Patenting monoclonal antibodies in India – evolving law and practice

As efforts continue to find an effective treatment and vaccine for covid-19, monoclonal antibodies have been at the forefront of research with reportedly more than 100 covid-19 antibody treatments at various stages of clinical trials – some designed solely to deal with secondary effects of SARS-CoV-2 (eg, inflammation), while others are designed to destroy the virus itself. Monoclonal antibodies have dominated biotechnology research in the past 25 years, and it is interesting to see how Indian patent law has responded to their protection.

What is a monoclonal antibody?

Akin to guided missiles targeting a specific foreign invader, antibodies are a part of our natural defence mechanism, produced by the immune system against foreign substances (antigens). Technological advancements have enabled bulk production of clones or synthetic copies of these antibodies (known as ‘monoclonal antibodies’), sharing the same specificity and selectivity towards a particular antigen.

Commercial production of antibodies uses a technique involving a hybridoma, produced by collecting a short-lived antibody-producing cell and fusing it with an immortal tumour cell called a ‘myeloma cell’. The hybridoma cells multiply indefinitely in the laboratory and can be used to produce a specific antibody at scale. Monoclonal antibodies are widely used in diagnostic and therapeutic applications – seven of the top 10 best-selling drugs of 2018 were monoclonal antibodies and this is the fastest growing segment of the global prescription-drug market (see Figure 1).

Given the significant time and cost involved in bringing monoclonal antibodies to market, to ensure returns for the creators (which incentivises a cycle of advancement), there should be a clear legal framework to ensure strong patent protection.

This chapter examines the nuances of antibody patenting from an Indian perspective and analyses some of the key questions faced while handling antibody patent applications before the Indian Patent Office (IPO).

Legal framework

The 2005 amendments to the Patents Act 1970 introduced the product patent regime to India which, among other things, permitted patents on antibody-based products subject to the fulfilment of other patentability criteria. An artificially synthesised, non-naturally occurring antibody constitutes patent-eligible matter and both product and process are patentable provided that they pass the triple test of novelty, inventive step and industrial application.

However, this alone is not sufficient to obtain a patent – another set of challenges awaits on account of the patentability exclusions laid down under Section 3 of the of the Patents Act:

• Section 3(c) bars patenting of naturally occurring substances;
• Section 3(d) prohibits patentability of a mere new form or new use of a known substance;
• Section 3(e) allows only synergistic compositions;
• Section 3(i) disallows methods of treatment or diagnosis, among other things; and
• Section 3(j) proscribes the patenting of animals, eukaryotic cells, hybridomas and essentially biological processes.

Follow-up inventions (eg, new medical use, method of treatment, mode of administration and dosage regimen) are not permitted in India.

The Guidelines for Examination for Biotechnology Applications 2013 fail to provide comprehensive guidance on antibody patenting.

Naturally occurring?

Section 3(c) excludes patentability of naturally occurring substances; however, the guidelines clarify that the scope of this provision is restricted only to those proteins that are ‘directly isolated from nature’.

Historically, the IPO has been granting patents on isolated monoclonal antibodies; however, a shift in practice was seen when the IPO began rejecting cases over monoclonal antibodies being naturally occurring (Cases refused by the IPO: 4718/CHENP/2007; 3702/DELNP/2010; 3327/CHENP/2010; 3349/CHENP/2005; 1161/KOLNP/2011; and 5542/CHENP/2010). Evidently, the point of contention here is that even although monoclonal antibodies are artificially produced, they are regarded as naturally occurring unless a distinction from the same is made.

Regarding the argument of human intervention involved in producing monoclonal antibodies, the IPO has taken the position that hybridoma technology is a standard method employing known techniques and merely producing a naturally occurring protein artificially does not render it patentable under Section 3(c). Shifting the burden of proof to the applicant to demonstrate that the claimed monoclonal antibody was not naturally occurring, the IPO has also disregarded arguments based on class switching and somatic mutations on account of being mechanisms inherent in the technique.

With some of these refusals being challenged before the Intellectual Property Appellate Board, it will be interesting to see how this higher authority will eventually interpret this provision.

