[author: Courtenay C. Brinckerhoff]

In a decision issued August 3, 2012 in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., the Federal Circuit held that the safe harbor provisions of 35 USC § 271(e)(1) can shield the defendants from liability for patent infringement arising out of their use of patented methods to satisfy FDA testing requirements for their approved products. Judge Moore wrote the opinion for the court, which was joined by Judge Dyk. Chief Judge Rader wrote a dissenting opinion, explaining his contrary view and asserting that the majority decision is in direct conflict with the court’s August 2011 decision in Classen Immunotherapies, Inc. v. Biogen Idec. Chief Judge Rader was in the majority in that decision, while Judge Moore dissented. A petition for certiorari in Classen is pending at the Supreme Court, and it is likely that the Supreme Court will have to resolve these conflicting views of the safe harbor.

The Products at Issue

The products at issue are generic versions of Lovenox®, which is used to treat and prevent blood clots. Lovenox® is a biological product, obtained from a form of heparin obtained from porcine intestinal mucosa. As explained in the Federal Circuit opinion:

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.

The generic products (referred to in the Federal Circuit opinion as “enoxaparin”) are synthetically prepared, low molecular weight versions of heparin. As explained in the Federal Circuit opinion:

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. … Additional diversity is introduced based on the way in which the heparin molecule is broken down into the low molecular weight heparin product. … Thus, unlike a typical small molecule drug like penicillin, enoxaparin is made up of a range of different molecules.

The FDA Approval Process

In a separate proceeding, the manufacturer of Lovenox®, Aventis Pharmaceuticals, Inc., had argued that generic versions of enoxaparin should not be able to use the Abbreviated New Drug Application (ANDA) process because of the inherent heterogeneity of the products. The FDA disagreed, and identified five criteria that it would use to evaluate generic products. These “standards for identity” included “[e]quivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species.” According to the FDA, such equivalence could be 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,” and separation, quantification, and identification of the disaccharides by a number of different techniques.

According to the FDA:

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. … 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.”

As noted in the Federal Circuit opinion, Amphastar was the first company to file an ANDA for a generic version of enoxaparin, but Momenta Pharmaceuticals, Inc. and Sandoz, Inc. (in collaboration) were the first to bring a product to market. When Amphastar’s product was approved, Momenta commenced the patent infringement litigation at issue.

The Patent at Issue

The patent at issue is Momenta’s U.S. Patent 7,575,886. As characterized in the Federal Circuit opinion, the ’886 patent “relates ‘to methods for analyzing heterogeneous populations of sulfated polysaccharides, e.g. heparin [and] . . . LMWH [e.g., enoxaparin.]” The court cited claim 6 as representative:

6. A method for analyzing an enoxaparin sample for the presence or amount of a non naturally occurring sugar associated with peak 9 of FIG. 1 that results from a method of making enoxaparin that included Β-eliminative cleavage with a benzyl ester and depolymerization, comprising:
providing an enoxaparin sample that has been exhaustively digested with two or more heparin degrading enzymes;
using a separation method to determine, in the enoxaparin sample that has been contacted with two or more heparin degrading enzymes, the presence of a structural signature associated with the non naturally occurring sugar associated with peak 9 of FIG. 1 that results from a method of making enoxaparin that includes Β-eliminative cleavage with a benzyl ester and depolymerization; and
making a determination about the enoxaparin sample based upon a comparison of the determination of the presence of a structural signature associated with the non naturally occurring sugar associated with peak 9 to a reference standard for enoxaparin, wherein the determination based upon the comparison to the reference standard regards the quality of the sample, to thereby analyze the enoxaparin sample.

Momenta alleged that Amphastar’s manufacturing method included the method(s) claimed in the ’886 patent. Indeed, Momenta asserted that “this infringing testing was necessary because the ‘FDA requires a generic manufacture to include in its manufacturing process the analysis of each batch of its enoxaparin drug substance to confirm that . . . [it] includes a 1,6-anhydro ring structure.’”

The District Court Decision

Momenta obtained a temporary restraining order and then a preliminary injunction to keep Amphastar’s product off the market. In deciding in favor of Momenta, the district court rejected Amphastar’s argument that its allegedly infringing activities fall under the safe harbor of 35 USC § 271(e)(1), which excludes from infringement activities that are “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.”

The district court cited the Federal Circuit’s August 2011 decision in Classen Immunotherapies, Inc. v. Biogen Idec, and noted that “the alleged infringing activity involves the use of plaintiffs’ patented quality control testing methods on each commercial batch of enoxaparin that will be sold after FDA approval.” The district court acknowledged that “Amphastar’s use of the patented method was for the purpose of developing information to submit to the FDA,” but “concluded that the safe harbor does not apply” because the safe harbor “does not permit a generic manufacturer to continue in … otherwise infringing activity after obtaining … approval.”

The Federal Circuit Decision

Amphastar appealed the preliminary injunction to the Federal Circuit, which stayed the preliminary injunction after hearing oral argument. The court’s August 3, 2012 decision represents its “final decision on the merits of Amphastar’s appeal.”

In the opinion for the court, Judge Moore began the analysis with the plain language of the statute, and found no basis for limiting the reach of the safe harbor to “activities reasonably related to development of information submitted in an ANDA.” Focusing on the broad language of the statute, Judge Moore wrote:

Instead, the safe harbor applies “to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.” As long as the allegedly infringing use is “for uses reasonably related” to the development and submission of that information it is not an act of infringement, regardless of where that requirement resides in the law.

