p at e n t s
Are the gene-patent storm clouds dissipating? A global snapshot Johnathon Liddicoat, Tess Whitton & Dianne Nicol
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In genetic diagnostics testing, what are the boundaries of the global patent problem, and is there a real risk that patents and licensing practices could impede access to tests?
M
uch has been written about the perceived and possible impediments posed by DNA sequence and associated method-of-use patents to the provision of genetic diagnostic testing services. These issues have recently soared into public consciousness owing to the protracted litigation concerning patents held by Myriad Genetics for genes associated with breast and ovarian cancer (BRCA1 and BRCA2) and entry into the debate of high-profile campaigners such as the actress Angelina Jolie. Surveys and case studies in the United States have provided useful empirical evidence on the negative effects of sequence and method patents and, more particularly, associated licensing practices, on the provision of genetic diagnostic services1–3. In 2010, the US Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS) completed an in-depth report on genetics diagnostic tests and patents that indicated that the true impact of DNA and method patents had not yet been fully felt. The committee noted that “a near perfect storm is developing at the confluence of clinical practice and patent law”4. One difficulty in predicting patent-based issues in the global context is that the evidence base from which to make this determination is focused largely on the situation in the United States. Surveys and interviews undertaken in other jurisdictions suggest that, so far, the global impact has been less profound5–9. A further difficulty is the lack of information on the number of relevant patents and their scope, even in the United States, where the patent landscape has been most intenJohnathon Liddicoat, Tess Whitton and Dianne Nicol are at the Centre for Law and Genetics, Faculty of Law, University of Tasmania, Hobart, Tasmania, Australia. e-mail: [email protected]
sively studied. A much-cited 2005 study by Jensen and Murray10 used bioinformatics techniques to determine the extent of patenting of the human genome by comparing gene sequences that were included in United States patents with publicly available human genome sequence information. The authors concluded: “Our results reveal that nearly 20% of human genes are explicitly claimed as US IP”10. However, closer analysis of the patent claims suggests that the Jensen-Murray results may overestimate the percentage of human genes subject to patent claims, because not all of the sequences referred to therein were explicitly claimed11–13. Further, many of those that were claimed were partial gene sequences14. Yet others have argued that, because claims to partial sequences are nonspecific, 41–100% of all human genes could be targeted if relevant patents were enforced in the United States15. Regardless, the potential for existing patents to contribute to any incipient patent storm outside the United States is largely unknown. Has the risk of a gene-patent storm dissipated? For almost two decades, Myriad enforced its patent rights related to testing for susceptibility to familial breast cancers by requiring that all testing in the United States be performed in its own laboratories2. This has limited both the options for women who want to be tested and the ability of laboratories to provide the tests. Myriad has not been the only company that has employed a business strategy that preserves exclusivity in the diagnostic testing marketplace. Others include Athena Diagnostics and PGxHealth2. The activities of this small number of companies, primarily in the United States, have triggered extensive academic commentary, law-reform inquiries and court challenges, in the United States and in other
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jurisdictions16. Myriad’s patents were challenged in the US Supreme Court on the basis that they failed to satisfy the threshold requirement of patentable subject matter. The court in Association for Molecular Pathology v. Myriad17 decided that isolated gene sequences that are identical to the naturally occurring form are not patentable subject matter. That decision has been described as a “surgical strike” on “cowboy business models”18. After the decision, Myriad initially continued to pursue US competitors for patent infringement, but these legal challenges now appear to have been settled out of court19. Whether this means that the storm clouds have now dissipated remains to be tested. The Myriad decision needs to be viewed in context. First, it relates only to isolated gene sequences that are identical to those in nature. The US Supreme Court specifically upheld the validity of claims to human-made DNA that is complementary to the messenger RNA translated from naturally occurring gene sequences. It is unclear whether other human interventions, such as the addition of methylated nucleotides, would be sufficient to cross the subject-matter threshold20. Second, there is continuing uncertainty about the patentability of methods that use gene sequences for diagnostic purposes21. In the earlier US Supreme Court case of Mayo Collaborative Services v. Prometheus Labs22, the court held that a method of comparing and analyzing rates of drug metabolism in the human body through comparison with reference data failed to satisfy the patentable subject-matter requirement on the basis that it amounted to patenting a law of nature. The Court subsequently reaffirmed Mayo in June 2014 in Alice Corp. Pty. Ltd. v. CLS Bank International23, establishing a two-step test to determine eligibility. The first question is 347
