Hepatitis Virus Timeline

Revised August 4, 2014

Prepared by KEI Staff.  This is a work in progress.  

Other KEI timelines here: http://keionline.org/timelines.  

Additional information from KEI on Hepatitis here: http://keionline.org/hepatitis.

The following URL links to this timeline: http://keionline.org/hcvtimeline.

Introduction and context

Hepatitis is a disease characterized by inflammation of the liver, and depending upon the cause and the patient, may lead to severe health problems or death.  Researchers have sought to identify various types of viruses that cause hepatitis, and to develop diagnostic tests, vaccines and treatments for those viruses.  In this timeline, there are events relating to Hepatitis A, B, C, D and E.  The short names for each virus are HAV, HBV, HCV, HDV and HEV.   The virus formerly known as Hepatitis G is now referred to as GB virus C (GBV-C).

Hepatitis is interesting to study for several reasons, including the diversity of ways that research and development has been financed, owned and progressed, and the differences in the populations affected by each virus.  

For HCV, the anticipated development of an oral-only treatment that is very inexpensive to manufacture, easy to administer, and highly effective in terms of providing a cure, provides an opportunity to vastly improve health outcomes.  The new drugs will be privately owned and very expensive.  

The large population of persons living with HCV makes the pricing issues over new HCV drugs particularly challenging, and receives extensive coverage in this timeline.

The following are some significant facts about the best known Hepatitis viruses, based largely (and often taken verbatim) but not entirely from the descriptions by the WHO:  

HAV:   Hepatitis A is a viral liver disease that can cause mild to severe illness.  Globally, there are an estimated 1.4 million cases of hepatitis A every year.  The hepatitis A  virus is primarily spread when an uninfected (and unvaccinated) person ingests food or water contaminated with the faeces of an infected person. The disease is closely associated with unsafe water, inadequate sanitation and poor personal hygiene. Unlike hepatitis B and C, hepatitis A infection does not cause chronic liver disease and is rarely fatal, but it can cause debilitating symptoms and fulminant hepatitis (acute liver failure), which is associated with high mortality.^[1]

HBV:   By some accounts, over 350 million people worldwide carry the hepatitis B virus. According to the WHO: More than 240 million people have chronic (long-term) liver infections, and more than 780,000 people die every year due to the acute or chronic consequences of hepatitis B. A vaccine against hepatitis B has been available since 1982. The hepatitis B vaccine is 95 percent effective in preventing infection and its chronic consequences, and was the first vaccine against a major human cancer. Hepatitis B prevalence is highest in sub-Saharan Africa and East Asia. Most people in these regions become infected with the hepatitis B virus during childhood and between 5–10 percent of the adult population is chronically infected. High rates of chronic infections are also found in the Amazon and the southern parts of eastern and central Europe. In the Middle East and the Indian subcontinent, an estimated 2–5 percent of the general population is chronically infected. Less than one percent of the population in western Europe and North America is chronically infected.  There are seven FDA approved drugs for HBV, none of which are considered a cure, but they do significantly decrease the risk of liver damage by slowing down or stopping the virus from reproducing.  The prices for some treatments are high.  A new Medicines Patent Pool license for tenofovir alafenamide (TAF) as a treatment for Hepatitis B may offer a lower cost treatment option in developing countries.

HCV: The WHO estimates 130–150 million people globally have chronic hepatitis C infection, and some experts suggest the infection rates are higher.  Some of those who are chronically infected will develop liver cirrhosis or liver cancer. The WHO estimates that 350,000 to 500,000 people die each year from hepatitis C-related liver diseases.^[2]  According to the CDC, in many developed countries, including the United States, the prevalence of HCV infection is less than 2 percent.  Within Europe, some countries have infection rates below .5 percent, and others have infection rates between 3 and 5 percent.  The CDC estimates prevalence to be higher than 2 percent in several countries in Latin America, Eastern Europe, and the former Soviet Union, and certain countries in Africa, the Middle East, and South Asia, and the highest (greater than 10 percent) in Egypt.  The most frequent mode of transmission in the United States is through sharing drug-injection equipment.^[3] 

In 1990 blood banks began screening blood donors for hepatitis C. In 1992 a blood test was developed to effectively screen blood before it was transfused. This reduced the risk of hepatitis C through a blood transfusion to approximately 0.01 percent leading to significant decreases in infections in the general population living in countries with well managed blood supplies.  

An SEC filing by Enanta describes the HCV virus as follows:^[4]

HCV is a small, single-stranded RNA virus. The specific genetic makeup, or genotype, of the virus can vary and at least six genotypes have been characterized in HCV-infected patients, with over 50 sub-types identified. Genotypes are designated with numbers (genotypes 1-6) and subtypes with letters (e.g. genotype 1a). HCV genotypes 1, 2, 3, and 4 are found worldwide, but their prevalence varies among geographic regions. Genotype 1, including its subtypes 1a and 1b, is the most common genotype globally, accounting for approximately 74% of all HCV infections. It is estimated that patients with genotype 2 or 3 represent approximately 12% of the worldwide chronically infected HCV population, with approximately 6% comprised of genotypes 4 through 6 and the remaining 8% of patients in other undesignated categories. The specific genotype and subtype of HCV in a patient appears to play a significant role in the degree of efficacy of standard of care therapy. Genotype 1 is the most difficult genotype to treat and the most common in North America and Europe.

About one quarter of HIV-infected persons in the United States are also infected with Hepatitis C virus (HCV). Hepatitis C is more prevalent among African Americans than among persons of any other racial group in the United States. Although rates of initial infection are comparable to other racial groups, the chronic HCV infection rate is higher among African Americans than among white individuals.

As of July 2014, there were eleven FDA approved drugs to treat the hepatitis C infection, but access to diagnosis and treatment is currently low. A new oral only treatment that is inexpensive to manufacture and offers a cure is expected in 2014, and could potentially radically change the possibilities for treatment, but disputes over the pricing of the new HCV drugs have yet to be resolved. There is currently no vaccine for hepatitis C.

HDV: Studies reported in 1977 found that some patients with a more damaging form of HBV infection were also infected with a second virus that is known as hepatitis delta virus, hepatitis D virus or simply HDV. The genomes of HBV and HDV are very different and replicate by different mechanisms. An estimated 15-20 Million individuals are infected with HDV worldwide. Hepatitis delta is the most severe form of chronic viral hepatitis, and there is no testing or identification of HDV infection.  Migrant populations and special risks groups show particular high HDV prevalences. Screening for HDV is limited, and the only available treatment for chronic HDV has a 25 percent success rate, involves at least weekly injections of high doses of pegylated interferons for one year.

HEV:  According to WHO: Outbreaks and sporadic cases of hepatitis E occur around the world. These outbreaks frequently occur in resource-limited countries with limited access to essential water, sanitation, hygiene and health services, and may affect several hundred to several thousand persons. In recent years, some of these outbreaks have occurred in areas of conflict and humanitarian emergencies, such as war zones, and in camps for refugees or internally displaced populations (IDP). An estimated 20 million infections and 3.3 million acute cases occur annually worldwide with an estimated 56,600 deaths.

Key Figures

Raymond R. Schinazi.  One of several key figures in the development of new treatments for hepatitis is Dr. Raymond R. Schinazi.  Schinazi is a founder or co-founder of Triangle Pharmaceuticals, Pharmasset, Idenix and several other companies, including at present, RFS Pharma.  Schinazi is listed as an inventor on 92 US patents, including 49 that disclose federal funding for the inventions. From 1991 to 2012, Schinazi was a principal investigator in 64 NIH grants involving $10.5 million.^[5]  Schinazi has worked with a number of Universities, including Emory, Yale, the University of Georgia, among others, and he has a long association with the Atlanta Veterans Affairs Medical Center. The first of the 49 USPTO patents that disclose federal funding was filed on 1986, and the last one was filed in 2009.  Among the federal agencies listed as funders of Schinazi’s various inventions were the NIH, the Veterans Administration and the National Science Foundation.^[6]

Other key figures will be profiled later.

