Momenta Pharms., Inc. v. Amphastar Pharms., Inc.

Citation103 U.S.P.Q.2d 1800,686 F.3d 1348
Decision Date03 August 2012
Docket NumberNos. 2012–1062,2012–1103,2012–1104.,s. 2012–1062
PartiesMOMENTA PHARMACEUTICALS, INC., Plaintiff–Appellee, and Sandoz, Inc., Plaintiff–Appellee, v. AMPHASTAR PHARMACEUTICALS, INC., International Medication Systems, Ltd., Watson Pharmaceuticals, Inc., and Watson Pharma., Inc., Defendants–Appellants.
CourtUnited States Courts of Appeals. United States Court of Appeals for the Federal Circuit

OPINION TEXT STARTS HERE

Robert S. Frank, Jr., Choate Hall & Stewart LLP, of Boston, MA, argued for both plaintiffs-appellees. With him on the brief was Eric J. Marandett. Of counsel on the brief for plaintiff-appellee for Sandoz, Inc., was Thomas P. Steindler, McDermott, Will & Emery LLP, of Washington, DC.

Patricia A. Millett, Akin Gump Strauss Hauer & Feld LLP, of Washington, DC, argued for plaintiffs-appellants. With her on the brief were Anthony T. Pierce, Mark Mansour, Emily C. Johnson and James E. Tysse; and L. Rachel Lerman, of Los Angeles, CA.

Before RADER, Chief Judge, DYK and MOORE, Circuit Judges.

Opinion for the court filed by Circuit Judge MOORE. Dissenting opinion filed by Chief Judge RADER.

MOORE, Circuit Judge.

Amphastar Pharmaceuticals, Inc., International Medication Systems, Ltd., Watson Pharmaceuticals, Inc., and Watson Pharma., Inc. (collectively, Amphastar) appeal the district court's order denying the Emergency Motion to Dissolve or Stay the preliminary injunction entered in this case. Because the district court applied an unduly narrow interpretation of the Hatch–Waxman safe harbor, 35 U.S.C. § 271(e)(1), we vacate the grant of a preliminary injunction and remand for further proceedings consistent with this opinion.

Background

This case is a patent litigation involving a generic version of Lovenox (enoxaparin), a drug that prevents blood clots. Enoxaparin is a low molecular weight version of heparin, a naturally occurring molecule. Heparin is a polymer, known as a polysaccharide, made up of long chains of sugar molecules. Heparin is not a single defined molecule. Instead, heparin molecules have considerable diversity in (1) the length of the polysaccharide chain and (2) in the component disaccharide units and the corresponding distribution of disaccharide unit sequences in the polysaccharide chains. FDA Letter to Aventis Pharmaceuticals, Inc., July 23, 2010, FDA Docket No. FDA–2003–P–0273 (FDA Letter), J.A. 291. For example, the molecular weight of heparin molecules varies between 5,000 and 40,000 daltons. Id. Likewise, the disaccharide units can vary between two different uronic acid components, and each of four positions on the disaccharide unit can be modified. Id., J.A. 291–92. The natural diversity inherent to heparin stems from the biosynthetic pathway used to produce the molecule. Id., J.A. 292.

Enoxaparin is produced by breaking the heparin polysaccharide into smaller pieces, called oligosaccharides. Because the heparin starting material is a diverse set of molecules, enoxaparin is also made up of different chain lengths and disaccharide units corresponding to the diversity in the original mix of heparin molecules. Id. Additional diversity is introduced based on the way in which the heparin molecule is broken down into the low molecular weight heparin product. Id., JA 292–93. Thus, unlike a typical small molecule drug like penicillin, enoxaparin is made up of a range of different molecules.

This molecular diversity raises a potential problem in light of the Food and Drug Administration's (FDA's) abbreviated new drug application (ANDA) approval process. ANDAs are typically used by generic companies to obtain approval to market a generic version of an existing drug. Unlike a new drug application (NDA), an ANDA applicant is not required to submit the same extensive clinical studies typically needed to prove the drug's safety and efficacy. Instead, the ANDA applicant must submit studies to establish that its drug is bio-equivalent to the reference drug. The ANDA must also include sufficient information to establish that the generic drug has the same active ingredients as the reference drug.

