NEWS

Pricing Human Genes: The Patent Rush Pushes On

Tom Reynolds

On December 10, the U.S. Patent and Trademark Office celebrated its 6 millionth patent, granted to Palm Computing Inc. of Santa Clara, Calif., for the technology to instantly synchronize data in a handheld organizer with a personal computer.

About a year earlier, the PTO assigned patent 5,853,988 to the Massachusetts Eye and Ear Infirmary in Boston and the Whitehead Institute, part of the Massachusetts Institute of Technology in Cambridge, Mass. Although there was no fanfare at the PTO that day, the pair of patents neatly encapsulates the two revolutions — information technology and biotechnology — that are reshaping the world.

Patent 5,853,988 assigned the rights to the retinoblastoma tumor suppressor gene. Based on research done at the two institutions in the 1980s and early 1990s, the patent gives MEEI and Whitehead exclusive rights for 20 years to commercially develop the RB gene to detect mutations, and potentially to treat the eye tumors they cause.

Hundreds more cancer genes are no doubt lurking among the pile of 6,500 that Celera Genomics of Rockville, Md., provisionally submitted to the PTO in October, little more than a month after it began sequencing the human genome. If nothing before had, that action put the science and biotechnology world on notice that Celera means business. It also stoked the fears of scientists who worry about maintaining broad access to genomic information, and of critics who further complain that patenting human genes means surrendering mankind's biological birthright to industry as a profit-making tool.

Not that Celera is making a profit — at least not yet. But its parent company, PE Corp. of Norwalk, Conn., (formerly Perkin-Elmer) has enough faith in its future to pump in hundreds of millions of dollars to hire star scientists and buy the world's fastest DNA-sequencing and computing equipment. At its nucleus is J. Craig Venter, Ph.D., who left the National Institutes of Health in 1992 to start The Institute for Genomic Research. Celera — from "celerity," or swiftness — was born 5 years later when Venter was wooed away from TIGR, enticed by PE's vision of beating the international Human Genome Project to the full human DNA sequence in the face of HGP's gigantic head start. Former National Cancer Institute director Samuel Broder, M.D., is Celera's chief medical officer.



View larger version (140K):
[in this window]
[in a new window]
 
Dr. J. Craig Venter

 
Twenty years ago, PTO held that life forms (and by extension, their genes) were unpatentable because they were products of nature. But a 1980 Supreme Court decision reversed that policy, opening the floodgates for the patenting of genes, transgenic animals, and other biotech products. The court ruled in Diamond vs. Chakrabarty that an oil-spill-eating strain of bacteria created by General Electric microbiologist Ananda Chakrabarty, Ph.D., was patentable. The reasoning was that patent laws, written in an era when today's manipulations of nature were unimaginable, make no distinction between living and nonliving matter.

Since the PTO began counting in 1992, about 2,000 patents on genes or partial genes have been issued, and about 10,000 applications have been submitted, a PTO spokeswoman said. Those numbers include plant and animal as well as human genes; no separate count of human genes is available.

One by One

Most early gene patents were issued one by one after research teams cloned individual genes. But several companies have jumped into the race to sequence the genome and patent the information, most notably Incyte Pharmaceuticals Inc., of Palo Alto, Calif., and Human Genome Sciences of Rockville. According to the Human Genome Sciences Web site, the company has been issued patents on 85 human genes and has filed patent applications that describe the medical use of 7,400 more.

Both Celera and Incyte say patenting genes is only a sideline. Their primary focus is on developing comprehensive databases of biological information that drug companies and research institutions will pay to access. Celera's first handful of subscribers, including Pfizer Inc., New York, and other pharmaceutical giants, pay up to $5 million per year for database access, but the company plans to charge university laboratories and other non-profits far less, perhaps $5,000 to $20,000 annually, said Paul Gilman, Ph.D., Celera's director of policy planning.

Last November Incyte, which claims to own "the most comprehensive library of biological information in the world" announced its own deal with Pfizer, to sequence genes for pharmaceutically relevant drug targets. The information will be made available to all the company's subscribers, which already include more than a dozen big names in the drug industry.

Celera's Gilman downplayed the significance of the company's 6,500-gene submission. He said the provisional applications simply buy time to sift through them and find the most potentially valuable, and to identify companies interested in commercializing them. After a year, when the provisional applications expire, the company will pursue patent protection for the genes of its first choice, probably a few hundred, and drop the remaining 95% or more. Provisional applications are not examined by PTO, said Richard Schwartz, Ph.D., a technical center practice specialist at the patent office. So if an applicant decides after a year not to go forward with one, there is nothing stopping someone else from pursuing a patent on the same gene.

Furthermore, multiple patents might be issued for a single gene if researchers discover different functions independently. "We might know that one of our patented genes does ‘A,' but no one's terribly interested in commercializing that," Gilman explained. "Someone else could come along and say ‘in this organ, the gene does B.' "

Genetic Tags

A major controversy surrounds the patentability of DNA segments known as expressed sequence tags, or ESTs. These are short sequences of cDNA that are unique to one gene and thus can serve as tags to quickly locate the gene.

Both Incyte and Human Genome Sciences have filed patent applications for millions of ESTs. According to Incyte's Web site, its database "contains 4.3 million ESTs, 3.3 million of which are Incyte-proprietary. This represents an estimated 90% of expressed human genes."

The first EST patent was awarded to Incyte in November 1998 for human kinase homologues. PTO's Schwartz said only a handful have been granted since then, and most of these, including Incyte's, "squeaked out when they really shouldn't have.

"We have a blue ribbon panel of examiners who are privy to all the nuances of EST cases," he said, but the approved applications did not explicitly mention ESTs and were mistakenly reviewed by another section.

Schwartz said all EST applications will now be reviewed by the special panel and that PTO is revising its guidelines so that gene patent applications will have to meet a stricter standard of utility. Demonstration of utility is one of the basic requirements for patenting. Without it, an application will be rejected. But the definition of utility can be slippery, and Schwartz said EST applications are notorious for vague utility claims. When EST applications began to flood in, PTO officials made a list of acceptable utilities for ESTs. These included probing for a gene known to be useful, chromosome mapping, and forensic identification. The problem was, the latter two could apply to virtually any DNA sequence.

"Word got around . . . and we started seeing those utilities in every application," Schwartz said. "Then suddenly there was a lot of commentary in places like law reviews, saying these utilities were not true, but were just being put in as boilerplate, as place holders, so that once they get their patent they can determine what the thing's really useful for." He compared this tactic to claiming that a piston has utility as a paperweight, or a transgenic mouse as snake food.

To prevent patent seekers from using these so-called throwaway utilities, the new guidelines will require that an application show the "specific and substantial" utility of each sequence.

Although Celera's Venter invented the EST method, the company does not use it, and plans to seeks patents only for full gene sequences. Although an EST makes it possible to find a gene, Gilman said, the tag may not even be in the gene itself, but in a DNA sequence leading up to it.

"An EST is in no way predictive of the gene," he said. "You can't look at the sequence and say, ‘that's an ion channel.' " While patenting ESTs as tags may be OK, he said, it does not logically follow that identifying an EST should confer the rights to the whole gene. Celera's full sequence applications, he said, contain at least a rough idea of what the gene does, typically based on computer modeling and homology to known genes, he said.

"That's another issue we're grappling with right now," Schwartz said. "How much is enough? Based on a short sequence, how much protection should one have?"

Note: A second installment to this story will appear in the February 2 News: What does gene patenting mean for science, medicine, and society?



             
Copyright © 2000 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement