This article was originally published on November 30th 2017 by Hamish McDougall and Alaric DeArment of BioPharm Insight, part of GlobalData.
- Polymorph differences support noninfringement argument
- Trace solvate amount could destabalise to hemihydrate
- Settlement similar to deal with Natco possible
Celgene’s (NASDAQ:CELG) Revlimid (lenalidomide) patent defence against generic challenger Dr. Reddy’s Laboratories (NYSE:RDY) hinges on the generic polymorph’s stability, with the general instability of polymorph structures over time favoring Celgene, experts said.
While Dr. Reddy’s distinct polymorph structure may help support its case for noninfringement, the potential for the lenalidmoide polymorph’s “presence” within the generic structure remains the major debated risk of infringement, and the debate will come down to definitions of “substantial” presence by both parties, experts added.
Celgene has a compound patent for Revlimid (US 5,635,517) expiring in October 2019, but also other methods-of-use patents (7,189,740 and 7,968,569) expiring in 2023 and a polymorph patent (US 7,465,800) expiring in 2027. Revlimid – approved for multiple myeloma, deletion-5q myelodysplastic syndrome and mantle cell lymphoma – generated global sales of USD 6.9bn in 2016, forecasted to peak at USD 14.4bn by 2024. However, Dr Reddy’s generic pursuit threatens Celgene’s projections if it successfully launches before patent expirations.
Analysts have discussed Celgene’s patent defence extensively in the last quarter, particularly focusing on a potential 2020 generic launch through challenging methods-of-use patents. However, the general consensus concludes this as unlikely especially with an expired IPR deadline for Dr Reddy’s to challenge the 2023 patents. They also noted the polymorphic structure of Dr Reddy’s generic is likely distinct enough to argue noninfringement.
However, because drugs with polymorph structures tend to be unstable and can convert to different forms, should Dr. Reddy’s polymorph demonstrate trace amounts of Revlimid hemihydrate, this could negatively affect its noninfringement defence, experts said. The polymorph’s stability polymorph depends upon manufacturing processes and potentially storage, two experts noted.
Over the past year, several generics have filed ANDAs for Revlimid generics, including Dr. Reddy’s, Zydus (BOM:531335) and Cipla (NSE:CIPLA), triggering Hatch-Waxman lawsuits from Celgene.
Dr. Reddy’s seeks FDA approval of its generic lenalidomide products, which contain a stable form of lenalidomide, and has filed Paragraph IV certifications for several Orange Book-listed Revlimid patents, a company spokesperson said, adding that despite ongoing litigation, the company remains confident in its invalidity and noninfringement defences.
A New Jersey district court clerk confirmed opening claims will be heard for both parties in December 2017, with a telephone conference scheduled for February 2018.
Celgene did not respond to a request for comment.
Defence dependent on polymorph stability
Lenalidomide exhibits polymorphism, the ability of a solid chemical to exist in one form or crystal structure, noted one patent attorney and pharmacist Cindy Chau, research chemist, National Cancer Institute, Bethesda, Maryland. Often trace amounts of lenalidomide can switch back and forth between different forms or polymorphs and many companies, including Dr Reddy’s, have tried developing stable lenalidomide polymorphs to prevent the polymorph changing, they explained.
Previously, in a case with Natco Pharma (BOM:524816) versus Celgene, a judge ruled that Revlimid had a broad “hemihydrate” polymorph structure, noted a second patent attorney. The court issued a Markman decision in 2014, and the companies settled in 2015. However, patents in Dr Reddy’s ANDA appear to refer to a different polymorphic structure, a solvate, the second attonrye explained, adding this importantly allows the drug to be distinct for the company to present a strong noninfringement defence given the structures’ chemical distinctiveness.
However, much of Celgene’s defence will not rest on the polymorphs’ distinctiveness, and there is a risk of trace amounts of its polymorph being found in Dr Reddy’s product, said Stacie Ropka, partner, law firm Axinn, Veltrop & Hardrider, Hartford, Connecticut , the two unnamed patent attorneys and James McCormack, professor, pharmaceutical sciences, University of British Columbia, Vancouver. Sometimes when a polymorph is manufactured it is impure, with trace amounts of another polymorph, and should the hemihydrate form be detected in Dr Reddy’s structure, it would negatively impact Dr Reddy’s ability to argue noninfringement, said Ropka and McCormack. However, both sides will argue what counts as a “substantial” amount of the other polymorph, noted Ropka. Polymorph chemistry cases are complex and hard-fought and often come down to very fine margins regarding trace amounts, she said.
Ropka noted Revlimid has about two years’ shelf life before it must be discarded. All experts agreed as polymorphs are unstable structures, shifting between the various polymorph forms is entirely possible during a two-year shelf life. A polymorph can change into something on the shelf and in that time a company could demonstrate it has a different polymorph within the product, said Ropka.
Much depends on Dr Reddy’s manufacturing process, said Chau. It’s important to know how they can keep that polymorphic form stable at the end manufacturing stage, and the challenge is to keep the synthetic stage at its exact state in order to avoid trace amounts of Celgene’s polymorph appearing in Dr Reddy’s product over time, lest there be a case for infringement, she said.
If a company like Dr Reddy’s creates a more efficient manufacturing process, it can likely create a more stable polymorph, Chau explained. It may also depend on the storage process, she noted.
If trace amounts of the hemihydrate are more stable than the solvate, more is likely to convert into that more stable hemihydrate form, the first patent attorney said, adding this will lead to increased concentrations of the hemihydrate contamination. However, this depends on the Dr Reddy’s solvate’s stability compared to the hemihydrate, he added, noting he was unaware of the nuanced differences in their respective stabilities.
The second patent attorney noted Dr Reddy’s not pursuing an IPR before the October 2017 deadline likely reflects its confidence on a strong noninfringement position. Invalidating patents via IPR is preferable, as that allows further generic competition to enter the market on the back of success, he explained.
The first attorney noted previous lenalidomide generic litigation, with Nacto choosing settlement with Celgene in December 2015 despite its anhydrous polymorph. In that case, Celgene agreed to license its patents to Natco required for manufacturing and selling unlimited quantities of lenalidomide in the US starting 31 January 2026, before the 2027 patents’ expiry, he said. Natco also receives a volume-limited license to sell generic lenalidomide in the US beginning March 2022, according to public information. Dr. Reddy’s could reach a similar settlement agreement with Celgene, agreed Ropka and the first patent attorney. However, Ropka noted Celgene would base its decision on its perception of the strength of Dr. Reddy’s noninfringement defence.
Celgene’s market cap is USD 81bn.
by Hamish McDougall in London and Alaric DeArment in New York