The India Patent Office in its order issued on 18th November 20161, has denied a patent for the prostate cancer drug sold under the brand name Xtandi (generic name Enzalutamide). Xtandi was developed at the University of California, Los Angeles (UCLA) (Applicant) for fighting prostate cancer which is commercially sold in India by ASTELLAS PHARMA. The drug is currently sold at Rs 3.35 lakh2 for a pack of 112 capsules normally to be taken by a patient in a month's time, accordingly, which amounts to Rs.11,000 approximately per day.

The provision of pre-grant opposition under Indian Patents Act enables any person to file notice of opposition on Form 7A at the Indian Patent Office (IPO) after the publication of an application for patent. Therefore, by way of pre-grant oppositions any person can assist the Controller of Patents in evaluating the application for patent. IPO has seen a surge of pre-grant opposition, especially in pharmaceutical applications and the said applications are scrutinized in detail because of the same. IPO is often regarded as being stringent on allowing grant of patent on drug compositions. The TRIPS agreement3 contains flexibilities that were enhanced and clarified during the 2001 Doha Declaration on TRIPS and Public Health. The said agreement states, for instance, that for pharmaceutical patents, there is a flexibility to interpret and implement TRIPS provisions in a manner supportive of the government's right to protect public health.

Coming back to the instant case of Xtandi, the pre-grant oppositions was filed by a bunch of companies, including, Fresenius Kabi Oncology (Opponent 1), BDR Pharma (Opponent 2) and Indian Pharmaceutical Alliance (Opponent 4) as well as individuals: Mr.Umesh Shah (Opponent 3) and Ms. Sheela Pawar (Opponent 5). The main grounds of opposition were lack of novelty, lack of inventive step, and that the claimed compound did not constitute an invention under Section 3(d) relating discovery of new form of known compound and with efficacy test and Section 3(e) relating to mere admixture resulting in aggregation of properties of compounds of the Patents Act, 1970.

The Application:

The present application relates to diarylhydantoin compounds including diarylthiohydantoins and methods for synthesizing them. The claimed compounds of the said application are used for the treatment of hormone refractory prostrate cancer. The application was initially filed as PCT national phase with 46 claims. In the reply to first examination repot (FER) issued by the Patent Office, the Applicant reduced the number of claims to 15 and further only 3 claims were retained pursuant to an official hearing with the Controller of Patents.

Grounds of Opposition and Prior Art relied on:

The following are the grounds and the documents relied on by the opponents:

S. No. Sections Documents Cited Comments
1 Section 25(1)(b)- Lack of Novelty US5411981 (US'981) US6087509(US'509) 2440/DEL/1996 US 5434176(US'176) US 5750553(US'553)
  • US'981 already disclosed Enzalutamide; US'509 disclosed a family of compounds phenyl, phenylimidazolidines represented by a Markush structure including the compound claimed in the present invention. US'509 also disclosed the use of compounds for anti-androgenic activity useful against tumors.
2 Section 25(1)(e)-Lack of Inventive step US5411981(US'981)
  • Obvious selection of cyano group, CF3(Trifluoromethyl), fluoro-N-Methylbenzamide (or aryl substituted with fluoro and methylcarbamoyl) groups from the generic disclosure of US'981, US'257 and US'505
  • Formation of imidazolidine ring already a known process in view of US'578
  • US'509 disclosed compounds which are similar to enzalutamide maintain the same hydantonin moiety attached to a phenyl ring further substituted by a cyano and a trifluoromethyl group.
3 Section 25(1)(f) Not an invention u/s 3(d) Not an invention u/s 3(e) US4511981(US'981)
  • US'981 disclosed compounds which are structurally similar to Enzalutamide. Therefore, enzalutamide is a derivative of the known compounds of US'981.
  • The compounds claimed in claims 3-12 of the present application is a mere admixture of the compounds Enzalutamide as claimed in claim 1 and there is no demonstrated synergy in the present application.
4 Section 25(1)(g)- Lack of clarity and Sufficiency
  • Best mode of performing the invention is not mentioned.
  • Markush structure mentioned in the specification of present application encompasses several diaryl hydantonin compounds
  • Superiority of compound RD162' is not demonstrated in the specification.
5 Section 25(1)(h)- Section 8 requirement not completed The details with respect to all the foreign applications in respect of the same/substantially same invention were not disclosed completely in accordance with the requirement of Section 8(1) and (2) of the Act.

