T 2565/19 (TRH receptor/Trinity College) 29-11-2022

Reasons for the Decision

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

Main request - Claim 1

Inventive step (Article 56 EPC)

Claim construction

2. The claim is for a method of discriminating between a thyrotropin releasing hormone (TRH) receptor subtype in human central nervous system (CNS) tissue (i.e. the receptor that is the subject-matter of claim 5 of the main request) and a TRH receptor subtype in human pituitary tissue. The claimed method involves "use" of a THR analogue peptide ligand ("the compound"), defined in the claim, which binds to the TRH receptor sub-type in human CNS tissues but does not bind to the TRH receptor sub-type in human pituitary tissue.

3. For the purposes of assessing inventive step, the board construes the claim as relating to a method including a process step of determining the binding of the "compound" to human CNS tissue and human pituitary tissue, where the "compound" binds to the TRH receptor subtype in human CNS tissues but does not bind to the TRH receptor sub-type in human pituitary tissue. This construction is in agreement with the appellant's, who was of the view that the claim recites process steps because it implicitly includes a step of determining binding. In claim 1 of auxiliary request 7, this step was made explicit.

4. In appeal, the appellant challenged the examining division's finding that the claimed subject-matter lacked an inventive step based on the disclosure in document D2 alone.

5. Document D2 discloses competition experiments in rats which showed that the compound Glp-Asn-Pro-D-Tyr-D-TrpNH2 (a peptide falling under general formula set out in the claim) was unable to displace the hormone TRH from rat pituitary tissue and TRHR1 expressing cells, consistent with its lack of binding to pituitary membranes and TSH-releasing activity. In contrast, it was able to displace the hormone from rat hippocampal membranes, but unable to displace it in TRHR2-expressing cells (see abstract). The authors of document D2 concluded "this study reveals for the first time significant differences in the binding properties of native and heterologously expressed TRH receptors. Also, the results raise the possibility that Glp-Asn-Pro-D-Tyr-D-TrpNH2 is not displacing [**(3)H][3-Me-His**(2)]TRH from a known TRH receptor in rat cortex, but rather a hitherto unidentified TRH receptor" (see abstract). This conclusion is further explained on page 29, where several explanations for observed results are posited.

6. The first is "that the opportunity to form receptor-receptor hetero-oligomers may be lacking in cells selectively expressing a single receptor". The second is that "the ligand binding specificities of a number of class B GPCRs is altered by receptor activity-modifying proteins (RAMPs), which interact directly with the receptor". The third is "the possibility that Glp-Asn-Pro-D-Tyr-D-TrpNH2 may not be displacing [**(3)H][3-Me-His**(2)]TRH from a known TRH receptor in rat brain, but a hitherto unidentified TRH receptor subtype that is present both in rat brain cortex and hippocampus". This possibility is emphasised in the document's concluding section on page 30: "Significantly, the data presented herein open up critical issues with regard to the use of cell lines expressing a homo- or hetero- class of TRHR subtype in pharmacology and drug screening studies. It may be speculated that an additional receptor may possibly be involved in TRH behavioral responses, however this would require further investigation".

7. In summary, document D2 postulates the existence of a new TRH receptor in rat brain cortex, differing from known receptors TRH1 and TRH2. In coming to this conclusion document D2 explicitly discloses use of Glp-Asn-Pro-D-Tyr-D-TrpNH2 in a method that is inherently suitable for discriminating between binding to a TRH receptor subtype in the CNS and to a TRH receptor subtype in pituitary tissue (see page 27, left-hand column, final paragraph to page 29, penultimate paragraph).

8. Thus, the claimed method differs from the method disclosed in document D2 in that it is done on human tissue instead of rat tissue. The technical effect of this difference is that the claimed method can be used to discriminate between TRH receptor sub-types in human cortex and pituitary, as opposed to ones in rat cortex and rat pituitary.

9. In view of the difference between the closest prior art and the claimed subject-matter and the technical effect of this difference, the problem to be solved can be seen as the provision of a method which can be used to discriminate between a TRH receptor sub-type in human cortex from one in human pituitary.

