The use of rivaroxaban and the anticipated launch of Sandoz’s generic product
Rivaroxaban is used as an anticoagulant for the treatment of thromboembolic disorders (TEDs). Bayer markets its rivaroxaban product under the name Xeralto. Bayer was the owner of EP 1 261 606 B1 that protects the active ingredient rivaroxaban. Based on said patent, Bayer was granted SPC no. 300370 that will expire on 1 April 2024.
Sandoz is planning to launch a generic product containing rivaroxaban in the Netherlands after expiration of the SPC. Sandoz started invalidity proceedings claiming that EP 961 is invalid due to lack of inventive step. Bayer instituted a counterclaim requesting: 1) an injunction against Sandoz for (likely) future infringement of the NL part of EP 961 and 2) a declaration that any offering or placing on the market of Sandoz' product (e.g. listing the product in the ‘G-Standaard’), or importing or storing the product for those purposes, is an infringing act.
What preceded
EP 961 was granted on 22 April 2015. Opposition was filed by fifteen parties. In 2018 the Opposition Division revoked EP 961 for lack of inventive step. In appeal, the Technical Board of Appeal (“TBA’’) maintained the patent as granted. Since then, multiple national suits have been filed to invalidate EP 961 e.g. in Germany, Norway and in the United Kingdom. In its decision of 9 June 2023 the Court of Oslo concluded that the patent was inventive.
Difference between the TBA and NL proceedings
The main difference is that the TBA found EP 961 inventive based on Kubitza I & II and the Harder Abstract, whereas in the Dutch (and Norwegian) proceedings Sandoz introduced the ‘’Harder Poster’’ as new prior art, which was not introduced in the opposition. The Harder Poster reveals parameters in the pharmaco-dynamics that suggest suitability for a once-daily dosing.
After summarising the reasoning of the TBA, the District Court of The Hague discusses the Norwegian decision in the parallel proceedings, where the Harder Poster has been taken into account in assessing inventive step.
The District Court’s assessment of inventive step
Following the parties, the District Court applies the PSA and takes the Harder Poster as the closest prior art. The difference between the Harder Poster and the claimed invention is that the latter concerns the medical use of rivaroxaban in the claimed dosage regimen. Harder is a phase I study on the pharmacodynamic effects of rivaroxaban on eight healthy subjects, but not a study on what the effects and therapeutic efficacy are in patients. The technical effect of the distinguishing feature is that rivaroxaban in the dosage regimen (once daily for at least five days with a rapid release dosage form) is effective and safe in TED patients. According to the Court the objective technical problem is: “finding an oral dosage regimen of rivaroxaban that is safe and effective against TEDs”. This is almost the same as defined by the TBA, albeit that the Court does not concur with the TBA’s (additional) objective of finding a ‘convenient’ dosage regimen as part of the problem to be solved. To assess inventive step, it must be assessed whether, based on the technical problem, the invention was obvious for the average skilled person on the priority date.
According to the Court an inventive step is lacking if the person skilled in the art, based on the relevant state of the art, would have solved the problem as claimed in the patent. As the invention is the result of further research, the invention is not only obvious if the skilled person had carried out that research and the results are clearly predictable, but also if there is an incentive in the state of the art that there is a reasonable expectation of success. This means that the skilled person is able to predict a reasonable successful outcome of the research project within an acceptable time period. The hope to succeed is insufficient.
The Court points out that the Harder Poster does not provide a reasonable prediction that rivaroxaban would be safe and effective in patients in a once-daily dose. It does not provide convincing results to support this, as the study was conducted in only eight healthy subjects, lacks data on half-life time, whereas the type of tests used were of an experimental nature. Moreover, the skilled person would not have a reasonable expectation of success, because of numerous negative pointers, like 1) the high (and life-threatening) risk of over- and under-dosing patients in anticoagulant research would make him cautious to extrapolate results in phase I studies to a phase II study, 2) Harder does not provide half-time data, which is an important indicator for determining dosing frequency, 3) the negative research experience with a comparable Xa inhibitor, razaxaban, leading to severe bleeding in patients and 4) some medical-ethics committees rejected Bayer’s proposal to test once daily dosing of rivaroxaban in clinical trials.
The District Court also assesses Sandoz’ argument that the skilled person, starting to test two- or three-day doses in a phase II study would, through routine steps, ultimately end up with a once-daily dosing regimen. But the Court rejects this view as Sandoz failed to describe how the skilled person would have overcome the negative pointers and would endeavor to also try a once-daily doses with a reasonable expectation of success.
Conclusion
Based on its own assessment and with reference to the Norwegian judgment and the TBA decision, the District Court rejects Sandoz' claim for invalidity and holds EP 961 inventive. Both counterclaims of Bayer are granted.
