THE HUMAN BLUEPRINT: Patenting Life?
Gene Research Success Spurs Profit Debate
By Justin Gillis

Washington Post Staff Writer
Saturday, December 30, 2000


So many years later, as they sat in their living room recounting the short life of Jonathan Greenberg, his parents would recall a particular moment. At six months the baby was not developing normally, and the Greenbergs, of Homewood, Ill., took him to a smart young Chicago neurologist. Worried, she whispered in the baby's ear: "I hope this isn't anything like I think it is."

It was.

In that moment Dan and Debbie Greenberg's lives were propelled onto a new course, one that put them at the center of a worldwide effort to understand the dread genetic ailment called Canavan disease. Years of struggle culminated in success in 1994, when a doctor recruited by the Greenbergs discovered the gene whose mutant form caused the ailment, making it possible to warn parents at risk of having a Canavan child and raising the chance for future treatments.

But then the Greenbergs' lives took yet another twist. The main sponsor of the doctor's research, Miami Children's Hospital, applied for and received U.S. Patent No. 5,679,635, giving the institution extraordinarily broad rights to the Canavan gene.

The Greenbergs, and many families they had drawn into the effort, had no idea the research for which they gave the very flesh and blood of their children would be turned into a patent. They were distraught when Miami Children's -- defending its right to profit from the research -- cracked down on academic laboratories that had started offering Canavan testing.

"All of us felt that was a real slap in the face," Dan Greenberg said. "It was a common understanding that we were all doing this to benefit the public good."

The Canavan case, which recently landed in federal court in Chicago, is one of the first of what could be many disputes over the patenting of genes. As a new era dawns in the commercialization of biological knowledge, companies such as Human Genome Sciences Inc. of Rockville and Incyte Genomics Inc. of Palo Alto, Calif., are flooding patent offices with tens of thousands of applications, fueling an international debate.

Patent disputes within industries are routine these days, but this is no ordinary fight: The very idea of handing out private property rights on components of human life has provoked a deep emotional reaction in many people, suggesting to some that greed has no limits.

Defenders of such patents -- biotechnology firms, joined by some researchers in academia and the pharmaceutical industry -- get emotional themselves in arguing that without patents society won't benefit from revelations about the molecular roots of disease.

In this view, the true promise of the Human Genome Project -- the ongoing effort to create complete, accurate human genetic maps -- will be realized only if companies invest huge sums to develop new treatments. The money must be raised in the capital markets, and the companies contend that patents are the only means they have to recover their investment and profit from their research.

Wall Street attaches enormous significance to gene patents. When a statement last spring by President Clinton and British Prime Minister Tony Blair was briefly misunderstood as portending changes in patent law, billions of dollars evaporated from the stock market overnight.

"We've got hundreds of billions of dollars of genetic research that we need to do," said Chuck Ludlam, vice president for government relations at the Biotechnology Industry Organization. "The idea that that will happen without patents is completely unrealistic. If we aren't able to do that research, many people will suffer or die who do not need to."

On the other side are some academic researchers, medical ethicists and patient groups who argue that private ownership of the basic building blocks of life is likely to slow down, not accelerate, medical progress. They contend that such ownership creates barriers to research and testing.

Though they lament that they are outgunned by corporate interests, these critics are accelerating their own efforts on a variety of fronts, arguing to governments, courts and the public that gene patents are nothing less than immoral -- that scientists are "patenting life." They have mounted street demonstrations, filed lawsuits and run newspaper advertisements attacking gene patents.

C. Scott Littleton, a professor of anthropology at Occidental College in Los Angeles, finds himself explaining to students that human genes arose over millions of years of evolution -- but are being claimed as property rights in a single generation.

"I think the idea that a company can 'own' a gene is yet another prime example of global capitalism gone mad and inherently absurd," he said.

In the middle of this debate are ordinary citizens, often uncomfortable with the idea that something as fundamental as a gene can be patented but eager to see new medicines developed quickly.

Although the case law is clear -- genes are patentable discoveries, and have been for two decades -- such patents were relatively rare until recently. Nowadays, as biotech companies rapidly create a web of interlocking ownership rights around the human genome, even optimists acknowledge that it will be a challenge to work out all the legalities in a way that allows research and testing to proceed apace.

Many people are striving for compromise in the patent dispute, and institutions such as Johns Hopkins University have balanced competing interests in their handling of gene patents.

Q. Todd Dickinson, head of the U.S. Patent and Trademark Office and a supporter of gene patents, emphasizes the importance of this search for common ground. He warns biotech companies that the patents should be made available to other companies and to academic researchers on reasonable terms. If they are not, he said, the companies risk a public backlash that could prompt Congress or the courts to weaken the patent laws.

The companies "could wind up undermining the whole patent system," Dickinson said.

Traditional Legal Device

Patents are an old legal device designed to encourage innovation by granting inventors short-term monopoly rights. In the United States, patents were authorized in the Constitution, and over the years a highly specialized body of law has evolved for adjudicating patent issues.

It was put to a test in the 1970s, when a new technology sprang from the university laboratories around San Francisco Bay.

