Cashing in on gene sequences

Of course, in the modern age, even God’s language is up for sale. For more than 20 years, investigators have been patenting gene sequences and selling rights to their use, a practice that is exploding in the biotechnology era. John Doll, biotechnology director at the U.S. Patent and Trademark Office (PTO),describes the steady increase in gene-patent applications as “exponential . . . a tidal wave.” Approximately 2000 patents for gene sequences have been awarded so far, and nearly 70,000 applications are currently in the pipeline at the PTO awaiting review. Those who seek the patents usually want to protect research investments in one of two markets: gene- and protein-based drug development or diagnostic testing that searches for gene sequences linked to a given illness. (In the latter example, clinicians pay the holder of a gene patent royalties each time the test is administered.)

To obtain a patent, petitioners must file an application with the PTO, an administrative organization with no regulatory authority of its own. “Our job is to interpret the laws of the Congress as best we can and get judicial advice from the courts when we need it,” said Doll. The PTO reviews patents and bases its approval decisions on whether or not the applicant satisfies requirements under a pair of statutes: 35 USC 101, which describes criteria for patentable material, and 35 USC 112, which describes how supporting evidence from the applicant should be presented. If the patent is denied, the applicant can appeal to the PTO’s Board of Patent Appeals and Interferences, and after that, directly to the federal courts.

A growing controversy
As the applications pile up on the PTO’s doorstep, the entire premise of gene patents is boiling over in controversy. Some vociferous critics, including Massachusetts Institute of Technology professor Jonathan King, believe that the legal right to claim ownership over genetic information is fundamentally wrong. “Genes derive from millions of years of evolution and are, in the deepest sense, products of nature,” he says. “They are not the inventions of individuals, corporations, or institutions.”

More moderate critics grudgingly acknowledge the patents as necessary to attract private investment, but worry that they impede access to genetic innovations in health care and stifle research.

Proponents like Philip Reilly, CEO of Waltham, MA–based Interleukin Gene tics, Inc., counter that without patents for intellectual property, the $20 billion spent annually by biotechnology and pharmaceutical companies on gene research would dry up overnight. “Our success depends entirely on the ability to tell our partners that we have patent protection on the products they invest in,” he says. “We devote nearly as many resources to securing patents as we do on the research itself.”

Out in the cold
Recent events illustrate the debate. In one example, a gene called CCR5—which facilitates penetration into a living cell by the HIV virus—was patented by Human Genome Sciences (HGS), a biotechnology company based in Rockville, MD. This preemptive strike left researchers that actually established CCR5’s role in HIV infection out in the cold.

Researchers who want to continue their investigations on the gene without risking a lawsuit now have to buy a license from HGS. Some critics suggest licensing fees like this could make it difficult for budget-hungry research organizations, especially university laboratories, to continue their work.

“The extent to which the patents impede research depends on how restrictive the licensing requirements are,” said Rodney Howell, the outgoing president of the American College of Medical Genetics. “Some licenses make the sequences readily available, and some are very limiting.”

Another highly publicized case involved a pair of genes implicated in ovarian and breast cancer—BRCA1 and BRCA2—patented by Myriad Genetics Laboratories in Salt Lake City, UT. Soon after the patent was issued, Myriad sent a letter to the Genetics Diagnostics Center at the University of Pennsylvania, which was performing diagnostic tests by screening for the gene, and told researchers there that they would have to pay a fee each time the test was performed. Similar instances have arisen with other genes as well, leaving some critics speculating about the potential impact on genetic screening services provided to the public.

Proponents argue that the CCR5 and BRC gene situations are rare, attract an inordinate amount of publicity, and scare the public unnecessarily. “Most patent holders are eager to see research done on their gene,” says Reilly. “They will let academics use it, the catch being that they usually want the right of first refusal on any research findings.”

A look back
The birth of gene patenting arguably dates to 1980, the year the U.S. Supreme Court heard a case over patentingan oil-eating microbe in Diamond vs Chakrabarty and ruled that living inventions and discoveries could be defined as “patentable subject matter” as long as they were “new, useful, and nonobvious”—a pivotal decision that is considered by some experts to have spawned the entire biotechnology industry.

The controversy began to emerge in the early 1990s. That was when the NIH, under the leadership of Bernadine Healy and encouraged by a senior scientist named Craig Venter, sought thousands of patents for little snippets of DNA called expressed sequence tags, or ESTs. In the scientific outcry over this unprecedented activity, several senior NIH officials either left the government agency or lost their jobs. Venter went on to form the Rockville, MD–based Celera Genomics, the company that shares the credit with the publicly funded Human Genome Project for cracking the humangenetic code last June. The NIH has since come out in opposition to patenting ESTs.

To an extent, ESTs are among the most controversial issues in the debate. A slew of individuals and organizations has attempted to patent these fragments by gambling on a legal loophole and proposing generic or even frivolous uses. The fear among the scientific community is that allowing patents on ESTs with only a vague function could favor companies with the resources to churn out potentially active DNA sequences. This could lead to monopolies over the human genome that might impede more broadly based research.

Awaiting the guidelines
Recently, new draft guidelines issued by the PTO have attempted to clarify more precisely the conditions under which patents for ESTs will be issued. Entitled Revised Interim Utility Examination Guidelines, and released for public comment in December 1999, they were expected to be finalized in December 2000, but, as of press time, were still under review with an unspecified release date. The PTO also released training manuals for gene patent applicants at the same time as the draft guidelines. According to Doll, the guidelines stipulate that ESTs can be patented as long as they are novel, specific, substantial, and satisfy statutory requirements for “real-world utility”—for example, screening for disease risk or making a new drug. “But this is a complex area,” he admits. “Questions will continue to arise over what constitutes patentable genetic material.”

What many stakeholders believe the guidelines do not adequately address are attempts by some to patent genes based on sequence homology or similarity to other genes with a known function, as determined in computer database searches. Genes can be grouped into families based on structural similarities, but knowing the sequence tells you nothing about the physiological function of the gene. Without knowledge of the gene’s function, suggests David Altshuler, director for medical and population genetics at the Whitehead Institute, a biomedical research facility based in Cambridge, MA, there isn’t any clear way to demonstrate real-world utility. Consequently, he believes that there are serious doubts about the legality of a gene’s patentability.

Ultimately, it will take years before all of these issues are resolved. In the meantime, legal experts and scientists are defining new territory in the world of genomics. Most seem to agree that patents can play a critical role in the advancement of the science, but that the role needs to be more clearly defined.

Altshulersuggests that patents make two important contributions to society: They provide a mechanism for attracting private investment, and they force companies to disclose genetic information to the public.

At the PTO, Doll agrees: “I think we’re on the verge of seeing some phenomenal advances based on private research and the patents issued by this office,” he says. But he acknowledges a certain degree of public unease with the concept. “It’s hard to explain to the public that we’re not patenting the gene as it exists in their body,” he explains.

Rather, genes as defined for the purposes of genomics are isolated DNA sequences that have been removed from the natural context of the human body and rendered useful by crafting them in specific ways for medical use.

The ongoing question is how patent law will facilitate ready access to genomic information and services to the public. An important goal will be to structure the system in ways that prevent monopolistic gene-licensing schemes and prohibitive royalties that stand in the way of the public benefiting from these new and exciting technologies.