Patenting of Antibodies in the European Patent Office and the New “Guidelines” – Boon or Bane?

Marta Kawczyńska (PL), European and Polish Patent Attorney, Polservice Patent and Trademark Attorneys, Warsaw

Jürgen Meier (DE), European and German Patent Attorney, Vossius and Partner, Munich

Antibody technology, whether in the context of biotechnological research tools or in pharmaceutical settings, is a rapidly developing and ever evolving field, as demonstrated by the current COVID-19 pandemic. Appropriate IP protection for inventions based on these conventionally large proteinaceous molecules is of paramount importance for innovators, in particular considering the extensive, time consuming research and development processes, not to mention huge investment costs, before an actual product enters the market.

The EPO is rightfully considered as one of the key Intellectual Property Offices for patent examination. It is globally recognized not only for the quality and reliability of its procedures and its consistency and transparency, but also for the well-established case law of the (Technical) Boards of Appeal. This reputation, also in the life science field, is also based on the comprehensive “Guidelines for Examination”. These are made available internally to EPO examiners, but more importantly also to the public, in particular patent applicants, their representatives and all other interested parties. The latest version of the “Guidelines” enters into force on 1 March 2021 and now includes a highly welcomed section directed explicitly to the patentability of antibodies, section G II, 5.6.

The specificity and complexity of antibody inventions made it at times difficult to directly apply the previous “Guidelines”. Specifically, these were drafted primarily in view of other fields of technology, including e.g. pharmaceuticals based on so called “small (chemical) molecules”. However, antibodies and antibody-derived proteinaceous constructs tend to be rather complex molecules that may elicit different and complex physiological responses or functions, especially in a therapeutic and/or diagnostic setting. Whereas naturally occurring antibodies are conventionally characterized as large biological “Y-shaped” molecules composed of two identical “heavy chains” and two identical “light chains”, new antibody formats and/or antibody derivatives have made their important entrée in the world of pharma. Both conventional antibodies as well as these new formats and derivatives are considered “biologics”. Although it is evident that these biologics are subject to the same patentability requirements as other products (with the exception of the specifics of Rules 27 to 29 EPC^{Rule 28 EPC relates to exceptions to patentability. It provides that European patents shall not be granted in respect of biotechnological inventions which concern either the cloning of human beings, modifying the germ line genetic identity of human beings, the use of human embryos for industrial or commercial purposes, or modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal. Accordingly, neither nucleic acids nor proteins, including antibodies, are affected by the exclusions established in Rule 28 EPC.
Furthermore, Rule 29(2) EPC makes it clear that an element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of said element is identical to that of a natural element. In T 272/95 ‘Relaxin/HOWARD FLOREY INSTITUTE’, it was confirmed that inventions falling under this category, i.e. even naturally occurring elements, are not excluded from patentability. This was also acknowledged, inter alia, in T 1213/05 ‘Breast and ovarian cancer/UNIVERSITY OF UTAH’.} which mirror the provisions of European Union Directive 98/44/EC on the legal protection of biotechnological inventions (the ‘Biotech Directive’)), the unique biological and/or physiological features of these active molecules also need to be considered when assessing patentability before the EPO. Therefore, the updated version of the “Guidelines” now comprises detailed information on the approach of the EPO to antibody patentability, in particular in relation to the allowable claim formats and the assessment of “inventive step”. This newly introduced section G-II 5.6 provides parties with guidance as to how antibodies/antibody constructs may be defined, e.g. by their own structure (the “Guidelines” relate here to amino acid sequences or to encoding nucleic acid sequences), by reference to the (target) antigen and/or the “epitope”, by the production process, or by reference to their functional and structural features. In sections G-II, 5.6.1.2 and 3, the “Guidelines” provide that an antibody can be, for example, functionally defined by the antigen it binds to, but, in addition, may also be characterised by functional features defining further properties. As examples, the “Guidelines” refer here to binding affinity, neutralizing properties, induction of apoptosis, internalisation of receptors, and inactivation or activation of receptors. The “Guidelines” now caution that, if an antibody is exclusively defined by functional properties, the EPO is to carefully assess “whether the application provides an enabling disclosure across the whole scope claimed” and “whether the functional definition allows the skilled person to clearly determine the limits of the claim”.