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pat e n t s whether the patent claims are directed toward patent-ineligible matter—for example, laws of nature, abstract ideas or natural phenomena. If so, the next step is to assess whether something additional is claimed to ensure that the patent does not amount to a claim on the prohibited content itself, such as a narrow application of the principle or use in a machine with a specific purpose. The implications of these decisions for diagnostic method claims are, at present, unclear24. Third, the decision in Myriad, as well as those in Mayo and Alice, is directly applicable only in the United States. The more recent decision of the Full Court of the Federal Court of Australia in D’Arcy v. Myriad Genetics25, although now on appeal to the High Court of Australia, illustrates the point that other countries are not bound to follow US law. The court in D’Arcy decided that isolated sequences claimed in the Australian patent, broadly equivalent to one of the BRCA patents in Myriad, were patentable subject matter. In Europe, Myriad’s BRCA patent portfolio was subject to a series of more narrow legal challenges relating to specific technical problems with particular patents in the early 2000s (ref. 26). Although the narrow grounds for these challenges meant that the decisions did not profoundly affect laws relating to gene patenting more generally, they “arguably kick-start[ed] the worldwide discussion of their legal and ethical validity”26. Last, Myriad and other patent holders have had limited success enforcing their patents in countries outside the United States. In Europe, for example, providers of diagnostic tests have, of late, largely been able to ignore intellectual property issues. It was reported in 2009 that there was little evidence that patents had harmed health care in Europe7. Although the authors expressed concern that the situation could change in the subsequent five years, the study has not been replicated and there have been no other reports of significant patent enforcement actions against European test providers to date. The reasons for the lower-than-expected impact of gene patents on genetic testing in Europe have not been
definitively elucidated. This may be attributable to many factors—including, on one hand, lack of interest in pursuing a licensing deal on the part of patentees, or, on the other hand, lack of knowledge, willful blindness or ignoring of patent protection on the part of the test providers5,7—in addition to the nature of the patents themselves. For these reasons, it seems premature to conclude that Myriad and other US cases have on their own brought to an end the gene-patent controversy in the global context. There was a well-reported surge in filings for patents claiming DNA sequences, methods and other DNArelated products in the 1990s (refs. 11,21,27). Analysis of patterns in filing activity in later years indicates that the surge has not continued11,21,28,29. Moreover, many of the applications filed in the 1990s were not pursued to examination, and others that were granted were allowed to lapse11,21,27,28. Other commentators predict an inevitable extinction—a “Darwinian fate”—for gene patents30. Hopkins et al. confirmed that there is a “wide divergence in numbers of granted patents between the US and other regions”28. However, the actual numbers and types of valid sequence and method patents currently in force, both in the United States and globally, are largely unknown. The difference in impact of gene patents between countries is also not yet clear30. One way of providing a more accurate picture of the impact of individual patent claims on genetic diagnostic testing is to undertake a manual claim-by-claim analysis rather than to rely on bioinformatics tools. This approach was adopted by Huys et al. for patents claiming rights linked to the 22 most commonly undertaken genetic diagnostic tests31. The researchers found that 15 of those tests had the potential to be ‘blocked’ by patents in the United States or Europe31 (Box 1). A blocking claim was classified as one that, using native laws of interpretation, would be almost impossible to circumvent if best-practice guidelines were followed in performing the required test. Of the 35 patents identified as having claims that were blocking, 24 had been granted in the
Box 1 Definitions of blocking patent, simple patent family and extended patent family ‘Blocking’ claims, and therefore blocking patents, are defined as patents with claims that have been interpreted to be almost impossible to circumvent if best-practice guidelines are followed in performing the test31. A ‘simple patent family’ consists of patents that have exactly the same priority or combination of priority documents34. An ‘extended patent family’ consists of patents that share, directly or indirectly, at least one priority document. It includes patents that have the same scope but lack a common priority document34.
