Two live attenuated oral rotavirus vaccines being collaboratively developed by Wyeth-Ayerst Labs., a subsidiary of American Home Products Corp. (Philadelphia, PA), and the National Inst. of Allergy and Infectious Diseases (NIAID, NIH; Bethesda, MD) have shown protective efficacy in large-scale trials reported in the April issue of the Journal of the American Medical Association (p. 1191-6). This placebo-controlled, prospective, double-blind trial compared two NIAID vaccines in 1,006 healthy infants, aged 4 to 6 weeks at enrollment, vaccinated between August 1989 and February 1990 (covering two rotavirus seasons). Two vaccines were tested--a monovalent and a tetravalent vaccine. Wyeth-Ayerst is currently conducting Phase III trials and expects to file for approvals in 1996. The vaccine will be marketed under the trade name Rotamune. Over 3,000 infants have received the vaccines to date.
The approach taken with these vaccines involves use of rhesus rotavirus (RRV) strains, nonpathogenic to humans, with selected human gene substitutions. There are four main pathogenic human rotavirus serotypes and it remains unknown whether immunity to each or a combination is required for protection. The rotavirus genome consists of 11 segments. The VP7 outer capsid protein segment of RRV serotype 3 strain MMU 18006 was substituted with VP7 from human rotavirus, enabling the live attenuated rhesus rotavirus to induce immunity against human rotavirus VP7 protein. The monovalent vaccine that was tested contained VP7 from human rotavirus serotype 1, the most common human rotavirus, along with ten other RRV genes. This vaccine was compared against a tetravalent vaccine containing four RRV viruses with VP7 substitutions from human rotavirus serotypes 1, 2 and 4, along with RRV itself which has a VP7 gene corresponding to human rotavirus serotype 3. This was the first large trial of such a tetravalent rotavirus vaccine.
A total of 898 infants received the full course of three oral vaccine or placebo doses at least two weeks apart. Outcome measurements included comparisons of the incidence of fever, diarrhea and vomiting; measurement of rotavirus IgA and neutralizing antibodies to rhesus rotavirus and four human rotavirus serotypes; and efficacy determined by the reduction in the incidence of rotaviral gastroenteritis. The clinical researchers, led by Dr. D.I. Bernstein, J.N. Gamble Inst. for Medical Research (Cincinnati, OH), report, "The relative efficacy against rotavirus over the 2 years of observation was 40% (98.3% confidence interval, 7% to 62%) for the monovalent and 57% (98.3% confidence interval, 29% to 74%) for the tetravalent vaccine. In post ad hoc analysis, the relative efficacy against very severe rotavirus gastroenteritis was 73% and 82% for monovalent and tetravalent vaccine recipients, respectively. Also, a 67% and 78% reduction in medical visits for rotavirus gastroenteritis was observed. Both vaccines protected against disease caused by serotype 1 rotavirus, but only the tetravalent vaccine reduced the incidence of disease caused by non-serotype 1 rotavirus infection detected in the second season. It is unclear, however, whether this result represents serotype-specific protection or a difference in the duration of protection." Adverse effects were few, mild and generally limited to a slight increase in the incidence of fever in infants after the first dose of tetravalent vaccine but not the monovalent vaccine.
The clinical researchers conclude, "Vaccination with both vaccines was safe and significantly reduced the incidence of rotavirus gastroenteritis, but only the tetravalent vaccine provided protection against non-serotype 1 rotaviruses during the second year follow-up." The tetravalent vaccine provided over 80% protective efficacy against severe illness, 49% against milder illness and 92% against diarrhea episodes lasting more than three days. Severe, often life-threatening, rotavirus infection with diarrhea and dehydration is the primary target for these vaccines. The tetravalent vaccine's 78% reduction in visits to physicians indicates such a vaccine would further reduce rotavirus-associated health care costs. In comparison, the monovalent vaccine provided only about 40% protective efficacy against all rotavirus diarrheas, 31% against milder illness and 73% for the most severe cases, with a 67% reduction in physician office visits.
The approach used in the tested vaccines is described in U.S. patents 4,704,275 and 4,751,080 assigned to NIH and exclusively licensed to Wyeth-Ayerst Labs. A similar rotavirus vaccine patent (4,571,385) by many of the same NIAID inventors has also been exclusively licensed to Wyeth-Ayerst Labs. Wyeth-Ayerst Labs. has been collaborating with NIAID for development and clinical trials with rotavirus vaccines through a Collaborative Research and Development Agreement (CRADA) that apparently started in 1988. Another NIAID rotavirus vaccine patent (4,927,628) concerning substitutions in the fourth rotavirus gene (VP4) has been exclusively licensed to Lederle Praxis Biologicals Inc., now also a subsidiary of American Home Products. As discussed in the November 1994 Bulletin (p. 331), American Home Products agreed to license out or divest some rotavirus vaccine technology as a condition for completing this recent acquisition. With its own vaccines showing efficacy, presumably the company will divest the VP4 substitution technology. A review of rotavirus vaccine development by NIAID researchers was published in Trends in Microbiology, vol. 2, no. 7, July 1994.
Rotavirus gastroenteritis is the leading cause of diarrhea in children worldwide. As stated by Dr. R. Chanock, NIAID, an inventor of the vaccines, "Rotaviruses, first detected 21 years ago, are the single most important recognized cause of diarrhea among infants and children younger than two years the world over. Our goal with this vaccine is to prevent the most severe rotaviral diarrhea, which leads to dehydration and death." In the U.S. alone, an effective rotavirus vaccine would annually prevent over one million cases of severe rotaviral diarrhea in children under five years old of which 65,000 cases require hospitalization and 150 result in death. In lesser developed countries, moderate to severe rotaviral diarrhea annually affects at least 18 million infants and children, causing about 870,000 deaths in children less than five years old. Rotaviruses infect over 90% of children by age three in both developed and lesser developed countries, causing 35%-50% of severe diarrhea episodes in infants and young children. Hygiene and public health efforts have little effect on the prevention of rotavirus infections. Adults can suffer from rotavirus diarrhea, but due to previous exposures this is usually asymptomatic or they suffer only mild symptoms. The goal of most rotavirus vaccine research has been the prevention of severe diarrhea that leads to dehydration and often death, rather than prevention of infection or mild illness. This is considered feasible, since natural infections attenuate the severity of subsequent infections but do not prevent asymptomatic or mild infections. Induction of mucosal and local cellular immunity in the intestines, such as might be expected from a live vaccine, appears to play an important role in the prevention of rotavirus infection.
