Over the years, a large number of patents have been granted for antibodies all over the world. The world is also seeing a shift towards biologic based drugs. Most of the top-selling drugs in 2018 were monoclonal antibodies with HUMIRA® leading the list. With the progress in the art and growing case law in this area, the criteria for patentability of antibodies are becoming increasingly strict, with restrictions on the scope of the claims.

What are antibodies?

Antibodies, also known as immunoglobulins (Ig), are protein complexes produced by the immune system in response to the presence of an antigen, for example, a foreign particle or a pathogen. Antibodies are capable of binding with corresponding antigens with high specificity. An antigen has an antigenic determinant called epitope, which is recognized by a region called paratope on an antibody.

Polyclonal antibodies are a collection of many different antibodies, each generated from different B-cell clones or lineages. The polyclonal antibodies are secreted in the presence of an antigen and different antibodies in the collection interact with different epitopes on the same antigen.

A monoclonal antibody represents an antibody from a single antibody-producing B cell and only binds with one unique epitope. Technically, each individual antibody in a polyclonal antibody mixture is a monoclonal antibody. However, this term generally refers to antibodies produced using hybridoma cell lines.

Due to their specificity and selectivity antibodies are widely used in diagnostic and therapeutic applications.

Patenting antibodies: In India and abroad

The patents for antibodies may relate to the antibody itself, compositions containing one or more antibodies, methods of generating the antibody, therapeutic or diagnostic methods involving the use to the antibody and/or second medical use of the antibody, depending on the allowable subject matter and patentability criteria of a particular jurisdiction. Being protein complexes, patentability of antibodies is judged by a standard similar for patentability of a chemical compound. However, due to the very nature of antibodies, one cannot assume a one-size-fits-all approach to patent applications covering antibodies. The criteria can be very different in different jurisdictions. 

There are several ways of defining an antibody. An antibody, in general, can be defined by its structural features i.e. the amino acid sequences of Complementarity Determining Region(s) {CDR(s)} and framework regions or by its functional features, for example, the antigen or the epitope it binds to. It may also be defined by the hybridoma cell line used for its generation. In jurisdictions where it is allowed, an antibody may also be defined by its use. The table below provides examples for defining an antibody in a claim:

Reference to Example
Antigen A monoclonal antibody or an antibody fragment containing an antigen-binding region thereof that binds to XYZ protein on a plasmacytoid dendritic cell.
Epitope An antibody, characterized in that it binds to an epitope comprising a sequence set forth in SEQ ID NO: 1.
Amino acid sequence An antibody comprising a heavy chain comprising a variable domain that comprises the sequence given in SEQ ID NO:9; and a light chain comprising a variable domain that comprises the sequence given in SEQ ID NO:7.
Hybridoma A monoclonal antibody produced by the hybridoma cell line deposited under ATCC Accession No. HZ 8092 and clones thereof.
Use or application An antibody that binds selectively to XYZ and kills leukemic stem cells for use in a method of treatment of a human patient having leukemia.

The claims directed to antibodies defined only by their target i.e. an antigen or an epitope are allowed in cases where the antigen or the epitope are new. Such claims provide very broad protection covering all possible antibodies capable of binding the target. Therefore, they are scrutinized heavily. For example, the European Patent Office (the 'EPO') now requires detailed information about the identification of the epitope, and how binding to it is to be assessed. The EPO may also require detailed information regarding any novel and inventive features of an antibody that are claimed by virtue of its binding to a specific epitope. One is also required to submit evidence that prior art antibodies do not bind to the same epitope. The complete specification should clearly define the epitope, and the specification should also enable a person skilled in the art to produce antibodies binding to the epitope. The EPO may also require evidence to establish that it is at least plausible that all antibodies binding to the particular epitope can be expected to share the resulting properties.

