Gene patents raise concerns for researchers, clinicians

The proliferation of patents for specific gene sequences may increase costs and decrease quality of diagnostic laboratory testing, limiting access for patients and training opportunities for physicians.

By Vida Foubister, amednews staff. Feb. 21, 2000.

Just as the discovery of genes that have implications for the diagnosis and management of inherited human diseases is becoming commonplace, new restrictions on who can use this information and in what settings are emerging.

Patents have been issued for DNA sequences since 1980. But their enforcement, by both private companies and public researchers and institutions, is a relatively new phenomenon that is raising concerns among clinicians and researchers who rely on this genetic information.

"This is a break with the whole history of laboratory testing, in which somebody develops a test and it's immediately available to the entire medical community," said Valerie Ng, MD, PhD, immediate past president of the Academy of Clinical Laboratory Physicians and Scientists.

At the heart of the emerging debate over the restrictive licensing of diagnostic tests by patent holders is the question whether gene sequences are bona fide inventions.

The U.S. Patent and Trademark Office, which to date has issued about 2,000 plant or animal or human gene patents, said a gene sequence can be patented if it can meet a three-pronged test for utility: Its utility must be specific to the gene sequence in question, not to genes in general; it must have a real world substantial utility, not just a throwaway utility; and it must be credible to a person of ordinary skill in the art.

"What we describe in our patents is not a tool to find a drug, it is the drug," said William Haseltine, PhD, CEO and chair of Human Genome Sciences Inc., a Rockville, Md.-based biopharmaceutical company that has filed patents on nearly 7,500 genes, of which 110 have been issued. "They're as important to us in our industry as the chemical formula is to Merck."

While Human Genome Sciences is patenting genes to protect potential gene, protein or antibody-based drugs that the company or its partners develop, others are patenting sequences for their use in genetic testing. Celera Genomics and Incyte Pharmaceuticals Inc., two companies that are leading the race with Human Genome Sciences to patent numerous gene sequences, declined to comment for this article.

Though many questions remain about patenting naturally occurring genetic sequences, it's the patenting of these disease-specific sequences that's raised the most concern.

"The Patent and Trademark Office has issued patents with far too broad a right to patent holders; they essentially end up owning a disease rather than some specific development for a test," said Michael Watson, PhD, a professor of pediatrics and genetics at Washington University School of Medicine, St. Louis.

Exclusivity can limit quality, training

Patents on disease genes, even without enforcement, can hinder the development and further refinement of diagnostic tests.

Jon F. Merz, PhD, an assistant professor of bioethics at the University of Pennsylvania, Philadelphia, has preliminary data showing that about 20% of more than 100 laboratories surveyed last summer did not develop a test for hemochromatosis in part because the gene was patented.

"Why spend the resources to develop the test if you're going to be shut down?" he said.

Even if the patent holders do give laboratories the option of buying a license to offer the test, they're free to set the terms. Laboratories are usually charged both an upfront usage fee and a per test fee, often at rates that small diagnostic laboratories cannot afford.

"If a [company] offers nonexclusive licenses but it sets royalty terms unreasonably high, it can shut out other labs," said Jonathan F. Tait, MD, PhD, associate professor and director of the Molecular Diagnosis Laboratory at the University of Washington, Seattle.

Exclusive licensing also raises questions about quality, because it eliminates chances for comparing results among laboratories. The nationwide proficiency testing required under the Clinical Laboratory Improvement Amendments, where a lab is sent unknown specimens and must report its results, becomes pointless.

"If you have a patented gene that only one laboratory is using, I don't think we'd set up this program," said Wayne W. Grody, MD, PhD, of the University of California, Los Angeles, School of Medicine. "If we did, the comparison group would be one, so it wouldn't be too meaningful."

Second opinions, a long-standing medical practice, can be difficult to obtain when there are only a handful of laboratories (perhaps only one) licensed to perform the test.

