Patent Evergreening- Not so green after all!

The article provides a play-by-play of events that led to the Indian Patent Office vide refusing a patent grant on an anti-Tuberculosis (TB) drug, Bedaquiline.
 SS Rana & Co - Renu Bala Rampal , Soujanya Sikha
SS Rana & Co - Renu Bala Rampal , Soujanya Sikha

The Indian Patent Office vide order of the Controller dated March 23, 2023, refused a patent grant to the application no: 1220/MUMNP/2009 titled “Fumerate Salt of (Alpha S, Beta R) -6-BROMO-ALPHA-[2-(DIMETHYLAMINO)-ETHYL]-2-METHOXY-ALPHA-1-NAPHTHALENYL-BETA-PHENYL-3-QUINOLINEETHANOL” [the salt of TMC 207] which is also known as Bedaquiline.

The significance of this order is that it will prevent extending the monopoly of the applicant on the anti-Tuberculosis (TB) drug Bedaquiline as the applicant was already awarded the Indian Patent Number: 236811 for a similar compound on November 23, 2009. This will allow generic companies to launch their products containing Bedaquiline as the patent is scheduled to expire on July 18, 2023. The use of Bedaquiline is generally found to be highly effective when the normal treatment plan for TB fails.

The applicant is a Belgian company called JANSSEN PHARMACEUTICAL N.V. which is part of Johnson and Johnson Pharmaceutical Research and Development.

There were a total of five claims in the amended application. The principal claim of the application mentions “a solid pharmaceutical composition comprising of a pharmaceutically acceptable carrier and as active ingredient, a therapeutically effective amount of the fumarate salt of (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-betaphenyl-3-quinollineethanol and as a wetting agent, a polyethylene glycol sorbitan fatty acid ester, wherein the composition comprises by weight based on the total weight of the composition:

(a) from 5 to 50% of active ingredient;

(b) from 0.01 to 5% of said wetting agent;

(c) from 40 to 92% of a diluent; and

(d) from 0.1 to 5% of a glidant.

The timeline of events leading to the Controller’s decision can be traced as follows:

  • A PCT national phase application (PCT /EP 2007/063186) was filed by the applicant on June 29, 2009 for Bedaquiline. The application number assigned was 1220/MUMNP/2009 (the application hereon).

  • A request for examination was filed by the applicant on April 23, 2010 as per the provisions of section 11-B of the Indian Patents Act 1970 (the act).

  • The application was published as per the provisions of section 11-A of the act on August 14, 2009.

  • A response to FER issued on March 12, 2012 was filed by the agent to the applicant on January 28, 2013.

  • Prior to hearing, two pre-grant oppositions were filed [u/s 25 (1)] of the Patent act by the parties viz. Network of Maharashtra people living with HIV (Opponent: 1) and Nandita Venkatesan and Phumeza Tisile both survivors of TB (Opponent: 2) in the year 2013 and 2019 respectively.

Grounds for Opposition:

  • The first ground was that the invention as claimed in the application was not an invention as it does not involve an inventive step and is not in accordance within the meaning of section 2(1)(j) and 2(1) (ja) i.e., novelty and non-obviousness respectively.

  • Further, the invention was objected under Sections 25(1) (b)-25 (1) (g) of the act.

  • With reference to section 25(1) (h) the applicant was alleged to have not disclosed relevant information as a part of requirement under section 8 of the act.

  • The invention was considered non-patentable under section 3(d) and 3(e) of the act.

Road to Controller’s decision:

1. A total of ten exhibits were cited to the controller by the opponent 1 and five exhibits by the opponent 2 in the Pre-grant opposition statement:

Opponent 1:

Exhibit A- Indian Patent No: 236811 titled “A novel substituted quinoline compound”.

Exhibit B- Prior art- A method of preparation of water soluble compounds through salt formation

Exhibit C- A book of Remington’s Pharmaceutical Sciences Chapter 90

Exhibit D-  European Patent EPO 575890B1: The fumerate salt of a Quinoline derivative

Exhibit E- A patent application WO92/10191: Quinoline derivatives with Pharmaceutical salts and Esters

Exhibit F- Concept of Optical Isomerism in drugs which is already known in the art

Exhibit G- Theory and Practice of Industrial Pharmacy by Liberman and Lachman, Chapter 11

Exhibit H- A book of Remington’s Pharmaceutical Sciences, Chapter 90

Exhibit I- Theory and Practice of Industrial Pharmacy by Liberman and Lachman, Chapter 12

Exhibit J- US patent no: 5145684 titled “Surface modified drug Nanoparticles”

  • With reference to exhibit A, it is the patent whose evergreening is challenged in the present invention.

  • With reference to exhibit B, it discloses that the use of salt form of drug increases its solubility. This information has been a part of scientific world for over three decades. The same applied to exhibit C as formation of solid forms is known to person skilled in the art (POSITA) i.e., related to Pharmaceutical sciences.

  • Exhibit D was found to disclose Quinoline derivatives of Fumarates which was also claimed in the claim 1 of the present application, which claims Fumarate salt of TMC 207. Similar grounds were applicable to exhibit E as well.

