The present blog entry is rather long. This is however necessary, since a decision of a TBA-EPO is compared with a decision of a UPC-CFI LD Munich.
EP 2 493 466 B1 relates to a novel antitumoral use of cabazitaxel in the treatment of prostate cancer and has been claimed under Art 54(5) EPC.
The question at stake can be summarised as follows: did the TROPIC study gave rise to a reasonable expectation of success or not, see D1 and/or D2.
1. French decision on EP 2 493 466 B1
For information in the decision NO. RG 21/06416-N° Portalis 352J-W-B7F-CUMКО, dated 06.09.2024, the Paris Court of first instance (TJP), the FR part of EP 2 493 466 B1 was cancelled. Referring to T 2506/12, Reasons 3.12.2. the TJP considered that the TROPIC study gave rise to a reasonable expectation of success and therefore claim 1 lacked IS.
2. Brief outline of the procedure before the EPO
12 oppositions were originally filed. The OD decided to reject the oppositions and the board confirmed the rejection in T 0136/24 of 03.06.2025.
Objections as to added-matter, lack of sufficiency, non-validity of the priority and lack of IS were filed, but we will concentrate here on the lack of IS in relation to areasonable expectation of success.
Petitions for review under Art 112a EPC are ongoing before the EBA under R 1/25. R 18/25, R 20/25 and R 21/25 have been consolidated in a single procedure.
2.a The opponents’ points of view
The opponents essentially argued that, for a second medical use claim, where the prior art disclosed that a clinical study with the same active agent(s) for the same therapeutic indication had been proposed or was underway, it was established jurisprudence of the boards that a reasonable expectation of success was generally implied by the mere fact that the study had been authorised, unless there was some evidence of a dissuading teaching in the prior art.
In other words, the announcement of a clinical study established a legal presumption of reasonable expectation of success, with the consequence that a patent proprietor had the burden of rebutting such a legal presumption by showing that the skilled person would have been dissuaded by the prior art from following the study protocol with a reasonable expectation of success and so achieve its inevitable outcome.
According to the opponents, this general principle, furthermore supported by general guidelines on clinical studies in oncology, applied in the present case.
No dissuading element, negative pointer, was known in the prior art. Rather, in addition to the announcement of the TROPIC study, the available evidence on cabazitaxel would have further incentivised the skilled person to follow this path.
The opponents considered the following aspect as positive pointers:
(a) Cabazitaxel was of the same class as docetaxel, which was known for its efficacy in mCRPC and its superiority in comparison with a mitoxantrone-based regimen, and had, furthermore, been designed to overcome cellular resistance to docetaxel.
(b) The data known from preclinical, Phase I and Phase II testing were encouraging.
(c) The fact that it was a higher-level, Pphase III, clinical study that had been approved and that Phase II had been skipped would have increased the expectation of success.
(d) The skilled person would have inferred that the regulatory agency had been supplied by the study sponsors with additional data in favour of cabazitaxel not publicly available at the time and that this additional information would have contributed to an expectation of success on the part of the regulatory agency.
(e) The fact that the study was nearing completion at the priority date of the patent in suit, i.e. that it had not been terminated prematurely, would have increased the skilled person’s expectation of success.
(f) Without a realistic expectation of success, the patent proprietor as the study sponsor would not have invested money into the TROPIC study without a reasonable expectation of success.
2.b The proprietor’s point of view
The proprietor rebutted the opponents’ arguments.
For the proprietor, irrespective of the starting point under consideration, the technical effect of improved overall survival should always be taken into account in the formulation of the OTP since this was the invention’s contribution to the art in a situation where the standard of care at the time, mitoxantrone plus prednisone, was, at best, a palliative therapy.
2.c The board’s decision
The feature distinguishing the subject-matter of claim 1 from the disclosure of the experimental arm of the TROPIC study in D1/D2 is the effective treatment of the claimed therapeutic indication.
Since the claim contains the achievement of the therapeutic effect as a functional technical feature, non-working embodiments are excluded.
