Noninvasive prenatal genetic testing (NIPT) is an advance in the detection of fetal chromosomal aneuploidies that analyzes cell-free fetal DNA in the blood of a pregnant woman. Since its introduction to clinical practice in Hong Kong in 2011, NIPT has quickly spread across the globe. While many professional societies currently recommend that NIPT be used as a screening method, not a diagnostic test, its high sensitivity (true positive rate) and specificity (true negative rate) make it an attractive alternative to the serum screens and invasive tests currently in use. Professional societies also recommend that NIPT be accompanied by genetic counseling so that families can make informed reproductive choices. If NIPT becomes more widely adopted, States will have to implement regulation and oversight to ensure it fits into existing legal frameworks, with particular attention to returning fetal sex information in areas where sex-based abortions are prevalent. Although there are additional challenges for NIPT uptake in the developing world, including the lack of health care professionals and infrastructure, the use of NIPT in low-resource settings could potentially reduce the need for skilled clinicians who perform invasive testing. Future advances in NIPT technology promise to expand the range of conditions that can be detected, including single gene disorders. With these advances come questions of how to handle incidental findings and variants of unknown significance. Moving forward, it is essential that all stakeholders have a voice in crafting policies to ensure the ethical and equitable use of NIPT across the world.
noninvasive prenatal testing (NIPT); implementation; global; ethics; genetic testing; chromosome aneuploidies
Noninvasive prenatal genetic testing is becoming available worldwide—particularly in low- and middle-income countries—but practical and ethical challenges must be overcome.
Cell-free fetal DNA-based noninvasive prenatal testing (NIPT) could significantly change the paradigm of prenatal testing and screening. Intellectual property (IP) and commercialization promise to be important components of the emerging debate about clinical implementation of these technologies. We have assembled information about types of testing, prices, turnaround times and reimbursement of recently launched commercial tests in the United States from the trade press, news articles, and scientific, legal, and business publications. We also describe the patenting and licensing landscape of technologies underlying these tests and ongoing patent litigation in the United States. Finally, we discuss how IP issues may affect clinical translation of NIPT and their potential implications for stakeholders. Fetal medicine professionals (clinicians and researchers), genetic counselors, insurers, regulators, test developers and patients may be able to use this information to make informed decisions about clinical implementation of current and emerging noninvasive prenatal tests.
There has been much investment in research on the ethical, legal and social issues (ELSI) associated with genetic and genomic research. This research should inform the development of the relevant policy. So far, much of the relevant policy - such as in the areas of patents, genetic testing and genetic discrimination - seems to be informed more by speculation of harm and anecdote than by available evidence. Although a quest for evidence cannot always be allowed to delay policy choice, it seems axiomatic to us that policy options are improved by the incorporation of evidence.
From 2006–2010, Duke University’s Center for Public Genomics prepared
eight case studies examining the effects of gene patent licensing practices on clinical access to
genetic testing for ten clinical conditions. One of these case studies focused on the successful
licensing practices employed by the University of Michigan and the Hospital for Sick Children in
Toronto for patents covering the CFTR gene and its ΔF508 mutation that
causes a majority of cystic fibrosis cases. Since the licensing of these patents has not impeded
clinical access to genetic testing, we sought to understand how this successful licensing model was
developed and whether it might be applicable to other gene patents. We interviewed four key players
who either were involved in the initial discussions regarding the structure of licensing or who have
recently managed the licenses and collected related documents.
Important features of the licensing planning process included thoughtful consideration of
potential uses of the patent; anticipation of future scientific discoveries and technological
advances; engagement of relevant stakeholders, including the Cystic Fibrosis Foundation; and using
separate licenses for in-house diagnostics versus kit manufacture. These features led to the
development of a licensing model that has not only allowed the patent holders to avoid the
controversy that has plagued other gene patents, but has also allowed research, development of new
therapeutics, and wide-spread dissemination of genetic testing for cystic fibrosis. Although this
licensing model may not be applicable to all gene patents, it serves as a model in which gene patent
licensing can successfully enable innovation, investment in therapeutics research, and protect
intellectual property while respecting the needs of patients, scientists, and public health.
Prostaglandin E2 (PGE2) plays an important role in the normal physiology of many organ systems. Increased levels of this lipid mediator are associated with many disease states, and it potently regulates inflammatory responses. Three enzymes capable of in vitro synthesis of PGE2 from the cyclooxygenase metabolite PGH2 have been described. Here, we examine the contribution of one of these enzymes to PGE2 production, mPges-2, which encodes microsomal prostaglandin synthase-2 (mPGES-2), by generating mice homozygous for the null allele of this gene. Loss of mPges-2 expression did not result in a measurable decrease in PGE2 levels in any tissue or cell type examined from healthy mice. Taken together, analysis of the mPGES-2 deficient mouse lines does not substantiate the contention that mPGES-2 is a PGE2 synthase.
