WAS THE FDA EXEMPTION TO PATENT INFRINGEMENT, 35 USC § 271(e)

Boston College Intellectual Property & Technology Forum http://www.bciptf.org

Copyright © 2007 Boston College Intellectual Property & Technology Forum, Paul Wiegel, Esq.

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WAS THE FDA EXEMPTION TO PATENT INFRINGEMENT, 35 U.S.C. § 271(e)(1), INTENDED TO EXEMPT A

PHARMACEUTICAL MANUFACTURER'S ACTIVITIES IN THE DEVELOPMENT OF NEW DRUGS?

Paul Wiegel, Esq.

Candidate for LL.M. in Intellectual Property, Max Planck Institute, 2007

J.D., University of Baltimore School of Law, 2006

B.S. Biology, Pennsylvania State University, 1997

INTRODUCTION

The general rule of patent infringement, 35 U.S.C. § 271(a), states: “whoever without authority makes, uses, offers to sell, or sells any patented invention, within the United States or imports into the United States any patented invention during the term of the patent therefor, infringes the patent.” Congress created the so-called FDA exemption with the Drug Price Competition and Patent Term Restoration Act of 1984 (“1984 Act”), later codified in 35 U.S.C. § 271(e)(1), which states: [i]t 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 ... 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. [1] Attached as Appendix A. The FDA exemption was created as a part of a legislative package intended to speed generic pharmaceuticals to the market in hopes of reducing the price of pharmaceuticals and increasing access. [2] Included in the legislation was a compromise between the interests of the brand and generic pharmaceutical industries. In order to speed generics to the market, the generic pharmaceutical companies were given the ability to file an ANDA, an abbreviated application for marketing approval, and the FDA exemption from patent infringement. [3] The ANDA allows a generic manufacturer to file for FDA approval prior to the expiration of the brand patent. The FDA exemption allows the generic manufacturer to do the studies necessary to prove bioequivalence, a requirement of the ANDA, while the brand medication's patent is still in force. In exchange, the brand pharmaceutical industry received the ability to extend the terms of their patents to compensate for the long regulatory approval process. The legislative history of the FDA exemption clearly shows that it was intended to apply only to generic pharmaceuticals. The legislation, in part, was meant to cure the unfair patent term extension that resulted when a generic manufacturer had to wait until the expiration of the brand patent before applying to the FDA for regulatory approval. [4] It was hoped that the legislation would get generic drugs to the market around two years earlier than under the prior system. [5] Both the Supreme Court and the Federal Circuit have interpreted the text of the FDA exemption. In Eli Lilly and Company v. Medtronic, Inc., the Supreme Court interpreted the exemption to include medical devices. [6] In Intermedics, Inc. v. Ventritex Co., Inc., the Federal Circuit held that an intent to commercialize prior to the expiration of the patent did not violate the exemption. [7] In the subsequent Merck v. Integra case, the Supreme Court and the Federal Circuit considered the meaning of the phrase “solely for uses reasonably related to the development and submission of information under a Federal law.” [8] At first instance, the Federal Circuit interpreted this language narrowly. [9] In the majority opinion, Judge Rader focused on the word “solely” in the statute and viewed it as limiting. [10] Applying the statute narrowly, the court found that the Scripps experiments, which were designed to identify a new drug candidate, did not fall within



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the exemption. [11] Judge Rader also held that if the FDA exemption were interpreted broadly so as to include the Scripps experiments then the exemption may unintentionally destroy the patent protection for all research tools. [12] On appeal, the United States Supreme Court interpreted the exemption as including “all uses of patented compounds ‘reasonably related’ to the process of developing information for submission under any federal law regulating the manufacture, use, or distribution of drugs.” [13] This interpretation creates a vast exemption to patent infringement that goes well beyond the scope of Congress's intent and well beyond reason. The FDA exemption was not created to assist in the generation of new drug candidates, which are included in the broad interpretation of the “reasonably related” language by the Supreme Court in Merck. Applying the Supreme Court's interpretation to the facts of Merck means that a pharmaceutical manufacturer may use the patented products and methods of another manufacturer to identify new drug candidates and not infringe. In fact there is almost no limit to what can be considered “reasonably related” to the development of information for submission to the FDA since a great deal of the research and development in the natural sciences is directed at identifying new drugs. Patented research tools are particularly vulnerable because they are often used in basic research that may now be considered “reasonably related” to submission to the FDA. Arguably, any use of the two research method patents at issue in Merck, the '997 and '237 patents, could be considered “reasonably related” under the Supreme Court's broad interpretation. [14] Such development of new drugs using others' patented technology was not meant to fall under Congress's exemption to patent infringement.

BACKGROUND

I. Prior to the enactment of the 1984 Act Prior to the enactment of the Drug Price Competition and Patent Term Restoration Act of 1984, the Federal Circuit considered an exemption for information submitted to the FDA in Roche Products, Inc. v. Bolar Pharmaceutical Co., Inc. 733 F.2d 858 (Fed. Cir. 1984). Roche, a research-oriented pharmaceutical company, owned the rights to the patent claiming flurazepam hydrochloride, with the brand name Dalmane. [15] Prior to the expiration of the Dalmane patent, Bolar, a generic drug manufacturer, obtained a quantity of Dalmane and began the testing necessary to obtain regulatory approval on its generic equivalent. [16] Bolar intended to market the generic after the patent on Dalmane expired. [17] Roche sued Bolar claiming infringement, and Bolar, in response, argued for the creation of a new FDA exemption for reasons of the public policy favoring generic drugs. [18] Bolar argued that pharmaceutical companies gain “a de-facto monopoly upwards of [two] years by enjoining FDA-required testing of a generic drug until the patent on the drug's active ingredient expires.” [19] Preferring to leave the creation of an exemption to Congress, which was then debating legislation addressing this issue, the court held that Bolar infringed Roche's patent. [20]

II. Statutory interpretation Congress responded within months of the Roche decision by enacting the FDA exemption, as a part of the Drug Price Competition and Patent Term Restoration Act of 1984. From an initial reading of the FDA exemption, it is difficult to determine the statute's scope. Even the Supreme Court, when concluding that medical devices were included within the scope of the FDA exemption, stated that if only patents related to drugs were meant to be exempt then “there were infinitely more clear and simple ways” for Congress to express its intent. [21] For this reason, it is helpful to look to traditional statutory interpretation techniques in determining the meaning of the FDA exemption. First, “where the language is plain and admits of no more than one meaning, the duty of interpretation does not arise, and the rules which are to aid doubtful meanings need no discussion.” [22] Additional approaches to statutory interpretation are applied when a plain language interpretation of a statute leads to “absurd or wholly impracticable consequences.” [23] A second approach evaluates the title of the act as it is sometimes persuasive as to the statute's meaning, even though “the title of an act cannot overcome the meaning of plain and unambiguous words used in its body.” [24] A third approach that is applied in cases of doubtful interpretation interprets a statute in light of the legislative history aiding the courts in reaching the true intent of the legislation. [25]



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A. Plain meaning The FDA exemption states: “[i]t 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 ... 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.” [26] Two questions emerge from a reading of the statute: 1) What is considered a patented invention, and 2) what does the federal law which regulates the manufacture, use, or sale of drugs require?