"If there is some problem with testing at a given laboratory, there's no way you're ever going to have an option of finding out," Dr. Tait said.

As these tests become concentrated in fewer and fewer labs, opportunities for medical training are also limited.

"The way physicians learn about how to use tests is to actually see tests and do tests and interpret them and study them," Dr. Tait said.

"So if all the testing in the country is sent to one particular laboratory, then the people who are in training are denied the ability to participate directly in training and learn from it."

Pushing for access

The monopolistic nature of these patents and their licensing could also price out many patients, limiting their access to new genetic information about themselves, their children and their future children.

"It has the potential to create the haves and have-nots in terms of genetic information about health," said Jeffrey P. Kahn, MPH, PhD, the director of the Center for Bioethics at the University of Minnesota, Minneapolis.

These concerns led several groups, including the Academy of Clinical Laboratory Physicians and Scientists and the American College of Medical Genetics, to develop position statements opposing patent licensing agreements that limit clinical care and medical training and research.

The AMA doesn't oppose gene patents per se but has policy that states "if you're going to patent it, don't restrict its application to patient care," said Herbert Rakatansky, MD, chair of the Council on Judicial and Ethical Affairs.

John Doll, director of biotechnology at the Patent and Trademark Office, however, said gene patents are no more restrictive than existing patents on medical equipment.

"There are patents on x-ray machines, on NMRs, on ultrasound -- [for] almost every piece of equipment that the doctor uses on you in any diagnostic test, you're paying a royalty to the person that patented that machine," he said.

However, the medical community's outcry against patents on medical processes led Congress to pass a law in 1996 holding physicians and institutions free of liability for infringing such patents. That legislation excluded clinical laboratory services, but a consortium of medical groups plan to begin pushing for changes that would guarantee access to genetic tests at a reasonable cost.

"As we define the genome and we characterize genes, both normal and abnormal, that have diagnostic value, we think those should be in the public arena," said R. Rodney Howell, MD, president of the American College of Medical Genetics and professor and chair of the Dept. of Pediatrics at the University of Miami.

ADDITIONAL INFORMATION:

Firm's patents on breast cancer genes illustrate concerns

When Myriad Genetics Inc. began enforcing its exclusive patents for BRAC1 and BRAC2 genes in the United States, scientists feared that the cost of having the company provide its full-sequence genetic analysis would limit their research. Although about a dozen diagnostic laboratories have been licensed by Myriad to perform a breast cancer screening test, all others can no longer offer either type of testing commercially.

In response, the National Cancer Institute brokered a deal with the Salt Lake City-based company last month that offers a reduced testing rate to all NCI and National Institutes of Health-sponsored research institutions and investigators. A full-sequence analysis of both genes will cost $1,200; for BRAC1 only, $600; and for BRAC2 only, $750. A "reach through" clause in the agreement will prevent Myriad from accessing or asserting an interest in research findings that result from these tests.

Now that Myriad has patents pending on these genes in Europe, British researchers have begun to question the public's continued access to breast cancer screening. In particular, public service labs might have to stop offering BRAC1 and BRAC2 testing.

Though a reasonable fee would be accepted in Britain, there's a genuine concern that Myriad's scientific contribution pales in comparison to the profits it stands to reap.

"If you've found a chemical that works in an animal model, to take it to clinical trials, the [Food and Drug Administration] and all the rest of it is hugely expensive. There it seems to me a company is justified in protecting its commercial interest to cover the cost of that development," said Walter Bodmer, PhD, honorary head of the Imperial Cancer Research Fund's lab of cancer and immunogenetics. "But when you're dealing with diagnostics, a little lab like mine can discover a new diagnostic and it can be applied without very much effort and cost."

Myriad spokesman William A. Hockett III disagreed.

"A lot of laboratories are doing more of a screening test, or they're testing for one gene only, which we think is of very limited utility and could provide some really distressful results," he said.

That should change when Myriad introduces the test, added Hockett. "Access will be wider and the quality of testing will go up."