In the United States, until recently, the position was that a claim directed to an "antibody capable of binding to antigen X" would have sufficient support in a written description that disclosed fully characterized antigens. This was called 'newly characterized antigen test'. In a recent Federal Circuit decision in Amgen Inc.v. Sanofi (872 F.3d 1367 (Fed. Cir. 2017), the court rejected this test stating that the test flouted basic legal principles of the written description requirement because it allowed patentees to claim antibodies by describing something that is not in the invention, i.e., the antigen." Subsequently, the United States Patent and Trademark Office (the 'USPTO') issued a memo clarifying its guidance concerning the written description requirement for claims directed to antibodies. Taking note of the decision, the memorandum stated that "in view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered an adequate written description of a claimed antibody to that newly characterized antigen, even when the preparation of such an antibody is routine and conventional." 

Unlike other jurisdictions, therapeutic and diagnostic methods that are performed on the body or result in the identification of a medical condition are specifically excluded from patentability in India. Further, use or second medical use is also not considered patentable in India. One can, however, patent an antibody if it fulfils the patentability requirement and does not fall under any of the exceptions laid down in the Patents Act, 1970 (the Act). Thus, the claimed antibody-like any other invention to be patented must be novel, inventive and useful. Additionally, the claimed antibody must be structurally and functionally different from an antibody occurring in nature. If a new form of an existing antibody is claimed, it must also exhibit improved efficacy compared to the existing antibody. Any structural difference with respect to the naturally occurring antibodies must confer some unexpected advantage or surprising effect on the claimed antibody. The synergistic compositions of antibodies are also patentable. 

The case precedent around the patentability of antibodies in India is found in decisions of the Controllers of the Indian Patent Office (IPO). An analysis of Indian patents covering antibodies and Controller's decisions suggests that the IPO has been inconsistent when it comes to examining patent applications covering antibodies. 

In most cases, Controllers appear to require that the claimed antibody be defined by structural and technical features. The claims defining of the antibody only by functional feature(s), by the target or cell line are often objected to. The reasoning for rejection is that such claims make the claimed antibody indistinguishable from naturally occurring products and encompass a vast genus of antibodies. Therefore, the claim directed to an antibody must recite the amino acid sequence of the antibody. Further, the claimed sequence must be structurally different from any naturally occurring or other known antibodies to be consistent with the requirement of section 3(c). The list below gives examples of some of the Indian applications for antibodies examined by the IPO.

In 2880/DEL/2011, a claim directed to "A monoclonal antibody specific for C-terminal region of recombinant Extractable Antigen-1 (rEA1-C) of Bacillus anthracis having a hypothetical amino acid sequence Seq ID No: 1, wherein the monoclonal antibody does not show any cross-reactivity with other strains of Bacillus" was rejected. The Controller reasoned that the claim covered any antibody specific for rEA1-C. The description failed to disclose any such antibody. The antibody was not described in terms of structural and technical features anywhere in the description.

In 1298/CHENP/2010, a claim directed to antibody defined in terms of the amino acid sequence it recognized and medical condition it treated was rejected. The Controller while rejecting the claim stated that the claimed antibody was not defined in terms of its technical/structural features. The Controller also stated that once an antigen is known the production of monoclonal and polyclonal antibodies specific for that antigen is a routine procedure.

As mentioned above, section 3(c) expressly excludes 'naturally occurring substances' from patentability. However, technically monoclonal antibodies produced by hybridoma technologies are not a product of nature. However, in the case of monoclonal antibodies as well it is required that the claimed antibody is not only structurally different but also exhibit improved efficacy. In 3327/CHENP/2010 the Controller rejected a claim for an isolated monoclonal antibody. The Controller reasoned that the claimed antibodies were produced by standard methods and known techniques. The applicant's argument regarding the class switching and somatic mutation was not accepted since they were considered inherent in hybridoma technology. According to the Controller, no technical evidence was provided by the applicant to show that there was any modification in the process that resulted in a product distinct with regard to its properties from the products known in the art. Further, the Controller noted that all the sequences were of natural origin.