The Timeline

The timeline was created as a collaborative effort, and several specific entries rely extensively on third party documents, which should be (but probably are not always) cited in the footnotes.  The most extensive sources for the dates and events are academic articles, company SEC reports and press releases, court cases, patent filings, and the FDA.  We created this document, which will be updated for a while, to help us better understand the market for diagnostic tests, vaccines and drugs to treat hepatitis, and, to be a research tool available to anyone interested in similar issues.  Comments or corrections can be sent to James.Love@Keionline.org or elizabeth.rajasingh@keionline.org.

A long time ago

According to many historians of science, the history of viral hepatitis goes back thousands of years and were outbreaks of jaundice epidemics in China 5,000 years ago and in Babylon more than 2,500 years ago. The catastrophic history of what was called then great jaundice epidemics and pandemics is relatively well known and generally associated with major wars^[7]. 

460-375 BC

In On Airs, Waters, and Places, Hippocrates describes the clinical features of epidemics of jaundice, and the significance of the outbreaks in several military campaigns.  

Middle ages to the 18th Century

The first recorded reference to the contagious nature of jaundice appears to have been in the 8th century A.D., in a letter from Pope Zacharias to St. Boniface, Archbishop of Mainz. For Military historians of science and medicines such as Joe Dean and Brigadier General Andre J. Ognibene, jaundice was clearly a common disorder in the Middle Ages when "campaign jaundice" was described as "following cholera and bubonic plague in importance as a cause of pandemics in Europe"^[8]. In the Middle Ages, a Spanish doctor named Moses Maimonides (1113-1204) described the disease. Sydenham, in London, had already recorded some observations of epidemic jaundice for the period between 1624 to 1689.  

Von Bormann et al. (1943), described an outbreak occurring in Germany in 1629 and the first definitive description of a jaundice epidemic in civilians was recorded in Germany in 1791 by Herlit.  

1883

1883.  In Bremen, 1289 shipyard employees received vaccinations after a smallpox outbreak, and these vaccinations were suspected to have caused 191 workers to develop jaundice.   An influential epidemiological study of the event is provided by Lührman in 1885.^[9]  According to Lührman, only workers who had received the vaccinations developed jaundice, and none of the workers who did not receive the vaccination developed jaundice.^[10] 

1942 to 1950

Beginning in 1942, research in Germany, England and the US confirm the transmissibility of viral hepatitis A and B and described their characteristics.

1947.  MacCallum and Bauer propose the current nomenclature of hepatitis A for infectious hepatitis and hepatitis B for “homologous serum” hepatitis.^[11]

1953-1956

1955 - 1956.  The first retrospectively documented hepatitis E outbreak occurs in India.^[12]

1960

1960 July.   Working at the Bronx Veterans Administration, Rosalyn S. Yalow and Solomon A. Berson publish “Immunoassay of Endogenous Plasma Insulin in Man,”^[13]  describing Radioimmunoassay (RIA), a very sensitive in vitro assay technique used to measure concentrations of antigens by use of antibodies.  This will later be used to screen blood for hepatitis.  In 1977 Yalow will win the Nobel prize for this invention.

1964

1964.   Baruch Blumberg, Harvey J. Alter and Sam Visnich discover an antigen associated with blood samples from Australian aboriginals, which they initially believe has a strong association with leukemia.

1965

1965. Baruch Blumberg, Harvey J. Alter and Sam Visnich, publish “A ‘new’ antigen in leukemia sera”, in JAMA. The connection to hepatitis had not yet been made.^[14]  The new antigen is named the Australian antigen. ^[15]

1966

1966. Baruch Blumberg and colleagues establish that the Australia Antigen is associated with acute viral hepatitis.

1967

1967. Blumberg and colleagues publish a report of their 1966 research: “A. I. A serum antigen (Australia antigen) in Down’s syndrome leukemia and hepatitis.”^[16]

1968

1968. Baruch Blumberg is “informed by the Federal government, who provided most of the funds” for his work, “that they would like to see applications of the basic research they had funded for many years.”^[17]

1969

1969 Oct 8. Baruch S Blumberg and Irving Millman file application for US Patent 3,636,191, “Vaccine against viral hepatitis and process.”

1970

1970 April 4. David Dane, Colin Cameron and Moya Briggs, researchers from the Middlesex Hospital School of Medicine, identify the complete hepatitis B virus in serum using electron microscopy.  The virus is sometimes referred to as “the Dane particle.”^[18]

1970 May.   John Walsh, Rosalyn Yalow and Solomon Berson publish “Detection of Australia Antigen and Antibody by Means of Radioimmunoassay Techniques” in the Journal of Infectious Disease.^[19] 

1972

1972 January 8. The Blumberg/Millman Patent 3,636,191 is issued.

1972.  Robert Purcell from the NIH and colleagues at CDC develop the first hepatitis B animal model, described by the NIH as “a breakthrough that finally allowed researchers to observe the course of disease.”^[20]

1973

1973.  Robert Purcell, Albert Kapikian, and Stephen Feinstone of the US National Institute of Allergy and Infectious Diseases isolate and characterize the Hepatitis A virus (HAV).

1976

1976 October 6.  Merck signs a non-exclusive license with the NTIS for the Blumberg/Millman patent 3,636,1919, for use in a vaccine for Hepatitis B.  The license provides for a royalty of 2 percent for domestic sales and 1 percent for foreign sales, and no royalty for sales directly to the United States government.

1976 October 14.  Baruch S. Blumberg receives the The Nobel Prize in Physiology or Medicine for his work on Hepatitis B.

1977

1977 February.  HEW secretary Joseph Califano blocks 30 patent applications and three IPAs applications, and reverses a proposal for more liberal University patenting of recombinant DNA technologies.^[21]

1977 October.  Rosalyn Yalow becomes the  second woman to win the Nobel Prize in Physiology or Medicine.  The Nobel committee honor is for her role in devising the radioimmunoassay (RIA) technique^[22] made possible the screening the blood of donors for such diseases as hepatitis, among other uses.^[23], ^[24].  Yalow and her colleague Solomon Berson developed the technology while working for the Veterans Administration in New York, and refused to patent the technology.  One account of the decision to not patent is provided by Eugene Straus, a colleague:^[25]

"We never thought of patenting RIA," Yalow says, looking down her nose as though a dead fish had been placed before her.  "Of course, others suggested this to us, but patents are about keeping things away from people for the purpose of making money.  We wanted others to be able to use RIA. Now some people assume that I'm sorry, but I'm not.  Anyway, we had no time for such nonsense."  

Another account:^[26]

Berson and Yalow acted in unison in their work and together they decided not to patent their radioimmunoassay.  

"This was a conscious decision on our part.  The radioimmunoassay technique was a joint discover by myself and Solomon A. Berson.  Sol and I worked together for eighteen years before he left the Veterans Administration and became Chairman of Medicines at the Mount Sinai School of Medicine in 1968.  He died four years later.  In 1972, a young doctor of medicine, Eugene Straus joined me.”

“When Sol and I discovered the radioimmunoassay technique, at the beginning it had a slow start, but we knew it could catch up quickly because it was a very sensitive and very useful too.  We were very determined not to take out a patent on it but to do everything to help it spread.  We organized courses to teach physicians to use the technique.

From the New York Times report of the Nobel prize.^[27]

Dr. Yalow said that all of the funding for the research had come from the Veterans Administration.  Although the V.A.'s medical care system has come under fire from a National Academy of Science study group, the agency's medical research program has been held in high regard.  Dr. Yalow, in praising the support of the V.A. has given her, said that she never considered leaving the Bronx V.A. hospital because "they took me when I was a nobody and they gave me the chance to work freely."  The only tragedy in today's Nobel award," she added,is that Dr. Berson did not live to share it.

The following April, after winning the prize, Yalow was the subject of a long profile in the New York Times, written by Elizabeth Stone, titled, “A MME. Curie from the Bronx.”  From the Stone Article:^[28]

"We did not patent the radioimmunoassay," says Dr. Yalow. "Scientists don't always think of things as being patentable. We made a scientific discovery. Once it was published, it was open to the world. I have no doubt that if I wanted to, I could be a consultant to any of the drug companies. I choose not to do this because as their employee, I would not be free to speak my mind about policies in the use of radioimmunoassay procedures. I've been known to say that I think there's very much of an overuse of radioimmunoassay, that it's being sold for diagnostic testing where in fact it isn't very useful."

