When generating antibodies for a target is more than routine (T 0435/20)

The patent case law in Europe and the US diverges on the question of how routine it is to find new antibodies for a known target. In the US, claims directed to a group of antibodies functionally defined by the sequence of their target (so-called epitope claims), generally fall foul of the strict US written description and enablement requirements. By contrast, the EPO considers it routine for a skilled person to generate antibodies against a known target. In Europe, functional claims directed to a genus of antibodies for a new target identified in the patent do not therefore face the same sufficiency hurdles as they do in the US. Conversely, in Europe, inventors of new antibodies to known targets face a tough battle convincing EPO Examiners of inventive step. 

Antibody screen

In this context, the recent decision from the EPO Boards of Appeal in T 0435/20 is interesting for its finding that an antibody epitope claim was insufficiently disclosed (i.e. contrary to the broad summary of EPO case law summarised above). The facts of the case, and particularly the perceived challenge of generating new antibodies against a conformational epitope, convinced the Board of Appeal that generating new antibodies falling under the scope of the claim would be overly burdensome for the skilled person. The decision in T 0435/20 is thus the exception that proves the rule. 

Background: Patenting antibodies in Europe

In Europe, it is possible to obtain broad protection for antibody therapeutics based on their function. A broad genus of antibodies may be defined in a patent claim by the sequence of its target, "epitope", or its other functional properties (EPO Guidelines for Examination, G.II, 5.6) (IPKat). The epitope of a class of antibodies may itself be defined in a number ways. A continuous or linear epitope defines a sequence of consecutive residues present in the target. A discontinuous/conformational epitope takes account of the structure of the target, according to which an antibody may bind stretches of sequence that are brought into close proximity by the structural folds in the target protein. 

Types of epitope

T 0435/20 related to European patent EP1931710 claiming a genus of anti-IL23 antibodies binding to a defined epitope in IL-23.The defined epitope was discontinuous/conformational, comprising two separate stretches of sequence within IL-23: "an epitope comprising residues 82-95 and residues 133-140 of SEQ ID NO: 29"

The main issue on appeal was whether the claimed invention was sufficiently disclosed (Article 83 EPC).  

Principles of sufficiency

The golden rule of sufficiency is that a patent must provide sufficient information for a skilled person (together with common general knowledge) to be able to perform the claimed invention without undue burden (Article 83 EPC). It is also necessary that the skilled person be able to perform the invention over the whole claimed range. For simple mechanical inventions, or inventions defined solely by structural features, there is usually not much doubt that a skilled person would be able to carry out the invention over the whole claimed range. By contrast, defining an invention according to its functional features places a greater burden on the patentee with respect to the "whole claimed range" sufficiency requirement. In order for the sufficiency requirement to be satisfied, it has to be possible for a skilled person to work out whether the whole spectrum of potential embodiments actually perform the claimed function. Put another way, it has to be plausible or credible that a skilled person would be able to work the invention across the whole scope of the claim (IPKat). 

The patent in question in the present case disclosed a single mouse antibody (and its humanised form) capable of binding the p19 subunit of human IL-23. The description included data demonstrating that the example antibody had a discontinuous epitope comprised within the stretches of sequence defined in the claim. The broad functional language of the claim meant that the claim was not limited to the sequence or structure of the example antibody, but included in its scope any antibody specific for p19- IL-23 that had the same or similar discontinuous epitope as the example antibody. 

The patent did not include any information on how the antibody was generated and selected. The data in the patent instead focused on the functional characteristics of the antibody (affinity, potency and characterisation of the epitope). The patent was challenged for insufficiency on the grounds that a skilled person would not be able to make other antibodies falling under the scope of the claim without undue burden. 

The undue burden of discontinuous epitopes

The EPO normally argues, in inventive step objections, that raising new antibodies based on a known target or epitope is routine. Antibodies may be raised against antigens or sections of the target protein containing the epitope. However, in the present case, the difficulty level in finding other antibodies falling under the scope of the claim was increased by the fact that the epitope was discontinuous. The binding of an antibody to a target based on a discontinuous epitope requires the protein to be folded into the correct conformation based on complicated interactions between pieces of linear protein sequence. This complicates the screening process. Particularly, it is difficult to know how much of the protein is needed to ensure that the conformational epitope is present, and thus what antigen to use. 

The Patentee in the present case argued that a skilled person would still be able to generate antibodies according to the invention by raising antibodies to IL-23 to generate a pool of antibodies. From this pool, the skilled person could then select the antibodies that bound to the claimed conformational epitope by assessing the epitope binding of each antibody in the pool. However, the Board of Appeal disagreed that this process could be achieved without undue burden. 

One of the problems for the Patentee in this case was that the patent did not even disclose a suitable assay by which a skilled person could test the ability of the antibodies in the pool to bind the p19 IL23 target, let alone the specifically claimed epitope. The Board of Appeal further noted that there was no guarantee that even a single antibody in a pool of antibodies raised against IL-23 would bind the same epitope as that of the claimed antibody:

58. In summary, given the lack of relevant guidance in the patent or in the common general knowledge, the skilled person attempting to carry out the claimed invention is confronted with having to develop an elaborate screening strategy, without a reasonable expectation of success. Indeed such a screening strategy relies on chance, without the skilled person having any knowledge of the likelihood of success.

59. Finally, if after such a screening process, the antibody taken forward for epitope determination does not have the required specificity, i.e. in case of failure, neither the patent nor the common general knowledge provides adequate information regarding what should be changed or how to guarantee success.

The Board of Appeal concluded that the broad functional claim was not sufficiently disclosed across the whole scope of the claim. Particularly, a skilled person would not know either from the patent or common general knowledge the nature of the antigen required to raise new antibodies falling under the scope of the claim. For the Board of Appeal, the skilled person would not even know what screening process to use in order to select such antibodies. These inadequacies in the information provided in the patent, the Board of Appeal summarised, amounted to serious doubts that a skilled person would be able to perform the invention over the whole scope of the claim. 

The decision that the patent as granted was insufficient was thus maintained and the appeal dismissed.  

Final thoughts

The decision in T 0435/20 is a reminder that, whilst it is possible to point to general principles of patent case law surrounding challenging technical fields, the facts of a particular case may provide the exception that proves the rule. The EPO has established as a general principle that generating new antibodies against a known target or epitope is to be usually considered routine. However, T 0435/20 demonstrates that the lack of any direction from the patent or common general knowledge as to the appropriate methods and tests for generating new antibodies against a target, can be evidence of undue burden. Such arguments should be as applicable to supporting inventive step as they are to an insufficiency attack. 

Further reading

• Patenting Antibodies: The epitope claim is dead, long live the epitope claim (15 Nov 2021)
• EPO Board of Appeal maintains functional epitope antibody genus claim (T 1964/18) (6 April 2022)