For the board, the OTP is to put into practice the effective treatment of prostate cancer with cabazitaxel in co-administration with prednisone in patients with mCRPC who have been previously treated with a docetaxel-based regimen and who have prostate cancer that progressed during or after that treatment.
The decisive issue for obviousness is thus whether the skilled person would have had a reasonable expectation of success with regard to the experimental arm of the TROPIC study.
Starting from the concept of the TROPIC study, including from its experimental arm, the skilled person would still have equated success with an increase in overall survival relative to the comparative arm.
The boards have developed a large body of decisions dealing with reasonable expectation of success, including in cases of second medical use where clinical studies were announced in the prior art.
This case law mainly focuses on balancing positive and negative pointers. As such pointers are necessarily always linked with the individual circumstances of the case at issue, it cannot be concluded, without taking the circumstances of each case into account, whether there would have been a reasonable expectation of success.
Contrary to the opponents’ argument, the analysis of the cited jurisprudence of the boards did not lead to the conclusion that ongoing clinical studies automatically establish a legal presumption of success.
The board relied inter alia on T 1941/21 and did not follow T 96/20. The board also held in T 239/16 was different from that in the case at issue.
Pointer (a)
The fact that cabazitaxel was of the same class as docetaxel would, in general, have dissuaded the skilled person from expecting an increase in overall survival for a patient group that had progressed during or after docetaxel treatment. The available data were not yet clear enough to predict that this effect would indeed be achieved.
Pointer (b)
The data from the preclinical phase were sparse and incomplete. No relevant cell lines had been tested in vitro, and the results of the xenograft experiments were mixed. The Phase I clinical data were furthermore not of the type to allow any insights on a possible increase in overall survival.
As overall survival is linked to type of cancer and stage of disease progression, as a matter of principle, a Phase II clinical study on breast cancer cannot be taken into account for prostate cancer.
Pointer (c)
Under usual circumstances, the fact that a phase III clinical trial is carried out might indeed provide a pointer indicating a successful development path of a new drug/new drug application. In the case in hand, the usual path of drug development is only poorly reflected.
The phase II study in breast cancer was not followed by a phase III study as this line of development was discontinued. Thus, the TROPIC study cannot be considered a confirmatory study as earlier data are lacking and indeed only a single patient in the population to be treated had been reported in phase I.
Pointer (d)
Given that the majority of phase III clinical studies fail, it would amount to speculation to hypothesise how the risk assessment in one particular case, here the TROPIC study, would have been carried out by the regulatory authorities.
Confidential data may of course be the foundation of a rationale under which a clinical study is carried out. However, this is irrelevant in the context of assessing IS because such data, due to their confidential nature, were not available to the skilled person. They thus cannot be taken into account.
In addition, the alternative explanation provided by the patent proprietor is plausible and cannot be ruled out, namely that the extremely poor prospects for patients with mCRPC, especially docetaxel-refractory mCRPC, was a major factor in the TROPIC study being permitted to proceed. The risk/benefit assessment would have been strongly in favour of proceeding with the study.
Pointer (e)
The fact that a study is nearing completion per se, in the absence of knowledge of the parameters selected for monitoring, is neither a positive nor a negative pointer when assessing expectation of success.
Pointer (f)
No particular inference can been drawn from the fact that the patent proprietor decided to continue the development of cabazitaxel for mCRPC rather than breast cancer.
The board thus concluded that the claimed subject-matter involves an IS in the setting starting from the experimental arm of the TROPIC study.
The conclusion was the same whether the starting point is the experimental arm or the control arm of the TROPIC study.
Taking the phase I study results as starting point, there was as well no expectation of success.
3. Brief outline of the procedure before the UPC
The proprietor, Sanofi, claimed infringement before the CFI-LD Munich and the alleged infringers filed a counterclaim for revocation. D1/D2 in the UPC procedure are the same as D1/D2 before the EPO.
In a joint decision of 12.06.2025, the UPC-CFI LD Munich, UPC_CFI_146/2024=UPC_CFI_496/2024, UPC_CFI_147/2024 –UPC_CFI_374/2024=UPC_CFI_148/2024 – UPC_CFI_503/2024,the patent was revoked for lack IS.