1977.  Dr. Daniel W. Bradley of the CDC begins research that led, after many years of effort, to his successful isolation of a concentrated and purified form of the hepatitis C virus (HCV), including characterization of various properties of the virus.

1978

1978 September 13.  Senators Bayh and Dole introduce a bill to allow universities to have greater rights in inventions funded by the federal government.

1978.  Hepatitis E is first recognised during an epidemic in Kashmir Valley.^[29]

1978 December 19.  Bristol-Myers receives FDA marketing approval for cisplatin as a treatment for cancer. Cisplatin’s use as a cancer treatment was led by Barnett Rosenberg  from Michigan State University, and his colleague Loretta Van Camp, and licensed to Bristol-Myers by the Research Corporation, a non-profit organization that managed the commercialization of patents for several universities.  The drug was among the first expensive cancer drugs, and it changed expectations about the potential profitability of treatments for severe illnesses, and controversies over the licensing of the drug played a role in the passage of the Bayh-Dole Act in 1980, which made it easier for Universities and their researchers to own federally funded inventions, and also to the 1984 amendments to the Bayh-Dole Act which liberalized rules for life-of-patent exclusive rights to patents on federally funded inventions.

1979

1979 August 3. Baruch S Blumberg testifies in favor of the Bayh-Dole Act, and against a proposal for a “pay-back” provision to return a share of royalties to the funding agencies.^[30]

1980

1980 June 16. The U.S. Supreme Court ruled in Diamond v. Chakrabarty, 447 U.S. 303 (1980), that micro-organisms could be patented.

1980 December 12. The U.S. Bayh-Dole Act was enacted (also in Public Law 96-517), codified in 35 U.S.C. § 200-212

1981

1981. Chiron is founded by William J. Rutter, Professor Edward Penhoet, and Pablo D.T. Valenzuela.  Rutter and Valenzuela were at the University of California San Francisco (UCSF), and Penhoet at the University of California at Berkeley.  Professor Penhoet later described Chiron as "as close to a virtual corporation as you can be, "focusing on licensing its technologies.^[31] From 1990 to 1995, Rutter was the principal investigator for 12 NIH grants involving $2.7 million in funding, including six from NIAID with the title “Molecular Analysis of Hepatitis B Virus.” Through his association with UCSF, Rutter is listed as an inventor for 22 patents assigned to the University of California filed from 1981 to 1995, of which only two disclosed federal funding of the invention.^[32]  Chiron will eventually be assigned 21 patents that disclose federal funding of the invention, including 8 that mention hepatitis.^[33] 

1981. The FDA approves the hepatitis B vaccine, the first vaccine to protect against cancer (primary liver cancer).^[34]

1982

1982.  Chiron Corporation enters into a collaboration with the Centers for Disease Control (CDC).  CDC scientist Dr. Daniel W. Bradley works with Chiron to clone HCV viruses from samples provided by Dr. Bradley.^[35]

1982.  FDA approves the first hepatitis B vaccine.

1982.  Raymond F. Schinazi becomes a researcher at the Atlanta Veterans Administration Medical Center.

1983

1983. Two separate research groups isolate the virus that is eventually named HIV.

1983.   Mikhail Balayan, a Russian virologist, first visualized Hepatitis E,^[36] which he obtained from a Soviet military camp located in Afghanistan where an outbreak had occurred.   It was not easy.

“Dr. Balayan was investigating an outbreak of non-A, non-B hepatitis in a central Asian part of the Soviet Union. Though he wanted to bring samples back to his Moscow laboratory, he lacked refrigeration. So he made a shake of yogurt and an infected patient’s stool, drank it, went back to Moscow, and waited. When he became seriously ill a few weeks later, he started collecting and analyzing his own samples. In these he found a new virus that produced liver injury in laboratory animals and could be seen by electron microscopy. It looked a lot like hepatitis A virus, but he could show that it was not, because he already had antibodies against the hepatitis A virus and these did not react with the new virus.”^[37]

1984

1984.  Digene Corporation is founded, as a molecular diagnostics company with company headquarters in Gaithersburg, Maryland, USA.  

1984 September 1.  The costs of hepatitis B vaccine and its administration became a covered benefit under Medicare Part B.

1984 September 24.  That Hatch-Waxman Act becomes law.

1984  October 30.  Congress eliminates the means test for Orphan Drug exclusivity.

1984 November 8.  Congress allows Universities and private companies, regardless of size, to obtain exclusive licenses for the life of a government funded patent.

1986

1986.  SmithKline Beecham initiated a CRADA with NIAID's Laboratory of Infectious Diseases, Hepatitis Viruses Section, to develop an inactivated vaccine for the hepatitis A virus.  GlaxoSmithKline would later license the vaccine technology in Europe in 1991 and in the United States in 1995, marketing a vaccine under the brand name Havrix.  This is just one of many NIH/Industry CRADAs involving hepatitis research and development.  (KEI is seeking to a obtain a more complete list from the NIH).

1986 June 4.  FDA approves  INTERFERON ALFA-2A, marketed by Hoffman-la Roche as ROFERON A.

1987

1987. Michael Houghton, Qui-Lim Choo, and George Kuo of Chiron Corporation and Daniel W. Bradley of CDC discover fragments what is later named Hepatitis C virus (HCV).

1986 March 19. Burroughs Wellcome receives FDA approval for AZT and announces a price of $10,000 per year, shocking patients and changing expectations about the feasible price of a treatment for an infectious disease.^[38] 

1989

1989.  After public outcry over the pricing of AZT, the Administration of George HW Bush adopted a policy of requiring firms to sign "reasonable pricing" clauses in return for

entering into Cooperative Research and Development Agreements (CRADAs) with the

federal government, or entering into an exclusive licenses to federal government owned research on pharmaceuticals.

1989 April 21. QL Choo et al publishes an article in Science describing cDNA clone on HCV, then described as non-A, non-B viral hepatitis.^[39]  Daniel W. Bradley of the CDC is listed as a co-author in the paper.

1989 May 25.  USTR publishes its first Special 301 list, identifying foreign countries that do not have sufficient levels of intellectual property protections.

1989 June 28.  Gregory Reyes, Daniel Bradley, Linda Rabin and Kirk Fry file for a patent titled Post-transfusion, non-A, non-B hepatitis virus polynucleotides.  The patent, later issued as patent 5,218,099 on June 8, 1993, is assigned to Genelabs and the United States Government.

1989 September.  Glenna Hendricks files a patent application for HCV that names Daniel Bradley as an inventor along with three Chiron scientists.^[40]

1989 October. Chiron writes  to CDC proposing to establish “an overall mechanism that would compensate Dr. Bradley's contribution regardless of his status as an inventor, resolve any inventorship dispute and protect Chiron's commercial interests.”^[41]

1990

1990. Blood banks begin screening blood donors HCV.

1990 March 12.   Represented by Joseph Califano, the former Secretary of HEW, Chiron reaches an agreement with the federal government under which they would pay CDC $1,912,500 and pay Dr. Bradley $337,500 over five years.  Bradley later sues claiming duress and fraud.  

1990 March 16.   Science publishes, a paper coauthored by Gregory Reyes and colleagues at GeneLabs, and Daniel Bradley at the CDC, titled “Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis,” reporting they have cloned and sequenced the genome of the virus collected earlier by Mikhail Balayan, and renamed it Hepatitis E.

