Merck Sharp & Dohme Corp. v. Amneal Pharms. LLC

Case Name: Merck Sharp & Dohme Corp. v. Amneal Pharms. LLC, Civ. No. 15-250-SLR, 2017 U.S. Dist. LEXIS 12165 (D. Del. Jan. 30, 2017) (Robinson, J.) 

Drug Product and U.S. Patent: Nasonex® (mometasone furoate nasal spray); U.S. Patent No. 6,127,353 (“the ’353 patent”)

Nature of the Case and Issue(s) Presented: Anhydrous mometasone furoate (“MFA”) was first synthesized and patented by Merck in the early 1980s. It was kept on the “backburner” for further research. Years later, scientists found that MFA dissolved in a new pharmaceutical solvent and developed MFA for the treatment of psoriasis, a skin condition. In the late 1980s, Merck sought to develop mometasone furoate for nasal applications. As a result of this project, mometasone furoate monohydrate (“MFM”) was developed. MFA and MFM are polymorphs. MFM differs from MFA in that every molecule of MFM is associated with a molecule of water, whereas no water is present in the crystal lattice structure of MFA. The difference between the molecular structures of MFM and MFA causes changes to the solid structure of the two crystalline forms.

The ’353 patent claimed MFM, a process for preparing MFM by crystallization from a saturated aqueous water-miscible organic solution, and aqueous stable pharmaceutical compositions of MFM. Amneal’s ANDA product used MFA as the active pharmaceutical ingredient. The issue was whether Amneal’s ANDA product contained any patented MFM during its two-year shelf life. The court held a two-day bench trial, and found that it did not.

Why Amneal Prevailed: To prove its case, Merck tested seven slides prepared from one bottle of Amneal’s Exhibit Batch. Its expert performed StreamLine spectroscopy on the slides and generated Raman maps made up of millions of individual spectra. He compared certain individual spectra (under 10% of spectra generated) to reference spectra of MFM and MFA generated on the same equipment. According to Merck’s expert, MFM had a characteristic peak around 1709 cm-1, MFA had a characteristic peak at 1725 cm-1, and the two polymorphs shared a peak in the range of 1640-1680 cm-1. Merck’s expert identified five MFM crystals on three slides; each of the spectra indicated the presence of both MFM and MFA. Amneal’s expert analyzed the spectra and opined that a “shoulder peak” indicative of MFA “could be easily misinterpreted … as a peak in that space and be mis-represented as MFM,” given the concentrations and the signal to noise levels. He further explained that the spectra showed that “this is primarily the MFA form, which is indicated by th[e] secondary doublet and the primary peaks …, which are indicative of both forms,” and that Merck’s expert misinterpreted these data as MFM. He concluded that MFM was not present. Merck’s expert relied on his identification of one peak on a Raman spectra to conclude that MFM particles were present in the tested batch. He opined that a single peak was sufficient to identify MFM in the ANDA product, but admitted that he could not see any other characteristic peaks for MFM because of the signal-to-noise limitation. In contrast, Amneal’s expert testified that three peaks were generally used to identify a polymorph in an unknown sample. In a technically-related case, Schering Corp. v. Apotex Inc., 2012 U.S. Dist. LEXIS 83414, the court evaluated expert testimony regarding Raman-spectroscopy results performed on the product at issue in that case and found that at least three peaks on a spectrum must be used to identify material, based on accepted practices. Thus, the court assigned little weight to Merck’s expert’s identification of MFM based on a single peak under these circumstances.

Amneal also tested samples from its exhibit batch. Not surprisingly, Merck urged the court to assign no weight to Amneal’s testing and related testimony based on the fact that such experiments only indicated the presence or lack of MFM at that specific point in time, not whether “MFM forms … during the product’s proposed two-year shelf life.” But neither expert had opined on a “growth rate.” The court therefore found that Amneal’s testing was at least as relevant as the conclusions drawn by Merck’s testing. Weighing the evidence, the court found that Merck had not carried its burden to prove, by a preponderance of the evidence, that MFM was present in Amneal’s ANDA product during its two-year shelf life.