20/08/2019
At the European Patent Office, protection can be sought for antibodies in a number of ways. This article provides a brief review of how antibodies can be characterised, and when a particular characterisation may be appropriate.
Definition of an antibody by its target
This may include wording such as the following.
Claim: “An antibody that specifically binds antigen X”
It may be possible to obtain patent protection for such a claim if antigen X is unknown but is well defined in the application.
European Patent No. 0186833 (T 0542/95)
“A monoclonal antibody which specifically recognises and binds a cytotoxin having M.W. of 17,000 ± 500D as determined by polyacrylamide SDS gel electrophoresis, which cytotoxin
(i) exhibits a cytotoxic effect on CHI-sensitized SV-80 cells and
(ii) is obtainable in a state of enhanced purity by adsorption of the cytotoxin from said preparation onto controlled pore glass beads (CPG) and desorption.”
If antigen X is known, but antibodies binding to antigen X are unknown, the claims will be novel, but a finding of inventive step is likely to depend on whether or not there is an unexpected/surprising technical effect. For instance, if an antibody is found to have a particular beneficial technical effect on the target protein, such as activating a receptor, then this may assist in arguing for the presence of an inventive step. If the antibody has no technical effect and can be produced by conventional methods, it is likely to be viewed as obvious.
Alternatively, an inventive step may be acknowledged if there had previously been difficulty in obtaining an antibody to that particular target using routine screening and production methods, and the applicant has used a non-obvious method to obtain the antibody.
If antigen X is known and an antibody that binds to antigen X is also known, then it may be possible to obtain a patentable claim by further defining the target. This may be achieved by reciting specificity for an epitope on the same target, which is different to the epitope bound by the known antibody. This may include wording such as the following.
Claim: “An antibody that specifically binds to a peptide of SEQ ID NO: 1 on receptor X.
European Patent No. EP2293819
“An antibody or a fragment thereof that recognises an epitope of a HER2 receptor truncated form defined by SEQ ID NO: 1, said epitope being defined by a sequence included in SEQ ID NO: 2, wherein the antibody or fragment thereof is suitable to distinguish the protein of SEQ ID NO: 1 from the HER2 receptor.”
Care must be taken if the epitope is a conformational epitope which cannot be defined by its primary sequence. In this situation, the disparate parts of the epitope and their positions should be clearly defined in the context of the target.
European Patent application No. 02752184.8 (T1318/13)
“An isolated antibody that recognizes and selectively binds a three-dimensional epitope of parathyroid hormone, wherein the three-dimensional epitope of parathyroid hormone comprises amino acids located between amino acids 1-13 of SEQ ID NO: 1 and includes the first amino terminal amino acid of native PTH along with the intact helix of the amino terminus”.
It may be possible to define a target indirectly, in relation to a reference antibody.
Claim: “An antibody which competes with an antibody having VH sequence 1 and VL sequence 2”
The reference antibody must be fully characterised, preferably by its sequence, or by reference to an antibody obtainable from a deposit.
European Patent No. EP1037926 (T1859/08)
“… an anti-ErbB2 antibody …, wherein said antibody binds to epitope 4D5 within the ErbB2 extracellular domain sequence as determined by a cross-blocking assay using said antibody and antibody 4D5 obtainable from deposit ATCC CRL 10463…”
An antibody that binds the same target as a known antibody, but which binds to a different epitope may only be considered inventive if it displays unexpected properties. This may include, for example, higher affinity, lower immunogenicity, improved stability or improved bioavailability.
Definition of an antibody by its effect
This may include claim wording such as the following.
Claim: “A monoclonal antibody that specifically binds to antigen X with a binding affinity of…”
Claim: “A monoclonal antibody that induces apoptosis of a cell upon binding to receptor X on a surface of the cell”
European Patent No. 0896586 (T 2045/09)
“1. An antibody which binds to ErbB3 protein and (i) reduces heregulin-induced formation of an ErbB2-ErbB3 protein complex in a cell which expresses ErbB2 and ErbB3, and (ii) reduces heregulin-induced ErbB2 activation in a cell which expresses ErbB2 and ErbB3, and (iii) increases the binding affinity of heregulin for ErbB3 protein“.
At first glance, it may appear that such claims would be prone to a finding of lack of clarity by the EPO on the basis that one is simply claiming the underlying ‘problem’ without specifying the means to solve that problem. Nevertheless, such claims may be allowable if the functional features can be directly and positively verified by tests or procedures adequately specified in the description or known to the person skilled in the art and which do not require undue experimentation. Ideally, the application should disclose a way of repeatedly producing further antibodies having its function.