  • Exhibit F directed towards the concept of optical isomerism in drugs and such a concept was found to be already known in the prior art.

  • Exhibit G, H and I are also prior arts which are excerpts from a well-known book taken as reference by Pharmaceutical professionals.

  • The exhibit J had disclosed the phenomenon of use of wetting agents which were meant to modify the surface. The claim of the present application mentioned a Fumarate salt of Bedaquiline citing that polyethylene glycol sorbitan fatty acid ester (TWEEN 20) being used as a wetting agent. This was an obvious improvement and it was alleged that the applicant cannot claim novelty over the use of excipients.

Opponent 2:

Exhibit A - WO 2004/011436 titled “Quinoline derivatives and their use as mycobacterial inhibitors.

Exhibit B - WO2005/117875 titled, “Use of substituted Quinoline derivatives for the treatment of drug resistant mycobacterial diseases.

Exhibit C - WO2006067048 titled, “Quinoline derivatives for the treatment of latent tuberculosis”

Exhibit D - WO2006024667 titled “Fumarate of 4-((4-((4-(2-cyanoethenyl)-2,6- dimethylphenyl)amino)- 2-pyrimidinyl)amino)benzonitrile”

Exhibit E - US 6,534, 508 titled “Methods and Composition for treating infection using optically pure (S)-Lomefloxacin”

2. Further, there were five patent applications that were cited in the hearing notice as a prior art (first four of which are the exhibits A-D by the opponent 2). D1 disclosed the antimicrobial agent for treatment of TB. D2 disclosed conversion of diasteriomeric salts salt forms by reaction with suitable chiral acids which is already disclosed. D3 disclosed common wetting agents. The present application disclosed the same weight percentages of wetting agents as in D4. Similar issues were cited in document D5. The opponents clearly proved that present application was a verbatim copy of many aspects including weight percentages mentioned in document D3.

3. Further, under section 3(d) where mere discovery of new form of a known substance i.e., preparation of a water soluble salt of the same also did not qualify for patentability of said invention. The alpha and beta forms of Fumarate salt of TMC 207 has already been claimed in the Indian patent no: 236811 (Exhibit A of Opponent 1).

4. The opponents further stated that the compound so claimed in the present invention was a mere admixture of existing components and disqualifies for a patent under section 3(e).

The applicant argued that the cited prior art documents (five) failed to disclose each and every specific feature as claimed in the present application. Further, the applicant dropped the protection sought for fumarate salt of Bedaquiline at the amendment stage. The applicant instead emphasised on the use of wetting agent as the main aspect of invention and this was already disclosed in the cited prior arts. The applicant also argued that there was a significant increase in bioavailability in use of 0.01 to 5% of wetting agent. The support submitted was found to be an afterward support where a whopping 159% increase of bioavailability was cited and was contested.

Controller’s Decision:

There were four hearings held on November 18, 2022; November 24, 2022; November 30, 2022; and on January 17, 2023 respectively.  Dr. Latika Dawara in her order dated March 23, 2023 upheld the opposition to said application on following grounds:

  • The compound Bedaquiline was already covered in the patent granted (suit patent) to the applicant. In short it was a matter of evergreening of the suit patent, thus upholding rejection under section 3(d) of the Indian Patents act 1970.

  • The claimed compound was nothing but a mere admixture as the use of 0.01 to 5% of wetting agent to increase the bio-availability does not mean that there was a significant notable increase in the therapeutic efficacy of the compound. There was no significant experimental data/ credible evidence with reference to efficacy provided for the same.

  • The non-obviousness/lack of inventive step of all the claims 1-5 was also upheld. This was specifically stated with reference to prior arts D1 and D3 cited in the hearing notice.

  • The essence of the invention which was claiming the Bedaquiline salt and the wetting agent TWEEN 20 was not having enough details and there was not enough experimental data supporting the efficacy due to the addition of wetting agent to the Bedaquiline salt.

  • Further, the application failed to produce any evidence showing any synergistic effect of the formulation claimed over the suit patent.

  • The controller however, overruled the objection related to applicant not disclosing the details under section 8 as the applicant had already submitted the details of current status of corresponding applications in other countries through an updated form 3.

  • The controller also overruled the challenge by opponent 2 on the grounds of insufficiency of disclosure under section 25(1) (g) citing that there was working example of the invention disclosed in the complete specification.

Conclusion:

India accounts for 22% of World’s TB patients (Global TB report 2022). The “One world TB summit” was organized on the occasion of world TB day on March 24, 2023, in the ancient city of Varanasi, where the Prime Minister of India apprised the world about India’s efforts to eradicate TB by 2025. Further, April 01, 2023 marks a decade since the Novartis v Union of India’s landmark judgement which paved the way for prevention of evergreening of patents in India. Thus the controller’s judgement with reference to the application of Janssen Pharmaceuticals comes as a befitting tribute to the Novartis judgement and it also thwarted another attempt of evergreening of patents where the patients were long deprived of affordable healthcare.

Renu Bala Rampal is an Associate Partner and Soujanya Sikha is a Patent Agent at S.S. Rana & Co.

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