Applicant's Arguments:

  • With regards to lack of novelty, the applicant submitted that the cited prior art documents do not disclose any diaryl compound or any other compound that is even closer to the structure of Enzalutamide.
  • With regards to lack of inventive step, the applicant submitted that citation US'981 does not talk about methylcarbamyl group and that US'981 suggests acetamido group which is different than the methylcarbamoyl group. The Applicant further submitted that the compounds disclosed or taught under the cited documents are structurally dissimilar and have dissimilar modes of action and therefore the said documents fail to guide the person skilled in the art to perform the present invention as envisaged in the present patent application.
  • With regard to Section 3(d), the Applicant submitted that Enzalutamide the claimed compound is a New Chemical Entity (NCE) and the same is not a salt, ester, ether, polymorph, derivative, etc. of a known substance. Therefore, Enzalutamide cannot be regarded as the known substance under Section 3(d).
  • With regard to Section 3(e), the Applicant submitted that the revised claims disclose a novel diaryl thiohydathoin compound, Enzalutamide, a new chemical entity and therefore the combinations of Enzalutamide would be new and inventive which cannot be considered as an aggregation of the known properties of the components.
  • In response to ground of lack of clarity and sufficiency as per Section 25(1)(g), the Applicant submitted that the present invention is sufficiently disclosed to the fullest extent with sufficient working examples, synthetic schemes and test procedures to determine the biological activity of the disclosed compounds.

RD162 is specifically disclosed as Example 56 in the complete specification. In response to ground of non-compliance with Section 8, the Applicant submitted that, the information related to the corresponding foreign patent applications has been submitted to the Learned Controller at regular intervals, therefore the Applicant pleaded to dismiss the aforesaid ground of opposition.

Section 25(1)(b)

The Controller observed that none of the documents cited by the Opponents specifically disclosed the structure of the compound as claimed in the present application either by the way of claim or as an example. The claimed compound can only be arrived by suitable substitutions of different R group and X,Y,A,B etc. The Controller further pointed that to arrive at the structure of Enzalutamide, a person has to pick some suitable substituents from the definition given in markush structure as given in prior art and hence picking and putting is not allowable in ascertaining the novelty of the claimed invention. Therefore, the Controller dismissed the ground, reasoning that the claimed compound is novel and not anticipated in view of the cited prior art documents.

Section 25(1)(e)

The Controller observed that US'981 clearly mentioned that even moderately sized groups are not favored at ortho and meta position of the aryl ring. That leads to the only option is halogens out of the disclosure given in US'981 at this position. The Controller further mentioned that the applicant has failed to show in their application that fluoro substitution has any effect on the activity and there is no difference in activity of RD153 and compound that doesn't have fluoro substitution at this position and Enzalutamide. Also, the fluoro-N-Methylbenzamide moiety is clearly in the prior art US'257. Further, the formation of imidazolidine ring was already known in the art in view of US'578. Hence, the Controller stated that the claimed invention lacked inventive step in vide of US'981 in combination with US'257 and US'578.

Section 25(1)(f)

As the claimed compound Enzalutamide lacks novelty and inventive step due to the aforementioned reasons, the applicant's claim that the compound is a new chemical entity was denied by the Controller. Further the applicant failed to demonstrate an improvement in efficacy thereby making the claim unpatentable under section 3(d) of the Act.

The Controller further stated that the applicant in the present invention failed to show any synergistic effect when the compound Enzalutamide is used as a composition. Hence, the Controller accepted the opponent's objection to the application under to Section 3(e) of the Act.

Section 25(1)(g)

The Controller refused the ground of opposition for lack of sufficiency as the specification fully and sufficiently describes the claimed invention. Enzalutamide (RD 162') is specifically disclosed as Example 56 in the complete specification and its process for preparation is also disclosed.

Section 25(1)(h)

The Controller stated that the requirement of Section 8(1) and 8(2) was complied on different dates by filing the information regarding corresponding applications in other jurisdictions. Therefore, in view of the aforestated, the Controller dismissed the ground stated under section 8.


The Controller in his decision, refused to grant patent over Xtandi, as the claimed invention lacked inventive step under Section 2(1)(ja) and is not patentable as the claims falls under Section 3(d) and 3(e) of the Act.





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