T 0524/11 (Anemia treatment/AMGEN) 16-02-2016

Reasons for the Decision

1. The appeal is admissible.

2. The duly summoned respondent did not attend the oral proceedings, as announced in its letter of 15 January 2016. In accordance with Rule 115(2) EPC and Article 15(3) RPBA, the board decided to continue the proceedings.

Main request - claim 1

3. The subject-matter of claim 1 of the main request (see sections VIII and X) is a combination of the subject-matter of claims 1, 5, 7, 13 and 14 as granted (see section II). The request is identical to auxiliary request 6 filed by the appellant with its statement of grounds of appeal (see section VI), except that the wording "wherein the target hematocrit is at least 30 %" replaces the wording "wherein the target hematocrit is at least about 30 %" (italic emphasis added by the board).

Clarity, added matter and Rule 80 EPC

4. The board is satisfied that the amendments to the patent with the claims of the main request comply with the requirements of Article 84 EPC and Article 123(2) and (3) EPC and Rule 80 EPC and notes that the respondent has not argued otherwise.

Novelty

5. Claim 1 is for the use of an analog of erythropoietin (Epo), i.e. Asn30 Thr32 Val87 Asn88 Thr90 Epo, which comprises two additional N-linked carbohydrate chains at positions 30 and 88, for the preparation of a pharmaceutical composition for raising and maintaining the hematocrit, wherein the analog is to be administered one time per month.

6. The board is satisfied that none of the cited prior-art documents discloses an administration regimen for an analog of erythropoietin which is one time per month. The board notes, furthermore, that the Enlarged Board of Appeal in decision G 2/08 (OJ 2010, 456) has acknowledged that a dosage regimen which was not comprised in the state of the art can confer novelty on the subject-matter of a medical use claim. Accordingly, the board is satisfied that the subject-matter of claim 1 is novel. The board notes that the respondent has not disputed novelty.

Inventive step

Closest prior art

7. The board concurs with the respondent that the disclosure in document D1 represents the closest prior art for the purpose of the assessment of inventive step of the subject-matter of claim 1, i.e. the sole independent claim of the main request.

8. Document Dl describes an Epo analog designated "NESP" reportedly containing, as compared to recombinant human Epo (rHuEpo), in its amino acid sequence two new consensus N-linked carbohydrate sites at positions which do not disrupt the tertiary structure or interfere with receptor binding, and therefore contains five N-linked oligosaccharide chains (see first and second paragraphs). Document D1 is silent on the exact position of the two extra N-linked glycosylation sites in the amino acid sequence. It discloses however that the "consequences of the increased carbohydrate content are an approximate 3-fold increase in serum half-life of NESP and thereby an increase in its in vivo potency compared with rHuEPO. NESP is approximately 3.6 times as potent as rHuEPO in increasing the hematocrit in normal mice" and that "the longer half-life allows NESP to be administered once weekly or once every other week, whereas EPO is only marginally effective at these dosing frequencies. On a one time per week dosing schedule, NESP is 20-fold more efficacious than rHuEPO" (for both see third paragraph). Document D1 continues that "[R]ecently, a pharmacological study demonstrated that, consistent with the animal studies, NESP has a significantly longer serum half-life than rHuEPO in chronic renal failure patients. This increased serum half-life and biological activity may likely confer the clinical advantage of less frequent dosing." (see fourth paragraph; emphasis added by the board).

9. In the context of the structure of the NEPS Epo analog the respondent has argued that since document D2, a post-published document from the same authors as document D1, demonstrated that the amino acid sequence of NESP differed from that of human Epo at five positions (i.e. Asn30, Thr32, Val87, Asn88 and Thr90), thereby providing two additional N-linked carbohydrate attachments at the residues at positions 30 and 88, the structural features of NESP were if not explicitly inherently disclosed in document Dl.

10. Article 56 EPC refers to "the state of the art" as the reference point for determining whether a person skilled in the art considers an invention obvious or not. The "state of the art" is thereby defined in Article 54(2) EPC comprising everything made available to the public before the date of filing of the European patent application. It is uncontested that document D2 was published after the date of filing of the patent application underlying the patent in suit. Furthermore, the board notes that the respondent has not argued that document D2 shows that the skilled person, when contemplating the disclosure in document D1, would immediately understand the structural details of NESP as disclosed in document D2. Consequently, the board judges that the disclosure in document D2 cannot be taken into account for the purpose of the assessment of inventive step.

The problem to be solved

11. The difference between the subject-matter of claim 1 and the disclosure in document D1 is thus inter alia that the claim defines the precise structural identity of an Epo analog and the technical effect that the analog can be administered in a regimen of one time per month, i.e. a regimen with intervals which are significantly longer than once a week or once every other week as disclosed in document D1. Accordingly, the problem to be solved by the invention forming the subject-matter of claim 1 is the provision of an Epo analog which can be administered in a regimen which is significantly longer than the administration regimen of once a week or once every other week.