1. A patented invention A patented invention is the “teaching” that is claimed in an issued patent. [27] Typical claims in pharmaceutical patents include: 1) a composition of matter, 2) a method of manufacture, 3) a method of treatment, [28] and 4) a method of administration. In recent years, some pharmaceutical patent applications also claim research methods such as the screening for biological agents effective in inhibiting tumor cell growth [29] and for identifying ligands of a certain protein important for treating a certain disease. [30] These research methods claim the process in which a patentee searched for and likely discovered the new therapeutic agent. In Merck, the patented invention included the following: the '525 patent claimed a peptide having cell-attachment promoting activity, the '734 patent claimed a cell surface receptor capable of binding to specific polypeptide, the '997 patent claimed a method of altering cell attachment activity of cells, comprising contacting the cells with an RGD peptide, and the '237 patent claimed a method of controlling the peptide mediated attachment of animal cells. [31] It is important to notice that both product and process patents are at issue in this case. It is yet unclear whether the statutory language “patented invention” is intended to include both product and method patents.

2. The Federal Food, Drug and Cosmetic Act (FDCA) requirements The FDCA regulates the manufacture, use, or sale of drugs and describes the information that must be submitted to the Food and Drug Administration (FDA) in order to obtain a regulatory approval. [32] There are three types of applications that are submitted to the FDA: the Investigational New Drug Application (IND), the New Drug Application (NDA), and the Abbreviated New Drug Application (ANDA). [33] After a new drug is identified, screened for therapeutic effect and its safety is evaluated in animals, the owner can apply for an IND. [34] The IND allows the FDA to evaluate whether a new drug is safe for use in human clinical trials. [35] Once an IND is granted, the product may be used in clinical trials on humans, and then can be distributed in interstate commerce for use by investigators. [36] The next step for a pharmaceutical is the NDA application. [37] The NDA is the final stage of regulatory approval that determines whether a new drug will be approved for sale and marketing in the United States. [38] Alternatively, the ANDA is exclusively for generic drugs. [39] An ANDA allows the FDA to evaluate whether a generic drug is bioequivalent to the brand medication that it hopes to replace. [40] Once an ANDA is granted, the generic manufacturer can make and sell its generic equivalent. [41] The IND, NDA, and ANDA applications all have specific requirements. An IND, in part, must include animal safety data, a description of possible side effects or risks to be anticipated, and any special precautions that must be taken during study in humans. An NDA, in part, must contain full reports on the drug's safety and efficacy, a description of the methods of clinical study, manufacture and packaging, and specimens of the proposed labeling. [42] An ANDA, in part, must contain information to prove that the active ingredient of the generic is the same as the brand in its chemical composition, route of administration, and dosage. [43] B. Title of the Act In addition to the plain meaning of the statute, the title of the Act that created the FDA exemption is persuasive as to its interpretation as applying to only generic drugs. [44] The FDA exemption was created by Congress as a part of the Drug Price Competition and Patent Term Restoration Act of 1984. From a reading of the title, the statute was likely drafted in order to create competition in the drug market based upon drug price and to restore the terms of patents. The sections of the statute that intended to have an effect on drug price are in Title I, which allows generic



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drug manufacturers to file an ANDA prior to the expiration of the patent of the original brand, and Title II, Section 202, which creates the FDA exemption to patent infringement. [45] It is likely that a statute that intends to create competition in the drug market based upon drug price is meant to increase access to generic drugs, not new drugs, because brand pharmaceutical manufacturers seldom bring new drugs to the market at a price substantially lower than their brand competitors. Generic pharmaceuticals, in contrast, often enter the market at a substantially lower price than their brand counterparts. Thus, the FDA exemption and the ANDA application were drafted together, under a title suggesting that both worked to create drug price competition. Accordingly, one way for Congress to create drug price competition in the market would be to accelerate the progress of generic pharmaceuticals to the market. It is likely that because the concurrent ANDA application process applies only to generic drugs, and the legislative history described below so suggests, the FDA exemption was also intended to apply only to generic drugs. C. Legislative history Strong arguments exist that because the language of FDA exemption is not clear on its face, the legislative history should be consulted to understand its meaning. [46] The exemption's lack of clarity is demonstrated by the Supreme Court's debate in Eli Lilly concerning whether “a federal law which regulates the manufacture, use or sale of drugs” was meant to refer to only individual provisions that regulate drugs, or to the entirety of any act where at least some provisions regulate drugs. [47] If the Supreme Court struggled with the meaning of language of the FDA exemption, it is clear that a look to the legislative history could be helpful in understanding the intent of the statute.

1. The 1984 Act was intended to make generic drugs available more quickly. The legislative history is full of excerpts where Congress expressly stated that the FDA exemption was intended to apply only to generic drugs. Further, the legislative history suggests that the exemption was created to cure the unfair extension of a brand's patent term that resulted from a generic drug company having to wait until the brand patent expired before the generic drug company could conduct the tests necessary to gain FDA approval. [48] First, “Title II provides that it is not an act of patent infringement for a generic drug maker to import or to test a patented drug in preparation for seeking FDA approval if marketing of the drug would occur after expiration of the patent.” [49] A good question to ask is “[w]ho would want to use a patented product for successful experimentation, make a breakthrough discovery, but not market that new discovery until the patent on the product used for experimentation expired?” [50] The answer is clear, that only generic pharmaceutical manufacturers would be able to benefit from this type of experimentation, as only their products will not be marketed until the expiration of the patent on the brand. In response to the House Bill that resulted in the 1984 Act, the pharmaceutical manufacturers argued that the FDA exemption would constitute an unconstitutional taking of property under the Fifth Amendment. [51] The House Judiciary Committee rejected this argument, by affirming that “the only activity which will be permitted by the bill is a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute.” [52] The Committee concluded that the FDA exemption was essential to the goal of getting generic substitutes to the market as quickly as possible and would likely bring generic drugs to the market between eighteen months and two years earlier than without this provision. [53]

2. What if the infringing company does not apply for FDA approval? The legislative history clearly states its intention to allow generic pharmaceutical manufacturers to use patented products in order to show bioequivalence to the FDA. But if a generic manufacturer never actually submits the information gained by infringing the branded product, is it then liable for infringement? This issue of whether or not information obtained by infringement is submitted to the FDA arose in Merck. Congress discussed this issue and concluded that a party is still protected even if they decide not to submit an application to the FDA as long as the studies were done to determine whether an application would be sought. [54]



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III. Drug Process In order to better understand the facts and issues involved in Merck, an overview of the pharmaceutical production process may be helpful. Generally, the process of bringing a new drug to the market can be divided into three stages: identification, preclinical, and clinical. [55] The identification stage includes the discovery of new chemical compounds that may have a therapeutic effect. [56] These chemical compounds are identified by the use of computer simulations and combinatorial chemistry that screen compounds for therapeutic activity. [57] The preclinical stage is made up of laboratory and animal testing of compounds to ensure their safety for use in humans. [58] Preclinical laboratory testing provides the product's pharmacokinetic, toxicologic, biologic, and chemical properties for inclusion in an IND application submitted to the FDA. [59] The final pre-market stage, clinical testing, analyzes drug effects on human beings to determine the drug's effective dose, side effects, and overall safety and effectiveness in humans. [60]