In 3349/CHENP/2005, too, the Controller held a claim for an antibody to be indefinitive as the antibody was not defined in terms of structural/technical features. The Controller stated that the claimed antibody could not be distinguished from a naturally occurring antibody as the claim did not recite any particular recombination or alteration in the structure of the antibody. The Controller rejected the applicant's argument that the "claimed antibodies are not known products existing in nature"as "in humans, antibodies to a naturally occurring protein such as MASP-2 do not exist due to immune tolerance to self-antigens" and "moreover, antibodies against human MASP-2 do not naturally exist in non-human mammalian subjects". The Controller reasoned that the argument was not corroborated with any evidence. The Controller further stated that when there is a naturally existing protein then it is presumed that there will be an existence of an antibody against that protein when that protein comes into contact with any of the immune system.On the argument that the antibodies are produced by a human intervention, the Controller stated that merely producing a naturally occurring protein artificially cannot make them patentable under section 3(c). Similarly, in 1161/KOLNP/2011 also the Controller rejected the argument that the claimed isolated human monoclonal antibody was not naturally occurring as it was produced by human intervention by recombinant DNA technology.

In 3411/DELNP/2006 and 6845/CHENP/2010 also claimed antibodies defined only by the antigen of a specific sequence it targeted was rejected.

However, there are examples of Indian patent where the Controllers have allowed claims directed to an antibody that has only been defined in terms of the antigen or epitope it binds or the functional features of the antibodies. For example, in 2581/KOLNP/2006, a claim directed to "An anti-myostatin monoclonal antibody or a functional fragment thereof that specifically binds a polypeptide consisting of amino acids 40-64 of a mature form of human myostatin (SEQ ID NO: 46) ........." was allowed. The epitope mentioned here was found to be novel. In 4482/CHENP/2010, a claim directed to "A recombinant human monoclonal antibody, or antigen binding portion thereof, that specifically binds to C. difficile toxin B (toxin B), wherein the antibody, or antigen binding portion thereof, specifically binds to toxin B with a KD of less than 20 x 10-6 M was allowed. Although the claimed antibody was defined by amino acid sequences in the detailed description and dependent claims, the independent claim did not recite the sequences of the antibody. In 3045/DELNP/2011, the Controller allowed a claim for an antibody that was defined only by a novel antigen.  

Practice guidance

The various decisions of the IPO offer some indication around the patentability of antibodies and provide some guidance for structuring claims and patent applications around antibodies.

Although a new amino acid sequence will fulfil the requirement of novelty, one is required to demonstrate the unexpected/surprising effect or advantage to fulfil the requirement of inventive step. Thus, one must show that the antibody under consideration has some functional characteristic(s), which could not reasonably have been predicted from the prior art. Also, if the claimed antibody is a new form or version of a known antibody, one is required to show that the claimed antibody exhibits improved efficacy vis-à-vis the known antibody to avoid rejection under section 3(d) of the Act. If a murine antibody was already known, then a claim to a humanized antibody would not be automatically inventive because it is now considered to be routine to prepare a humanized antibody. One has to show that such an antibody is not only inventive but also exhibits improved efficacy. Examples of an antibody fulfilling the inventive step requirement are an antibody having unexpected, advantageous properties such as higher binding affinity; an unexpected antagonistic or agonistic effect; low cross-reactivity.

The complete specification must include sufficient experimental data for at least one exemplary antibody that indicates that the claimed antibody binds to its target and is inventive. The IPO accepts additional supplementary data filed later as evidence of the feature(s) of the claimed antibody under certain circumstances. It is important that the feature(s) relied upon were at least plausible at the filing date in order for it to be taken in to account when assessing inventive step. To fulfil the requirement under section 3(d), one is required to submit comparative data showing that the claimed antibody is more efficacious compared to the corresponding known antibody. The IPO usually accepts additional comparative data submitted during prosecution to overcome the objection under Section 3(d). The compositions of antibodies are only patentable if they exhibit synergism. Therefore, experimental data showing synergism must be submitted to fulfil the requirement of inventive step and section 3(e) of the Act.

As can be seen above, the IPO requires that the claimed antibody is defined in terms of structural and technical features. Therefore, even if the antigen is new it is recommended that the sequences of the antibody are submitted.

The Act also requires that the source and geographical location of all the biological material used in the invention are indicated in the specification. The specification can be amended to include this information during the prosecution as well.

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.