The EPO’s current examination practice and its well-established case law on the patentability of antibodies have found an adequate reflection in these new “Guidelines”. The newly introduced section appears to be balanced, recognizing the complexity and peculiarities of the field, while providing reasonable options for antibodies to be defined without hampering further developments and inventions in this field.

It is of note that prior to the development of the new “Guidelines”, the EPO also routinely and rightfully granted patents for antibodies that were the “forerunners” in the field, taking “functional features” of such forerunners into account. The allowability of functional features was considered and confirmed in very early decisions of the Technical Boards of Appeal, such as inter alia T 430/92 ‘Growth of Tulips/SUMITOMO’ and T 412/06 ‘Proteinase inhibitor/MAX-PLANCK-GESELLSCHAFT’.

Compound claims reciting “functional features” of a novel and inventive antibody accepted by the EPO may have a broad scope of protection because they do not limit the claimed antibody to any particular structure (and thus potentially encompass a wide variety of amino acid sequences). However, one must be able to distinguish the claimed antibody from those known in the art based on their clearly defined and specific (biological/biophysical) activity. Such distinguishing functional features may potentially include any feature identified by the inventor, as long as these features are novel, inventive and enabled over the full range as claimed. Such features may correspond to in vivo and/or in vitro activities and also include those determined in cell-free assays (e.g. antibody affinity, cross-reactivity) and/or in cell cultures (e.g. anti-proliferative or stimulatory activity). It is also understood that the selection of a specific type of antibody for further study, for example in clinical trials, may be based on (a) feature(s), which will differentiate the antibody under investigation from already known antibodies with known properties.

In accordance with the new “Guidelines”, it appears to be feasible that functionally defined antibody claims and claims directed to a novel and inventive (biological, medical and/or diagnostic) use of an antibody can meet the patentability requirements before the EPO, provided the description in the application and the knowledge already available in the prior art allow the skilled person to find such antibodies. In this respect, the time it takes to obtain, screen for and/or make corresponding antibodies seems to be of minimal consideration. This is in line with case law of the EPO and, in this regard, it may be decisive, again, that the application as filed comprises enough technical guidance ‘to reproduce the invention to practice without undue burden’. As reflected in the “Guidelines”, this is nothing exceptional and is based on several decisions of the Technical Boards of Appeal, e.g. T 617/07 ‘Monoclonal NGF-antagonist antibodies/LAY Line’ or T 1300/05 ‘RET screening assay/PROGENICS’, e.g. illustrating that functional features, in particular specific binding, can characterize claimed antibodies.

It should also be noted that, in our opinion, there is no harm to third parties (or the public) in claiming antibodies based on functional features, e.g. the specific binding to a novel and inventive antigen/epitope/target/etc. The EPO, again rightfully, considers that an inventor is entitled to patent protection for an ‘antibody specifically binding to a defined antigen/epitope/target’ when a novel and inventive antigen/epitope/target/etc. is provided. This is because the EPO sees the preparation of antibodies, such as polyclonals or monoclonals, as a routine technique readily mastered by the skilled person. However, if functionally defined antibodies are claimed, and the claimed function goes beyond ‘specifically binding’, additional support in the experimental part of the application will be required. Again, in our opinion, the public is protected from allegedly “senseless” antibody claims because the Technical Boards of Appeal have repeatedly emphasized that an effort to define a feature in functional terms had to be abandoned where it would jeopardize the clarity of a claim as required by Article 84 EPC.

Examples of the EPO’s previous correct approaches to the patentability of (allegedly) broad antibody claims, e.g. when a novel and inventive antigen and/or antibodies targeting such novel “antigens” are found, are inter alia, illustrated by T 18/09 ‘Neutrokine/HUMAN GENOME SCIENCES’ or by T 1902/11, ‘Human IL-23/MERCK SHARP & DOHME’ (see Reason 56).

