Ricki Lewis

When the founding fathers penned the patent provision of the U.S. Constitution, they probably pictured devices, not the stuff of human heredity, as patent fodder. Today, with the human genome project spawning discoveries weekly, the U.S. Patent and Trademark Office (PTO) is buried in applications for inventions that include DNA sequences.

The purpose of a patent is to allow an inventor time to develop a salable product. During the 20 years of patent protection, another party can use the invention to develop a product only with a licensing agreement. (However, basic researchers can use it freely.) This period of exclusivity fosters commercial development of the invention by discouraging competition. "The claims section, at the back of the patent application, defines what the patent rights are. The object of a patent is to prevent others from making, using, and selling what's covered," says Michael Goldman, a patent attorney with the firm Nixon, Hargrave, in Rochester, N.Y. Adds Dr. Craig Venter, president and director of the Institute for Genome Research, a non-profit research facility in Rockville, Md.: "A patent serves a purpose in society. The goal of patenting a gene is not to make anyone rich, but to force disclosure of secret information." He offers the example of biotech company Genentech's patent on the human insulin gene, which enabled pharmaceutical company Eli Lilly to develop Humulin, the human insulin that people with diabetes use.

Yet the patenting of genes is not without controversy. Some critics reject the entire concept, while others have objections to the patenting of only specific types of DNA sequences. Should the blueprints of life be considered a licensable, marketable commodity, just like any other invention? Should there be any limits to the patenting of genes?

Patenting life
According to the first Patent Act, passed in 1790, a patentable invention or discovery must be artificial, non-obvious, novel, and useful. In 1981, the case of Diamond vs. Chakrabarty established the patentability of life forms, with a bacterium harboring four rings of DNA not found together in nature, forming an "oil eater" that consumes pollutants in water. Current "gene patents," however, refer to DNA sequences with a known function or use that are altered in some way from their form inside a cell.

A patented gene differs from its intracellular counterpart in that it is no longer part of a chromosome. Also, a patent typically claims only the protein-encoding part of a gene, not the regions without apparent function. "When you isolate something as it appears in its natural state you change it, even if the only change is the isolation. You have left behind the natural product and created something artificial. No isolated gene sequence occurs in nature," says Harold Edgar, professor of law at Columbia University. In 1990, the PTO changed its regulations to include rules for filing claims on DNA sequences.

Since that time, some groups have objected to patenting DNA, focusing on its special role in carrying the information to construct a human. Dr. Mark Hanson, project director of religion and biotechnology policy at the Hastings Center, a bioethics think tank in Garrison, N.Y., explains the religious challenge to patenting genes. "DNA is considered to be so intimately related to species identity that no parts of it should be controlled by corporate interests. In the case of human beings, human DNA is unique because it is human, and therefore possessing intrinsic value of a sacred kind. As one critic puts it, DNA bears the image of God."

A second objection to patenting genes is that DNA is a product of nature, not human ingenuity. The Council for Responsible Genetics, a Cambridge, Mass.-based organization of scientists, public health advocates, and consumers, takes this view. They have an online petition that states: "The plants, animals, and microorganisms comprising life on Earth are part of the natural world into which we are all born. The conversion of these species, their molecules, or parts into corporate property through patent monopolies is counter to the interests of the peoples of this country and of the world. No individual, institution, or corporation ... should be able to hold patents on organs, cells, genes, or proteins, whether naturally occurring, genetically altered, or otherwise modified."

But there may be a compromise--patents that describe a procedure, rather than claim a molecule. "One possibility that is acceptable to those religious leaders who oppose gene patenting is 'process patents,' whereby the processes involved in the manipulation of particular genes to serve a certain function are patented rather than the genes themselves," says Hanson. But as the genome project reveals specific genes that cause particular disorders, patents filed for the purpose of developing clinical tests will have to state the gene's identity, if not its sequence.

Among scientists, the controversy over gene patenting concerns not its special status, but its utility, which might not be recognized until long after a DNA sequence is deciphered. Dr. Isidore Edelman, Robert Wood Johnson Jr. Professor Emeritus and director of the Columbia Genome Center, explains that "utility" has four medical meanings. "The DNA sequence contributes to prevention of disease, such as a vaccine; provides a diagnosis; serves as a therapeutic; or may be of use in genetic counseling." A vaccine might consist of a DNA sequence unique to a disease-causing virus or bacterium. A diagnostic test might be a DNA sequence, called a probe, that binds to DNA from an infectious agent and carries a detectable label, such as a fluorescent molecule. Gene therapy might consist of a normal version of a gene to replace a malfunctioning one. Genetic testing and counseling could provide information about an individual's likelihood of developing a specific condition or disease.

What, exactly, is a gene patent?
Between 1981 and 1995, 1,175 patents mentioning human DNA sequences were granted worldwide. However, this doesn't necessarily mean that all of them were "gene patents." Searching patent databases identifies any claim that includes the phrase "DNA sequence." This might be an entire gene sequence, the protein-encoding portion of a gene, or just a DNA snippet useful as a probe to locate, or map, genes on chromosomes. Nor must patentable genes come from humans. Columbia University received a patent in 1996 for the DNA sequence encoding a green fluorescent protein from a jellyfish, discovered by Dr. Martin Chalfie, a professor of biological sciences, and Douglas Prasher of the Woods Hole Oceanographic Institute. Tacked onto other genes to highlight their activation, the protein has become a vital tool in cell biology research.

A major problem in patenting a gene is that, as a large informational molecule, its sequence can vary in nearly limitless ways. Consider the gene that encodes erythropoietin (EPO), a kidney hormone that signals the bone marrow to produce more red blood cells and has a $1.5 billion market as a drug to treat anemia. "There are millions of possible alternative EPO sequences. Claiming one doesn't automatically give you a claim on all others," says Edgar.

But the question of patentability of gene variants remains fuzzy. "How much variation must there be between your claimed gene and mine to avoid infringement? For ordinary chemical patents, a single claim embraces many analogs," says Edgar. But this is not comparable to DNA, where the consequences of changing a base are not always predictable. "We know that a small change in a gene sequence can have unbelievable effects--but often none at all. Clearly if the variation you discover in DNA is one that codes for something different, then it is patentable," Edgar adds.

Genes as research tools
Disease-causing genes are not the only types of DNA with utility. Researchers use small pieces of DNA to map genes on chromosomes. The biotechnology community is split on whether such short DNA sequences should be patentable.

In 1991, the National Institutes of Health withdrew patent applications for thousands of expressed sequence tags (ESTs), which are pieces of protein-encoding genes used to map and discover entire genes. The rationale for the turnaround was that an EST itself has no specific function but is a research tool. "Instead of taking a decade to find one gene, this method allows an investigator to find 1,000 genes at a time," says Venter, who developed EST technology but holds no patents on it. He believes that patenting something with such wide utility is "fundamentally wrong and an abuse of the system, like buying and selling gene futures."

Many ESTs are available to researchers from GenBank, a database at the National Center for Biotechnology Information, although some companies are still trying to patent newly discovered ESTs. However, the companies that hold patents on ESTs have generally granted free or low-cost licenses to non-profit organizations.

More recently, the patenting debate has centered around SNPs, or single nucleotide polymorphisms. A polymorphism is a chromosomal site where the DNA base varies in a population, but does not alter a trait; it is more or less a harmless glitch. Several large pharmaceutical companies are collaborating with biotechnology companies to patent SNPs for use in gene discovery. However, an advisory council to the National Human Genome Research Institute is attempting to keep SNPs free for research use, a view that Edelman shares. "These polymorphisms are certainly useful but lack the test of novelty. About 500 are already in the public domain. They should belong to the community of scientists."

Another example of using genes as research tools is the Human Genome Diversity Project, headed by Dr. L. Luca Cavalli-Sforza, a population geneticist at the Stanford University School of Medicine. The project proposes to sample DNA from 500 indigenous populations around the world. Original plans called for using the data to study disease-causing genes, which led to concerns that participants would be asked to donate tissue but would not directly benefit from any discoveries. Although the project is not slated to begin until 1999 and all the details have not been worked out, a National Research Council committee of scientists, ethicists, and lawyers has recommended limiting the project to investigating human evolution. Plus, the samples will not bear individual names, to protect privacy. "The project will contribute to understanding a very basic issue, the evolution of man, what our own genetic roots are," says Edelman.

The breast cancer saga
Breast cancer gene discoveries have been at the forefront of the debate on the ethics of patenting genes that have utility as diagnostic tests. The genes BRCA1 and BRCA2 account for 5 percent to 10 percent of breast cancer cases. The crux of the controversy is that these genes can be used to develop new diagnostic tests, but the results of the tests, if made available to insurers or employers, could be used to discriminate.

In 1996, Jeremy Rifkin, president of the Foundation for Economic Trends, led more than 250 women's groups in an international campaign to oppose patenting of breast cancer genes, because of the possible misuse of test results. They felt that a gene patent meant ownership of a body part, but scientists claim otherwise. "When people have patents on genes, it means they have the right to commercially develop products. It doesn't mean that Genentech owns my insulin gene, but the right to make a commercial product and sell it," says Venter.

The case of the patent on BRCA2 may set an example for future gene patents and tests. The patent on this gene, issued by the British Patent Office on Nov. 27, 1997, to the Institute of Cancer Research (ICR) in London and Duke University, covers the protein-encoding portion of the gene, and the claims include development of pharmaceuticals, diagnostic tests, and a method to produce the protein. (A U.S. patent decision on this gene isn't expected for two years.). Oncormed, Inc., of Gaithersburg, Md., obtained from ICR an exclusive worldwide license to the gene patent, with the understanding that it will sublicense use of the BRCA2 sequence in testing to hospitals, non-profit organizations, and other companies, and do so for free to the U.K. National Health Service. The patent holders also have stipulated that a BRCA2 test include physician-provided counseling and not be advertised directly to the public.

Despite these safeguards, some researchers and bioethicists question placing responsibility for administering a genetic test in the hands of a commercial organization, rather than government. As the debate continues, gene-based medical tests--made possible by gene patenting--are already being cleared for marketing by the U.S. Food and Drug Administration. And as these tests, and eventually treatments, provide new medical options, they will continue to raise questions. Says Hanson, "Beyond challenges to what we understand the meaning of DNA to be, the increasing commercialization of genetic technologies will introduce many challenges to human values and issues of human and other species identity." But, notes Edelman: "The only vehicle we have for bringing technology into the clinic and to the bedside is through a commercial organization. And that process begins with a patent."

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Related links

Statement on the patenting of human genes and DNA sequences, Committee for Public Relations and Ethical Issues, German Society of Human Genetics

Position paper on patenting of expressed sequence tags, American Society of Human Genetics

National Information Resource on Ethics and Human Genetics, Kennedy Institute of Ethics, Georgetown University

Genetics and Public Issues program, National Center for Genome Resources

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RICKI LEWIS, Ph.D., is author of Human Genetics: Concepts and Applications (McGraw-Hill College Publishing, 1997) and Life (1998). She has a Ph.D. in genetics and is a genetics counselor.