[working title] A Patent Theory of Medicine and Disease
The federal patent power derived from the Constitution is both a grant of exclusive power and a limitation. The constitutional authority granted to Congress is limited to the promotion, advancement and innovation of those ideas that contribute to the sum of useful knowledge. The patent monopoly was intended to be an inducement to disclose inventions. Thomas Jefferson wrote, “[i]nventions… cannot, in nature, be a subject of property. Society may give an exclusive right to the profits arising from them, as an encouragement to men to pursue ideas which may produce utility, but this may or may not be done, according to the will and convenience of the society, without claim or complaint from anybody.” The tension between the incentives to pursue inventions and the balancing of societal benefit is evidenced by the difficulty in formulating conditions for patentability. Between 1790 and 1950, the Patent Act was revised, amended, or codified fifty times. The questions of under what circumstance patens might progress, and whether this progress is worth the social cost, are ongoing. Modern societies’ pharmaceutical and biotechnology companies, for example, can accrue a profit during the patent period that far exceeds the patented product’s development costs. Critics decry this situation in which patents facilitate monopolistic pricing in affluent markets with price inelastic demand. This is the current norm, however, and modern medicine depends upon pharmaceutical and biotechnological innovation. Since the completion of the Human Genome Project in 2003, DNA has become more significant to advances in biotechnology and to the development of new drugs. This has contributed to the relative uniqueness of medicine in patent law because medical diagnoses and treatment include both the physical property rights of individuals (e.g., tissue, DNA, etc.) as well as the intellectual property rights of inventors. This entanglement of physical and intellectual property has generated much patent litigation, including the recent Supreme Court opinion holding that naturally occurring DNA is not patentable subject matter.The Myriad decision notwithstanding, many important legal questions remain unresolved. Can one obtain a patent, and thus the exclusive right, to conduct specific research on naturally-occurring gene sequences taken from a human body? If not, what sort of transformation renders isolated DNA sequences sufficiently altered in order to become patent eligible? Does the human patient relinquish all legal claims to his or her DNA upon the removal of cells from the body? If the patient does have a legal claim to discarded tissue or DNA, does the patient have a right to share in profits on technology derived from the research? If so, precisely what is the patient’s contribution to the invention? The petitioners in Myriad claimed that the case was the first to present these questions. This claim might be true of the narrowly defined legal issue, but, epistemologically, such questions certainly pre-date the Myriad litigation.
The Fascinating Case of HIV
The discovery of the human immunodeficiency virus (HIV) is worthy of analysis when examining the evolution of patent rights in medicine and genetics. HIV provides a modern example of how patent law can affect both the diagnosis and treatment of a disease. HIV is unique because it can be studied chronologically from its discovery in humans through the production of screening tests and into the development of six major classes of antiretroviral drugs. This rapid scientific progress provides an opportunity to study how patent law has been shaped at each stage of scientific development and to explore the significant questions raised regarding ownership and assignment of patent rights.
Patenting the HIV Test
HIV was first reported in the Centers for Disease Control Morbidity and Mortality Weekly Report on June 5, 1981. This report described five cases of Pneumocystis pneumonia (a parasitic opportunistic infection) within the United States. The same parasitic infection was observed in immunosuppressed patients in France as early as 1978; another case was described in Denmark in 1977. By August of 1982, the Centers for Disease Control had named the newly discovered disease Acquired Immune Deficiency Syndrome (AIDS). However, the causative viral agent was not identified until 1983. Physicians at the Pasteur Institute in France had isolated the virus from the lymphatic tissue of an infected patient whom they suspected was suffering from AIDS. Further, the French researchers were able to definitively classify the virus as a retrovirus. On May 20, 1983, The French researchers published their discovery in Science, referring to the virus as lymphadenopathy associated virus (LAV). Appearing in the same issue of Science was another article written by Dr. Robert Gallo, an American virologist with whom the French researchers were collaborating. Similarly, this article also identified the virus as belonging to the retrovirus family and suggested it was the causative agent of AIDS. Approximately one year later, Dr. Gallo published another article indicating the virus as the primary cause of AIDS; this virus was referred to as human T-lymphotropic virus type III (HTLV-III). The term, “HIV,” was not officially adopted until 1986.