PHS/NIH Abandons "Reasonable Pricing" Licensing/CRADA Policy
The National Institutes of Health (NIH; Bethesda, MD), which sets the technology transfer policies for the other components of the Public Health Service (PHS; including CDC, FDA), has abandoned use of the "reasonable pricing" clause in exclusive licenses and Collaborative Research and Development Agreements (CRADAs). This clause has been inserted in essentially all PHS exclusive licenses and CRADAs since 1989 and requires "that there be a reasonable relationship between the pricing of a licensed product, the public investment in that product, and the health and safety needs of the public. Accordingly, exclusive commercialization licenses granted for NIH/ADAMHA intellectual property may require that this relationship be supported by reasonable evidence." Although this clause and the term "reasonable" have never been defined or enforced, the "reasonable pricing" policy has been a significant deterrent and disincentive for industry to license or collaborate, even informally, with NIH. Many companies, particularly larger pharmaceutical and biotechnology companies, have rightfully feared that this clause could be used to require them to justify their pricing strategies to NIH and perhaps even to Congress and the public. "Reasonable pricing" has also been interpreted as allowing government to set price controls on licensed products and technologies.
Although most public discussion of "reasonable pricing" has centered on CRADAs, it primarily applies to exclusive licenses. CRADAs allow collaborating companies the option (almost always exercised) to exclusively license jointly developed inventions. "Reasonable pricing" has caused many companies to avoid both collaboration and licensing with NIH. The chilling effect of "reasonable pricing" is particularly evident in the relatively low number of NIH-industry CRADAs. For example, over 200 (85%) recently initiated federal CRADAs in biomedical areas have been outside of PHS/NIH. While NIH concluded fewer than 35 biomedical-related CRADAs in fiscal year 1994, the Department of Energy initiated over 60 and the Army initiated about 65. PHS/NIH granted only three exclusive licenses in FY1994, but many more are expected to be concluded now that policies have changed.
The "reasonable pricing" policy was instituted in 1989, primarily as a political response to the introductory pricing of AZT by Burroughs Wellcome Co. in the $8,000-$10,000/year range. The federal government is actually the largest purchaser of drugs (e.g., for Medicare, military and veterans' hospitals) and approval of AZT initially required a special act of Congress to authorize about one-quarter billion dollars for its purchase. With the prevailing attitude that AZT was overpriced and that NIH deserved co-inventorship status or at least significantly subsidized development and clinical trials with AZT, the "reasonable pricing" policy was instituted as a means to protect the government's and public interest in assuring reasonable prices and access to NIH inventions, particularly breakthrough therapeutics. However, the Republican administration at the time apparently did a good job of making this clause hard to interpret. In fact, this policy has never been enforced and no major products or technologies covered by the clause have yet come to market. The undefined and ambiguous nature of the clause has had a chilling effect on industry and has resulted in the mainstream biotechnology and pharmaceutical industries largely avoiding or passing over NIH licensing and collaborative opportunities. Many of the licenses and CRADAs executed in recent years have involved small biotechnology companies for whom undefined product pricing restrictions are of little immediate concern.
The recent issuance of a broad patent covering all ex vivo gene therapy (discussed in the story below) underscores the significance of NIH as the single most important source for new, particularly broadly enabling, technologies for the biotechnology and pharmaceutical industries. This is particularly true for technologies relevant to the treatment of viral diseases. As discussed in the March 1994 Bulletin (p. 75), NIH (and the federal government as a whole) has the largest portfolio of inventions available for licensing in the biotechnology, pharmaceutical and antiviral areas, many of these being broadly enabling technologies. For example, in the antiviral/virus-related area alone, NIH holds key patents covering first generation antisense oligonucleotide technologies including phosphorothioate oligonucleotides and triple-helix forming oligonucleotides; holds basic patents concerning immunotoxins and methods for conjugation of therapeutic proteins with antibodies; invented and exclusively licensed Havrix, the first hepatitis A virus vaccine (discussed in last month's Bulletin, p. 67), and the first parvovirus vaccine to enter trials (discussed in the lead story); is the sole or co-assignee of basic patents covering many new viruses including HIV, human herpesvirus-6, HTLV-I strains, and hepatitis E and G (formerly X) viruses; holds key patents on many retroviral, adeno-associated virus and other viral gene therapy vectors; holds key patents covering vaccinia virus promoters universally used for mammalian cell recombinant protein expression; discovered and exclusively licensed DDI and DDC and played an important role in the discovery of AZT; developed intranasal influenza vaccines (discussed in an article below); invented reconstituted parvovirus capsids for vaccines and as gene therapy vectors; and developed respiratory syncytial virus immune globulin (RespiGam) expected to be approved this year. Essentially all of these technologies have been licensed, usually nonexclusively, but many of these are exclusively licensed for specific therapeutic indications. A number of specific antiviral drugs, vaccine and immune modulators, most of which have been exclusively licensed, are currently in or approaching clinical trials for HIV and other viral indications including fludarabine (F-araA), Peptide T, liposomal nystatin, N-(phosphonoacetyl)-L-aspartic acid (PALA), prostratin, magainin peptides, napthoquinones (conocurvone), dimeric dideoxynucleosides, HIV TAR-based gene therapies and IL-2 receptor-targeted immunotoxins.
The abandonment of "reasonable pricing" licensing policies by NIH apparently signals a new openness to industry collaboration and licensing. NIH can finally transfer technologies like most every other public and private sector organization worldwide--negotiating a fair return (for itself and the public) through royalties with no intrusive pricing-related restrictions or oversight. With industry having largely avoided NIH technologies in recent years, this opens up considerable opportunities worthy of investigation.
The Biotechnology Information Institute (Bulletin publisher) also publishes the Federal Bio-Technology Transfer Directory, the only information resource providing access to NIH and other federal technology transfer opportunities and activities. The Directory database currently contains over 3,400 entries--over 1,400 patents and 900 applications, over 1,200 licenses (300 exclusive) and 830 CRADAs. Over 75% of entries are recent (since 1990). In the antiviral/virus-related areas alone (over 600 total entries), there are 170 patents, 136 assigned to PHS/NIH; 250 patent applications, 231 assigned to PHS/NIH; 149 CRADAs, 93 involving PHS/NIH; 173 licensed inventions, 163 licensed by PHS/NIH; and 409 licenses granted, 397 from PHS/NIH including 72 exclusive licenses. Nearly 550 antiviral/virus-related federal inventions, including over 425 from PHS/NIH, remain available for licensing (i.e., are not exclusively licensed, although many exclusively licensed inventions are still available for other fields of use). Even if organizations are not interested in licensing opportunities, the Directory is the only source for competitive intelligence concerning federal and NIH licensing and CRADAs.
The Federal Bio-Technology Transfer Directory will soon be available in database formats, including an Internet WWW subscription-access database and for uploading on purchasers' own computers. Those interested can contact the publisher for further information. Summary information about NIH and federal technology transfer can also be examined at our WWW site (http://www.bioinfo.com).
