After Dorothea Lange’s photo Migrant Mother appeared in the San Francisco News in 1936, the US government allocated $200,000 to establish a migrant camp for homeless workers. After Upton Sinclair’s The Jungle, a novel about conditions in the meat-packing industry, was published in 1906, Congress passed the Pure Food and Drug Act and the Meat Inspection Act the same year. Today, Michael Crichton’s latest blockbuster, Next, off ers up a fictional look at the life sciences industry, complete with a seven-page appendix of policy recommendations.
Crichton, a Harvard-trained doctor, may set scientists’ teeth on edge with his mixture of insider detail and outlandish scenarios, but his market penetration - best-selling novels (often made into very big movies such as Jurassic Park) - is surely a force to be reckoned with. Can public perception, fueled by such commercial fantasies, spur policy changes that will affect the biotech industry? Reviewing Next in the Wall Street Journal, Matt Ridley, author of The Red Queen and Genome, expressed support for Crichton’s advice to policymakers to ban gene patents and to establish clear guidelines for patients’ control over research on their tissues samples, but to avoid bans on research (such as embryonic stem cell research). “These suggestions are good ones,” wrote Ridley. “They may chafe some biotech companies, but they are essentially pro-market and pro-research.” And members of Congress seemed to agree. In February of this year, two congressmen, Xavier Becerra, a Democrat from California, and Dave Weldon, a Republican from Florida, introduced the Genomic Research and Accessibility Act to ban the practice of patenting genes found in nature.
Whether or not pop fiction can lead to policy change, the real stories underlying the fiction - the kinds of stories being widely covered by journalists - have led the public to eye researchers with some suspicion. In the actual incident that provided the inspiration for Next, a university-based doctor led his patient to believe he was still ill. He had the patient returning for follow-up visits over a period of years, while the doctor harvested blood, sperm, and bone marrow and sold a cell line made from the patient’s tissue. The doctor received money and stock options. When the patient sued him, the California Supreme Court held that the patient could not have a property interest in his own tissue, but the doctor could. However, the court did protect the patient in another way: Concerned about the divided loyalties of doctors who have ties to biotech companies, the court ruled that patients have a right of informed consent to know whether their physicians have a personal interest - financial or purely intellectual - that might affect their judgment. “A physician who adds his own research interest to this balance may be tempted to order a scientifically useful procedure or test that offers marginal, or no, benefits to the patient,” the court said.
This issue is now being revisited by the Eighth Circuit Court of Appeals, in Washington University v. Catalona. Two decades ago, William Catalona, an internationally known cancer surgeon in St. Louis, Missouri, began asking his patients if they were willing to let him use for research purposes the tissue he removed from them. Over the years, he amassed more than 30,000 tissue samples and a wealth of data. In 1986, Catalona developed a simple blood test to screen for prostate cancer, the PSA, or prostate specific antigen test, and he undertook the research necessary to obtain approval by the US Food and Drug Administration. About 75 percent of American men over age 50 have had a PSA test for prostate cancer. Catalona’s current work focuses on genetic markers for prostate cancer.
Catalona’s employer, Washington University, had other ideas about the best use of the tissue samples. The university began to see the samples not solely as the means by which human subjects participated in prostate cancer research, but as a capital resource for the university. Many other medical centers had begun to enhance their bottom line by selling the raw material of patients’ pathology samples and blood tests to biotech companies for use in the companies’ research.
The issue came to a head when Catalona was asked to give a lecture at the annual meeting of the American Urological Association. He decided to compare all the predictive tests for prostate cancer through a blind study in which tissue samples from patients known to have prostate cancer and from men without prostate cancer were assayed using each of the existing tests. As part of the study, he planned to send samples to Beckman Coulter, which had acquired Hybritech, a life sciences and diagnostic company that had created a new assay.
An email from the office of technology management to the university’s vice chancellor of research stated: “Bill Catalona wants to send nearly 2,000 documented samples to Hybertech for free. Just from a cost recovery scenario, this should be worth nearly $100,000 to the university. The only consideration Hybertech is offering is the potential for Catalona to get a publication. It is my opinion this is an unacceptable proposal.”