IV. The FDA exemption as interpreted by the courts. A. Eli Lilly and Company v. Medtronic, Inc. Fifteen years before Merck, the Supreme Court first interpreted the FDA exemption to include medical devices in addition to drugs. [61] In Eli Lilly and Company v. Medtronic, Inc., Eli-Lilly's predecessor-in-interest sued to enjoin Medtronic from testing and marketing an implantable cardiac defibrillator. [62] The District Court below found that the FDA exemption did not apply to medical devices. [63] However, on appeal, the Court of Appeals for the Federal Circuit reversed, holding that medical devices did fit within the FDA exemption. The case was remanded for a determination of the issue of whether Medtronic's activities had been undertaken to develop information reasonably related to the development and submission of information necessary to obtain regulatory approval under the FDCA. [64] This decision was appealed to the Supreme Court, which separated the FDA exemption into elements and analyzed each individually. [65] First, the Supreme Court stated that a “patented invention” is defined in 35 U.S.C. § 100(a) to include all inventions, not just drug-related inventions. [66] Second, a “federal law” was determined to refer to an entire Act, such as the FDCA, wherein at least some part regulates drugs and not just the isolated sections of a statute that regulate drugs. [67] Third, the Court argued that if Congress had intended that only drug patents were to be included in the exemption, then “there were available infinitely more clear and simple ways of expressing that intent.” [68] The Supreme Court argued that § 201, which deals with the extension of patents, and § 202, which creates the FDA exemption, are a part of a single legislative package. [69] Since § 201 defines “product” broadly to include a medical device, food additive or color additive, § 202 also should be viewed broadly to include medical devices. [70] From this structure, the Court reasoned that Congress likely intended both the § 201 extension and § 202 exemption to apply to the same products. [71] Therefore, the Court concluded that “any federal law” is broad enough to include medical devices, but conceded that “it is somewhat difficult to understand why anyone would want it to mean that.” [72] In its opinion, the Supreme Court reviewed the legislative history and agreed that the 1984 Act was designed to respond to the unintended extension of a patent when a generic competitor cannot begin bioequivalence studies until the brand medication's patent expires. [73] Additionally, the Court stated that the 1984 Act created the ANDA, in combination with the FDA exemption, to enable drugs to obtain marketing approval and to get to market in an abbreviated amount of time. [74] Although considered, the court disregarded the legislative history and applied a plain meaning interpretation of the statute to include medical devices. [75] The dissent, however, argued that the phrase “a Federal law which regulated the manufacture, use or sale of drugs” refers only to laws that regulate drugs, and not anything else. [76] The dissent supported its argument by providing examples of dozens of courts that interpreted the same phrase “any law which regulates ...” to include only the statutory sections that regulated the subject listed in the statute. [77] Through this analogy, the dissent argued that § 271(e)(1) applies only to the statutory sections of the FDCA that regulate drugs, not to the entire FDCA or any other act. [78]



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B. Intermedics, Inc. v. Ventritex Co., Inc., 991 F.2d 808 (Fed. Cir. 1993). Another interpretation of the FDA exemption came twelve years before Merck in Intermedics, Inc. v. Ventritex Co., Inc., which considered whether an intent to commercialize prior to the expiration of the patentee's patent violated the FDA exemption. [79] The court found no such limitation in the exemption and held that the intent to commercialize prior to the expiration of the patent did not violate the exemption. [80] In Intermedics, the defendant Ventritex developed an implantable defibrillator and began clinical trials in order to obtain FDA approval. [81] Ventritex even sold and demonstrated the defibrillator at trade shows. [82] Intermedics sued alleging patent infringement. [83] Since the Supreme Court in Eli Lilly held that medical devices were included in the FDA exemption, the Federal Circuit limited its analysis “solely for uses reasonably related to generating data to submit to the FDA.” [84] The court held that even if these activities were infringement, they were exempt because their use was reasonably related to procuring FDA approval. [85]

V. The Facts of Merck In order to predict the future effect of the Supreme Court's holding in Merck v. Integra, it is important to understand the facts. In Integra Lifesciences I, Ltd. v. Merck KGaA, Integra sued Merck for alleged infringements of its RGD peptide patents during experimentation for development of new drug candidates. [86] Integra was the owner of U.S. patent numbers 4,792,525, 5,695,997, 4,879,237, 4,789,734, and 4,988,621, all of which related to the RGD peptide. [87] [88] The RGD peptide promotes cell adhesion by interacting with alpha v beta 3 receptors on the surface of cells. [89] This increase in cell adhesion is thought to result in the promotion of wound healing and a potential increase in the biocompatibility of prosthetics. [90] Dr. David Cheresh, a Scripps Research Institute scientist hired by Merck, recognized that blocking the alpha v beta 3 receptors inhibited angiogenesis, a valuable characteristic in the treatment of tumors. [91] Merck KGaA (“Merck”), Scripps, and Dr. Cheresh worked to identify potential drug candidates that might inhibit angiogenesis. [92] Dr. Cheresh identified the RGD peptides EMD 66203, 85189, and 121974 as potential candidates for development. [93] Scripps conducted several experiments, in vivo and in vitro, in order to evaluate the specificity, efficacy, toxicity, and mechanism of action of the identified peptides. [94] These tests used the RGD peptides as controls against which to measure the efficacy of the new test drugs. [95] Integra learned of these experiments and, believing that the activities infringed on its patents, offered Merck the opportunity to license its peptides, which Merck subsequently refused. [96] Although not admitted as evidence at trial, an IND was later filed for EMD 121974 in 1998. [97]

VI. The Federal Circuit opinion in Merck v. Integra The Federal Circuit relied on both legislative history and the text of the Drug Price Competition and Patent Term Restoration Act of 1984 (the 1984 Act) to decide that Merck infringed on Integra's patents and the FDA exemption did not apply. In its opinion, the court stated that the 1984 Act had the following two purposes: 1) “to restore patent term to pharmaceutical inventions to compensate” for the lengthy FDA approval process, and 2) “to ensure that a patentee's rights did not de facto extend past the expiration of the patent term because a generic competitor also could not enter the market without regulatory approval.” [98] The Federal Circuit also cited the legislative history when it stated that 1) pre-market approval activities “conducted for the sole purposes of sales after patent expiration” are exempt; [99] and 2) the pre-market activity was “a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute.” [100] In its analysis of the 1984 Act's text, the Federal Circuit focused on the “solely”-language and interpreted it as limiting what is considered “reasonably related” to submission to the FDA. [101] The Federal Circuit interpreted the FDA exemption to apply to activities “‘solely for uses reasonably related to the development and submission of information’ to the FDA.” [102] Applying the terms of the 1984 Act's legislative history and textual interpretation to the instant case, the Federal Circuit determined that the exemption was too narrow to include Merck's activities. The court described the Scripps-Merck experiments broadly as preclinical studies that were designed to identify the best drug candidate, but did not result in the supply of information for submission to the FDA. [103] In the context of this case, the word



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“preclinical” included the identification phase of research. [104] The court held that the general biomedical research done by Scripps-Merck did not fall within the FDA exemption because the research during the identification phase did not contribute “relatively directly” to information the FDA considers in approving a drug. [105] The court followed that the “reasonably related” language does not allow for an interpretation broad enough to include any stage of development merely because the products will also need FDA approval. [106] The court supported its holding by reemphasizing the express objective of the 1984 Act “to facilitate the immediate entry of safe, effective generic drugs into the marketplace upon expiration of a pioneer drug patent.” [107] The court noted that the ANDA and FDA exemptions work together towards this goal, [108] and that generic drug companies could not perform the bioequivalency testing required for an ANDA unless the FDA exemption protected those activities. [109] Finally, the Federal Circuit concluded that expanding the FDA exemption to include the facts of this case would make the patents to research tools worthless. [110]

VII. Amicus submitted on appeal to Supreme Court. In order to gain a broader understanding of the issues at hand and to help the reader evaluate the credibility of each parties' arguments, a representative group of the Amicus filed to the Supreme Court must be reviewed. A. Arguments for a broad interpretation of the exemption.