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United States and 11 in Europe. Nearly half of the claims analyzed were labeled as difficult to circumvent, around one-third were easy to circumvent and 15% were labeled as almost impossible to circumvent. Method claims were generally found to be more difficult to circumvent than sequence claims. Patent-search process Scope. We mapped the global landscape for patents based on the 35 patents identified as problematic in the study by Huys et al 31. Our study diverges from that analysis in one way. As noted earlier, the authors linked these patents to 15 of the 22 most common genetic diagnostic tests. In so doing, they treated spinocerebellar ataxia types 1 and 6 as a single disease. As these diseases are linked to mutations in two different genes and have relatively distinct phenotypes, we treated them as separate diseases, bringing the total number of common genetic tests to 23 (refs. 32,33). Patent identification. Using the European and US patent numbers provided by Huys et al.31, we used two methods to examine the extent of global protection: the first using the European Patent Office (EPO) list of ‘simple’ family patents; the second using the EPO list of ‘extended’ family patents34 (Box 1). Simple patent families were used to provide a conservative estimate of whether a familial patent exists in other countries. Extended patent families were primarily used to capture all possible familial patents. The aim of this study was not to undertake a specific claim-by-claim analysis for each patent in each jurisdiction, but rather to identify general trends in global patenting and patent maintenance for families of the patents identified by Huys et al.31 as having claims that are almost impossible to circumvent using bestpractice guidelines for genetic testing. For this reason, the results presented here should not been seen as representing a freedom-tooperate analysis. Legal status. The legal status of each patent, including all applications and European designations, was initially obtained from the EPO, then cross-referenced against each country’s patent office database. Any discrepancy between the EPO and the country’s patent office was resolved in preference of the latter. The databases were accessed between 1 and 3 December 2013. Where the status could not be determined from an individual country’s patent office, either because of inaccessible patent data (e.g., Monaco Patent Office) or because the date of patent lapse was not present (e.g., Austrian Patent Office, Japan Patent Office), reliance was placed solely on information
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pat e n t s
Table 1 Number of genetic diagnostics tests with at least one potentially blocking patent per country
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Country
Applied for or designated (extended family)
Applied for or designated (simple family)
In force (extended family)
In force (simple family)
United States
15
14
13
13
Canada
12
10
9
8
Japan
13
8
9
7
UK
13
11
5
5
France
12
10
5
5
Germany
12
10
5
5
Liechtenstein
12
10
4
4
Switzerland
12
10
4
4
Luxembourg
10
9
4
4
Australia
12
8
4
2
Italy
12
10
3
3
The Netherlands
11
10
3
3
Spain
11
10
3
3
Belgium
10
9
3
3
Ireland
9
8
3
3
Austria
11
10
2
2
Denmark
11
10
2
2
Greece
9
8
2
2
Portugal
8
8
2
2
New Zealand
4
4
2
2
Sweden
11
10
1
1
Monaco
8
7
1
1
Finland
6
6
1
1
Hungary
1
1
1
1
South Korea
1
1
1
1
South Africa
1
0
1
0
China
2
2
0
0
Cyprus
2
2
0
0
Brazil
1
1
0
0
Czech Republic
1
1
0
0
Israel
1
1
0
0
Mexico
1
1
0
0
Norway
1
1
0
0
Poland
1
1
0
0
Russia
1
1
0
0
provided by the EPO. If an English language version of the website or search was not supported, we relied on translations performed by Google Chrome. Where neither the country’s patent office website nor the EPO showed the relevant information (e.g., lapse date or fee payments), we contacted the patent office directly (see Supplementary Table 1 for the location of resources used for each jurisdiction). Granted patents were recorded only if they were in force as of 3 December 2013. Applications or designations were recorded if they had been made at any time. Table 1 shows the number of genetic diagnostic tests that are exposed to simple and extended families of the patents identified by Huys et al.31 as almost impossible to circumvent for each country.
