Although it is not unique to the field, the approach of the European Patent Office (EPO) can present significant challenges to applicants seeking to pursue claims to conventional antibody molecules. This briefing explores what we consider to be the basic principles of the EPO’s approach to this type of invention.
Some commentators have suggested that conventional antibodies (as opposed to next generation formats such as bispecifics) are regarded as a special case by the EPO when evaluating inventive step / obviousness. It is implied that the EPO sets a higher patentability threshold for inventions in this field as compared to, for example, small molecule therapeutics. However, this perception likely reflects no more than the crowded nature of the antibody field, which has matured rapidly. As a result, EPO Examiners are able to make a large (and increasing) number of assumptions regarding the background knowledge of the skilled person. For example, in the absence of evidence to the contrary, the EPO considers it to be routine to raise an antibody to a known target. The EPO also considers it to be routine to optimise certain characteristics of an antibody, such as affinity or immunogenicity.
Nonetheless, the EPO continues to grant many patents relating to antibodies, and in doing so applies the same patentability criteria as to other inventions. The types of claim that may result are explained below, and are also summarised in Figure 1 at the end of this briefing.
For more comprehensive advice regarding the drafting and prosecution of antibody inventions, please see our related briefing Antibodies in the European Patent Office – Advanced Guide to Drafting and Prosecution or ask your usual J A Kemp contact.
Scenarios Likely to Result in broad Claims
Broad antibody claims typically arise from two basic scenarios. In the first scenario, the target is a newly-identified molecule, or is a molecule to which it has previously proven difficult to raise an antibody. In such cases, the antibody may be defined solely in terms of the target bound. For example:
“An antibody which specifically binds to
In the second scenario, the target is found to have a previously unappreciated role in a disease. That is, the target is found to be associated with a new medical use. In such cases, the antibody may be defined by reference to the target bound and the new medical use. For example:
“An antibody which specifically binds to
These two basic scenarios are discussed in more detail below.
Newly-Identified or Difficult Target
The extensive mapping of genomes and proteomes means that truly “new” targets are very rare. However, an applicant who identifies, for example, a new polypeptide (potentially including new mutant forms of a known polypeptide) can expect to obtain broad claims to any antibody that specifically binds to the new polypeptide. It is not typically necessary to provide evidence that an antibody has actually been produced if the target is susceptible to routine methods of antibody production.
An applicant who develops a method allowing an antibody to be raised for a known target which was not susceptible to routine methods can also expect to obtain broad claims. The EPO effectively views such a target as a special category of new target – it is “newly available” for antibody production. Inventions of this type are though increasingly rare. Methods of antibody production have developed such that few targets are not now susceptible to them, and overcoming technical difficulties is frequently seen as routine. If the EPO can be persuaded otherwise for a particular case, the patent application will need to include clear evidence that an antibody to the target has indeed been raised, as well as sufficient information to allow this to be repeated.
New Medical Use
Where a known target molecule is found to have a previously unappreciated role in a disease, it may be possible to obtain claims directed to any antibody that specifically binds to the target for use in a particular method of treatment. In a typical scenario of this type, the target has a known association with one disease, but is subsequently found to have a role in a different (new) disease that was not previously appreciated. Under such circumstances the claims will be limited to an antibody for use in a method of treating the new disease, but will cover any anti-target antibody for the said use.
It will be necessary to establish that the new medical use is not obvious from any previous disclosure regarding the target or existing antibodies that bind to it. It will also be necessary to establish that it is at least plausible that an antibody binding to the target will have a therapeutic effect. This will be assessed case-by-case, but merely showing that the target is expressed during the disease is unlikely to be sufficient and some form of direct evidence will likely be required. The EPO will generally accept that in vitro functional data is sufficient, particularly if it derives from a disease model or other assay relevant to the indication. In vivo data from animal models is helpful but not required. It is not normally expected that a patent application for this type of “first in class” invention will include in vivo data from human clinical trials.
Similar considerations may apply if it was previously thought that the only antibodies that could be produced to a target were pharmaceutically irrelevant (for example due to low affinity), but it is subsequently found that they have a therapeutic effect1. In such cases a claim to a pharmaceutical composition comprising any antibody specific for the target may be possible.
Scenarios which may Result in Narrower Claims
It is unlikely that broad antibody claims will be available if both the target and associated medical uses are known. However, grant of narrower claims may still be possible for developments both of the medical use and of the antibody. These are not mutually exclusive categories and both may give rise to valuable protection.
New Development of a Known Medical Use
For the purposes of this category of invention, antibodies should be treated no differently to any other pharmaceutical product. The Enlarged Board of Appeal of the EPO has established2 that claims to second/further medical uses of a substance may be based not only on the treatment of a different disease, but also on the treatment of the same disease by a method which differs for example in the dosage, formulation, administration regime, group of subjects or route of administration. In each case, as with any known therapeutic, it will be necessary to establish that the difference gives rise to a technical effect (typically an advantage) which was not obvious from the prior art (e.g. surprisingly enhanced efficacy for topical versus parenteral administration). It will likely be necessary to include experimental evidence of the technical effect in the patent application.
Similarly, it may be possible to claim a medical use comprising co-administration of the antibody with another therapeutic (combination or co-administration), or any combination of these types. In each case, as with any combination of known therapeutics, it will be necessary to establish that the combination results in a technical effect (typically an advantage) which was not obvious from the prior art (e.g. synergistic increase in efficacy).