Scientists learned to slice and dice deoxyribonucleic acid, or DNA, the basic carrier of heredity and the stuff of which genes are made. They learned to pull it out of one organism and insert it into another. Bacteria, they realized, could be made to take up human genes and make the proteins encoded by those genes.

At Genentech Inc. of South San Francisco, the world's first biotechnology company, scientists learned to produce huge supplies of insulin, to treat diabetics, and human growth hormone, to treat dwarfism. The products had previously been derived from human blood or animal organs, creating shortages and safety problems.

The need for improved versions of these drugs was so clear, and the research that went into producing them so expensive and difficult, that few objections were raised when Genentech and university researchers received patents on the human genes involved. Without those patents, Genentech executives say now, the products probably would not have been brought to market, and the biotech industry might have died aborning.

As Genentech's work progressed, it remained unclear just how far old law could be stretched to accommodate the new biology. The U.S. Supreme Court answered that question in 1980. In Diamond v. Chakrabarty, the court ruled 5-4 that a living organism, a bacterium genetically modified by General Electric Co. to break down oil spills, could be patented.

The court's majority found that a genetically modified bacterium fit Thomas Jefferson's language in the Patent Act of 1793, making a new "composition of matter" patentable. The case was hard-fought, and to this day many people disagree with it. But it became the cornerstone of all subsequent biotechnology law, and by now hundreds of billions of dollars of investment decisions have been based on the rules the court set down.

Diamond v. Chakrabarty did not directly tackle the patentability of genes, but attorneys reasoned that if whole organisms were patentable, surely inert pieces of them would be -- assuming those pieces could be shown to be useful, a fundamental requirement of the patent law. The courts endorsed this view.

A main objection that opponents make to genetic patenting is that genes are "products of nature" analogous to a newly discovered mineral or chemical element, and therefore ought to be off-limits. The courts have recognized a "products of nature" doctrine and used it to reject some patent applications.

But a counter-principle has evolved: Even a product of nature can be patented if a discoverer has devised a new process of purification or collection that makes a substance available in previously unknown quantity or purity. Examples patented in this century include adrenaline and purified Vitamin B12.

Given such precedents and the strong language of the Diamond v. Chakrabarty ruling, it was an easy step for the courts to extend the doctrine to genes. One reason is that isolating a gene for medical use is not simply a matter of plucking it out of the body. The "genes" that researchers patent barely resemble genes as they exist in nature.

Inside human cells, genes are broken up into bits and pieces interspersed with long stretches of apparently meaningless DNA. One of the critical -- and difficult -- tasks performed by biotechnology researchers is to identify the useful parts of a gene and string them together into one contiguous stretch of DNA.

It is these artificial constructs -- in effect, edited, man-made versions of genes -- that companies typically patent.

Advocates of gene patents cite the sophistication of this work in arguing that ownership rights are not being granted to scientists simply because they stumble on an aspect of nature, but rather because they are deploying complex techniques to manipulate nature in the service of human goals.

"We are not 'patenting life,' " Bruce Lehman said in a speech in 1998, shortly before he left his post as head of the U.S. Patent and Trademark Office. "God, I suppose, has a patent on life. We are patenting technology."

Analogous to Others

It was such genetic manipulation that allowed scientists over the past decade to determine the cause of Canavan disease. Though rare, Canavan is analogous, in its inheritance patterns and in the research effort needed to understand it, to hundreds of other genetic diseases.

Canavan occurs most commonly in Jews of European ancestry. The ailment involves a defect in biological machinery that helps build brain and nerve tissue. Catastrophic brain damage results: Children with the disease never learn to walk, talk or feed themselves, and invariably die young.

Dan and Debbie Greenberg had no idea, before conceiving their son Jonathan and their daughter Amy, that they were carriers for Canavan disease. It turned out that each had one good copy and one bad copy of an essential gene. Jonathan and Amy had the misfortune to inherit two bad copies; they died, at 11 and 16, respectively.


The Greenbergs, though devastated, did not accept their family tragedy helplessly. While raising three other children, they organized against Canavan disease. They recruited an energetic doctor, Reuben Matalon, to seek the precise genetic cause. They contacted Canavan families worldwide for emotional support and as blood and tissue donors for the research.

One family -- the Szwarcs of Melbourne, Australia, which saw two of four sons die of Canavan -- even flew to the United States with preserved autopsy samples.

Through all of this, no one spoke of patents or profits. In 1993, Matalon -- by then working with a team at Miami Children's Hospital -- announced his success at isolating the responsible gene, which encoded a brain enzyme called aspartoacylase. The 854th chemical unit on a normal copy of the gene was a compound called adenine. On the mutated variant found in sick children, the adenine had been replaced by cystosine, a change sufficient to disable the enzyme. The children's brains would never develop past infancy.

Working from Matalon's papers, academic laboratories began to offer testing for Canavan disease to people who might be carriers. Pregnant couples who were carriers could undergo early prenatal testing to determine if the baby had Canavan. Work on potential treatments could begin. Along with the other parents, the Greenbergs felt they had wrung an accomplishment from their tragedy.

