Diagnostic Testing and the Ethics of Patenting DNA

In the early 1980s, Dan Greenberg had two children born with Canavan disease, a fatal, autosomal recessive, degenerative brain disorder. He recruited a scientist, Dr. Reuben Matalon, to work on discovering a cause for the disease in the hope that couples could be offered carrier screening before starting a family, something that had not been available for Greenberg and his wife. Greenberg also mobilized many other families affected by Canavan, who donated blood and tissue samples for the effort. Thus, in 1994, the gene that caused this condition was discovered, immediately making it possible to inform parents of their risk for having a child with Canavan, as well as providing the opportunity for research of treatments. In 1997, however, the sponsor of the research, Miami Children's Hospital (MCH), filed and received a patent on the Canavan gene and mutations causing the disorder. Shortly thereafter, MCH began to crack down on various academic labs that had begun offering Canavan carrier testing. This deeply offended the Greenbergs and many other donors who had worked so selflessly toward discovery of the genetic basis of Canavan disease (Gillis, 2000).

As the patent owner, MCH has the legal right to exclusively perform Canavan genetic testing or to demand licensing fees and royalties from non-patent holders who want to perform clinical testing. The Greenbergs and other Canavan families believe that this patent makes screening for Canavan disease less widely available and more expensive than it should be. This example is just one of a number of situations that raise the question of whether gene patenting is helpful or harmful to society.

The patent system is intended to promote innovation by rewarding inventors with exclusive rights to use their inventions for a defined amount of time. A patent holder can give permission to others to use his or her invention by granting a license, which usually requires the payment of a licensing fee and ongoing royalty collections.

For some scientists, the concept of patents and other intellectual property protections is troubling, because logic dictates that science will advance more rapidly if researchers enjoy free access to knowledge. In direct contrast, however, is the fact that exclusive rights to intellectual property are required for multimillion-dollar investments in research and development.

Under current patent law in both Europe and the United States, genes can be patented if certain other requirements are met, such as isolating the gene from its natural environment and demonstrating a utility of the nucleotide sequence. Treating a human DNA sequence as a complex chemical that is, therefore, eligible for patent might make sense when this sequence is used to produce recombinant drugs and vaccines. Recombinant drug production, for example, involves the creation of nucleic acids that did not previously exist in nature (cDNA), which are then used to produce other chemicals that are of medical value. Enormous financial investments are required to develop, test, and obtain regulatory approval for these pharmaceutical products, and most people would agree that a company should be able to protect these investments by patenting their invention.

The idea of patenting human genes began with the 1980 case of Diamond v. Chakrabarty, in which the U.S. Supreme Court ruled that man-made, living organisms could be patented, because they did not occur naturally. This, together with the long-standing precedent allowing the patenting of chemical compounds, opened the door for biotechnology companies to patent human genes. Initially, patents were issued on whole genes with known function. Then, inventors began to seek patents on sequences of DNA that were less than a whole gene and often of unknown function. Eventually, many researchers realized that future gene discoveries containing already-patented sequences would be at the mercy of the previous patent holders, and they therefore called for severe limitations on gene patenting. However, research and development companies asserted that they would continue to make their yearly investments of hundreds of millions of dollars only if patent protections and market exclusivity could be assured.

In response to these valid and opposing points, the United States Patent and Trademark Office (USPTO) updated the guidelines used to determine the validity of rights to human DNA sequences in 2001. According to the revised guidelines, a novel DNA sequence is patentable only if a demonstrable usefulness of the DNA sequence is disclosed in the application:

If a patent application discloses only nucleic acid molecular structure for a newly discovered gene, and offers no utility for the claimed isolated gene, then the claimed invention is not patentable. But when the inventor also discloses how to use the purified gene isolated from its natural state, the application satisfies the ‘utility' requirement. That is, where the application discloses a specific, substantial, and credible utility for the claimed isolated and purified gene, the isolated and purified gene composition may be patentable . . . Like other chemical compounds, DNA molecules are eligible for patents when isolated from their natural state and purified, or when synthesized in a laboratory from chemical starting materials... The courts interpret the statutory term ‘useful' to require disclosure of at least one available practical benefit to the public. The USPTO Guidelines reflect this determination by requiring the disclosure of at least one specific, substantial, and credible utility. If no such utility is disclosed or readily apparent from an application, the Office should reject the claim. (United States Patent and Trademark Office, 2001)

