Safe Harbor Exemption under 271(e)(1): What's not included after Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, 686 F.3d 1348, 103 USPQ2d 1800 (Fed. Cir 2012) Tracy U. Palovich, PhD Colleen M. Schaller Patent Agent Associate Howson & Howson LLP Blue Bell, Pennsylvania The protection of subject matter requiring review by the FDA plays an integral part in the fate of pharmaceutical and biotechnology companies. However, the FDA approval process is by no means a simple task. In fact, before 1984, FDA approval of a drug might not have occurred until long after the patent expired. Consequently, a generic competitor could immediately seek to enter the market, with no set period of exclusivity for the brand name drug. On the other hand, it was also impossible for generic companies to begin the necessary comparison of their generic counterpart drug with the reference drug until expiration of the reference patent. This loss of time equated to a de facto extension of the reference patent and the loss of millions of dollars by the generic company. In 1984, Congress, recognizing the issues, sought to address the competing interests of 1) FDA approval of new pharmaceuticals and 2) the use of patented technology by competitors to get FDA approval for generic counterpart drugs. Accordingly, Congress passed the Drug Price Competition and Patent Term Restoration Act ("Hatch-Waxman Act") and addressed both of these issues. Under Title II of the Hatch-Waxman Act, codified as 35 U.S.C. 156, pharmaceutical companies could obtain a five-year extension of their patent term beyond the standard patent term, for delays in regulatory review and approval. In exchange for the extension granted to the pharmaceutical companies, generic companies were permitted, under Title I of the Act, codified as 35 U.S.C. 271(e)(1), to utilize the patented technology in their efforts to submit information to the FDA in an Abbreviated New Drug Application (ANDA) FN1 without infringing the patent. 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 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 37 U.S.C. 271(e)(1) (emphasis added) 113
FN1. It is to be noted that the exemption is not applicable only to "the research relevant to filing an ANDA for approval of a generic drug." Merck KGaA v. Integra Lifesciences I, Ltd, 545 U.S. 193, 206 (2005). Rather, the use of patented inventions in activities that produce the types of information that are relevant to an Investigational New Drug Application (IND) or New Drug Application (NDA) is also eligible for protection. Id. at 208. Despite Congress' stated intentions, the language of the law is vague. This has led to a variety of lawsuits and resulting case law, with the courts interpreting the metes and bounds of the statutory language. Of significance, and in recent years, the courts addressed the hot ticket item of whether the infringing act was solely done in an effort to submit information which was required under a Federal law. This issue is addressed here. I. Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) In the Merck decision, the Supreme Court has taken an expansive view of activities related to submission of information under a Federal law which are covered by the 271(e)(1) exemption. The Court found that the "exemption from infringement extends to all uses of patented inventions that are reasonably related to the development and submission of any information under the [Food, Drug and Cosmetic Act]." Id. at 202 (emphasis in original). According to the Court, under certain circumstances, this includes the use of patented inventions in "experimentation on drugs that are not ultimately the subject of an FDA submission" or "experiments that are not ultimately submitted to the FDA." Id. at 206. In Merck, the Supreme Court took an expansive view of what activities are protected in the preclinical setting, without discussion of post-fda approval activities. Since this decision, the Federal Circuit has struggled with what postapproval activities are also protected by the 271(e)(1) safe harbor provision. II. Classen Immunotherapies v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011), cert. denied, 133 S. Ct. 973 (2013) Classen owned 3 patents drawn to methods of optimizing vaccine immunization schedules related to possible associations with chronic immune-related illnesses. Classen alleged infringement by Biogen and GlaxoSmithKline (collectively "Biogen") for conducting studies after FDA approval "to evaluate suggested associations between childhood vaccinations, particularly against hepatitis B and Haemophilus influenza and risk of developing type 1 diabetes; and to determine 114
