The Indian Patent office in its latest ruling of 13th January 2015 rejected the patent application by Gilead, covering important metabolites for its blockbuster Hepatitis C drug sofosbuvir, marketed as Sovaldi, entitled, “Modified fluorinated nucleoside analogues”. The timing of decision has created a stir among legal and diplomatic circles coming close on the heels of US President Obama’s visit to India. This is likely to bring IP issues to the forefront with USTR already putting pressure on India threatening sanctions.
The application was filed in December 2005 (originally with 131 claims, later reduced to 10 claims at the time of final hearing). A request for examining the said application was filed by the applicant in May 2006, subsequent to which an examination report was issued by the office raising certain objections to the grant on 6th April, 2009. Indian patent law requires that an application should address all the objections raised in the examination report within 1 year of issuance of examination report. Hence, the last day for the application to be put in order for grant was April 06, 2010. The applicant filed their response on 18th March, 2010. Not satisfied with the response, the office issued a second set of objections 4 years later, on 07th May 2014 and offered a hearing on 24th July, 2014.
The application also faced pre grant oppositions from:
- NATCO- a generic Pharmaceutical company in India;
- non-profit organisation- Initiative for Medicines, Access & Knowledge (I-MAK); and
- the Delhi Network of Positive People (DNP+).
It is interesting to note that while the application was filed as early as 2005; the first pre grant opposition was filed in this decade long prosecution only after almost 9 years in March 2014. Again, important from a prosecution point, the instant decision is solely based on the observations of and objections raised by the patent office itself and does not consider/address the contentions of the oppositions as filed by the opponents as these oppositions were held to be infructuous with the rejection of the application.
In its 35 page decision, the Controller accepted the submissions of the applicant against the pending objections on novelty & Inventive Step (Indian equivalent of non-obviousness) after acknowledging that same set of claims have been granted in several jurisdictions which also require the invention to pass the test of novelty and non-obviousness for the grant of patent, specifically citing Patent Nos. 4958158 and 5266357 granted by Japan Patent Office and Patent Nos. 7429572 and 8415322 granted by USPTO. However, holding that the claimed invention was in fact a ‘derivative’ of a ‘known compound’ and hence subject to the requirements of section 3 (d) to prove enhanced efficacy. The controller held applicant failed to do so; the controller therefore finally rejected the application.
Section 3 (d) objection and failure to prove enhancement of known efficacy:
Section 3 (d) of the Indian Patent lists certain inventions which are not patentable:
…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.
Explanation.—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 substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy;
The examiner in the instant case held that the claimed compound is a derivative of already disclosed, ‘structurally and functionally similar compound with changes of orientation of FLUORINE in sugar moiety of the claimed compound.’ The controller while acknowledging that such variation of orientation of the groups can make the compound novel and Inventive, however, in the eyes of section 3(d) this novel and inventive substance is “considered to be the same substance, unless they differ significantly in properties with regard to efficacy”.
In response, the applicants stressed that the claimed compounds were NOT new forms of known compounds and do not fall within the ambit of Section 3(d). The applicant also submitted that the attempt by the office to define every new compound as merely a derivative of some known structural chemical core thereby barring patentability, despite the compound’s novelty and inventiveness in the unpredictable chemical arts is an improper use of 3(d). Notwithstanding the submission, the applicant also provided a comparison of the compounds of the invention vis-s-vis cited arts including various 2’-substituted nucleosides with regards to potency/activity and [low] toxicity highlighting the fact that the data presented for the biological profile of present invention which includes both the intrinsic potency against HCV and cytotoxicity, exhibits better and unexpected activity over the structurally closest compound.
The Controller Disagreed on both the submissions (the invention is NOT a new form of known substance and data is sufficient to meet enhanced efficacy requirement of 3 (d)), the controller made the following observations:
- The closest prior art is structurally close to the presently claimed compound and therefore is the same compound. Furthermore, the ‘similar compound’ and the presently claimed compound have the same use in the treatment of HCV infection and flavivirus infection, therefore the claimed compound is a derivative of the ‘similar compound’.
- “The claimed compound may have passed the test of novelty on minor changes in the molecule but to qualify section 3 (d) which this compound does not show the properties with regard to the therapeutic efficacy”.
- “In such circumstances the applicants must have shown the therapeutic efficacy data to show the significant difference in the properties with regard to efficacy by providing the clinical trials etc. The applicants showed the cytotoxcity data to prove the difference in properties which is insufficient to prove significant increase in the therapeutic efficacy”.
- The observations of the controller on determination of the claimed compound to be a derivative of a known one seem proper. The controller held that that the only difference in the present case lies in the orientation of fluoro group of compound, unlike in the case of Erlotinib and Gefitinib, where the Delhi High Court in Roche Vs Cipla held these ‘similar compounds’, to be ‘different compounds and not a derivative of the other’ as the two differed in the substitution of a methyl group with ethnyl group at the third meta position.
- The observation of Controller on cytotoxcity data is somewhat confusing. It has been acknowledged that the applicants showed the cytotoxcity data to prove the difference in properties and passed the novelty test but could not show significant increase in the therapeutic efficacy. The examiner in this case appears to have taken a strict interpretation of how to prove “enhanced efficacy” which has been held to be supported by clinical trials. It is of course debatable issue, as proving enhanced efficacy on the basis of clinical trials can be onerous for a patentee in every case and most importantly such studies are ongoing activities, results of which are not available at the time of filing of the application.
- Earlier, the Madras High Court in Novartis (Glivec) case had held that the term “enhancement of known efficacy” is not vague, and the term “efficacy” meant therapeutic efficacy. This interpretation was further affirmed by the Supreme Court and while deciding the appeal from the Novartis case. It was further clarified that whether or not increase in bioavailability leads to enhancement of therapeutic efficacy in any given case must be specially claimed and established by research data. Going by the meaning for the word “efficacy” and “therapeutic”, an applicant is expected to show how effective the new discovery made would be in healing a disease / having a good effect on the body. This means that the said new form of a drug should elicit a therapeutic effect by minimization of dose and lowered side effects. It is also important to note that an increased bioavailability may result in increased toxicity also. Hence, would a lowered toxicity (which might be a result of low absorption/low bioavailability) mean increase in therapeutic efficacy? There are decisions where the Patent office has accepted selective absorption or low toxicity as an indication of enhanced efficacy if substantiated by research data. It may therefore be said that to overcome the rejections placed under section 3 (d), one may consider providing the necessary data for proving enhanced ‘therapeutic efficacy’, which may include selective absorption at a particular site or even low toxicity as evidenced by the animal studies.
Gilead in a press note has confirmed that it would appeal the decision. The Appeal will once again test the existing interpretation of “enhancement of known efficacy” and sharpen debate on Section 3(d) of the Indian Patent Act being TRIPS compliant.