Chronic Hepatitis (Chc), Viral Polymerase Nucleotide Inhibitor & Process Patents Review and Evaluation, Preparation of Sofosbuvir

The World Health Organization’s (WHO) 2014 Guidelines for the screening, care and treatment of persons with hepatitis C infection state that worldwide more than 185 million people are infected with the hepatitis C virus (HCV) [3]. Of these people, 350 000 to 500 000 die each year. An estimated one third of those who become chronically infected develop liver cirrhosis or hepatocellular carcinoma. HCV infection can be cured, but most people infected with the virus are unaware of their infection and so do not seek timely treatment. Furthermore, treatment remains unavailable for many who have been diagnosed. Several medicines are available to treat HCV, including pegylated interferon and ribavirin but treatment duration is long, involves weekly injections, and side effects are considerable. With the development of new direct-acting antivirals, the treatment landscape is rapidly changing [4]. These new antivirals are expected to reach cure rates of more than 90% in persons with HCV infection across different genotypes, with fewer side effects and a shorter duration of treatment. Two new compounds, simeprevir and sofosbuvir, have recently been approved in the United States and Europe and are recommended by the new WHO treatment guidelines.

5'-monophosphate, a nucleotide analogue inhibitor of the HCV polymerase, which is critical for viral RNA replication. Sofosbuvir was invented by Pharmasset Ltd and developed by Gilead Sciences [5] (hereby referred to as the 'Sponsor').

Discussion
Resolution WHA67.6 adopted by the Sixty-Seventh World Health Assembly, requested the Director-General "to work with national authorities, upon their request, to promote comprehensive, equitable access to prevention, diagnosis and treatment for viral hepatitis" and "to assist Member States to ensure equitable access to quality, effective, affordable and safe hepatitis B and HCV treatments and diagnostics, in particular in developing countries". Ensuring access to new treatments is a challenging task. In order for countries to identify ways of increasing access and affordability of new HCV medicines, they need clarity about patent status [6]. To assess whether a medicine is patent protected in a certain country requires expert knowledge and access to specialized databases that are not easily available [7]. The WHO Global strategy and plan of action on public health, innovation and intellectual property provides WHO with a mandate to support efforts to determine the patent

Patent Evaluation
As per the EMEA scientific discussion "Sofosbuvir is chiral molecule and possesses 6 stereogenic centers which are well controlled by the synthetic process and the specifications of raw materials. The absolute and relative configuration of these chiral centers was established by single crystal X-ray crystallography.
Eight polymorphic forms of Sofosbuvir have been observed and the manufacturing process consistently produces Sofosbuvir as the most thermodynamically stable polymorphic form, containing a small amount of a metastable [5] form which were determined to be pharmaceutically equivalent as per ICH Q6A (decision tree #4). Other polymorphic forms are excluded by the manufacturing process and their absence is confirmed by DSC "Sofosbuviris specifically disclosed in US 7,964,580 [9] ( Figure 1). This patent discloses a process for the preparation of Sofosbuvir by using the chloro as an activating group. This patent has not provided any insight about the impurity concern as well as disclosure of any purity and their levels in the final product. The process was found to be cumbersome and involves the formation of many impurities. Further, the use of intermediate-2 in the synthesis of Sofosbuvir yields the final API in poor yield, which was about 20%. In view of this, it is necessary to develop a process resulting in the product, which is complying with the 1CH requirements of quality parameters besides industrially viable process. Ross et al in US 8,735,569 [10] disclose a process for the preparation of Sofosbuvir by protecting the hydroxyl group with pentafluoro phenol. The process is as disclosed below: ( Figure   2) The present inventors found that the overall yield appears to be only 35-40% to get the desired isomer. This patent has not disclosed any generalized impurities formed during the process development. This patent has also not disclosed the content of total impurities formed (Table 1).

WO2010135569A1
The patent application WO2010135569A15 contains productby-process claims. A product-by-process claim is directed to a product that is defined by its process of preparation. This

Conclusion
The search revealed patents filed with respect to sofosbuvir by