whether timing of vaccination influences risk". 659 F.Supp.3d 1057 at 1073. Biogen maintained that, although its work was performed after FDA approval of the subject vaccines, its activities were directed to actions conducted for purposes of complying with FDA regulations. Therefore Biogen asserted the activities fell within the 271(e)(1) exemption. Relying heavily on the legislative history of the Hatch-Waxman Act, the Federal Circuit refused to extend the 271(e)(1) exemption and found Biogen's acts infringing. In a 2-1 decision, Chief Judge Rader, writing for the Classen majority (with Judge Moore dissenting) held that: 271(e)(1) provides an exception to the law of infringement in order to expedite development of information for regulatory approval of generic counterparts of patented products. The statute does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained. Classen at 1070 (emphasis added). For most of the pharmaceutical community, this decision seemed to clarify the actions which could be safely undertaken relating to the FDA. Specifically, it appeared as though the Court was restricting 271(e)(1) to acts performed before FDA approval of a drug. III. Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc. 882 F.Supp.2d 184 D.Mass., 2011 ("Momenta I") & Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc. 686 F.3d 1348, 103 U.S.P.Q.2d 1800, 2012 ("Momenta II") Almost one year later, the Federal Circuit faced a similar issue in Momenta II which involved enoxaparin, a drug that prevents blood clots. Enoxaparin is produced directly from heparin and, due to the composition of heparin, enoxaparin is made up of a range of different molecules. In such cases, where the identity of the drug is complex, an: ANDA Applicant must submit studies to establish that its drug is bio-equivalent to the reference drug [and] include sufficient information to establish that the generic drug has the same active ingredients as the reference drug. 686 F. 3d 1348 at 1350. Spurred by a request by Sanofi-Aventis, the marketer of the brand name drug, Lovenox, the FDA identified five criteria required to prove that generic 115
enoxaparin is the same as the active ingredient in Lovenox. One of the requirements was to show that the generic drug can be broken down into smaller blocks containing a 1,6-anhydro ring structure. Momenta is the assignee of U.S. Patent No. 7,575,886 which is drawn to methods for analyzing compounds such as heparin and enoxaparin, specifically for the aforementioned 1,6-anhydro ring. In the usual course of action, Momenta and Amphastar separately filed ANDAs for enoxaparin. Although Amphastar filed its ANDA first, Momenta was the first to receive FDA approval to market enoxaparin, more than one year before Amphastar was approved. To stem the potential loss in revenue estimated at about 1 billion dollars per year, Momenta asserted its patent two days after Amphastar's approval. Momenta claimed that Amphastar used Momenta's patented technology to analyze their samples of enoxaparin without Momenta's permission. Relying on Classen, Momenta alleged that Amphastar's activity was "post-approval" and outside of the safe-harbor exemption. Momenta II at 1353. Momenta further asserted that the records were never, in fact, submitted to the FDA, but instead were retained in case the FDA requested such data under Federal law. See, 21 C.F.R. 211.180(a). In response, Amphastar argued that the use of Momenta's claimed method fell within the scope of 271(e)(1). In view of Classen, the patent community was not surprised that the District Court decision turned on the distinction between pre- and post-approval activity. In finding in favor of Momenta, the District Court noted: Although the safe harbor provision permits otherwise infringing activity that is conducted to obtain regulatory approval of a product, it does not permit a generic manufacturer to continue in that otherwise infringing activity after obtaining such approval... Momenta I at 197. Upon appeal to the Federal Circuit, Amphastar argued that the District Court was overly-restrictive, while Momenta argued that 271(e)(1) does not apply to activities which occur after FDA approval while referencing the Classen decision. In another 2-1 decision, the Court found the language of the statute to be unambiguous, eschewing the weight afforded to the legislative history by the majority in Classen. This time, with Judge Moore writing for the majority and Chief Judge Rader dissenting, the Court held that: 116
