INTRODUCTION

With advancement and growth of medical science, we are witnessing a gradual shift toward biologic based drugs. To encourage development in the field a lot of patents have been granted to antibodies across various jurisdictions. However, the significant increase in the number of patent applications being filed for antibodies has led to stricter criteria for patentability of antibodies as well as restrictions being imposed on the scope of claims.

Antibodies, also called immunoglobulin (Ig), are protein complexes. They are produced by our immune system whenever it detects presence of any antigen (foreign material or pathogen). Antibodies are capable of binding with corresponding antigens with high specificity. An antigen has an antigenic determinant called an epitope, which is recognized by a region called a paratope on an antibody.

A patent may be granted to an antibody based on several factors depending upon the allowable subject matter and patentability criteria of a particular jurisdiction. A patent granted may refer 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. The standard for determining the patentability of an antibody is similar to the standard used for chemical compounds. However, a set standard does not mean that one-size-fits-all approach is applicable to patent applications for antibodies owing to the very nature of antibodies. Different jurisdictions have evolved different criteria to ascertain patentability of an antibody.

PATENTING ANTIBODIES IN INDIA AND ABROAD

There are several ways in which an antibody can be defined depending upon the factor being relied upon for such definition. 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. An antibody may also be defined with reference to its use in certain jurisdictions.  Some of the ways in which an antibody can be defined are enlisted below:

  • 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 of 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.

It must be noted that an antibody can be defined with reference to its target only when the target (antigen or epitope) is new. This is because such claims seek an extensive protection encompassing all the possible antibodies which are capable of binding the target. Such applications, therefore, are meticulously examined.

Approach in Europe: The European Patent Office (EPO) mandates that an application must contain detailed information necessary for identification of the epitope and must also provide criteria for assessment binding to it. Any novel or inventive feature of an antibody, attributed to it owing to its ability to bind to a specific epitope, must also be elaborated upon in the application. Further, evidence must also be produced to show that no prior antibodies are capable of binding with the same epitope. The complete specification should be such that it must be enough to enable an individual, who has the necessary skills, to produce antibodies binding to the epitope. The EPO may also cause the evidence to be furnished so as to establish that all antibodies binding to the particular epitope are expected to show the resulting properties.

Approach in the USA: Until a few years back, ‘newly characterised antigen test’ was used in the USA. According to this test, a claim with respect to an antibody capable of binding with an antigen must contain sufficient support in a written description that disclosed fully characterized antigens. The test was rejected in the case of Amgen Inc. vs. Sanofi by the Federal Circuit observing that test was not in line with the basic legal principles of the written description requirement as it permitted the patentees to claim antibodies by describing something that is not in the invention, i.e., the antigen. In furtherance of the decision of the court, the United States Patent and Trademark Office (the ‘USPTO’) issued a clarifying memo stating 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.”

PATENTABILITY IN INDIA

In order to understand the Indian position with regard to patentability of antibodies, rulings of Controllers of the Indian Patent Office (IPO) need to be looked into. An analysis of decisions reveals that the IPO has been inconsistent with its approach when it comes to patent applications related to antibodies.  

The stance of IPO can be better understood by looking at some of the applications examined by the Controllers. Some of the applications assessed by the IPO are:

2880/DEL/2011- A claim was filed with reference 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”. The said application was rejected by the Controller on the ground that the claim covered any antibody specific for rEA1-C, however, the description did not disclose any such antibody. The description of the antibody was not based on its structural and technical features.

1298/CHENP/2010- The IPO rejected an application which defined an antibody with reference the amino acid sequence and the medical condition it treated. The Controller observed that once an antigen is known the production of monoclonal and polyclonal antibodies specific for that antigen is a routine procedure and it noted that the definition of the antibody in the application was not based on its technical and structural features.

Section 3 (c) explicitly provides for exclusion of ‘naturally occurring substances’ from patentability. Monoclonal antibodies are produced by hybridoma technologies and technically speaking, are not products of nature. Further, it must be noted that in case of monoclonal antibodies it must not only be proved that the claimed bodies are structurally different but also that they have an improved efficacy.

3327/CHENP/2010- The said case involved rejection of a claim related to an isolated monoclonal antibody on the ground that it was produced by standard methods and known techniques. While defending the application, the applicants raised arguments regarding class switching and somatic mutation, however, the same were disregarded by the Controller. Controller noted that no evidence was produced to establish that there was any change in the process which made the product distinct from other known products, in terms of its properties. It was observed that all the sequences were of natural origin.

3349/CHENP/2005- Here also, the Controller rejected the claim for lack of a definition with regard to technical/structural features of the antibody and inability to distinguish the antibody in question from a naturally occurring antibody as the claim failed to portray any alteration or recombination in the structure of the antibody. The Applicant argued that claimed antibodies are not naturally occurring as antibodies to naturally occurring proteins such as MASP-2 do not exist due to immune tolerance to self-antigens. The said argument was rejected for lack of corroborative evidence. The Controller also noted that in case of a naturally occurring protein, it is always presumed that there will be an antibody against that protein when it will come in contact with immune system. Mere production of naturally occurring protein artificially, will not make its antibodies patentable by overcoming section 3(c).

1161/KOLNP/2011- While examining the claim, the Controller rejected the argument that isolated human monoclonal antibody was not naturally occurring as it was produced by human intervention by recombinant DNA technology.

3411/DELNP/2006 and 6845/CHENP/2010- In both these cases, the claims were rejected as they defined antibodies only with reference to antigens of a specific sequence, which they targeted.

However, there are certain cases wherein claims were allowed which defined an antibody only in terms of the antigen or epitope it binds to or the functional features of the antibodies.

2581/KOLNP/2006- A claim which defined antibody as “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 by the Controller on the ground that the epitope mentioned herein was novel.

4482/CHENP/2010- “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.” The dependent claims and description defined the antibody in terms of amino acid. However, in the said case, the independent claim did not define the antibody in terms of amino acid and yet the same was allowed.

3045/DELNP/2011- A claim which defined an antibody with reference to a novel antigen was allowed.

In most of the cases, the IPO has directed that the antibody be defined by structural and technical features. The claims which define antibodies with reference to their functional features, by target or cell line have been mostly objected to as they fail to distinguish an antibody from a naturally occurring substance and encompass a vast genus of antibodies. Thus, as can be observed from the abovesaid decisions, any claim must contain the amino acid sequence of the antibody and such sequence must be distinct from any naturally occurring substance and known antibodies so as to be in consonance with Section 3 (c) of the Act.