There as well the discussion centred on the reasonable expectation of success which could have been raised by the TROPIC study.
3.a The counterclaimants’ point of view
All three counterclaimants argued from the very beginning that the patent lacks an IS in relation to documents describing a Phase III clinical trial with cabazitaxel, cf. TROPIC study and D1/D2.
The counterclaimants argued that, according to settled case-law in France, Germany and at the EPO, the disclosure of phase III clinical trials relating to the claimed application gives rise to a reasonable expectation of success for the skilled person, unless there is evidence to the contrary.
In this context, they claim that pre-clinical data showed that cabazitaxel was effective on taxane-resistant cancer cell lines, in particular docetaxel.
A Phase I study of different types of cancer, including mCRPC, showed a promising safety profile of cabazitaxel and an effectiveness in PSA levels in two patients with this cancer; lastly, a Phase II study, conducted on breast cancer and not prostate cancer, showed an encouraging response to cabazitaxel in patients previously treated with docetaxel and having developed resistance to this molecule.
The difference in cancer at issue was not decisive, in their view, because they are tumours with common properties, for which the same molecule, docetaxel, is an approved standard treatment.
They considered that the chances of success of the TROPIC study were all the greater because its ambition was low, comparing cabazitaxel with mitoxantrone, which is known to be ineffective while being toxic.
3.b The proprietor’s point of view
Sanofi argued that the effect of the disclosure of a Phase III clinical trial on the IS must be analysed according to the specifics of each case.
This TROPIC study differed from the invention in that it is merely a description of a clinical trial which does not disclose any effect of the treatment, whereas the invention consists in providing a treatment which prolongs the life of patients, constituting the first effective second-line treatment in the indication in question.
The indication subject of the patent had been directly tested in a Phase III clinical trial, without a Phase II trial, which is rare but justified here, because of the ‘compelling need’ for treatment to extend the life of patients who previously died of their disease. For Sanofi, the expectation of success of the TROPIC trial was ‘dreadful’ and a reluctance to launch the study had been encountered.
3.c The LD-Munich decision
LD-Munich acknowledged that attaining the claimed therapeutic effect is regarded as a functional technical feature of the claim.
After explaining that the EPO, FR, IT, NL and SE, use the PSA to assess IS, other countries like DE have a more “holistic” approach, the CFI-LD Munich adopted the position of the CoA-UPC derived from the Order of the CoA-UPC in Nanostring/10X Genomics.
3.c.1 Assessment of IS at the UPC
It has first to be assessed what is object of the invention is, i.e. the “objective problem”, which must be assessed from the perspective of the skilled person with its CGK at the effective date of the claim.
This must be done by establishing what the invention adds to the state of the art, thus also considering the inventive concept underlying the invention, which must be based on the technical effect(s) that the skilled person on the basis of the application understands is (are) achieved with the claimed invention. In order to avoid hindsight, the “objective problem” should not contain pointers to the claimed solution.
There can be more than one realistic starting point and the claimed invention must be inventive starting from each of them.
The skilled person has no inventive skills and no imagination and requires a pointer or motivation that, starting from a realistic starting point, directs it to implement a next step in the direction of the claimed invention.
3.c.2 Reasonable expectation of success
A reasonable expectation of success implies the ability of the skilled person to predict rationally, on the basis of scientific appraisal of the known facts before a research project was started, the successful conclusion of that project within acceptable time limits. Whether there is a reasonable expectation of success depends on the circumstances of the case.
3.c.3 Objective technical problem
The CFI noted that the OTP adopted by the EPO deviates from the approach formulated by the CoA-UPC as its formulation of the OTP contains parts of the solution and thus does not avoid hindsight.
For the UPC, the OTP is to provide a therapeutic option for treating patients suffering of mCRPC who have been previously treated with docetaxel-based regimen and have prostate cancer that progressed during or after that treatment.
3.c.4 Further considerations
The panel relied on party experts, Dr Nelson (for the proprietor) and Dr Denmeade (for the counterclaimants) and summarised the phases leading to a marketing authorisation:
- Phase I is basically dedicated to initially understand whether and to what extend the drug shows some anti-tumour activity in humans and which dose is safe and tolerated.
