Experts Fret Over Effect of Gene Patents on Research

A newly issued patent on a gene that controls how AIDS begins infecting its victims is fueling controversy over who should own and profit from the torrent of genetic discoveries emerging from research labs and biotech companies across the country.

The patent, issued earlier this month to Maryland-based Human Genome Sciences, gives the company sweeping control over who gets to use the gene in commercial development of a new class of AIDS drugs, even though the firm knew nothing of the gene’s role in AIDS when it sought the patent.

Company executives said the firm deserves the patent because it isolated and decoded the gene and made some informed guesses about its function. The U.S. patent office apparently agreed and granted the company a 17-year claim not only to the gene itself but also to key techniques for putting it to use.

But the academic scientists who discovered the gene’s role in AIDS, as well as AIDS activists and some legal scholars, argue that the decision is a case of the patent system gone awry. They charge that the patent and thousands of other gene patents likely to be granted shortly will slow, not speed, the development of new drugs and entangle basic research for years to come.

In the end, the thing that most surprises the critics is what little difference the research that established the connection between the gene and AIDS made to the decision of who gets to own and profit from the discovery.

The gene provided the answer to a vexing mystery that academic research labs around the world were trying to solve five years ago: why some individuals who were repeatedly exposed to HIV, the virus that causes AIDS, never develop the disease.

Working properly, the gene produces a protein used as a “handle” by the virus to enter cells and begin infecting its victims. But in individuals with defective versions of the gene, no such protein is produced, and HIV cannot penetrate. The findings convinced the researchers that they were on the verge of a whole new way of treating the fatal disease--and perhaps profiting by their discoveries in the bargain.

However, Human Genome Sciences, which had already decoded the gene, had beaten the scientists to the patent office door.

After reviewing Human Genome Sciences’ patent, Stanford Law School professor John H. Barton noted that it was different from the earliest gene patents, which were awarded to companies and research centers that showed how a gene could be used to produce a valuable drug product, such as human growth hormone or insulin.

“All this patent does is carve out an area where nobody else can do research,” he said. “If [Human Genome Sciences] can keep you from making this [protein] in enough quantity to be able to do research, then they can in essence control the entire area. . . . If it doesn’t produce a product and keeps others from doing research that would, then that’s a big negative.”

Human Genome Sciences officials insist that the company’s patent will not impede research. They argue that the company is making the gene widely available to drug company clients in exchange for fees and future royalties and to academic researchers at no cost.

Biotech Companies Are Mining Gene Code

Human Genome Sciences is one of a new breed of biotechnology companies that are mining the human genetic code and filing patents on thousands of genes, in most cases without fully understanding their function or potential use in the treatment of disease. In the case of the AIDS gene, company officials acknowledge that they had no knowledge of the gene’s role in the disease when they applied for a patent in June 1995.

That is what has prompted the criticism.

“These guys are the robber barons of the genetic age,” complained Gregg Gonsalves, policy director for the Treatment Action Group, a New York-based organization that lobbies for AIDS research. “They are going to patent everything they can get their hands on and squeeze as much money out of it they can. This is not about making progress on AIDS; it is about making money.”

AIDS patients who find that existing drugs are no longer working need new ones immediately and have no time for settling disputes over intellectual property rights, Gonsalves said.

Company chairman and CEO William A. Haseltine makes it clear that the firm intends to strongly enforce its patent position.

“If somebody uses this gene in a drug discovery program after the patent has been issued to find drugs . . . and does it for commercial purposes, they have infringed the patent,” Haseltine warned. And if a company brings a drug to market after infringing the patent, “we’d be entitled not just to damages, but to double and triple damages.”

The company’s strong patent position was greeted warmly by the stock market, if not the scientific community. After the patent was announced, the company’s share price rose by 50% over the next two trading sessions.

And there may be many more such patents to follow. Haseltine said the company has identified in whole or in part 95% of the 100,000 or so human genes. The company has already received more than 100 human gene patents and has 7,500 patent applications pending.

