T 1345/20 (Diagnosis of Gaucher's disease/CENTOGENE) 26-09-2023

Reasons for the Decision

Main Request (claims as granted)

Article 100(b) EPC

1. Claim 1 of the main request is directed to an vitro method for diagnosing Gaucher's disease comprising detecting free lyso-Gb1 in a sample from a subject. Dependent claim 4 further defines the means of detection as being immunoassay, mass spectrometric analysis, biochip array, etc (for the full wording of the claims, see section VII. above). Hence claim 4 explicitly encompasses immunoassays as means of detection of free lyso-Gb1, to be used for the purpose of claim 1, i.e. for the diagnosis of Gaucher's disease. Accordingly, the enablement of the claimed method requires that immunoassays for detection of free lyso-Gb1 are sufficiently disclosed in the patent.

2. It is undisputed that neither the patent nor the prior art discloses how to generate and obtain an antibody or fragment thereof capable of detecting free lyso-Gb1, let alone at a concentration of 20 ng/ml or 5 ng/ml in blood or serum samples, respectively, which is capable of discriminating free lyso-Gb1 from glucosylceramide (GlcCer or Gb1) or from lyso-Gb3 in said samples, so as to enable the skilled person to perform immunoassays capable of diagnosing Gaucher's disease.

3. While the provision of antibodies against known targets is usually a matter of routine, as argued by the respondent and supported by case law (e.g. T 431/96), this is only the case if the skilled person knows from the disclosure in the patent or from common general knowledge (i) which antigens are suitable for raising antibodies having the desired properties and (ii) which screening process should be used to select these antibodies without undue burden (see decision T 435/20, reasons 28). The fact that the case underlying T 435/20 is related to non-contiguous epitopes of a protein rather than to small non-peptidic target molecules like in the present case (see below) does not disqualify the above mentioned conclusions which are generally applicable to any antigen. The overall rationale and teaching of T 435/20 is that raising and screening of antibodies is routine for an unconventional target antigen only if both the antigen for raising the desired antibodies and the process for selecting them are known.

4. The target molecule in the present case, glucosylsphingosine or lyso-Gb1, is a small molecule comprising a single hexose ring joined to a short (C13) lipid tail. It thus represents an especially challenging target for the design of a suitable antibody as it lacks features which are known to be suitable epitopes for antibody recognition, such as polypeptide or polysaccharide moieties. Hence it can be considered an unconventional target in the sense of decision T 435/20. There is no indication, either in the prior art or in the patent whether glucosylsphingosine is a suitable antigen, but even if it were, there is still no teaching which screening process would ensure a reliable selection of antibodies specifically detecting only free lyso-Gb1 at low concentration, knowing that there are many other structurally related small molecules, which could even be present at higher concentration in the sample from the subject to be diagnosed. Accordingly, the two criteria of T 435/20 (supra) for enablement of antibodies against an unconventional target are not fulfilled.

5. It is true, as argued by the respondent, that there is a legal presumption of validity once a patent is granted (T 63/06) and that the opponent bears the burden of proof when arguing that the claimed subject-matter is insufficiently disclosed (T 298/17, reasons 2.8). The patent contains no experimental evidence and/or information on how to obtain the above antibodies. It is therefore enough for the appellant to establish a lack of sufficiency of disclosure by merely raising serious doubts, e.g. by comprehensive and plausible arguments that the common general knowledge and the patent provide insufficient information to reliably obtain an anti-lyso-Gb1 necessary for the immunoassay of claim 4 (see T 63/06, headnotes, reasons point 3.3.1; Case law of the Boards of Appeal, 10th edition 2022, hereinafter "Case Law", III.G.5.2.2 c)). In such a case, it cannot be expected that the appellant has to prove that a claimed immunoassay cannot be performed, which would be tantamount to providing negative evidence, i.e. that no specific discriminating antibodies can be obtained. Serious doubts substantiated by verifiable facts (T 967/09, reasons 6.) are thus not necessary to establish a lack of sufficiency in the present case; it is enough that serious doubts are raised in the form of comprehensible and plausible arguments (T 63/06, reasons 3.3.2). Moreover, it is not required to prove that carrying out the invention is inherently impossible, but only to provide arguments casting doubt on whether the claimed immunoassay for free lyso-Gb1 can be carried out on the basis of the patent specification and common general knowledge without requiring significant experimentation and the exercise of inventive skill (Case Law, II.C.9.4). Hence the appellant's reasoned arguments reverse the burden of proof, so that it would then be for the respondent to prove that the skilled person could have performed the immunoassay without undue burden.

6. Under these circumstances and without the respondent having provided evidence to the contrary, the board considers that the appellant plausibly argued that common general knowledge would not enable the skilled person to put this feature into practice.

7. In this context, the board notes that the respondent's arguments based on the Guidelines for Examination in the European Patent Office March 2023, section G-II 5.6.2, are not persuasive either. Not only are the Guidelines for Examination not binding for the boards, but also the conclusions in the cited section are actually not applicable to the present case, as they only address how an inventive step is to be assessed for "a novel, further antibody binding to a known antigen". As explained above, this is not the case here. While the immunoassay in claim 4 involves the use of an antibody specifically binding to a known small target molecule, no such antibodies were available on the relevant date of the patent nor was the target molecule known to be an antigen at all.

8. Finally, as to the respondent's arguments, based on the statement in section 20.3.2 of the appealed decision, that antibodies for small molecule antigens - and particularly for lipids - existed in the prior art, the board notes that not only there is no evidence on file supporting this statement but, most importantly, no such antibody was deemed representative of the antibodies to be identified. The respondent has not explained how this knowledge would be of use to the skilled person when attempting to obtain antibodies to the particular small target molecule of the claimed method.

9. The board thus disagrees with the conclusions of the opposition division on section 20.3.2 of the appealed decision and comes to the conclusion that the claims of the main request are not sufficiently disclosed. Hence the ground for opposition under Article 100(b) EPC prejudices the maintenance of the patent as granted.