The scope of claim that may be available via this route will depend upon the data produced, since it will be necessary to show that the effect relied upon is achieved across substantially the whole scope claimed. This may require limitation to an antibody defined by a complete structural definition (including constant regions), if the EPO do not accept that the effect relied upon applies more generally, for example to all antibodies possessing the same six CDRs.
Ideally the data showing the effect should be present in the patent application. However, data generated post-filing may be used to supplement arguments later in prosecution, provided the effect relied upon is plausible at the filing date3.
New or Improved Characteristic of an Antibody
By contrast to its approach for small molecule therapeutics, the EPO does not in general consider that a unique structure can confer inventive step on an antibody to a known target. Thus, whilst an antibody comprising a unique primary sequence will be considered to be novel, structural non-obviousness arguments are unlikely to be accepted even when both variable region sequences are recited in full. This means that applicants will generally be unable to rely upon, for example, the determination of unique CDR and framework sequences to provide an inventive step.
Instead, the EPO has developed a requirement that a new antibody to a known target must demonstrate “an unexpected effect” relative to pre-existing antibodies to the same target4 in order for inventive step to be acknowledged. It will therefore generally be necessary to demonstrate that the antibody as claimed possesses a functional characteristic (or combination of characteristics) which could not reasonably have been predicted from the prior art.
At least some direct experimental evidence of the characteristic(s) relied upon should be provided in the patent application, for at least one exemplary antibody.
Under some circumstances it may be possible to rely upon supplementary data filed later as evidence of the characteristic(s), but there must be a connection to the characteristic(s) shown in the application as filed. The characteristic(s) relied upon must be at least plausible at the filing date5 in order for it to be taken in to account when assessing inventive step. Evidence even of a related characteristic may not be adequate to meet this requirement6.
In effect, for second and later generation antibody inventions, a unique sequence can be relied upon to provide novelty, but a demonstration of a new or surprising functional effect will be required to show inventive step.
Examples of the types of functional characteristic that applicants may seek to rely upon are shown in Figure 1. These examples should not be viewed as exhaustive or mutually exclusive. In practice a combination of these and other characteristics may well provide the best route to allowable claims.
If the EPO is persuaded that “an unexpected effect” is present and plausible, the breadth of claim that is allowed will depend upon the circumstances of each case – in particular the state of the prior art and the data available.
In rare cases, it may be possible to claim a general class of antibodies which achieves the said effect, defined solely in functional terms. For example:
“An antibody which binds specifically to
It will be necessary for the application to include sufficient information such that the skilled person can generate further examples of an antibody which meets the functional definition. The identification in the patent application of a specific, structurally-defined antibody which can be used as a reference / control in a screening method may be sufficient.
Where the above claim type is considered to be too broad, it may be possible to secure allowance by introducing a limitation defining the claimed antibodies by reference a specific antibody. For example:
“An antibody which binds specifically to
However, there will need to be clear evidence both that there is a link between the characteristic defined by reference to the specific antibody and possession of the unexpected characteristic, and also that prior art antibodies do not fall within the scope of the former (and thus inherently possess the latter). This may well be challenging. Characteristics defined by reference to a specified antibody typically include features such as “competes for binding with” or “binds to the same epitope as”. Such characteristics are often viewed as unclear by the EPO, and the as a minimum the specification will need to include detailed information regarding how the characteristic is be determined. This information may ultimately also need to be included in the claims.
Given the above, it is much more common that the EPO will require limitation of the claims to the specific sequences of an antibody or antibodies which are demonstrated to possess the unexpected characteristic(s). For example:
“An antibody which binds specifically to
It is often unnecessary to recite the unexpected characteristic(s) in such claims because the characteristic is deemed to be an inherent property of an antibody possessing the recited sequences.
Irrespective of the characteristic(s) relied upon, pursuit of this approach will likely require that applicants have provided a significant amount of structural information (primary amino acid sequences) in the patent application. Whether a particular antibody is claimed directly or is recited as a reference antibody, the EPO often insists that structural detail be provided at a level at least sufficient to define the target binding region of an antibody.
It is unlikely that an EPO Examiner will accept a definition of the target binding region with fewer than six CDR sequences and it is not unusual for complete variable region sequences to be required, as shown in the example claim above. To claim sequences more broadly will require data to demonstrate that the unexpected characteristic relied upon is achieved by substantially all antibodies falling within the scope of the claim. In some cases it may even be necessary to specify the isotype of the constant region if this is relevant to the unexpected characteristic.
Comprehensive Filing Strategy
A typical antibody development project will pass through different stages, and at each stage it may correspond more closely to one or the other of the scenarios outlined above. This briefing is intended to explain the EPO’s approach to antibody inventions at each of these stages, with suggestions as to how patentable claims may be achieved in each scenario. These suggestions are also summarised in Figure 1.
However, the scenarios that are described are not mutually exclusive. As with any therapeutic invention, a comprehensive filing strategy should seek to explore all of the available options for patent protection throughout the lifespan of the project and beyond. For example, an initial broad filing to a new medical indication should be followed with multiple narrower filings to antibodies with improved characteristics and/or developments of the treatment methodology.
1. Board of Appeal decision T601/05: claims to a pharmaceutical composition comprising human anti-TNFα antibodies were found to be inventive. At the time only low affinity human antibodies to the target could be generated, and it was thought that these were not suitable for pharmaceutical use.
2. Enlarged Board of Appeal decision G2/08
3. Board of Appeal decision T1329/04
4. Board of Appeal decision T735/00
5. Board of Appeal decision T1329/04
6. Board of Appeal decision T2637/11
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.