Sunitinib is a drug for treating cancers in the stomach, intestine, kidney and pancreas, marketed by Pfizer under the name Sutent®. The CN patent directed to sunitinib basic chemical structure has its full termed expired in Feb 2021. There is a crystal form patent directed to sunitinib malate, the chemical entity in the actual drug, with full term expiry in Aug 2022. However, this sunitinib malate crystal form I (crystal form I) patent CN100439360C ('360) has been invalidated in Apr 2021, opening the door to generics of sunitinib earlier in China.
The corresponding EP1419151B of '360 was maintained by the EPO after opposition with post-filing data showing that the free base crystal of sunitinib were small with poor filterability, while cystal form I has good filterability with full compatibility with commercial manufacturing processes.
By contrast, such improved filterability of crystal form I was dismissed in China. Specifically, the Re-examination and Invalidation Department RID of the CNIPA considered that improved crystallinity could be expected to result in larger crystal grain (and better stability and higher melting point), and therefore easier to filter.
The patentee also tried to argue for better solubility of crystal form I in '360. However, this was not accepted by the RID on the basis that since the solubility of the malic acid salt of sunitinib itself was not provided and compared with this crystal form I, existing data could only show that the improvement in solubility is due to the formation of the malic acid salt, but not necessarily due to the crystallization to form crystal form I. It appears that if the patentee could provide the solubility of the malic acid salt of sunitinib itself for comparison in the appeal, this could be a game changer.
With the help of Darts-IP, I have also compared data of invalidation results of crystal form patents in China, EPO, US, Japan, India, and South Korea. The total number of invalidation attempts in the US, Japan and India may be too few to be of statistical significance. While at the European Patent Office (EPO) there appears to be a higher chance to maintain the validity of a crystal-form patent, the opposite is true for China and South Korea. I have reviewed other relevant Chinese decisions and observed that the principles in the invalidation decision of '360 are generally applied in China. That is, relying only on improved qualities related to stability, for example operability, portability, storage, and so on (CN ZL 00802360.3; ZL 200610002509.5) could lead to the invalidation of a granted crystal-form patent. Merely providing an alternative crystal form is almost certain to be not good enough (as a crystallographer myself – while studying for my PhD – I have to admit making new crystal forms is a lot easier than before).
On the other hand, if the improved property of the new crystal form may be argued to be not directly related to the increased crystallinity, for example improved solubility, delivery, efficacy, then the chance of grant and/or surviving through invalidation challenge could be much improved, at least in China. In such case, however, proper comparison data should be provided, preferably in the specification. In the case of '360, not only the comparison data on improved solubility between malic acid salt of sunitinib and the free base sunitinib should be provided, but also the comparison data between amorphous malic acid salt of sunitinib and crystal form I should also be provided.
One encouragement from this '360 invalidation is that the RID accepted and considered the post-filing data, evidencing that post-filing data is now acceptable in China. Such acceptance has been specified in the Chinese Patent Examination Guidelines since 2017, although many Chinese examiners would try to pick the smallest problem to reject the post-filing data, like irrelevance, not exact correspondences with the conditions in the original disclosure, and so on.
My article with more details of the above has been published by the UK CIPA Journal Apr 2022 issue, which is available below:
cipa202204csunitinibrystalstatepatentinvalidation.pdf (teehowe.com)
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