India: Indian Patent Office's Consecutive Decision On Rejecting Tofacitinib Patent Application

Indian Patent Office (IPO) on September 3rd, 2015 denied Pfizer (Applicant) Inc's patent application on its rheumatoid arthritis drug Tofacitinib for the second time. The IPO rejected the Patent Application on the grounds of anticipation by prior claiming as well as on basis of Section 3(d) of the Patents Act (Act).

BRIEF BACKGROUND

Pfizer Products, Inc. (Pfizer) filed Indian patent application 991/MUMNP/2003¹ entitled "Chiral Salt Resolution" in the Indian Patent Office (IPO) on October 27, 2003. The '991 application 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 describes the enantiomer, 3-{(3R,4R)-4-Methyl-3-[methyl-(7Hpyrrolo[ 2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile, also known as tofacitinib. Tofacitinib, which is sold as XELJANZ®, is approved for use in the treatment of rheumatoid arthritis.

The said application is a national phase application of WO 02/096909 (PCT/IB02/01905) filed on May 29, 2002. The First Examination Report for the present invention was issued on 13th March, 2008 in which the Examiner rejected the claims due to lack of novelty based on the prior art (WO 0142246) as well on the basis of Section 3(d) of Indian Patent Act, 1970 The applicant filed a response on 27th January, 2009 with amended claims. Since there were outstanding objections related to Novelty, Section 3(d) and Section 8, the applicants were called for a hearing on January 22, 2015.

During the hearing, the Examiner raised a new objection for the first time that the claims were unpatentable under Section 3(d) of the India Patents Act 1970, as amended (Patent Act) and hence the application was rejected. Pfizer appealed and on October 31, 2014, the Intellectual Property Appellate Board (IPAB) contended that the patent office had violated the principles of natural justice thereby set aside the order and directed the IPO to reconsider the application.

IMPLICATION OF PRIOR ART AND PRIOR CLAIMING

On January 20, 2015, the applicant submitted copies of declarations of Dr. James D. Clark and Dr. Mark Edward Flanagan. The applicant further submitted the details of the corresponding applications mainly search and examination reports issued in other jurisdictions in order to comply with Section 8 requirements.

It is pertinent to mention that the present application 991/MUMNP/2003 has a filing date of May 29, 2002, claims a priority of May 31, 2001. D1 WO/0142246 (IN 241773) was filed on November 23, 2000, claims a priority date of December 10, 1999 and was published on June 14, 2001.

Although prior art D1 has an earlier priority and filing date than 991/MUMNP/2003, D1 was published after the priority date of present application 991/ MUMNP/2003.

With regards to Objection 1 of the hearing letter, the applicant submitted that D1 does not discloses or identify any known substance with known therapeutic efficacy for the application of Section 3(d) as D1 was published after the priority date of the present application.

With regards to the objection pertaining to section 3(d), the applicant submitted that while Section 3(d) is applicable to salts, isomers of known substance it is not applicable to the present application as the compound claimed (though an isomer) is not known to the public through prior publication. Therefore the claimed compound cannot be considered as "known substance" for the purpose of section 3(d).

On February 3, 2015, the applicant submitted an amended claim set amending claim 1 as recited below and canceling the remaining claim (claim 2).

Amended claim 1 "The compound 3-{(3R,4R)-4- Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-amino]-piperidin-1yl}-3-oxo-propionitrile or a pharmaceutically acceptable salt thereof."

ASSISTANT CONTROLLER'S FINDINGS ON "ANTICIPATION DUE TO PRIOR CLAIMING

The following are the teachings of D1 (WO 0142246) as mentioned in the order by the Assistant Controller:

1. D1 discloses the inhibitors of JAK3 as agents for the treatment of variety of diseases.

2. Example 14 of D1 discloses the compound of the present claim without reference to stereo chemical configuration. However, D1 teaches that the compounds have asymmetric centers and therefore exist in different enantiomeric and diasteromeric forms. D1 further discloses the use of pyrrole [2,3-d]pyrimidine compounds as immunosuppressive agents for organ transplants, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and other indications where immunosuppression would be desirable. The said reference in the prior art includes both the E and Z configurations. The Compound of formula 1 may also exist as tautomers. Therefore the present form (3R, 4R) of the compound claimed by the applicant is also disclosed in the prior art.

3. Claim 20 of D1 discloses a compound 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d] pytimidin-4-yl)amino]-piperidin-1-yl}-3- oxo-propionitrile The subject matter of D1 was filed as national phase application(IN/ PCT/2002/00588/DEL) on 10th June 2002 which was proceeded to grant on 24/07/2010 bearing Patent. No. IN241773.The prior national phase application no IN/PCT/2002/00588/ DEL makes sense that the compound claimed in claim 20 is known to the applicant as the applicant Pfizer product Inc. is the same for both the application.

