Biotech Industry in Turmoil: Human Genes Unpatentable?

“Eric Holder Hijacks the Patent System, Flunks Patents 101” emailed powerful Washington D.C. patent attorney Harold C. Wegner, at the firm Foley & Lardner, about the U.S. Attorney General’s court filing of Friday 29 October 2010, that says human and other genes are not patentable, thus reversing decades of government policy. Wegner said he’d talked recently with David J. Kappos, the director of the Patent Office. He said Mr. Kappos “seemed chagrined that the Department of Justice was taking a viewpoint very different from the patent office.” Kappos did not reply to a request for clarification by The New York Times.

Kevin E. Noonan, a Chicago patent lawyer and author of Patent Docs, a blog on biotech patent issues, said of the government’s brief: “It’s dumb. It shows a singular ignorance of the technology and the law at the same time.” Noonan said that the government’s stance could endanger innovation, since the same philosophy against patenting products isolated from nature (as human genes are) might be extended to protein-based drugs and antibiotics.

BIO, The Biotechnology Industry Organization, represents more than 1,200 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO, headed by James C. Greenwood and associated with the Council of State Biotechnology Associations (CSBA), warns that such a policy, if carried out, would “undermine U.S. global leadership and investment in the life sciences.”

The New York Times and other major American newspapers reported on a storm of protest, with quotes such as: “We’re telling the rest of the world to have high minimum standards to protect software, pharmaceuticals … and we’re violating minimum standards ourselves.” And “It’s dumb … It shows a singular ignorance of the technology and the law at the same time.”

On the other hand, Chris Hansen, an attorney at the ACLU (American Civil Liberties Union), which is representing the plaintiffs, said “Clearly, this is a major development. In effect, the United States government has joined the plaintiffs.” Yet Myriad, the defendant, said in a statement on Monday that the Justice Department agreed with the company on other issues about this contentious case.

What is the cause of all the turmoil? What was the policy, what is the policy, what might the policy become, what does this matter for business, and how might ordinary citizens be affected in their access to healthcare and medicine?

Let’s start with the United States Constitution. United States patent law was established in the 8th sentence of Section 8 (Article One, Section 8(8) of the U.S. Constitution) “to promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries.”

Congress turned these theoretical protections into a first-to-invent patent legal framework, even though almost every other nation’s patent laws are first-to-file systems. That technicality aside, the details are in Title 35 of the United States Code (U.S.C.) and this gives authority for the United States Patent and Trademark Office (PTO).

Under this system of American law, a patent is a right that excludes others from making, using, selling, offering for sale, exporting components to be assembled into an infringing device outside the U.S., importing the product of a patented process practiced outside the U.S., inducing others to infringe, offering a product specially adapted for practice of the patent, and a few other very carefully defined sets of consideration. Merely thinking about an invention, or drawing a diagram, or my writing this article, is not an infringement. Research for “purely philosophical” inquiry is not an infringement. However, research directed to commercial purposes is – unless the research is directed toward obtaining approval of the Food and Drug Administration for introduction of a generic version of a patented drug. That’s where the arguments began.

It all comes down to the balancing act between the benefits to society at large (“promote the Progress of Science and useful Arts”) and the money and respect earned by “Authors and Inventors” (and their employers and investors). “If you want to look at your own genome and see if you have a mutation, you should be able to do that without paying a license fee to someone else,” said Steven Salzberg, professor of computer science and genetics at the University of Maryland, and an advocate of do-it-yourself genetic testing.

The government’s new policy was outlined in an amicus brief (a brief by a friend of the court) in a lawsuit challenging patents held by Myriad Genetics and the University of Utah Research Foundation on two genes that are linked to breast and ovarian cancer. In March 2010, Judge Robert W. Sweet of the United States District Court in Manhattan had ruled that the Myriad patents were invalid. Now, with the case before the appeals court, the Justice Department has essentially agreed with him.