- In Phase II the focus lies in further defining the anti-tumoral activity with the dose tested in Phase I.
- In Phase III the anti-tumoral drug is tested against the standard of care.
According to Dr Denmeade, in oncology, it is not mandatory for a Phase III trial to receive DSMB (Data Safety Monitoring Board) approval based on patients with the same tumour type as in Phase II. Information on the safety, toxicity and management of the drug derived from a Phase II trial involving patients with a different tumour can be transferred if the tumours are comparable. This happens in about 1/3 of the oncological Phase III trials. Nowadays, it is even possible to skip Phase II completely.
Dr Nelson agreed, but pointed out that such an approach carries more risks, and that the tumours discussed (breast and prostate cancer) are, in his view, not comparable, which renders the results of the Phase II trial irrelevant to the approval of the Pphase III trial.
Both experts explained that the failure rate of Phase III trial in general is between 40 to 50 percent.
3.c.5 Reasonable expectation of success – Positive and negative pointers as indicators
The panel had to evaluate various indicators in the prior art and provide an overall assessment.
For the panel, the skilled person generally must have more information before he can use the results of a Phase II clinical study on breast cancer to predict how it might work with prostate cancer.
One prior art document (D7 at the EPO and at the UPC) made it clear how the treatments of breast cancer and prostate cancer are connected, which would have been hard to predict otherwise.
In 2008, the Pivot study (D13 at the EPO and at the UPC) revealed favourable outcomes for cabazitaxel in patients with taxane-resistant metastatic breast cancer.
A further document (D4 at the EPO and at the UPC) referred to a Phase I study on cabazitaxel, conducted in 25 patients with different tumours, eight of which were prostate cancer. This document concludes that there is encouraging antitumor activity in patients resistant to taxanes and considers that cabazitaxel is recommended for Phase II.
In the present case the Phase III trial TROPIC was almost complete, without interruption or discontinuation. This implied for the skilled person that this was effective in the treatment of patients with mCRPC previously treated with docetaxel.
Contrary to Sanofis’ view it is not unusual in the field of oncology that a clinical Pphase III trial is based on a Phase I trial including patients having different types of cancer besides the cancer type selected for the Phase III trial and a Phase II trial concerning a different type cancer as such of the Phase III trial.
The observation that one of the two patients in the Phase I study exhibited a response to treatment with docetaxel alone suggests the efficacy of docetaxel in treating this particular tumour type.
In conclusion, there was no evidence against cabazitaxel’s efficacy in the treatment of mCRPC as a second-line treatment after a docetaxel regimen has been discontinued.
The panel found thus that subject-matter of claim 1 was obvious in view of the Phase III TROPIC trial.
Comments
Non-convincing decision of the UPC
The decision of the LD Munich, as well as that the of the TJ Paris, fail to convince on a pure logical level.
As explained by the experts before the UPC, 40-50% of Phase III trials are discontinued. Completion of a Phase III study can thus not be necessarily considered as representing a reasonable expectation of success when, like in the present case, there was no Phase II trial and the results of the Phase I trial were rather shoddy. This is the more so since the reasons for the monitoring board for allowing a Phase III trial are apparently not public.
If completion of a Phase III trial would necessarily imply a reasonable expectation of success, this would deprive sponsors of Phase III trials of any possibility to recoup their investment in case of a positive result. Why should then pharmaceutical companies invest in such a trial?
From a purely logical point of view, a reasonable expectation of success can be expected if the results of Phase I and Phase II trials were clearly suggested in the prior art. This does not seem to have been the case in the present situation.
The TBA-EPO took great care to address all the points in dispute to come to the conclusion that there was no expectation of success in view of the TROPIC study. Expert declarations were also presented to the EPO, but they did not play any role in the proceedings. Expert declarations at the EPO are of relatively low importance as the TQJ at the EPO are versed in their tchnical domain and for the majority in the panel.
