Mometasone furoate – USA

On Feb 9, 2018, Federal Circuit affirmed a district court’s finding that Amneal doesn’t infringe a patent belonging to Merck in Nasonex® ANDA case.

Merck Sharp & Dohme Corp. (“Merck”) owns U.S. Patent No. 6,127,353, which claims mometasone furoate monohydrate (MFM), the active ingredient in Merck’s Nasonex® nasal product. Amneal Pharmaceuticals LLC (“Amneal”) submitted an Abbreviated New Drug Application (“ANDA”) to the U.S. Food & Drug Administration (“FDA”) seeking approval to market a generic mometasone furoate nasal spray comprising mometasone furoate anhydrous (MFA) as the active ingredient. Merck filed an infringement suit in the District of Delaware alleging that Amneal’s proposed ANDA product would infringe the ’353 patent if approved by the FDA. Specifically Merck alleged that although Amneal’s ANDA product contained MFA, its ANDA product would convert to the infringing MFM form over time. Following a bench trial, the district court found that Merck failed to prove by preponderant evidence that Amneal’s ANDA product will infringe the ’353 patent. On appeal, Merck argued that the district court abused its discretion by not compelling Amneal to produce additional samples of its ANDA product for testing before trial. Merck also argued that the district court’s noninfringement finding must be reversed because it was not based on Amneal’s final commercial product. Merck also challenged the district court’s fact-finding that a Raman spectroscopy three-peak analysis was required to confirm the infringing form of mometasone furoate in Amneal’s  product.

Amneal’s ANDA specification allowed for a maximum bulk suspension hold of up to four days, therefore the FDA required Amneal to complete a bulk-hold study. On February 29, 2016, Amneal responded to the FDA, providing data on samples from the Day 1 and Day 4 Batches from the requested bulk-hold study. Amneal did not provide the FDA data on samples from the A Batch. On May 9 and 13, 2016—six weeks before trial—Merck sought emergency relief from the district court, arguing that Amneal should have produced samples from the Day 4 and A Batches. Merck argued that because the Day 4 and A Batches underwent additional mixing, which can promote conversion of MFA to the infringing MFM form, Amneal should have produced samples from those batches for testing. Amneal argued that additional samples would have been cumulative of the Day 1 Batch samples already produced and maintained its representation that the Day 1 Batch samples were representative of its ANDA product.

Following two discovery hearings on the issue, the district court became aware of Amneal’s discovery violation and acknowledged that ideally Amneal should have produced samples of the Day 4 and A Batches. The district court determined, however, that it did not have enough information at the time to determine whether the Day 4 and A Batch samples were materially different from the Day 1 Batch samples. The district court concluded that it was “not persuaded sitting right here that mixing [] makes a substantive difference, and if it doesn’t, then it doesn’t matter that Amneal didn’t give [Merck] a sample of both [the Day 4 and A Batches] . . . [and] only gave [Merck the Day 1 Batch].” The district court did not compel Amneal to produce the additional samples. Nor did the court postpone trial. Instead, the district court gave Merck the opportunity to prove at trial that the Day 4 and A Batch samples were substantively different than the Day 1 Batch samples.

At trial, Merck’s expert, Dr. Matzger did not identify any MFM crystals in Exhibit Batches samples. But Dr. Matzger also tested samples from the Day 1 Batch and testified that he identified a single Raman peak at 1709 cm-1, which is characteristic of MFM. Dr. Matzger testified that although he tested the Exhibit and Day 1 Batch samples, he would have preferred to test samples of Amneal’s Day 4 and A Batches because they underwent additional mixing and thus were more representative of the final ANDA product. Amneal’s expert, Dr. Marquardt, testified that Dr. Matzger misinterpreted the data as identifying MFM in Amneal’s Day 1 Batch samples and opined that MFM was not present in Amneal’s final ANDA product. Dr. Marquardt further opined that three Raman peaks were required to confirm the presence of MFM rather than a single Raman peak. Amneal’s other expert, Dr. Rogers, opined that the likelihood of conversion of MFA to MFM was merely theoretical and unlikely due to the high energy required to convert between forms.