In light of the plausibility concept applied by the EPO, functionally defined antibody claims are often contested as allegedly attempting to monopolize antibodies that have certain properties ‘to be achieved’ (‘desiderata’). However, the Technical Boards of Appeal have scrutinized functional claims and have considered them permissible as long as the patentability requirements of novelty, inventive step, enablement and industrial applicability were met, and the teachings provided by the applicant were ‘plausible’ at the relevant filing date. This also holds true for antibody claims directed to a novel and inventive epitope/target/antigen.

Nevertheless, this patentability approach finds its limitations where it is not plausible from the application as filed that specific antibodies to said antigen can be obtained with ‘routine methods known in the art’. On the other hand, inventive step of a claim to a novel antibody specific for a known antigen is typically rejected by the EPO unless there is tangible evidence to doubt that the novel antibody could have been obtained by mere routine methods. Accordingly, and considering that the EPO does not accept a ‘structural non-obviousness approach’^{The EPO does not accept the principle of ‘structural non-obviousness’; see, e.g., Technical Board of Appeal, decision in T 605/14 of 7 June 2018, ‘Anti-angiopoietin-2 antibodies/MEDIMMUNE’, Reason 24 , and Technical Board of Appeal, decision in T 187/04 of 11 January 2007, ‘Antikörper/KREBSFORSCHUNGSZENTRUM’, Reason 11.} as applied by the USPTO, the provision of further antibodies with novel CDRs or novel variable regions (such as humanized antibodies) by applying such routine methods is not normally considered as inventive. Rather, it needs to be made plausible that these novel antibodies have an unexpected technical effect and/or superior properties for inventive step to be acknowledged. This principle was summarized in T 735/00 ‘Anti-CRP antibodies/IATRON LABORATORIES, INC.’ as follows:

“The case law in this field acknowledges inventive step if and when there is evidence that a claimed monoclonal antibody prepared by routine methods shows unexpected properties (cf decision T 645/02 of 16 July 2003). If, however, there are no unexpected effects achieved with a further monoclonal antibody compared with a [prior art] monoclonal antibody with essentially the same properties as desired the case law denies inventive step (cf decision T 512/94 of 23 June 1998).”

The holding of T 735/00 has been acknowledged as ‘established jurisprudence in the field of antibodies’; see, e.g. T 605/14, ‘Anti-angiopoietin-2 antibodies/MEDIMMUNE’, see in particular Reason 25.

Accordingly, the new “Guidelines” basically confirm previous case law of the EPO and make clear that strictly structural definitions by amino acid or nucleic acid sequences are not the sole allowable definitions for antibodies. Rather, functional definitions, e.g. by reference to the target antigen, and in certain circumstances, the use of sequence identity limitations, are also accepted. Therefore, and as mentioned in new section G-II 5.6.1.4. of the “Guidelines”, allowable antibody definitions may also comprise combinations of both structural and functional features. For example, it is possible “to claim antibodies by the sequences of both the variable domains or CDRs with less than 100% sequence identity when combined with a clear functional feature”. Again, as also recited in the new “Guidelines”, the corresponding functional feature is not limited to the (specific) binding to a target, but may, illustratively, comprise binding affinity, neutralising properties, induction of apoptosis, internalisation of receptors, and inhibition or activation of receptors (see, section G-II 5.6.1.3 of new “Guidelines” also referring to e.g., T 299/86, Reasons 3-6 and T 1300/05, Reasons 4-7).

Antibody claims reciting functional features that do not limit the antibody to any particular structure but potentially distinguish the claimed antibody from those already known in the art are normally based on one or more specific and unique activities. Such distinguishing and potentially superior functional features can comprise any feature identified by the applicant/patentee. However, the new “Guidelines” also caution that “if an antibody is claimed exclusively by functional features and the prior art discloses in an enabling manner an antibody directed to the same antigen using an immunisation and screening protocol that arrives at antibodies having the claimed properties, it has to be assumed that the prior-art antibody inherently displays the same functional properties as the claimed antibody, which thus lacks novelty”; see, again, G-II 5.6.1.3.

