Wednesday, 27 July 2011

Gilead's Patent Application in India Rejected for lack of Inventive Step (section 2 (1) (j)) and Efficacy (section 3(d))


Gilead Sciences, the biopharmaceutical company that discovers, develops and commercializes therapeutics was in news recently for allowing Medical Patent Pool to access some of its patents. Essentially, the agreement allowed an increased access to Gilead’s patents that cover HIV and Hepatitis B treatment.  The agreement allowed for the production of four HIV medicines, namely, Tenofovir (also used for treating Hepatitis B), Emtricitabine, Cobicistat and Elvitegravir, as well as a combination of these four medicines into a single pill called “Quad” by generic companies. This agreement was considered as a landmark step in making essential medicines available at a lower cost to developing countries as well as encouraging innovation at the same time. Indian generic companies were also selected to manufacture generic versions of the four medicines and distribute the generics in developing and poor countries.

In the middle of all these developments, I came across a very interesting decision by the Indian Patent Office concerning a patent application filed by Gilead. The application number is 602/DEL/2007, entitled “Nucleotide Analogs” and was rejected by the Indian Patent Office on July 20, 2011. The subject matter of the 602/DEL/2007 application relates to intermediates for phosphonomethoxy nucleotides analogs of formula 1a and was filed on March 20, 2007 at the Delhi branch of the Indian Patent Office. The application included a total of 35 claims at the time of filing, wherein claims 1-25 were product claims for formula 1a, claims 26-31 were process claims for preparation of formula 1a whereas Claims 32 and 35 were omnibus claims. [An ex-parte re-examination was requested for Gilead’s 6,043,320 patent for causing significant public harm. The 6,043,320 patent also disclosed intermediates for phosphonomethoxy nucleotides analogs of formula 1a]

Background Information about the 602/DEL/2007 application: The 602/DEL/2007 application was filed as a divisional application of 2076/DEL/1997, filed on July 25, 1997. The 2076/DEL/1997 claims priority from United State applications 08/686,838 and 60/022,708, dated July 26, 1996. The 602/DEL/2007 application was published u/s 11A on August 8, 2007. [Section 11A of the Indian Patent Act covers publication of applications]

During the examination of the 602/DEL/2007 application, the examiner raised objections to the 602/DEL/2007application under section 2(1) (j) that covers “Inventive Step” and the “always in news” section 3(d) that covers “New form/new use of known thing”. The examiner also raised objection for non-allowability of 602/DEL/2007 application under section 16 for filing identical set of claims as were in the parent application [2076/DEL/1997]. An opposition was raised on the 2076/DEL/1997 application under section 25 (1), Further, an opposition to the 602/DEL/2007 application was filed on September 22, 2009 by Cdymax India Pharma Ltd. The parent application was refused on merits of representations under section 25(1). Gilead’s argument, reproduced below from the Indian Patent office site, stated that in accordance with section 16(1), a divisional application can be filed by the applicant either suo moto or with view to remedy the objection raised by controller on the grounds of distinct invention. The 602/DEL/2007 application has been filed suo moto as the parent application has not been granted till now. Further, Gilead asserted that in assessment of the claims in divisional, there should be no commonality of claims between those granted in the parent application and those prosecuted in a divisional application.

Independent Claim of 602/DEL/2007:
1. A compound having formula (la)
A-OCH2P(O)(Z)2 wherein Z is independently -OC(R2)2OC(O)X(R)a, an ester, an amidate or H, but at least one Z is -OC(R2)2OC(O)X(R)a;
A is the residue of an antiviral phosphonnmetboxy nucleotide analog; X is N or O;
R2 independently is-H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or-OR3 in which R3 is C5-C12alkyl, C5-C12 alkenyl,C5-C12alkynyl or C5-C12 aryl;
R is independently -H, C5-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one  of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro,  -N(R4)2 or- OR3 where which R4 independently is -H or C1-C8 alkyl, provided that at least one R is not H; and a is 1 when X is O, or 1 or 2 when X is N;
with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be  -OR3 or (c) both N-linked R groups can be-H;
and the salts, hydrates tautomers and solvates thereof.

Independent claim of parent application 2076/DEL/1997:
1.A compound having formula (la)
A-OCH2P(O)(Z)2 wherein Z is independently -OC(R2)2OC(O)X(R)a, an ester, an amidate or H, but at least one Z is -OC(R2)2OC(O)X(R)a;
A is the residue of an antiviral phosphonnmetboxy nucleotide analog; X is N or O;
R2 independently is-H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or-OR3 in which R3 is C5-C12alkyl, C5-C12 alkenyl,C5-C12alkynyl or C5-C12 aryl;
R is independently -H, C5-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro,  -N(R4)2 or- OR3 where which R4 independently is -H or C1-C8 alkyl, provided that at least one R is not H; and a is 1 when X is O, or 1 or 2 when X is N;
with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be  -OR3 or (c) both N-linked R groups can be-H;
and the salts, hydrates tautomers and solvates thereof.

As one can observe that the independent claim of both the application are essentially the same. This is where the entire case gets interesting. According to section 16(3), a parent application and a further application cannot have a claim that is common to both the applications. Simply put, a further application may be filed if the claims of the complete specification relate to more than one invention. Moreover, an applicant for a patent is refused to re-file “refused claims” of a parent application in a divisional application. As the parent application 2076/DEL/1997 was refused as a result of the opposition filed under section 25(1), Gilead is prohibited from claiming the refused claims of the parent application 2076/DEL/1997 in the 602/DEL/2007 application. The 602/DEL/2007 cannot even exist as an independent application as the refused claims are already in the public domain.

I have reproduced the prior arts cited in the opposition that was filed against Gilead’s application. The patent office cited the below mentioned prior arts to come to the conclusion that Gilead’s application 602/DEL/2007 lacked “inventive step” (Novelty) and the nucleotides analogs in the 602/DEL/2007 application did not offer any therapeutic advantage [Section 3(d)] and thus fails to show “efficacy’. The prior arts that were cited in the opposition are:

Patent Literature:
WO 95/07920 - Nucleotide Analogs
WO 94/03467 - Antiretroviral Enantiomeric Nucleotide Analogs
US 4816570 - Biologically Reversible Phosphate and Phosphonate Protective Groups
US 4968788 - Biologically Reversible Phosphate and Phosphonate Protective Gruops
US 5177064 - Targeted Drug Delivery Via Phosphonate Derivatives

Non-Patent Literature:
1. C W Thomber ‘Isosterism and molecular modification in drug design’, Chem. Soc.            Reviews, 18 (1979), 563-580
2. Notari et al, Prodrug Design, Pharmaceutical Therapy, 14: 25-53 (1981)
3. Serafinowska et al,’Synthesis and in vivo evaluation of prodrugs of 9-[2-(phosphonomethoxy) ethoxy] adenine’, J. Med. Chem., 1995, 38, 1372-1379
4. Starrett et al., ‘Synthesis, oral bioavailability determination and in vitro evaluation of          prodrugs of the antiviral agent 9-[2- (phosphonomethoxy) ethyl] adenine (PMEA), J. Med. Chem., 1994, 37, 1857-1864

This is another important case where the Indian Patent office has rejected an application under section 2 (1) (j) and 3(d). What kinds of impact will the decision of the India Patent Office to reject the 602/DEL/2007 have on the future of relationship among the Medical Patent Pool, Gilead, and the Indian Generic companies, which increasingly find themselves involved in lawsuits with big pharmaceutical companies from around the world?

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