Info Service on Intellectual Property Issues (Mar14/09)
public opposition to Hepatitis C medicine patent claim
New Delhi, 24 Mar (K. M. Gopakumar) - Civil society organisations in India have launched an opposition to pharmaceutical transnational Gilead's patent application on a crucial medicine for Hepatitis C for lack of novelty, inventive step and efficacy.
The Delhi Network of Positive People (DNP+) and Initiative for Medicine and Access to Knowledge (I-MAK) have filed a new pre-grant opposition application challenging the validity of a patent application for Sofosbuvir, a crucial Hepatitis C antiviral in India.
(Under Section 25 of the Indian Patents Act, any person can in writing oppose the grant of a patent by filing a representation to the Controller of Patents. The grant of a patent can be opposed under 11 grounds that include lack of novelty, inventive step, disclosure of the invention etc.)
Sofosbuvir is a direct-acting antiviral (DAA) that obtained marketing approval from the European Medical Agency and the US Food and Drug Administration in 2013.
The DAA is expected to revolutionise the Hepatitis C treatment regime by replacing the pegylated interferon- based treatment regime. The available evidence shows that Sofosbuvir is one of the most promising DAAs.
This is the second pre-grant opposition filed by CSOs on Sofosbuvir.
The first pre-grant opposition was filed on 21 November 2013 by I-MAK, challenging the patent application on the pro-drug form of Sofosbuvir filed under patent application 3658/KOLNP/2009. The pro-drug application claims patent on an invention for a phosphoramidate pro-drug and its stereoisomers of a nucleoside derivative for treating viral diseases, including HCV.
According to the I-MAK opposition, the claim is not patentable due to lack of novelty because the pro-drug form in Gilead Pharmasset's 2007 application was already disclosed in an earlier 2005 application by the University of Cardiff (UK) for the treatment of cancer.
Further, I-MAK also pointed out that "the patent application is for old science, and patents should not be granted to products which are based on well-known techniques that are obvious to try. Several exhibits included with the opposition demonstrated how the ‘ProTide' pro-drug method had been used repeatedly in the past for drugs".
The patent claim is also opposed under Section 3(d) of the Indian Patents Act. This legal provision stipulates that new forms of known substances have to demonstrate that they enhance the therapeutic efficacy of the product in order to deserve a patent.
According to I-MAK, "the pro-drug step represents a new form of a known substance, and Gilead Pharmasset's patent application provides no data demonstrating enhancement in therapeutic efficacy over the free base compound".
The second opposition filed on 19 March 2014 targets the molecule itself. A successful opposition of the pro-drug would not provide the freedom of operation for generic companies to introduce the generic version of Sofosbuvir. Therefore, the second opposition, which challenges the patentability of Sofosbuvir, is critical for the introduction of generic versions.
According to the background note circulated by I-MAK and DNP+, the medicine is disclosed in various earlier patents, in particular WO2002/057425 and WO2004/002999 (under the World Intellectual Property Patent Cooperation Treaty). Therefore, Sofosbuvir is not a new drug and fails to satisfy the novelty requirement, one of the basic criteria for patent protection.
The pre-grant opposition application also cites the lack of inventive step as a ground for challenging the patent application. According to the background note, "the patent application is for old science, and patents should not be granted to products which are based on well-known techniques that are obvious to try".
The background note further states that "earlier documents discuss 2'-modified nucleoside analogs, their pro-drugs and pharmaceutical compositions. Sofosbuvir is based on 2'-modified nucleoside analogs with substitutions that have already been revealed or would have been minor changes to someone skilled in the art. Furthermore, as far back as 1996, literature shows that using 2'-modified nucleoside analogs, including uridine nucleoside derivatives as antiviral compounds would be useful. Gilead Pharmasset use a uridine derivative nucleoside for the free base compound application for sofosbuvir. Therefore, the claimed invention is obvious to a person skilled in the art and does not qualify for a patent protection."
In the challenge under Section 3(d) of the Indian Patents Act, I-MAK states that "Gilead's patent application covers a new form of 2'-modified nucleoside analogs, which already exist in the field and are classified as derivatives. Gilead Sciences has not provided evidence in its application that shows that these derivative compounds have enhanced efficacy over known forms".
"To get a patent under the law, you need to show that your drug is scientifically new. We believe that Gilead does not meet this lawful requirement. Opposing the patent at the examination stage is a way of ensuring patients have access to this drug at affordable prices without unnecessary patent barriers standing in the way," said Tahir Amin, Director of Intellectual Property at I-MAK.
(Both opposition applications can be accessed here: http://www.i-mak.org/sofosbuvir/)
Hepatitis C has been identified as a public health issue especially due to the lack of affordable treatment.
According to a World Health Organisation (WHO) background note, which was circulated for the 134th Executive Board Meeting in January 2014, 150 million people are chronically infected with Hepatitis C.
Every year Hepatitis C kills nearly 500,000 people. If untreated, Hepatitis C can cause liver cirrhosis or liver cancer. The highest number of people living with Hepatitis C are in China (29.7 million), India (18.2 million), Egypt (11.8 million), Indonesia (9.43 million ) and Pakistan (9.42 million).
Thus, the 134th WHO Executive Board meeting considered a resolution which will now come up for the consideration of the World Health Assembly in May this year that urges WHO Member Sates: "to consider, as necessary, national legislative mechanisms for the use of the flexibilities contained in the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) in order to promote access to specific pharmaceutical products; to consider, whenever necessary, the use of administrative and legal means in order to promote access to preventive, diagnostic and treatment technologies against viral hepatitis; ..."
The resolution thus asks Member States to consider the use of compulsory licence to ensure access to Hepatitis C treatment.
The Resolution also requests the WHO Director-General: "to support Member States with technical assistance in the use of trade-related aspects of intellectual property rights (TRIPS) flexibilities when needed, in accordance with the global strategy and plan of action on public health, innovation and intellectual property; to lead a discussion and work with key stakeholders to facilitate equitable access to quality, effective, affordable and safe hepatitis B and C treatments and diagnostics; ..."
On 27 February 2014, the Hepatitis C Coalition, representing access to treatment activists from 22 countries, stated that "AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Roche refused to provide a plan for equitable access to treatment for HCV, a curable infection that kills over 350,000 people each year".
The statement was issued after meeting with these companies in Bangkok.
As mentioned earlier, Sofosbuvir is expected to replace the current injection-based treatment to a once-daily oral therapy. Further, this drug reduces the course of treatment to 12 weeks from the current duration of 24-48 weeks.
Currently, Sofosbuvir is approved for use in combination with the existing interferon and Ribavirin. Sofosbuvir is approved in combination with Ribavirin for oral dual therapy of genotypes 2 and 3, and for triple therapy with injected pegylated interferon and Ribavirin for treatment-naive patients with HCV genotypes 1 and 4.
(A person is considered to be "treatment-naive" if they have never undergone treatment for a particular illness.)
However, Sofosbuvir is expected to be used in combination with other DAAs. There are other DAAs either in the market or in development.
The current treatment regime consists of a combination therapy of pegylated interferon and Ribavirin, which is administered through 24-38 weekly injections. The course of the treatment is determined by diseases genotype. The medicine has severe side effects.
Further, the high prices of the medicine and cost of laboratory testing compromise access to Hepatitis C treatment in developing countries. In the absence of a negotiated price, using pegylated interferon of the Originator (Roche and Merck) can cost between $10,000 to $20,000 for a 48-week treatment. In Egypt, through a price negotiation, the price has come down to $2,000.
Since pegylated interferon is a biologic, therefore, even in the absence of patent monopoly there is only limited competition in the market. Regulatory and technological bottlenecks are preventing pharmaceutical companies in developing countries from producing the low-cost pegylated interferon.
The marketing approval of Sofosbuvir, if not in combination, may not scale up the treatment immediately for all genotypes of Hepatitis C. For instance, Sofosbuvir is approved in combination with pegylated interferon and Ribavirin for treatment-naive patients with HCV genotypes 1 and 4. However, for genotypes 2 and 3, it is approved with Ribavirin, which is available at a very cheap price.
The primacy of Sofosbuvir over other approved DAAs comes from its ability to treat genotypes 1, 2, 3 and 4 of Hepatitis C. The other two products viz. Telapravir with brand names Incivek and Incivo (developed by Vertex and Johnson & Johnson) and Bocepravir with brand name Victrelis (Merck), are useful for the treatment of genotype 1 Hepatitis C.
Both medicines are used in combination with pegylated interferon alfa and Ribavirin. The literature shows nearly 90% cure rate with Sofosbuvir-based therapy.