At least since decision T 1329/04 ‘Factor IX/Johns Hopkins’, the ‘plausibility approach’ has become a further “standard” in the assessment of patentability. In the context of this “plausibility approach”, the EPO does not bar the patenting of antibodies by reference to functional features, including affinities to the target molecule, avidity, inhibitory or activating functions, binding specificities and the like. Nevertheless, and as now also reflected in the “Guidelines”, such technical features may be contested by examiners as not having been demonstrated for the entire class of antibodies covered by the claims, in particular, where the claims do not comprise additional (limiting) structural features. Accordingly, it is advisable to have a plausible/technical teaching in the patent application that supports the corresponding functional feature. As discussed above, these functional features are also critically scrutinized by the Examining Divisions/Opposition Divisions of the EPO for clarity and completeness of disclosure. Technical features expressed in functional terms must be able to be verified by tests or procedures adequately specified in the description, or generally known to the skilled person. Such tests and/or screening assays further need to be reproducible, and the specification has to provide means and methods allowing a skilled person to reliably obtain the corresponding parameters and/or concrete comparative values, e.g. binding or affinity constants. This appears to be a fair approach taken by the EPO.

As is evident in previous EPO decisions, e.g. T 617/07 or T 1300/05, and as now reflected in the “Guidelines”, the consideration of “functional” definitions during examination will also focus on whether disclosure is enabling and/or plausible so as to merit protection over the entire scope claimed. In the case of definitions by a combination of both structural and functional features, it is also envisaged that recitation of the variable domain sequence or sequences of six CDRs might not be required. Another allowable definition format, under certain conditions, is a definition of an antibody by the process of its production, e.g. immunization protocol, specific cell line used for the production, or deposited hybridoma producing the antibody. In light of the above, a further allowable claim format is the definition of an antibody by its binding partner/antigen/epitope, provided that its binding partner/antigen/epitope as such is sufficiently disclosed and clearly defined, for example by its specific amino acid residues or a clearly defined sequence fragment.

It is also of note that third parties are not barred from obtaining (additional) patent protection for specific (novel and inventive) antibodies that are, for example, characterized by clearly limited structural features. For these types of inventions it should be documented in the patent application that the claimed specific antibody has an unexpected, advantageous effect. Such exemplary effects can include its binding properties, activity in combination with other drugs, the provision of a truly novel clinical situation (then often in combination of a “second medical use claim”) and the treatment of a specific disease. Along these lines in a more restricted claim scope, for example the use of a specific (surprisingly advantageous) antibody in the treatment of a specific disease, even the same therapeutic antibody could be claimed in the use of the same disease as disclosed in the prior art. This is, inter alia, of particular relevance when a novel technical effect, not previously elucidated, is obtained by a biologic, like an antibody. Relevant decisions in this context are T 836/01 ‘Interferon-beta2/YEDA RESEARCH AND DEVELOPMENT CO. LTD.’ and T 1642/06 ‘Sigma receptor/SPRUCE/BARBARA, et al.’.

The EPO’s approach to establish inventive step does not appear to be entirely comparable to a “structural non-obvious approach” as applied by the USPTO. Yet, in both jurisdictions, patent protection for a specific antibody is achievable even where a certain “genus” of corresponding antibodies was known in the prior art. However, the approach for “inherent disclosure” before the USPTO and for “selection inventions” before the EPO are rather different. In the practice of the EPO, “unexpected technical effects” of a selected species merits patent protection even if the “genus” was known. In contrast, because there is no predictable relationship between the sequence of an antibody and its function, the USPTO takes the view that an antibody with a distinct sequence is likely to be patentable, even if it performs the same function as an antibody which is already known. This is, partially, based on the so-called doctrine of structural non-obviousness.