[T]he only coherent and consistent interpretation of "a Federal law which regulates the manufacture, use or sale of drugs" is that it must be broad enough to encompass submissions made pursuant to the Federal Food, Drug, and Cosmetic Act. Momenta II 686 F3d 1348, 1355, citing 35 USC 271(e)(1). The Court noted that, unlike the "closely related infringement provision" of 35 USC 271(e)(2), the safe harbor provision was not linked to an application submitted under the FDCA. Momenta II at 1356. Relying on Merck v. Integra, the Court found that its definition of submissions which fall within the safe harbor "extends to all uses of patented inventions that are reasonably related to the development and submission of any information under the FDCA". Id. at 1356, citing Merck KGaA v. Integra Lifesciences I, Ltd, 545 U.S. 193, 202 (2005) (emphasis in original). While the Court acknowledged it was bound by the Classen decision, it stated that its view of the Momenta facts did not run afoul of the precedent. Rather than turning on the "artificial" pre-/post-approval distinction, the Court found that because the submissions were "required to maintain FDA approval", and were not "routine" or "generated voluntarily by the manufacturer", they were covered by the safe harbor provision. IV. After Momenta II At first glance, it appears as though the Momenta II decision contradicted the Classen decision by the same Court. In fact, in his dissent, Chief Judge Rader paints a very detailed picture of his view on the Momenta II decision and maintains that the Court ignored the precedent set by Classen. Chief Judge Rader aggressively notes that " this result will render worthless manufacturing test method patents." Momenta II at 1362. However, careful analysis leads to the conclusion that Momenta II actually parallels the Classen decision and provides clearer guidance for brand-name and generic companies to follow. The Momenta II Court noted that the information generated by Amphastar was "reasonably related to the development and submission of information under a Federal law", i.e., it was required by the FDA. Id. at 1353, citing 35 USC 271(e)(1). The Court noted that Amphastar was required to collect and retain the batch testing data, and have it available for inspection by the FDA. If such data was not available upon request of the FDA, suspension or revocation of the ANDA approval could result. Thus, the Court held, the "submissions" were not routine. Id. at 1358. 117
This is in contrast to Classen, where the data in question was not required by the FDA for approval or continued approval of the ANDA. Rather it was a "routine submission" to the FDA. The Court confirmed that the FDA required data need not physically be submitted to the FDA in any form. It only need be collected and stored for later inspection by the FDA. Id. at 1357. Finally, the Court noted that the safe harbor provision doesn't require the use of a non-infringing analysis method. The requirement is that the method is utilized to produce mandated information to the FDA. Id. at 1359. In eschewing the pre-/post-appeal distinction put forth by Classen, Momenta II provides a logical distinction between whether or not the submissions are required by the FDA. This test neatly integrates the Merck, Classen and Momenta II decisions. Thus, after Momenta II, it would appear that all testing done using patented inventions, whether done pre- or post-fda approval, will qualify for the safe harbor, provided that they are reasonably related to the development and submission of information which is required by the FDA. It follows that activities that are not covered by the safe harbor after Momenta II are those that are not mandatory, i.e., related to submissions that are not required by a specific mandate. V. Going Forward? Even though those in the patent community are split, these two decisions may better prepare those in NDA, ANDA, and biologic businesses. In gauging the wealth of discussions about this issue, the following "best practices" may be considered: Ensure that post-approval activity is required by the FDA in order to fall under the requirements of the safe harbor provision. Understand what is required to actually maintain FDA approval of the ANDA. For existing FDA submission, determine if there are any activities which may be required by FDA but are not expressly mandated. Ensure that there is a link between the data generated and the legal duty to submit it to the FDA. Educate personnel in record keeping (internal and patent prosecution based) and regulatory filings to ensure consistency with safe harbor restrictions. Consider keeping certain "methods of analyzing" a trade secret. 118
This article provides practical and useful information on the subject matter covered and expresses only the views of the authors. If legal advice or other expert assistance is required, the services of a competent professional should be sought. 119