Microsomal Prostaglandin E2 Synthase-2; Prostaglandin E2
Genetic testing for spinocerebellar ataxia (SCA) is used in diagnosis of rare movement disorders. Such testing generally does not affect treatment, but confirmation of mutations in a known gene can confirm diagnosis and end an often years-long quest for the cause of distressing and disabling symptoms. Through interviews and a web forum hosted by the National Ataxia Foundation, patients and health professionals related their experiences with patents’ impact on access to genetic testing for SCA. In the United States, Athena Diagnostics holds either a patent or an exclusive license to a patent in the case of 6 SCA variants (SCA1-3 & 6-8) and two other hereditary ataxias (Friedreich’s Ataxia and Early Onset Ataxia). Athena has enforced its exclusive rights to SCA-related patents by sending cease and desist letters to multiple laboratories offering genetic testing for inherited neurological conditions, including SCA. Roughly half of web forum respondents had decided not to get genetic tests. Price, coverage and reimbursement by insurers and health plans, and fear of genetic discrimination were the main reasons cited for deciding not to get tested. Price was cited as an access concern by the physicians, and as sole US provider, coverage and reimbursement depend on having payment agreements between Athena and payers. In cases where payers do not reimburse, the patient is responsible for payment, although some patients can apply to the voluntary Athena Access and Patient Protection Programs offered by the company.
Patents; Intellectual Property; Spinocerebellar Ataxia; Ataxia; Athena Diagnostics; genetic testing
Hereditary hemochromatosis (HH) is an iron metabolism disorder that leads to excess iron buildup, especially in the heart, liver, and pancreas. Mutations in the HFE gene are the single most common cause of HH, which can be treated effectively if diagnosed early. Patents cover the HFE gene, related proteins, screening methods, and testing kits. Most initial testing for HH is biochemical, but HFE DNA testing or genotyping is used to confirm a diagnosis of inherited hemochromatosis. Concerns over patents covering HFE testing emerged in 2002, when scholars argued that exclusive licensing and the patent-enabled sole provider model then in place led to high prices and limited access. Critics of the sole provider model noted that the test was available at multiple laboratories prior to the enforcement of patents. By 2007, however, Bio-Rad, Limited, acquired the key intellectual property and sub-licensed it widely. In part because of broad, non-exclusive licensing, there are now multiple providers and testing technologies, and research continues. This case study illustrates how both changes in intellectual property ownership and evolving clinical utility of HFE genetic testing in the last decade have effected the licensing of patents and availability of genetic testing.
Patents; Intellectual Property; Hemochromatosis; HFE; genetic testing
Genetic testing for heritable hearing loss involves a mix of patented and unpatented genes, mutations and testing methods. More than half of all hearing loss is linked to inherited mutations, and five genes are most commonly tested in the United States. There are no patents on three of these genes, but Athena Diagnostics holds exclusive licenses to test for a common mutation in the GJB2 gene associated with about 50% of all cases, as well as mutations in the MTRNR1 gene. This fragmented intellectual property landscape made hearing loss a useful case study for assessing whether patent rights in genetic testing can proliferate or overlap, and whether it is possible to gather the rights necessary to perform testing. Testing for hearing loss is widely available, primarily from academic medical centers. Based on literature reviews and interviews with researchers, research on the genetics of hearing loss has generally not been impeded by patents. There is no consistent evidence of a premium in testing prices attributable to patent status. Athena Diagnostics has, however, used its intellectual property to discourage other providers from offering some tests. There is no definitive answer about the suitability of current patenting and licensing of commonly tested genes because of continuing legal uncertainty about the extent of enforcement of patent rights. Clinicians have also expressed concerns that multiplex tests will be difficult to develop because of overlapping intellectual property and conflict with Athena’s sole provider business model.
Patents; Intellectual Property; Hearing Loss; Deafness; Microarray Analysis; Athena Diagnostics; genetic testing
Cystic fibrosis (CF) is one of the most commonly tested autosomal recessive disorders in the US. Clinical CF is associated with mutations in the CFTR gene, of which the most common mutation among Caucasians, ΔF508, was identified in 1989. The University of Michigan, Johns Hopkins University, and the Hospital for Sick Children, where much of the initial research occurred, hold key patents for CF genetic sequences, mutations and methods for detecting them. Several patents including the one that covers detection of the ΔF508 mutation are jointly held by the University of Michigan and the Hospital for Sick Children in Toronto, with Michigan administering patent licensing in the US. The University of Michigan broadly licenses the ΔF508 patent for genetic testing with over 60 providers of genetic testing to date. Genetic testing is now used in newborn screening, diagnosis, and reproductive decisions. Interviews with key researchers and intellectual property managers, a survey of laboratories’ prices for CF genetic testing, a review of literature on CF tests’ cost effectiveness, and a review of the developing market for CF testing provide no evidence that patents have significantly hindered access to genetic tests for CF or prevented financially cost-effective screening. Current licensing practices for cystic fibrosis (CF) genetic testing appear to facilitate both academic research and commercial testing. More than one thousand different CFTR mutations have been identified, and research continues to determine their clinical significance. Patents have been nonexclusively licensed for diagnostic use, and have been variably licensed for gene transfer and other therapeutic applications. The Cystic Fibrosis Foundation has been engaged in licensing decisions, making CF a model of collaborative and cooperative patenting and licensing practice.
