Patenting 'Second Medical Use' Inventions in India - Saipriya Balasubramanian - Zacco
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Patenting ’Second Medical Use’ Inventions in India – Saipriya Balasubramanian

It is rarely simple to patent ‘second medical uses’ and patent offices across the globe, understandably, have additional requirements that must be fulfilled prior to receiving a new grant

Introduction It is indeed fascinating to know that new uses, abilities or medical applications can be identified from  known compounds and compositions. Often these can be protected through patents but it is not always possible to protect additional medical uses of a known substance in all  jurisdictions. For example, in India, a new use for a known substance always falls outside the purview of patent protection for the prime reason that the discovery of new properties, from known substances, are not considered ‘inventive’. The protection of second or further uses are  also dependent on what is disclosed to the public when compared with  prior art. However, there is a glimmer of hope for applicants looking to patent new uses for existing medicines in India, provided that the compositions are claimed as synergistic combinations and supported by the disclosure of data in their specification. Knowing how protection for new medical uses of known substances or  second medical uses can be pursued in India, as well as how to draft effective claim forms that are more likely to be accepted, will better equip applicants to develop claims in an application and increase the chances of a successful grant.

Section 3 of the Indian Patents Act, 1970 defines “What are not Inventions?” and section 3(d) and 3(e) specifically govern the protection of second medical uses.

Section 3(d)[1] of Indian Patents Act, 1970 and its implication on second medical use

Section 3(d) in The Patents Act, 1970- reads “the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.”

For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substances shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.

Apart from adhering to current criteria, including novelty, inventive step and industrial applicability, an invention has to clear the patent eligibility test based on its efficacy. According to Section 3(d), patent eligibility for a new use, or new form, of known compounds and compositions will be denied, unless such compounds/compositions contribute to higher therapeutic efficacy over the previous form. Derivatives of existing substances are considered to be identical to the existing substance, except for where a significant difference in properties results in a corresponding difference in efficacy.

Section 3(e)[2] of Indian Patents Act, 1970 and Synergy

Section 3(e) in The Patents Act, 1970- reads a substance obtained by a mere admixture resulting only in the aggregation of the properties of the components thereof or a process for producing such substance”.

According to the IPO Guidelines for Examination of Patent Applications in the field of Pharmaceuticals[3] (October 2014),  “if the functional interaction between the features achieves a combined technical effect which is greater than the sum of the technical effects of the individual features, it indicates that such a composition is more than a mere aggregation of the features”.

In this context, ‘synergy’ means a surprising effect/outcome of the combinations, prior art prejudice etc, which usually demonstrates the non-obvious nature of the invention. In chemical composition claims, Synergy refers to therapeutic activity such as, for example, compound ’A‘ in claimed range, with pharmaceutically acceptable excipients in claimed range, provides therapeutic activity.

To demonstrate the synergistic effect of compositions, it is important to present experimental data. The experimental data can be provided at the time of filing the complete specification, or as a reply to an objection raised by the Controller during prosecution of the application. However, such experimental data has to be sufficiently supported by the specification filed. Care has to be taken that no new data should be submitted that falls outside of the scope of contents for the specification disclosed.

Relationship between Second medical use and Synergy

For an applicant, filing an invention related to a second medical use of known substances will inevitably encounter objections under Section 3(d). The easiest way to avoid a section 3(d) objection is to include an argument that the subject application is not relevant to section 3(d), instead relating  to section 3(e) as it pertains to a combination/composition of known substances.

A common strategy adopted by applicants of pharmaceutical inventions has been to draft a formulation/composition/combination claim to move the application away from the scrutiny of section 3(d). In such cases, when the overall effect of the combination claim produces an unpredictable change from the individual derivatives’ functions, the result is termed ‘synergistic’. Hence, synergism is the combining of known derivatives to produce unique results.

Types of Second Medical Use Claims

As per European Patent Convention (EPC) Guidelines, Article 54 (4) and 54(5) provide  an exception to the general principle that product claims can only be obtained for novel products. Article 54(5)[4] forms the basis for  second and further medical uses,  stating that “Where a substance or composition is already known to have been used in a ’first medical use’, it may still be patentable under Art. 54(5) for any second or further use in a method provided that said use is novel and inventive.