Obviousness

10. The question to be answered in assessing the obviousness of the claimed method is whether the skilled person starting from the disclosure in document D2 and seeking to solve the technical problem formulated above, would have carried out the differential binding experiments disclosed in document D2 on human tissue.

11. The board considers that the answer to this question is yes. The reason for this is that it was common knowledge in the art (biomedicine) that animal models serve as a starting point for experiments using human material with the aim of ultimately addressing human health issues. This has not been disputed by the appellant. The board is therefore of the view that there existed in the art a general incentive to apply knowledge from animal models to humans. This incentive would have motivated the skilled person to determine whether results found in document D2 in an animal model were replicable in humans.

12. It is true that document D2 offers three alternative explanations for the results obtained. However, in the board's view this would not have prevented the skilled person from repeating the experiments of document D2 using human tissue, in view of the incentive, explained above. These considerations are sufficient to lead the skilled person to repeat the differential binding experiments done in rats in document D2, in human tissue. In fact, the appellant acknowledged during the oral proceedings that it was obvious for the skilled person to test all three theories suggested in document D2 on human tissue. Since the method of document D2 corresponds to the claimed method except that it is done on rat tissues, repeating it in human tissue would result in a method as claimed being carried out.

13. The appellant argued that the skilled person had to make at least four choices as to which steps to carry out (see section IX.). In view of the uncertainty inherent in each choice, the skilled person could not have considered that there was a reasonable expectation of success in finding a human homologue of a potential rat receptor. Further uncertainty was present because at the relevant date, the skilled person assumed that in humans, in contrast to the situation in rats, only one receptor sub-type was present.

14. It is correct that, in some decisions, especially in the field of biotechnology, the boards have asked whether in the cases in point it was obvious for the skilled person to try a suggested approach, route or method with a reasonable expectation of success (see Case Law of the Boards of Appeal of the European Patent Office 10th edition, 2022, I.D.7.1). However in the present case, the board does not consider this to be the right approach, for several reasons.

15. The importance of research on humans in a medical context would have led the skilled person to repeat the experiments done in rats in document D2 in humans, even in the face of alternative explanations for the results and even in the face of the knowledge that only one type of TRH receptor had been found in humans. This consideration is similar to the situations described in the case law where "neither the implementation nor the testing of an approach suggested by the prior art involves any particular technical difficulties". In such circumstances it has been held that the skilled person would have at least adopted a "try and see" attitude (see Case Law of the Boards of Appeal of the European Patent Office, 10th edition 2022, I.D.7.2).

16. The appellant also put forward that the skilled person, considering applying the methods disclosed in document D2 to human tissue, would have faced difficulties obtaining and working with human tissue due to the fact that it had to be obtained post-mortem and because many variables affected the quality of such tissue, as well as because of anatomical differences between rat and human tissue.

17. The board is not convinced by these arguments either. The board accepts it was common knowledge in the art that working with post-mortem human tissue and brain tissue in particular was associated with particular practical problems. However, given that the skilled person was seeking to replicate an animal model in humans, they had no choice but to turn to human tissue.

18. In view of the above considerations,the board concludes that the subject-matter of claim 1 lacks an inventive step.

Auxiliary request 1 - claim 1

19. Claim 1 of auxiliary request 1 is identical to claim 1 of the main request. It also lacks an inventive step.

Auxiliary request 5 - claim 1

20. This claim differs from claim 1 of the main request in that it more precisely defines the source tissue as "human hippocampal tissue" and the ligand analogue by means of an IC50 value.

21. The appellant argued that the amendment to specify the human tissue as hippocampal tissue and the inclusion of an IC50 value emphasised the non-obviousness of the claimed subject-matter because the skilled person would have expected that human hippocampal and pituitary tissue had a single common TRH receptor, whereas the rat tissue used in document D2 had two distinct receptors in hippocampal and pituitary tissue.

22. These arguments are not persuasive. The board's decision on obviousness of claim 1 of the main request already took into account that the skilled person knew that only a single type of TRH receptor type was known in humans. In relation to the inclusion of an IC50 value, the appellant provided no detailed reasoning as to why this should affect the evaluation of obviousness. Moreover, the appellant has never put forward that the claim relates to more than a single novel receptor sub-type, thus the IC50 value only serves as a further, functional definition of the ligand and does not limit or define the receptor at all. As such, it cannot affect the reasoning on inventive step given for claim 1 of the main request.