NIH/Genetic Therapy Receive Broad Gene Therapy Patent
A U.S. patent broadly covering ex vivo gene therapy has been granted to the National Institutes of Health (NIH; Bethesda, MD) which has already granted an exclusive worldwide license to Genetic Therapy, Inc. (GTI; Gaithersburg, MD). The official abstract and exemplary claim for this patent are in the "U.S. Patents" section below. The first claim of the patent covers, "A process for providing a human with a therapeutic protein comprising: introducing human cells into a human, said human cells having been treated in vitro to insert therein a DNA segment encoding a therapeutic protein, said human cells expressing in vivo in said human a therapeutically effective amount of said therapeutic protein." While the patent appears to broadly cover all ex vivo gene therapy, many companies and research organizations involved in gene therapy will likely be carefully reviewing the scope of this patent. Although the patent covers ex vivo gene therapy using any method for cell transformation, most development, examples and clinical testing have involved the use of retroviral vectors jointly developed by NIH and GTI. If the patent is interpreted as broadly covering all ex vivo gene therapy, challenges can be expected.
The impact of this patent on other companies is not yet known. Dr. M.J. Barrett, Chairman/CEO, GTI, remarked that his company plans "to undertake a strategy that could involve partnerships or in a few cases sub-licenses and cross-licenses. We hope to use it as a platform for the company to develop some serious corporate relationships...We don't think it would be consistent with our duties to give everybody licenses." GTI appears to be more interested in strategic linkages and collaborations with other companies, rather than following a strategy of granting nonexclusive (sub)licenses to all interested parties. The terms of GTI's license from NIH do not require it to sublicense or grant licenses to all interested parties. It is too early to determine the extent to which GTI's strategy may force some companies currently developing gene therapies to abandon their efforts. Besides this patent, GTI has exclusively licensed at least eight other patent properties from NIH, many developed jointly with NIH, and has nonexclusively licensed several other NIH gene therapy technologies. Many of these licensed technologies involve retroviral or other gene therapy vectors and specific therapeutic vector constructs for treatment of particular diseases, rather than claiming broad enabling technologies such as the recently issued patent.
The recent patent includes the use of retroviral vectors for ex vivo transformation of blood or other cells, so that transformed cells express therapeutic and/or marker proteins, and return of these cells to the patient. Of the approximate 100 gene therapy clinical trials conducted in the U.S. to date, about two-thirds or more involve this technology which might be termed first generation gene therapy technology. This technology was developed through formal Collaborative Research and Development Agreements (CRADAs) between NIH and GTI that began in 1988, with the first U.S. patent application filed in June 1989. CRADAs offer the collaborator the option to exclusively license inventions jointly developed with federal laboratories. Until recently (as discussed in the story above), exclusive licenses from NIH, including those resulting from CRADAs, included a clause requiring the licensee to assure "reasonable pricing" of resulting products. With the abandonment of this policy, GTI will have essentially no restrictions or oversight of the pricing of its gene therapies. In general, most commercial development of gene therapies is progressing beyond this first generation ex vivo therapy towards direct in vivo gene therapy, such as Viagene's direct injection retroviral and non-viral vectors (described in a story above).
Challenges to this patent may be expected. The first reaction of many companies and researchers involved in gene therapy was that the patent appeared to be too broad and that similar ex vivo gene therapy patents have issued with earlier priority dates. For example, the Whitehead Inst. (Cambridge, MA) has received two U.S. patents with earlier priority dates covering ex vivo epithelial cell gene therapy and three European patents covering transformation of epithelial cells, endothelial cells and fibroblasts. These patents have been exclusively licensed to Somatix Therapy Corp. (Alameda, CA) whose CEO remarked, "The mature thing to do is to enter into cross-license agreements and save money on attorneys. It's a huge market and there's no way all the gene therapy companies will get in each other's way. The smart thing is not to get in a big patent battle." However, NIH in collaboration with GTI was clearly the first to demonstrate the clinical efficacy of ex vivo gene therapy. As discussed in the March 31 issue of Science (p. 1899), several other researchers performed ex vivo gene therapy experiments as early as 1980 and others who were part of the NIH team working in this area may seek to have themselves added as inventors. This broad patent will likely be the subject of news stories and controversy for years.
Many patent experts expect the patent to either be subject to an interference proceeding or be challenged years from now when one or more products apparently covered by the patent approach market approval. There appears to be little incentive for companies developing similar gene therapies to initiate a challenge to the patent now. The recent change in U.S. Patent and Trademark Office policy to not strictly require demonstration of clinical utility (discussed in the February Bulletin, p. 45) may affect the validity of the claims of this patent. If previous in vitro work is interpreted as coming under the broad claims of the NIH/GTI patent, the claims could be substantially restricted or the entire NIH/GTI patent could be withdrawn. However, the inclusion of clinical data in the recent patent tends to provide support. Another broad patent in a related area, antisense oligonucleotide gene therapy involving Enzo Biochem Inc. and Calgene, Inc. (discussed in the May 1993 Bulletin, p. 137), that might provide guidance has just come to trial.
Aviron Licenses Intranasal Influenza Vaccine for Development Through NIH CRADA
Aviron, Inc. (Burlingame, CA) has announced that it has licensed intranasal cold-adapted live influenza virus vaccine technology from the Univ. of Michigan and concluded a Collaborative Research and Development Agreement (CRADA) with the National Inst. of Allergy and Infectious Diseases (NIAID, NIH; Bethesda, MD) for further development and clinical testing of candidate vaccines. Dr. J.L. Read, Chairman and CEO, Aviron, stated this is "the first practical approach to extending influenza prophylaxis to children. We believe this influenza vaccine...could double the current market for influenza vaccines. In the current managed care environment, we expect that a simple, cost-effective intranasal vaccine targeting a disease that results in annual treatment costs of over $8 billion will be well received. The ease of delivering the vaccine to young children leads us to believe that pediatric opinion leaders will support widespread use of this vaccine once further data are available."
The vaccine is formulated with a recombinant live cold-adapted influenza virus strain having a viral coat from a virulent influenza strain with an attenuated influenza virus core. The attenuated virus is capable of growing in the nasal passages which are cooler than body temperature. The vaccine is administered using a novel spray syringe which releases a large particle aerosol spray. By modification of the viral coat components, the antigen composition of Aviron's vaccines can be modified annually to provide protection from epidemic influenza strains. A trivalent vaccine is planned, comparable to the current trivalent inactivated vaccines. The vaccine was developed by Dr. H.F. Maassab, Univ. of Michigan, a member of Aviron's scientific advisory board. The first human trials with this type of vaccine began in 1975 and the vaccine has been studied in over 7,000 persons of all ages. The vaccine induces strong immune responses, including local cellular immunity in the nasal passages, after simple administration as a nasal spray. Significant prophylactic efficacy has been reported in children. Currently available influenza vaccines involve partially purified and inactivated influenza virus strains administered by injection.
Phase I/II clinical trials will start in adults and children this year with Phase III trials expected to begin in the winter influenza seasons of 1996-1997 and 1997-1998. NIAID will enroll subjects in these trials through its network of Vaccine Technology Evaluation Units (VTEUs). Aviron has received an exclusive worldwide license, excluding Japan, from the Univ. of Michigan for use of the vaccine delivery system and attenuated influenza virus vectors for delivery of multivalent vaccines and for gene therapy. The CRADA with NIAID provides for joint contributions by Aviron and NIH for clinical trials and includes providing Aviron with exclusive commercial rights to all data from earlier NIAID clinical trials with this vaccine. The details of the financial arrangements remain proprietary. Aviron expects to invest over $20 million of its own funds for clinical trials, manufacturing and regulatory filings. Aviron is developing other viral vaccines including vaccines for respiratory syncytial virus, varicella-zoster virus and cytomegalovirus and is in preclinical stages with recombinant herpes simplex virus and influenza virus vaccines.
