NATURE BIOTECHNOLOGY VOLUME 25 NUMBER 9 SEPTEMBER 2007 989

Gene patents and genetic testing in the United StatesRoger D Klein

As genetic testing moves into mainstream medicine, its restriction by gene patent holders will have far-reaching, detrimental effects on the healthcare system.

Roger D. Klein is at the H. Lee Moffitt Cancer Center & Research Institute and the Department of Interdisciplinary Oncology, University of South Florida Medical School, 12902 Magnolia Drive, Tampa, Florida 33612, USA. e-mail: roger.klein@moffitt.org

Molecular genetic testing has increasingly been incorporated into clinical medi-

cine, and this trend is likely to accelerate in the future1,2. However, the introduction of genetic testing into medical practice is beginning to collide head on with patents that claim own-ership of correlations between human genetic variants and predisposition to disease, response to therapeutic drugs and susceptibility to phar-macologic side effects. Holders or licensees of patents on genes, genetic variants and their bio-logical correlations are already using the threat of litigation to prevent pathologists and other laboratory professionals from performing clin-ical, diagnostic molecular genetic tests3.

There admittedly is limited published, empiric data that quantify the negative effects of such patents on the supply and cost of molecular genetic testing in the United States or elsewhere, not to mention the decreased innovation and diminished clinical knowledge that result from them. However, to practitioners in the emerging field of molecular diagnostics, the perni-cious effects of gene patents on clinical, diagnostic molecular genetic testing are common knowledge. Many providers have discontinued or have been prevented from providing genetic testing for inherited breast and ovarian cancer, severe neurodegenera-tive disorders like Duchenne muscular dys-trophy, a potentially lethal cardiac syndrome and a host of less commonly discussed con-ditions4–6. Given that almost all disease has a genetic component, this state of affairs bodes poorly for the future of healthcare generally.

Fortunately, in the United States, patent law precedents suggest that the legal threats described may lack substance7.

History of gene patentsLong controversial4, gene patents have recently been the subject of heightened media atten-tion. Author Michael Crichton joined the cho-rus of critics in his novel Next, going as far as to include an appendix to the book that exposed the “evils” of gene patents and advocated a ban on them. In February 2007, Congressmen Xavier Becarra (D-Calif.) and David Weldon (R-Fla.) introduced “The Genomic Research and Accessibility Act” (HR 977), a bill that would ban future patents on all nucleic acid sequences. Given this public debate, a review of the history of gene patenting is in order.

The legitimization of gene patents in the United States was an outgrowth of legal and political changes that were initiated in response to the economic dislocations of the late 1970s and early 1980s. During this period, the country was plagued by high unemployment, high inflation and a decline in economic confidence. In response, Congress took a number of steps to encour-age the growth of domestic technology industries. Among the most significant of these were changes to the US patent system.

To maximize the economic value derived from substantial federal investments in basic science research, in 1980 Congress passed the Bayh-Dole Act, which encouraged universi-ties to patent, and thereby commercialize, inventions arising out of government-spon-sored research grants8. In the years subse-quent to the passage of Bayh-Dole, federal financial commitments dedicated to biomed-ical research dramatically increased. National Institutes of Health funding of biomedi-cal research ballooned from approximately $5 billion in the late 1970s to $26 billion in 2003 (refs. 9,10). Because of these gov-

ernmental actions, the number of patents assigned to universities increased from 264 in 1979 to 3,291 in 2002 (refs. 11,12).

In another important event, in 1980 the US Supreme Court ruled in Diamond v. Chakrabarty13 that manmade, living organ-isms could be patented. In its decision, the Supreme Court urged a broad interpretation of patent eligibility, holding that “anything under the sun that is made by man,” includ-ing living organisms, can be patented.

Finally, in an effort to provide national uniformity and add greater certainty and expertise to the application of patent law, in 1982 Congress created the Court of Appeals for the Federal Circuit (CAFC), with exclusive jurisdiction for patent cases14. Since its incep-tion, Federal Circuit decisions have affected the biotech sector significantly by expanding patent-eligible subject matter and strength-ening the rights of patent holders relative to potential infringers. Many patents have since been issued on a range of biotech inven-tions, from transgenic mice and leukemia- derived cell lines to recombinant drugs and vaccines. Thousands of patents have also been awarded on human gene sequences4.