The opinion cites Supreme Court cases that also adopted an “expansive view” of the statute based on its plain language, including the 1990 Supreme Court decision in Eli Lilly & Co. v. Medtronic, Inc., and the 2005 Supreme Court decision in Merck KGaA v. Integra Lifesciences I, Ltd.

Having addressed this threshold question, the court then considered whether Amphastar’s activities could fall under the safe harbor.

It is not disputed by the parties that these records are produced in order to develop and submit to the FDA proof that the Amphastar products comply with a Federal law. The fact that the FDA does not in most cases actually inspect the records does not change the fact that they are for the “development and submission of information under a Federal law.” … Thus, we consider this information “submitted” for purposes of the statute.

The court characterized Classen as holding that “the scope of the safe harbor provision does not extend to ‘information that may be routinely reported to the FDA, long after marketing approval has been obtained,’” and distinguished it as follows:

This case, however, fits well within Classen because the information submitted is necessary both to the continued approval of the ANDA and to the ability to market the generic drug. Here, the submissions are not “routine submissions” to the FDA, but instead are submissions that are required to maintain FDA approval. Amphastar is required to conduct a laboratory determination of identity and strength of the active ingredient for each batch of enoxaparin.
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We also note that, unlike in Classen where the patented studies performed were not mandated by the FDA, the information here is not generated voluntarily by the manufacturer but is generated by FDA requirements the manufacturer is obligated under penalty of law to follow. Under such circumstances, the information can be said to have been gathered solely for submission to the FDA and not, as in Classen, primarily for non-FDA purposes.

If you read Classen, you might think that Federal Circuit held that “§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration.” Indeed, in her dissent in Classen, Judge Moore characterized the majority decision as follows:

The majority concludes that the district court incorrectly interpreted the safe harbor of § 271(e)(1) because, according to the majority, § 271(e)(1) is limited to pre-approval activities.

But in this case, Judge Moore rejects such an interpretation of Classen:

While Momenta urges us to adopt the pre-/post-approval distinction used by the district court, we cannot: Classen did not turn on this artificial distinction, and the plain language of the statute is not restricted to pre-approval activities.

Judge Moore summarizes the court’s current interpretation of the safe harbor by quoting from the statute:

We therefore hold that post-approval studies that are “reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs” fall within the scope of the § 271(e)(1) safe harbor.

The court rejected Momenta’s argument that the safe harbor should not apply “because there are FDA endorsed non-infringing alternatives.” Specifically, Momenta argued that the term “solely” in the statute means that the patented invention must be the “sole” means of providing the required information in order for the safe harbor to apply. The court disagreed:

The safe harbor … does not mandate the use of a non-infringing alternative when one exists. … The safe harbor’s protection is not limited to the dire situation where the patented invention is the only way to develop and submit the information. Instead, the safe harbor expressly allows the submitter the freedom to use an otherwise patented means to develop the necessary information demanded by the “Federal law.” This makes good sense because it eliminates liability for infringement when that act of infringement is, in effect, required by the federal government as part of the continuing safety and efficacy monitoring of an approved drug. It also avoids the situation here, where a drug has received approval, but is nevertheless kept from the market based on an FDA mandated testing requirement.

Turning back to the preliminary injunction before it, the court note that “Momenta’s admission that Amphastar’s testing is carried out to ‘satisfy the FDA’s requirements,’ … makes it unlikely that Momenta will succeed on the merits of its infringement claim.” Because the other district court findings “were all, to some extent, predicated on its erroneous conclusion that Momenta’s patent was likely infringed by Amphastar’s product,” the Federal Circuit vacated the preliminary injunction, and suggested that on remand the district court may be able to grant summary judgment of non-infringement in favor of Amphastar.

Chief Judge Rader’s Dissent

Chief Judge Rader joined the majority opinion in Classen (which was authored by Judge Newman), so it is not surprising that he dissented from the decision in Momenta. Instead of summarizing the 29-page dissent, I simply will provide an outline of Chief Judge Rader’s main points:

• Exceptions to the traditional property right to exclude should be construed narrowly.
• Amphastar is freeloading on Momenta’s invention:
  “Amphastar has not developed its own method, but instead delights in trespassing and refuses to pay a reasonable royalty to make the trespass lawful.”
• Interpreting § 271(e)(1) in light of its legislative history is consistent with Supreme Court precedent (including Eli Lilly & Co. v. Medtronic, Inc.), and demonstrates that the safe harbor was intended to apply “only in limited situations, namely pre-approval experiments to obtain FDA approval.”
• Classen indeed turned on a pre-/post-approval distinction; instead of issuing an inconsistent decision here, the issue should have been resolved en banc.
• The court’s decision could eviscerate method of manufacturing patents in the pharmaceutical space.
• The Supreme Court decisions in Eli Lilly & Co. v. Medtronic, Inc. and Merck KGaA v. Integra Lifesciences I, Ltd. support the Classen interpretation of the safe harbor.
• “Too often patent law is misunderstood as impeding more than promoting innovation.” To the contrary, the patent system “encourages publication and sharing of research results.” “Without this promise of exclusivity, researchers at corporations would be forced to turn to secrecy as the best protection for their inventions.”

Will the Supreme Court Resolve This Dispute?

As noted above, a petition for certiorari is pending in Classen. During its last session, the Supreme Court invited the Solicitor General to file a brief expressing the views of the United States on the issue of the scope of the “safe harbor.” Perhaps this conflicting decision from the Federal Circuit will give the Supreme Court another reason to grant certiorari, and once again interpret the difficult language of § 271(e)(1).