Patent applications or designations and patents currently in force were recorded for each country. Countries without relevant applications or designations were not recorded. Figure 1 shows the total number of countries that have relevant patent applications or designations and patents currently in force by disease. Variability in global strategies for patent protection Figure 1 and Supplementary Figure 1 illustrate that in most countries there is a wide divergence between the number of genetic diagnostic tests that would be affected if all applications or designations had been granted and remained on foot, and the number that could be affected by patents currently in force.
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There are many reasons for this disparity: the applications may never have been examined or may have been rejected, and the patents that were granted may have been allowed to lapse or simply expired. In general, less than half of all patent applications make it to expiry, irrespective of the nature of the underlying technology. For example, empirical data in the United States show that around 85% of patent applications are granted; of those granted, around half lapse for failure to pay maintenance fees35,36. Given the speculative nature of genetic technologies, it would not be surprising to see a similar rate of attrition. Table 1 and Figure 1 also illustrate differences between countries in the numbers of genetic diagnostic tests linked with problematic patent applications and with patents currently in force. Again, this result is not altogether unexpected. Although international agreements provide efficient means for filing and prosecuting patents in multiple countries, patentees must still nominate the countries in which they seek protection and pay filing, examination and maintenance fees in each. Moreover, though the international agreements specify basic requirements for patentable inventions, the specific details of what is and is not patentable can vary significantly between countries. Even though this may result in only small differences in the language of claims between jurisdictions, these differences may be sufficient to make it uneconomic for patent holders to maintain their patents in some jurisdictions. Thus, applicants will routinely make strategic decisions about where to file and where to request examination. As a matter of good business practice, they will continually review their patent portfolios for cost effectiveness. It has been reported that many gene patents have been abandoned in Europe and the United States21,27. Table 1 shows that abandonment is prevalent in European countries. In Austria and Denmark, for example, of the 11 genetic tests associated with relevant extended family patent applications or designations, only two currently have active extended family patents (cf US, with 13 of the 15 genetic tests associated with a patent application having an in force patent). Various strategies have been adopted for filing and maintenance of patents relevant to common genetic diagnostic tests (Fig. 1). In some instances, applications were filed in only a small number of countries (e.g., Rett syndrome, factor II thrombophilia, cystic fibrosis and myotonic dystrophy), and in others there were mass applications or designations in multiple countries but selective maintenance (e.g., for hemochromatosis, GJB2-related 349
pat e n t s 30
Granted and in effect
Designated
Applied for
25
20
15
10
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Fragile X syndrome (Gr)
Fragile X syndrome (Ap)
Charcot-Marie-Tooth type 1A (Gr)
Charcot-Marie-Tooth type 1A (Ap)
Familial adenomatous polyposis (Gr)
Rett syndrome (Gr)
Familial adenomatous polyposis (Ap)
Rett syndrome (Ap)
Factor II thrombophilia (Gr)
Cystic fibrosis (Gr)
Factor II thrombophilia (Ap)
Cystic fibrosis (Ap)
Myotonic dystrophy (Gr)
Myotonic dystrophy (AP)
GJB2-related hereditary hearing loss and deafness (Gr)
Spinocerebellar ataxia - SCA6 (Gr)
GJB2-related hereditary hearing loss and deafness (Ap)
Spinocerebellar ataxia - SCA1 (Gr)
Spinocerebellar ataxia - SCA6 (Ap)
Haemochromatosis (Gr)
Spinocerebellar ataxia - SCA1 (Ap)
Friedreich ataxia (Gr)
Haemochromatosis (Ap)
Friedreich ataxia (Ap)
Spinal musuclar atropy (Gr)
Spinal musuclar atropy (Ap)
Hereditary breast/ovarian cancer (Gr)
Hereditary breast/ovarian cancer (Ap)
Hereditary nonpolyposis colon cancer (Gr)
Factor V Leiden thrombophilia (Gr)
Hereditary nonpolyposis colon cancer (Ap)
© 2015 Nature America, Inc. All rights reserved.