As Steven Salzberg wrote this year in the journal Genome Biology: “As we learn more about the associations between genes and disease, a growing number of diagnostic tests have been developed to detect mutations that increase the risks of various diseases. However, anyone who wants to develop a diagnostic test or a treatment based on human genes faces a potential roadblock: gene patents. A 2005 study reported that 4,382 human genes (~20% of the total number in our genome) are covered by patents or other intellectual property claims. These patents cover a wide range of methods for assaying the DNA sequence of an individual for the presence of disease-associated mutations. For example, one of the most consequential gene patents covers mutations in the BRCA1 and BRCA2 genes, which are associated with a significantly increased risk of breast and ovarian cancer. The BRCA gene patents, which are held by Myriad Genetics, cover all known cancer-causing mutations in addition to those that might be discovered in the future. No one can develop a commercial diagnostic test or a treatment based on the BRCA gene sequences without a license from Myriad. Although a US federal court recently overturned seven of Myriad’s BRCA patents, Myriad is appealing the ruling, and it holds 16 other BRCA-related patents that it claims are unaffected by the court’s ruling.”

Nor is Myriad the only corporation in the eye of this hurricane. James P. Evans, a professor of genetics and medicine at the University of North Carolina who has studied gene patents, said that there were mainly two companies, Myriad and Athena Diagnostics (a reference laboratory dedicated to the development and commercialization of diagnostic testing for neurological disorders), basing their business on offering expensive genetic tests protected from competition by gene patents. Athena Diagnostics, James P. Evans said, was moving toward tests using multiple genes, or even a person’s entire genome sequence. Patents on each individual gene could be a barrier to development of those multigene tests.

Athena’s home page explains that they are “a leading provider of advanced neurological diagnostic assays. Our expertise includes diagnosis in the areas of: peripheral nerve disorders, neurogenetic disorders, Alzheimer’s disease, paraneoplastic syndromes, movement disorders, neuromuscular disorders, and ataxia. Our technologies are licensed predominantly from the academic research environment and represent our commitment to cutting-edge technology and our close relationships with world-renowned experts in neurology and genetics. The technical staff at Athena Diagnostics performs over 200 assays for neurological diseases using a variety of sophisticated laboratory methods. Assays are performed in our laboratory located in Worcester, Massachusetts, and are available only to physicians … In March 2006, Athena was acquired by Fisher Scientific International, which itself merged with Thermo Electron Corporation in November 2006 to form Thermo Fisher Scientific, the world leader in serving science with instruments, equipment, reagents, consumables, software and services.”

DNA sequencing is undergoing a dramatic decrease in cost, so the old method of testing for mutations one gene at a time is fast becoming obsolete. Very soon you will be able to fully sequence your own genome, or that of a child or pet, before testing the sequence for all known genetic mutations associated with a given disease, rather than to conduct multiple separate tests for each gene. Myriad right now charges more than $3,000 for its tests on the BRCA genes, while sequencing your own entire genome now costs less than $20,000. That figure will drop to $2,000, and then to $200, and probably down towards $20. More importantly for your future health, once your genome has been sequenced, it becomes a resource that you or your physician can use for re-testing as new disease-causing mutations are discovered.

The flip-flop in policy implied by Eric Holder’s actions last week seems to signal discussions among agencies within the Obama administration, including but certainly not limited to the National Institutes of Health (NIH) and the Patent and Trademark Office (PTO). Although, as the ACLU said, the United States government has essentially joined the plaintiffs; immediately, the new policy will have little public impact. PTO issued a statement saying that it would not put the policy into effect right away, nor start denying patents on genes because of this or related pending litigation.

The office intends to “maintain the status quo while this matter is pending resolution by the Federal Circuit Court of Appeals,” a spokesman said, pointing to this case on the cancer risk genes. A lower court had ruled against Myriad, deciding that human genes could not be patented. Another Obama administration official said it would be overly disruptive to change the longstanding patent policy at this time, since the court might end up ruling the other way on the case involving the cancer risk genes. Over two decades, the agency has issued thousands of patents on genes. The Patent Office seems to oppose the position written in the Justice Department’s brief, though none of the PTO lawyers were listed as authors.