As the conflict escalated, Catalona decided to leave Washington University for a new position at Northwestern University medical school in Chicago. He wrote to his patients, telling them they could continue to get their health care at Washington University, or he could see them at Northwestern. He also asked them to indicate whether they were willing to transfer their samples to Northwestern. Six thousand of his patients wrote that they wanted their samples to move with him.
When Catalona tried to transfer the tissue to Chicago to fulfi ll the patients’ wishes, Washington University sued him, claiming that the tissue was its property, and that the institution could do whatever it wanted with it. Patients joined the case and pointed out that the informed consent documents they signed reserved certain rights to them, including the right to withdraw from the research. The documents specified that they were providing the tissue to Catalona for a study of prostate cancer.
In April 2006, federal judge Stephen Limbaugh ruled that the patients had no property rights when it came to their tissue. Based on the university’s argument that recognizing patients’ rights to control what was done with their tissue would interfere with research, the judge went so far as to say that the patients’ informed consent documents were “inconsequential.” Washington University could indeed do whatever it wanted with the tissue, even if the actions taken violated the wishes of the patients from whom the tissue was extracted and contravened the promises that had been made to the patients about what would be done with their tissue. The opinion has created a stir, particularly because it conflicts with federal research regulations, which hold that, in federally funded research (as this was), the informed consent of patients is necessary before research can be undertaken on their personally identifiable tissue.
In December, 2006, the Eighth Circuit Court of Appeals heard oral argument in the case and will soon issue a decision. The underlying issue of conflicts over tissue and patents in biology goes back to the 1960s, when a University of Pennsylvania biologist named Leonard Hayflick developed, with federal funds, a fetal cell line known as WI-38. In 1962, his employer tried to patent the cell line, but the US Patent and Trademark Offi ce refused, based on its position at the time that patents were not allowed on living systems such as cells. Hayflick then received federal support to distribute WI-38 to vaccine manufacturers. Annoyed because these manufacturers were commercially benefiting from the use of his brainchild and he was not, Hayflick, in 1972, started his own company to market the cell line.
In 1975, the National Institutes of Health responded by accusing Hayflick of stealing government property (the cell line, whose creation was federally funded). He was by then a tenured professor at Stanford University, which handed him over to the local police, and he was investigated by the district attorney. That same year, Hayflick filed a lawsuit against the NIH, but in 1980 the rules changed with the passage of the federal Bayh-Dole Act. This measure allows researchers at universities and nonprofit institutions to apply for patents on federally funded inventions and discoveries. The NIH then settled the case, allowing Hayflick to sell WI-38. Overnight, behavior that once would have sent federally funded researchers to the slammer - personally profiting from research done at the taxpayers’ expense - was not only legal, but encouraged.
That same year, in Diamond v. Chakrabarty, the Supreme Court weighed in with a decision that substantially redefined the nature of patents. General Electric researcher Ananda Chakrabarty sought a patent on a living bacterium that was genetically engineered to clean up oil spills. The US Patent and Trade Office (Sidney Diamond was the commissioner of Patents and Trademarks) denied the patent application for the bacterium on the grounds that living organisms were not patentable. The high court allowed the patent, saying, “Anything under the sun that is made by man” could be patented. However, certain things had to remain part of the scientific commons: “The laws of nature, physical phenomena, and abstract ideas have been held not patentable. Thus, a new mineral discovered in the earth or a new plant found in the wild is not patentable subject matter. Likewise, Einstein could not patent his celebrated law that E=mc2, nor could Newton have patented the law of gravity. Such discoveries are ‘manifestations of ...nature, free to all men and reserved exclusively to none.’”
The real sea change in the relationship between biology and commerce, however, preceded Diamond v. Chakrabarty by seven years. In 1973, Herbert Boyer and Stanley Cohen invented (and later patented) the recombinant DNA technology that launched the biotech industry.
“The attitude today is exactly the opposite of what I experienced in 1976,” Leonard Hayflick noted in an article that appeared in Experimental Gerontology. Nowadays, he wrote, “if you do not hold a patent on a cell population, plasmid, or microorganism, or if you are not a stockholder or scientific adviser to a company that exploits such materials, you are a failure in biology.”
