It is estimated that more than $1 billion in R&D is spent on each new therapeutic monoclonal antibody, and so patent protection is essential to stimulate funding and provide a return on investment.
Questions of when to file a patent application, the type and amount of supporting data required, and the breadth of claim scope that may be reasonably expected, are therefore of central importance to antibody producers, for securing robust patent protection for their lead antibody candidate and preventing competitors from developing similar antibody-based therapeutics.
For the first time ever, in March 2021, the European Patent Office (EPO) Guidelines for Examination includes a section devoted to the examination of antibody-related patent claims (G-II-5.6). These Guidelines are based on case law of the EPO Boards of Appeal and provide guidance that is intended to harmonise the approach of all EPO Examiners to the examination of patent applications.
Patenting Antibodies at the EPO
The new antibody section in the EPO Guidelines is a welcome addition for practitioners in this field. It summarises the requirements for different approaches to defining antibodies in patent claims (e.g. by their sequence, function, or method of production), and importantly, also provides helpful guidance in relation to the assessment of inventive step of antibodies in Europe.
Historically, there has been a perception amongst some practitioners that the EPO treats antibody patent applications differently to other forms of technology, and even imposes a higher patentability threshold. In our experience, however, that is not actually the case. It may just appear that a higher standard is imposed for antibodies, because the established view of the EPO’s case law is that many aspects of the production of an antibody, including antibody generation, mutagenesis, affinity testing, etc., involve routine methods that form part of the skilled person’s common general knowledge. As a result, the bar for inventive step can appear to be very high in Europe, and the vast majority of antibody cases before the EPO Boards of Appeal are decided on inventive step. Often intertwined with inventive step in relation to the validity of antibody patents is the requirement for sufficiency of disclosure of any non-obvious aspect of a claimed antibody.
Conventional antibodies comprise two identical heavy chains and two identical light chains, folded into constant and variable domains. Each of the heavy and light chain variable domains (referred to as VH and VL) contains three hypervariable loops, known as complementarity determining regions (CDRs), interspersed between four less variable framework (FR) regions. It is the CDRs that provide the specific antigen recognition site of the antibody.
Patent claims may be directed to antibody variants, including inter alia antibody fragments, bispecific or multispecific antibodies, antibody fusion products and heavy-chain-only antibodies. The new EPO Guidelines do recognise these new antibody formats, but the specific guidance provided is directed towards conventional antibodies only.
In the new Guidelines, the EPO has included eight separate sections relating to different specific approaches by which antibodies may be defined and claimed in Europe. These can be summarised as follows:
1. claims based on the sequence (i.e. structure) of the antibody;
2. claims relating to the function or target of the antibody; and
3. claims reciting the method of antibody production.
Our practical advice and comments on the new Guidelines in relation to each of these approaches is discussed below.
1.Claims Directed to Antibody Sequence (i.e. Structure)
“… antibody comprising the CDRs of SEQ ID NOs: 1-6.”
The new Guidelines confirm the EPO’s longstanding practice for examining claims defining antibodies in terms of their amino acid sequence. The EPO has consistently taken the default position that the CDRs are responsible for binding to the antigen, and so a conventional antibody should be defined by at least the six CDRs, in order to be uniquely defined by its structure only and have its characteristic binding specificity.
It is clear from the new Guidelines that a sequence-based antibody patent claim will be considered to lack clarity (due to lacking an essential technical feature) if, in the case of a conventional antibody, it is defined by fewer than all six CDRs.
It is important to note, however, that the position set out in the Guidelines is just a starting position, and that these are just “guidelines”. An overriding principle is that the scope of the claims should be commensurate with the contribution made to the art. Thus, the requirement for the sequence of all six CDRs is not a legal requirement, but should be seen as a flexible starting position depending on the supporting data and the disclosure of the prior art.