1990 March 27.  The European Union tables a draft of the TRIPS Agreement, in negotiations to create the WTO.

1991

1991. FDA approves first alfa interferon (Schering’s Intron A) to treat HCV.^[42]

1992

1992 March 2. Chiron together with Ortho Diagnostic Systems, Inc. and Ortho Diagnostic Systems, Ltd, filed suit in the High Court for England and Wales against Murex Diagnostics, Ltd., “alleging infringement of Chiron's U.K. Patent No. 2,212,511 ("the '511 patent") as a result of Murex's manufacture and sale of HCV immunoassay kits in the U.K.”^[43]

1993

1993. Mr. Justice Aldous, the main High Court Patents Judge, gives judgement in Chiron v. Murex (in respect to HCV diagnostic kits) and Biogen v Medeva (in respect to HBV diagnostic kits), finding both patents to be valid and infringed.^[44]

1993 December 13. Chiron files a patent infringement action against Abbott Laboratories in the United States District Court for the Northern District of California. The suit, which alleges infringement of Chiron's U.S. Patent No. 5,156,949 ("the '949 patent"), “claiming the use of recombinant envelope antigens in immunoassays for HIV antibodies, is based on Abbott's sale of unlicensed HIV immunoassay tests which are believed to fall within the scope of one or more patent claims.” ^[45]

1994

1994.  Founding of Inhibitex, a firm located in Georgia. that will focus on research on hepatitis C.  The company is eventually sold in 2012 to BMS for $2.5 billion.  Inbibitex will be assigned six patents for inventions funded by the NIH or the US Department of Agriculture, and will license technologies from Universities in the United States, Ireland, Wales and Belgium.

1994 May 4. Chiron institutes summary legal proceedings against Organon Teknika, B.V., Akzo Pharma, B.V., Akzo Pharma International, B.V., Organon Teknika, N.V. [all subsidiaries of Akzo N.V. and United Biomedical, Inc., the supplier of Organon's HCV antigens and kits, in the District Court of the Hague, The Netherlands, alleging infringement of European Patent No. 318,216 ("the '216 patent") as a result of the defendants' manufacture and sale of HCV immunoassay kits.^[46]

1994 April 26. Abbott filed suit against Chiron in the United States District Court for the Northern District of Illinois, Eastern Division, alleging that the Company has, by making, using and selling nucleic acid hybridization assays, infringed three U.S. patents owned by third parties and licensed to Abbott.^[47]

1994 June 14. “Sorin Biomedica S.p.A. filed a lawsuit with the Court of Milan, Italy against Chiron Corporation and Ortho Diagnostic Systems S.p.A. for a declaration of nullity and noninfringement of the Italian counterpart to Chiron's European Patent 0 318 216 (the " '216 patent"). Sorin additionally filed a request with the Italian Ministry of Industry, Commerce and Artisanship ("ICA") for compulsory license to the '216 patent. Chiron filed a counterclaim and sought a finding that the patent is valid and infringed by Sorin. The ICA suspended Sorin's request for compulsory license pending the outcome of the litigation. On February 10, 1997, the Court enjoined Sorin from manufacturing or selling HCV immunoassay kits in Italy.”^[48]

1994.  Proceedings No. G1 06 of 1994 commenced in the Federal Court of Australia, New South Wales District Registry, General Division, between Murex and Chiron.

1994 October 6.  COMMISSION DECISION of 6 October 1994 relating to a proceeding pursuant to Article 85 of the EC Treaty and Article 53 of the EEA Agreement (IV/34.776 - Pasteur Mérieux-Merck)^[49].  From the decision:    

------------------------

(23) The Hepatitis B vaccine is no longer produced on a plasma basis, in view of the blood-related risks. All current formulations are produced by way of genetic engineering. This is, however, subject to different patent claims. There is, furthermore, considerable uncertainty as to the legal validity and precise scope of the different patent claims for Hepatitis B vaccine technology. Some patent applications have yet to be granted, and some of them may either be opposed or have already been partly or entirely revoked or are under appeal. For this reason, Merck and SKB decided to enter into cross-licensing arrangements in relation to rights which had been licensed by several research institutions to them. This cross-licence does not allow these parties to sub-license their acquired rights to other companies whereas a sub-licence to an affiliate such as a JV is allowed. Other producers which would like access to the patent rights involved, in order to avoid uncertainty and costs of litigation, therefore need at least a sub-licence of both Merck and SKB under their respective rights.

. . .

(51) In view of SKB's observation concerning access to vaccine technology, the parties amended their exclusive patent and know-how licences for the EEA to the JV by explicitly allowing the JV to sub- and or cross-license these intellectual property rights for the development and/or manufacture in the EEA of existing and future vaccines to other manufacturers. . .

---------------------

1994 November 22. Ciba-Geigy Ltd. of Basel, Switzerland agreed to acquire a 49.9 percent stake in the Chiron Corporation for about $2.1 billion, or $117 a share.^[50]

1994 November 29. The U.K.’s high court grants a permanent injunction against the sale of a hepatitis C test made by Murex Diagnostics Ltd and reaffirms an earlier ruling that the company had infringed a patent on hepatitis C by the Chiron Corporation of California, which discovered the virus in 1987.^[51]  Murex issues a statement, saying it will be seeking compulsory licenses to the patents in the UK.

"Today's ruling on the Murex(TM) anti-HCV assays strengthens our resolve to ultimately succeed in our fight against Chiron and Ortho's claim to an excessively-broad Hepatitis C monopoly," stated J. David Tholen, President and CEO of Murex. "We will also be seeking a decision from the U.K. government on invoking Crown Use to allow continuing supply of the Murex products to our U.K. customers. We will also be applying for a U.K. compulsory license under the Chiron patent when the three years' grace period expires in January, 1995.^[52]

1994 December 20. Dr. Bradley brings suit in the Northern District of California against Chiron, claiming the company had used his research to isolate and clone the hepatitis C virus and then shut him out of a patent resulting from the discovery and seeking to rescind a settlement the federal government reached with Chiron. Bradley says he signed the agreement because he had been diagnosed with prostate cancer and was concerned about his ability to provide financially for his family. He alleges mistake, fraud, and failure of consideration.^[53]

1994 December 28. Chiron responds to Dr. Bradley saying he did not contribute to the key part of the research and described the suit as part of a “desperate strategy” to challenge Chiron’s hepatitis C patents.^[54]

1994 November 24.  Ciba-Geigy announces agreement to acquire 49.9 percent of Chiron.^[55]

1995

1995.  FDA approves the first hepatitis A vaccine.

1995 April 12. The NIH relinquishes its right to require reasonable pricing of drugs and other products developed with federal funds, and subject reasonable pricing clauses in patent licenses and CRADA contracts.^[56]  The reasonable pricing provisions were introduced by President Bush in 1989.

1995 November 2. The Court of Appeal of England and Wales handed down its decision in the case of Chiron Corporation v. Murex Diagnostics, rejecting Murex’s appeal and confirming the High Court’s decision that the patent was valid and infringed. The case concerned Chiron's patent relating to HCV diagnostics kits.^[57] 

1995.   Dr. Raymond F. Schinazi and others found Triangle Pharmaceuticals.^[58] 

1996

1996 March 7. Ciba-Geigy and Sandoz agreed to the merger that created Novartis.   

1996 April.  Emtricitabine (FTC), which was discovered by Dr. Dennis C. Liotta, Dr. Raymond F. Schinazi, and Dr. Woo-Baeg Choi of Emory University on an NHI grant, was  licensed to Triangle Pharmaceuticals, a company partly founded by Schinazi,  by Emory, which employed Schinazi.  FTC will eventually be approved to treat HIV and HBV.

1996.  Chiron refers to “The "Australian Anti-Trust and Compulsory Licence Proceedings" as “Proceedings No. G380 of 1996 in the Federal Court of Australia, New South Wales District Registry, General Division.^[59]

1996  June.  In litigation in Australia involving Murex Diagnostics Australia and Chiron, Baruch Blumberg gave testimony criticizing the overly broad nature of Chiron's HCV Australia patent No 624105.  Blumberg said "Based on the unusually broad nature of the patent, if I were a research director for anti-virals and had the option of working on several viruses, the existence of this patent would weigh against my deciding to undertake HCV research.  A company, or even an academic laboratory, might well be deterred from conducting research on HCV because the patent is, in effect, intimidating."^[60]

1996 August 26.  Murex acquires license for HCV patents from Chiron.^[61] From an August 26, 1996 press release: “Chiron Corporation, its immunodiagnostics partner Ortho Diagnostic Systems, Inc., a Johnson & Johnson company, and International Murex Technologies Corporation announced today that the three companies have reached a worldwide agreement concerning tests for hepatitis C virus (HCV) under which all litigation between the companies will permanently cease.  The agreement grants Murex a license to sell HCV serotyping tests worldwide, and other HCV tests in selected countries excluding North America, European Economic Community members and Japan. . . . Murex also agreed as part of the settlement to withdraw its opposition to Chiron's HCV patents worldwide.”^[62]

1996 September 30. Hoffmann-La Roche, Gilead Sciences announce a collaboration to co-promote  Roferon -A (Interferon alfa-2a, recombinant) as a potential Hepatitis C Treatment in the U.S.^[63],^[64].