The coalescence of the preceding events set the stage for the enormous growth of the US biotech industry. US Food and Drug Administration (FDA) approvals for biotech drugs and vaccines grew from 2 in 1982 to 35 in 2002. The number of US biotech com-panies expanded from 225 in 1977 to 1,457 in 2001. Biotech employment mushroomed from 700 in 1980 to 191,000 in 2001. In addition, the industry’s growth has created hundreds of thousands of jobs in related industries15,16.

Gene patents versus genetic testingThe US Patent and Trademark Office and the CAFC have followed the Supreme Court’s mandate in Chakrabarty to interpret patent

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990 VOLUME 25 NUMBER 9 SEPTEMBER 2007 NATURE BIOTECHNOLOGY

eligibility broadly. In keeping with this trend, patents have been issued on human genes, genetic variants and more recently, genotype-phenotype correlations. Importantly, our legal system has treated DNA as a chemical despite its dual roles as a physical substance and a store of biological information. In Amgen v. Chugai Pharmaceutical Co.17, the CAFC wrote, “A gene is a chemical compound, albeit a com-plex one.”

Prior precedents in chemical law upheld the patenting of purified compounds like aspirin, epinephrine, vitamin B12 and pros-taglandins18–21. These precedents have been applied to isolated DNA sequences. The chemical analogy has allowed patents on iso-lated, purified human genes to circumvent the ‘product of nature’ doctrine, a longstand-ing legal prohibition against the patenting of natural substances.

When DNA is used as a chemical com-pound to produce recombinant drugs and vaccines, treating it as a complex chemical makes sense. Recombinant drug produc-tion, for example, involves creation of a nucleic acid that did not previously exist in nature (cDNA), which is then used to pro-duce another, medically valuable, chemi-cal. Enormous investments are required to develop, test and obtain regulatory approval for pharmaceutical products. Patents on the human genes used to manufacture new drugs are central to the process of obtaining the risk capital needed to introduce these important therapeutic agents into medical practice.

By contrast, genetic testing simply involves comparing a patient’s DNA sequence with a reference sequence. Technical advancements have made the process of setting up genetic tests scientifically straightforward, inexpen-sive and routine using PCR, thermocyclers, automated sequencers and other justifiably patented instruments and techniques. The Human Genome Project has made reference sequences freely available. Thus, many diag-nostic laboratories are capable of setting up internally developed genetic tests.

Genetic diseases that are inherited in a mendelian pattern are rare. Tests for most individual syndromes present in vitro diagnostics manufacturers with limited opportunities for financial gain. Thus, few FDA-approved test kits are available. Instead, research investments by diagnostics compa-nies have largely been focused on the devel-opment of novel test instruments, methods and reagents. The intellectual property accruing to these inventive activities, rather than gene patents, has been responsible for attracting substantial investment capital into

the field. These industry efforts have helped give diagnostic laboratories the ability to rapidly and inexpensively design, develop and validate many genetic tests. Ironically, however, the threat of enforcement of gene-related patents is reducing innovation in assay development and limiting the number of test providers, thereby raising healthcare costs and reducing or eliminating patient opportunities to send specimens to alternate laboratories to confirm the accuracy of test results.

Current US law does not appear to permit patents on human genes or patents on corre-lations between genetic variants and clinical phenotypes to be used to restrict diagnos-tic testing for inherited or acquired genetic traits. Dating back to litigation over Samuel Morse’s patents on the telegraph, US law has not allowed the patenting of natural phe-nomena22,23. In O’Reilly v. Morse, the validity of a patent on Morse’s invention was upheld. However, one claim in the patent went too far. In addition to patenting machinery that allowed him to transmit and print characters over wires, Morse also claimed the exclusive right to use electricity to do so.

The Supreme Court wisely recognized the dangers in allowing such patents on natural principles. In the deciding opinion, Justice Taney wrote, “If this claim can be maintained, it matters not by what process or machinery the result is accomplished. For aught that we now know some future inventor, in the onward march of science, may discover a mode of writing or print-ing at a distance...without using any part of the process or combination in the plaintiff ’s [Morse’s] specification. His invention may be less complicated—less liable to get out of order—less expensive in construction, and in its operation. But yet if it is covered by this patent the inventor could not use it, nor the public have the benefit of it without the permission of the patentee”22.

