Sofosbuvir: The Next Pre-Grant Opposition Target by I-MAK

After anti–influenza drug Tamiflu (Oseltamivir Phosphate) and antiretroviral drug Viread, Gilead Sciences is again back in news, this time with its hepatitis C (HCV) drug Sofosbuvir. Like Tamiflu and Viread pre-grant opposition, Sofosbuvir patent application is also facing pre-grant opposition. Non-profit group I-MAK (Initiative for medicines access and knowledge) has filed a pre-grant opposition against the Sofosbuvir patent application contending that Sofosbuvir is not a new drug but a modified version of earlier known compound, and therefore not eligible for patent protection under Section 3(d). In addition, I-MAK stresses that there is a widespread apprehension among the public that if this patent is granted against this pending application the price of this hepatitis C (HCV) drug will be very high.

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 Sofosbuvir under section 3(d).

Not a Drug but a Prodrug

Before debating the patentability issue of Sofosbuvir under the Patents Act 1970 it is important to explain what Sofosbuvir exactly is and how it is similar or dissimilar to earlier known compound.

Sofosbuvir is a nucleotide analogue for the treatment and cure of hepatitis C belonging to the class of hepatitis C virus (HCV) polymerase inhibitor. Sofosbuvir is, in fact, a prodrug of 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate which is an active antiviral agent.

Sofosbuvir which is a phosphoramidate prodrug of nucleoside derivatives is disclosed in U.S. Patent No. 7,964,580 and PCT Application No. 2008121634 assigned to Pharmacist, Inc and was developed to encounter the physicochemical and pharmacokinetics properties of nucleosides, including systemic absorption. The corresponding Indian Patent Application No. is 3658/KOLNP/2009. The patent application is currently awaiting examination in India. The patent claims pertain to phosphoramidate prodrug and its stereoisomers of a nucleoside derivative for treating viral diseases, including HCV. The compounds claimed are inhibitors of RNA-dependent RNA viral replication and the HCV NS5B polymerase. The phosphoramidate prodrug claimed is of the 5’ monophosphate derivative of the β-D- 2’-deoxy-2’-α-flouro-2’-β-C methyluridine nucleoside, also known as Sofosbuvir.

(2’R)-2’-deoxy-2’-flouro-2’-C-methyl nucleoside (β-D or β-L) which was disclosed in WO2005003147 (US7429572) exhibits greater specificity for HCV and includes a method for treating various viruses included HCV, or its pharmaceutically acceptable  salt or prodrug. The corresponding Indian Patent Application No. 2079/DELNP/2011. Gilead Sciences revealed an oral prodrug of (2’R)-2’-deoxy-2’-flouro-2’-C-methyl nucleoside (β-D or β-L)  — Sofosbuvir— having better physicochemical and pharmacokinetics properties as compared to (2’R)-2’-deoxy-2’-flouro-2’-C-methyl nucleoside (β-D or β-L). Sofosbuvir when orally administered is metabolized to form pharmacologically active metabolite 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate responsible for antiviral activity. Hence Sofosbuvir is an new form of a known compound and thereby making Sofosbuvir not eligible for patent protection India.

Grounds of Pregrant opposition

I-MAK has filed a pre-grant opposition against Gilead’s Indian patent application no. 3658/KOLNP/2009 on the grounds of lack of novelty Section 25 (1)(b), obviousness Section 25(1)(e), Section 3(d) and failure to furnish Section 8 details.

Lack of novelty: The earlier patent i.e. WO2005/003147 discloses both the parent structure of Sofosbuvir and also the stabilized phosphate prodrug form. Hence Sofosbuvir is not a new invention.

Obviousness: It is well known to a skilled person in the art that a prodrug of the compounds claimed would have advantages such as activating the phosphate and  improving the pharmacokinetic characteristics of the parent compounds  discussed in ‘147. Hence prodrug approach for Sofosbuvir would have been obvious to try and do not amount to a technical advance over the art and lack any inventive step

Section 3(d): 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. I-MAK opposed that Sofosbuvir is a new form of a known substance that does not result in an enhancement of the known efficacy of the known form.  It is necessary to show that the Sofosbuvir has better efficacy than the already known form. However the applicant has not included any comparative data in the 3658’ application. The Supreme Court also in the recent Novartis case ruled that an increased bioavailability alone may not necessarily lead to an enhancement of therapeutic efficacy.

Conclusion

Now, the critical question which would remain is whether Sofosbuvir has sufficient merit to overcome the barrier of section 3d. As it is technically clear that Sofosbuvir has significantly better physicochemical and pharmacokinetics properties as compared to earlier known compound, the likelihood of Sofosbuvir to overcome the ‘efficacy’ barrier of section 3(d) will be apparent only if they can show comparative data related to increase in enhanced therapeutic efficacy.

I-MAK also stated that undeserved patents of the nature  applied for in ‘3658 affords a company, such as the Applicant, artificial exclusive rights, which then allows it to price a medicine beyond the reach of not only Indian patients, but also many in need in other developing and even developed countries. However, even if a patent is granted and Gilead launches Sofosbuvir at a higher cost, 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.

About the Author: Ms. Harsha Rohatgi, Patent Associate, Khurana & Khurana, Advocates and IP Attorneys and can be reached at: harsha@khuranaandkhurana.com

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