To ensure clarity, any parameter or value specified in the claim must be unambiguous, bearing in mind that in some circumstances, different tests can provide different results. With this in mind, it is often prudent for the description to include the technique for measuring the property in general terms (e.g. binding affinity by surface plasmon resonance) and also include the specific experimental conditions that were actually used, such as temperature, ionic strength etc.
European Patent No. EP0929578 (T0418/07)
“1. An isolated human antibody, or antigen-binding portion thereof, with the following characteristics:
a) dissociates from human TNFα with a Koff rate constant of 1 x 10-3s-1 or less, as determined by surface plasmon resonance…
Although such claims recite the function/effect of the antibody, they should also identify the target. An antibody defined entirely by its effect (the target being unspecified) is likely to lack clarity or support, because it may not be possible to compare claims with the prior art to judge whether the antibody is novel.
Definition of an antibody by its structure
This may include wording such as the following.
Claim: “An antibody that binds to antigen X, comprising a heavy chain variable domain (VH) of SEQ ID NO: 1 and a light chain variable domain (VL) of SEQ ID NO:2.”
Claim: “An antibody that binds to antigen X, comprising CDRs of SEQ ID NOs: 1-6.”
The EPO frequently insists upon recitation of the VH and VL domain sequences, or at least all six CDR sequences.
Sometimes, the EPO may insist upon the VH and VL domain sequences if it is alleged there is doubt concerning whether a particular beneficial technical effect could be displayed by antibodies with all six CDRs but without the framework regions of the VH and VL domains. For example, if a new antibody displays a higher affinity than a known antibody, the EPO may insist upon recitation of the VH and VL domains, alleging that the choice of framework regions can influence the affinity. In some circumstances, it may be possible to resist limitations to the VH and VL domain sequences if, for example, the applicant is able to demonstrate that variability in the framework regions can be tolerated without significantly affecting binding affinity, or by including a functional feature.
In some circumstances, it may be possible to obtain broader protection through use of sequence homology limitations.
Claim: “An antibody that binds to antigen X, comprising a heavy chain variable domain (VH) that has at least 90% sequence identity to SEQ ID NO: 1 and a light chain variable domain (VL) that has at least 90% sequence identity SEQ ID NO:2.”
It may be possible to use a combination of structural and functional features to obtain an allowable claim, but without having to recite the VH and VL domain sequences, or all six CDR sequences.
European Patent No. EP0929578 (T0418/07)
“1. An isolated human antibody, or antigen-binding portion thereof, with the following characteristics:
a) dissociates from human TNFα with a Koff rate constant of 1 x 10-3s-1 or less, as determined by surface plasmon resonance;
b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO:3, or modified from SEQ ID NO:3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at position 1, 3, 4, 6, 7, 8, and/or 9;
c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, or modified from SEQ ID NO:4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.”
Definition of an antibody by hybridoma deposit number
This may include wording such as the following.
Claim: “A monoclonal antibody obtainable from the hybridoma cell line deposited under the accession number ATCC….”
European Patent No. 0018795 (T0513/94)
“Monoclonal antibody which is produced from hybridoma ATCC CRL 8001 (OKT3).”
The hybridoma cell line must be deposited with a recognised depository institution in order to be considered adequately disclosed. The target should at least be identified in the description.
Definition of an antibody by how it is made
In some very limited circumstances, it may be possible define an antibody based on how it is made. This may include wording such as the following.
Claim: “An antibody produced by immunization of a non-human animal with a peptide of SEQ ID NO: 1.”
This way of defining an antibody may only be permitted if it cannot be defined by any other means (e.g. by its structure), otherwise such claims are likely to be found to lack clarity.
Definition of an antibody by its use
Even if a particular antibody is known, it is possible to obtain protection for a specific use of that antibody, if that specific use is novel and inventive. This may include use of an antibody in a new assay, such as a diagnostic assay, or its use in a therapy. A new use in therapy may be worded as follows, although the known antibody could potentially be defined in any way described above.
Claim: “An antibody comprising a heavy chain variable domain (VH) of SEQ ID NO: 1 and a light chain variable domain (VL) of SEQ ID NO:2, for use in the treatment of disease X.”
Ideally, a patent application would include as many ways as possible for defining an antibody, such that the applicant has the greatest possible flexibility for making amendments to distinguish over newly cited prior art documents, or to ensure that the claims can be defined in a clear enough manner to satisfy the EPO.
This article is for general information only. Its content is not a statement of the law on any subject and does not constitute advice. Please contact Reddie & Grose LLP for advice before taking any action in reliance on it.
