretation of the patent law’s safe harbor potentially would have created
a chilling effect on the development of innovative, pioneer drugs and new generic
drugs. Limiting § 271(e)(1) to only clinical research appears contrary to the
objectives of the Hatch-Waxman Act: If a drug manufacturer could not perform the
preclinical studies needed to obtain FDA approval to conduct clinical studies, “the
[§ 271(e)(1)] exemption would never be reached because the underlying preliminary
research and development work could not be undertaken” without risking patent
The Supreme Court’s more expansive construction of § 271(e)(1) avoids this
result. Since “it will not always be clear to parties setting out to seek FDA approval
for their new product exactly which kinds of information, and in what quantities, it
will take to win that agency’s approval,” the safe harbor provision is needed to
immunize certain preclinical studies that use patented compounds.66 The Court also
provided an articulated standard for courts, scientists, drug companies, and patent
holders to follow concerning the scope of § 271(e)(1) coverage: Safe harbor applies
if there is a reasonable basis to believe that the preclinical experiments will produce
information that is relevant to an IND or NDA submission with the FDA. Failure to
meet this standard would constitute infringing conduct not exempted by § 271(e)(1).
By unanimous opinion, the Integra Court has emphatically clarified that preclinical
use of patented compounds in pharmaceutical research is not categorically
unprotected and can qualify for the patent law’s safe harbor as long as it comes
within this enunciated standard.
However, the Integra Court left unresolved the issue of whether research tools
come within the scope of the safe harbor exemption. It is important to note that
Integra does not affect the validity and value of patented research tools when they are
employed in basic research or for purposes unrelated to an FDA submission.67 Yet
the unauthorized use of research tools in the development of information for the FDA
regulatory process may constitute infringing conduct or could be exempted by the
patent law’s safe harbor. This legal uncertainty raises concerns about the
enforceability of research tool patents in this circumstance. Unless or until the
Supreme Court answers this question in a future case, Congress may desire to clarify
§ 271(e)(1)’s applicability to research tools.
65 Brief for United States as Amicus Curiae, at 14 (quoting Bristol-Myers Squibb Co. v.
Rhone-Poulenc Rorer, Inc., 2001 WL 1512597, at *6 (S.D.N.Y. Nov. 28, 2001)).
66 Integra, 125 S. Ct. at 2383 (citation omitted).
67 Brief for United States as Amicus Curiae, at 30.