4. Specifically, the Assistant Controller referred to Section 13(1)(b) which refers to "anticipation by prior claiming" and states that "the invention is claimed in any claim of any other complete specification published on or after the date of filing of the applicant's complete specification, being a specification filed in pursuance of an application for a patent made in India and date before or claiming the priority date earlier than that date". The Assistant Controller noted that for the purpose of determining novelty, an application for a patent filed in the Indian Patent Office before the filing date of a complete specification of a later filed application but published later, is prior art for the purposes of "prior claiming".

IMPLICATIONS OF SECTION 3(D) OF INDIAN PATENTS ACT, 1970

The Assistant Controller mentioned that he did not find any distinctive difference between the instant claimed compound and the priorly claimed document D1 except the fact the former is the enantiomer of the later. Further, the Asst. Controller stated that the applicant in order to prove enhanced efficacy factor of the claimed compound has taken shelter of the document published in Journal of Medicinal Chemistry on 19th November 2008 containing all four possible enantiomer of the base compound of D1 is misleading.

D1 (WO/0142246): discloses 3-{4-Methyl-3-[methyl- (7H-pyrrolo[2,3-d] pyrimidin-4-yl)-amino]-piperidin- 1yl}-3-oxo-propionitrile.

991/MUMNP/2003 (WO/02/096909): claims the enantiomer 3-[(3R,4R)-4-methyl-3-[methyl(7Hpyrrolo[ 2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl]-3- Oxopropanenitrile

The Asst. Controller stated that the Applicant has not given an experimental date to show the enhanced efficacy over the base compound.

The applicant submitted that 3-[(3R,4 R)-4-methyl-3- [methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] piperidin-1-yl]-3-oxopropanenitrile (Tofacitinib) has 2 chiral centers at C3 and C4, with 4 possible stereoisomers. According to the applicant, among the four possible Tofacitinib enantiomers 3R, 4R/ 3R, 4S/ 3S, 4S/ 3S, 4R, only the 3R, 4R enantiomer (Tofacitinib) exhibits high level of selectivity for the Jak family kinases. The applicant explained that the stereo specific nature of the of the compound1(3R,4R) and it is selectivity against over 300 kinases resulted in improved efficacy of the compound as the binding of the molecule to the protein target is what is responsible for any drug molecule to exhibit efficacy. The applicants relied on 2008 publication by the inventors and submitted that Tofacitnib i.e. the 3R, 4R enantiomer highly selective for Janus kinase family of receptors compared to the rest of enantiomers i.e. 3S, 4S; 3R, 4S; 3S, 4R.

However, the Controller stated that as per the provisions of Section 3(d) the enantiomer of the known compound 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pytimidin- 4-yl)amino]-piperidin-1-yl}-3-oxo-propionitrile which the applicant claims should show an enhanced efficacy over the compound of the prior art. Whereas the experimental data and explanation provided during hearing submission by the Applicant showed the efficacy of the claimed compound by comparing the compound with other enantiomeric forms.

The Asst. Controller said that the applicants should have demonstrated efficacy in the patent application and should not rely on a later publication(2008) to demonstrate efficacy. "The applicant did not prove the claimed compound to be of significant efficacy and such factors were never been a part of their disclosure in the specification filed in 31st May, 2001. Rather they have taken shelter of a document of the year 2008 which is not its invention and trying to correlate their invention with the findings of the said document. The applicant is supposed to establish the enhancement of therapeutic efficacy of the specifically claimed form over D1 by substantive research data. They failed to provide such findings even after lapses of plethora of opportunities."

CONCLUSION

From the above decision it is obvious that "The enhanced efficacy criteria can be seen as a refinement of non-obviousness principles or it could be perceived as an improved utility test where only new forms that demonstrate substantially different utility than what existed before are patentable". As per the provisions of Section 3(d) the enantiomer of the known compound which the applicant claims should show an enhanced efficacy over the compound of the prior art. However, in the present invention, the experimental data and explanation provided during hearing submission by the Applicant showed the efficacy of the claimed compound by comparing the compound with other enantiomeric forms. Further, the order clearly states that for the purpose of determining novelty, an application for a patent filed in the Indian Patent Office before the filing date of a complete specification of a later filed application but published later, is prior art for the purposes of "prior claiming". However, the order is unclear on whether it is mandatory to disclose information on a prior art application while prosecuting the patent application.

Footnotes

1 http // ipindiaservices.goviin /decision/991-MUMNP-2003-12609/991.MUMNP.03%20REnew.pdf

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