May 2010
Feature Story

William Check, PhD

It was an amazing affirmation, even though it was sheer coincidence. In an essay in the Wall Street Journal of April 10/11, physicist Paul Davies suggested several possible ways to detect signs of a visit from beings outside our solar system, including this biological approach:

“Life on Earth stores genetic information in DNA. A lot of DNA seems to be junk, however. If aliens, or their robotic surrogates, long ago wanted to leave us a message, they need not have used radio waves. They could have uploaded the data into the junk DNA of terrestrial organisms.”

Davies’ invoking of DNA as an informational molecule provided an exact and emphatic endorsement of the fundamental principle underlying the March 29 ruling by New York District Court Judge Robert W. Sweet granting summary judgment to the plaintiffs in the ACLU’s lawsuit challenging seven of Myriad Genetics’ patents on the BRCA 1 and 2 genes (www.aclu.org/free-speech-technology-and-liberty-womens-rights/association-molecular-pathology-et-al-v-uspto-et-al). In his ruling, Judge Sweet wrote: “DNA represents the physical embodiment of biological information, distinct in its essential characteristics from any other chemical found in nature. It is concluded that DNA’s existence in an ‘isolated’ form alters neither this fundamental quality of DNA as it exists in the body nor the information it encodes.”

Robert Cook-Deegan, MD, director of the Center for Genome Ethics, Law and Policy at Duke University’s Institute for Genome Sciences and Policy, notes that Judge Sweet spent 20 pages of his 152-page decision making the case that DNA is an informational molecule. “One thing that matters here that was not true in previous [gene patent] cases,” Dr. Cook-Deegan says, “is that the judge was seeing the patent through the lens of diagnostics.” For this suit, the ACLU recruited several pathology organizations, including the CAP and the Association for Molecular Pathology, as plaintiffs. “The informational argument is much more compelling [for diagnostics] than in the case of making a therapeutic molecule, where it is easier to say that there is an invention,” Dr. Cook-Deegan says. “Using a gene for diagnostics seems more like a discovery.”

“This ruling is much better than I expected,” says Roger D. Klein, MD, JD, medical director of molecular oncology at BloodCenter of Wisconsin, Milwaukee. “Judge Sweet ruled that Myriad was trying to patent natural products or natural laws that don’t fall within the scope of patent law.” Dr. Klein agrees that a major factor in the decision was the judge’s focus on science. “Judge Sweet had a profound grasp of the issues,” he says. “He recognized that the informational properties of DNA don’t change depending on whether it is in the cell or external to the cell. He is a conscientious and diligent judge who clearly went out of his way to understand the intricate scientific details as well as the effects of these types of patents on both clinical practice and scientific research.”

Judge Sweet’s own words verify Dr. Klein’s assessment of the judge’s rigorous and scientific orientation to the case. Regarding the question at issue—“Are isolated human genes and the comparison of their sequences patentable?”—the judge wrote: “Two complicated areas of science and law are involved: molecular biology and patent law. The task is to seek the governing principles in each and to determine the essential elements of the claimed biological compositions and processes and their relationship to the laws of nature.”

“This is a real victory for patients and medical care, for scientific research, and for the practice of molecular pathology,” Dr. Klein says. “As pathologists transition from making diagnoses solely based on morphology to incorporating molecular genetic markers to help guide therapy, this ruling prevents entities who have acquired exclusive rights to a gene or particular variation in a gene from blocking the advance of the field and obstructing medical practice.”

Whether the decision actually provides these benefits depends on its fate at the next two judicial levels—the Court of Appeals for the Federal Circuit (CAFC) and the Supreme Court (if it accepts an appeal). Myriad Genetics has already announced its intention to appeal to the CAFC. “We have to see if the District Court ruling emerges in anything like its current form,” Dr. Klein says.

The Association for Molecular Pathology acted as lead plaintiff in the suit. “I am delighted with the ruling,” says AMP president Karen Mann, MD, PhD, associate professor and director of molecular hematopathology at Emory University. “It validates AMP’s decision to be a plaintiff in the lawsuit.” She describes the judge’s opinion as “very thoughtful” and calls it a “positive development” —though not one that is changing her daily work at this point. Like Dr. Klein, Dr. Mann is aware of the long process of appeals that lies ahead and that the decision as written applies only to the two BRCA genes. Still, she believes it has great implications for all patented genes. “If this becomes generalized,” she says, “then it would really free up each lab’s ability to offer the full range of testing to their patients.”