Determining which team of scientists first discovered the virus was significant for two reasons. First, the scientists leading the team credited with initially discovering the HIV virus would become candidates for the Nobel Prize in Medicine and Physiology, a coveted achievement in the scientific community. Second (and perhaps more relevant to my discussion), the institute at which the scientists were working could be awarded exclusive patent rights to the first antibody test. After the actor Rock Hudson announced that he was infected with the AIDS virus in 1985, global media attention to the epidemic significantly increased. Hudson disclosed that he had flown to the Pasteur Institute in France to receive treatment. The increase in media attention led to public revelations surrounding the identification and patenting of the antibody test. The director of the Pasteur Institute appeared before the French-American Chamber of Commerce in San Francisco to explain that the French had applied for the patent on LAV in December of 1983. Dr. Robert Gallo, working for the National Cancer Institute, had applied for the patent on the HTLV-III antibody test in early 1984, after the French scientists. Dr. Gallo’s patent application, however, was approved by a patent examiner before the French application was approved, and so an acrimonious dispute arose between the two scientific teams. Without patent protection, the French scientists could not market or profit from any royalties derived from the LAV antigen test within the United States. In 1987, a settlement was reached between the two scientific teams stipulating that each party was a co-discoverer and had equal rights to claim priority in isolating the virus.
In 1993, an independent research group commissioned by the Office of Scientific Integrity at the National Institutes of Health analyzed both the LAV and HTLV-III samples and concluded that the two specimens shared identical genetic sequences. The group confirmed that, given the virus’s high mutation rate and genetic variability between infected individuals, these highly similar specimens had been acquired from the same patient at the Pasteur Institute. This article was published one year after the Federal Office of Research Integrity (ORI) found Dr. Robert Gallo to be guilty of scientific misconduct. The ORI report stated Dr. Gallo had deliberately misled his colleagues when he claimed he had independently grown and studied his HTLV-III variant and had not grown or studied the similar French virus LAV. It was determined that Dr. Gallo actually had grown and studied LAV in his lab from samples sent to him by the French team and had used this in furthering his own research, inappropriately taking full credit for the isolation of the virus in his 1984 publication. Dr. Gallo claimed that his viral samples were possibly contaminated by the French samples and maintained the validity of his independent discovery.
At the time of the formal misconduct report, both the French and United States Governments were receiving millions of dollars in annual royalties derived from patenting the HIV blood test. After the release of the ORI report, attorneys for the Pasteur Institute asked the United States to turn over approximately $50 million, half of the accrued profits from the HIV test since 1985. In 1992, Dr. Gallo was also facing charges of perjury and patent fraud.
[The following paragraph might be a digression more appropriately placed in a footnote?] Fraud, a form of inequitable conduct, is an affirmative defense to patent infringement and requires proof of intent to deceive the PTO, the highest level of proof. To properly plead inequitable conduct, a pleading must include the following: (1) state all substantive elements of inequitable conduct; (2) identify specific prior art that was allegedly known and not disclosed; (3) specifically identify any intentional misleading actions; and (4) allege sufficient underlying facts from which a court may reasonably infer that a party acted with the requisite state of mind. Deceptive intent is difficult to prove because it must be shown that material prior art that would have caused the patent not be issued was deliberately withheld. The publication of the 1993 article in Nature by the independent research group reinforced Gallo’s claim of sample contamination, thereby vitiating the requisite deceptive intent to prevail on a claim of inequitable conduct. Dr. Gallo never received the Nobel Prize for discovering HIV; in 2008, the leader of the French scientific team, Dr. Montagnier, was a co-recipient of the Nobel Prize in Physiology or Medicine for his discovery of HIV.
Delays in HIV Testing
The saga of the HIV test presents interesting issues regarding proprietary rights. Much attention was given to which scientific team or individual was the true discoverer of HIV. However, little attention was given to the question of who was actually harmed by delaying the public availability of the HIV test during the period of patent litigation. Although the scientific knowledge for the test was publicly known in 1983, the HIV antibody test was not available for use until 1985. During this time, HIV was known to be in the blood supply and continued to infect individuals receiving blood transfusions. It is estimated that 28,000 additional people were infected through the blood supply. Additionally, there was no way for those at risk or suspected to be suffering from AIDS to definitively know their HIV status. Given the long time period between exposure to HIV and the development of symptoms, an infected individual could unknowingly transmit the virus for many years.
The thousands of people infected were an unacceptable social cost. To the patent holders, the total cost incurred by developing an antibody test necessarily included each person infected while the patent validity was being challenged. Even if Mr. Gallo’s team misappropriated their sample from the French, it is very likely that they would have identified the virus anyway within a short period of time. Therefore, the real social value of the test perhaps should have been months, not twenty years. As this patent race suggests, there was too much incentive to make and patent the HIV test. In this sense, the development of the test turned into rent-seeking behavior since both the French and American scientists and their respective medical institutions expended resources to gain benefits at the expense of one another and to the detriment of the public.