S.No Type Relevant provision of EPC Relevant Indian Provision
1 Purpose-limited process claims (Swiss type claims)   Form- Use of substance X for the manufacture of medicament for the treatment of disease Y Article 54(4) and Article 54(5) Such claim formats are not accepted in India, under Section 3(i), being treated as a method of treatment for the human body.
2 Purpose-limited product claims   Form- Substance X for use in the treatment of disease Y Article 54(4) and Article 54(5) Such claim formats are objected to in India, under Section 3(d,) which clearly excludes new uses of known substances from patentability.

Categories of Second Medical use Claims

  1. Formulation/composition: This category covers a new formulation of a known compound. If the new formulation uses new ingredients then it can be filed as a primary patent claim. If different combinations of known ingredients are used, they are usually subject matter for second medical use claims. Most of the formulations are administered wherein the active pharmaceutical ingredient is present along with excipients. Such formulations pertain to specific dosage regimen, mode of administration (tablets, suspension, intra-venous) and compositions that are designed for timed or sustained release.

Therefore, if a combination results in improved efficacy, lower toxicity, improved bioavailability, less adverse side effects, requirement of lesser doses of the APIs, etc., then such effects can be declared to be ‘synergistic’ and result in more than the additive effect.

For instance, the First Examination Report (FER) for the application 2668/DEL/2015 was issued on 20/07/2018 on the grounds of lack of novelty, inventive step, and section 3(e). The subject matter of the application is related to a herbicidal composition, comprising of aryloxyphenoxypropionic ester, acetoacetate synthase (ALS) inhibitors and additives blended to a certain ratio. The inventive herbicidal composition exhibited higher weed control efficiency when compared to solo formulation. The proposed invention also lowered the recommended dosage of individual herbicides achieving a higher yield. The court upheld that, within a composition, if the functional interaction between the features achieves a combined technical effect greater than the combined technical effects of the individual features, this indicates that the composition is more than a mere aggregation of the features. They held that the complete specification of the impugned application exhibits synergistic effect, which is sufficient to overcome a section 3(e) objection.

  1. Combinations: This category covers combinations that contain more than one single active ingredient and the claims are related to combinations of drugs. For example, in application number 2343/KOLNP/2010, a patent was granted for a “drug delivery system for administration of a water soluble cationic and amphiphilic pharmaceutically active substance” as the Controller found the invention to be a novel and inventive combination of drugs that demonstrated synergy, to overcome the section 3(e) objection.
  2. Physical Variant: This category covers claims related to a Polymorphic variant of previously known chemical compounds such as crystal, amorphous powder having a definite particle size. For example, in Indian patent application 106/DELNP/2008, titled “POLYMORPHIC FORMS OF RIFAMIXIN, PROCESS FOR THEIR PRODUCTION AND USE THEREOF IN MEDICINAL PREPARATIONS”, the IPO granted a patent for the polymorph of a known compound, notwithstanding objections u/s. 3(d) of the Patents Act, 1970. The judgement was based on the reason that the enhancement in efficacy was due to the fact that the polymorph had an in vivo absorption level about 100 times lower than the original form, resulting in a corresponding reduction toxicity.
  3. Isomers/Enantiomers: This category covers drugs with the same chemical formula, but different structural configurations. A specific isomeric or enantiomeric form should have improved physical or chemical properties compared to the original drug, and a patent is usually sought for a mixture of such variants.

For example, Indian patent application 991/MUMNP/2003 (‘991 application) entitled “Chiral Salt Resolution” describes methods for effecting chiral salt resolution from racemic mixtures of enantiomers, particularly precursor enantiomers, for use in making pyrrolo[2,3-d]pyrimidine compounds. The pyrrolo[2,3-d]pyrimidine compounds are inhibitors of protein kinases, such as the enzyme Janus Kinase 3 (JAK3).