1. Brief of Amicus Curiae Wyeth in Support of Petitioner. Wyeth in its Brief of Amicus Curiae argued for a broad interpretation of the exemption, relying on precedent prior to the Federal Circuit's decision in Merck, and predicted a “chilling effect” on new drug development if the court interpreted the exemption narrowly. Wyeth argued that, under the Supreme Court's interpretation of the FDA exemption in Eli Lilly, the test is whether the alleged infringing use of the patented products was “reasonably related” to acquiring FDA approval. [111] Wyeth further argued that the fundamental purpose of the FDA exemption was to permit companies to develop information for submission to the FDA without fear of patent infringement actions. [112] The information, however, need not actually be submitted to the FDA in order for a drug developer to qualify for the exemption. [113] Wyeth then concluded that all activities “reasonably related” to the development and submission of information to the FDA should be exempt. [114] Wyeth argued that the activities performed in Merck are crucial to the development of new medicines and for this reason should be exempted. [115] Additionally, Wyeth concluded that the Federal Circuit's narrow interpretation of the FDA exemption, if affirmed, would “chill the pharmaceutical industry's incentive to conduct new drug research and development” and because many countries have broader research exemptions to infringement, it is likely that the companies will “outsource new drug development abroad.” [116]

2. Brief for the United States as Amicus Curiae. The United States, writing in support of Merck, emphasized that a narrow interpretation of the exemption, distinguishing between clinical and preclinical research, would delay the marketing of valuable new drugs, and cautioned that licensing will not remedy the problem. [117] The United States described the Federal Circuit decision as holding that “‘pre-clinical’ research regarding a potential new drug is not protected by the FDA exemption because that exemption is limited to the ‘clinical’ research necessary to obtain ultimate FDA approval of a new drug.” [118] The United States argued that this holding “poses a direct and substantial threat to new drug research by dramatically narrowing the scope of protections enacted by Congress in §271(e)(1).” [119] A broader interpretation allowing research involving a patented invention, however, would facilitate marketing of new and promising drugs to the public immediately upon expiration of the patent. [120] The United States also argued that the line should be drawn between basic research and pre-clinical studies that are relevant to an IND and not between pre-clinical and clinical research as the Federal Circuit determined. [121] The United States continued that “[u]nder the Federal Circuit's decision, a manufacturer aware of a promising new cure involving a patented invention could not undertake the pre-clinical studies needed to secure FDA permission to conduct clinical studies, which in turn are required for FDA approval of a new drug.” [122] In response to Integra's comment “that drug manufacturers can attempt to negotiate license agreements with



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patent holders,” [123] the United States answered that licensing is not always a realistic option in terms of cost and researcher motivation. If any researcher could always license patented technology required for her studies, it would render the language of § 271(e)(1) superfluous. [124] Indeed, in reality, a researcher may face several obstacles in obtaining a license. “For competitive reasons, a drug company might be unwilling to license patented technology to a competitor, even when, as here, the patent holder itself is unable to convert the patented technology into a useful drug.” [125] The United States concluded that “even if the possibility of licensing will not stop research in its tracks, it will increase the cost and thus decrease the level of such research relative to what Congress intended.” [126]

3. Brief for the Pharmaceutical Research and Manufacturers of America as Amicus Curiae in Support of Petitioner. The Pharmaceutical Research and Manufacturers of America (PhRMA) recommended a broad interpretation of the exemption because preclinical studies contribute information about new drugs to the FDA and enable new drugs to reach the market more quickly. [127] PhRMA argued that “[i]n Eli Lilly, this court interpreted section 271(e)(1) to encompass the entire range of FDA premarket review.” [128] “Consequently, all activities ‘reasonably related’ to acquiring FDA [approval] including preclinical studies, should fall within the” exemption. [129] PhRMA argued that preclinical studies must be included as they provide substantial information about a drug candidate's safety and efficacy. [130] In addition, PhRMA argued that the exemption must include preclinical studies; otherwise, these studies would be not begin until the patent expired, and the regulatory approval process could not begin until their completion. [131] This would delay access to lifesaving drugs by a decade or more. [132] B. Arguments for a narrow interpretation of the exemption.

1. Brief in Opposition of Writ of Certiorari. Integra argued that the FDA exemption should not be extended to basic research aimed at identifying new drug candidates that may someday be submitted to the FDA for approval. [133] Intregra continued that basic research used to identify and develop new drugs is too remote to be considered “reasonably related” to the FDA regulatory process. [134] Integra concluded that if the exemption is expanded to include basic research, it will “deprive all biomedical ‘tool patents' useful to the drug research process of legal protection.” [135] Integra went on to evaluate Merck's activities in light of the statute's “reasonably related” language requiring a proximate relationship between the experiments and the FDA approval process. [136] The phrase “reasonably related” has been interpreted to mean that the activity is “‘to contribute (relatively directly) to the generation of the kinds of information likely to be relevant’ to the FDA approval process.” [137] Integra then described the research sponsored by Merck, which included screening dozens of compounds in a general search for new pharmaceutical compounds, as only general biomedical research, not clinical testing to supply information to the FDA. [138] Thus, Merck's research could not be considered reasonably related to reporting to the FDA. [139] Integra concluded its brief with policy considerations, citing that the purpose of the Drug Price Competition and Patent Term Restoration Act of 1984 was to remedy the unwarranted extension of the patent term on a pioneering drug's sales to consumers due to the inability of competitors to begin testing for FDA approval of a generic version of that drug until after the patent term expired. [140] Integra commented that Congress's objective was getting safe and effective generic substitutes on the market as quickly as possible after the expiration of the patent. [141]

2. Brief of Amicus Curiae Vaccinex, Inc. In Support of Respondents. Vaccinex, Inc., a biotech company engaged in the discovery of human antibodies and their subsequent development into novel therapeutic drugs, argued in its brief for a narrow interpretation of the exemption. [142] Vaccinex possesses patents on antibody discovery technology used for the selection of antibodies from libraries expressed in mammalian cells. [143] In its brief, Vaccinex argued that the most important use of research tools is during the “identification, characterization and optimization of potential new drugs.” [144] Vaccinex continued that this use is not use “solely and reasonably” related to submission of data to the FDA. [145] In response to other amicus briefs concluding that the expansion of the FDA exemption is essential to the development of new drugs,



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Vaccinex argued that licensing research tools, not pharmaceuticals, is central to the development of new drugs. [146] The argument that research tool manufacturers are unlikely to license their tools is flawed because the majority of patent tool companies' revenue comes from licensing agreements and the sale of their research tools. [147] To withhold a license would reduce revenue. [148] In other words, the reduction in patent protection that would result from the expansion of the FDA exemption would likely reduce the incentive and financial support to producing research tools and thus hinder the identification and development of new drugs. [149] Vaccinex also argued that the expansion of the exemption relies heavily on the “reasonably related” language and minimized the “solely” language. [150] “None of the activities in the basic research phase can be ‘solely’ used for developing information for submission to the FDA”. [151] Research tools used in the basic research phase enable the discovery that a drug may be effective. [152] It cannot be known at the time of the use of the tool if any information will ever be submitted to the FDA. [153] Thus, Vaccinex argued that a line should be drawn between basic research, identification, and screening on one hand, and pre-clinical development and clinical study on the other. [154] The basic research, identification and screening performed by Merck should not fall within the exemption because they are not typically “solely” used to submit information to the FDA. [155]