The delay in testing illustrates how medical issues are unique in patent law because the issuance and litigation of a patent can directly affect public health. Disease outbreaks like HIV present a time-sensitive problem. An individual needs to know if he or she is infected and if so, needs to be accurately diagnosed and treated. Patents evolved out of property ownership and ideas. When these ideas affect human health, this adds another dimension to the patent discussion because litigation costs can include quality of life and mortality of people. Therefore, the cost of the patent includes risk and opportunity that is experienced differently in society. Medicine has now developed into an area that is qualitatively different than areas where patents were historically used.
Additionally, little attention was given to the French patient who had provided the lymphatic tissue samples. The biological samples from which the test was developed came from Dr. Montagnier’s patient, Frederic Brugiere.
Should Mr. Brugiere be entitled to any royalties derived from the HIV test? Should his heirs? Considering the rapidity of mutation in HIV and the wide genetic variation this produces in infected individuals, does this uniqueness impart a specific physical property right that also can be considered an intellectual property right? As further research on HIV progressed, these questions would re-emerge.
The CCR5 Δ32 Mutation
The CCR5 gene normally encodes for a protein that is expressed on the surfaces of certain immune cells, i.e., T-cells and macrophages. This expressed protein is known to be an important co-receptor that allows HIV and similarly-acting pathogens to enter the host immune cell. Individuals resistant to HIV infection carry a mutated form of this gene referred to as delta thirty-two (Δ32). Individuals having the homozygous genotype (i.e., two mutated gene copies) are immune to HIV infection, while individuals having the heterozygous genotype (i.e., one mutated gene copy) experience a delayed progression of HIV disease.
Steve Chron’s partner was one of the first people in the United States to die from AIDS. During the height of the AIDS epidemic in the nineteen-eighties and nineteen-nineties, Mr. Chron continued to test negative for HIV. Surprised by his HIV-negative status, he approached an immunologist at the Aaron Diamond AIDS Research Center who was studying the blood of high-risk, HIV-negative individuals. The immunologist discovered that he could not infect Chron’s cells with HIV. Further genetic research revealed that Chron possessed some sort of mechanism that was preventing HIV from binding to the cell receptors; this blocking mechanism was identified as the Δ32 mutation.
Erich Karl Fuchs was another individual who donated his blood to be studied at the Aaron Diamond AIDS Research Center. Like Mr. Chron, Mr. Fuchs was part of a high-risk group, yet continued to test HIV-negative. Further research revealed that Mr. Fuchs was also carrying the Δ32 mutation. Eventually, this research led to three medically significant inventions. On May 2, 1994, the research center’s patent application was granted for the first invention: a genetic test that identified individuals with the Δ32 mutation. The second invention following this test was the development of an entirely novel class of antiretroviral drugs. Approved by the FDA in 2007, maraviroc acts as a CCR5 receptor antagonist, inhibiting viral entry into the host cell. In 2008, the third significant medical innovation occurred when a HIV infected man received two bone marrow transplants to treat leukemia. The blood cells used in the transplants came from a donor having the Δ32 mutation. After the transplants, the recipient tested negative for HIV; five years later, after discontinuing all HIV antiretroviral treatment, he continued to test negative. Using the bone marrow recipient as a template, biotechnology researchers are currently attempting to achieve the same results through gene therapy in another patient.
[To be discussed further in a revised draft:]
Ownership of DNA. Did any of these volunteers have a right to share in profits from the Δ32 mutation test? Does the length of time a genetic mutation has been present in humans reinforce an argument for any derivative inventions to remain in the commons? Should this commons be converted into private property? Can the patent claim be limited to only HIV innovations if other diseases are affected by the Δ32 mutation?
People do not want to be exploited. However, patents protect ideas. Who is the true inventor? The person who intellectually develops upon the DNA, i.e., the researcher.
What was the opportunity cost during patent test litigation? Those people who could not be tested + each person infected through the blood banks. The infected persons are the opportunity cost of the delay.
Is it hard to measure the true opportunity cost because we don’t know exactly how many people were infected during this time, but know that some people were. We cannot measure who did not get something.
The demand for novel HIV drugs (e.g., maraviroc) is different in countries.
There is inelastic demand in the US and elastic demand in developing nations; income inelasticity.
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