On the evidence presented, the court concluded that Merck has not demonstrated that the additional samples would yield different results. Consequently, the court denies Merck’s alternative request for the production of [the Day 4 and A Batch] samples and a new trial. Regarding infringement, the district court credited Amneal’s expert that three Raman peaks were required to identify MFM in Amneal’s ANDA product.  As a result, the district court “assigned little weight to Dr. Matzger’s identification of MFM based on a single peak. The district court concluded that based on the “lack of MFM in the Exhibit Batches and opposing conclusions on the same testing of the [Day 1 Batch],” Merck failed to carry its burden of proving by a preponderance of the evidence that MFM is present in Amneal’s ANDA product. Merck appealed.

Federal circuit upon appeal held that district court did not abuse its discretion in choosing this particular approach as opposed to ordering additional discovery and delaying trial. The district court took adequate steps to ensure that proceeding with trial would not prejudice Merck. Also the court allowed Merck the opportunity to prove at trial that the Day 4 and A Batch samples were different than the Day 1 Batch samples for purposes of infringement. Therefore it cannot be said that Merck was prejudiced by the district court’s decision to proceed to trial. And in fact at trial, Merck attempted to prove that mixing promotes conversion of MFA to MFM such that the additional mixing of Amneal’s Day 4 and A Batches would likely convert the MFA to MFM.  In light of the competing evidence in the record, CAFC discerned no clear error in the district court’s finding that the trial evidence failed to demonstrate that the MFA in Amneal’s product would have converted to MFM based on Amneal’s additional mixing. As the district court found, Merck presented little more than theoretical evidence to show that the Day 4 and A Batch samples would be more likely to undergo conversion than the Day 1 Batch samples. Federal circuit also rejected Merck’s argument that it could not prove conversion without testing the Day 4 and A Batch samples. Merck had samples of Amneal’s Exhibit and Day 1 Batches, but made no attempt to experiment with Amneal’s ANDA product to demonstrate conversion by additional mixing and passage of time alone, let alone by matching the mixing, in both speed and duration, that Amneal carried out to arrive at the Day 4 and A Batch samples.

Having concluded that the district court did not abuse its discretion in denying discovery of the Day 4 and A Batch samples, CAFC next turned to Merck’s argument that the district court erred in relying on Amneal’s Day 1 Batch samples to find that Amneal will not infringe the ’353 patent. Merck argued that the district court’s finding of noninfringement must be reversed as a matter of law because the district court improperly based its noninfringement finding on Amneal’s intermediate product (the Day 1 Batch samples) rather than its final, commercial-sized product (the A Batch samples). Federal circuit said that Merck was allowed an opportunity to prove at trial that samples of the Day 4 and A Batches would have materially differed from the Day 1 Batch samples. But Merck failed to do so. Based on the lack of conclusive evidence that Amneal’s additional mixing would have caused conversion in the Day 4 and A Batches, we cannot say that the district court erred in finding that Amneal’s Day 1 Batch samples were adequate to represent Amneal’s final ANDA product for purposes of determining infringement.

Federal circuit also discerned no clear error in the district court’s fact-finding of noninfringement. Although Dr. Matzger testified that he identified a single Raman peak characteristic of MFM in Amneal’s Day 1 Batch samples, his testimony was rebutted. Amneal’s expert, Dr. Marquardt, opined that Dr. Matzger misinterpreted his data and testified that MFM was not present in the Day 1 Batch samples. Dr. Marquardt also disagreed that a single Raman peak was sufficient to distinguish between MFA and MFM. Because its noninfringement finding is supported by the record, CAFC concluded that the district court did not clearly err in its noninfringement finding. Specifically because the district court’s finding that three Raman peaks were required to identify MFM is supported by Dr. Marquardt’s testimony, CAFC concluded that the district court did not clearly err in so finding.