0
Factor V Leiden thrombophilia (Ap)
5
Figure 1 Number of countries with at least one extended patent family application or designation, by disease. Ap, application (which also includes European patent designations); Gr, granted and in effect on 3 December 2013. Created using extended patent family data and ordered by patents in effect. Data on protection by simple patent family are presented in Supplementary Figure 1.
hearing loss and deafness and spinocerebellar ataxia). Other applicants chose to file and maintain patents in a large number of countries (especially those relating to factor V Leiden (FVL), but also for hereditary nonpolyposis colon cancer (HNPCC), hereditary breast and ovarian cancer (BRCA) and Friedreich ataxia (FRDA)). Patent term expiry, which is currently 20 years from the filing date, must also be taken into consideration when interpreting the results (although it should be noted that the rules relating to expiry changed for some countries in the mid-1990s). In the intervening period between the study by Huys et al.31 and the current study, US patent protection relating to Charcot-Marie-Tooth neuropathy type 1A expired (US 5306616), as did European patent protection relating to fragile X (EP 0580621) and familial adenomatous polyposis (EP 0569527). In the time between collection of the patent data for this study and publication, European patent protection for HNPCC (EP 0760867) and for FVL (EP 350
0690991, EP 0696325) has expired. Looking to the future, European patents for BRCA are due to expire later in 2015 (EP 0699754, 0705902, 0705903), and for FRDA in 2017 (EP 0885309). Accordingly, the patent landscape will continue to change over the next few years. A match between global patent protection and enforcement strategies? Before conducting this study, we expected that more aggressive enforcement strategies would be underpinned by greater patent protection on a global scale. To this end, we expected that the BRCA tests would be subject to the broadest global patent protection. Our results show that this expectation has played out to some extent (Fig. 1), with patent applications or designations relating to BRCA tests being filed in the second-highest number of countries (26, compared with 28 for FVL). However, the relevant BRCA patents have been maintained in only 12 (46%) of those countries. As a consequence, at the time that the data for this study were collected, the tests for FVL and HNPCC
were subject to broader global patent protection than is BRCA. Myriad may have let patent protection in some countries lapse because it was not in their interests, on the basis that “Myriad’s sole-provider model has not worked in jurisdictions outside of the United States”37. In contrast, patents relating to HNPCC tests, which were, until expiry of the European patents, subject to broader global patent protection than was BRCA, were nonexclusively licensed37. In the case of FVL, global patent protection is near the end of its life cycle and has already expired in some jurisdictions. However, at the time that data were collected for this study, it was still protected in 25 of the 28 countries in which applications were filed (89%), strongly suggesting that it had some value to the patentees. However, this test has largely gone un-noticed in commentary on business models and patents affecting diagnostic tests1,4,6. There is only one recorded instance in the United States of laboratories not supplying the FVL test because of a patent1. There is also a recorded instance of enforcement in France, where the exclusive licensee of the European patents was successful in proving infringement by a competitor producing diagnostics tests38. It has been suggested that a number of commercial kits have been made available for FVL testing without a license from the patentee or its exclusive licensee39. A recently published recommendation on best practices for testing for FVL and related diseases, which provides guidelines for in-house testing, makes no mention of concerns about patent enforcement40, further suggesting that this patent is not unduly impeding the provision of FVL tests. This is a little surprising, not only because the patent has been maintained globally, but also because FVL is one of the most common genetic disorders, with approximately 3–8% of general European and US populations heterozygous for the associated mutation41. Thus, it does not necessarily follow that maintaining patent protection globally is tied to a sole provider or aggressive enforcement business strategy. In some instances, patent protection is used to generate nonexclusive licensing fees for in-house use or provide a revenue stream through royalty payments from commercial test kits. Alternatively, claims that could otherwise be detrimental to other diagnostic providers may instead be used as part of a broader strategy to develop and commercialize further inventions, such as other biochemical tests, research tools and therapies13. Potential blocking of genetic diagnostics tests: a global problem? The United States, Canada and Japan have