Obviousness

12. It can be taken from point 8 above that document Dl describes an Epo analog designated "NESP", containing five N-linked oligosaccharide chains, that has, an increased serum half-life and in vivo potency as compared to rHuEPO and is approximately 3.6 times as potent as rHuEPO in increasing the hematocrit in normal mice. In this context document D1 discloses that the longer half-life allows NESP to be administered once weekly or once every other week. Document D1 furthermore discloses that, consistent with the animal studies, NESP has a significantly longer serum half-life than rHuEPO in chronic renal failure patients, i.e. human patients, which may likely confer "the clinical advantage of less frequent dosing".

13. The board notes therefore that document D1 does not contain a pointer for the skilled person to the effect that the NESP analog disclosed therein would be suitable for a dosage regimen which is significantly longer than the administration regimen of once a week or once every other week.

14. The board is satisfied that none of the other prior-art documents under consideration in the present appeal proceedings discloses, explicitly or implicitly, pointers to the possibility that certain Epo analogs allow a dosage regimen less frequent than once a week or once every other week, let alone one time per month as required by the subject-matter of claim 1. The board notes that the respondent has not argued so either.

15. When arguing that the subject-matter of claim 1 lacked inventive step, the respondent referred rather to document D3, which disclosed hyperglycosylated Epo analogs having additional N-glycosylation at sites in the molecule which are expected not to perturb the secondary structure or tertiary conformation required for biological activity. Table 6 disclosed biological activity data for Epo analogs with additional glycosylation sites, including one analog, designated "N47", which was identical to the analog underlying the patent in suit. This analog had a substantially higher biological activity than human Epo. The document further disclosed a direct relationship between the sialic acid content, clearance half-life and the ability of Epo analogs to increase the hematocrit of treated mice, regardless of the strength of receptor binding. Document D3 stated that for a given analog the "required dosage will be in amounts sufficient to raise the hematocrit of patients..." The latter made it clear that dosing the analogs was merely a matter of routine experimentation for the skilled person. In view of this guidance in document D3, the skilled person, when starting from document Dl, was not only prompted to administer Epo analog N47 less frequently than human Epo but also in a dosage regimen of only one time per month.

16. The board notes that, independently of the question whether or not the skilled person would in an obvious manner identify compound "N47" as disclosed in document D3 to be identical or equivalent to the "NESP" analog as disclosed in document D1, document D3 suggests that hyperglycosylated Epo analogs can be administered less frequently than rHuEpo, a suggestion not going beyond the statements made in document D1 (see point 13 above). The board accordingly considers that the skilled person seeking to solve the technical problem and contemplating the state of the art would not have selected in an obvious manner the compound N47 as disclosed in document D3 and administered the compound in a regime of one time per month.

17. In the context of inventive step the respondent has submitted the additional argument that, "due to the open-ended range [that the target haematocrit is "at least 30 %"] the claim cannot be inventive over the whole range claimed, since treatment leading to a haematocrit exceeding 33% or 36% at most is to be avoided for medical reasons. If the hematocrit [sic] exceeds 40%, the dose should even be discontinued".

18. The board notes in this context however that the feature "wherein the target haematocrit is at least 30%" is not the technical effect on which inventive step of the claimed subject-matter hinges (see point 16). Furthermore, the feature rather refers to a minimum and medically meaningful haematocrit to be obtained by the invention in the claim ("target") rather than to a haematocrit which is medically meaningless and hence should be avoided. Accordingly, the board is of the opinion that in the present case it is immaterial for the purpose of the assessment of obviousness whether or not the feature that the target haematocrit is at least 30%, is open-ended. Accordingly, the respondent's argument fails also in this respect.

19. In view of the above considerations the board judges that the subject-matter of claim 1 was not rendered obvious to the skilled person by the prior art and that consequently it involves an inventive step (Article 56 EPC). The same applies to the subject-matter of claims 2 to 4 of the main request which are dependent on claim 1.

Sufficiency of disclosure

20. The respondent has argued that the patent in suit lacked sufficiency of disclosure of the claimed invention if the assessment of inventive step were to be based on the fact that, at the priority date, no molecules allowing the dosing regime of the claim had been disclosed or that the skilled person was unable, without inventive ingenuity, to identify NESP as disclosed in document D1 or a molecule having the same properties.

21. The board notes that the assessment of inventive step above has neither relied on, nor makes reference to, those findings which the respondent considers a basis for a finding of lack of sufficiency of disclosure.

22. Accordingly, the board notes that no arguments have been brought forward that would persuade the board to come to a judgement that the invention as claimed is not sufficiently disclosed in the patent in suit.