Cabometyx® (cabozantinib (L)-malate)
Case Name: Exelixis, Inc. v. MSN Labs. Private Ltd., No. 22-228-RGA, 2024 WL 4491176 (D. Del. Oct. 15, 2024) (Andrews, J.)
Drug Product and Patent(s)-in-Suit: Cabometyx® (cabozantinib (L)-malate); U.S. Patents Nos. 11,298,349 (“the ’349 patent”), 11,091,439 (“the ’439 patent”), 11,091,440 (“the ’440 patent”), and 11,098,015 (“the ’015 patent”)
Nature of the Case and Issue(s) Presented: Cabometyx is indicated for the treatment of kidney cancer, liver cancer, and differentiated thyroid cancer. The ’349 patent is directed to a pharmaceutical composition of cabozantinib (L)-malate that includes certain excipients and lacks a harmful genotoxic impurity. The ’439 patent, ’440 patent, and ’015 patent (the “Malate Salt Patents”) claim a crystalline cabozantinib malate salt. MSN argued that it did not infringe the ’349 patent and that the Malate Salt Patents were invalid for lack of written description and for obviousness-type double patenting.
Why Exelixis Prevailed. MSN did not infringe the ’349 patent. The only dispute between the parties regarding infringement was whether MSN’s formulation included a glidant. Exelixis defined glidant as “a material that improves the flow of a drug powder mixture.” Conversely, MSN defined glidant as a material that improves flow of a powder blend through five specific mechanisms outlined by its expert. The court disagreed with MSN, as neither the claims nor specification of the ’349 patent stated that a glidant must improve flow through any specific mechanisms. The court was also persuaded by the fact that Remington and Swarbrick defined a glidant in such a way that supported Exelixis’s definition. Nevertheless, MSN argued that it did not infringe and presented data from a laboratory notebook allegedly showing that the excipient in question, GRASTAR, did not improve flow. The court found these data unreliable and disregarded MSN’s argument. Based on the evidence of record, the court concluded that GRASTAR was a commonly used glidant. And despite finding that the literature described GRASTAR as a glidant, it explained that there was no evidence that the GRASTAR in MSN’s formulation improved flow of the API. In particular, because Exelixis’s expert testified only that GRASTAR would “be expected” to potentially enhance the flowability of MSN’s formulation, the court concluded that Exelixis did not meet its burden to prove infringement.
The Malate Salt Patents were not invalid for lack of written description. The parties agreed that the specification of the Malate Salt Patents disclosed two types of crystalline cabozantinib L malate: N-1 and N-2. And despite disclosing only two examples, the Court found adequate written description because the specification disclosed structural features common to all members of the genus such that a POSA could visualize or recognize the members of that genus. In particular, the Court found that because the specification disclosed the chemical name and formula of cabozantinib (L)-malate, as well as that the structure was crystalline, it identified structural features commonly possessed by members of the genus.
The Malate Salt Patents were not invalid for obvious-type double patenting. While the court separately analyzed each asserted claim of the Malate Salt Patents for obvious-type double patenting, the ’439 patent is representative of the court’s analysis. MSN argued that the ’439 patent was invalid for obvious-type double patenting as a result of a different patent owned by Exelixis, U.S. Patent No. 7,579,473 (“the ’473 patent). The court first construed the claims of the two patents to determine whether there were any differences. Here, the court found that crystalline (L)-malate, claimed in the ’439 patent, was a pharmaceutically acceptable salt of cabozantinib, which was recited in the ’473 patent. As a result, the ’439 patent was directed to a species of the ’473 patent: crystalline cabozantinib (L)-malate. At step two, MSN argued that a POSA would be motivated to make a salt of cabozantinib. Exelixis disagreed, arguing that the prior art reported no problems with the free base, meaning that a POSA would have no reason to make a cabozantinib salt. The court rejected Exelixis’s argument and found that a POSA would have wanted to form a salt to increase the solubility, dissolution rate, and other properties of the cabozantinib API.
The court next addressed the selection of the malic acid salt. Here, the court found that because a POSA would follow a hierarchical approach to testing counterions, he/she would not reach far enough down the list to test malic acid. The court also concluded that MSN presented no evidence that a POSA would have had a reasonable expectation of success in forming a crystalline salt. As a result, the court found that the Malate Salt Patents were not invalid for obviousness-type double patenting.