Auxiliary request 6 - claim 1

Claim 1 includes the feature that the TRH receptor is pharmacologically distinct from the TRH receptor found in human pituitary tissue. This feature also does not change the claimed receptor from the one defined in claim 1 of the main request and therefore has no effect board's considerations on obviousness.

Auxiliary requests 7 to 10 - claim 1

23. Similarly, claim 1 of auxiliary requests 7 to 10 corresponds to claim 1 of auxiliary request 1, amended with the aim of improving clarity and/or compliance with Article 53(c) EPC. However, none of these amendments overcome the problem of the lack of inventive step identified for claim 1 of the main request. They lack an inventive step for the same reasons.

Auxiliary request 2 - claim 1

Clarity (Article 84 EPC)

24. Under Article 84 EPC "The claims shall define the matter for which protection is sought. They shall be clear and concise and be supported by the description".

25. According the Enlarged Board of Appeal (EBA) in decision G 2/88 (OJ 1990, 93), "The purpose of claims under the EPC is to enable the protection conferred by the patent (or patent application) to be determined (Article 69 EPC), and thus the rights of the patent owner within the designated Contracting States (Article 64 EPC), having regard to the patentability requirements of Articles 52 to 57 EPC. It follows that the technical features of the invention are the physical features which are essential to it" (see reasons 2.5). Furthermore, "the claims of a European patent should clearly define the technical features of the subject invention and thus its technical subject-matter, in order that the protection conferred by the patent can be determined and a comparison can be made with the state of the art to ensure that the claimed invention is inter alia novel." (see reasons, 7)

26. The case law has further established that "Claims lack clarity if the exact distinctions which delimit the scope of protection cannot be learnt from them" (see Case Law of the Boards of Appeal of the European Patent Office, 10th edition, II.A.3.1 and the decisions cited there).

27. The claim is for an isolated TRH receptor, i.e. a product. The claimed receptor is defined only by locational and functional features, i.e. the tissue from which it can be isolated: "from human CNS tissue" and its ability to bind the compounds defined in the claim: "wherein the compound having the structure Glp-W-Pro-X binds to the TRH receptor sub-type in human CNS tissues but does not bind to the TRH receptor sub-type in human pituitary tissue". Neither of these features conveys any structural information about the claimed product. In other words, the language of the claim does not include or imply anything about the structure of the claimed chemical entity, for instance whether it is a protein or not, or if it were a protein, what its sequence might be.

28. In the absence of any structural features, the claim cannot be considered as clear because it fails to "enable the protection conferred by the patent (or patent application) to be determined" (Id.) and it does not define the claimed subject-matter in a manner which allows a meaningful comparison with the state of the art to be made. Indeed, in the absence of any structural information about the claimed subject-matter, it is not possible to determine if the claimed product is novel. For instance, there is no way of ruling out that the functional and locational features defined in the claim do not simply re-characterise a known molecule.

29. The appellant argued that a receptor can be defined solely by its binding properties to its ligand. It was argued that this was in line with "the definition of a receptor from a number of online scientific dictionaries, all of which show that in the art a receptor is defined in terms of its specific binding to a ligand". Moreover, it argued that it was not a requirement of the EPC, that an applicant had to sequence a protein in order to be entitled to claim it.

30. It is of course correct that the EPC does not set any specific requirements as to which features are required to meet the requirements of Article 84 EPC for clarity in any particular technical field. Instead, the Boards, in the case law, have developed the criteria to be used to determine whether or not a claim is clear. Applying these criteria leads to the conclusion that the claim lacks clarity, as set out in point 28. above.

31. In view of the above considerations, the board concludes that claim 1 lacks clarity and does not meet the requirements of Article 84 EPC.

Auxiliary request 4 - claim 1

32. Claim 1 of auxiliary request 4 is an amended version of claim 5 of the main request. The amendments however do not overcome the clarity issues identified for claim 5 of the main request because they only further define binding characteristics of the ligand of the claimed receptor but not the receptor itself. A further definition of the ligand cannot serve to clearly describe the claimed receptor.

33. In view of the above considerations, no claim request meets the requirements of the EPC.