The AIDS gene patent was issued just as the U.S. Patent and Trademark Office is proposing to toughen its standards by requiring applicants to do more to demonstrate the function and usefulness of their discoveries. The office has issued more than 400 human gene patents, but there are tens of thousands more applications awaiting approval.

The new standards are in response to advances in technology that permit companies to isolate human genes and gene fragments by the thousands using high-speed automated machines for deciphering the genetic code. With the help of supercomputers that search databases of existing knowledge of human and animal genes for similarities, the companies are able to make sophisticated guesses about the function of a gene and its potential application to disease treatment and diagnosis.

Officials at the National Institutes of Health have complained that the proposed patent office guidelines, due to be adopted next month, do not raise the bar high enough on human gene patents and would keep in place a policy that creates barriers to research and drug development.

The awarding of the AIDS gene patent to Human Genome Sciences has become an example for critics of what’s gone wrong with U.S. patent policy.

“If the patent office awards a patent to someone who clones a gene, even though they have no notion of its function and no real idea of its use, that would be like saying, ‘I found a fungus, therefore I should get credit for penicillin,’ ” said Dr. Robert Gallo, who is now at the University of Maryland and headed a group that worked on the problem of how HIV infects cells.

“The kind of work that is being done at federally funded labs is figuring out the functions of various molecules,” said New York University’s Dr. Dan R. Littman, another scientist who contributed to solving the HIV mystery. “Now you have companies coming from a completely different direction and not even trying to understand function before seeking patents. . . . They can just sit there and wait for others to do the research for them.”

Human Genome Sciences chairman Haseltine paints a different picture. He said that unlike other companies that mine the human genetic code, his company does extensive work after isolating and decoding a gene--for example, inserting the gene into special cells grown in test tubes to determine the gene’s function.

“We did real biology,” Haseltine said. “We didn’t just find a gene and patent it.”

Early on, he said, the company focused on a class of genes that produce protein receptors--substances that are weaved into the fabric of cell surfaces, sitting like a satellite dish and picking up chemical signals from elsewhere in the body.

Similar protein receptors are known to play important roles in human biology.

In June 1995, the company applied for a patent for one of those genes, which produced a protein receptor that the company identified as “HDGNR10.”

The patent spells out precisely the chemical building blocks that make up the gene and the protein. And it discusses how blocking or stimulating the gene or the protein could have an impact on a variety of diseases, including cancer, blood disorders, allergies and arthritis. There is no mention of AIDS or HIV in the patent. There is only a single passing reference to the fact that proteins in the same class as HDGNR10 can be targets of viruses.

That was enough, Haseltine said, to give the firm a patent that covers not only the gene and the protein product itself--what’s called a “composition of matter patent”--but also the use of the gene in discovering new anti-AIDS drugs.

“In this case, we were clever enough to guess right that this is a viral receptor,” Haseltine said.

Unaware that the patent application had been filed, a number of academic research labs were in hot pursuit of a genetic explanation for why some patients infected with HIV develop AIDS relatively slowly and why others, despite multiple exposures, do not develop AIDS at all.

Isolating a Protein and Its Role in AIDS

In late 1995, Gallo’s group reported finding that chemicals called chemokines, which were released by certain white cells and were known to latch onto proteins on the surface of blood cells, also seemed to suppress HIV infections. This sent other researchers looking for the sites where the chemokines could interfere with HIV.

Over the next several months, a number of researchers independently discovered that HIV entered cells by grabbing hold of certain protein receptors that acted like handles for the virus on the cell surface. The most important of these is called the CCR5 receptor. The academic scientists isolated the protein and found the gene that produced it.

To clinch the role of the gene in AIDS, researchers were also able to show that cells with a defective CCR5 gene--taken from individuals who were exposed to HIV but who did not have AIDS--did not produce the CCR5 protein and could not be infected with the virus.