1996 November 11.  The FDA approves Roferon A for treatment of chronic HCV.

1997

1997. FDA approves consensus interferon (Amgen- not InterMune-Infergen) to treat HCV.

1997 January. “Chiron, together with Ortho-Clinical Diagnostics, Inc., files suit against F. Hoffman-LaRoche AG ("Roche Germany") for infringement of immunoassay technology under the '216 patent. The suit seeks damages and injunctive relief preventing further manufacture or sale in Germany of infringing HCV immunoassay kits. Roche Germany asserted certain claims and defenses in this matter. In April 1999, following a trial, the Court issued a decision granting Chiron's application and entered an injunction. Roche has appealed the decision.

Chiron also files a suit against Roche in Dusseldorf, Germany, for infringement of Chiron's European Patent 0 181 150 relating to HIV probes technology. The suit seeks injunctive relief and damages. Trial of this matter took place in February 2000 and a judgment is expected in May 2000.”^[65]

1998

1998.  Incubated by Harvard, Enanta Pharmaceuticals Inc. is founded.  

1998. Pharmasset is founded by Dr. Raymond Schinazi, a scientist associated with Emory University and the Atlanta Veterans Administration, and Dr. Dennis Liotta, a scientist at Emory University.

1998.  Raymond F. Schinazi also founds Idenix Pharmaceuticals, Inc., which, like Pharmasset, focuses on the  discovery and development of pharmaceutical products to treat viral and infectious diseases including hepatitis B and hepatitis C.

1998. Daniel Bradley drops suit against Chiron after losing an appeal.

1998. The Veteran Affairs’ HIV/Hepatitis QUERI is started.

1998 January. “Chiron initiated an action against F. Hoffman-LaRoche, Ltd., several of its affiliated companies (collectively, "Roche") and Daniel Bradley in the United States District Court for the Northern District of California. The Company asserts that Roche's manufacture and sale of Amplicor-Registered Trademark- HCV Test and Amplicor-Registered Trademark- HCV Monitor Test infringes Chiron's U.S. Patent Nos. 5,712,088 (the "'088 patent") 5,714,596 (the "'596 patent") and 5,863,719 (the "'719 patent") The action also asserts that Bradley breached a 1990 settlement agreement with Chiron, that Roche wrongfully induced this breach, and that Bradley committed slander of title with respect to Chiron's HCV technology. The action seeks damages, injunctive relief and a declaratory judgment that Chiron is the sole and exclusive owner of its HCV technology. Roche filed a counterclaim requesting a declaratory judgment of non-infringement and invalidity and also alleging infringement of U.S. Patent No. 5,580,718 (the "'718 patent"), owned by Hoffman-LaRoche, Inc., which allegedly relates to nucleic acid-based assays for the detection of HCV. The counterclaim of infringement seeks damages and injunctive relief. Chiron is defending on the basis of invalidity and non-infringement of the '718 patent and seeks a declaration of invalidity of U.S. Patent No. 5,527,669 (the "'669 patent"), a related patent also owned by Hoffman-LaRoche. The parties' cross-motions for summary judgment on Roche's license based defenses were resolved in Chiron's favor by a Court order dated June 23, 1999. The order, which is subject to appeal, holds that Roche has neither express nor implied license rights to Chiron's HCV technology. The Court found that foreign and domestic rights were assigned by Bradley to Chiron under the 1990 settlement, that Bradley's earlier litigation against Chiron was RESJUDICATA as to foreign rights, and that Bradley's assignment of such rights to Roche breached his settlement agreement with Chiron. In October 1999, Roche filed counterclaims against Chiron which challenge the validity and enforceability of the patents in suit.”^[66]

1998. FDA approves Rebetron (Schering’s Intron A plus Ribavirin) to treat HCV.

1998 March 16.   Abbott Laboratories acquires International Murex Technologies Corporation.^[67] 

1998 April 3.  Chiron files a complaint with the International Trade Commission objecting to the importation of recombinantly produced hepatitis B vaccines supplied by SmithKline Beecham, on the grounds that the imported vaccines infringe four claims in a Chiron process patent.

1998 December 8.  The National Institute of Diabetes and Digestive and Kidney Diseases publish a notice of an Licensing Opportunity and/or a Cooperative Research and Development Agreement (CRADA) for the development a hepatitis C virus (HCV) vaccine based upon the synthesis and purification of non- infectious HCV-like particles containing HCV structural proteins.

1999

1999.  Raymond Schinazi receives $125,000 from the Office of Research and Development for the Veterans Health Administration, in the Department of Veterans Affairs to study the Mechanism of Action of Antiviral Drugs.  This is one of several grants and contracts with the VA.

1999. The VA issues guidelines to all facilities for screening, counseling and drug therapies for hepatitis C and established first centers of excellence in hepatitis C treatment and research in Miami and San Francisco.^[68]

1999 December 1. Chiron Corporation announces that it has settled its lawsuit against Gilead Sciences for infringement of Chiron's United States hepatitis C virus protease patents -- numbers 5,371,017; 5,585,258 and 5,597,691.^[69]

2000

2000. Roche asks the German government to grant a compulsory license on a patent protecting the Blood Screening HIV Probe owned by Chiron.

2000 July. Chiron initiated an action against Roche Diagnostics GmbH “asserting that Roche's manufacture and sale of products regarding HCV nucleic acid test and immunoassay technology infringe Chiron's German Patent Nos. DD 298 527 (the " '527 patent"), DD 298 524 (the " '524 patent"), DD 287 104 (the " '104 patent"), DD 297 446 (the " '446 patent") and Chiron's European Patent No. EP 0 450 931 (the " '931 patent")”. (Source, Chiron SEC form 10-k for period ending December 31, 2000)

2000 July. Chiron initiated action against Roche Diagnostics GmbH asserting that Roche's manufacture and sale of HCV immunoassay products infringe the '931 patent. In January 2001, this action was referred to the District Court of Mannheim. Roche appealed the referral, and in February 2001, the Verwaltungsgericht transferred the action to the Administrative Appeal Court. (Source, Chiron SEC form 10-K for period ending December 31, 2000).

2000 October 1. Chiron announces that it has reached a broad patent license agreement with Roche for probe-based clinical diagnostics for the hepatitis C virus and human immunodeficiency virus. The license agreement in clinical diagnostics allows for settlement of pending litigation in the United States, Italy, Japan, the Netherlands, Belgium, Germany and Australia regarding HCV and HIV nucleic acid technology. The settlement will enable Roche to continue to market probe-based hepatitis C virus and human immunodeficiency virus diagnostic product. Chiron will also grant a limited license to Roche for nucleic acid testing of blood intended for transfusion.^[70]

2000 October.   Harvey Alter (NIH) and Michael Houghton (Chiron) awarded the Albert Lasker Clinical Medical Research Award “for pioneering work leading to the discovery of the virus that causes hepatitis C and the development of screening methods that reduced the risk of blood transfusion-associated hepatitis in the U.S. from 30 percent in 1970 to virtually zero in 2000.”^[71]

2000 November. Innogenetics N.V. brought a complaint against Chiron and Ortho-Clinical Diagnostics Systems Inc. ("Ortho") before the Commission of the European Communities (the "Commission"). Innogenetics N.V. alleges that Chiron and Ortho violate Articles 81 and 82 of the European Economic Community Treaty relating to competitive practices. Pursuant to the complaint, the Commission has sought information from Chiron and Ortho related to HCV and HIV licensing practices in the European Union.^[72] 

2000 December. Roche initiated two nullity actions against Chiron's German national patents (the '104, '524 and '527 patents), and the European '931 patent in the German Federal Patent Court ("Bundespatentgericht"). In January 2001, the Bundespatentgericht divided the German patent suit into three individual actions.^[73]

2001

2001 January 19. FDA approves Peg-Interon (Schering’s pegylated interferon alpha-2b), the first pegylated interferon to treat HCV. The sustained virological response rates are 14 percent for genotype 1 and 47 percent for genotypes 2 and 3.