As also reflected in the new “Guidelines”, the EPO would allow patent protection for antibodies that are, for example, identified and/or elucidated via non-routine methods and/or when it can be plausibly documented that “routine methods of production” would not lead to success, i.e. defining antibodies by their “production process”. An example for corresponding case law is T 1280/08 ‘Immunoglobulin products/STATENS SERUM INSTITUT’. Here, the Board considered a process for purifying immunoglobulin G (IgG) from a crude immunoglobulin-containing plasma protein fraction. It followed the patentee’s argumentation for patentability in that the provision of the required new process for purifying IgG from plasma was not an easy task due to the high complexity of the starting material and the fragility of the immunoglobulins.

Additionally, in the case of assessment of inventive step of antibody inventions, the approaches taken by the Examining Divisions, the Opposition Divisions as well as the Technical Boards of Appeal, in particular the long established “problem-solution-approach”, seem to be fairly balanced and flexible. Specifically, any novel antibody can be considered inventive if it provides for an unexpected (surprising) technical effect and if the application shows that such effect was obtained or at least made plausible. Again, this consistent approach of the EPO appears to be well reflected in the new “Guidelines”, providing an illustrative, non-exhaustive, list of surprising technical effects that may be considered. It must be noted, however, that the existence of a surprising technical effect is not necessarily required for an acknowledgement of inventive step. Art. 56 EPC does not require that the problem to be solved by the invention be new. In accordance with the established case law, an alternative solution to a known problem might be inventive provided that the problem has been solved in another, non-obvious way; this is also reflected in the “Case Law of the Boards of Appeal” book (2019) under “Inventive Step” I.D.4.5 on page 195 and referring in this context to T 92/92, with reference to T 495/91, T 780/94, T 1074/93, T 323/03, T 824/05. What is especially evident in view of, e.g. T 588/93, is that for an acknowledgement of inventive step, it was not necessary to show any improvement over the prior art. Thus, a prior art solution to the technical problem does not automatically preclude that a later, different, solution possess an inventive step (T 1791/08). The condition for acknowledgement of inventive step in such a case is that the alternative solution must solve the problem in another, non-obvious way.

According to the new “Guidelines”, structural non-obviousness, or unpredictability, does not justify inventive step of a novel antibody binding to the same antigen as known antibodies if the novel antibody is solely structurally different from the known antibodies. As explained in the “Guidelines”, a sole structural difference of an antibody binding to the same antigen as known ”prior art” antibodies is thus not sufficient to acknowledge inventive step. This is premised on the position that using known methods to produce alternative antibodies is considered obvious for the skilled person, even though the structural features of such antibodies, i.e. their amino acid sequences, are different from and not predictable based on the known antibodies (see “Guidelines” G-II 5.6.2, also T 605/14 ‘Anti-angiopoietin-2 antibodies/MEDIMMUNE’).

A purely “structure-based inventive step” approach^{A comparison to the practice of the USPTO is not helpful in this context because it would require a more holistic comparison of the whole patenting processes by the EPO and the USPTO, e.g. on inherent disclosure and selection inventions (s.a.).} , i.e. only based on a change in structure, even a minor one, without any shown or plausible unexpected technical effect or without any contribution to the state of the art may bear the danger of leading to a certain increase of “me-too patents”. Such “me-too patents” could potentially devaluate the patent of the original invention. Whereas this may lead to an overall weakening of the underlying incentive, the patent system is conceived to support the high investments required to develop new and innovative antibodies. Therefore, each antibody claim needs to be assessed (and examined) individually and even a minor modification of a previously provided “structure” may lead to a novel and inventive “functional feature”, as also reflected in T 67/11 ‘Humanized antibodies / CENTRO DE INMUNOLOGIA MOLECULAR’, e.g. in Reason 24.

In any event, and also in the light of the new “Guidelines, the good news is that any antibody invention before the EPO can still be considered inventive if the application itself demonstrates or renders it plausible that a technical problem has been overcome by the provision of said antibody and/or that difficulties of technical nature in obtaining said antibody or difficulties in its production process have been successfully overcome.

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