In the late 1980s, when the Human Genome Project was just getting under way, Walter Gilbert, husband of poet Celia Gilbert, announced a scheme to copyright DNA, just as you would a line of verse. His plan was to own the C A T T A G T A?, et cetera, sequence and to charge a fee for access to information about which sequences corresponded with which genes. The idea went nowhere. The idea of an individual having dominion over the common language of genes seemed overreaching and ludicrous. It also violated the principle articulated by the Supreme Court.
Key researchers expressed concern. C. Thomas Caskey, then at Baylor University, and Leroy Hood, then at Cal Tech, made the point that if scientists were allowed to gain intellectual property rights to genes and reap financial rewards whenever anyone used the gene in diagnosis or treatment, they would be less likely to share copies of the genes they discovered or even to share information about those genes.
Diamond v. Chakrabarty gave molecular biologists the assurance that they would own any life forms they invented by combining genes in novel ways. But in the 1990s, when the Human Genome Project proposed to spend $3 billion in taxpayer money to identify the full complement of human genes, most biologists still had no expectation that they could patent the nucleotide sequence and gain exclusive rights over it for the next 20-year patent period. In fact, the idea at that time seemed absurd. Intellectual property law, confirmed by the Chakrabarty decision, prohibits patenting scientific formulas or products of nature. Nonetheless, the US Patent and Trademark Office began to issue patents on human genes, and questions arose as to whether these patents were stifling or encouraging research and innovation.
When movie producer Jonathan Shestack’s son was diagnosed with autism, he contacted genetic scientists at top universities so that he could fund research to discover genes related to autism. At each university, he was told that the researcher did not have enough tissue samples from families with autism to undertake analyses to find the genes. Shestack asked the reasonable question: “Why don’t you share samples with other universities?” The researchers told him that they were not willing to share samples because they each wanted to be the one to find the gene so they could patent it and receive royalties.
Studies confirm that information and material that once would have been shared is now held back because a patent will not be granted for any invention that has been disclosed in a publication more than a year prior to the patent application. For example, the scientific report of the discovery of the hemachromatosis gene was not submitted for publication until more than a year after the patent on the gene was filed. The fact that people with the disease could have been diagnosed and cured during that time was subordinated to proprietary concerns.
David Blumenthal and his colleagues at the Harvard Institute of Health Policy found that one of every five professors in the life sciences had delayed publication of research results for at least half a year in order to protect financial interests. Those scientists who directly engaged in the commercialization of their research were three times as likely to delay publication and twice as likely to refuse to share information as those doing basic work. Among the life scientists, geneticists were the most likely to withhold data from other researchers.
In 2006, Blumenthal and colleagues reported on their survey of life scientists at the 100 most research-intensive universities in the US. Among the results: 44 percent of geneticists and 32 percent of other life scientists reported that they had withheld data, either in oral exchanges or as part of the publishing process. The research being published in the literature was incomplete - 16 percent of geneticists had withheld information in their manuscripts to protect their lead, 12 percent to protect trade secrets, 6 percent to allow time for patents, and 2 percent to protect commercial value.
A 2006 survey of more than 1,000 doctoral students and post-docs in the life sciences found profound effects of data withholding on the next generation of scientists. Forty-nine percent said withholding of information had a negative effect on the rate of discovery in their laboratory, and 33 percent felt it interfered with their education. On the one hand, we have a capitalist market economy based on the theory that the most effi cient production of goods and services emerges from free enterprise. Patents protect the property rights of inventors, encouraging investment in hopes of profits. On the other hand, patents and copyrights exclude; in this context, some scientifically valuable information isn’t published (at least until its profit potential has been realized). In the area of gene patents, the correct scope of patentability remains an open question.
Genes are of interest to researchers because they determine the characteristics of proteins and enzymes that guide the structure and functions of cell activity. A person with a patent on a genetic sequence now has a 20-year monopoly on any uses of that gene - even future uses the gene discoverer never anticipated. If doctors or health care institutions wish to use a genetic test to identify a mutation in that gene, or researchers want to use gene therapy to treat a disease related to that gene, they must first obtain the consent of the patent holder. The patent holder can stop them entirely or demand a royalty for use of the gene. The original patent holder has total rights, even if a second researcher independently discovers that gene or develops a test for it. The patent holder can charge whatever he or she wants for a test using the patented gene -or even prohibit people from being tested altogether. Unlike copyright law, there is no fair use exception in patent law. Unlike the patent law of other countries, the US does not have a statutory exception that would allow a scientist to use the patented nucleotide sequence for research purposes without the patent holder’s permission.