Patents; Intellectual Property; Cystic Fibrosis; University of Michigan; University of Toronto; Hospital for Sick Children; CFTR
Genetic testing for Long QT syndrome (LQTS) exemplifies patenting and exclusive licensing with different outcomes at different times. Exclusive licensing from the University of Utah changed the business model from sole provider to two US providers of LQTS testing. LQTS is associated with mutations in many genes, ten of which are now tested by two competing firms in the United States, PGxHealth and GeneDx. Until 2009, PGxHealth was sole provider, based largely on exclusive rights to patents from the University of Utah and other academic institutions. University of Utah patents were initially licensed to DNA Sciences, whose patent rights were acquired by Gennaissance, and then by Clinical Data, Inc., which owns PGxHealth. In 2002, DNA Sciences “cleared the market” by sending cease and desist patent enforcement letters to university and reference laboratories offering LQTS genetic testing. There was no test on the market for a one- to two-year period. From 2005-2008, most LQTS-related patents were controlled by Clinical Data, Inc., and its subsidiary PGxHealth. BioReference Laboratories, Inc., secured countervailing exclusive patent rights starting in 2006, also from the University of Utah, and broke the PGxHealth monopoly in early 2009, creating a duopoly for genetic testing in the United States, and expanding the number of genes for which commercial testing is available from five to ten.
Patents; Intellectual Property; Long QT Syndrome; Arrhythmia; University of Utah; genetic testing
Genetic testing for Tay-Sachs and Canavan disease is particularly important for Ashkenazi Jews, as both conditions are more frequent in that population. This comparative case study was possible because of different patenting and licensing practices. The role of DNA testing differs between Tay-Sachs and Canavan diseases. The first-line screening test for Tay-Sachs remains an enzyme activity test, rather than genotyping. Genotyping is used for preimplantation diagnosis and confirmatory testing. In contrast, DNA-based testing is the basis for Canavan screening and diagnosis. The HEXA gene was cloned at the National Institutes of Health, and the gene was patented but has not been licensed. The ASPA gene was cloned and patented by Miami Childrens Hospital (MCH). MCH did not inform family members and patient groups that had contributed to the gene discovery that it was applying for a patent, and pursued restrictive licensing practices when a patent issued in 1997. This led to intense controversy, litigation, and a sealed, nonpublic 2003 settlement that apparently allowed for nonexclusive licensing. A survey of laboratories revealed a possible price premium for ASPA testing, with per-unit costs higher than for other genetic tests in the SACGHS case studies. The main conclusion from comparing genetic testing for Tay-Sachs and Canavan diseases, however, is that patenting and licensing conducted without communication with patients and advocates causes mistrust and can lead to controversy and litigation, a negative model to contrast with the positive model of patenting and licensing for genetic testing of cystic fibrosis.
Patents; Intellectual Property; Tay-Sachs Disease; Canavan Disease; Patient Advocacy; genetic testing
Genetic testing for inherited susceptibility to breast and ovarian cancer can be compared to similar testing for colorectal cancer as a “natural experiment.” Inherited susceptibility accounts for a similar fraction of both cancers and genetic testing results guide decisions about options for prophylactic surgery in both sets of conditions. One major difference is that in the United States, Myriad Genetics is the sole provider of genetic testing, because it has sole control of relevant patents for BRCA1 and BRCA2 genes whereas genetic testing for familial colorectal cancer is available from multiple laboratories. Colorectal cancer-associated genes are also patented, but they have been nonexclusively licensed. Prices for BRCA1 and 2 testing do not reflect an obvious price premium attributable to exclusive patent rights compared to colorectal cancer testing, and indeed Myriad’s per unit costs are somewhat lower for BRCA1/2 testing than testing for colorectal cancer susceptibility. Myriad has not enforced patents against basic research, and negotiated a Memorandum of Understanding with the National Cancer Institute in 1999 for institutional BRCA testing in clinical research. The main impact of patenting and licensing in BRCA compared to colorectal cancer is the business model of genetic testing, with a sole provider for BRCA and multiple laboratories for colorectal cancer genetic testing. Myriad’s sole provider model has not worked in jurisdictions outside the United States, largely because of differences in breadth of patent protection, responses of government health services, and difficulty in patent enforcement.