3. Brief of Amicus Curiae, Benitec Australia Ltd. in Support of Integra Lifesciences I, Ltd. and The Burnham Institute. Benitec is a biotechnology company that pioneered RNAi technology and whose DNA-directed RNA interference (ddRNAi) proprietary technology is used in developing treatments for diseases such as HIV/AIDS, HCV, cancer, and autoimmune diseases. [156] Benitec argued that the FDA exemption should not be expanded to include research whose primary purpose is the identification, development, and submission of new drugs. [157] Since “only 1 in 1000 identified and developed drugs are submitted to the FDA … [m]ost of the information generated in the research, discovery and development phases will not be presented to the FDA.” [158] Benetic therefore argued that the exemption should be limited to allow drug makers to infringe only while generating information intended for submission to the FDA for the purposes of seeking regulatory approval. [159] Benetic emphasized that the tests drug makers like Merck conduct to identify and develop new drugs are different than the experiments to which they subject new drugs for FDA approval. [160] Experiments gathering information for FDA approval can only be performed after the identification of a drug has occurred. [161] In Merck, the goal of the research in question was to identify a new product that could later be developed and brought to market. [162] “The experiments and testing done by Merck ... [are] those done by all drug makers to identify, characterize and develop a new drug.” [163] These experiments include modification to the structure of molecular entities, receptor binding assays, mechanism of action studies, and pharmacokinetic studies. [164] To include all of these experiments “no matter how attenuated from the FDA's approval process will essentially exempt all biomedical experiments and testing from infringement liability.” [165] Benetic also argued that if the exemption is expanded, the standard will become one in which the infringer's subjective conclusion controls whether infringement has occurred, resulting in a decrease in value of research tools. [166] This expansion of the exemption will result in a total vitiation of the research tool patent owner's rights, where the owners of research tools will have no patent rights to assert against new drug makers at any point during their drug research. [167] The expansion of the FDA exemption will allow the drug industry to save a lot of money since the industry will be allowed to infringe the patents of research tools while attempting to research, identify, characterize, and develop new drugs to submit to the FDA, and the drug manufacturers will no longer have to pay the license fees owed to the owners of the research tool industry. [168] For example, the patents of Polymerase Chain Reaction methods, screening methods, and research reagents whose sole use is in drug identification, characterization, and/or development may lose all value. [169] Benetic concluded that if the exemption is expanded, there will be no incentive to expend the resources necessary to create new, innovative research methods. [170] “In turn, companies will choose to retain methodologies as trade secrets instead of seeking patent protection,” thus slowing the innovation of new methods. [171]

VIII. The Supreme Court Decision



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The Supreme Court decided the issue of “whether uses of patented inventions in preclinical research, the results of which are not ultimately included in a submission to the FDA, are exempted from infringement by 35 U.S.C. §271(e)(1).” [172] The Supreme Court interpreted the FDA exemption to extend to “all uses of patented compounds ‘reasonably related’ to the process of developing information for submission under any federal law regulating the manufacture, use, or distribution of drugs.” [173] It was held that preclinical studies are reasonably related as they are regularly submitted to the FDA as a part of the approval process. [174] The Court exempted from infringement preclinical studies, both in vitro and in vivo, that are related to a drug's efficacy, mechanism of action, pharmacokinetics, and pharmacology. [175] The Supreme Court stated that they do not express a view as to whether the use of patented research tools falls within the FDA exemption, since Integra never argued that the RGD peptide was a research tool. [176] However, the Supreme Court limited the scope of the exemption by stating that “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.”’ [177] The Supreme Court stated that “the exemption is sufficiently broad to protect the use of patented compounds” when the experimentation is on drugs that are not ultimately the subject of an FDA submission and the use of the patented compounds is in experiments that are not ultimately submitted to the FDA. [178] The Court continued that since scientific research is unpredictable, the alternative interpretation would limit the scope of the exemption to activities necessary to seek approval of only generic drugs. The statute does not contain this limitation. [179] The Court argued further that Congress did not limit the exemption to the development of information for submission to the FDA, nor did it limit the exempt activities to research relevant to filing an ANDA. [180] “Rather, it exempted from infringement all uses of patented compounds ‘reasonably related’ to the process of developing information for submission under any federal law regulating the manufacture, use, or distribution of drugs.” [181] This interpretation necessarily includes preclinical studies as long as the resulting information is relevant to an IND or NDA. [182]

IX. Remand to the Federal Circuit The Federal Circuit interpreted the Supreme Court's opinion to hold that the FDA exemption includes experiments on products as long as the particular biological process and physiological effect of the product had been identified prior to the experiments and that the experiments were reasonably related to the type of information that is submitted in an IND application. [183] Applying this holding to the facts, the Federal Circuit concluded that each of the experiments were done to identify new candidates that inhibit angiogenesis and are of the type that would be included in an IND--thus they all fall within the exemption. [184] The court categorically analyzed each experiment by Scripps and concluded that each was of the type included in an IND as they studied the “mechanism of action, efficacy, pharmacology, pharmacokinetics, and safety” of the drug candidates. [185] On remand, Integra argued that the experiments done were discovery and thus should fall outside of the exemption. [186] The court responded, citing the Supreme Court's opinion, that the stage of experimentation is not determinative, as long as the biological properties and physiological effect are known. [187] In summary, the court's brief opinion identified each of the experiments as falling within the FDA exemption, thus avoiding infringement. Despite the ease by which the majority analyzed the facts, Judge Rader persisted with a dissent criticizing the effect of the case on research tools. [188] Judge Rader pointed out that the court ignored the distinction between product and process patents. [189] Judge Rader recited the Supreme Court's holding which identified “patented compounds” as falling within the FDA exemption, but noted that the facts of the case include process patents, which should fall outside of the exemption as they are mere laboratory methods that are not the type of information that would be submitted to the FDA. [190] Judge Rader went on to examine each of the patents at issue, which was not done by the majority or the Supreme Court, and identified the two patents which were used solely as research tools. [191] It is hard not to agree with Judge Rader, as the core of a patent infringement suit is the claims at issue and under what circumstances the individual claims may have been infringed. The prior appellate opinions in this case failed to analyze the patents' claims and failed to walk through each of the experiments to see if they infringed any of the patents at issue.



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X. An alternative approach

In the final part of Judge Rader's dissent he identified two German opinions that shed light on this case. [192] In the cases, Klinische Versuche I (Clinical Trials I) and Klinische Versuche II (Clinical Trials II), the German Supreme Court analyzed the general experimental use exemption, not the FDA exemption (Bolar exemption). Their rationale is informative. [193] Both cases exempted experiments that were performed on the patented product itself, but found experiments that were done to identify new drugs infringed. [194] Specifically, Clinical Trials I exempted experiments performed on a patented product that identified new indications, or medical uses. [195] Clinical Trials II exempted experiments performed on a patented product to obtain regulatory approval, such as those done by generic manufacturers in order to obtain regulatory approval by the time the brand patent expires. [196] The German court specifically identified research tools as falling outside of the research exemption, as they are experiments that are done to identify new drugs, not those done on the “object itself.” [197] This German distinction between the use of the product itself versus uses to identify new products clearly identifies the boundaries of the experimental use exception. In comparison, the United States Supreme Court blurred the line when it stated that “patent compounds” are exempt, yet the facts of the case included the use of patented processes. Therefore, in the United States, it is yet unclear whether the use of patent processes that can only serve as research tools fall within the exemption.

CONCLUSIONS

XI. What does Merck mean for patented research tools? It is still unclear what the Supreme Court considers preclinical research qualifying for the exemption, and whether research tools are included in that category. Generally, preclinical research includes pharmacological and toxicology testing of compounds in the laboratory and on animals to determine their safety for human use. [198] However, on the facts, Merck used Integra's patented product, initially, to identify new therapeutically effective drugs. [199] This type of research is normally not considered preclinical research, but instead is considered basic research. [200] The Supreme Court included both in vitro and in vivo experiments that are related to a drug's efficacy, mechanism of action, pharmacokinetics, and pharmacology within its analysis of preclinical research. [201] Therefore, it could be argued that preclinical research, as used by the Supreme Court, includes all of the types of research activities used by Merck. This would include all stages of pharmaceutical research: identification, preclinical, and clinical. Using the Supreme Court's standard exempting “all uses of patented compounds ‘reasonably related’ to the process of developing information for submission under any federal law regulating … drugs”, [202] the use of patented research tools would be exempted from infringement. Although the Supreme Court did not rule explicitly on whether §271(e)(1) exempts research tools from infringement in development of information for submission to the FDA, [203] the facts of the case demonstrate that Merck used Integra's patented product as a research tool used to identify new drug candidates. [204] The Supreme Court relied on Federal Circuit Judge Newman's dissent in the lower appeal which states the: “[u]se of an existing tool in one's research is quite different from study of the tool itself.” [205] This standard creates too fine a distinction as to what is considered an infringing use. In Merck, Merck's experiments used Integra's patented RGD peptides as controls against which to measure the efficacy of its test drugs. [206] Merck also used the RGD peptides to assist in the identification of drugs that could block the receptors to which the RGD peptides attached. [207] However, Merck still had to acquire Integra's peptide, by purchasing or manufacturing it, in violation of an existing patent. Both uses are infringing, but for the FDA exemption as interpreted by the Supreme Court. In addition, the Supreme Court failed to distinguish between product and process patents. The Supreme Court stated that “patented compounds” fall within the exemption, but the litigation in Merck was also based on two method patents whose use is likely limited to basic research. [208] The Courts failed to appreciate this distinction, and thus in future litigation the facts of Merck could be applied to many research methods that can be used to identify new drugs after the biological function and physiological process is well understood. If research methods fall within the FDA exemption, it is possible that Judge Rader's predictions for the future downfall of the research



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tool industry may come true. XII. The Federal Circuit's original narrow interpretation of the FDA exemption, which is based upon the legislative

history, is the more reasonable interpretation. At what point does clear legislative intent trump what is admitted to be unclear statutory drafting? The Federal Circuit in Merck argued that the legislative intent of the FDA exemption is clear and thus should be interpreted narrowly. [209] However, the Supreme Court argued that the FDA exemption, on its face, does not limit its scope and thus should be interpreted broadly to include all uses of patented compounds “reasonably related” to the process of developing information for submission under any federal law. [210] The Supreme Court is well aware of how long it can take Congress to re-write a statute, yet in the span of writing one decision the Court has erased years of debate in Congress. The legislative history is clear on the narrow scope of the FDA exemption, and the Federal Circuit in Merck agreed that the purpose of the FDA exemption was “to ensure that a patentee's rights did not de facto extend past the expiration of the patent term because a generic competitor also could not enter the market without regulatory approval.” [211] In addition, the Federal Circuit stated that the FDA exemption, as directed in the legislative history, allowed “a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute.” [212] Additionally, the Federal Circuit interpreted “solely” as limiting the “reasonably related” requirement [213] and reiterated Congress's purpose of facilitating the entry of generic drugs into the marketplace upon the expiration of a pioneer drug patent. [214] The Federal Circuit concluded that expanding the FDA exemption to “include the Scripps Merck activities would effectively vitiate the exclusive rights of patentees owning biotechnology tool patents.” [215] In contrast, the Supreme Court held that the use of patented inventions in preclinical research, the results of which are not ultimately submitted to the FDA, is exempted from infringement by the FDA exemption. [216] The Supreme Court's rationale supporting this broader holding includes their interpretation of the FDA exemption to mean that “all uses of patented compounds ‘reasonably related’ to the process of developing information for submission under any federal law regulating the manufacture, use, or distribution of drugs.” [217] This interpretation leaves pharmaceutical companies wondering where to draw the line on “reasonably related,” because it potentially includes the use of patented research tools and any patent infringement that occurs as a part of the development of new drugs. In fact, it is hard to determine what use of patented compounds is not reasonably related to the development of information for submission to the FDA, as all pharmaceutical research has some relationship to the ultimate outcome of applying to the FDA for regulatory approval. What does this mean for centrifuges, pipettes, screening technologies, genomic databases, polymerase chain reaction techniques, and computer modeling programs? All of these products are patented, and their uses are reasonably related to the process of developing information for submission under any federal law regulating drugs.

XIII. The FDA exemption should not apply to new drugs. Congress stated in its legislative history that the FDA exemption was intended to apply to generic drugs. [218] This limitation makes sense in the context of the Drug Price Competition and Patent Term Restoration Act of 1984 which also extended the ANDA application for generic drugs. Prior to creation of the FDA exemption, the generic manufacturer would have to wait until the brand product's patent expired before beginning the bioequivalency studies required by the ANDA from generic manufacturers. The process of obtaining an ANDA approval takes approximately 18-24 months, thus unfairly extending the branded patent's term for almost two years. [219] The FDA exemption was created to cure the unfair term extension, by allowing generic drug manufacturers to use the patented brand products for the limited purpose of proving bioequivalence. [220] Once the FDA was satisfied that the generic was bioequivalent, the FDA would withhold regulatory approval until the brand patent expired. [221] Upon expiration, the generic would immediately begin its marketing and manufacture, thus bringing less expensive equivalent medications to the market. In the amicus briefs to the Supreme Court in Merck, the major pharmaceutical manufacturers stated that the



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FDA exemption was intended to apply to the development of new drugs. [222] But where did this idea come from, considering that not one word of the 100-plus pages of legislative history mentions the FDA exemption applying to the development of new drugs? [223] The idea that the FDA exemption should apply to new drugs may have come out of Ventritex. [224] In Ventritex, the FDA exemption was allowed to apply to medical devices that intended to be marketed prior to the expiration of another patented product. [225] The court so held this despite the legislative history stating that the FDA exemption would only apply to products that would not be marketed until the original patent owner's patent had expired. [226] It is clear that only generics would benefit from the 1984 exemption since they are the only products that do not intend to market until after the brand's patent has expired. [227] The pharmaceutical companies argue that the FDA exemption includes new drugs because the purpose of the 1984 Act was to increase innovation in the industry. [228] But, nowhere in the legislative history did Congress propose to create an exemption that would enhance innovation in the pharmaceutical industry. [229] Indeed, the title of the statute is the “Drug Price Competition and Patent Term Restoration Act,” not the “Drug Innovation Act.” Pursuant to their stated goal of bringing prices down, Congress combined the ANDA and the FDA exemption to bring generics to the market more quickly. An examination of the market in the early 1980s also suggests that it is highly unlikely that Congress would create an exemption to patent infringement for the development of new drugs. The 1980s were a boom time of innovation and profitability for the pharmaceutical industry. The main concern at the time was that pharmaceuticals cost too much and the belief acted upon by the legislature was that generics would reduce the prices of pharmaceuticals and therefore the access to life-saving medicines. Both the Federal Circuit on remand and the Supreme Court focused on the type of experiments that were done and whether they could be used in an FDA application. The proper focus, however, should have been on whether the FDA exemption intended to allow a company to use another's patented products and methods to generate new drugs without infringing. Viewing the facts from this perspective the German Clinical Trials I and II cases are instructive. The German Court was able to clearly distinguish between experiments done on the object of the patented invention, the compound itself, or those done in order to develop new drugs. Experiments that were done to learn more about a patented invention such as to identify a new indication or medical use fell within the exemption. Experiments used to identify new drugs did not fall within the exemption. This distinction clearly protects research tools, whereas, the holding of Merck v. Integra when applied to the research method patents at issue leaves a great deal of legal uncertainty regarding their enforceability.

XIV. If Congress intended to limit the exemption to apply only to generics, then they must amend the statute.

On its face, the FDA exemption can be read as broadly as the Supreme Court interpreted it. However, as the Supreme Court said in Eli Lilly, “it is somewhat difficult to understand why anyone would want it to” read broadly. [230] As shown by the Federal Circuit's analysis, the FDA exemption can be read along with the legislative history to apply narrowly and to fit within the purpose that Congress provided. [231] Because the FDA exemption has been interpreted by the Supreme Court too broadly, Congress should amend the statute. The Supreme Court suggested that if the FDA exemption would have been written to include the word “ANDA,” then it would have held that the FDA exemption applied only to generic drugs. [232] If Congress intended to limit the FDA exemption to only generic drugs, it should amend 35 U.S.C. § 271 to read: “[i]t 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 … solely for uses reasonably related to the development and submission of information for an ANDA application to the FDA.” This amendment would reflect Congress's original intent to reduce the costs of drugs resulting in increased access. In addition, this language would create legal certainty within an industry that is relied upon to continually research and innovate new life-saving medications.