Jan Nowak, PhD, MD, president of AMP at the time it joined the suit, is pleased, too, with the decision. “I expected it would take longer for a decision to come out,” says Dr. Nowak, who is director of the molecular diagnostics laboratory in the Department of Pathology and Laboratory Medicine at Evanston (Ill.) Hospital, NorthShore University HealthSystem. “I was surprised it came so abruptly.”

The more he studies the decision, he says, the more he likes the way it was written. “What is remarkable is that Judge Sweet understood the science. A big part of what he wrote is a review of molecular biology. It was clear to him that applications of patent law in the past were inappropriate for what DNA is. We know DNA defines genes. That was a remarkable discovery, probably one of the major scientific discoveries of the 20th century. Many people still don’t appreciate the significance of that, but the judge took the time to understand it. And he concluded that genes are naturally occurring entities. You can’t patent them.”

Dr. Nowak says that most people who dislike this ruling argue from a business sense. “We plaintiffs don’t stand to make money out of this,” he says. “That is not why we joined the suit.”

In the opinion of Chris Hansen, JD, lead counsel in the suit and senior staff attorney at the ACLU, one reason why the judge took the case seriously enough to do his homework is that several pathology organizations, as well as the American College of Medical Genetics, joined as plaintiffs. “I think that the nature of the plaintiffs, the fact that organizations like CAP were willing to join in, was a critical factor in persuading the court,” Hansen says. “It made the case respectable. It showed the importance of this case to the medical community.”

In addition to arguing against the validity of the patents themselves, the ACLU suit argued that Myriad could not patent a correlation, the process by which it compared one gene sequence or its variations to another to determine whether an individual woman was at increased risk of breast or ovarian cancer. Judge Sweet also upheld this argument, ruling that such comparisons are “abstract mental processes” and thus “unpatentable subject matter.”

One clue as to how this argument might fare in the Supreme Court arose in a 2006 decision, LabCorp v. Metabolite Laboratories, in which a method for correlating homocysteine blood levels with a deficiency of cobalamin or folate was at issue. The Supreme Court decided not to rule in that case, since—unlike in the ACLU/ Myriad Genetics case—the argument that the process is unpatentable was not raised in the lower courts. However, Hansen points out, Justice Stephen Breyer, joined by Justices David Souter and John Paul Stevens, wrote a dissent in which he accepted the argument for invalidating the patent—that this comparison process was an unpatentable “natural phenomenon.” One of those justices has since retired; another will do so soon. To say that the conservative justices who were on the court in 2006 would reject this argument is incorrect, in Hansen’s view. “You can’t interpret a vote not to rule in the case as meaning that they tacitly affirmed the validity of the patent,” he says.

Barbara Caulfield, former general counsel for Affymetrix and current managing partner of the Silicon Valley office of Dewey & LeBoeuf and co-chair of the intellectual property litigation group, takes a sweeping view of the ruling. “Judge Sweet said that patents on genes, because they are naturally occurring phenomena, are not valid,” Caulfield says. “This means that every gene patent—and there are over 10,000 patents issued on DNA sequences—is now questionable. Certainly the case will be appealed to the CAFC and probably to the U.S. Supreme Court. But right now we have ambiguity as to the validity of gene patents.” This ambiguity, she believes, will call forth more competition in tests for BRCA 1 and 2. “Tests will become better and cheaper and will become more available to patients in the U.S.,” she predicts.

In the long run, if the ruling is upheld, it could be applied to other gene patents. In that case, Caulfield foresees an acceleration in research on the human genome. “There will be more of a financial incentive for companies to be invested in research and to develop more diagnostic tests and treatments because they will not be impeded by existing gene patents,” she says. “People who own gene patents are upset. Not only did they see themselves having a head start but also control of a gene for 20 years. That might be to their financial advantage, but it may not be best for developing personalized medicine.”

In a way, this ruling reflects increased sophistication about genomics. “As soon as knowledge broadens, you need to have more innovation,” Caulfield says. “Knowledge of the genome broadened in the last five or 10 years, so now we need more innovation. For somebody to own a whole segment of the human genome stifles innovation.” To some extent, the genome is the modern biotech version of the transistor, she says. “Everyone uses the principles of transistors in every computer. Once you really know how it works, the applications are almost limitless. But you need the ability to innovate.”

In the wake of Judge Sweet’s ruling, the debate over gene patents took on a new tone very much in line with Caulfield’s thinking about the need for innovation. It was as though people were acknowledging that invalidation of gene patents was a necessary step to prepare the ground for technological advances, in the same way that clearing a field prepares it for planting. For instance, Andrew Pollack wrote in the New York Times on March 31:

“[T]he industry is already moving to a period of somewhat less dependence on DNA patents for its sustenance. Diagnostic laboratories, for instance, are shifting from testing individual genes to testing multiple genes or even a person’s entire genome. When hundreds or thousands of genes are tested at once, patents on each individual gene can become a hindrance to innovation rather than a spur.”

