Intellectual Property Bulletin Winter 2013: Murky Waters: Post-Approval Regulatory Activities and the § 271(e)(1) Safe Harbor

by Fenwick & West LLP

On January 14, 2013, the U.S. Supreme Court refused to consider the U.S. Court of Appeals for the Federal Circuit's exclusion in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011), of post-approval regulatory activity from the safe harbor established by 35 U.S.C. § 271(e)(1).  The Supreme Court's denial of the petition for certiorari filed by GlaxoSmithKline (Glaxo) should not be interpreted, however, as approval of the narrow construction adopted below by a divided Federal Circuit panel. 

To the contrary, it is likely that the Supreme Court refused to hear this case because the Federal Circuit all but overruled Classen in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., 686 F.3d 1348 (Fed. Cir. 2012)1

But given the split in Federal Circuit jurisprudence, the competing public policy considerations, and the need of the pharmaceutical industry for bright-line guidance as to which post-approval regulatory activities fall within the scope of § 271(e)(1) and which fall without, it seems likely that the Supreme Court will soon have another opportunity to construe the scope of the safe harbor—perhaps in the Momenta decision itself.

The § 271(e)(1) Safe Harbor

Generally, a patent is infringed when the patented invention is made, used, offered for sale, or sold in the United States, or imported into the United States, without authority.  35 U.S.C. § 271(a).  In 1984, however, Congress exempted from patent infringement certain activities related to satisfying federal regulatory requirements.  As amended, this exemption—codified at 35 U.S.C. § 271(e)(1)—applies to otherwise infringing activities that are undertaken "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."  Congress created the § 271(e)(1) safe harbor as part of its attempt to balance competing societal interests in promoting innovation through patent protection and hastening the market entry of generic drugs.

The Supreme Court has twice considered the scope of the exemption established by § 271(e)(1), and in both cases adopted a broad, inclusive construction.  First, the Court held in Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (1990), that the § 271(e)(1) safe harbor encompasses not only pharmaceutical products but also medical devices.  And in Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 208 (2005), the Court concluded that, whether or not ultimately submitted to the FDA, preclinical research is also protected within the § 271(e)(1) safe harbor "as long as there is a reasonable basis for believing that the experiments will produce the types of information that are relevant to an IND or NDA."  In so holding, the Supreme Court observed that § 271(e)(1) encompasses "a wide berth," as it "exempt[s] 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."  The Supreme Court has not, however, considered whether regulatory activities undertaken after a drug's approval by the FDA fall within the confines of the § 271(e)(1) safe harbor.

Post-Approval Regulatory Activities—Take One: Classen

Classen Immunotherapies sued Biogen IDEC, Glaxo, and several additional pharmaceutical companies for infringement of patents relating to methods for improving the safety of vaccine administration schedules.  According to these patents, the development of certain chronic disorders can be affected by the timing of infant immunizations.  After Dr. Classen published articles suggesting such a relationship, a study sponsored by the Centers for Disease Control and Prevention (CDC) examined the vaccination histories of more than 1000 children and found no association between vaccination schedules and development of diabetes.  Classen charged Biogen and Glaxo with infringement based largely on their participation in the CDC-sponsored study.  Relying on the Supreme Court's broad language in Merck, the district court granted summary judgment to Biogen and Glaxo on the basis that their activities fell within the § 271(e)(1) safe harbor, reasoning that evaluation of vaccination risks was reasonably related to information required by the FDA, such as annual reports of post-marketing studies as well as reports of adverse reactions.  Classen Immunotherapies, Inc. v. Biogen IDEC, 381 F. Supp. 2d 452 (D. Md. 2005).

A divided panel of the Federal Circuit vacated the district court's judgment of non-infringement based on the § 271(e)(1) safe harbor2.  In a decision written by Judge Newman and joined by Judge Rader, the panel majority held that "§ 271(e)(1) provides an exception to the law of infringement in order to expedite development of information for regulatory approval . . . [and] does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained" (emphasis added).  In reaching this conclusion, the majority relied on legislative history, as well as the Supreme Court's decisions in Eli Lilly and Merck, noting that all of these sources discussed § 271(e)(1) solely in the context of pre-approval activity.  Accordingly, the majority rejected encompassing post-approval activity within the safe harbor as "a massive enlargement of the statutory exemption."

Judge Moore dissented from the majority's limitation of § 271(e)(1) to pre-approval activities.  Judge Moore observed that nothing in the plain language of the statute supported such a limitation in the scope of the safe harbor; that the Supreme Court in Merck, although considering pre-approval activities, "repeatedly underscored the breadth of the statute's text;" and that the legislative history does not speak to whether § 271(e)(1) extends to post-approval activities.

The Federal Circuit refused to rehear the case en banc.

Post-Approval Regulatory Activities—Take Two: Momenta

Less than a year later, however, a divided panel of the Federal Circuit all but overruled Classen.  At issue in Momenta was the manufacturing process for a generic version of Lovenox (enoxaparin), a heparin derivative used to prevent blood clots.  The FDA required each generic manufacturer to prove on an ongoing basis that its drug contains about 20 percent of a 1,6-anhydro disaccharide derivative.  Amphastar chose to satisfy this requirement by implementing during its manufacturing process a batch-testing method that allegedly infringed Momenta's patent.  Relying on Classen, the district court concluded that Amphastar's batch-testing method was a post-approval activity that did not fall within the § 271(e)(1) safe harbor, and granted Momenta a preliminary injunction.