APPENDIX A 35 U.S.C. §271(e)(1): 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



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those terms are used in the Federal Food, Drug, and Cosmetic Act and the Act of March 4, 1913) which is primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology, or other processes involving site specific genetic manipulation techniques) 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.

[1]. 35 U.S.C. § 271(e)(1). [2]. 1984 U.S.C.C.A.N. 2692-93. [3]. See H.R. Report No. 857, reprinted in 1984 U.S.C.C.A.N. 2686-9. [4]. 1984 U.S.C.C.A.N. at 2647. [5]. Id. [6]. Eli Lilly and Company v. Medtronic, Inc., 496 U.S. 661, 668 (1990). [7]. Intermedics, Inc. v. Ventritex Co., Inc., 991 F.2d 808, 813 (Fed. Cir. 1993). [8]. Integra Lifesciences I, Ltd. v. Merck KGaA, 331 F.3d 860, 865 (Fed. Cir. 2003). [9]. Id. [10]. Id. Judge Rader was in a unique position to properly interpret the FDA exemption as he was previously the Chief Counsel of the Senate Subcommittee on Patents, Trademarks, and Copyrights the year that the Drug Price Competition and Patent Term Restoration Act was enacted. United States Court of Appeals for the Federal Circuit, Judicial Biographies, at http:// www.cafc.uscourts.gov/judgbios.html. [11]. Id. at 866. [12]. Id. at 867. [13]. Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 206 (2005) (italics in original). [14]. See Integra Lifesciences I, Ltd. v. Merck KGaA, 496 F.3d 1334, 1350 (C.A.Fed.,2007) (Rader, J. dissenting); See U.S. Patent No. 5,695,997 (issued December 9, 1997) (Claim 1. A method of altering cell attachment activity of cells, comprising: contacting the cells with a substantially pure soluble peptide including RGDX where X is an amino acid and the peptide has cell attachment activity; see U.S. Patent No. 4,879,237 (issued November 7, 1989) (Claim 1. A method of controlling the Arg-Gly-Asp mediated attachment of animal cells to substrates comprising the steps of: (a) contacting a substrate normally capable of accepting cells with cells normally capable of attaching to such substrate; and (b) contacting the substrate with a solution containing a polypeptide consisting essentially of the sequence GLY-ARG-GLY-ASP-ALA-PRO. [15]. Roche Products, Inc. v. Bolar Pharmaceutical Co., Inc., 733 F.2d 858, 860 (Fed. Cir.1984). [16]. Id. [17]. Id. [18]. Id. at 862.



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[19]. Id. at 864. [20]. Id. at 865. [21]. Eli Lilly and Co., 496 U.S. at 667 (the court interpreted the scope of the FDA exemption to include medical devices, despite the clear language “a Federal law which regulates …drugs”). [22]. Caminetti v. U.S., 242 U.S. 470, 485 (1917). [23]. Caminetti, 242 U.S. at 490. [24]. Id. at 489. [25]. Id. at 490. [26]. 35 U.S.C.§ 217(e)(1). [27]. Phillips v. AWH Corp., 415 F.3d 1303, 1312 (2005 Fed. Cir.) [28]. See U.S. Patent No. 4,381,313 (issued April 26, 1983). [29]. U.S. Patent Application No. 20050216961. [30]. U.S. Patent Applications No. 20050202515. [31]. U.S. Patent No. 4,792,525 (issued December 20, 1988), Claim 8; U.S. Patent No. 4,789,734 (issued December 6, 1988), Claim 1; U.S. Patent No. 5,695,997 (issued December 9, 1997), Claim 1; U.S. Patent No. 4,879,237 (issued November 7, 1989), Claim 1. [32]. 21 U.S.C. § 355 (b, i, j) (West, Westlaw 2005 through P.L. 109-363 approved 10-17-06). [33]. Id. [34]. Center for Drug Evaluation and Research, United States Food and Drug Administration, Investigational New Drug Application, http:// www.fda.gov/cder/handbook/indbox.htm (last visited December 12, 2005). [35]. Id. [36]. Id. [37]. Center for Drug Evaluation and Research, United States Food and Drug Administration, New Drug Application Process, http:// www.fda.gov/cder/regulatory/applications/NDA.htm#Introduction (last visited December 12, 2005). [38]. Id. [39]. Center for Drug Evaluation and Research, United States Food and Drug Administration, Abbreviated New Drug Application Process for Generic Drugs, http://www.fda.gov/cder/regulatory/applications/anda.htm (last visited December 12, 2005).



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[40]. Id. [41]. Id. [42]. 21 C.F.R. §§ 314.50(d)(2), (d)(5). [43]. 21 U.S.C. §§ 355(j)(2)(A)(i)-(v). [44]. See Caminetti, 242 U.S. at 489. [45]. Pub. L. No. 98-417, 98 Stat. 1585, 1984 U.S.S.C.A.N. 2647 (codified in 21 U.S.C. § 355 and 35 U.S.C. § 271(e)(1)). [46]. See Caminetti, 242 U.S. at 490. [47]. Eli Lilly, 496 U.S. at 665-66. [48]. See H.R. Report No. 857, reprinted in 1984 U.S.C.C.A.N. 2647. [49]. Id. at 2648. [50]. Id. [51]. See Id. at 2691. [52]. Id. at 2692. [53]. Id. at 2692-93, 2713. [54]. Id. [55]. See PhRMA, Research and Development, http://www.phrma.org/index.php? option=com_content&task=view&id=382&Itemid= (last visited September 23, 2007). [56]. See Id. [57]. See Id. [58]. Id. [59]. 496 U.S. 661 (1990). [60]. Id. [61]. Eli Lilly, 496 U.S. at 668. [62]. Id. at 664. [63]. Id. (italics added). [64]. Id.



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[65]. See Id. at 665. [66]. Id. [67]. Id. at 666. (The court argued that if the statute read “pertains” instead of “regulates” then the FDA exemption could be read to refer only to individual provisions and not the entire act. [68]. Id. at 667. [69]. Id. [70]. Id. at 671-74. [71]. Id. at 672. [72]. Id. at 668 (italics in original). [73]. See Id. at 670. [74]. Id. at 676. [75]. Id. [76]. Id. at 680. [77]. Id. at 681-82. [78]. Id. [79]. Intermedics, Inc. v. Ventritex Co., Inc., 991 F.2d 808 (Fed. Cir. 1993). [80]. Id. at 813. [81]. Id. at 808. [82]. Id. at 808. [83]. Id. [84]. Id. at 808. [85]. Id. at 810. [86]. Integra Lifesciences I, Ltd. v. Merck KGaA, 331 F.3d 860 (Fed. Cir. 2003). [87]. Id. at 862. [88]. Patent '525 claimed the RGD peptide's composition of matter and a method for promoting cell attachment to a substrate. Patent '997 claimed a method of altering cell attachment activity by contacting cells with the peptide and a method of blocking cell surface receptors. Patent '237 claimed a method of controlling the attachment of animal



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cells to substrates. Patent '734 claimed the composition of matter of the cell surface receptor. Patent '621 claimed a method for affecting animal cell aggregation. [89]. Id. at 862-63. [90]. Id. at 863. [91]. Id. [92]. Id. [93]. Id. [94]. Id. [95]. Merck, 545 U.S. at 199. [96]. Integra, 331 F.3d at 863. [97]. Merck, 545 U.S. at 199. [98]. Integra, 331 F.3d at 865. [99]. Id. [100]. Id. (quoting H.R.Rep. No. 857, at 8, reprinted in 1984 U.S.C.C.A.N. at 2692). [101]. Id. [102]. Id. at 866 (quoting 35 U.S.C. § 271(e)(1)). [103]. Id. [104]. See Id. [105]. Id. 866-67. [106]. Id. at 867. [107]. Id. at 866-67. [108]. See Id. at 867. [109]. See Id. [110]. Id. [111]. Id. at 3. [112]. Id.



