Gene Patents

Nearly 30,000 human genes have been patented in the United States (R. Cook-Deegan, personal communication, 2003). Patents will often be secured in countries throughout the world where the patent owner thinks there may be a viable market. Patents are granted by the U.S. government to inventors for new, nonobvious, and useful inventions and discoveries, and similar standards of patentability are applied around the globe. A patent grants to its owner the right to exclude others from making, using, or selling a patented machine or composition of matter, or from using a patented method, for a period of 20 years from the date of filing a patent application.

A patent grants what is called a negative right—the right to enjoin others from using the invention without permission, and a patent owner may turn to the federal government to use its judicial and police powers to block others from making, using, or selling the invention, and to collect damages from those who infringe. A patent owner generally is not under any legal compunction to ''work'' or license others to use a patented invention, and, as a general rule, a patent even may be used wholly to keep products from coming to market.[1]

Human gene patents result from the cloning and description of the sequence of a gene, the role or function of which is somewhat understood. The U.S. Patent and Trademark Office requires that a patent applicant make a credible assertion of the specific and substantial utility of the genetic invention.[2] Under this kind of rationale, early patent applications by the U.S. National Institutes of Health covering thousands of expressed sequence tags, which are unique nucleotide strings randomly culled out of the genome but have no known function other than as a distinctive marker, were disallowed.

Gene patents cover three distinct types of invention: 1) diagnostics; 2) compositions of matter; and 3) functional use. I will discuss each in turn, with examples and highlights of areas of concern and what is known about each. This overview is centered on U.S. patent law and what is known about how gene patents are being used in the United States. Some of the problems discussed have begun to spill over to Europe and Canada. This is not meant to be a comprehensive international review,[3] but only an attempt to demonstrate the breadth of gene patents, discuss concerns about how they are being used, and summarize relevant empirical data.

First, what we have called disease gene patents claim (claims define the scope of patent protection) the characterization of an individual's genetic makeup at a disease-associated locus when performed for the purpose of diagnosis or prognosis.[4] These patents typically cover all known methods of testing, including the use of hybridization, Southern analysis, polymerase chain reaction (PCR), and even DNA chips. Because the fundamental discovery patented is the statistical observation of a genetic difference and a phenotypic difference (such as the occurrence of disease), then any method for testing for that genetic difference can be covered by the patent.[5]

Well-known examples of disease gene patents include those covering genes implicated in breast and ovarian cancers (BRCA1 and BRCA2), colon cancers (HNPCC and FAP), cystic fibrosis (CFTR), hemochromatosis (HFE), and a growing number of neurological diseases including late-onset Alzheimer's disease (AD; Apo-E), Canavan disease, Charcot-Marie-Tooth disease (CMT-1A and CMT-X), spinal muscular atrophy (SMN1), spinocerebellar ataxia (SCA1-SCA12), and others.

There are several characteristics of genes and disease gene patents that demonstrate how the genome is being divided by small patent claims to overlapping genetic territory. First, any one gene may have multiple patents claiming the diagnosis of different polymorphisms. Thus several patents have been issued for testing of different mutations in the CFTR gene.[6] Furthermore, some diseases (at least the phenotypic expressions of them) are caused by multiple genes, such as Charcot-Marie-Tooth disease.[7] Questions about ownership and access get messy when there are many hundreds of known mutations in multiple causative genes, as exemplified by BRCA1 and BRCA2, for which there are at least a dozen U.S. patents on tests of these two genes.[8] Finally, patents can issue on the same exact molecular test when it is performed for different diagnostic or prognostic purposes. For example, an Apo-E test, in which the number of E2, E3, and E4 alleles carried by a patient is assessed, can be performed to: 1) determine whether a patient is at risk for early-onset AD;[9] 2) assess an AD patient's prognosis;[10] 3) determine a course of therapy based on pharmacoge-netic receptivity;[11] and 4) assess a patient's prostate cancer risk.[12] In each of these cases, a patent thicket is created, which can lead to difficulties in securing licenses and expenses in paying multiple ''stacked'' royalties to multiple patent owners.[13]

To the best of our knowledge, the owners of the overwhelming majority of issued gene patents have not aggressively enforced their rights against clinical molecular diagnostics laboratories. Nonetheless, a majority of genetics laboratories across the United States report that they have had one or more of the above disease gene patents asserted against them.[14,15] In some cases, these patent owners have been willing to grant a license to laboratories performing a home-brew test. Per-test royalties of which we have become aware include US$2 for the DF508 mutation of CFTR (University of Michigan), US$5 for Gaucher's disease (Scripps Institute), US$12.50 for Canavan disease (Miami Children's Hospital), and, reportedly, more than US$20 for HFE (Bio-Rad). In some cases, an up-front license fee has been demanded as well.[16]

Of course, clinical and research laboratories typically pay royalties for the use of patented technologies. For example, the price of widely used PCR machines and reagents includes a premium paid for the exclusivity granted by the patents. In addition, a royalty of about 9% is paid for all testings done by licensed laboratories.1-14-1 The most recent patents enforced against biotechnology companies and testing laboratories are those that claim the extremely broad uses of intronic sequences for generating haplotypes and identifying allelic variation.[17] Disease gene patents vary in significant ways from these more typical patented tools that are used by laboratories for testing a variety of specific disease genes. Critically, because a disease gene patent claims all methods of testing for a specific gene, there is no plausible way of working around these patents and the patents may be used to monopolize a test.

Fortunately, in only a handful of cases have patent owners refused to grant licenses to laboratories to allow them to perform specific tests. Instead, these owners have used the patents to monopolize the testing service and to require physicians and laboratories to send samples for testing to the owner or its limited licensees. Thus, tests for breast and ovarian cancer genes (Myriad Genetics) and a set of neurological disorders (Athena Diagnostics) are generally available from only these commercial laboratories. SmithKline Beecham Clinical Laboratories made a brief attempt at capturing the testing market for hemo-chromatosis before the business unit was sold to Quest Diagnostics.1-16-1 Myriad has extended its reach beyond the U.S. borders, seeking to enforce its BRCA patents in France,[18] Canada,[19] and the UK.[20] The test for Canavan disease, despite being easily included in panel assays that many laboratories can run, was restricted to selected laboratories around the United States by the

patent owner.[21]

In these cases, laboratories have been told where patient samples must be sent to have the patented tests performed and how much it will cost. Being compelled to stop providing testing services has serious implications for the ability of molecular pathologists to maintain currency in their field, to treat their patients with comprehensive medical services, to train residents and fellows, to perform research, and to run their laboratories in an efficient manner. Hospital-based laboratories must often eat part of the fixed monopoly costs of the tests, which they are compelled to offer patients but for which health insurance may not cover the full price. Seen in this light, these patents raise the costs of clinical services and restrict physicians' ability to practice medicine.[1,22]

The second broad type of genetic invention relates to compositions of matter (i.e., chemicals and materials), including the isolated and purified gene (cDNA) and all derivative products (e.g., recombinant proteins or drugs, viral vectors, and gene transfer ''therapies,'' and trans-fected cells, cell lines, and higher-order animal models in which the patented gene has been inserted or knocked out). Examples of recombinant products include insulin and human growth hormone. According to the Biotechnology Industry Organization, there are more than 155 biotechnology drugs and vaccines that have been approved by the U.S. Food and Drug Administration, and more than 370 others in clinical trials.[23]

The primary concern about gene patents is that they will make it more difficult to perform research. In the United States, there is no statutory research exemption, but only an extremely narrow court-defined exemption. As recently summarized by the Court of Appeals for the Federal Circuit in a suit against Duke University,

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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