This understanding appears to have been confirmed in a recent decision of the EPO Boards of Appeal, T0941/16, in which the Board allowed an applicant to submit evidence in support of an antibody claimed on the basis of only “at least three” CDR sequences, in combination with a functional feature. In that case, the applicant was unable to secure allowance for such a broad claim, but the Decision does suggest that the Board would have been happy to allow a claim defining the antibody with broad scope in the CDR sequences had the applicant been able to provide convincing evidence in support of this breadth of claim.
Therefore, the message to applicants is that, where a patent is sought for an antibody defined by the CDR sequences, the applicant should be prepared to provide evidence supporting sequence variation, or else they may be required to limit the claim to include the sequences of all six CDRs.
In some circumstances, such as if mutational analysis data are available before filing, it may be possible to obtain claims specifying residues within CDRs at which sequence variation can be accommodated. In practice, it may be necessary to support this type of claim language with a functional limitation such as a binding affinity.
Indeed, if the data are available, it may be possible, in principle, to define the antibody on the basis of the specific arrangement and identity of the precise amino acids of the antibody (i.e. the paratope) that interact with the epitope on the antigen, but such a claim would need to be underpinned by considerable supporting data. For example, the three-dimensional arrangement of the paratope could be demonstrated and defined, or alternatively, it would need to be demonstrated that the residues between those that interact directly with the target epitope can be varied without otherwise affecting the antibody.
Accordingly, it may be possible to obtain an allowable sequence-based antibody patent claim that is broader than the specific sequences of all six CDRs, through the use of specified amino acid substitutions in defined positions of the CDRs, if the supporting data are available, and, of course, depending on the prior art.
In this regard, it is relevant to note that the new Guidelines state that when the CDRs are not defined by their specific amino acid sequence, they must be defined according to a numbering scheme, such as Kabat, Chothia, or IMGT (the international ImMunoGeneTics system).
In relation to the inventive step of antibodies defined on the basis of their protein sequence (i.e. structure), the new Guidelines emphasise that the EPO does not recognise the principle of structural non-obviousness. So, if the target of a novel antibody is not novel, inventive step is not acknowledged solely on the basis that the novel antibody is structurally different, by virtue of its sequence, from known antibodies that bind to the same target. For an inventive step to be acknowledged in Europe, it is not enough that the sequence of an antibody could not have been predicted in advance. Likewise, simply producing a new antibody to a known target using a routine technique is also considered to be obvious.
An inventive step may be recognised, however, if the antibody can be shown to provide a surprising technical effect, rather than being a “mere alternative” to known antibodies. The new Guidelines list examples of surprising technical effects that may support an inventive step, including improved affinity, improved therapeutic activity, reduced toxicity or immunogenicity, an unexpected species cross-reactivity or a new type of antibody format with proven binding activity. The new Guidelines also state that “the main characteristics of the method for determining the property must also be indicated in the claim or indicated by reference to the description”. Therefore, it is important that details for measuring the alleged improved property are provided in the specification.
VH and VL Sequences
“… antibody comprising a VL domain comprising SEQ ID NO: 1 and a VH domain comprising SEQ ID NO: 2.”
In many circumstances, the EPO may require the entire VH and VL domain sequences to be recited in the claim, rather than just the CDR sequences.
In particular, the new Guidelines state that, if the surprising technical effect of the new antibodies relates to the binding affinity, the default position for examination is that the VH and VL domain sequences, including the framework regions, of the antibody must be recited in the claim. The EPO’s view is that the framework regions influence the affinity of the antibody for the target epitope, because they provide the three dimensional scaffold for the CDRs, and so they must be specified in the patent claim, in order for the improved affinity to be provided across the full claim scope.
It must be restated, however, that this is simply a guideline. EPO Examiners have leeway to determine whether this type of limitation is necessary, based on the prior art and, in particular, the data in the specification, and whether it can be shown that variability in the framework regions can be tolerated, while still exhibiting increased binding affinity.