Meanwhile, in a significant development, while dismissing four pre-grant oppositions filed by Indian parties, in a recent order of 30 June 2020, the IPO granted a patent (IN340060) to one of the best-selling monoclonal antibodies: Nivolumab (Opdivo) – the first ever anti-programmed death receptor-1 antibody approved for cancer treatment (ER Squibb & Sons LLC v Indian Pharmaceutical Alliance, 2020). The patent claimed an isolated monoclonal antibody which binds to human programmed death receptor-1, defined by the sequences (SEQ) of its six complementarity-determining regions (CDRs) in variable domain – three each on the light (VL) and heavy (VH) chains – responsible for binding to the antigen.

In line with the IPO’s general position, the opponents had asserted that isolating a naturally occurring antibody using standard or routine techniques, with no evident recombination or alteration in structure, is not tantamount to human intervention and therefore fails to qualify for patentability under Section 3(c).

The applicants had argued novelty in the specific CDRs that were not disclosed in the prior art and the substantial human intervention involved in producing such monoclonal antibodies artificially. The applicants also relied on the patents on human monoclonal antibodies, granted by the IPO itself and the grant of the US counterpart, which, following the strict ruling in Association for Molecular Pathology v Myriad Genetics (2013) and the USPTO Eligibility Guidelines for the Examination of Nature-based Products, was deemed patent eligible.

When the matter came before the controller, in notably stark contrast to the position taken by the IPO in its earlier refusals, the controller acknowledged the artificial structure of the monoclonal antibody in terms of its six CDRs and shifted the onus to the opponent to establish how the claimed antibody was naturally occurring. What also helped was the sequences being indicated as ‘artificial’ in the amended sequence listing.

The decision assumes significance in terms of the clarity that it provides to an often loosely interpreted provision in determining patentability of monoclonal antibodies under Section 3(c). It also goes on to demonstrate how scrutiny of grey areas, especially in the field of biotechnology, are the foremost way of bringing more clarity to the law and shaping Indian jurisprudence.

Broad antibody claims

Another crucial question in antibody patenting is whether broad antibody claims are allowed in India? From the practice viewpoint, the IPO invariably requires an antibody to be characterised by its structural (sequences) and technical features (function), supported by examples. However, this is often a challenge while trying to cover a broader scope especially, since an antibody, because of its very nature, can be defined – not just by its structure, but also by its source and function (see Figure 2).

Hybridoma cell lines per se are not patentable u/s 3(j), however, the IPO allows an antibody when defined by the accession number of the specific hybridoma producing it.

When it comes to defining the monoclonal antibody by its function (eg, sequence of the antigen or epitope to which it binds), such a claim is in fact broadest in scope as it provides protection over the entire genus, covering all the antibodies capable of binding to the target.

However, unlike in the United States where such claims are assessed based on the ‘doctrine of antibody exception’, there are no equivalent guidelines in India. There are also no judicial precedents and the examination is therefore largely guided by the decisions of the IPO alone. As many of the scientific and legal principles around antibody patenting remain untested in courts, there is also a lack of uniformity in the examination of antibody claims, as often different yardsticks are employed by different examiners across the four different branches of the IPO.

An analysis of IPO decisions shows that monoclonal antibodies defined only by their target (antigen or epitope) have been allowed in the past where the target was found to be novel (eg, patent number IN254039). However, in the case of a known antigen, the IPO rejected a broad antibody claim (1298/CHENP/2010) reasoning that it is routine to generate and select monoclonal antibodies that bind to such antigen, and that monoclonal antibodies should be defined by their structure instead of function alone.

In some instances, the IPO has also allowed claims directed to an antibody defined only by its function (ie, binding affinity) (patent number IN272873), although sequences here were disclosed in the specification.

In most cases however, and more uniformly in recent ones, the IPO has required restricting the scope of broad antibody claims to monoclonal antibodies defined by the six CDRs or VH/VL domains. Even though it is contended that all six CDRs are necessary to create a functional antibody, there have been instances where, based on the inventive contribution, the IPO has found it sufficient to define the antibody only by its three CDRs of VH region (patent number IN329773).

An interesting case in point is Amgen’s Evolocumab (Repatha), an antibody that reduces bad cholesterol – low-density lipoprotein – in the body by binding to the protein known as PCSK9.

In the United States, under the doctrine of antibody exception, for a long time broad antibody claims such as ‘antibody capable of binding to antigen X’ were considered to be adequately described if the specification fully characterised the antigen (‘newly characterised antigen test’).

In 2014, when Sanofi received US Food and Drug Administration approval for its biosimilar version Praluent (Alirocumab), Amgen sued Sanofi for infringement of its two patents (US 8,829,165 and US 8,859,741) where monoclonal antibodies were defined broadly by the sequences of the residues and epitope on the PCSK9 protein.