Licensing Opportunities
The National Institutes of Health is actively seeking licensees for, "HIV Nucleocapsid Protein Capture Assay and Method of Use," U.S. patent application 07/967,658, by Drs. L.O. Arthur and L.E. Henderson, National Cancer Inst. This concerns novel antigen capture assays for detection of HIV p7 antibodies useful for detection and diagnosis of HIV-infection including determining the prognosis of HIV-infected patients; detecting HIV in infants born to infected mothers; and detection and quantification of HIV in the laboratory (e.g., virus production, infectivity assays, neutralization assays, and in vitro drug efficacy studies). The p7 capture assays have been shown to accurately detect diluted HIV-1 in plasma taken from HIV-infected persons at levels that conventional HIV p24 assays were not able to detect HIV-1 (due to p24 antigen-antibody complexes formed by detergent lysis of the virus). HIV p7 antibodies can be accurately detected at levels as low as 4 pg/ml and these assays are currently being further refined. Immunodiagnostics based on HIV p7 may eventually replace the HIV p24 antigen capture assays widely used for blood screening and diagnosis of HIV-infection. HIV p7 nucleoprotein precursor is expressed by HIV gag, along with HIV p24, p17, p2, p1 and p6, and exists in equimolar amounts with these other precursor polyproteins. The National Institutes of Health has a number of other HIV vaccine and diagnostics-related inventions available for licensing, including basic patents covering HIV, its culture and cloned antigens. For further information contact:
Mr. Steve Ferguson
Office of Technology Transfer
6011 Executive Boulevard, Suite 325
Rockville, MD 20852-3804
Phone: 301-496-7735; Fax: 301-402-0220
FDA Approves Hepatitis A Virus Vaccine (from March 1995 Antiviral Agents Bulletin)
Hepatitis A Vaccine, Inactivated from SmithKline Beecham Biologicals (SKB; Rixensart, Belgium), a subsidiary of SmithKline Beecham PLC, has been approved by the FDA for prevention of hepatitis A virus infections. The vaccine, marketed under the trade name Havrix, is the world's first hepatitis A vaccine and is indicated for active immunization of persons at risk for hepatitis A exposure. There are an estimated 10 million cases of hepatitis A infection worldwide each year with most infections occurring in lesser developed countries. The vaccine's major market is among more affluent travelers from developed countries and military personnel. Havrix is currently available in over 40 countries worldwide including major markets in Europe and millions of vaccine doses have been administered to date. Another inactivated, alum-adjuvanted hepatitis A vaccine, Vaqta from Merck & Co., is available in some countries and is approaching approval in the U.S.
Havrix is prepared from formalin-inactivated hepatitis A virus strain HM-175 grown in continuous culture in primary African green monkey kidney (AGMK) cells. The vaccine uses a conventional alum adjuvant. Strain HM-175 contains mutations involved in culture adaptation which enable it to grow well in culture and which attenuate its human pathogenicity. The hepatitis A virus is a small, single-stranded RNA virus infection which commonly causes hepatitis. For further information, see publications including "Production, Quality Control and Characterization of an Inactivated Hepatitis A Vaccine," Vaccine, vol. 10, sup. 1, p. S99-101, 1992. Official U.S. labeling information is not yet available from FDA or SKB.
SKB reports cumulative worldwide Havrix sales of $82 million through the third quarter of 1994. The vaccine is administered to adults as an initial injection (1,440 units; about $44) followed by a booster 6-12 months later. The primary injection provides protection for up to one year and the booster further extends protection. Children receive an initial injection (360 units; about $15) followed by two booster doses. Thus, adult vaccination costs about $88 and pediatric vaccination costs about $45. The vaccine is supplied in prefilled disposable syringes.
As discussed in the February 1994 Bulletin (p. 35), the Vaccines and Related Biological Products Advisory Committee, FDA, reviewed Havrix and recommended its approval over a year ago. It has taken over a full year for FDA to resolve remaining issues and approve Havrix. Varivax (discussed in a story above) similarly has been available in many other countries and was similarly delayed by FDA. Both of these vaccines are commonly cited by FDA critics who view the agency as needlessly delaying approvable products.
Havrix is based on NIAID inventions, and both NIAID and the U.S. Army have played a major role in its development. Strain HM-175 and the inactivated vaccine were originally developed by NIAID researchers (including Purcell, R.H.; Gust, I.D.; Daemer, R.J.; and Feinstone, S.M.) and covered by U.S. patents assigned to NIH (including numbers 4,894,228; 4,532,215; 4,636,469; and 4,620,978). SKB already holds a nonexclusive license for these inventions from NIH which reports that this technology is still available for nonexclusive licensing. Even with SKB and Merck marketing hepatitis A vaccines in most countries, there may still be opportunities for other companies to develop markets in various countries and niches for Havrix-equivalent vaccines. Because SKB has a nonexclusive license, it is exempt from NIH requirements (expected to be changed soon) concerning "reasonable pricing" of inventions exclusively licensed from NIH. Preclinical studies and Phase I trials were conducted by NIAID. Both NIAID and the Centers for Disease Control and Prevention (CDC) assisted with Havrix development through formal Collaborative Research and Development Agreements (CRADAs) with SKB that began in November 1988.
The Walter Reed Army Institute of Research (WRAIR; Washington, DC) entered into a CRADA with SKB in 1991 that supported the U.S. Army (with assistance from CDC) conducting large-scale efficacy trials in Thailand. This included a controlled trial in 40,000 children administered either Havrix or Engerix-B (hepatitis B vaccine also from SKB). Havrix provided over 94% protection among the children in this study. About 3,000 episodes of illness were reported with only 60 acute cases of hepatitis A reported among Havrix vaccine recipients. In three other clinical trials in nearly 500 adult volunteers administered a single dose of Havrix, hepatitis A neutralizing antibodies were elicited in over 96% of the subjects after one month. The vaccine is generally well tolerated. The most common adverse effects noted in clinical trials have been soreness at the injection site (56% of adults, 15% of children) and headache (14% of adults, 5% of children). For a discussion of the Army's involvement in the development of Havrix and hepatitis A vaccines, see "Hepatitis A in the U.S. Army: Epidemiology and Vaccine Development," Vaccine, vol. 10, sup. 1, p S75-9, 1992.