The specification of ‘991 application describes the enantiomer, 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile, also known as tofacitinib. In this example, tofacitinib was an enantiomer of the previously published compound D1. The IPO alleged that ‘991 application did not include any study data showing an efficacy improvement of tofacitinib over D1. The provisions of section 3(d) stood as a strong barrier in the absence of any experimental data backing the efficacy argument and  the Controller rejected the 991 application. Hoping to overturn the rejection by  the IPO, the Applicant filed an appeal at the erstwhile Intellectual Property Appellate Board (IPAB) who upheld the patent in order OA/2/2016/PT/MUM/3482. It was held that even after acknowledging the affidavits submitted by the Applicant, the IPO had erred in their opinion that the Appellants (the Applicant) did not provide data comparing the compound in the application and the compound in example 14 of WO0142246. Tofacitinib, clearly had a significantly higher potency, between four to six times greater, which is biologically and statistically meaningful in terms of the ability of the compound to bring out the desired therapeutic effect. This was acknowledged and led to grant of IN352215.

  1. Prodrugs: This category covers prodrugs (inactive compounds), which are metabolized in the body and produce an active ingredient. For instance, IN201617016278, titled “Novel Prodrug salts” proceeded to grant for objection under “Invention u/s 2(1)(j)”. The applicant’s submission was found to be satisfactory in light of the submission and accompanying data provided, as none of the cited prior art documents D1and D2, independently or in combination, disclosed the claimed compounds and process of preparation thereof. The applicant had successfully established absence of any suggestion/teaching in prior art that would make a person with the relevant skills pick the -CH2CH2-trimethylsilyl protecting group in order to remove the contaminant, in this case the dechlorinated product in the claimed process.
  2. Salts: Salt form of drugs are synthesised to achieve various advantages, such as improved stability and bioavailability. Converting a drug into a salt by manipulating its chemical stability renders the complex easier to administer, and allows manipulation of the agent’s pharmacokinetic profile. In 1960/DELNP/2007, titled “THERMODYNAMICALLY STABLE FORM OF A TOSYLATE SALT”, the Controller opined that polymorphic forms of 4-{4-[({[4-chloro-3-trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl pyridine-2- carboxamide also known as Sorafenib, as claimed, was not supported by any examples or data detailing enhanced efficacy over that of known substances. This included the metastable form and the process of preparation of polymorph-I, neither involving any new reactant nor resulting in any new product. The claims that covered pharmaceutical compositions involving polymorph-I, were not backed by any data or examples showing unexpected/synergistic effects. The application was refused on the grounds of lack of inventive step (Section 2(1)(ja)), Section 3(d),Section 3(e) and Section 25(1)(h) of the Patents Act, 1970.
  3. Use and Method of Treatment: Newly discovered use claims for known compounds. Claims reciting ‘use’, ‘method of treatment’ claims and ‘Swiss-type’ claims are not allowed in India under Section 2(1)(j) of the Act, since this section only allows for product claims or process claims. Method of treatment claims provide protection for the manner of administering particular drugs to individuals/patients for the purpose of treating diseases. For example, Application number 1974/MUMNP/2011 proceeded to grant when the originally filed claim “Diagnostic method for the identification of a subject suffering from a primary non-infectious disease…” was amended to “An in vitro method for the identification of a subject suffering from a primary non-infectious disease…”.

Conclusion

Though the Indian legal system is governed by blanket provisions for patentability exclusion of second medical uses, this article intends to provide insight into how drafting of second medical use claims have gradually found their way into the Indian jurisdiction. Second medical use patents are very valuable, considering the technical and commercial contribution they offer to society. In practical terms, second medical use patent applications  often encounter a  ’lack of novelty’ objection in light of prior art and,  in such cases, it is important to highlight the technical advantage achieved with such products when introduced to a new environment or process. While India is a strong proponent of ‘anti-ever greening’ of patents, it is open to grant for inventions of second use through synergistic effect. This is however, only if the application is adequately supported by experimental and comparative data that demonstrates the technical effect of the claimed composition to be greater than the aggregation of individual ingredients.

[1] https://ipindia.gov.in/writereaddata/Portal/IPOAct/1_31_1_patent-act-1970-11march2015.pdf

[2] https://ipindia.gov.in/writereaddata/Portal/IPOAct/1_31_1_patent-act-1970-11march2015.pdf

[3] https://ipindia.gov.in/writereaddata/Portal/IPOGuidelinesManuals/1_37_1_3-guidelines-for-examination-of-patent-applications-pharmaceutical.pdf

[4] https://www.epo.org/law-practice/legal-texts/html/guidelines/e/g_vi_7_1.htm