The message to applicants is that it may help to avoid having to recite the full VH and VL sequences in the claim if it can be demonstrated that the antibody provides a surprising technical effect other than (or in addition to) improved affinity. This could include, for example, improved antibody solubility, reduced propensity to aggregate, higher melting temperature, or improved thermal stability, which enable improved antibody production yields. The Guidelines provide examples of other possible technical effects (see above), but in principle any surprising technical advantage or improvement may support an inventive step.
Combination of Functional and Structural Features
“… antibody comprising at least 90% sequence identity to the VH and VL regions of SEQ ID NOs: 1 and 2, and that is capable of reducing the binding of ligand X to receptor Y”
By defining an antibody both on the basis of its sequence and also on the basis of a well-characterised target or other functional feature, it is possible to obtain allowable patent claims with less than 100% sequence identity to the six CDRs or variable regions. This is the most common type of antibody claim currently under examination at the EPO. Moreover, in our recent experience, this is also generally the format of patent claim that is most likely to be successful at the EPO.
This approach can be particularly useful when the functional feature relates to the technical effect on which an inventive step is based. The EPO’s starting position is that antibodies specific for a known target will lack an inventive step unless an unexpected effect is plausibly demonstrated by the data in the specification. Thus, patentability is likely to be a question of the magnitude of the unexpected effect in view of the prior art, and the extent of the data supporting the effect.
2. Claims Directed to Antibody Function or Target
In our experience, it can be challenging to obtain patent protection in cases where no individual antibody is disclosed in the patent specification, and which rely on defining the antibody exclusively by reference to its target antigen.
However, if the target is novel and non-obvious, then broad antibody claims that are not structurally limited can nevertheless be obtained. Identifying entirely new targets is becoming increasingly difficult, however, and as a result, in order to obtain allowance, it is generally the case that antibody patent claims are required to include an antibody sequence limitation of some sort in addition to the functional limitation.
Reference to the Target Antigen
The Guidelines provide a number of specific examples of antigen-defined antibody claims.
“… antibody that specifically binds antigen X”.
“… antibody that specifically binds to SEQ. ID. NO: Y”.
In order to claim an antibody in this way, the target antigen must be well-defined in the specification. The new Guidelines make it clear that if the antigen is defined by a protein sequence, no sequence variability and no open language (such as “an antigen comprising …”) can be used in the definition of the antigen. If the antigen is not precisely defined, the subject-matter of the claim will be considered to lack novelty on the basis that existing antibodies will bind to the undefined region of the target antigen.
If the target antigen is a novel target, then it may be possible to obtain allowable claims with a relatively broad claim scope, due to the novelty and non-obviousness of the target.
Indeed, we have recently obtained allowable claims in the format “An antibody that specifically binds to SEQ ID NO: 1, but does not bind to SEQ ID NO: 2”, where SEQ ID NO: 1 encodes a novel and non-obvious diagnostic target, and the claim provides no sequence definition of the antibody itself at all.
If the target antigen is known, however, the EPO’s default position is that it is within the skilled person’s common general knowledge to be able to produce antibodies to that known target. Such antibodies are likely to be considered to lack an inventive step unless an unexpected technical effect can be plausibly demonstrated. For example, if the known target is a receptor, then data demonstrating that the antibody can activate or inhibit the activation of the target receptor may support an inventive step.
Alternatively, an inventive step may be acknowledged if the antibody could not have been produced by routine methods. In that case, for sufficiency of disclosure, the specification must also provide details of the non-obvious method required to obtain the claimed antibody.
Reference to the Epitope
“… antibody that specifically binds to a peptide of SEQ ID NO: 1 on antigen X.”
If the target antigen is known, it may be possible to specify a novel target in the claim on the basis of binding to a specific epitope on the known antigen. For inventive step, it will also be necessary to show that the antibody provides an unexpected technical effect, i.e. why binding to one epitope rather than another on the same antigen is advantageous.