Gilead's pricing of Sofosbuvir (brand name Sovaldi) has already come under attack. Sofosbuvir is priced at $84,000 for a 12-week treatment. The cost will go up if the treatment is required for 24 weeks.
According to a New York Times editorial dated 15 March 2014, "Gilead justifies the price is consistent with the cost of previous treatment regimens (a contention disputed by independent experts) and is reasonable given that the drug can have fewer side effects and cures a higher percentage of patients compared with other drugs".
However, critics point out that Gilead's high pricing is to recover the $11.2 billion for Pharmasset, which originally developed the drug in 2012.
A Financial Times (FT) report dated 27 January 2014 states: "Andrew Hill, a researcher at Liverpool University, argues that the new HCV drugs could be manufactured for just $100 to $200 for a course of treatment, and that high volume sales would offset lower prices".
According to Hill, with the current price, treating all people infected with Hepatitis C would cost GBP13 billion, which is more than the UK National Health System's budget for medicines.
The medicine is expected to be the next blockbuster. According to the FT report, it is expected to generate a turnover of $2.5 billion this year. The estimated annual sales would reach $7.4 billion by 2018.
Gilead closely guards its proprietary control on Sofosbuvir. The FT report states: "Gilead delayed the launch of life-changing combination HCV therapy by refusing to test Sovaldi in combination with Bristol-Myers Squibb's compound daclatasvir, despite results showing that the two drugs together generate high cure rates. Instead, Gilead combined Sovaldi with ledipasvir, its own experimental combination treatment, which had been further behind in the race to win regulatory approval".
Gilead has devised a dual strategy to maintain its market monopoly and at the same time to address the criticism on overpricing in the developing country markets.
First, it will introduce the product at a discounted price in developing countries where there is a high prevalence of Hepatitis C through price negotiations. Secondly, it will offer voluntary licenses to generic companies, especially Indian companies, to provide market access to roughly 60 developing country markets with low prevalence of Hepatitis C.
A report by The Hindu Business Line dated 3 February 2014 quotes Gregg H. Alton, Gilead's Executive Vice- President, Corporate and Medical Affairs: "We are going to give license to Indian companies, so there will be Indian production of our hepatitis C product. We are in discussions right now. ... Gilead's soon-to-be-sealed deal will include royalty payments and cover about 60 low and middle-income countries."
The Hindu Business Line report also states that "Gilead proposes to peg its imported branded product at about $2,000, he indicated, adding discussions were under way with patient-groups before the price is finalised".
However, critics point out that major markets where the disease has high prevalence have been excluded from the voluntary license.
Pauline Londeix and Chioe Forette, in their paper titled "New Treatments for Hepatitis C Virus: Strategies for Achieving Universal Access", state that the proposed voluntary license leaves out 77.4 million people with HCV from access to Sofosbuvir in low-income and middle-income countries.
A Reuters report dated 21 March states that Gilead finalised an agreement with the Government of Egypt to supply Sofosbuvir for $900 for a 12-week course of treatment. This is almost 1% of the US price where it charges $84,000 for 12 weeks of treatment.
This dual strategy of tier pricing and voluntary licensing of Gilead aims to tackle the use of patent flexibilities such as compulsory license and thus prevent genuine generic competition.
According to one observer, if successful, the pre-grant opposition in India would hamper Gilead's strategy.
Third World Network also learned that an Indian generic company has filed a pre-grant opposition on Sofosbuvir.
Unlike pegylated interferon, which is a biologic medicine, Sofosbuvir does not face any major technological or regulatory bottlenecks. Therefore, generic companies can introduce the generic version of Sofosbuvir in less than a year.
The press release of DNP+ states: "New DAAs - including sofosbuvir approved by the USFDA (US Food and Drug Administration) in December 2013 and many others in late-stage development - can be produced generically in India and marketed at very affordable prices, just like antiretrovirals (ARVs) used in the treatment of HIV. For example, a twelve-week course of sofosbuvir, produced generically, is estimated to cost between $130-$270; daclatasvir, a highly effective drug from a different class, produced by BMS, may cost just US$10-$30 per treatment course".
An observer says that generic companies could introduce the generic version of Sofosbuvir for less than 1% of the US price, especially in the light of Gilead's nearly 99% discount to the Government of Egypt.