Will Exelixis’ patents hold back generic competition for Cabometyx?
Zachary Silbersher
Exelixis ($EXEL) recently received a Paragraph IV certification against its drug, Cabometyx, which is indicated for kidney cancer and as a second-line treatment for liver cancer. The certification was sent by MSN Pharmaceuticals. A lawsuit is likely to be filed by Exelixis against MSN within 45 days of the Paragraph IV certification. How well-positioned is Exelixis to fight this generic challenge?
The Orange Book currently lists six patents covering Cabometyx. The earliest expiring patent is in 2024, and the last expiring patent is in 2033. MSN’s Paragraph IV certification indicates that MSN does not seek to distribute its generic of Cabometyx before expiration of the two earliest expiring patents, U.S. Patent Nos. 7,579,473 and 8,497,284. Those two patents expire in 2026 and 2024, respectively. Thus, unless other generics emerge, Cabometyx is unlikely to face generic competition for at least another seven years.
After that, Exelixis will have to rely upon its other four patents, including 8,877,776; 9,724,342; 10,034,873 and 10,039,757. The ‘776 patent is essentially a compound or composition of matter patent. The patent specifically covers the (L)-malate salt of cabozantinib. The ‘757 patent and the ‘873 patents are method of use and formulation patents. The ‘757 patent is directed to treating kidney cancer with a particular pharmaceutical formulation. The ‘873 patent is directed to treating liver cancer with a particular pharmaceutical formulation. The ‘342 patent is also directed to a pharmaceutical formulation for cabozantinib, without specifying a particular indication.
Generally, these patents appear that they will likely be infringed by any proposed potential generic, including MSN’s. For instance, claim 1 of the ‘873 and ‘757 patent each requires a pharmaceutical composition including weight percentages of the following ingredients, cabozantinib, lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The FDA label for Cabometyx (at Section 11) indicates that the drug formulation includes these ingredients.
Any generic would most likely have to copy the label for Cabometyx. The label does not specify the weight percentages of each ingredient. To the extent a proposed generic has altered the weight percentages, that could technically be a basis for a generic to avoid infringement by designing around these three patents. Given that any pending ANDA for Cabometyx is not publicly-disclosed at this time, that determination will likely have to weight further litigation.
The claims of all four patents are technically directed to the L-malate of cabozantinib, whereas the FDA label for Cabometyx describes the active ingredient is the “(S)-malate salt of cabozantinib.” That is unlikely to be a basis to show non-infringement to the extent persons of ordinary skill would view them to be the same.
That said, Exelixis is likely to face invalidity challenges to its four patents. The ‘757, ‘873 and ‘342 patents cover related inventions, namely, pharmaceutical formulations for cabozantinib. The prosecution histories for each patent indicate they are directed to the same formulation, which was originally claimed in the ‘324 patent. To the extent there is any invalidity weakness in that formulation, it is likely to infect all three patents. Indeed, the ‘873 and ‘757 patents did not receive any rejections during prosecutions.
The prosecution history for the ‘342 patent indicates that the patent application was initially rejected by the Patent Office for including a relatively obvious pharmaceutical formulation. The patent, however, was allowed based upon purported surprising test results discovered by Exelixis. Specifically, preparation of formulation claimed in the ‘342 patent allegedly required reaction of cabozantinib with L-malic acid. That can give rise to 6,7-dimethoxy-quinoline-4-ol as a decomposition product, which is toxic. The claimed formulation was purportedly difficult because it required exposure to moisture, which can yield the 6,7-dimethoxy-quinoline-4-ol degradant. Nevertheless, Exelixis argued to the Patent Office that it allegedly surprisingly discovered a storage-stable tablet formulation that purportedly minimized this degradant.
MSN is likely to challenge the validity of these patents by challenging Exelixis’ test results as well as arguing that, contrary to what Exelixis told the Patent Office, those results were not in fact unexpected or surprising. Importantly, MSN can expedite this challenge by filing petitions for inter partes review. Those IPR petitions would need to be filed within approximately one year from now, but can be filed earlier. Those IPRs, if they are filed, will provide greater clarity into handicapping MSN’s chances of invalidating the ‘342, ‘873 and ‘757 patents. Given that MSN has already agreed not to enter the market until 2026, this is not a case where the generic challenger is likely to be in a rush to invalidate patents as quickly as possible.
The ‘776 patent also did not receive any rejections during prosecution before the Patent Office. That can be either good or bad, indicating either that the technology is strong enough from a validity perspective that the Examiner could not uncover any damning prior art. On the other hand, it could mean the patent application as not sufficiently stress-tested, opening a pathway for a generic challenger. In this case, the patent itself covers a compound, which suggests that at this time, the former scenario is more likely to be true.
Overall, Exelixis appears relatively well-positioned at this time against MSN’s generic challenge. Most importantly, MSN has already agreed not to enter before expiration of the ‘473 patent, which is not for another roughly seven years. Even after that, Exelixis has four patents running past 2030. That said, MSN is likely to mount both non-infringement and invalidity challenges, which will most likely require a matter of years for resolution, barring any settlement.