As illustrated in the Canavan example, holders of patents on genes, genetic variants, and their biological correlations can and do prevent pathologists and other laboratory professionals from performing clinical, diagnostic molecular genetic tests without paying a royalty fee, a result that is clearly at odds with the original intent of the research. Indeed, in response to MCH's enforcement of its 1997 patent rights, Dan Greenberg and the other Canavan families challenged the ownership and licensing of the Canavan gene in court. A confidential settlement between the parties was finally reached in 2003, and it includes the continuation of licensing and royalty fee collections by MCH for clinical testing for Canavan gene mutations but allows license-free use of the gene for research purposes (Canavan Foundation, 2003). Because of cases like this one, disease-specific advocacy groups are taking steps to protect their interests while still encouraging meaningful contributions to the research enterprise.

Gene patents are being challenged elsewhere in the world as well. For instance, between 2000 and 2003, Myriad Genetics was awarded several patents in the U.S. and other countries covering sequences, mutations, and detection methods for the breast cancer susceptibility genes BRCA1 and BRCA2. Myriad continues to be the only company providing BRCA1/2 genetic testing in the U.S. The company's proprietary test, BRCAnalysis, costs approximately $3,120 and includes comprehensive sequencing of both genes and screening for a panel of five common rearrangements (Lublin, n.d.). Once a mutation is identified by Myriad, family members can receive follow-up testing from a lab licensed by Myriad to look for mutations identified by direct sequencing analysis (Hollon, 2000). Myriad's patents prohibit other labs from developing unique and possibly more affordable or effective genetic tests for the BRCA genes. Nonetheless, there are a few specific types of BRCA testing, such as site-specific mutation testing, that are not covered by Myriad's patents. This allows in vitro fertilization (IVF) clinics to offer preimplantation genetic diagnosis (PGD) for known parental BRCA mutations without a license from Myriad.

French scientists, including Dominique Stoppa-Lyonnet, at the Institut Curie claim that Myriad's test misses 10%-20% of BRCA changes, a fact that has challenged the patents Myriad holds in Europe (Benowitz, 2002). Formal objections to the Myriad BRCA1 patents that had been granted in 2001 by the European Patent Office (EPO) resulted in the revocation of one BRCA1 patent and the amendment of another. These actions have allowed European labs the freedom to develop and use their own methods to detect mutations in the BRCA1 gene (Figure 1).

In addition, a 2003 patent granted by the EPO originally entitled Myriad to exclusive use of the BRCA2 gene sequence, as well as use of information regarding this sequence for diagnosis, risk assessment, and/or therapy. After this patent was challenged, Myriad reworded the patent to specifically cover the use of a DNA probe that identifies one mutation that is almost exclusive to Ashkenazi Jewish populations. As a result, Ashkenazi Jewish women seeking comprehensive BRCA testing have to identify themselves as Ashkenazi Jewish and have their samples tested by a lab licensed by Myriad, thereby incurring additional costs (Abbott, 2005). This patent was challenged again in 2005, but it was upheld by the EPO.

Intellectual property rights and continued progress in scientific research don't always have to be at odds, however. Consider the case of PXE International, which was founded in 1995 by the Terry family; this family has two children with pseudoxanthoma elasticum (PXE). In addition to providing support to affected families, PXE International has created research consortia and patient registries, maintains a bank of biological samples, conducts natural-history studies, and initiates and funds clinical studies. From the outset, the PXE families made certain they had a say in the terms under which the PXE gene patent might be licensed for testing or drug development. They decided that, as the price of access to the PXE tissue bank, researchers would have to agree to make the patient group a coapplicant on any patent filing. True to the agreement, the PXE gene patent issued in 2004 lists PXE International as co-owner. This ensures that PXE patients have a voice when critical decisions are made about the use of the PXE gene in testing and research purposes.

Hopefully, this case will serve as a model for the successful balance between the motivations of the private interests that fund research and the public's desire for treatments and cures.