Most persons in poorer, lesser developed countries where the disease is endemic become infected with hepatitis A and develop protective immunity during childhood and have no need to receive the vaccine. For example, 95% of the population in Mexico has been infected with hepatitis A by the age of 10. Most persons in the U.S. and other developed countries with high standards and infrastructure for public sanitation are not exposed during childhood and lack immunity. Hepatitis A virus is highly transmissible and a single infected person can lead to a community-wide epidemic. The disease is typically spread by the fecal-oral route, through close person-to-person contact or by ingestion of fecal contaminated food or water. Contamination sources include drinking water and ice; fruits, salads and foods handled by infected persons; and ingestion of shellfish (e.g., oysters, clams, mussels) from hepatitis A-infected waters. Many outbreaks are attributed to infected food handlers. Breakdown in sanitation facilities, such as after floods and natural disasters, can also cause outbreaks. Transmission rates are high within families with transmission rates up to 45% reported among children and 20% among susceptible adults in developed countries. Infected persons shed virus for about two weeks before the onset of symptoms, further complicating control of the disease.
Hepatitis A causes acute liver disease and debilitating symptoms that can last for up to one year after the acute infection subsides. Respiratory symptoms, rash and joint pain occur in some patients. Severity can range from few and mild symptoms (as is common in young children) to more serious symptoms in 75-90% of infected adults. An estimated 67% of cases occur in children and young adults, while over 70% of hepatitis A-related mortality occurs in those over 49 years old. Hepatitis A infection is often asymptomatic in children under two years of age, and these children often transmit infection to others, especially in day care and other common child care facilities. While disease resolves itself in most patients within 6-12 months, relapse and extended illness has been reported in about 20% of cases. Mortality rates for hepatitis A infection are low, about 6/1,000 cases, but mortality rates are higher in older persons, about 27/1,000 cases in those over 49 years old.
Hepatitis A is the most common traveler-related disease now preventable by vaccine. Hepatitis A occurs about 100 times more often in unvaccinated travelers than does typhoid fever and about 1,000 times more often than cholera. The major U.S. market for Havrix will be the over 24 million U.S. citizens who annually visit regions where the disease is endemic with another sizeable market being U.S. military personnel stationed overseas. Unlike Varivax (discussed in a story above), for which universal vaccination is recommended, most use of Havrix in the U.S. and other countries will be in travelers to regions where hepatitis A is endemic, including parts of Mexico and Central America, the Caribbean, South America, Africa, Asia (except Japan), the Mediterranean basin, Eastern Europe and the Middle East. Havrix will also be used by persons in certain occupations at risk for hepatitis A infection, including military personnel, certain health care professionals, sewage workers and staff in day care, disabled care and other institutional settings.
No antiviral drugs are available for hepatitis A treatment. Hepatitis A immune globulin is available for passive immunization, both for pre-exposure prophylaxis and post-exposure prophylaxis during the incubation period. While hepatitis A immune globulin provides 80-90% protection against clinical illness, this is costly, requires repeated doses, carries risks due to its being derived from human blood, and is not practical for large-scale prophylactic use. Even high doses (e.g., 5 ml) provide 3-5 months of protection at most, requiring re-inoculation among frequent travelers and those residing in endemic areas. Also, as sanitation and use of Havrix and other hepatitis A vaccines increase, the availability of high titer hepatitis A plasma will decrease. In fact, last month, Armour Pharmaceutical Co., the sole U.S. manufacturer and marketer of hepatitis A immune globulin, reported that the product is in short supply. The Department of Defense (DOD), the largest purchaser of hepatitis A immune globulin, had essentially exhausted the available supplies for use in military personnel sent to Haiti and the Middle East. Several other U.S. companies that previously produced hepatitis A immune globulin have abandoned the product in recent years. Armour currently produces between 1.5-2 million doses annually. The company reports that the DOD has reduced its orders by 25% and the company is increasing production by 25% to meet demand. Supplies are expected to return to normal in several months.
Awareness of the need (and now the opportunity) for protection against hepatitis A among travelers in the U.S. and other developed countries is low, and the public and medical community will have to be educated about the availability and utility of Havrix. A 1994 Roper Starch survey found that most Americans are unaware of hepatitis A risks. The survey found that: over half of those persons having traveled outside the U.S. in the last 2-3 years visited areas where the disease is endemic; that only 2% of travelers sought available protection (hepatitis A immune globulin); nearly 75% of Americans have no knowledge of hepatitis A or its risks; 44% have no knowledge of risk factors for hepatitis A; only 2% recognized that travel is a risk factor for hepatitis A; and that only 4% recognized poor sanitation as a risk factor. When instructed about hepatitis A and related risk factors, 58% responded that they would be likely to seek vaccination if they expected to encounter potential risks. Presuming that 10% (2.4 million) of U.S. travelers to areas where the disease is endemic receive Havrix, this will provide SKB with additional sales of over $200 million. As the market for Havrix grows, it will become a major source of royalty income, providing millions of dollars annually, for NIAID and NIH.
The CDC reports 143,000 cases of hepatitis A in the U.S. each year costing the economy an estimated $200 million, but the disease is considered underreported. Direct medical care alone typically costs $2,800 for each case requiring hospitalization and $700 for other cases. Acute infection typically involves loss of an average of 30 work days (estimated $2,600 in lost wages) with symptoms including jaundice, fever, nausea, vomiting, diarrhea and appetite loss. The disease is a threat to travelers even if they stay in expensive Western-style resorts and hotels overseas.
Besides travelers to lesser developed parts of the world, hepatitis A is a threat to various persons (and those coming into contact with these persons) including: ethnic and geographic populations that experience cyclic epidemics, such as among native peoples in Alaska and North America; homosexuals; injectable drug users; military personnel and others housed in confined conditions with poor sanitation facilities; health care workers in contact with fecal material; child day care workers; primate handlers; and laboratory workers possibly handling hepatitis A samples.
Interleukin-2 Shows Efficacy for Immune Restoration in HIV-Infection (from March 1995 Antiviral Agents Bulletin)
Dr. H.C. Lane, NIAID, and collaborators reported in the March 2 issue of the New England Journal of Medicine results from a 25-patient clinical trial demonstrating that recombinant interleukin-2 (IL-2; Proleukin) from Chiron Corp. (Emeryville, CA) produced sustained increases in aspects of immune response in HIV-infected patients tested for up to two years. Dr. Lane stated, "This study provides the strongest evidence so far that it may be possible to rebuild and maintain the damaged immune systems of HIV-infected individuals." Significant improvements and the maintenance of CD4+ T-cell counts was observed in less advanced patients. IL-2 from Chiron is currently approved in the U.S. and other countries for treatment of metastatic renal cancer.
Patients were administered IL-2, initially at 18 million IU (with later reductions to as low as 6 million IU in some patients) by continuous infusion for five days every two months. All patients also received at least one antiretroviral drug during treatment. Upon entry, 10 patients had CD4+ T-cell counts greater than 200, and these patients received from 4-13 courses of IL-2 administration and were followed for 22-40 months. Another 15 patients with CD4+ T-cell counts below 200 were also enrolled and similarly treated.
