How big is your boat? The 'experimental use' safe harbour

Momenta Pharmaceuticals Inc v Amphastar Pharmaceuticals Inc (Federal Circuit, August 3, 2012) is the latest decision examining the scope of the ‘experimental use’ exception to infringement afforded by 35 USC §271(e)(1).

The Court of Appeals for the Federal Circuit (CAFC) panel of Judges Rader, Dyk and Moore found that the statute exempted from infringement acts that occurred after approval by the Food and Drug Administration (FDA) for marketing of a ‘biosimilar’ drug that were required to be performed to comply with FDA regulations relating to documenting the composition of the drug. There is a split among the judges as to whether the safe harbour established by 35 USC §271(e)(1) encompasses acts occurring after FDA approval for marketing is obtained, so this case seems destined to go to the Supreme Court.

Momenta Pharmaceuticals is preceded by two Supreme Court decisions and one other CAFC decision that map the shores of the safe harbour. Eli Lilly & Co v Medtronic Inc (1990) held that the safe harbour provision extended beyond drug compounds to medical devices. Merck KGaA v Integra Lifesciences I Ltd (2005) held that the safe harbour extended back in time to shelter activities relating to pre-clinical studies and the use of a patented compound other than for therapeutic study for clinical approval.

Classen Immunotherapies Inc v Biogen (CAFC 2011) examined a boundary similar to that tested in Momenta Pharmaceuticals: whether post-marketing approval use of a patented method that produced (as a by-product) information that is required to be reported to the FDA is inside or outside the harbour.

Momenta Pharmaceuticals manufactures and sells the generic blood clot preventer, enoxaparin, which is a mixture of short sugar chains produced by enzymatic hydrolysis of heparin. The mixture is complex and diverse with respect to both the particular structure of the disaccharides and their length distribution. The complexity arises partly from the source of the heparin that is hydrolysed and partly from the particulars of the hydrolysis.

Momenta Pharmaceuticals owns US Patent 7575886 (’886), which claims a method for analysing an enoxaparin sample to determine its oligosaccharide composition, particularly to determine, in the enoxaparin sample that has been contacted with two or more heparin-degrading enzymes, the presence of an analytic signature associated with a nonnaturally occurring sugar that results from a method of making enoxaparin that includes beta-eliminative cleavage with a benzyl ester and depolymerisation.

The FDA considered that the amount of the “nonnaturally occurring sugar associated with peak 9 of Figure 1” (a sugar with a 1,6-anhydro ring structure) was useful as a marker for the overall composition of an enoxaparin sample and adopted a standard for marketing of enoxaparin that lots must be characterised by methods covered by the ’886 patent and the results documented and held for inspection pursuant to 21 USC §§331(a) and 351(b), and 21 CFR §211.180(a).

Therefore, any lot of enoxaparin must be characterised by the analytic method of the ’886 patent before shipping, and the manufacturer must keep the record of the analysis available for inspection by the FDA at any time. Biosimilar producers can expect to see such manufacturing standards for marketing adopted in view of the structural complexity of biological drugs.

Momenta Pharmaceuticals arose on appeal of a preliminary injunction precluding Amphastar from selling enoxaparin. Amphastar asserts that the District Court improperly concluded that Momenta Pharmaceuticals was likely to prevail on the merits of its infringement case, since Amphastar’s use of the patented analytic method for characterising its lots of enoxaparin was required by the FDA for marketing of its product, and so protected by the safe harbour of 35 USC §271(e)(1).

Judge Moore, writing for the majority, found that the language of 35 USC §271 is unambiguous, so it is unnecessary to look further for evidence of meaning of its terms. Accordingly, she declined to consider the historical context in which the statute was written. She applied her strict textual approach to the phrase in the statute: “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”.

An expansive interpretation of this phrase led to a holding 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”. This conclusion in turn suggested that Momenta Pharmaceuticals was not likely to prevail on the merits of its infringement assertion, and so the preliminary injunction in place was vacated.

The decision in Momenta Pharmaceuticals looks as though it is directly contrary to the result reached in Classen, which is binding precedent upon the CAFC. The Classen panel found that the safe harbour of 35 USC §271(e)(1) extended only to pre-marketing activity relating to developing information useful for obtaining marketing approval in the first instance.

Judge Moore side-stepped Classen by asserting that the information developed by the studies performed by the infringers did not need to be reported to the FDA by any statute or regulation, but instead was merely part of “routine” reporting.

However, the studies performed by the infringers in Classen were considered by them to identify “adverse events” resulting from administration of their product vaccines, which had to be reported to the FDA under 21 CFR §600.80.

On the other hand, the studies conducted by the infringers in Classen were not mandated by the FDA to be conducted in the first place. Judge Moore summarised the situation, saying: “Accordingly, 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’.”

Maybe it would be better to say that the scope of the safe harbour provision does not extend to activity that is not begun based on a statutory requirement of the FDA.

Judge Rader was a member of both of the Classen and Momenta Pharmaceutical panels; and wrote a concurring opinion in Classen and a vigorous dissent in Momenta Pharmaceuticals. Judge Rader looked to the historical context of the Hatch-Waxman legislation and the intent of Congress to correct perceived distortions of the term of exclusivity created by overlapping exclusivities generated by the property right of a patent and the marketing regulations of the Food, Drug and Cosmetic Act.

Judge Rader narrowly interprets the statute to encompass only activities relating to obtaining market approval in the first instance, his opinion being this is the only conclusion that can be reached based on the intent of Congress in writing 35 USC §271.

The split in the CAFC (and $1 billion per year at stake) seems certain to send Momenta Pharmaceuticals to en banc review, and probably from there to the US Supreme Court.

So, biosimilar manufacturers wait for the final word on whether activity conducted after marketing of a pharmaceutical product has been approved—whether undertaken due to a statutory requirement or merely because the activity showed results that would have to be reported to the FDA—is sheltered by the 35 USC §271(e)(1) safe harbour, or if that is where ‘there be dragons’.