Tuesday, May 23, 2006

Viread: The Next ‘Pre-grant Opposition’ Target

After infamous anti-influenza drug Tamiflu (Oseltamivir Phosphate), Gilead Sciences is again back in news but this time with its antiretroviral drug Viread. Like Tamiflu pre-grant opposition, Viread patent application is also facing pre-grant opposition. Lawyers, from Bangalore-based Alternate Law Forum, have filed a pre-grant opposition against the Viread patent application on the behalf of two NGOs --- Delhi Network of Positive People and Indian Network for People Living with H.I.V./AIDS --- contending that Viread is not a new drug but a modified version of earlier known compound, and therefore not eligible for patent protection under post-product patent regime. In addition, there is widespread apprehension among the public that if patent is granted against this pending application the prices for this antiretroviral drug may shot up up as Indian companies would be required to pay royalties Gilead Sciences to legally continue their generic copies as per new Patent Amendment Act. Presently, Cipla and Ranbaxy are manufacturing and marketing generic versions of Viread in India. Under section 25 (1) of the Patents Act 1970 any person can file an opposition against the grant of patent on the specified eleven ‘ mutually exclusive’ grounds. Nowhere mere public apprehension is considered to be valid ground to oppose patent application. Following the Gleevac case, here again section 3 (d) of the Patents Act 1970 is likely to play a critical part in the pre-grant opposition, questioning the patentability of Viread under newly amended section 3(d). Not a Drug but a Prodrug Before debating the patentability issue of Viread under the Patents Act 1970 it is important to explain what Viread exactly is and how it is similar or dissimilar to earlier known compound. Viread is an antiretroviral drug belonging to the class of acyclic nucleoside phosphonate analogs having anti-human immunodeficiency virus activity. Generically known as Tenofovir Disoproxil Fumarate (TDF) --- Viread is, in fact, prodrug of Tenofovir which is disclosed in U.S. Patent No. 5,922,695 assigned to Gilead Sciences Inc. and was developed to encounter the bioavailability problems associated with tenofovir.

Tenofovir which was disclosed in U.S. Patent No. 4,808,716 exhibits ionic nature at physiological pH and low cellular permeability and thereby demonstrated low oral bioavailability during preclinical trials. After more than 10 years of discovering Tenofovir, Gilead Sciences revealed a lipophilic oral prodrug of tenofovir --- Tenofovir Disoproxil, a bis (isopropyloxycarbonyloxymethyl) ester of Tenofovir --- having better oral bioavailability as compared to Tenofovir. TDF when orally administered metabolized by diester hydrolysis to tenofovir in the systemic circulation, which is subsequently metabolized by phosphorylation to form pharmacologically active metabolite tenofovir diphosphate responsible for antiretroviral activity. Pre-1995 compound Gilead Sciences disclosed Tenofovir Disoproxil Fumarate in U.S. Provisional Application Serial No. 60/022,708 filed July 26, 1996 against which U.S. Patent Nos. 5,922,695 (genus patent) and 5,977,089 (species patent) were issued on July 13, 1999 and November 02, 1999 respectively. Even though TDF is a new form of a known compound, Tenofovir, it was disclosed after 1995 and thereby making Viread eligible for patent protection in India. Now, the critical question is whether Viread has sufficient merit to overcome the barrier of section 3 (d). The Word is ‘Efficacy’ According to section 3 (d), the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance will not be considered as a patentable invention. Further, in the explanation part it is specifically mentioned that salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance will be considered to be same substance, unless they differ significantly in properties with regard to efficacy. Considering section 3 (d) along with its explanation, it is clear that a new form of a known compound with improved efficacy would be enough to overcome barrier of section 3(d) and thereby sufficient to stand the requirement of inventive-step under section 2 (1) (ja). As it is technically clear that TDF has significantly better oral bioavailability as compared to earlier known tenofovir, the likelihood of Viread to overcome the ‘efficacy’ barrier of section 3(d) is apparent. Generics 'Dilemma' Tenofovir Disoproxil Fumarate tablet was given marketing approval in India on August 17, 2005. So, the next critical question would be whether generic companies infringes Gilead’s patent if granted by the Patent Office. Answer is Yes! According to section 11A of the Patents Act, 1970 all patent applications will be publish after completion of 18 months, after which application will be open for pre-grant opposition. Further section 11A (7) states that an applicant, on and from the date of publication of the application for patent and until the date of grant of a patent in respect of such application, will have the like privileges and rights as if a patent for the invention had been granted on the date of publication of the application with a proviso that the applicant will not be entitled to institute any proceedings for infringement until the patent has been granted with a further proviso thatthe rights of a patentee in respect of applications made under section 5 (2) before the 1st day of January, 2005 shall accrue from the date of grant of the patent with yet another proviso that after a patent is granted in respect of applications made under 5 (2), the patent-holder will only be entitled to receive reasonable royalty from such enterprises which have made significant investment and were producing and marketing the concerned product prior to the 1.1.2005 and which continue to manufacture the product covered by the patent on the date of grant of the patent and no infringement proceedings will be instituted against such enterprises. Proviso of section 11A (7) of the Patents Act, 1970 clearly states that a patent-holder cannot a bring an infringement suit against generic manufactures which have made significant investment and were producing and marketing the concerned product prior to the 1.1.2005 and will continue to manufacture the product covered by the patent on the date of grant of the patent by paying reasonable royalty to the patentee. Proviso clearly emphasizes that generics should be producing and marketing the patented product prior to 1.1.2005 which is, in fact, not the case with Viread. Generic companies got marketing approval form the Drug Controller General of India (DCGI) on August 17, 2005 and started marketing their generic versions after 1.1.2005. Under newly amended patent act, it is apparent that in case of patent issuance against the pending patent application for Viread, Gilead is not bond by the proviso of section 11A and can institute patent infringement lawsuit against generic manufactures, if they continue to market their generic versions after patent is granted. Irrational Apprehension Opposing Viread patent application on the grounds of apprehension that it would make antiretroviral drug dearer is completely irrational. Presently, a strip of 30 tablets of generic Viread costs around Rs. 4000 in India which itself is expensive for Indian public. Even if patent is granted and Gilead launches Viread at higher cost then Government can curtail its price under Drug Prices Control Order, 1995 which can further be monitored and revised time to time by National Pharmaceutical Pricing Authority. Government also have the option to invoke compulsory license is case of adverse situations. But presently, it seems to be that only generics want to have the whole cake.

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