A divided panel of the Federal Circuit vacated the district court's decision.  The majority, consisting of Judge Moore (the dissenting judge in Classen) and Judge Dyk, acknowledged Classen as holding that § 271(e)(1) "does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained" (quoting Classen).  Having said that, however, the majority refused to distinguish pre-approval and post-approval regulatory activity for purposes of the safe harbor, observing that "Classen did not turn on this artificial distinction, and the plain language of the statute is not restricted to pre-approval activities." 

Having opened the § 271(e)(1) safe harbor to post-approval regulatory activity, the majority then concluded that Amphastar's batch testing using Momenta's patented method fell within the confines of the § 271(e)(1) safe harbor.  According to the majority, Amphastar's testing of each batch of generic enoxaparin was "anything but ‘routine'" because the FDA required that Amphastar demonstrate that its generic enoxaparin possessed the specified composition as a predicate for approval and release of each manufactured batch into commerce.  By contrast, the majority further reasoned, the infringing studies at issue in Classen were not themselves mandated by the FDA, but rather were conducted voluntarily for reasons largely unrelated to FDA regulatory approval.  Nor did the majority find persuasive the fact that Amphastar could have developed an alternative, noninfringing method to test batches of its generic enoxaparin.  ("The safe harbor . . . does not mandate the use of a noninfringing alternative when one exists."). 

Judge Rader, a member of the majority Classen panel, penned a lengthy dissent from the Momenta majority's opinion.  According to Judge Rader, the Momenta majority ignored the statutory text and legislative history of § 271(e)(1), as well as the binding precedent in Classen explicitly excluding post-approval regulatory activities from the scope of the safe harbor.  In addition to expanding upon the analysis in Classen, Judge Rader emphasized that the majority's "interpretation of § 271(e)(1) would essentiSally render manufacturing patents worthless."

As in Classen, however, and despite the seemingly inconsistent ruling of the Momenta panel, the Federal Circuit refused to rehear the case en banc.


Notwithstanding the contrary assertions of Judges Moore and Dyk, the Federal Circuit's decisions in Classen and Momenta are difficult to reconcile.  The most natural reading of Classen excludes all post-approval regulatory activity from the § 271(e)(1) safe harbor.  Momenta, by contrast, reaches the opposite conclusion.  This inconsistency in the Federal Circuit's § 271(e)(1) jurisprudence is particularly troubling given the weighty public policy considerations at play.

On the one hand—as detailed in the Classen certiorari briefing of Glaxo, amicus Pharmaceutical Research and Manufacturers of America (PhRMA), and, by request of the Supreme Court, the United States—the Classen decision appears to ignore the realities of FDA pharmaceutical regulation.  Simply put, the FDA's oversight does not end with the approval of a drug.  For example, the FDA may require post-approval studies to assess safety risks that emerge only after a drug has been approved, or to assess the efficacy of a drug whose approval was expedited because it was used to treat a serious or life-threatening disease for which current treatments are inadequate. 

21 U.S.C. §§ 355(o)(3)(A), 356(c)(2)(A).  Pioneer pharmaceutical manufacturers may also voluntarily undertake post-approval studies in order to obtain FDA approval of new indications for an already approved drug.  21 C.F.R. § 314.70.  Exclusion of such post-approval regulatory activity from the § 271(e)(1) safe harbor thus has the potential to discourage manufacturers from seeking new uses for their pharmaceuticals, as well as to expose them to liability where studies required by the FDA infringe another's patent.

On the other hand, as emphasized by Judge Rader, never before has § 271(e)(1) been interpreted to allow sales of the infringing product during the life of the blocking patent.  For example, a manufacturer seeking approval for a generic drug is allowed to infringe a patent covering the branded pharmaceutical prior to that patent's expiration in order to generate data required by the FDA for ANDA approval, but, following approval, is not allowed to market the generic drug until after the branded manufacturer's patent has expired.  The Momenta decision, by contrast, allows Amphastar to infringe Momenta's patent while selling the infringing generic drug.  Such an exemption from patent infringement is unprecedented.

In this latter respect, the implications of the Momenta decision are likely particularly troubling to the manufacturers of biosimilars, the "generic" versions of complex biological products, such as proteins.  Such manufacturers may, like Momenta, seek patent protection for the analytical and quality control methods that they often must develop to satisfy FDA regulations requiring a demonstration that the biosimilar "is highly similar to the reference product." 

42 U.S.C. § (k)(2)(A)(i)(I)(aa).  Momenta strips such patents of all value, allowing competing biosimilar manufacturers to use the patented methodology with impunity.  Thus, under Momenta, pioneer pharmaceutical companies also seeking to market biosimilars could find their innovations taken by follow-on biosimilar manufacturers.

Given the clear split in Federal Circuit jurisprudence as to whether post-approval regulatory activities fall within the § 271(e)(1) safe harbor, and the associated contrary public policy considerations, the Supreme Court's guidance on this issue would be welcome.  Although the Court's denial of Glaxo's certiorari petition may signal its approval of the Momenta decision, only time will tell.  The particular facts of future cases may, however, be better suited for allowing the Supreme Court not only to opine on the scope of § 271(e)(1), but also to delineate bright-line limits to exemption of post-approval regulatory activities from patent infringement.  As Momenta has itself recently petitioned for certiorari, that opportunity may be at hand.

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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