The obvious complication with using an ANDA application to gain approval for enoxaparin is that it is a mixture of a number of different low molecular weight heparin molecules. In fact, Aventis, which marketed Lovenox, asked the FDA to deny approval for a generic version of enoxaparin via an ANDA unless the applicant either (1) completely characterized enoxaparin by isolating, purifying, and sequencing each of its unique polysaccharide chains, which Aventis claimed was impossible; (2) used Aventis's manufacturing process; or (3) conducted clinical trials to prove safety and efficacy (the very type of duplicative studies the ANDA approval process was designed to avoid). FDA Letter, J.A. 286. The FDA rejected Aventis's arguments, and instead explained that the ANDA “statutory provisions do not describe the type or amount of information that an ANDA applicant must submit to demonstrate that the active ingredient in the generic drug product is the same as the active ingredient in the [reference drug].” Id., J.A. 294. As a result, the FDA concluded that Congress recognized that the FDA has “broad discretion with respect to the information [it] may consider in making a finding on the ‘sameness' of an active ingredient.” Id.

Consistent with this discretion, the FDA identified five criteria, or “standards for identity,” that “together provide sufficient information to conclude that generic enoxaparin has the ‘same’ active ingredient as Lovenox.” Id., J.A. 295. These criteria included, inter alia, [e]quivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species.” Id. The FDA explained that such equivalence is proven by “exhaustive digestion of enoxaparin with purified heparin digesting enzymes (heparinases I, II, III) and nitrous acid, among other means, to yield the constituent disaccharide building blocks comprising enoxaparin.” Id., J.A. 300. These disaccharides can then potentially be “separated and quantified” by a number of techniques, including capillary electrophoresis (CE), reverse phase high performance liquid chromatography (RP–HPLC), and strong anion exchange high performance liquid chromatography (SAX–HPLC). Id.

The FDA also suggested the identity of the disaccharides could be determined via standard techniques, including mass spectroscopy, NMR spectroscopy, modifying reagents, or modifying enzymes. These techniques identify the nature of the constituent sugars and their substitution patterns, including the sulfation and acetylation patterns, as well as “whether the disaccharide possesses, among other structures, a ... 1, 6 anhydro ring” structure. Id., J.A. 300–01. Detecting the presence of a 1, 6 anhydro ring structure is particularly important for proving equivalence because [e]quivalence in disaccharide building blocks together with equivalence in molecular weight distribution shows that generic enoxaparin contains the 1, 6 anhydro ring structure at the reducing ends of between 15 percent and 25 percent of its poly(oligo)saccharide chains.” Id. n. 68, J.A. 301.

Amphastar was the first company to file an ANDA for a generic version of enoxaparin. It submitted its ANDA to the FDA in March 2003, and subsequently engaged in a lengthy patent litigation with Sanofi–Aventis. Amphastar received FDA approval to market its generic enoxaparin on September 19, 2011. Despite the fact that Amphastar was the first company to file an ANDA, Momenta Pharmaceuticals, Inc. and Sandoz, Inc. (collectively Momenta), who collaborated to develop a generic enoxaparin product, were the first to bring generic enoxaparin to the market-place. Momenta received FDA approval to market enoxaparin in July 2010, more than a year before Amphastar's approval. Being the only generic version of enoxaparin has it benefits: its sales generated revenues of $260 million per quarter. J.A. 189. The approval of Amphastar's version of enoxaparin, and the resultant ruinous competition of another generic version of the drug, threatened this unique market position. Understandably unwilling to give up a billion dollars in yearly revenue, Momenta initiated the present litigation two days after Amphastar received final FDA approval to market its generic enoxaparin.

Momenta is the assignee of United States Patent No. 7,575,886 ('886 patent). The '886 patent generally relates “to methods for analyzing heterogeneous populations of sulfated polysaccharides, e.g. heparin [and] ... LMWH [e.g., enoxaparin.] '886 patent col.4 ll.53–55. Claim 6 is typical. It is a method for analyzing an enoxaparin sample “for the presence or amount of a non naturally occurring sugar ... that results from a method of making enoxaparin that included ß-eliminative cleavage with a benzyl ester and depolymerization.” Id. col.64 ll.35–39. Momenta also asserted independent claims 15, which assesses the level of non-naturally occurring sugar, and 53, which allows selection of an appropriate batch. These claims are similar to claim 6. The asserted claims generally require digestion of an enoxaparin sample with a heparin degrading enzyme, followed by the use of a separation method to detect the presence of the non-naturally occurring sugar resulting from the B-eliminative cleavage. The signal corresponding to the non-naturally occurring sugar can then be used to analyze the test sample based on a comparison with a reference standard. Id. col.64 ll.40–57.

Momenta alleged that Amphastar infringed the '886 patent by “manufacturing generic enoxaparin for commercial sale” using the claimed methods. J.A. 58. Momenta asserted that Amphastar “included in their process for manufacturing batches of enoxaparin sodium ... a method for determining that a defined percentage of the oligosaccharide chains that make up enoxaparin include ... a non-naturally occurring sugar that includes a 1, 6–anhydro ring structure, which method infringes the '886 patent.” J.A. 57. Momenta also alleged...

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