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.

File History

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:

  1. 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’.
  2. “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”.
  3. “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”.

Our comment

  1. 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.
  2. 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.
  3. 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.