In the remote forests of Papua New Guinea, researchers working with the National Institutes of Health stumbled on a medical mystery. They found that members of a primitive tribe called the Hagahai were infected with a variant of a virus that usually causes leukemia. But the Hagahai didn't come down with the disease. The scientists, including American anthropologist Carol Jenkins, cultured blood from tribe members--and applied for a patent on it.
The discovery dangled tantalizing clues about the disease, and resistance to it. Any commercial gains from the research were intended to be transferred to the tribe. But when the patent was issued last year it drew outrage from American religious groups who opposed it on moral grounds, arguing that it is wrong to patent life. Third World activists accused the NIH of "genetic colonialism."
Last month, the NIH quelled the furor by offering to withdraw the Hagahai patent. But conflict over gene patents is not going away. At international conferences, in courtrooms, and in the pages of prestigious science journals, biologists, lawyers, and many others are trying to hash out what it means to patent a gene--and how to do it.
THOUSANDS OF CLAIMS. Confusion over gene patents is no surprise. To many nonscientists, the very notion at first seems alien: You might as well patent an eye, and charge everyone a license to see. But the subject is critical in biotechnology, because the industry is grounded in firm protection for intellectual property. Any change in the current patent system has important consequences for the industry and for medical research.
Some of the problems are purely logistical. Biotech startups have swamped the U.S. patent office with thousands of claims for gene patents. Unable to keep up, the office has proposed measures to limit applications--a move likely to spur further controversy.
Then there are the legal battles. Because decisions on what a patent covers can come only from the judges who will rule on infringement cases, "there will soon be a flood of litigation to sort it all out," says Smith Barney biotech analyst Reijer Lenstra. "The lawyers will be very happy."
When you consider how difficult it has been to locate and decode genes, the idea of patenting them begins to make sense. In each human cell, there are 46 chromosomes that make up the whole human genome. These are densely coiled strands of helical DNA, itself constructed from a sequence of four subunits designated by the letters A, T, C, and G. The human genome has about three billion such subunits. It's the order, or sequence, of those subunits that determines a gene's function.
Hidden in the human genome are some 100,000 genes, which, among other things, provide the blueprints for all the proteins cells produce. Locating specific genes linked with diseases is costly, and companies seeking those genes want patents to protect their investments. Since the early 1980s, the Patent & Trademark Office has issued about 800 patents on human gene sequences and hundreds more on related proteins. "If we want a healthy biotech industry to find new treatments for diseases, we must not tamper with the patent system," says Bruce Lehman, commissioner of the patent office.
New technology, though, has made it possible for companies to snatch up thousands of genes and gene fragments without any knowledge of their function or their relevance to disease. Some applications seek to cover as many as 20,000 such fragments.
Critics of this approach to filing applications argue that the fragments shouldn't receive patents, because their functions and usefulness are unclear. What's more, the patent office is stuck with the mammoth task of determining whether any of these sequences have been claimed previously by anyone else. "It would require us to literally shut down all our mainframe computers and devote them to running the sequences in just one application for months," says Lehman. To stem the tide, his office has just released an official notice restricting the number of sequences to 10 per application.
NO PUBLIC ACCESS. Companies in the business of finding genes, such as Human Genome Sciences Inc. in Rockville, Md., argue that even gene fragments can merit patents, so long as they are useful as well as novel. And the companies claim that limiting the number of sequences per application will dramatically drive up the cost of patenting thousands of sequences. That might hinder companies' ability to recoup their investments. Instead of seeking patent protection, companies may now keep the results of their gene prospecting locked in their own corporate labs, thus limiting public access to important information.
Delays in the issuance of pat-ents leave bio-tech companies in limbo. Myriad Genetics Inc. in Salt Lake City is still waiting for a patent two years after it discovered a breast cancer gene called BRCA1. Myriad wants to use the gene to produce a test to diagnose susceptibility to breast cancer. But while Myriad waits, rival Oncormed Inc. in Gaithersburg, Md., is already selling its own BRCA1-based test. Myriad's only option may be to take action in the courts.