Courts used to recognize the judge-made “experimental use” exception to patent liability. However, the 2002 Duke v. Madey case made clear that university researchers and scientists involved in R&D at companies are not covered by a research exemption. The court held that the “experimental use defense is very narrow and limited to actions performed for amusement, to satisfy idle curiosity, or for strictly philosophical inquiry.” The court pointed out that universities now commercialize their research.
“Duke, like other major research institutions of higher learning, is not shy in pursuing an aggressive patent licensing program from which it derives a not insubstantial revenue stream.”
Proponents of gene patents argue that they are not really patenting a product of nature, but an “isolated and purified” version of a natural product, which is allowable under patent law. However, the cases allowing isolated and purified products of nature to be patented require that the resulting product have properties that do not occur in nature. The person claiming ownership of an “isolated and purified” human gene is seeking a monopoly on its natural functions - the ability of a gene sequence to anneal to its complementary strand (which allows diagnosis) and the ability to produce proteins.
Gene patents provide a perplexing question of what the best intellectual property scheme is for encouraging innovation in the genetic realm. David Lentini, a San Francisco patent lawyer, wrote in a February 19, 2007, “Letter to the Editor” of The New York Times, “Gene patents are vital to the biotechnology and pharmaceutical industries. Why would anyone risk the billions needed to transform basic science into lifesaving products if someone else could simply copy those products without risk?” Lentini makes an important point about the necessity of patent protection for innovation, but patenting the sequences themselves might actually deter the innovation he is striving for.
It’s worth considering his example in detail. First, is the patent incentive necessary for the discovery of the sequence? Probably not, given that researchers were searching for genes before they knew they could patent the sequence, and many genetics researchers, including Nobel laureate John Sultson, actually oppose gene sequence patents. Moreover, the discovery of gene sequences is substantially enabled by taxpayer funds. The National Institutes of Health contributed $5 million to sequencing the BRCA 1 gene, which was then patented by Myriad.
Second, if someone owns the sequence on a breast cancer gene, what is the incentive for another researcher to develop a better test or a gene therapy for breast cancer? Any such product will infringe the original patent, which means that, once the new product is created, the patent holder could charge an exorbitant amount for the use of the sequence in the therapy - or prevent the researcher from distributing the therapy. And it’s rare that a gene therapy developer needs to license just one gene. Multiple genes contribute to most diseases - and there are often separate patents on mutations of the genes. In an article in Science, Michael Heller and Rebecca Eisenberg express concern about the “privatization of upstream biomedical research.” They note that: “because patents matter more to the pharmaceutical and biotechnology industries than to other industries, firms in these industries may be less willing to participate in patent pools that undermine the gains from exclusivity. Moreover, the lack of substitutes for certain biomedical discoveries (such as patented genes or receptors) may increase the leverage of some patent holders, thereby aggravating holdout problems. Rivals may not be able to invent around patents in research aimed at understanding the genetic basis of diseases as they occur in nature.”
And what is the effect of gene sequence patents on the application of the scientific method of hypothesis generation, discovery, and replication? In one survey, half of gene patent holders said they would require a license for researchers to study the prevalence of mutations in the patented gene in the population. Twenty-eight percent of geneticists surveyed reported that they were unable to duplicate published research because other academic scientists refused to share information, data, or materials. This goes to the heart of science - which is based on confirmation of scientific data through replication.
Companies now sequence disease-causing bacteria and virus genes. In fact, in one situation, a company wants to introduce inexpensive, quick public health testing for a common infectious disease, but the company holding the patent on the infectious disease has forbidden it. In the future, a person might want to have hundreds or thousands of sections of their genome tested from a single blood sample, but patents on the underlying sequences make such a technology prohibitively expensive. Just do the math: Say a person wants to test herself for the 13 genes associated with asthma, maybe even throwing in tests for a few snippets of DNA related to treatment of her migraines and a dozen genes related to cardiovascular disease. At the Myriad rate per sequence tested, the test becomes unaffordable. The technology is already available but cannot be implemented due to the financial and practical limitations put in place by gene patent holders. Already, one in four laboratories has stopped performing certain genetic tests because of patent restrictions or excessive royalty costs. More than half had not developed a test for fear of running afoul of patent law.