As Steven Salzberg continues: “In contrast to whole-genome sequencing, standard methods for identifying mutations in BRCA1 and BRCA2 use PCR to amplify the genome regions containing each mutation. As more mutations are discovered, these tests need to be augmented with additional PCR assays, adding to their cost. The commercial assay available from Myriad Genetics interrogates a limited number of sites by PCR and sequencing, which can miss clinically relevant mutations; for example, a recent study reported that 12% of women from high-risk families with deleterious mutations in BRCA1 or BRCA2 had false negative results from this assay. Even if the test were perfect, a gene-centered approach will be far more expensive over time than a computational assay based on an individual’s genome, because the genome only needs to be sequenced once, after which it can be used to test all 22,000+ human genes.

“Regardless of how easy it might be to test for mutations, the restrictive nature of the BRCA gene patents means that anyone wishing to examine any mutation in BRCA1 or BRCA2 will have to obtain permission from the patent holder Myriad Genetics. This restriction applies even if testing your own genome. If you wanted to look at other genes, you would have to pay license fees for any of them that were protected by patents. In practice, although it may seem absurd, this means that before scanning your own genome sequence, you might be required by law to pay thousands of license fees to multiple patent holders.

“We believe that any individual should be allowed to interrogate his or her genome for all mutations of interest, regardless of whether a private company claims to ‘own’ the rights to particular gene mutations. To challenge the restrictive gene patenting system, we have developed a computational assay that, as a proof-of-concept, tests for 68 known variants of the BRCA1 and BRCA2 genes. In other words, we empower any individual using our software (whether this is a private individual, a clinician or a clinical or basic researcher) to test for these mutations and circumvent the gene patents. Here we demonstrate the method on the publicly available DNA sequence from three human genomes: a Caucasian female, an African male and an Asian male.

“We have made the software freely available (at http://cbcb.umd.edu/software/BRCA-diagnostic) under an open source license, allowing others to use, modify and redistribute it. The software is flexible and can easily be adapted to search for mutations in other genes. The method uses the raw sequence reads that are produced by a high-throughput sequencer; it does not require genome assembly nor any other processing of the raw data. This software provides a relatively simple, do-it-yourself home testing method for interrogating a genome for the presence of mutations in the BRCA genes. All one needs, besides the software, is the sequence data from an individual human.”

“We did it,” said Salzberg, “to show how it would be easy today for someone to get their genome sequenced and to do their own genetic testing.”

It is uncertain what will happen in Appellate Court. In its brief there, Myriad argued that the plaintiffs did not have standing to sue because Myriad was not accusing them of infringement. Judge Sweet in the lower court had rejected those arguments. If the appeals court accepted them, it could decide the case without having to weigh the merits of gene patents. Or it might consider these merits. We can’t predict whether or not the policy against gene patents would then be put into effect.

I see two very different futures. In one, I’ll soon be buying a gene testing kit for $19.95 at a local drug store, to find out if I’m susceptible to the kind of cancer that killed my mother and her mother, or my father and his sister. In another future, patent lawyers for biotechnology companies would perform that same service, but for the cost of an automobile. This is a far more important legal story than which celebrity goes to jail for failing which drug test.

This story is about your future, and the breakthroughs in health and medicine. And who’s in charge: the public at large, or the technology’s inventors.

 

References

Gene Patent Ruling Is Criticized by Industry,” Andrew Pollack. The New York Times November 1, 2010.

Do-it-yourself genetic testing,” S.L. Salzberg and M. Pertea. Genome Biology. 2010, 11:404. []

Between a chicken and a grape: estimating the number of human genes,” M. Pertea and S.L. Salzberg. Genome Biology. 2010, 11:206. []

Assembly of large genomes using second-generation sequencing,”  M.C. Schatz, A.L. Delcher, and S.L. Salzberg. Genome Research. 2010, 1165-1173.

 

Jonathan Vos Post is co-webmaster, Vice President, and Chief Information Officer of Magic Dragon Multimedia.  He has taught art, astronomy, biology, chemistry, computer science, English composition and English Literature at various California colleges.  Von Post has collaborated with Isaac Asimov, Ray Bradbury, Richard Feynman, David Brin and Arthur C. Clarke, and has innumerable published articles, short stories and poems to his credit.

 

See Also

Rethinking the Promise of Genomics

The New Era of Health and Medicine as an Information Technology is Broader than Individual Genes

ACLU v. The Gene Patents

 

 

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