Patents; Intellectual Property; breast cancer; colorectal cancer colon cancer; Lynch syndrome; FAP; familial adenomatous polyposis; BRCA; APC; MSH; Myriad Genetics; genetic testing
Gene patents have generally not impeded biomedical research, but some problems that arise in genetic diagnostics can be attributed to exclusively licensed gene patents. Gene patents for therapeutics have often been litigated but have received surprisingly little public outcry. In stark contrast, genetic diagnostics have been highly controversial but rarely litigated: no case has gone to trial and there is little case law to guide policy. Most recently the Secretary's Advisory Committee for Genetics Health and Society (SACGHS) released a draft report examining how patenting and licensing affect access to clinical genetic testing in the US. The SACGHS reported that patents neither greatly hindered nor facilitated patient access to genetic testing; both the harms and the benefits of patents on genetic diagnostics have been exaggerated. Problems do occur when patents are exclusively licensed to a single provider and no alternative is available. Courts have been changing the thresholds for what can be patented, and how strongly patents can be enforced. Technologies for sequencing, genotyping and gene expression profiling promise to guide clinical decisions in managing common chronic diseases and infectious diseases, and will likely be an integral part of personalized medicine. Developing such genomic tests may require mapping a complex intellectual property landscape and cutting through thickets of patented DNA sequences and related methods. Our preliminary studies have found patent claims that, if strictly enforced, might block the use of multi-gene tests or full-genome sequence data. Yet new technologies promise to reduce the costs of complete genomic sequencing to prices that are comparable to current genetic tests for a single condition. Courts, companies, and policy makers seem unlikely to allow intellectual property to obstruct such technological advance, but prudent policy will depend on careful analysis and foresight. The SACGHS report signals that the US government is paying attention, and increases the odds that policy will foster socially beneficial uses of genetic testing while preserving intellectual property incentives and mitigating the problems that arise from legal monopolies.
Comparison of mammary tumor gene-expression profiles from thirteen murine models using microarrays and with that of human breast tumors showed that many of the defining characteristics of human subtypes were conserved among mouse models.
Although numerous mouse models of breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human phenotypes. To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors.
Unsupervised hierarchical clustering analysis showed that six models (TgWAP-Myc, TgMMTV-Neu, TgMMTV-PyMT, TgWAP-Int3, TgWAP-Tag, and TgC3(1)-Tag) yielded tumors with distinctive and homogeneous expression patterns within each strain. However, in each of four other models (TgWAP-T121, TgMMTV-Wnt1, Brca1Co/Co;TgMMTV-Cre;p53+/- and DMBA-induced), tumors with a variety of histologies and expression profiles developed. In many models, similarities to human breast tumors were recognized, including proliferation and human breast tumor subtype signatures. Significantly, tumors of several models displayed characteristics of human basal-like breast tumors, including two models with induced Brca1 deficiencies. Tumors of other murine models shared features and trended towards significance of gene enrichment with human luminal tumors; however, these murine tumors lacked expression of estrogen receptor (ER) and ER-regulated genes. TgMMTV-Neu tumors did not have a significant gene overlap with the human HER2+/ER- subtype and were more similar to human luminal tumors.
Many of the defining characteristics of human subtypes were conserved among the mouse models. Although no single mouse model recapitulated all the expression features of a given human subtype, these shared expression features provide a common framework for an improved integration of murine mammary tumor models with human breast tumors.
Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Although developmental expression patterns and functional overexpression in vitro have associated these kinases with growth suppression and differentiation, their physiological functions remain largely unknown. We therefore generated mice carrying a null mutation in iyk, the mouse homolog of Frk/rak. We report here that frk/rak−/− mice are viable, show similar growth rates to wild-type animals, and are fertile. Furthermore, a 2-year study of health and survival did not identify differences in the incidence and spectrum of spontaneous tumors or provide evidence of hyperplasias in frk/rak−/− epithelial tissues. Histological analysis of organs failed to reveal any morphological changes in epithelial tissues that normally express high levels of Frk/rak. Ultrastructural analysis of intestinal enterocytes did not identify defects in brush border morphology or structural polarization, demonstrating that Frk/rak is dispensable for intestinal cytodifferentiation. Additionally, frk/rak-null mice do not display altered sensitivity to intestinal damage induced by ionizing radiation. cDNA microarray analysis revealed an increase in c-src expression and identified subtle changes in the expression of genes regulated by thyroid hormones. Significant decreases in the circulating levels of T3 but not T4 hormone are consistent with this observation and reminiscent of euthyroid sick syndrome, a stress-associated clinical condition.