Countless other patent time bombs are ticking. In some cases, the fuse is rapid public disclosure of gene fragments. For more than two years, a Merck & Co.-funded effort at Washington University in St. Louis has been funneling gene data into public databases. Merck says the goal is to speed discovery of full genes with medical significance. But early publication of gene snippets means that when someone comes along with the whole gene, the patent office could rule that the gene had, in effect, already been found.
The courts will probably have to decide such matters through lawsuits. But many think letting judges assign value to gene patents isn't an ideal solution. Litigation is an expensive and inefficient process. By the time a decision comes down, says Reid Adler, an attorney at Morrison & Foerster in Washington, "we get an answer that is true for technology that's five years old."
Indeed, patent experts are scrutinizing two ongoing cases that will have a major impact on the value of biotech patents. In one, the Supreme Court is being asked to rule on the "doctrine of equivalence." An example: One protein can be produced by more than one gene. So if you patent one gene, can somebody patent another that makes the same protein? The Court will decide. In a second closely watched case, an appeals court will rule whether a patent on a protein called interleukin was interpreted too broadly. The result, some attorneys believe, may be a trend toward narrower--and less valuable--patents.
Some religious organizations would like to see gene patents scrapped entirely. Biotech gadfly Jeremy Rifkin, head of the Washington-based Foundation on Economic Trends, has put together a coalition spanning Southern Baptists, mainline Protestants, Catholic bishops, Muslims, Hindus, and Buddhists--all opposed to patenting genes.
Their basic argument is that genes are chemical compounds that exist in nature--unlike any other patented invention. Rifkin says the human genome "should remain open as a genetic commons." As a test case, his group is fighting the pending patent on the BRCA1 breast cancer gene.
Attorney Reid Adler counters that there is a big difference between an animal in nature that happens to have certain genes and a drug such as blockbuster EPO--Amgen Inc.'s red-blood-cell booster--ready for administration to a dialysis patient. "What companies are patenting is not what's found in nature, but what is extracted, manipulated, trimmed. It's an industrial tool."
Much of the Third World seems firmly planted in Rifkin's camp. Last year, protests flared over a patent that W.R. Grace & Co. received on a "bio-friendly" pesticide. Their objection: It was formulated from seeds of the neem tree, which Asian Indians have used for centuries as a natural pesticide. Grace was stunned by the uproar. Ultimately, it sold off the whole product line. The patent is now being reexamined.
MONEY FACTOR. Cases like this--and the storm over the Hagahai patent--have made health authorities in several Third World countries reluctant to cooperate with U.S. genomics companies. That's a pity, because such countries often have remote, isolated populations in which it is easy to trace disease heredity. Blood samples collected from these groups can facilitate the discovery of disease genes--and in doing so speed up drug development.
But local authorities in India and other parts of the Third World are wary. They anticipate that local blood samples could yield gene discoveries that will net drug companies millions of dollars in license fees or eventual drug sales. Without a clear legal framework forcing drug multinationals to share the wealth, they worry that the companies will abscond with both the blueprint for their "biodiversity" and its rewards.
Agriculture is another area where gene manipulation and patent confusion are rampant. Japan and China are locked in a battle over which country was first to engineer hardy transgenic rice. Earlier this year, Monsanto Co. launched a new breed of soybean that had been genetically altered to withstand a Monsanto weed killer called Roundup. To prevent farmers from simply preserving and replanting some of the soybeans the following year, Monsanto forced some 10,000 of them to sign licenses on the soybeans--and promise, in writing, not to replant.
That system may work in the U.S. But when it comes to dealing with neighbors, life won't be so simple. Europe bans patents on transgenic plants outright. Canada bars patents on genetically altered animals. How these disagreements are resolved will determine just how quickly biotechnology will bear fruit.