The natural phenomenon doctrine has repeatedly been reaffirmed by the Supreme Court, most recently in Diamond v. Diehr23, a dispute in which the Court upheld the validity of a patent on a process for molding uncured synthetic rubber into cured prod-ucts. Justice Rehnquist authored the Court’s opinion. “This Court has undoubtedly rec-ognized limits to 101, and every discovery is not embraced within the statutory terms,” he wrote. “Excluded from such patent pro-tection are laws of nature, natural phenom-ena, and abstract ideas.” Rehnquist quoted from previous Supreme Court decisions: “A principle, in the abstract, is a fundamental truth...these cannot be patented as no one

can claim in either of them an exclusive right.” “We recognize, of course, that when a claim recites a mathematical formula (or scientific principle or phenomenon of nature) an inquiry must be made into whether the claim is seeking protection for that formula in the abstract” (emphasis added).

This ‘natural phenomenon’ doctrine, as distinct from the ‘product-of-nature’ doc-trine discussed in the context of drug pro-duction, prohibits the patenting of laws of nature, for example gravity, and relativity. Arguably, it also prevents patenting of bio-logical relationships like the correlations between genetic changes and physical char-acteristics that are at the heart of genetic testing. Gene patents for drug production have been useful and societally beneficial, whereas their extension to molecular genetic testing has not. As genetic testing moves into mainstream medicine, its restriction by gene-related patents will have far-reaching, detrimental effects on our nation’s health. It is in all of our interests that courts not expand the scope of gene-related patents to include genetic testing.

COMPETING INTERESTS STATEMENTThe author declares no competing financial interests.

1. Klein, R.D. & Kant, J.A. Arch. Pathol. Lab. Med. 130, 1603–1604 (2006).

2. Klein, R.D. Clin. Chem. 53, 1007–1009 (2007).3. Klein, R.D. Genet. Eng. News 27, 12 (2007).4. Caulfield, T., Cook-Deegan, R.M., Kieff, F.S., Walsh,

J.P. Nat. Biotechnol. 24, 1091–1094 (2006).5. Leonard, D.G.B. Acad. Med. 77, 1388–1391

(2002).6. Cho, M.K., Illangasekare, S., Weaver, M.A., Leonard,

D.G.B. & Merz, J.F. J. Mol. Diagn. 5, 3–8 (2003).7. Klein, R.D. N. Engl. J. Med. 356, 753–754 (2007).8. 35 USC §§ 200–212 (2000).9. Moses, H., Dorsey, E.R., Matheson, D.H.M. & Their,

S.O. JAMA 294, 1333–1342 (2005).10. http://www.aaas.org/spp/rd/discip05.pdf11. Rai A.K., Eisenberg R.S. Law & Contemp. Probs. 66,

289–314 (2003).12. http://www.uspto.gov/web/offices/ac/ido/oeip/taf/univ/

asgn/table_1_2005.htm13. Diamond v. Chakrabarty, 447 US 303 (1980).14. Federal Courts Improvement Act of 1982, 96 Stat. 25,

codified as 28 USC 1295 (2000).15. http://www.bio.org/ataglance/bio/16. Lee, S.B. & Wolfe, L.B. Biotechnology indus-

try, in Encyclopaedia of Occupational Health and Safety, edn. 4. International Labour Organization, http://www.ilo.org/encyclopaedia/?d&nd=857200178&prevDoc=857200175

17. Amgen v. Chugai Pharmaceutical Co., 927 F.2d 1200 (1990), cert. denied, 502 US 856 (1991).

18. Kuehmsted v. Farbenfabriken, 179 F. 701 (7th Cir. 1910), cert. denied, 220 US 622 (1911) (acetyl sali-cylic acid).

19. Parke-Davis & Co. v. H.K. Mulford & Co., 189 F. 95 (SDNY 1911), aff’d, 196 F. 496 (2d Cir. 1912) (epi-nephrine).

20. Merck & Co. v. Olin Mathieson Chemical Corp., 253 F.2d 156 (4th Cir. 1958) (Vitamin B12);

21. In re Bergstrom, 427 F.2d 1394 (CCPA 1970) (PGE, PGF).

22. O’Reilly v. Morse, 56 (How.) US 62 (1853).23. Diamond v. Diehr, 450 US 175 (1981).

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