2001 May 11, 2001. A combined hepatitis A inactivated and hepatitis B (recombinant) vaccine (Twinrix by SmithKline Beecham) are licensed.

2001 May 22.  A licensing agreement is reached between Roche and Chiron in regards to the blood screening HIV probe owned by Chiron. In return for its license, Roche agrees to end its attempts to obtain a compulsory license.

2001 August 7.  The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) publishes a request for proposals in the form of capability statements from companies for a Cooperative Research and Development Agreement (CRADA) to provide active agent(s) to study important issues surrounding viral resistance to interferon in hepatitis C, particularly in African Americans.  The CRADA will involve a multicenter, clinical trial to study viral resistance to pegylated interferon therapy in combination with ribavirin in patients who have chronic hepatitis C, genotype 1.  The NIDDK later enters into a CRADA with Roche.

2001 August 13.  Roche and Schering-Plough enter into a licensing agreement that resolves patent disputes with regards to their peginterferon products. The agreement allows both companies to manufacture and market their respective products without fear of patent infringement.^[74]

2002

2002. Genentech’s Pegasys is approved to treat hepatitis C (BLA 103964). The sustained virological response rate for Pegasys is 28 percent for genotype 1 and 56 percent for genotypes 2 and 3.

2002 March.  Novartis acquires 51 percent stake in Idenix.^[75]

2002 December 4.  Gilead announces it will acquire Triangle Pharmaceuticals for $464 million.^[76] The press release focuses on Triangle products for HCV and HBV.

2003

2003 January 1.  Vertex announces it is “restructuring” an agreement with Eli Lilly, ending Lilly’s involvement in the development and commercialization of VX-950, a novel, oral hepatitis C viral protease inhibitor.^[77]

2003 November.  Novartis acquires 51 percent of Idenix Pharmaceuticals.

2004

2004 March 2. CDC reviews a 14-year-old government agreement with Chiron that allows the company "so much control" over hepatitis C research that competitors say they have abandoned plans to enter the field. Chiron holds a total of 100 hepatitis C-related patents in 20 countries.^[78]

2004 June 22. Chiron announces it will no longer require licensors to pay upfront fees and make annual payments to obtain rights to its patents covering the genetic makeup of HCV, a move designed to respond to criticism from the CDC and others that its licensing policies were discouraging the development of new drugs.^[79]

2004 September 13. Chiron grants a nonexclusive license to InterMune for the research, development and commercialization of therapeutics against HCV drug targets.^[80]

2004. September.  Raymond Schinazi founds RFS Pharma.

2004 October 27. Roche reaches an agreement with Pharmasset to develop nucleoside polymerase inhibitors for the treatment of chronic hepatitis C. Under the terms of the deal, Roche will have worldwide rights, excluding Latin America and Korea, to Pharmasset's PSI-6130 drug and its prodrugs. “Pharmasset will receive an upfront fee, research and development support, and milestone payments that could total $168 million for PSI-6130, the lead nucleoside compound of the partnership. In addition, Pharmasset will receive royalties on product sales and retain certain co-promotion rights in the US.” ^[81], ^[82].

2005

2005 October 31. Novartis bids $5.1 billion to buy Chiron, then the world’s fifth-biggest vaccine maker.^[83]

2006

2006 February 6. In the review of the merger between Novartis and Chiron, the FTC notes that Roche, in which Novartis has a 6.3 percent share, and Chiron are the only two suppliers for a number of blood testing products, creating concern about the effect the proposed merger could have on the degree of competition between Chiron and Roche. The Commission determines that Novartis’ minority shareholding in Roche is not sufficient to provide Novartis with the ability to exercise influence on Roche’s strategy in the field of blood testing and to provide Novartis with the economic incentive to distort competition between Chiron and Roche.^[84]

2006 February 21. The Indian Patent Office (IPD) grants a patent for Roche’s HCV drug Pegasys.^[85]

2006 June 30.  Vertex Pharmaceuticals and Janssen Pharmaceutica, N.V., a Johnson & Johnson company, announced they will collaborate to develop and commercialize Vertex's investigational hepatitis C virus (HCV) protease inhibitor, VX-950. Under the agreement, Janssen will have exclusive rights in Europe, South America, the Middle East, Africa and Australia, and Vertex will retain exclusive commercial rights to VX-950 in North America. Tibotec Pharmaceuticals, Ltd., another Johnson & Johnson company, will lead the development and commercialization of VX-950 for Janssen.^[86]

2006 October 25.  The US FDA approves Telbivudine, marketed by Novartis under the trade name Tyzeka, as a treatment for HBV.  The FDA Orange Book currently lists 7 patents for this drug, including five inventions patented by Gilles Gosselin^[87] (Montpellier, FR), Jean-Louis Imbach (Montpellier, FR), and Martin Bryant (Carlisle, MA).   Of the five patents, three were filed on  August 10, 1999 and include assignments to the Centre National de la Recherche Scientifique (Paris, FR), and Novirio Pharmaceuticals Limited (Grand Cayman, KY) or Idenix Pharmaceuticals Inc. (Cambridge, MA), and one was filed on December 14, 2001 by the same inventors, and assigned to Idenix Pharmaceuticals Inc. (Cambridge, MA).  Three patents were filed after the registration of the drug.  In July 2014, the price in the United States was more than $1,000 per month for 30 x 600 mg tablets for a product with manufacturing costs as low as $.25 per tablet.

2006 December 12.  Abbott announces an agreement with Enanta to develop and commercialize hepatitis C virus (HCV) NS3 and NS3/4A protease inhibitors.^[88] The companies’ press release stated:

“Abbott and Enanta Pharmaceuticals announced today that the companies have signed a worldwide agreement to develop and commercialize hepatitis C virus (HCV) NS3 and NS3/4A protease inhibitors. Enanta has discovered several HCV protease inhibitors that have demonstrated attractive efficacy and pharmacokinetic profiles in pre-clinical studies.”

2006 December 31.  Roche and Pharmasset end their October 29, 2004 collaboration agreement for the development of PSI-6130 for the treatment of chronic hepatitis C virus infection.^[89] 

2007

2007. Pharmasset earns $20.0 million in milestone payments from Roche as part of a collaboration for the development of R7128 for the treatment of chronic HCV infection.^[90]

2008

2008 January 17.  In an injunction proceeding, the CAFC grants Abbott a compulsory license to use patent 5,846,704 held by Innogenetics, N.V., regarding methods of genotyping HCV.  The court ordered royalties are in Euros per assay kit.  

2008 March 21. Pharmasset files patent application no. US 12/053,015  for patent no. US 7,964,580 B2, pertaining to nucleoside phosphoramidates and their use as agents for treating viral diseases.^[91]

2008 April 14. Innogenetics NV strikes a $9.5 million settlement and licensing agreement with Abbott Laboratories that resolves a long-standing patent dispute between the two companies over hepatitis C virus testing. “The agreement will grant Abbott a nonexclusive license to sell hepatitis C virus genotyping products based on real-time technologies. In exchange, Innogenetics will receive royalties for each hepatitis C test that Abbott sells worldwide during the patent term.”^[92]

2008 April 25.  Solvay Pharmaceuticals S.A. announces its intention to acquire Innogenetics, a transaction completed in the fall.

2008 June 3.  Gen-Probe launches unsuccessful offer to buy Innogenetics, losing out to Solvay.

2008 September 22.  Solvay Group acquires 84.3 percent of Innogenetics shares.

2008 September 25.  The Veterans Administration enters into a CRADA with GKS to study the Impact of Abacavir on Early Virologic Response to Combination Hepatitis Combination Hepatitis C Virus (HCV) Virus (HCV Therapy in HIV/HCV Coinfected Patients. This is one of two three Merck CRADAs for HCV, and one of 50 VA CRADAs involving trials for HCV from 2008 to 2011, including 13 with Schering/Merck, six with Roche/Genetech, four each for BMS and Pfizer, three for Conatus, and two each with Gilead and Idenix, among others, just for that period.^[93]

2009

2009 January 6.  Genelabs Technologies is acquired by SmithKline Beecham Corporation.^[94]

2009 January 15.   Veterans Administration enters into a CRADA with Gilead Sciences, for a Phase 2b trial comparing GS-9190, in Combination with Peginterferon Alfa 2a and Ribavirin, to Peginterferon Alfa 2a and Ribavirin for the Treatment of Genotype-1 Chronic Hepatitis C virus (HCV) infection.  

