EP 3 071 219 B1 relates to methods and pharmaceutical compositions for treating or preventing antibody-mediated rejection in organ transplant patients using a C1-esterase inhibitor.
Brief outline of the case
After having decided that the MR and AR1-3 had problems under Art 123(2), the OD decided maintenance according to AR4.
The proprietor and the opponent appealed the decision.
The board decided first on AR4 and found that the disclosure was insufficient. All the valid requests had the same problem and the patent was revoked.
The proprietor’s point of view
The standard for regulatory approval was much higher than that set out in Art 83, and thus it was not necessary for the standard required for regulatory approval to be met in order to satisfy Art 83.
The Phase II clinical trial data reported in the patent were promising enough to warrant a Phase III trial being conducted.
The clinical trial was stopped at month 36 due to a “futility issue“. This depended on the pre-specified criteria for futility of clinical trials. Accordingly, this conclusion was associated with considerations resulting from setting the parameters forming pre-specified criteria for futility, and thus was not tied specifically to the futility of a technical effect in the sense of Art 83.
In view of the positive results demonstrated by the data in the patent, and the fact that a link between the observed physiological effects and the disease was established in the patent, the disclosure of the patent satisfied Art 83, see T 609/02, Reasons 9.
The opponent’s point of view
None of the data in the patent demonstrated a meaningful difference between the groups in the occurrence of transplant glomerulopathy (TG, or any other parameters) which could be specifically attributed to the intvention. TG occurred in both groups (3/7 vs. 1/7) and no difference between those groups in terms of therapeutic effect had been plausibly established.
In view of the small number of patients, the opponent considered that a treatment effect had not been demonstrated.
The disclosure of a patent was insufficient if the invention could not be reproduced across the whole breadth of the claims. Even a plausible disclosure of a therapeutic effect still had to be subject to refutation by evidence that the therapeutic effect was not in fact attained, the standard of proof being “serious doubts, substantiated by verifiable facts”.
The board’s decision
The patent contains data from a randomised, double-blind, placebo-controlled pilot study to evaluate the safety and efficacy of C1 esterase inhibitor [human] for the treatment of acute antibody-mediated rejection in recipients of donor-sensitised kidney transplants.
The subjects, there being seven in each arm, received a total of seven doses of the study drug or placebo over a two-week period corresponding to the dosage regimen defined in the claim.
The “biochemical data” reported in the patent and referred to in the decision under appeal is the creatinine clearance in patients during the 13 days of treatment; however, as pointed out by the opponent and not disputed by the proprietor, when the difference in initial creatinine clearance is removed, no meaningful difference between the study arms can be identified.
The board therefore concluded that the only relevant data in the patent are finding CG in 1 out of 7 patients in the drug arm compared with 3 out of 7 patients in the placebo arm.
The board, started from the assumption that the OD was correct in finding that the experimental data provided in the patent, together with the mechanistic explanation provided in paragraphs [0032] to [0039] and Figure 1, made it plausible or credible to the skilled person at the time of filing that a therapeutic effect on AMR could be achieved.
However, this in itself is not enough to demonstrate that the invention is sufficiently disclosed if the opponent provides evidence which raises serious doubts that the therapeutic effect can indeed be achieved.
Post-published documents relate to the phase III clinical trial, which was carried out using the same dosage regimen as in the examples of the patent and falling under the terms of the claim.
The study was terminated after 36 months because “[f]ollowing a prescheduled interim analysis performed by the DMC, it was determined that the study met the pre-specified criteria for futility“.
The board considered that the level of efficacy which had been pre-specified for futility is not relevant for the question of sufficiency of disclosure in the present case.
What is crucial is that the skilled person, with the teaching of the patent in hand and applying CGK, was able to reproduce the invention, i.e. to achieve a therapeutic effect on kidney transplant AMR when administering C1-INH intravenously using the dosage regimen indicated in the claim.
One of the post published documents shows the complete absence of any therapeutic effect with the claimed dosage regimen.
The board considered this sufficient to raise serious doubts based on verifiable facts that the claimed treatment achieves a therapeutic effect.
In view of this evidence it is not sufficient for the proprietor to refer to potential beneficial effects that might arise when following up with patients for a longer period of time.
In conclusion, a phase III clinical trial with the same setup as the examples in the patent and using the dosage regimen which is an embodiment of the claim could not reproduce the claimed subject-matter as it did not exhibit any efficacy after 36 months.
The patent proprietor had thus not dispelled the serious doubts regarding the presence of a treatment effect in view of these data. Therefore, the invention as claimed is not reproducible.
Comments
The case is interesting in hat it shows that an effect can be held credible on the basis of data contained in the patent relating to a small number of patients.
On the other hand, the fact that a clinical trial is stopped after 36 months is sufficient to allow serious doubts about sufficiency. That the trial could have continued for a longer period of time is not enough to consider that an effect is achieved.
On the other hand, the standard required for regulatory approval has nothing to do with satisfying the requirements of Art 83.
What look credible during examination coan be shown not to be achieved during clinical trial.
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