Similar thoughts were expressed in the Genomics Law Report (www.genomicslawreport.com). And Forbes magazine said the case “is the first battle in which the future of medicine confronted the past—and the future won” (www.forbes.com/2010/03/31/gene-patent-myriad-business-healthcare-dna-biotech.html). “Far from hurting biotech innovation, eliminating pure gene patents will greatly speed innovation in the biotech sector,” Forbes writer Matthew Herper continued. “Instead of tying up basic genetic information with patents, the biotech industry will have to become more like the computer industry. It will compete on the quality of its machines and software algorithms, not by making scientific discoveries and locking up the information for decades with a patent.” One critical biotech innovation will be whole-gene sequencing, Herper noted, and added, “A $3,000 gene test no longer makes sense in a world of $3,000 gene sequences.”

Many people in the biotech industry have a much less optimistic view of Judge Sweet’s ruling. Kevin Noonan, PhD, a biotechnology and patent lawyer and partner at McDonnell Boehnen Hulbert & Berghoff LLP, Chicago, warns that if the ruling is upheld, “There will be a major push to turn everything into a trade secret. Research into genomics and personalized medicine would move away from traditional partnerships between academics who have to publish and for-profit companies.” Most common diseases—cancer, heart disease—are multigenic. Underlying ge­netic variants can be sought through a targeted bioinformatics approach analyzing hundreds or thousands of samples in tissue repositories. “If you are a company, you would go in and just detect [genes and variants] using the power of modern sequencing,” Dr. Noonan says. “You can pretty much find half a dozen or a dozen of these things that show up in people who have disease and not in people who don’t. You could take these sequences, put them on a gene chip, and encrypt them. You would never have to disclose that to anyone.”

Leaving aside the disappointing results so far from genomewide association studies and growing doubt among scientists about the assumptions underlying such studies, academic researchers are already doing the studies using the latest next-generation sequencers. Why should companies be more successful? “Today there are collaborations between academia and private industry,” Dr. Noonan responds. “In the future, if the only way a company has to go forward is to maintain discoveries as trade secrets, industry will say, ‘I can’t use what university researchers do.’ They will stop funding academics and bring research in-house and do it secretly.”

In Dr. Noonan’s opinion, university labs will find it more difficult than they think to do BRCA testing. He extols Myriad’s track record. “I have never heard anyone allege that they have made a mistake,” he says. “In 15 years Myriad has not reported any result that was contrary to facts. That is a lot harder than [academic labs] think.” Dr. Noonan discounts the finding by Mary-Claire King, PhD, the scientist who discovered the BRCA genes, that Myriad was missing certain mutations. “They haven’t reported incorrect results,” he maintains.

What about the fact that not-for-profit labs do complex genetic testing routinely?

“It may come as something of a shock to all my friends in the research and patient communities,” Dr. Noonan says, “but the focus a company brings to this work may not be something they can achieve in academia.”

While Myriad’s appeal proceeds, the Genomics Law Report notes several practical considerations:

“It is possible that the District Court’s judgment invalidating the Myriad patents will be stayed, or suspended, during that appeal. Judge Sweet’s order will not affect any patents not directly involved in the case, nor be binding on any other court, and it is highly unlikely that the USPTO [U.S. Patent and Trademark Office] will change its gene patent examination standards just because of this decision.”

As to the outcome of the appeal, the law report hazards this prediction: “Our initial guess is that the [CAFC] will end up affirming Judge Sweet on some or all of the process claims, but will cut way back on his broad attack on gene patents.”

Dr. Cook-Deegan also thinks it unlikely that Judge Sweet’s ruling will stand in toto. He notes that there have been 11 gene patent cases on therapeutic proteins and interferon that have been decided by the CAFC. “My reading of this ruling suggests that the patents in those previous cases would also be invalidated unless they can come up with a reason this case is distinguishable in not ‘patenting isolated DNA,’ as Judge Sweet argued it,” he says. “Faced with that choice, I suspect the CAFC will either find an argument that Judge Sweet is wrong as a matter of law, rather than face overturning those previous decisions, or find an argument that allows them to invalidate these composition of matter gene claims in Myriad’s patents but also allow the previous decisions to stand. But I’ll be pretty surprised if they say, ‘You’re right, DNA is not patentable.’”

This ruling was a surprise, though, and “We could be surprised again,” Dr. Cook-Deegan says, and adds, “Hold on to your seats—this is the first step in many before we know what this ruling means.”