2009 July 5. Veterans Administration enter into CRADA with Valeant Pharmaceuticals to study the impact of anemia upon treatment completion rates and clinical outcomes in HCV infected persons.

2009 March 20.  Merck announces plan to acquire Shering-Plough.^[95]

2009 September 28.  Abbott Laboratories announces deal to acquire the pharmaceutical unit of Belgian conglomerate Solvay for roughly $7 billion.  The acquisition includes shares in Innogenetics.

2010

2010 July 20.  Fujirebio, a Miraca Holdings group company, announces agreement with Abbott to acquire Innogenetics. ^[96]

2010 October. Bristol-Myers Squibb acquired ZymoGenetics in October 2010 after entering into a strategic collaboration to co-develop PEG-Interferon lambda.^[97]

2011

2011 July 12. Gilead licenses several patents to the Medicines Patent Pool (MPP), which in turn are available as open license to generic drug manufacturers.  While HIV is the focus of the licensing agreement, Gilead agrees to a field of use that specifically includes hepatitis B for tenofovir, effectively expanding the MPP scope.  (The Gilead licenses are expanded on July 22, 2014 to include the use of tenofovir alafenamide (TAF) for hepatitis B.)

2011 March 7.   Pharmasset publishes a research abstract for the  European Association for the Study of the Liver (EASL), which holds its annual meeting March 30 through April 3.  According to reports, Pharmasset’s combination of PSI-938 and PSI-7977 (Sofosbuvir) triggered the complete elimination of the virus in 15 of 16 patients after only 14 days of treatment.^[98] 

2011 March 31. Pharmasset LLC files patent application no. US 13/076,552 for patent no. US 8,618,076 B2, a continuation-in-part of U.S. patent application Ser. No. 12/783,680 filed on May 20, 2010.^[99]

2011 May 3. Pharmasset LLC files patent application no. US 13/099,671 for patent no. US 8,334,270 B2, which is a continuation of U.S. patent application ser. no. 12/053,015, filed Mar. 21, 2008.^[100]

2011 May 9. Veterans Administration enters into a CRADA with Genetech for a trial to evaluate the HCV  Protease Inhibitor Danoprevir boosted with low dose Ritonavir (DNV/r) and Copegus, in combination with the HCV Polymerase Inhibitor Prodrug RO5024048 and/or Pegasyss in chronic hepatitis C genotype 1 patients who failed with previous course of Peginterferon alfa plus ribabirin combination therapy.

2011 September 16. Gilead files a provisional patent application covering the combination of sofosbuvir and ledipasvir, in anticipation of a merger with Pharmasset LLC.^[101]

2011 October 21. Abbvie files two patent applications “disclosing its treatment regimen for curing HCV genotype 1 patients with combinations of DAA’s [including sofosbuvir and ledipasvir), and without interferon, for short treatment durations.”^[102]

2011 November 21. “Gilead Sciences, Inc. and Pharmasset, Inc. announce that the companies have signed a definitive agreement under which Gilead will acquire Pharmasset for $137 per share in cash. The transaction, which values Pharmasset at approximately $11 billion, was unanimously approved by Pharmasset's Board of Directors.”^[103]

2012

2012.  The Chinese Ministry of Science and Technology approves a vaccine for the prevention of hepatitis E, known as HEV 239, sold under the name Hecolin by Xiamen Innovax Biotech.

2012 January 7.  Bristol-Myers Squibb announces it will acquire Inhibitex for $2.5 billion.^[104]  The BMS press release notes “"The acquisition of Inhibitex builds on Bristol-Myers Squibb's long history of discovering, developing and delivering innovative new medicines in virology and enriches our portfolio of investigational medicines for hepatitis C," said Lamberto Andreotti, chief executive officer, Bristol-Myers Squibb.^[105]

2012 February 21.  Enanta Pharmaceuticals announced a collaboration and license agreement with Novartis for the worldwide development, manufacture and commercialization of EDP-239, from its NS5A hepatitis C virus (HCV) inhibitor program. Enanta earlier received IND approval for EDP-239 from the FDA.

2012 March 6. Idenix Pharmaceuticals announces declaration of a patent interference by the USPTO between Idenix's U.S. Patent Application no. 12/131,868 and Pharmasset Inc.'s (acquired by Gilead Sciences) U.S. Patent no. 7,429,572, both related to certain nucleoside compounds useful in treating patients with hepatitis C virus (HCV) infection.^[106]

2012 August 1. Novartis restructures investment in Idenix.  “Idenix regaining worldwide rights to its current and future development-stage drug candidates in any therapeutic area.  In exchange, Idenix has agreed to pay Novartis a royalty based on worldwide product sales of Idenix' future hepatitis C virus (HCV) drugs, unless they are used in combination with drugs from Novartis. The royalty percentage will vary based on the commercialized Idenix HCV drug.”^[107]

2012 September 11. Gilead Pharmasset LLC files patent application no. US 13/609,614 for patent no. US8,580,765 B2, a continuation of U.S. patent application Ser. No. 13/099,671, filed May 3, 2011, now U.S. Pat. No. 8,334,270 which is a continuation of U.S. patent application Ser. No. 12/053,015, filed Mar. 21, 2008, now U.S. Pat. No. 7,964,580.^[108]

2012 October 23.  “RFS Pharma announced the receipt of an R01 grant from the National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (NIH) in association with a collaborative academic institution. RFS Pharma will receive US$525,000 as part of this grant and the principal objective will be to evaluate natural products isolated from plants, bacteria and fungi against viral hepatitis infections. The extracts that demonstrate excellent activity and no toxicity will be further isolated and characterized at the molecular level. As part of this collaboration, RFS Pharma will test more than 5,000 natural products from the National Cancer Institute (NCI) repository.”^[109]

2012  November 2. Roche’s Indian patent of the Hepatitis C drug, Pegasys, is revoked by India’s Appellate Board following a challenge by the Sankalp Rehabilitation Trust.^[110]

2012 November 20.  Conatus receives and FDA Orphan Designation for Emricasan, for a liver transplant related HCV.^[111] 

2013

2013 January. “Idenix announced a non-exclusive collaboration with Janssen Pharmaceuticals, Inc. for the clinical development of all-oral direct-acting antiviral HCV combination therapies. The collaboration will evaluate combinations including samatasvir, Idenix’s once-daily pan-genotypic NS5A inhibitor, Olyso (simeprevir), a once-daily protease inhibitor jointly developed by Janssen and Medivir AB, and TMC647055, a once-daily non-nucleoside polymerase inhibitor, boosted with low-dose ritonavir, being developed by Janssen.”^[112]

2013 January 10. Gilead Pharmasset LLC files patent application no. US 13/738,425 for patent no. US8,633,309 B2.^[113]

2013 January 25. Idenix enters into a non-exclusive collaboration agreement with Janssen Pharmaceuticals, Inc for the clinical evaluation of all oral DAA HCV combination therapies.

