Indian Patent Office Rejects Pfizer’s Patent for Tofacitinib – Again!

Background

Pfizer Products, Inc. (Pfizer) filed Indian patent application 991/MUMNP/2003 (‘991 application) entitled “Chiral Salt Resolution” in the Indian Patent Office (IPO) on October 27, 2003. The ‘991 application is a national phase application of WO 02/096909 (PCT/IB02/01905) filed on May 29, 2002. WO 02/096909 claims priority to U.S. application no. 60/294,775 filed on May 31, 2001 and U.S. application no. 60/341,048 filed on December 6, 2001.

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-(7H-pyrrolo[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 closest prior art, WO 01/42246 (D1), also owned by Pfizer, was filed on November 23, 2000 and published on June 14, 2001. D1 claims priority to U.S. application no. 60/170,179 filed on December 10, 1999. D1 relates to pyrrolo[2,3-d]pyrimidine compounds (which are inhibitors of protein kinases, such as JAK3) and the use of these compounds in the treatment of various diseases, such as lupus, multiple sclerosis, rheumatoid arthritis, etc. Example 14 of D1 discloses 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1yl}-3-oxo-propionitrile, the racemate of the enantiomer claimed in claim 1 of the ‘991 application. Additionally, D1 discloses all conformational isomers (e g., cis and trans isomers). Although D1 does not disclose any specific enantiomers, it teaches that compounds have asymmetric centers and thus exist in different enantiomeric and diastereomeric forms. Specifically, the specification states, “This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. In this regard, the invention includes both the E and Z configurations. The compounds of formula I may also exist as tautomers.”

Although D1 published after the earliest claimed priority date of the ‘991 application (May 31, 2001), it claimed an earlier priority date (December 10, 1999). D1 was also filed in India and granted as Indian Patent No. IN 241773.

A first examination report was issued in the ‘991 application on March 13, 2008. Pfizer filed a reply and amended claims on January 27, 2009. The Examiner issued a hearing letter ordering the Applicant to attend a hearing on January 22, 2015. During the hearing, the Examiner raised a new objection that the claims were unpatentable under Section 3(d) of the India Patents Act 1970, as amended (Patent Act). Ultimately, the application was rejected. Pfizer appealed and on October 31, 2014, the Intellectual Property Appellate Board (IPAB) set aside the order and directed the IPO to reconsider the application.

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

Amended claim 1:

  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. 

In addition, Pfizer submitted copies of declarations of Dr. James D. Clark and Dr. Mark Edward Flanagan.

A hearing was held on January 22, 2015. The issues discussed were: (1) lack of novelty of claim 1 in view of D1; and (2) the unpatentability of claim 1 under Section 3(d) of the Patent Act.

During the hearing, Pfizer argued that D1 was not prior art and hence not novelty destroying because it was published after the priority date of the ‘991 application. With respect to the rejection of the claim under Section 3(d), Pfizer argued that this section was not applicable to the ‘991 application. Specifically, Pfizer argued that Section 3(d) applied to salts and isomers of a known substance. Although the rejected application was directed to an isomer, there was no known substance known to the public through a prior publication. Although D1 was filed earlier, it was not prior art. Therefore, because the compound of example 14 was a published after the priority date of the ‘991 application, it could not be considered a “known substance” for purposes of Section 3(d).

September 3, 2015 Decision by the Assistant Controller of Patents and Designs (Assistant Controller)

Regarding the novelty rejection, the Assistant Controller rejected Pfizer’s argument that D1 was not prior art. 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”.

The Assistant Controller also noted that Pfizer was the applicant for both the ‘991 application and D1. Moreover, the Assistant Controller did not find any “distinctive” difference between the claimed compound and the compound disclosed in D1, noting that the compound claimed in the ‘991 was the enantiomer of the compound disclosed in D1. Additionally, the Assistant Controller stated that Pfizer failed to furnish comparative data distinguishing the features of the claimed compound over D1 (which was a similar compound). Instead, Pfizer provided comparative data of the four enantiomeric forms of the compound disclosed in D1 and published in 2008 in the Journal of Medicinal Chemistry (Journal), which, according to the Assistant Controller, was irrelevant.

Regarding the rejection under Article 3(d), the Assistant Controller referred to the decision in Novartis AG v/s Union of India (Civil Appeal Nos. 2706-2716 of 2013) which held that an applicant must establish the therapeutic enhanced efficacy of the claimed compound over a base compound. According to the Assistant Controller, Pfizer failed to provide experimental data demonstrating that 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1yl}-3-oxo-propionitrile exhibited enhanced efficacy over the compound in D1 (namely, 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1yl}-3-oxo-propionitrile). Instead, Pfizer submitted experimental data comparing the efficacy of the claimed compound with three other possible enantiomers disclosed in the Journal. No where did the Journal provide data demonstrating enhanced efficacy of the claimed compound with the compound disclosed in D1. Specifically, the Assistant Controller stated, “[T]he 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.”

The Assistant Controller concluded:

From the present amended claim 1, it can be concluded that the compound claimed in claim 1 is the enantiomer of compound of the cited document 1 and hence not novel and inventive as stated above. However, in absence of disclosure of any test result and comparative data over the base compound 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1yl}-3-oxo-propionitrile (compound in D1), I do not admit that the claimed compound has enhanced efficacy over the base compound in D1 and hence not patentable under Section 3(d) of Patents Act. The applicant’s contention that D1 can’t be the document to assess the patentability aspect of the invention claimed, since not known only to the public is not acknowledged.

After having considered the submissions submitted by the applicant in the hearing, the written submission and amended claims filed, in view of the above discussions and findings by me, it is hereby ordered that the invention disclosed and claimed in the instant application i.e., ‘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’ (amended claim 1 submitted on 30/01/2015) is not considered as an invention under the provisions of the Act as discussed above and I therefore, hereby refuse this Application No. 991/MUMNP/2003 to proceed further.

This post was written by Lisa Mueller and Nidhi Anand of Chadha & Chadha

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