On Jan. 19, 2023, Delaware court found compound patent valid and polymorph patent non-infringed in a Hatch-Waxman litigation.

 

Exelixis (Plaintiff) is the holder of New Drug Application (NDA) for Cabometyx®, a tablet containing the active pharmaceutical ingredient cabozantinib (S)-malate. MSN pharmaceutical (Defendant) filed ANDA with USFDA to market generic version. Exelixis sued MSN for infringement of US 7,579,473 (compound patent) and US 8,877,776 (polymorph patent).

 

Invalidity of US’473:

Claim 5 of the ‘4 73 patent requires the chemical structure of cabozantinib or a pharmaceutically acceptable salt thereof. MSN argued that claim 5 of the ‘ 473 patent is invalid as obvious based on a lead compound analysis of example 5 of prior art, Kirin. Court found that POSA would not have been motivated to select Kirin’s Example 5 as a lead compound. Furthermore, even if Example 5 was selected as a lead compound, a POSA would not have found it obvious to modify Example 5 to reach cabozantinib.

MSN argued that, considering Kirin, a POSA would have started with the exemplary compounds with the highest potency, then narrowed them down based on toxicity, bioavailability, and potential for irreversible inhibition. Kirin discloses 333 exemplary compound with ‘IC50 values’ as a potency criteria. Many of the most potent exemplary compounds, as measured by their IC50 values, in order are thioureas, ureas and malonamide. MSN argued that POSA would not have considered thioureas because of their toxicities and ureas because of their lack of irreversible inhibition. Therefore, the next remaining most potent of Kirin’ s compounds include a malonamide (Example 269), and malonamide (Example 5). Out of these 2 malonamides, POSA would have disregarded Example 269 because it did not have a desirable oral bioavailability profile and therefore, POSA would have selected Example 5. Court disagreed and said that MSN’s iterative deprioritization of the 14 compounds that are more potent than Example 5 appears to rely on improper hindsight. Kirin identifies five compounds as “most preferred,” none of which are malonamides. Kirin provides in vivo test results for 23 compounds, none of which are malonamides. MSN overreached in its categorical deprioritization of thioureas based on potential toxicity concerns. At the time of the invention, there were multiple thioureas in clinical use or trials. Kirin also suggested either that ureas were thought to be able to form irreversible inhibitors or that was not a great concern to a POSA. Again, Dr. MacMillan convincingly testified that, while Example 269 does not meet Lipinski’ s criteria for molecular weight, a POSA would not have been troubled because only one of Lipinski’ s criteria was violated. Therefore, considering the evidence, Court found that MSN has not shown by clear and convincing evidence that a POSA would have identified Example 5 as a lead compound.

With respect to motivation to modify lead compound, Court said that POSA would not have been motivated to modify Example 5 to include a cyclopropyl group. A POSA would have been concerned that this modification would have unpredictable effects, and a POSA would not have been motivated to pursue an irreversible inhibitor. Modifying Example 5 to include a cyclopropyl group could unpredictably alter the compound’ s functionality, toxicity, and potency. Therefore, MSN has not proven that a POSA would have had a reasonable expectation of success in performing proposed modification due to the modification’ s unpredictability.

 

Infringement of US’776:

Claim 1 of US’776 patent requires cabozantinib maleate in crystalline Form N-2 with certain 13C NMR and XRPD values. MSN contends that its tablets will include only Form S of cabozantinib, where MSN formulated Form S
as a design around for Form N-2. Exelixis disagrees, arguing that Form S is unstable and, over time, will convert to Form N-2, thus causing infringement. At trial, Exelixis provided no direct evidence of 13C NMR or XRPD test results detecting Form N-2 in MSN’ s tablets. Instead, Exelixis presented evidence that Dr. Munson detected Form N-2 in
MSN’ s API through 13C NMR testing. Dr. Munson’ s testing of MSN’ s API did not detect Form N-2 in MSN’ s three-year-old as-provided samples, however, Dr. Munson only detected Form N-2 in MSN’ s API after subjecting
the test samples to “accelerated conditions (40°C at 75% RH)” in an open container. Court said that Dr. Munson’s results from using accelerated conditions are not representative of how MSN’ s API or tablets will behave in the real world over time. Dr. Munson received samples of MSN’ s API that had already been manufactured and, thereby,
“had already been subjected to eight hours … at 55 to 65 degrees C.” Therefore, Form N-2 would already have been present in Dr. Munson’ s API samples if the API manufacturing conditions caused Form N-2 to form. Second, Dr. Munson let the API sit in open petri dishes at a high temperature and humidity, MSN’s ANDA prescribes storing the API “in well closed containers at 2 to 8°C temperature and protect[ed] from moisture.” Moreover, Dr. Munson applied the accelerated conditions to samples containing only MSN’ s API, MSN’s ANDA requires that MSN’ s API be combined with excipients before the granulating, drying, and coating steps of tablet manufacturing begin. This lack of excipients is significant because “excipients can act to stabilize an API”. Therefore, Dr. Munson’ s accelerated conditions are not representative of the conditions MSN’ s tablets will likely face.

Thus, Dr. Munson’ s testimony lacks credibility when he described that his “accelerated conditions are conditions that were going to be slightly higher humidity, slightly higher temperature, something that may be representative of potential storage conditions or also manufacturing conditions”. Therefore, Exelixis has not proven by a preponderance of the evidence that MSN’s API will infringe claim 1 of the ‘776 patent.