Matalon, meanwhile, discharged a duty he felt toward hospital administrators. "When I discovered this thing, I discussed this with some people and they said, 'Your obligation is to tell your administration that this is a patentable discovery,' " he said. "I did."

The patent was awarded in 1997. A year later, having borne considerable costs for the research, the hospital sought to profit from its discovery. As part of that effort, it started cracking down on academic laboratories offering Canavan tests for a fee.

When they learned of the patent and ensuing efforts to enforce it, the Canavan parents were deeply offended. "We had no idea anyone was really proceeding along those lines," Dan Greenberg said.

Miami Children's Hospital's efforts to commercialize the patent have gone through various permutations, including a failed attempt to license it to a single company. It is unclear on what terms the patent is now being offered for licensing, since the hospital will not discuss it. Some academic labs have deals with the hospital allowing them to resume testing, but others still refuse to sign, calling the terms unacceptable.

The dispute has disrupted carrier screening for Canavan disease in some places and made it more expensive in others.

Matalon, who has left Miami for a post in Texas, emphasized that he has received no personal gain from the patent. In a written statement, executives of Miami Children's said getting some financial return from the discovery was fair because "privately financed scientists, supported by Miami Children's Hospital, unlocked those secrets and as a result of this, mankind benefits."

But the parents perceive a situation in which screening for the disease is less widely available and more expensive than it should be. The parents ran a newspaper advertisement in Miami criticizing the hospital, and they asked it to dedicate the patent to the public. That request was rejected. A few weeks ago, the parents and several allied groups sued Miami Children's and Matalon, alleging breach of duty, unjust enrichment and other wrongs.


"What they're doing is immoral," Barbara Szwarc said from Melbourne. "They've made it into a profiteering venture when young children's lives are at stake."

Several similar disputes about patents and genetic testing have cropped up around the country. Another type of patent dispute involves rights to research tools. These grow from the same body of law as human gene patents, but they are often patents on living animals or bacterial cells, such as a mouse created at Harvard University that is useful in cancer research. Attempts by companies to charge high prices or to limit the use of such tools have provoked numerous skirmishes.

Still another concern in recent years has centered on the habit of some biotech companies of filing for patents on small fragments of genes, without bothering to work out the entire structure of the gene or learn much about its biology.

Such patents are likely to be of little commercial value, since there aren't many uses for fragments of genes. Moreover, the U.S. Patent and Trademark Office is adopting rules that are likely to make fragmentary patents hard to get. But thousands of such patent applications are pending, and there is lingering concern among academics and even some biotech companies that they could complicate gene research.

Hunt for Accord

Amid the debate, there's also a search for common ground.

After Johns Hopkins University researchers Bert Vogelstein, Kenneth Kinzler and their colleagues received a patent on a new technique that helps to pinpoint genes involved in disease, the school crafted a license that, for a price, gave commercial rights to the technology to a single company, Genzyme Corp. of Cambridge, Mass., which uses it to find cancer treatments.

At the same time, Hopkins retained the right to authorize free use of the technology by academic researchers. About 300 laboratories have signed up, and the university's handling of the patent has created a worldwide research community that is using the technology to gain new insight into many kinds of disease.

As the Hopkins case illustrates, the central issue is not whether to have gene patents -- barring a sweeping and unlikely change in the law, they are a foregone conclusion -- but rather how those patents are used after they are granted. In this view, relatively broad, open licensing of the sort Hopkins pursued can speed up research and still allow companies to profit from new treatments, while overly restrictive policies like those in the Canavan case can create problems and ill will.

The Genetic Alliance, a Washington umbrella group representing many organizations fighting genetic disease, decided not long ago to study the issue of gene patents. Its experts started out suspicious, but wound up feeling that such patents were probably essential to the development of new medicines. Instead of a broad attack on the patent system, the group has decided to monitor the way patents are being licensed.

"It is not as simple as, 'Patents, good or bad?' or 'Licensing, good or bad?' " said Mary Davidson, executive director of the Genetic Alliance. "Our mission is to be sure all this research benefits real people."

She cited the case of Sharon and Patrick Terry of Sharon, Mass. When the Terrys learned that their two children had a rare genetic ailment that could shorten their lives, they founded a group to help push research forward. Realizing that blood and tissue samples would be needed, they created a central repository under the group's control.

The Terrys also decided they would not oppose the patenting of the gene for their children's disease, pseudoxanthoma elasticum or PXE. "I'm not against patenting," Sharon Terry said. "The structure of the free-market enterprise system in the United States is such that patents work." She hopes, in fact, that patent rights will induce companies to develop treatments for the disease.

What the Terrys are against is naivete.

They knew the terms under which the PXE gene patent might be licensed for testing or drug development would be all-important. They decided that as the price of access to the tissue bank, researchers would have to agree to make the patient group a co-applicant on any patent filing. This is precisely what happened after a researcher in Hawaii discovered the gene whose mutant form causes PXE.

The goal is not profit, Sharon Terry said, but to ensure that PXE patients have a voice when critical decisions are made. If it's approved, the patent is likely to be made broadly available for research and testing.

The Terrys recommend this approach to other patient groups concerned about genetic patenting. "We saw early on," Sharon Terry said, "that we needed to keep control."

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