Zolmitriptan – USA

On Jun 28, 2018, the Federal Circuit affirmed district court’s decision that formulation patents of drug, ZOMIG® are valid.

Lannett appealed from the decision of the District of Delaware concluding, after a bench trial, that claims 4, 11, 12, and 14 of U.S. Patent 6,760,237 (“the ’237 patent”) and claims 6 and 14– 16 of U.S. Patent 7,220,767 (“the ’767 patent”) were not shown to be invalid.

AstraZeneca owns NDA for Zomig® (zolmitriptan) Nasal Spray, 2.5 mg/spray and 5 mg/spray, approved by USFDA for treatment of migraine. AstraZeneca owns and Impax is the exclusive licensee of the ’237 and ’767 patents, which relate to formulations of zolmitriptan for intranasal administration. The claims at issue in this appeal are directed to pharmaceutical formulations with particular pH in the range 3.5 to 5.5, intranasal administration devices, or aqueous solutions, of zolmitriptan. Other formulation claims of the ’237 and ’767 patents at issue include similar limitations with regard to pH ranges and buffering, and some formulation claims include additional limitations relating to sterility. In June 2014, Lannett notified AstraZeneca that it had filed an ANDA with P-IV seeking approval for a generic version of Zomig® Nasal Spray, alleging non-infringement and/or invalidity of the ’237 and ’767 patents.

In July 2014, AstraZeneca (Appellees) filed suit against Lannett in the District of Delaware for infringement of the ’237 and ’767 patents. In December 2015, the district court issued its claim construction opinion and order. The court agreed with Appellees that the preamble of “[a] pharmaceutical formulation suitable for intranasal administration” is limiting. The court also adopted Appellees’ construction of “zolmitriptan” as meaning its chemical name and structure, declining to adopt Lannett’s proposed construction that would include “ionic and covalently bonded forms thereof that preserve the pharmaceutical activity of the structure.” The court, however, agreed with Lannett regarding the construction of the word “buffer,” adopting the “functional definition” proposed by Lannett. In September 2016, a four-day bench trial was held on the issues of infringement and validity. Following the bench trial, the parties stipulated that Lannett’s product described in its ANDA with a target pH of 5, if approved by the FDA, will infringe the ’237 and ’767 patents. In March 2017, the district court issued its decision on validity, holding that Lannett failed to prove by clear and convincing evidence that the asserted claims were invalid based on anticipation & obviousness challenges. Specifically, in reaching the non-obviousness conclusion, the court found that: (1) the prior art, including Chauveau, taught away from formulating zolmitriptan for intranasal administration because zolmitriptan was known to be active, not by itself, but through its more potent metabolite, 183C91; (2) the prior art at the time failed to teach that zolmitriptan by itself, as contrasted with its metabolite, would have been effective; and (3) a skilled artisan would not have been motivated to make with a reasonable expectation of success nasal formulations of zolmitriptan.

Lannett appealed. During appeal Lannett did not argue anticipation as a defense and did not challenge the district court’s claim constructions. The sole issue on appeal was whether it would have been obvious to make zolmitriptan into a nasal spray. On appeal, Lannett contended that the district court erred in concluding that the claims at issue would not have been obvious, based on an erroneous finding that the prior art taught away from nasal formulations of zolmitriptan. According to Lannett, the court improperly disregarded express teachings in the prior art. Lannett alleged that it made a strong showing of obviousness, and therefore, even accepting the district court’s findings of teaching away and objective indicia of nonobviousness, the court still erred in its ultimate conclusion of obviousness.

Federal circuit said that the prior art, Chauveau is generally directed to formulating an active ingredient using capryl caproyl macrogol glycerides for oromucosal administration of the active ingredient. Chauveau discusses that its teachings can be applied to formulations for buccal, nasal, or pharyngeal administration, among which the nasal route is preferred. The court found that Chauveau “offers a laundry list of potential active ingredients,” including “over twenty-five categories or examples of medications.” At the end of the list, Chauveau states that “[t]he active substance can also be, in particular, an antimigraine active substance, such as a triptan, such as sumatriptan or zolmitriptan.” Court held that, Chauveau, as a whole, is not about intranasal formulations of zolmitriptan, which is barely mentioned. It is about formulations of a wide variety of compounds with capryl caproyl macrogol glycerides. Zolmitriptan is mentioned once, with no further mention in an example or claim. Specifically, the court found that the prior art taught that zolmitriptan has a “unique attribute” in that its “[f]irst pass metabolism results in an active metabolite, 183C91, which is two to eight times more powerful than zolmitriptan itself.” The court credited Appellees’ expert, Dr. Rapoport, who provided his opinion on the state of the prior art in support of this finding. The court also noted that Lannett’s expert did not dispute the relevance of zolmitriptan’s active metabolite in considering whether to develop zolmitriptan formulations. Contrary to Lannett’s contentions, the district court found that zolmitriptan’s more potent, active metabolite was actually thought to be significant for its efficacy by a person of skill in the art at the time. Specifically, the court credited Appellees’ evidence of expert testimony and studies and found that a skilled artisan would have expected delayed or lower therapeutic effectiveness from zolmitriptan if administered nasally because it would have been “absolutely counterintuitive to make a nasal spray when you have an active metabolite which is more potent . . . than the drug itself.” As such, the court found that “because of zolmitriptan’s reliance on its active metabolite, the prior art failed to teach that zolmitriptan by itself would be effective.” Thus district court did not err in its findings.

The district court also considered evidence of secondary considerations, including the 2012 license agreement between Impax and AstraZeneca covering the Zomig® products for which Impax paid $130 million. The court found that this 2012 agreement favored Appellees as it found a nexus between the agreement and the ’237 and ’767 patents. However, it found that Appellees’ other evidence of secondary considerations was inconclusive. Federal circuit held that in view of other underlying factual findings, it is sufficient for us to find that the district court did not clearly err in finding that the 2012 agreement is at least in part attributable to the patents at issue.

Federal circuit then considered whether the district court reached a legally erroneous conclusion of non-obviousness. The court called this case indeed a “close one.” Federal circuit deferred to the district court in its fact findings, including what Chauveau discloses and the state of the prior art as a whole. And especially court persuaded by the testimony of Appellees’ expert, Dr. Rapoport, on which the district court relied, who opined that it would have been “absolutely counterintuitive” to make an intranasal formulation of zolmitriptan, given that its activity primarily came from its metabolite, and the agreement between AstraZeneca and Impax covering the intranasal product and its patents for which the latter paid $130 million. Federal circuit therefore concluded that the district court did not commit reversible error in its non-obviousness conclusion. Thus, Lannett failed to prove by clear and convincing evidence that the claims of the ’237 and ’767 patents are invalid.