After 12 months, CD4+ T-cell counts rose and were maintained by over 50% in 6 of the 10 patients who entered the trial with CD4+ T-cell counts over 200, while the counts of the other 4 remained stable or declined only slightly. Dramatic CD4+ T-cell count increases were observed in several of these less advanced patients, including a rise in one individual from 554 to 1,998 (a value above normal for healthy persons) after 12 months of treatment. Dose reductions were required in 8 of the 10 less advanced patients, primarily because of fever and flu-like symptoms.
Seven of the 10 patients entering the trial with CD4+ T-cell counts above 200 showed a decrease of at least 25% in the proportion of CD8+ lymphocytes with surface HLA-DR, a marker of aberrant T-cell activation. Increases in HLA-DR on CD8+ T-cells have been associated with more rapid progression of HIV-infection. Also, the percentage of HLA-DR positive cells was increased (>= 15%) in each of these 10 patients. The percentage of lymphocytes expressing surface high-affinity receptors for IL-2, associated with increased sensitivity to IL-2, increased in 9 of the 10 patients. Increases in IL-2 receptor affinity may play a role in sustaining increases in CD4+ T-cells. The percentage of CD4+ T-cells positive for the alpha chain of the p55 portion of the IL-2 receptor also increased. A decline was observed in lymphocytes positive for CD38, another marker of cell activation.
However, among the 15 patients who entered the study with CD4+ T-cell counts below 200, only two showed a 50% increase. IL-2 appeared to have little effect on disease progression in the more advanced patients. Among the 15 patients with CD4+ T-cell counts below 200 upon entry, few immunologic responses were observed, HIV replication and viral load increased and substantial toxicity was observed. Of the two patients in this group that did show a sustained increase in CD4+ T-cell counts, both had higher counts (about 150) upon entry. No significant increases were observed in the other 13 patients and side effects were "considerably more severe" in these more advanced patients.
A major concern with IL-2 treatment of HIV-infected patients was that HIV replication might be increased through IL-2-mediated activation of HIV-infected lymphocytes. No consistent changes in HIV p24 levels were observed in patients' blood, but branched-chain DNA (bDNA) assays revealed a transient increase in HIV RNA levels in the blood of 4 of the 10 patients with baseline CD4+ T-cell counts above 200 shortly after each IL-2 infusion. The investigators suggest that treatment with anti-HIV drugs be combined with IL-2 treatment to minimize any adverse effects from HIV activation that might result from IL-2 treatment. The investigators conclude, "Among the four [less advanced] patients with the most dramatic increases in CD4+ T-cell counts, HIV RNA was undetectable throughout therapy," and no consistent increase was observed in the other patients tested with the bDNA assay.
Side effects, often severe, were common in all patients and included rash, lowering of blood pressure, flu-like symptoms, diarrhea and laboratory anomalies including reduced calcium, albumin and magnesium in the blood. "While receiving infusions of IL-2, patients were extremely uncomfortable, often with symptoms worse than a very bad bout of the flu. Fortunately, none of the side effects we have observed thus far in these studies appear to be life-threatening."
IL-2, formerly called T-cell growth factor, is a cytokine normally produced by T-cells with potent immune stimulation effects including the proliferation and differentiation of T-cells, B-cells, natural killer cells and other cells of the immune system. IL-2 was one of the first agents to be studied for treatment of HIV-infection and AIDS. In 1982, even before HIV was isolated and identified as linked to AIDS, Dr. Lane and collaborators from the FDA demonstrated that IL-2 could enhance the activity of immune cells isolated from AIDS patients, inducing the proliferation and differentiation of peripheral blood mononuclear cells. Clinical trials at NIH with IL-2 in AIDS patients began in 1983, about the same time that trials for cancer treatment began. Techniques for treatment of HIV-infection have subsequently been significantly refined through in vitro studies and a series of small clinical trials.
Dr. A. Fauci, Director, NIAID, remarked, "The development of this regimen, which involves alternately stimulating the immune system with IL-2 and then letting it rest, is the culmination of 13 years of laboratory studies and clinical research. This work is a model of NIAID's `bench-to-bedside' philosophy of research: doing laboratory and preclinical studies, learning from preliminary clinical studies, going back to the laboratory bench for further refinement, and then treating patients with the improved regimen." Implicit in Dr. Fauci's comments is that NIH is among the few organizations able to fund and follow through on such long-term development efforts. Further NIH research and trials will concentrate on the timing of treatments, finding the lowest effective dose with reduced adverse effects, and will likely include AZT and/or other anti-HIV drugs in combination with IL-2. NIAID has recently started three IL-2 trials--one trial is examining the timing of IL-2 infusions and changes in CD4+ T-cell counts; another study is examining the safety and efficacy of subcutaneous IL-2 administration; and another is examining the effects of further increasing IL-2 dosage, expected to block tumor necrosis factor (TNF) production, which may decrease side effects and activation of HIV replication (associated with TNF).
IL-2 has demonstrated significant effects on immunologic markers for efficacy for treatment of less advanced HIV-infected patients, but with significant side effects. IL-2 appears to be capable of reversing major aspects of HIV-related immune deficiency and maintaining major aspects of immune response in HIV-infected persons with CD4+ T-cell counts above 200. Whether these immunological improvements will translate into improved survival and clinical efficacy remains to be determined.
Genelabs and Chiron Cross-License and Form Alliance for Hepatitis G and C (from March 1995 Antiviral Agents Bulletin)
Genelabs Technologies, Inc. (Redwood City, CA) has announced a cross-licensing and collaborative agreement with Chiron Corp. (Emeryville, CA) to enhance each companies' efforts to develop diagnostic products for hepatitis C and G virus. As discussed in last month's Bulletin (p. 38), Genelabs in collaboration with the Centers for Disease Control and Prevention (CDC) and the National Inst. of Allergy and Infectious Diseases (NIAID) has discovered a new blood-borne hepatitis virus, hepatitis G virus (HGV; formerly called hepatitis X virus), and had earlier nonexclusively licensed this technology to Boehringer Mannheim GmbH and Abbott Labs. (which has abandoned its license).
Genelabs now has similarly nonexclusively licensed HGV and hepatitis E virus (which it discovered earlier) to Chiron for the development of diagnostic and screening products. Although not discussed in public disclosures, this cross-licensing most likely also covers vaccines and perhaps gene therapies and other therapeutics. For Genelabs, this new agreement and associated cash infusion came at a very opportune time. The company had only $7.5 million at the close of the fiscal year (September 30) and has an estimated burn rate of about $1 million/month. Genelabs' 1994 fiscal year revenues were $11-12 million. Genelabs will retain rights to commercialize HGV Western blot and rapid diagnostic tests in Asian markets other than Japan.
Genelabs and Chiron also "have agreed to cross-license to each other certain product and market rights for hepatitis and retrovirus technologies, including Chiron's hepatitis C virus (HCV)." As discussed in an article in last month's Bulletin (p. 44) concerning a patent dispute over HCV, Chiron was the first to isolate and clone HCV and has been assigned full patent rights for HCV. By cross-licensing HCV technologies, this agreement resolves potential patent disputes between the two companies. Chiron has significant HIV-related technology, including patents based on the first sequencing of the HIV genome (HIVSF) in collaboration with Dr. J. Levy, Univ. of California (San Francisco, CA).
