Exception proving the rule: a functional claim directed towards new antibodies targeting a conformational epitope is considered to be insufficiently disclosed

• An invention may be regarded as sufficiently disclosed even if it requires a certain amount of experimentation by the skilled person to carry it out, as long as this experimentation is not an undue burden for the skilled person;
• The skilled person wanting to perform the claimed invention would have to develop a screening process for identifying antibodies that bind IL-23p19 while ensuring not to miss antibodies that bind the claimed conformational epitope, an undertaking that cannot be regarded as routine.

Background

European patent no. 1931710 related to antibodies targeting a conformational epitope, i.e., an antigenic determinant composed of discontinuous amino acid residues that come together to form an antibody-binding surface with a three-dimensional structure, in the p19 subunit of IL-23. The conformational epitope comprised two separate stretches of sequence within IL-23. In particular, claims 1 and 2 of the granted patent read as follows:

1. An antibody, or antigen binding fragment thereof, that binds to human IL-23p19 at an epitope comprising residues 82-95 and residues 133-140 of SEQ ID NO: 29.
2. The antibody, or antigen binding fragment thereof, of Claim 1, that binds to an epitope comprising residues E82, G86, S87, D88, T91, G92, E93, P94, S95, H106, P133, S134, Q135, P136, W137, R139 and L140 of SEQ ID NO: 29."

The OD held that the patent did not disclose the invention in claim 1 in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art (art. 100(b) EPC and Art 83 EPC). As a result, the patent was revoked.

The Appeal

P appealed this decision and argued that the teaching in the patent, taking into account the common general knowledge about generating and screening antibodies, would have led the skilled person to the antibodies binding the IL-23 target at the claimed conformational epitope, without undue burden (similar to T431/96). Specifically, the teaching in the patent would have led the skilled person to (i) use an IL-23 heterodimer (composed of two subunits, p19 an p40) as the immunogen to raise antibodies that bind the IL-23p19 subunit at the claimed conformational epitope, and to (ii) screen the resulting antibodies by conventional specificity-screening assays for antibodies that bind specifically at the IL-23p19 subunit. This would be followed by optional further screening to arrive at a subset of antibodies most likely to bind the claimed epitope. Thus, the skilled person would arrive at antibodies that bind to IL-23p19 at the claimed conformational epitope without an undue burden of experimentation.

Disclosure of the Invention

The Board acknowledged that raising and screening antibodies only involved routine experimentation. However, this was the case only if the skilled person knew from the disclosure in the patent or from common general knowledge (i) which antigens would be suitable for raising antibodies having the desired properties and (ii) which screening process should be used to select these antibodies without undue burden (see also decision T431/96, Reasons, points 6, 7, 10- 12). Thus, the generation and screening of antibodies that bind (anywhere) to the p19 subunit of IL-23 would indeed not involve an undue burden for the skilled person.

However, the claims of the patent in suit encompassed antibodies that are functionally defined by their ability to bind to IL-23p19 and contact several of the amino acid residues within both amino acid stretches recited in the claim. The Board therefore believed that the patent disclosed neither a suitable antigen nor a screening process that would ensure the reliable generation and selection of antibodies having these required properties by applying routine methodology and a reasonable amount of experimentation.

Specifically, the Board did not agree with P that the patent taught the skilled person to use an IL-23 heterodimer as the immunogen to raise antibodies that bind to the IL-23p19 subunit at the claimed conformational epitope. It was common ground that by using the IL-23 heterodimer for immunisation, the skilled person would obtain a pool of antibodies recognising (linear and conformational) epitopes anywhere on the surface of the IL-23 heterodimer and its subunits p19 and p40. Since the generation of antibodies to the claimed epitope on p19 cannot be controlled by using the IL-23 heterodimer, it is a matter of chance whether the antibody pool comprises an antibody that has the same specificity as the functionally claimed anti-IL23p19 antibodies. Therefore, if the skilled person were to choose the IL-23 heterodimer for raising antibodies, they would obtain a pool of antibodies, which may or may not comprise antibodies having the required properties. The Board held that starting from the above-mentioned pool of antibodies, the skilled person would not be able to arrive at the claimed antibodies without undue burden because the patent did not disclose:

1. which antigen to use in conventional assays (such as ELISA) to screen the pool of antibodies that was raised by immunisation with the IL-23 heterodimer in order to obtain those antibodies binding a conformational epitope on the p19 subunit of IL-23. None of the documents relied on by P provided support that the skilled person could have used a routine ELISA to identify and isolate antibodies that bind a conformational epitope on the p19 subunit of IL23; and
2. how optional additional pre-screening to limit the pool of anti-IL23p19 antibodies with conventional cross-blocking assays would result in a subset of antibodies that bind at the claimed epitope. Indeed, the patent even confirmed that not all cross-blocking antibodies necessarily bind at precisely the same epitope, since cross-blocking may result from steric hindrance.

Given the lack of proper guidance in the patent or in the common general knowledge, the skilled person attempting to carry out the claimed invention would be confronted with the need to develop an elaborate screening strategy without reasonable expectation of success. Such a screening strategy would rely on chance. Finally, the Board reasoned that, if after such a screening process the antibody taken forward for epitope determination did not have the required specificity, i.e., in case of failure, neither the patent nor the common general knowledge provided adequate information regarding what should be changed or how to guarantee success.

Decision of the Board (of Appeal)

Based on the evidence on file, the Board decided that in the present case, critical information on the antigen suitable for raising antibodies with the desired properties and screening assays for reliably identifying them was lacking. Moreover, the Board held that they had not seen any evidence that antibodies binding at the claimed epitope could be generated frequently enough and could be identified reliably enough to guarantee success. Therefore, the functional definition of the claimed antibody amounts to an invitation to perform a research program without any guarantee of success. Such a situation was considered to amount to an undue burden for the skilled person.

As a result, it was decided that the claimed invention was not sufficiently disclosed in the patent and that the ground for opposition under Article 100(b) EPC prejudiced the maintenance of the patent as granted.

Summary written by the NLO EPO Case Law Team