For the UPC to claim that if one of the two patients in the Phase I study exhibited a response to treatment with docetaxel alone suggests the efficacy of docetaxel in treating this particular tumour type, is daring to say the least. One could also say that it remained a gamble when looking at the TBA-EPO decision on pointers (a) and (b).
This is the more so since in the present case there was no Phase II study for prostate cancer, but a Phase III, whilst there was no Phase III study for breast cancer. Whether both types of cancer react to cabazitaxel, does not mean that a priori, the result for breast cancer can be transferred to prostate cancer.
The UPC panel also appears to have heavily relied on experts opinion, without however submitting those experts to cross-examination. This is not foreseen at the UPC, but could have been useful in the present case.
One important aspect seems for the TBA-EPO was the fact that the majority of Phase III clinical studies fail, and the passage from Phase I to Phase III without a Phase II in case of prostate cancer, although breast and prostate cancer are meant to be comparable in their reaction to docetaxel, cf. the TBA-EPO decision on pointers (c) and (d).
The last word is not yet said, be it in FR or at the UPC, as it reasonable to think that the CFI-LD Munich and the TJP decisions will be appealed by the proprietor.
Some oddities in the UPC decision
When the CFI-UPC LD Munich consider that the OTP adopted by the EPO contains parts of the solution and thus does not avoid hindsight, this incorrect, if not misleading, in that the definition of the OTP is fundamentally different at the EPO and at the UPC.
However, when one compares the OTP defined by the EPO and that of the UPC it is difficult to see a difference, see above. This is due to the formulation of the claim as second medical indication under Art 54(5), in which the effect has to be the treatment of a medical condition.
The problem with divergent decisions of the EPO and of the UPC
On the one hand, the patent has been maintained as granted by the EPO but revoked by the UPC.
When divergent decisions are taken by the EPO and the UPC, one of the parties loses out. Here it is the proprietor.
It ought to be reminded here that the Chair of the UPC-CoA expressed the opinion that for the sake of harmonisation, a subsequent deciding body should take over the decision of the first deciding body. It will be interesting to see whether the UPC-CoA applies this maxim in the present case.
The proprietor has, according to the EPO, a valid patent, and it is certainly difficult for it to accept that the UPC revoked its patent, on the basis of the same documents. It is just a matter of interpretation. Since the EPO has considered the patent valid, after a much more careful analysis of the circumstances than at the UPC, it cannot be excluded that it could indeed be infringed by the counterclaimants.
The potential problem of diverging decisions on validity between the UPC and the EPO has been carefully dodged by the proponents of the UPC. Now we have, to my knowlwdge, a first case in which we end in a kind of mess.
It would have been much preferable to come to an agreement on the consequence of diverging decisions between the UPC and the EPO. I cannot remember that the parliaments in the ratifying states have ever been informed of the possible consequences of diverging decisions.
In view of the fact that a panel of a TBA-EPO consist of 2 TQJ and 1 LQJ, the likelihood is that a decision of a TBA-EPO is more convincing at the end of the day than a decision taken by 3 LQJ, completed here by 1 TQJ.
If a national court, like in the present case revokes the patent for its territory, the consequences are limited. If the UPC revokes a patent, the consequences are way harder for the proprietor, especially in view of the long-arm the UPC wants to exert.
Petitions for review under Art 112a EPC have been filed at the EBA after the final rejection of the opposition. The success rate of such a petition is rather small, even if the proceedings are reopened. Not much hope should be invested in those petitions. This is the more so in that no objection under R 106 EPC has been raised.
The revenge of the LQJ over the TQJ
Although the LD Munich panel comprised one TQJ, and even if it disagreed, the latter had no chance to bring is point of view forward over three LQJ. If he wants to be reappointed in a further case, he better not antagonise the LQJ.
This also explains why the LD Munich explained that it rather followed the decision of the TPJ than that of the TBA-EPO. The decision of the TPJ is even less convincing as it only relies on T 2506/12, whereas this decision is not representative of the case law of the EPO in this matter, in spite of what the TPJ said. The circumstances of the case need to be explored.
A word of warning
The present comments might be incorrect, as I am not versed at all in oncology. They are a personal opinion which can be rebutted, but for this, I need compelling arguments.
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