If the antibody is defined on the basis of binding specificity to a “linear epitope”, then the same considerations are likely to apply as for any target antigen, as discussed above. Thus, the epitope will need to be precisely defined in the claim using closed language.
On the other hand, if the epitope is non-linear or “discontinuous”, then additional considerations in relation to sufficiency of disclosure are likely to apply. In this case, not only will the specific amino acid residues of the epitope need to be clearly identified, but in addition, the new Guidelines state that the method for determining the discontinuous epitope must also be indicated in the claim, and the application must provide an enabling disclosure allowing the skilled person to determine whether further antibodies would bind this non-linear epitope.
The application must also enable the production, without undue burden, of additional antibodies binding to the same epitope.
In addition, since an antibody defined in this way cannot be easily compared with known antibodies binding to the same antigen, the same principles will apply as discussed below in relation to functional features.
Reference to Functional Features
Antibodies may also be defined on the basis of functional features other than the target antigen. The new Guidelines list a number of examples of possible functional features, including binding affinity, neutralising properties, induction of apoptosis, internalisation of receptors, and inhibition or activation of receptors.
“… antibody that binds to antigen X with a binding affinity of greater than…”.
“… antibody that binds to antigen X on the surface of a cell and induces apoptosis of the cell”.
If antibodies are claimed purely on the basis of functional features, then the burden of proof is on the applicant to show that the claimed antibodies are novel over prior art antibodies directed to the same antigen.
There is also a significant burden on the applicant in terms of sufficiency of disclosure for this type of patent claim. For example, the specification must provide an enabling disclosure across the whole scope claimed. In addition, the functional definition must allow the skilled person to clearly determine the limits of the claim. It may also be necessary to show that the functional features can be verified by a suitable method known to the skilled person or detailed in the specification.
Indirect Definition of the Target Antigen
In principle, it may be possible to define an antibody by the indirect definition of a target antigen, such as by means of competition with a reference antibody.
“… antibody which competes with an antibody produced by the hybridoma cell line deposited under the accession number…”
There is no mention, however, of this particular antibody claim format in the new Guidelines, which is surprising because antibody claims in this format are allowable, at least in principle.
In general, in order to claim an antibody in this way, the reference antibody must be well-defined, for example, by sequence or by reference to a hybridoma.
3. Claims Directed to Antibody Production Method
An antibody may be defined by means of the immunisation protocol used to derive the antibody.
“… antibody produced by immunization of a non-human animal with a peptide of SEQ ID NO: 1.”
The use of this type of product-by-process claim format is generally only allowable at the EPO if the product cannot be defined by any other means. In principle, however, this is not the case with antibodies, which can be defined by their sequences. It may be possible, however, in certain circumstances, to use this type of antibody claim format.
In order to avoid an allegation of lack of clarity in view of the inherent variability in this method of antibody production, it is likely to be necessary for the immunogen to be precisely defined.
Antibodies may be defined by means of a deposited hybridoma cell line capable producing the antibodies.
“… antibody produced by the hybridoma cell line deposited under the accession number…”.
The EPO’s general requirements for deposited biological materials will apply.
The content of the new antibody-related section of the Guidelines for Examination is consistent with our recent experience prosecuting antibody patent claims before the EPO.
The new Guidelines are a welcome addition and will ensure consistency of approach at the EPO, and they will provide additional certainty for applicants and assist the drafting of antibody-related patent applications.
It is important to remember, however, that as stated in the Guidelines themselves, “these Guidelines provide guidance in respect of the practice in proceedings before the EPO”, they “do not constitute legal provisions”, and “must be regarded as general instructions that may need to be adapted to the individual case”.
Thus, the Guidelines are simply guidelines. The allowable scope of an antibody patent claim should be commensurate with the contribution made to the art and will, therefore, depend on the strength of the supporting data and the disclosure of the prior art. In order to determine the best strategy for your particular circumstances we recommend seeking early advice.