The discovery of the CCR5 gene was widely celebrated as a major advancement in AIDS research, paving the way for new drugs to treat the disease by blocking the cell surface protein.

“The likelihood is that this is the molecule that needs to be used for the virus to go from one person to another,” said NYU’s Littman.

The gene and the protein it produced were identical to those isolated by Human Genome Sciences--something that the academic researchers could not know because the company’s patent application, although filed, was still not publicly disclosed.

In patenting, said Human Genome Sciences chairman Haseltine, “you are rewarded for speculation. If you teach what to do and you are right, you don’t have to show it yourself. You are rewarded for intelligent and correct guesses. . . .

“The patent office does not reward perspiration,” he said. “They [patent officials] reward priority. They don’t care if someone spent 20 years to find an invention or 20 minutes.”

Other defenders of the patent system argue that scientists simply don’t understand a system that rewards those who isolate substances from nature, even without knowing the best use for their discoveries.

“In chemical patent law for a 100 years, everywhere in the world, if you discover a compound that has any use, even a marginal use, you are entitled to a patent on the compound,” said Jorge Goldstein, a Washington, D.C., patent attorney who represents Human Genome Sciences.

He said that if a scientist discovers a new chemical for use as an antiseptic in hospitals, he still is entitled to a patent that would cover all of its future uses, even if it turns out to be a great anti-cancer drug. “If you use it, you are going to have to pay me a royalty, even though I did not discover its hot commercial use, but a marginal one,” Goldstein said. “That’s been the law for a hundred years. Biotech hasn’t changed anything.”

However, some legal scholars believe that there is something different about gene patents.

University of Michigan law professor Rebecca S. Eisenberg worries that awarding such patents will impede those who work on developing new drugs by forcing them to pay licensing fees and royalties both to those who isolated the gene as well as those who later discover its role in disease. “Each of the licenses cost something, and if there is a proliferation of these claims it becomes daunting to pull together all the licenses,” she said.

And, indeed, a number of research centers have applied for, and in some cases have received, patents in this area.

“If someone in a company wants to use the CCR5 cloned gene, they may need two licenses,” Haseltine said, “our license for composition of matter and a license [from NIH research by Edward Berger] to practice HIV inhibition.”

On the other hand, companies that developed drugs before the Human Genome Sciences patent was issued can proceed without paying royalties, Haseltine said.

In fact, Schering-Plough Corp. is already working on AIDS drugs that block the CCR5 protein, said Robert J. Consalvo, director of external affairs for the New Jersey-based drug company. The drugs, he said, “were discovered by us prior to the HGS patent.”

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The Sequencers vs. the Researchers

A small biotech company called Human Genome Sciences has won a patent on an AIDS gene even though it did none of the research showing the gene’s role in the disease. Here is the chain of events:

1986--British researcher Robin Weiss shows there must be a second route, other than the one already known, for HIV, the virus that causes AIDS, to enter cells and infect people.

June 5, 1995--Human Genome Sciences applies for a patent on a gene that produces a “receptor” protein that is later called CCR5. Receptors let things that are outside cells enter them. Company executives have no idea that CCR5 is an HIV receptor.

December 1995--U.S. researcher Robert Gallo, the co-discoverer of HIV, and colleagues find three chemicals that inhibit the AIDS virus. Gallo does not know how the chemicals work.

February 1996--Edward Berger at the NIH discovers that Gallo’s inhibitors work in late-stage AIDS by blocking a receptor on the surface of T-cells.

June 1996--In a period of just 10 days, five groups of scientists publish papers saying CCR5 is the receptor for virtually all strains of HIV.

January 2000--Schering-Plough researchers tell a San Francisco AIDS conference they have discovered new inhibitors. Merck researchers are known to have made similar discoveries.

Feb. 15, 2000--The U.S. Patent and Trademark Office grants HGS a patent on the gene that makes CCR5 and on techniques for producing CCR5 artificially. The decision sends HGS stock flying and dismays researchers.