2013 April 8. The New Drug Application for sofosbuvir is submitted and receives the FDA’s Breakthrough Therapy Designation, which grants priority review status to drug candidates that may offer major treatment advantages over existing options.^[114]

2013 March 4. Data presented at the 20th Conference of Retroviruses and Opportunistic Infections shows that an interferon-free regimen of sofosbuvir, ledipasvir and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100 percent for patients with HCV genotype 1.^[115]

2013 April 26.  At the European Association for the Study of the Liver (EASL) 48th Annual meeting in the Netherlands, a study was presented that found that 41 of 41 patients treated with Bristol Myers Squibb’s daclatasvir and Gilead’s sofosbuvir were virus free after treatment.  All the patients had failed prior treatment with either Vertex Pharmaceutical’s Incivek or Merck’s Victrelis.^[116]

2013 June 30. In an SEC filing, Gilead reveals that Roche initiated arbitration against them. Roche asserted they have an exclusive license to sofosbuvir because it is a prodrug of PSI-6130, a drug to which they have the rights due to a 2004 research collaboration.^[117]

2013 August 5. Merck claims that sofosbuvir’s structure is covered by their patents for families of nucleoside derivatives that block RNA viral polymerase. Merck notifies Gilead that it would grant the firm a license to the two patents in question in exchange for a 10 percent royalty on the sales of the drug.^[118]

2013 August 30. Gilead files a preemptive suit seeking a court order that the experimental HCV drug sofosbuvir doesn’t infringe patents.^[119]

2013 September 16. Dr. Robert Fantant, professor of internal medicine and medical director of liver transplantation at University of Michigan Health System, obtains emergency approval from the FDA to us sofosbuvir for HCV transplant patient.

2013 October 25. The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issues a “compassionate use” opinion for Sofosbuvir in patients who have chronic HCV infection and are awaiting a liver transplant or have already received one. This is only the third time CHMP issues a compassionate use designation for a drug.^[120]

2013 November 21. I-MAK files an opposition at the Kolkata Patent Office against Gilead Pharmasset’s application for sofosbuvir (Application No. 3658/KOLNP/2009), a nucleotide prodrug, saying “India’s patent law doesn’t give monopolies for old science”^[121]

2013 November 22.  FDA approves Olysio, generic name simprevir,^[122] a drug developed by Medivir and Johnson & Johnson's pharmaceutical division Janssen Pharmaceutica.

2013 December 2.  Idenix announces that it filed two lawsuits against Gilead: a patent infringement lawsuit in the United States District Court in Boston, Massachusetts (Idenix U.S. Patents 6,914,054 and 7,608,597) and a separate patent infringement and interference lawsuit in the United States District Court in Wilmington, Delaware (Idenix U.S. Patent 7,608,600 and Gilead U.S. Patent 8,415,322).^[123] 

2013 December 6. FDA approves  sofosbuvir for the treatment of chronic Hepatitis C.^[124]

2013 December 18. Gilead files declaratory judgment action against Abbvie and Abbott Laboratories Inc., alleging that the ‘159 and ‘386 patents are invalid and unenforceable and claiming “Abbott embarked on an unlawful scheme designed to attempt to block the Gilead Combination (as well as other companies’ potential combinations) from reaching patients.”^[125]

2014

2014 January 6.  Andrew Hill, Saye Khoo, Joe Fortunak, Bryony Simmons and Nathan Ford publish, "Minimum Costs for Producing Hepatitis C Direct-Acting Antivirals for Use in Large-Scale Treatment Access Programs in Developing Countries" in the journal Clinical Infectious Diseases.  They suggest "minimum target prices of $100–$250 per 12-week treatment course" for treatment regimes for HCV.^[126]

2014 January 19.  The USPTO determines that Idenix is not entitled to priority of invention and judgment was entered in favor of Gilead. Idenix challenges the decision in the U.S. District Court for the District of Delaware. RE: 2012 patent interference.^[127]

2014 January 30. Gilead shares reach a then high of $77.92 after experts estimate Gilead will control 80 to 90 percent of the HCV market after the launch of Sofosbuvir.^[128]

2014 February 18. AbbVie files a lawsuit concerning “Gilead’s intention to willfully infringe AbbVie’s patents covering a revolutionary method of curing patients infected with hepatitis C virus” and seeks monetary damages.^[129]

2014 March 12. The American Association for the Study of Liver Disease (AASLD) and the Infectious Disease Society of America (IDSA) recommend sofosbuvir for patients with HCV genotype 1, 2, 3, 4, 5 & 6.^[130]

2014 March 14. Idenix Pharmaceuticals announces that it has filed patent infringement lawsuits against Gilead Sciences and its subsidiaries in France, Germany and the U.K. The lawsuit alleges that Gilead infringes Idenix’s recently granted, co-owned European patent EP 1 523 489 that covers 2'-methyl-2'-fluoro nucleosides for treating the hepatitis C virus.^[131]

2014 March 25.  House ranking members Henry Waxman, Frank Pallone Jr. and Diana DeGette send a letter to Gilead Sciences demanding a justification for the price of its sofosbuvir drug by April 3 2014. They cite research suggesting sofosbuvir will increase Medicare Part D drug spending by as much as $6.5 billion in 2015 alone.^[132]

2014 March 27. Gilead Sciences offers to supply sofosbuvir to Egypt at a 99 percent discount of the U .S. price. The HCV drug will cost $900 for a 12-week course of treatment, compared to the $84,000 price in the United States.^[133]

2014 April 3. Gilead Sciences makes discount agreements with several health insurers for its HCV drug, sofosbuvir. Gilead already provides a mandated discount to U.S. government health plans and insurers of about 23 percent.^[134]

2014 April 8. Preliminary examination of the patent application on sofosbuvir in Egypt suggests that it is unlikely to be granted.^[135]

2014 May 13. California lawmakers single out the high price of sofosbuvir with a new bill that would limit out-of-pocket cost on prescription drugs and would require coverage of hepatitis C screenings.^[136]

2014 May 22. The National Association of Medicaid Directors releases a report questioning the quality, results and bias of sofosbuvir studies. Four of five guideline panel chairs and 15 of 21 panel members, which establishes the guidelines for sofosbuvir’s use,  had financial relationships with Gilead. Additionally, the available research consists of just 10 studies, none of which compared sofosbuvir with another regimen or the current standard of care.^[137]

2014 June 9. Merck and Idenix Pharmaceuticals, Inc. announce the companies have entered into a definitive agreement under which Merck will acquire Idenix for $24.50 per share in cash, for a total of $3.85 billion.^[138]

2014 July 7. The Japanese Ministry of Health, Labor and Welfare approved the combination of Bristol-Myers Squibb’s daclastivr and asunaprevir for “treatment of patients with genotype 1 chronic hepatitis C virus infection (HCV), including those with compensated cirrhosis.”^[139] 

2014 July 11. The U.S. Senate Finance Committee launches an investigation into Gilead Sciences’ high pricing of sofosbuvir, saying the price “appears to be higher than expected given the costs of development and production and the steep discounts offered in other countries”. A letter sent to Gilead’s CEO asks 21 questions and seeks several documents regarding the purchasing of Pharmasset, the company that developed sofosbuvir, by two weeks time.^[140]

2014 July 21. The Egyptian Ministry of Health signs a memorandum of understanding with Gilead Sciences to supply its HCV drug, sofosbuvir, at 1 percent of its original price. Around 170,000 doses will be available by the end of September and the drug will be priced at EGP 2,200.^[141]

2014 July 22.   Gilead expands its Medicines Patent Pool (MPP) license, and among other things, includes patents to tenofovir alafenamide (TAF), a nucleotide reverse transcriptase inhibitor and a novel prodrug of tenofovir that reportedly has greater antiviral activity and better distribution into lymphoid tissues than that tenofovir disoproxil fumarate (TDF).  Among the advantages of TAF are that can be manufactured for a small fraction of the cost of TDF.  The licence will allow manufacturers in India and China to develop generic versions of TAF for 112 countries in the developing world.  In the new license, Gilead specifically includes a field of use for both TDF and TAF to treat hepatitis B.

“Field” shall mean the treatment and prophylaxis of HIV infection, provided, however, that (a) for Product containing TDF as its sole active pharmaceutical ingredient, the Field shall include the treatment and prophylaxis of Hepatitis B Virus infection, and (b) for Product containing TAF, EVG or COBI, the Field shall include any use that is consistent with the label approved by the FDA or applicable foreign regulatory authority for the use of such Product containing TAF, EVG or COBI, including if so approved, for the treatment and prophylaxis of Hepatitis B Virus for TAF.

2014 July 30.  The Associated Press reports that Illinois's Medicaid program is putting tight restrictions in place to limit access to treatments for hepatitis C,  including requiring patients to meet 25 criteria and get prior approval before the government program will pay for the new drug.^[142]