Chiron will pay Genelabs licensing and milestone payments for HGV and make an equity investment in the company expected to total $24 million. Future royalty payments between the two companies will be based on sales of each other's products. Chiron will pay Genelabs up to $9 million for the development of HGV diagnostics. While a definitive agreement is being negotiated, Chiron will pay Genelabs $5 million, creditable toward Chiron's royalty payments, and will purchase $10 million of newly issued Genelabs preferred stock. After five years, Chiron can convert this into common stock at a price of up to $3 a share or apply the stock towards purchase of a company to be formed by Genelabs to hold all of its diagnostic products and technologies. Chiron would have to purchase the remainder of Genelabs' HGV diagnostic assets at market price. The current agreement includes mechanisms for negotiation of a purchase price. Chiron's cross-licensing of hepatitis and retrovirus technologies to Genelabs requires the approval of Chiron's business partner in viral diagnostics, Ortho Diagnostic Systems, Inc., a subsidiary of Johnson & Johnson Co. (New Brunswick, NJ). Chiron intends to offer Ortho participation as an equal partner in its new business alliance.
Dr. F.C. Kung, President and CEO, Genelabs, remarked, "We view this relationship as a perfect fit for the continued development and worldwide commercialization of our newly discovered hepatitis G virus. Chiron and Ortho have already been through the process of diagnostic product development for HCV, and they know the market for transfusion-associated hepatitis well. With their help and our experience in commercializing our discovery of hepatitis E virus, Genelabs has the ability to get the product approved on an international basis quickly. Genelabs is also excited about gaining access to HCV for our diagnostic business. We now have the additional key technology and product diversity to participate more significantly in the emerging Asian markets for biotechnology-based healthcare products." As stated by Dr. E.E. Penhoet, President and CEO, Chiron, "This agreement significantly strengthens the already important position of the Chiron-Ortho joint venture as a leader in hepatitis and retrovirus diagnostics, and creates opportunities for Genelabs to continue building its diagnostics business. We believe that HGV is a relevant infectious agent. Probe tests, immunoassays and blood screening tests for HGV will be necessary and valuable products in Chiron's encompassing approach to the diagnosis, treatment and prevention of all types of hepatitis."
Thus, Genelabs and Chiron have formed an alliance for development of products for diagnosis and treatment of recently characterized hepatitis viruses (C, E and G) that will allow each company to dominate worldwide development of related diagnostic products and vaccines. Chiron has the option to acquire and consolidate both companies' hepatitis-related businesses in five years at predictable costs. Genelabs gains funds for continued operations and growth, and can still nonexclusively license its technologies to other companies.
Genelabs Discovers New Hepatitis Virus (from February 1995 Antiviral Agents Bulletin)
Genelabs Technologies, Inc. (Redwood City, CA) has reported discovery of a new blood-transmissible human hepatitis virus, formerly called the hepatitis X virus and now tentatively called the hepatitis G virus (HGV). The discovery was made in collaboration with researchers at the Centers for Disease Control and Prevention (CDC; Atlanta, GA) and the National Institutes of Health (NIH; Bethesda, MD), apparently through Genelabs' Collaborative Research and Development Agreement (CRADA) with CDC for hepatitis X-related research. The company's disclosure was hastily made after a CDC researcher, apparently without the knowledge of the company, disclosed their discovery at a recent meeting on blood transfusion safety.
Few details about the virus have been disclosed yet. However, Genelabs confirms that "the new virus is associated with hepatitis and can be transmitted through transfusion of contaminated blood. Presence of the new virus has been detected in blood samples obtained from patients in the United States, Europe, Japan and elsewhere." This new virus may account for residual cases of viral hepatitis that remain unaccounted for after the implementation of diagnostic methods for hepatitis A, B and C viruses. Company and federal scientists are currently conducting studies to determine the epidemiology and clinical significance of the new virus, and diagnostic methods are being developed for clinical use.
This is the second new hepatitis virus discovered by Genelabs in collaboration with federal researchers. Company and CDC researchers jointly reported identification of hepatitis E virus in 1989. Separate from the recent discovery, Genelabs announced termination of its HGV-related diagnostics nonexclusive licensing and financing agreement with Abbott Labs. Boehringer Mannheim GmbH continues to be a non-exclusive licensee and recently made a $1 million milestone payment to Genelabs related to discovery of HGV. As reported in the June 1993 Bulletin (p. 171), this license agreement was somewhat unusual in that it involved a rather high ($10 million) up front payment for a nonexclusive license with undisclosed royalty and development/approval milestone payments. This is indicative of the potential high commercial value related to identification and development of diagnostics (and vaccines) for a new pathogenic virus. As reported in the Federal Bio-Technology Transfer Directory published by the Biotechnology Information Institute (Rockville, MD), Genelabs has already been granted an exclusive license for HGV from the U.S. Public Health Service (PHS) for patent applications including U.S. 07/922,493 filed jointly with CDC. It is interesting to note that Dr. D.W. Bradley, formerly with CDC and discussed below concerning a new dispute over discovery of hepatitis C virus, is reported by PHS to be an inventor on this patent application and was the principal investigator for Genelabs' CRADA with CDC.
Drug-Sensitive HIV May Be Useful for Vaccines (news brief from February 1995 Antiviral Agents Bulletin) - Drs. S.M. Smith and K.T. Jeang, NIAID, reported at the recent National Conference on Human Retroviruses and Related Infections (Washington, DC) about the development of recombinant HIV clones that are sensitive to antiviral drug therapy. This technology may enable elimination of live, attenuated HIV vaccines from the body after induction of immunity, alleviating much of the concern that prophylactic live HIV vaccines may mutate and become pathogenic in vivo. A gene for herpesvirus thymidine kinase (Tk) was inserted into HIV in place of its nef gene which was deleted. Expression of thymidine kinase in infected cells allows for the metabolic activation (phosphorylation) of drugs, such as ganciclovir and acyclovir, to active metabolites. This is similar to approaches being used in many gene therapies in development which use thymidine kinase as a marker to enable identification and selective elimination of transformed cells. The researchers found that the HIV (Tk+, nef-) clones infected HIV-susceptible cells and that subsequent treatment with ganciclovir eliminated these cells. Besides substantially weakening the pathogenicity of HIV by nef and other gene deletions, the HIV-Tk clones may be useful to induce immunity and then could be eliminated by administration of ganciclovir or another Tk-activated drug. HIV-Tk clone-infected cell lines treated with ganciclovir demonstrated no significant increase in cell death, HIV reverse transcriptase activity or other indications of active HIV-infection. Many researchers are skeptical about the ability of any recombinant protein-based vaccines to induce protective immunity against HIV-infection and believe that live viral vaccine-based strategies may be required to develop effective HIV vaccines with long-lasting cellular and humoral immunity.
