T 0096/20 - Clinical trial document as prior art

Key points

• The Board provides some comments regarding inventive step of a second medical use claim, in cases wherein a clinical trial protocol has already been published. 
• The Board: “Clinical trials are conventionally based on earlier preclinical studies, and the potential therapeutics tested in clinical trials are duly selected based on experimental data suggesting their success (see e.g. decision T 239/16, point 6.5 of the Reasons). ”
• “Thus, the board considers that the announcement of a detailed safety and efficacy clinical trial protocol for a particular therapeutic and disease provided the skilled person with a reasonable expectation of the success of this particular therapeutic, unless there was evidence to the contrary in the state of the art. In the case in hand, the board holds that no such evidence to the contrary has been brought forward by the appellant.” 
• “the board concludes that no evidence is on file calling into question that MG could be treated with eculizumab in humans, as proposed in the phase 2 clinical trial study disclosed in document D4. In view of the above considerations, the board holds that the subject-matter of claim 1 of the main request was obvious to the skilled person.” 
• Note, there is recently also some case law suggesting that patent applications pertaining to second medical uses are already plausible if the skilled person has no doubt. (T0033/19, r.5).

 

T 0096/20 - 

https://www.epo.org/law-practice/case-law-appeals/recent/t200096eu1.html

Reasons for the Decision

1. The appeal complies with Articles 106 to 108 and Rule 99 EPC and is admissible.

Inventive step (Article 56 EPC)

Main request and auxiliary request 1 - claim 1

Closest prior art and objective technical problem

2. Claimed is an inhibitor of human complement component C5 for use in treating MG in a human, wherein the inhibitor is an anti-C5 antibody (see section V.). One example of such compounds is eculizumab (see application page 8, line 11).

3. The examining division considered that the protocol of a safety and efficacy clinical trial of eculizumab in patients with refractory generalised MG disclosed in document D4 represented the closest prior art, and formulated the objective technical problem as "the provision of evidence-based medical application of an anti-C5 antibody in human [sic]".

4. According to established jurisprudence of the boards of appeal, the closest prior art should be a teaching directed to the same purpose or effect as the claimed invention (see Case Law of the Boards of Appeal of the European Patent Office, 9th edition, 2019, I.D.3.2.). The board therefore holds that actual therapies for treatment of MG in humans, such as therapies with immunosuppressants including prednisone, methotrexate, cyclosporine and cyclophosphamide, also disclosed in document D4 (page 1), represent the closest prior art, rather than the clinical trial protocol which is also disclosed there.

5. The claimed subject-matter differs from the known MG therapies in humans in that the therapeutic is an inhibitor of human complement component C5, wherein the inhibitor is an anti-C5 antibody ("C5 antibody").

6. The application does not attribute a particular technical effect to the claimed therapeutic in the claimed use, which goes beyond the technical effect of the known MG therapies. The objective technical problem can thus be formulated as the provision of an alternative treatment of MG in humans. This has not been contested by the appellant.

Obviousness

7. Document D4 discloses a protocol of a safety and efficacy clinical trial of eculizumab in patients with refractory generalised MG. The results of this clinical trial are not disclosed. Thus, document D4 proposes the antibody eculizumab (an inhibitory C5 antibody) as an alternative therapeutic for refractory generalised MG in humans.

8. Clinical trials are conventionally based on earlier preclinical studies, and the potential therapeutics tested in clinical trials are duly selected based on experimental data suggesting their success (see e.g. decision T 239/16, point 6.5 of the Reasons).

9. Thus, the board considers that the announcement of a detailed safety and efficacy clinical trial protocol for a particular therapeutic and disease provided the skilled person with a reasonable expectation of the success of this particular therapeutic, unless there was evidence to the contrary in the state of the art. In the case in hand, the board holds that no such evidence to the contrary has been brought forward by the appellant.

10. The appellant has submitted that the disclosure of the clinical trial protocol of document D4 constituted, at most, an invitation for the skilled person to try the treatment of MG with eculizumab. Indeed, MG was particularly difficult to treat in humans, as was evident from document D7 which disclosed that no therapy for generalised MG had been approved in more than 60 years.

11. The board however fails to see how the mere fact that no MG therapy has been approved for a long time would have diminished the expectation of success for the specific clinical trial disclosed in document D4.

12. The appellant further submitted that many clinical trials directed at treating a complement-associated disorder with a complement inhibitor had failed, as evident from the disclosures in documents D11 and D13.

13. The studies disclosed in documents D11 and D13 concern complement inhibitors other than eculizumab (sCR-1 and pexelizumab) to treat diseases different from MG (acute respiratory distress syndrome and acute myocardial infarction). Furthermore, the complement cascade is a complex system involving multiple proteins having been implicated in a large number of different diseases. In view of this complexity, the board is satisfied that the failure of other complement inhibitors to treat diseases unrelated to MG did not necessarily call into question the skilled person's expectation that MG could be treated successfully with eculizumab. In fact, in the board's view, only evidence relating to the same compound and disease would be suitable for this purpose.

14. Consequently, the board concludes that the disclosure of documents D11 and D13 did not call into question the expectation of success the skilled person had from document D4 announcing a phase 2 clinical trial for the treatment of MG with eculizumab.

15. The appellant further submitted that the teaching in document D2 did "not support" the skilled person's expectation of successful treatment of MG in humans with eculizumab, since the experimental animal model used in document D2 was not a suitable model for human MG, as it represented only the effector stage of the disease (see document D5, page 16, right-hand column, first full paragraph).

16. The board considers that the disclosure of the clinical trial in document D4 as such provided the skilled person setting out to provide an alternative therapeutic for the treatment of MG with a reasonable expectation that the treatment of MG in humans with eculizumab would be successful (see point 9.).

17. Furthermore, the teaching of document D2 does not call into question this expectation. In fact, it discloses successful treatment of experimental MG induced in mice with an anti-C5 antibody, which in 2008, i.e. after publication of document D5's review on MG animal models, was considered "so encouraging that human clinical trials using eculizumab are expected to begin within the next year" (document Dl, second last paragraph on page 2). The skilled person would thus have considered, even after the publication of document D5, that the animal model used in document D2 was a suitable animal model for human MG and that the successful treatment of experimental MG induced in mice with an anti-C5 antibody would be encouraging for treating MG in humans.

18. Thus, the board concludes that no evidence is on file calling into question that MG could be treated with eculizumab in humans, as proposed in the phase 2 clinical trial study disclosed in document D4.

19. In view of the above considerations, the board holds that the subject-matter of claim 1 of the main request was obvious to the skilled person. Consequently, the subject-matter of claim 1 of the main request and claim 1 of auxiliary request 1 does not involve an inventive step within the meaning of Article 56 EPC.

Auxiliary requests 2 and 3

20. The subject-matter of claim 1 of each of auxiliary requests 2 and 3 differs from the subject-matter of claim 1 of the main request in that the anti-C5 antibody is now explicitly defined as being eculizumab (see section V.).

21. The appellant did not submit any tailor-made arguments for this claimed invention in the context of inventive step.

22. The board considers that the teaching of document D4 provided a reasonable expectation of success for the treatment of MG with the specific anti-C5 antibody eculizumab (see point 16.). The same considerations as for claim 1 of the main request and auxiliary request 1 hence apply to claim 1 of each of auxiliary requests 2 and 3.

23. Consequently, the board holds that the subject-matter of claim 1 of each of auxiliary requests 2 and 3 does not involve an inventive step within the meaning of Article 56 EPC, either.

Order

For these reasons it is decided that:

The appeal is dismissed.