Patent Office Now at Heart of Gene Debate

With the feat of deciphering the human genetic code only months from completion, medical science appears to be on the verge of a new golden age in which diseases that long defied treatment may suddenly prove curable.

But amid the grand hopes lurk doubts about who will get to own and profit from the new genetic discoveries--and whether sweeping private ownership could slow, rather than speed, innovation.

Some medical centers already report cutting back on genetic research for fear of patent infringement. The University of Pennsylvania’s genetics lab, for example, sharply curtailed a breast cancer testing program two years ago after a Utah company, Myriad Genetics, won patents on two genes associated with the disease and notified the university that it could use them only with the firm’s permission.

“Patients still keep coming, begging me to do the research, but I cannot anymore,” said Arupa Ganguly, the lab’s research director.

In response to a drumbeat of concern, the government’s chief arbiter of ownership, the Patent and Trademark Office, has quietly proposed two rules changes that are intended to narrow what drug-makers and biotech companies can claim of the genetic code. Patent officials say the new rules, if adopted after a public comment period that ends in late March, could lead to the rejection of 500 to 1,000 cases in a backlog of about 10,000 patent applications for human genetic material.

“We’ve raised the bar” on what’s needed for patenting genetic material, said John Doll, the office’s head of biotech examination. One of the patent office’s changes would hold applicants to a stricter standard of use for the piece of the code that they seek to patent; the other addresses how long a segment of the code a patent applicant can control by winning a patent on only a very small piece.

But leaders of the nation’s medical and scientific communities, including some of the government’s own top scientists, charge that the bar would still be far too low.

They contend that without more stringent limits, ownership of the human genetic code could be balkanized, with companies and organizations claiming large and overlapping swaths, then fighting over the contested portions. They warn that the perverse result could be to make it harder, not easier, to conduct research, devise new treatments and invent innovative drugs.

“This is a land grab of historic proportions,” said Michael S. Watson, a leader of the American College of Medical Genetics, the national professional organization of genetic practitioners. “It’s as if somebody just discovered English and allowed the alphabet to be patented.”

Part of a Series of Controversies

The uproar is the latest in a series of controversies that has erupted since gene patents were first issued in the 1970s. As in other highly charged debates such as the one over abortion, both sides have shown a hair-trigger readiness to take polarized positions.

Critics have expressed revulsion at the very notion that someone could own the genetic code, the chemical latticework of a person’s DNA molecules that determines what traits are passed from parent to child and how every cell in the body works. They have warned that to permit patents is to invite market forces into areas where they should not be allowed.

“Patents are there to protect inventions,” said Judith Tsipis, an official with the National Tay-Sachs & Allied Diseases Assn., whose son died two years ago of a genetic disease. “The sequence of my child’s gene is . . . not an invention.”

Defenders, every bit as adamant, have argued that permitting broad patenting pieces of the genetic code is society’s most powerful tool for encouraging new drugs and treatments. They have pointed to the U.S. patent system’s two-century record of speeding good things to the public. Patents give their holders control over their inventions for 20 years as a means of encouraging commercial development and full disclosure of the invention so that others can avoid duplicating the effort.

“From the cotton gin to the computer, America has been a model of technological development . . . , and patents have provided protection for the fledgling enterprises that were based on that innovation,” said Patent Commissioner Q. Todd Dickinson.

The latest debate promises to resurrect all the old arguments over genetic patents. But it is shaping up to be much more sharply focused and vastly more urgent.

That’s because the job of deciphering the entire human code, a goal that long appeared reachable only 10 or 15 years from now, suddenly seems to be just months from completion. And much of the work is being done by a group of patent-seeking private companies, rather than the publicly funded Human Genome Project, which is releasing its findings to all comers.

At the same time, some companies and organizations with rights to pieces of already deciphered code have sought to enforce their patents in ways that critics say has damaged medical care, research and product development.

In the University of Pennsylvania case, researchers argue that patent holder Myriad Genetics used its ownership claims on two genes to stifle development of new tests and treatments for breast cancer.

Early work on the genes, called BRCA1 and BRCA2, followed what used to be a familiar pattern. Scientists at several institutions raced to locate and decode the genes, which are linked to families with high rates of breast and ovarian cancers. Myriad, collaborating with the National Institutes of Health, got to BRCA1 first and later claimed it was first to BRCA2 as well.

Researchers, including Penn’s Ganguly, followed up by developing tests for variations in the genes that can signal susceptibility to disease. By 1998, the Penn lab was performing more than 700 tests a year.

That’s when Myriad used its patent to pull the plug. It notified Ganguly and her colleagues that they could no longer do more than a handful of tests. The company also required the genes’ co-discoverer, former NIH collaborator Phillip Futreal, to pay Myriad for tests he needed for his research. And it set a $2,580 fee for the test, more than twice that charged by most other labs, including Penn’s.

Last week, after a furor over the fee, the company relented and agreed to charge only $1,200 when federally funded research such as Futreal’s is involved.

Myriad spokesman Bill Hockett said the company could not have raised the $10 million that it says it cost the firm to decode the genes and develop products without patent protection. He said the $2,580 fee is a reasonable charge.

But both patients and researchers were outraged. “We were pretty upset when . . . we learned about the extent of the patent they filed,” said Fran Visco, president of the National Breast Cancer Coalition. “We certainly have no problem with somebody coming up with a test and patenting that test. But they shouldn’t be able to patent the knowledge.”