Hepatitis C Virus Patent Dispute (article from February 1995 Antiviral Agents Bulletin)
Dr. D.W. Bradley, formerly with the Centers for Disease Control and Prevention (Atlanta, GA), has filed suit against Chiron Corp. (Emeryville, CA), challenging the status of its recently issued U.S. patent (5,350,671) covering hepatitis C virus (HCV) clones, diagnostics and vaccines. Dr. Bradley seeks to invalidate the patent, have himself included as a co-inventor and receive damages and royalty income from Chiron. The suit filed in the Northern District of California (San Francisco, CA) also names several Chiron officials and scientists and Ortho Diagnostics Systems (a subsidiary of Johnson & Johnson Co.; Chiron's partner in HCV diagnostics marketing) as defendants. The Department of Health and Human Services (parent of CDC) is an involuntary defendant, cited for a 1990 agreement with Chiron that conceded all patent rights to Chiron. Dr. Bradley is currently retired and serves as Chairman, Steering Committee on Polio and Hepatitis Vaccines, World Health Organization. Note, U.S. patent 5,350,671, "HCV Immunoassays Employing C Domain Antigens," (for abstract and first claim, see October 1994 Bulletin, p. 306) was erroneously reported in Dr. Bradley's court filing and by other publications as U.S. patent 5,530,671.
Dr. Bradley claimed he supplied Chiron with high titer HCV-infected plasma from infected chimpanzees that was instrumental in Chiron's isolation and cloning of HCV; that he developed critical findings about the virus, including its having an RNA genome and an envelope; and that he provided Chiron with assistance regarding cloning methods, specifically concerning the use of lambda gtll expression screening. Dr. Bradley began work on what was then called non-A, non-B hepatitis (later to be designated HCV) in 1977, joined CDC in 1982 where he primarily worked on HCV and continued there until last year. He is acknowledged as having first infected chimpanzees with HCV and demonstrating that chimpanzees develop hepatitis symptoms and are a useful animal model for study of HCV. Dr. Bradley claims he provided Chiron with "over 2,500 ml of a very rare commodity, a unique commodity," namely HCV-infected chimpanzee plasma that was essential to Chiron's isolation and cloning efforts. Dr. Bradley shared in much of the scientific recognition and several awards for his contribution to the cloning of HCV.
The dispute between Dr. Bradley and Chiron can be traced back to 1986 when the parties failed to agree on terms for Dr. Bradley to provide infected plasma to Chiron. The disagreement continued and was exacerbated in 1988 when Chiron announced its cloning of the HCV genome (and failed to include Dr. Bradley on its patent applications). Dr. Bradley's complaint alleges that NIH (which handles most patent matters for CDC) proposed to Chiron that it should receive co-ownership of HCV patents based on Dr. Bradley's contribution, in exchange for which NIH would grant the company a 3% royalty for a ten-year period. Chiron rejected this demand. In 1990, CDC reached a settlement with Chiron (to which Dr. Bradley was also a party) in which it renounced interest in HCV patents. In return, Chiron paid $2.25 million to CDC to fund HCV vaccine research through a Collaborative Research and Development Agreement (CRADA) for which Dr. Bradley was the CDC's principal investigator and agreed to personally pay Dr. Bradley $67,500/year for five years in recognition of his contributions. However, Dr. Bradley claims he was not a party to these negotiations and alleges he "signed the agreement under duress," lacking a full understanding of its consequences and was concerned about providing for his family after recently being diagnosed as having prostate cancer. A legal review of Dr. Bradley's claims was included by Chiron in its U.S. patent submission in 1991.
As is normal and expected in such cases, the parties involved issued statements supporting their positions and rebutting those of their adversaries. Chiron alleges that Dr. Bradley's suit is part of a "desperate strategy" by companies (e.g., Organon Teknika Ltd., Murex Diagnostics Ltd. and United Biomedical; see October 1994 Bulletin, p. 300) which have been unsuccessful in their challenges of Chiron's HCV patents in the U.S. and other countries. Dr. Bradley is represented by the same firm that represents Organon Teknika in its HCV patent disputes. Chiron claims that Dr. Bradley was not a co-inventor and cites the March 1990 agreement with both CDC and Dr. Bradley which includes their abandoning any future HCV patent-related claims against Chiron. Dr. Bradley's suit alleges that his "victory would save at least $30 million annually in health care costs," presumably through a reduction in the cost of HCV immunodiagnostics used to screen blood products for HCV antibodies that would result from government nonexclusive licensing of HCV patents. The suit also alleges that Chiron "has built a worldwide reputation and billion-dollar business largely due to Dr. Bradley's research and inventive ideas. This is a classic example of corporate greed resulting in an exorbitant cost for public health care and the diminution of one of those `faceless' government researchers' dedication to hard work."
Note, Dr. Bradley's co-inventorship claim is primarily based on his providing HCV-infected plasma to Chiron, not that he performed the actual cloning, although some of his suggestions may have been adopted by Chiron, and Dr. Bradley did not directly participate in the development of cDNA libraries or cloning of HCV by Chiron. The U.S. patent's claims refer only to HCV compositions (e.g., clones, genes, antigens) and do not refer to methods used for HCV isolation and cloning. In general, the supply of raw materials or proposals for specific procedures are not sufficient to require co-inventorship status for U.S. patents. As stated by one of Chiron's attorney's, it is highly unlikely that "merely providing materials or theorizing about the nature of the virus or the type of procedures necessary for its isolation constitute qualitative enough contributions to the claimed invention."
Previous patent disputes, particularly between Amgen and Chugai Pharmaceuticals concerning recombinant erythropoietin (EPO), have resulted in rulings that generally cite the actual isolation and cloning of a gene (the claimed invention), not just its purification and general characterization, as the moment of invention. However, evaluation of the contributions of individuals still plays a significant role in determining inventorship rights. Chiron alleges that although Dr. Bradley may have been right regarding some characteristics of HCV and his suggestions for action (which were not critical to the actual invention--HCV cloning and gene sequences), this does not constitute inventorship. A similar doctrine was recently upheld for the granting of sole inventorship rights for AZT to Burroughs Wellcome Co. In this case, NIH researchers provided the technology that enabled screening of AZT for anti-HIV efficacy and blindly screened AZT and other substances provided by the company.
U.S. Bioscience Licenses Fluorinated Nucleosides for HIV-Infection (news brief from February 1995 Antiviral Agents Bulletin)
The National Institutes of Health has granted a worldwide license for 2'-fluoro-2',3'-dideoxyadenosine (F-ddA) and 2'-fluoro-2',3'-dideoxyinosine (F-ddI) to U.S. Bioscience, Inc. (West Conshohocken, PA). NIH intentions to grant this license and further information about these drugs were reported in the June 1994 Bulletin (p. 174). F-ddA and its metabolite, F-ddI, are acid-stable inhibitors of HIV reverse transcriptase with efficacy in SCID mice comparable to that of AZT. F-ddA has not demonstrated cross-resistance to AZT, DDC or DDI and is synergistic with AZT. Clinical trials will be conducted in collaboration with NIH, most likely through a Collaborative Research and Development Agreement (CRADA).