Most drugs work on only a percentage of patients who use them. Patients get a prescription, try the pills for a while, and if the drugs are ineffective or harmful, they switch to another prescription. Physicians and patients have longed for a way to determine in advance which drugs are appropriate for which patients. Many groups, including the nonprofit Personalized Medicine Coalition, are working to assure better medical outcomes by using genetic markers to determine which medications or other treatment strategies are appropriate for which patients. But will patients actually get the benefit of pharmacogenomics - or will patents on genetic sequences stand in the way? One pharmaceutical company has fi led for a patent on the gene sequence that can be used to determine the effectiveness of its asthma inhaler. But the company says it will not develop the test - or let anyone else develop it. By controlling uses of a patented gene sequence, a company can continue to sell its drugs to more people by not weeding out those for whom it will be ineffective. But doctors express concern that, even if this company’s behavior is not representative of the industry as a whole, keeping a drug effectiveness test secret will mean that some patients will not be receiving the medication that is right for them.
These problems are so troubling that the American Society of Human Genetics, the American College of Medical Genetics, and the College of American Pathologists oppose gene patents, viewing them as a threat to medical advances and patient care. The World Medical Association takes the position that genes are the common heritage of mankind.
Beyond concerns about philosophy and altruism lurk compelling questions for CEOs. What is the best business model? Small biotech companies whose main asset is a particular gene patent vigorously defend the practice of patenting nucleotide sequences. But increasingly, big pharma wants to be able to use SNPs and sequences in drug target research without the risk of infringing dozens of patents. And companies like Affymetrix that produce chips and systems for DNA testing oppose the patenting of genes. Their technology - which makes it feasible to test for thousand of genes with a single chip - is not commercially viable if the royalty for each gene is in the thousands of dollars.
The ability to patent genetic sequences has also led medical researchers to patent other types of scientific information. Researchers from Columbia University and the University of Colorado patented the fact that a high level of homocysteine in a person’s body was correlated with vitamin B deficiency and patented a particular test for homocysteine levels. Someone else invented a better test for those levels,
but it was considered a violation of the patent for a physician to use that better test because once he got the results, he would have to think about the patented medical fact: that the patient might have vitamin B deficiency. The Federal Circuit - the court that hears all patent appeals after the trial court - held that a laboratory induced infringement of that patent (and thus was liable for more than $2 million in damages) based on the publication of an article for physicians about this law of nature - the relationship between levels of homocysteine and vitamin deficiency. Astonishingly, the Federal Circuit effectively held that physicians would infringe the patent merely by thinking about the relationship between homocysteine and vitamin deficiency.
Whatever such an opinion means for the world of biotech, it brings into the public eye the question of whether certain industry practices have gone too far. The biotech industry needs to weigh in with a view - or even multiple views - about which, if any, of the behaviors of researchers and companies in the actual cases cross some ethical or legal line. Conflicts like the Catalona case seed distrust, deterring people from donating their tissue for research, and hence depriving the biotech industry of the raw material needed for the discovery of genetic sequences and related products.
Crichton’s oeuvre offers an intriguing thought problem to jump-start such a discussion. In the writer’s first wildly successful techno-thriller, The Andromeda Strain, the Department of Defense launches Project SCOOP, a secret mission to collect potential vectors for germ warfare from Earth’s upper atmosphere. What they unwittingly capture and bring back, however, is a pathogen that turns blood to powder, wiping out all but two residents of the small desert town where the returning satellite touches down. Five intrepid scientists collaborate, at great personal risk, in a race to understand the extraterrestrial microbe and to find a cure before all humanity perishes. If The Andromeda Strain were placed into today’s research milieu, would the five university scientists charged with saving the world accomplish their mission? Or would they each keep information from the other to preserve their competitive advantage, then try to patent the organism?
May 15, 2007
http://www.burrillreport.com/article-patenting_life.html