Sanofi responded by challenging the validity of the patents on the ground of lack of written description. While rejecting the well-characterised antigen test, the Federal Circuit in Amgen Inc v Sanofi (872 F.3d 1367 (Fed Cir 2017)) stated 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 the invention, (ie, the antigen). The patents were invalidated. Subsequently, the USPTO issued a memo stating that “a newly characterized antigen alone should not be considered an adequate written description”.

In Europe, a patent from the same family, which defined the monoclonal antibody by the sequence of the ‘competing antibody’, faced multiple oppositions. The Opposition Board, however, rendered its decision in 2019 maintaining the patent albeit amended, but concluding that “given that competing antibodies must have similar affinity and binding site, it has been made plausible that they will show the same activity”.

The Indian counterpart in this case proceeded to grant in 2018 with patent number IN303779. In response to the examination report, while the claims were amended in conformity with the granted European patent claims (ie, the monoclonal antibody defined by the sequence of the competing antibody), the claims were required to be restricted in scope by defining the sequences of all the six CDRs. The case underpins the IPO’s current position regardless of the scope of claims allowed in other jurisdictions. A divisional application was, however, filed here with claims of original scope and it would be interesting to see if the developments in Amgen v Sanofi will influence its fate.

In terms of scope, as a general rule, defining a monoclonal antibody by its CDRs is broader than reciting the full-length antibody sequence, as the scope of protection provided by the former allows covering variations in the framework region while keeping the CDRs constant.

Sufficiency of disclosure

In terms of the threshold for sufficiency of disclosure, while there is no single rule that applies to all, the Biotech Guidelines indicate that “claims to antibodies are unsupported if the role of the target protein in a specific disease has not been identified and proved by sufficient data”. Further, Section 10(4) and (5) of the Patents Act, requires a specification to “fully and particularly describe the invention” and claims to be “fairly based on the matter disclosed in the specification”; the Pharma Guidelines (2014) require the description to contain one or more examples, covering the full breadth of the claimed invention to show enablement.

Consequently, the IPO requires defining monoclonal antibodies by their structural-technical features, supported by one or more examples, providing a reasonable representation over the whole breadth of the claims and sequence listing. Scope may be extended to other possibilities of routine experimentation (eg, chimeric, humanised and human variants) to which data may be extrapolated.

Source and geographical origin of biological material and details of deposit are also required.

Demonstrating inventive merits

For a novel antibody, there is a two-pronged test of inventive step – there should be a technical advancement and such technical advancement should be non-obvious to a person skilled in the art on the priority date. Since, hybridoma technology is regarded as a conventional technique and humanisation of murine antibodies to chimeric or humanised forms – a process of routine experimentation – it is imperative that the claimed monoclonal antibodies are shown to have unexpected and advantageous properties through experimental data over the known antibodies. Additional post-filing data submitted in the form of an affidavit is acceptable, provided features relied on were at least plausible at the filing date. Minor modifications (eg, as small as a single point mutation) are also allowed when supported by data and strong arguments.

Overcoming Section 3(d)

A provision unique to India, Section 3(d) bars patenting a new form of a known substance, which does not result in enhancement of known efficacy, or a new property or new use of a known substance. To overcome this objection, it must be shown through comparative data that the claimed monoclonal antibodies demonstrate improved efficacy over the known monoclonal antibody. However, unlike small-molecule drugs, where Section 3(d) must be addressed only through enhancement in therapeutic efficacy, in case of monoclonal antibodies, a wider set of parameters may be relied on to counter it (eg, antagonistic/agonistic effect, inhibitory/activating activity, tissue penetration, reduced immunogenicity, higher binding affinity, low cross reactivity, better neutralising ability and reduced side effects). While dealing with this objection, one must bear in mind that Section 3(d) does not ipso facto apply to all pharmaceutical inventions and the IPO must first identify the known substance over which improvement must be shown. Also, a comparison with only the closest prior art is sufficient.

Comment

The high cost associated with developing and commercialising monoclonal antibodies requires a sound patent system; however, in the absence of clear guidelines and judicial precedents, Indian jurisprudence on antibody patenting remains at a nascent stage. Given the inconsistencies in IPO practices, the best way forward is to push back unreasonable requirements to various degrees depending on the facts and circumstances of the case, and to challenge the grey areas before the higher authorities to bring more clarity to the law.