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[113]. Id. at 4 (citing H.R. Rep. No. 98-857 (Pt. 1),1), at 45 (1984) which states: “[a] party which develops such information, but decides not to submit an application for approval, is protected as long as the development was done to determine whether or not an application for approval would be sought”). [114]. Id. at 10-11. [115]. Id. at 6-8. [116]. Id. at 12. [117]. Brief for the United States as Amicus Curiae, Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (No. 03-1237). [118]. Id. at 8. [119]. Id. [120]. Id. at 10. [121]. Id. [122]. Id. at 19. [123]. Id. [124]. Id. [125]. Id. at 19-20. [126]. Id. at 19. [127]. Brief for the Pharmaceutical Research and Manufacturers of America as Amicus Curiae in Support of Petitioner at 4, Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (No. 03-1237). [128]. Id. at 4 (citing Eli Lilly and Co. v. Medtronic, Inc., 496 U.S. 661, 666-67 (1990)). [129]. Id. at 4. [130]. Id. at 6. [131]. Id. [132]. Id. at 14. [133]. Brief in Opposition of Integra Lifesciences I, Ltd. and the Burnham Institute at 1, Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (No. 03-1237). [134]. Id. at 2. [135]. Id.



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[136]. Id. at 9. [137]. Id. at 11 (citing Intermedics, Inc. v. Ventritex, Inc, 775 F.Supp. 1269, 1280 (N.D.Cal. 1991)). [138]. Id. at 5. [139]. Id. at 11-12. [140]. Id. at 12. [141]. Id. at 13 (citing H.R. Rep. No. 98-857(II), at 9 (1984), reprinted in 1984 U.S.C.C.A.N. 2686, 2683). [142]. Brief of Amicus Curiae Vaccinex, Inc. In Support of Respondents at 1, Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (No. 03-1237). [143]. Id. [144]. Id. [145]. Id. at 2. [146]. Id. [147]. Id. at 11. [148]. Id. [149]. Id. at 12. [150]. Id. at 13. [151]. Id. at 15. [152]. Id. at 16. [153]. Id. [154]. Id. [155]. Id. at 17. [156]. Brief of Amicus Curiae, Benitec Australia Ltd. in Support of Integra Lifsciences I, Ltd. and The Burnham Institute at 6, Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (No. 03-1237). [157]. Id. [158]. Id. at 3. [159]. Id. [160]. Id. at 14.



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[161]. Id. [162]. Id. at 14-5. [163]. Id. at 15. [164]. Id. [165]. Id. [166]. Id. at 6. [167]. Id. at 7. [168]. Id. at 9. [169]. See Id. at 10. [170]. Id. [171]. Id. [172]. Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 195 (2005). [173]. Id. at 206. [174]. Id. at 202. [175]. Id. at 204. [176]. Id. at 205, note7. [177]. Id. at 205-06. [178]. Id. at 206. [179]. Id. [180]. Id. [181]. Id. (italics in original). [182]. Id. [183]. Integra Lifesciences I, Ltd. v. Merck KGaA, 496 F.3d 1334, 1340 (Fed. Cir. 2007) [184]. Id. [185]. Id. at 1342-4.



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[186]. Id. at 1346-7. [187]. Id. [188]. Id. at 1348-9. [189]. Id. [190]. Id. [191]. Id. at 1350-2. [192]. Id. at 1353. [193]. Klinische Versuche I (Clinical Trials) [1995] BGH (Germany); Klinishe Versuche II (Clinical Trials) [1998] BGH (Germany); German Patent Act, Article 11.2 (1981); In Europe, the FDA exemption is known as the Bolar exemption. [194]. Id. [195]. Klinische Versuche I. [196]. Klinishe Versuche II. [197]. Klinische Versuche I. [198]. See PhRMA, Research and Development, http:// www.phrma.org/index.php?option=com_content&task=view&id=382&Itemid= (last visited September 23, 2007). [199]. Integra, 331 F.3d at 863. [200]. See Id. [201]. Merck, 545 U.S. at 203. [202]. Id. at 206 (italics in original). [203]. Id. at 205, note 7. [204]. Integra, 331 F.3d at 863. [205]. Merck, 545 U.S. at 205, note 7 (citing Integra, 331 F.3d at 878). [206]. Id. at 199. [207]. Integra, 331 F.3d at 863. [208]. See U.S. Patent No. 4,792,525 (issued December 20, 1988) (Claim 8. A substantially pure peptide including as the cell-attachment-promoting constituent the amino acid sequence Arg-Gly-Arg-R wherein R is Ser, Cys, Thr or other amino acid, said peptide having cell-attachment promoting activity, and said peptide not being a naturally occurring peptide); see U.S. Patent No. 4,789,734 (issued December 6, 1988) (Claim 1. A substantially purified cell



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surface receptor derived from mesenchymal tissue and capable of binding to a peptide containing the amino acid sequence Arg-Gly-Asp, comprising a glycoprotein composed of at least two polypeptides of about 115 and 125 kD, respectively, as determined by SDS-PAGE under reducing conditions which selectively binds to vitronectin, but not to fibronectin; see U.S. Patent No. 5,695,997 (issued December 9, 1997) (Claim 1); see U.S. Patent No. 4,879,237 (issued November 7, 1989) (Claim 1); Integra Lifesciences I, Ltd. v. Merck KGaA, 496 F.3d 1334, 1348 (Fed.,Cir. 2007) (Rader, J., dissenting) [209]. Id. at 867-68. [210]. Merck, 545 U.S. at 206. [211]. Integra, 331 F.3d at 865. [212]. Id. [213]. Id. at 866. [214]. Id. at 866-867. [215]. Id. at 867. [216]. Merck, 545 U.S. at 206. [217]. Id. (italics in original). [218]. See H.R. Report No. 857, reprinted in 1984 U.S.S.C.A.N. 2647, 2648-49. [219]. Id. at 2647-8. [220]. Id. at 2689. [221]. 21 U.S.C. §§ 355(j)(2)(A)(i)-(v). [222]. Brief of Amicus Curiae Wyeth in Support of Petitioner at 2, 5, Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (No. 03-1237); Brief for the Pharmaceutical Research and Manufacturers of America as Amicus Curiae in Support of Petitioner at 4, Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (No. 03-1237). [223]. See H.R. Report No. 857, reprinted in 1984 U.S.S.C.A.N. 2647. [224]. Intermedics, Inc. v. Ventritex Co., Inc., 991 F.2d 808 (Fed. Cir. 1993). [225]. Id. at 813. [226]. Id. [227]. H.R. Report No. 857, reprinted in 1984 U.S.S.C.A.N. 2647, 2678. [228]. Brief of Amicus Curiae Wyeth at 2, 5; Brief of the Pharmaceutical Research and Manufacturers of America at 4. [229]. See H.R. Report No. 857, reprinted in 1984 U.S.S.C.A.N. 2647.



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[230]. Eli Lilly, 496 U.S. at 668. [231]. Integra, 331 F.3d at 860. [232]. See Merck, 545 U.S. at 206.

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WAS THE FDA EXEMPTION TO PATENT INFRINGEMENT, 35 USC § 271(e)