Canavan Test Patent Angers Parents

In a separate case involving Canavan disease, a rare and fatal hereditary brain disorder, patients’ families complain that Miami Children’s Hospital is charging steep fees for tests that became possible only because the patients participated in lengthy clinical studies. Based on the studies, the hospital received a patent on the gene that causes Canavan.

The families say that it was they who first pressed Dr. Reuben Matalon to search for the cause of the disease that was killing their children. They say that it was the blood, urine and skin that the children gave when they were alive and the brain tissue that was provided after they died that pointed Matalon to the defective gene.

The families were furious when they learned that the Miami hospital, where Matalon worked at the time, had sought and won a patent that locked up almost every imaginable use of the gene and had begun charging for diagnostic tests.

“If someone had told me from Day One that they were going to make money from this, I very well might not have cooperated,” said Dan Greenberg, a Chicago-area lawyer and father of two Canavan children.

Matalon, now at the University of Texas, said that he did not apply for the patent, but was required under his employment contract to let the hospital do so. He said he receives none of the $12.50 patent fee the hospital collects for each test. “I’m not in the patent business,” he said.

Marc Golden, a marketing executive who handles the hospital’s patent rights, defended the patent on the Canavan gene as a just reward for bringing a genetic test to market. Greenberg’s rejoinder: “Don’t patent that which is naturally occurring on Earth in all of our bodies. Leave that to us.”

At one time, many critics and policymakers thought there was a simple solution to the problems surrounding genetic patenting. That was to permit patents on uses of the genetic code--such as new tests and treatments--but not on the code itself. However, the courts refused to go along with the idea, ruling that under a variety of circumstances, genetic material can indeed be patented.

The courts’ stand did not make much difference as long as little of the code had been cracked. But in the last few years, companies have perfected spectacularly powerful, automated decoding machines.

The machines have focused attention on whether the information pouring from them is of the same quality as that which scientists generated using older methods, and whether the patent applications based on their output meet standards for patentable inventions.

Under the law, an invention must be “useful,” “novel” and “non-obvious” to be patentable. Dickinson, the patent commissioner, is quick to point out that the law specifically says an inventor does not have to have worked hard to be owed patent protection. But that, in effect, is what a growing number of commentators argue can be read into the other provisions of the law: that applicants must meet some minimal standard of earning a patent in order to get one.

Meeting such standards was not hard when scientists began identifying, isolating and copying human genes in the 1970s. Then, they started with human hormones that they knew were important and worked backward to the genes that controlled their production.

The work was painfully slow by today’s standards and taught researchers a great deal about how the genes work that produce insulin, human growth hormone and erythropoietin, which stimulates red blood cell production. There was little dispute that those who discovered genes had earned the right to patent them.

But matters grew a great deal more complicated when researchers began using automated decoding machines. That let them figure out a great deal more of what the raw code was, but they learned a great deal less about how it functioned. They could make guesses by using supercomputers to compare newly decoded human genes to those of simpler organisms, such as bacteria, whose operations had already been mapped out. But they had little of the direct, hands-on knowledge that the old method produced.

“It’s a highly automated process that involves very little human invention--or even human intervention,” said Dr. Francis Collins, director of the National Human Genome Research Institute, which is directing the publicly funded effort to decipher the genetic code, and a critic of the new patent rules.

The initial argument against patenting information generated by the new technique was a blunt one. Since machines generated the findings, not human beings, there was no invention involved and hence nothing to patent. James Watson, who shared the Nobel Prize for discovering the structure of DNA, once described the work of a pioneer of the automated method, J. Craig Venter, as something that could have been done by a monkey. (Watson later apologized.)

But as Venter, now chief executive of Celera Genomics, one of the country’s most aggressive gene sequencers, and others have improved their techniques, critics have changed their line of attack. They now concede that some of the findings generated by the new methods deserve to be patented, but argue that the patents should be as narrowly drawn as possible to avoid a balkanization of the overall code.

“The experiment I’m worried about is the one where you want to look across the whole genome,” said Collins. “Can you imagine how horrendously difficult that would be if large quantities have patent barriers around them?”

Collins is pursuing a double-pronged strategy to limit those difficulties. First, he and colleagues with the publicly funded Human Genome Project are rushing to decipher the full genetic code and release it. They hope this will limit the patent claims of private sequencers to the code’s uses, rather than to the code itself.

Second, they are quietly pressuring the patent office to issue stricter rules than those it has proposed. Collins said he hopes the rules will be stringent enough to knock out 3,000 patent applications rather than the 1,000 that patent officials expect to be rejected.

Need for Decision on Gene Patents Is Now

Whatever the outcome of the debate, a decision on how to handle the new generation of human gene patents is needed quickly. The patent office is being flooded with foot-thick applications that are spilling from shelves and piling up on floors. Meanwhile, patents are reaching ever deeper into the genetic code and by now touch even the research work of such patent critics as Collins.

The human genome institute director was a co-discoverer, while at the University of Michigan, of a gene responsible for cystic fibrosis, a hereditary disease that can destroy the lungs and cause early death. The university patented the gene in 1989 and has warned testing labs around the world that they must pay licensing fees to use it.

Collins tracked down the gene before the advent of the new automated methods. He signed away financial rights to the discovery. He wonders whether it should have been patented at all. “I have some misgivings about whether this will turn out to have been a good thing,” he said recently; “whether it will meet the standard of having helped the public and not hurt.”