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pat e n t s the highest numbers of common genetic tests susceptible to patent enforcement (Table 1). However, since the US Supreme Court decision in Myriad, the risk that genetic diagnostic test providers could face enforcement actions has diminished considerably. In Canada, the Children’s Hospital of Eastern Ontario has begun a court case challenging the validity of patents related to long QT syndrome. Once decided, this case may, like Myriad, have broader implications for enforcement of patents against providers of genetic diagnostic tests. At the other end, nine countries have no relevant extended family patents currently in force (Table 1). Of the remainder, 23 countries have relevant extended family patents associated with common genetic tests, and in 16 of these countries, three or fewer genetic tests are susceptible to potentially blocking clams. Before conducting this study, we hypothesized that more tests would be susceptible to patent enforcement in countries with higher spending on health care per capita and higher numbers of in-force patents across all technologies. The countries with the most patents in Table 1 generally conform to these expectations. However, on the basis of healthcare spending, Norway and Denmark are notable exceptions. Data from the Organization for Economic Co-operation and Development (OECD) on global health spending per capita for 2011 (at 2005 purchasing power parity rates)42, show that Norway is second on the total health spending list, after the United States, yet our study has identified no genetic diagnostic tests with potentially blocking patent claims in that country. Denmark is ninth on the list and has two. This may highlight difficulties in patent examination and/or enforcement in those jurisdictions, low levels of genetic diagnostic testing or a combination of factors. Data presented in a report by the European Union Committee of Experts on Rare Diseases provides evidence that the number of different genes for which tests are available within jurisdiction varies widely between European countries. Interestingly, there is some indication of a correlation between the number of different genetic tests and number of active patents. The report provides data from a 2011 survey, which shows that genetic testing was available for 139 genes in Denmark and 110 in Norway, compared with 1,449 in Germany and 1,129 in France43. According to 2013 World Intellectual Property Organization (WIPO) patent statistics, China currently has the third-largest number of patents in force, and South Korea, the fourth-largest44. Yet no extended patent
family members relevant to genetic diagnostic tests were identified in China and only one in South Korea. This may be explained by the fact that many of the patents for the diseases listed are relatively old, and both countries have only recently emerged as jurisdictions with large numbers of patents44. Conclusions The clearest outcome from this study is that the risk that blocking patent claims could impede access to a broad range of common genetic tests is a distinctly North American problem (with some parallels in Japan). This is not particularly surprising in light of the fact that the United States has the highest numbers of patents in force and pending applications in the world44. According to WIPO data, the United States has approximately four times as many inforce patents compared to Germany, 23 times as many as Mexico and 33 times as many as Italy. Decisions of the US Supreme Court are resolving some of the issues associated with problematic patents, but, as noted above, there are still many uncertainties. To date there has not been the same level of judicial scrutiny in Canada and Japan; as such, further investigation of the patent and genetic diagnostic testing landscapes is warranted in those jurisdictions. Our results provide evidence that the likelihood that the specific set of patents identified by Huys et al.31 could impede genetic testing on a global scale is remote, because many of those patents are not currently in force in countries other than the United States. On this basis, we argue that it would be unwise to extrapolate concerns about the overreach of gene patents and licensing practices from the United States to other jurisdictions. In context, this study puts the hype associated with DNA sequence and method patents into perspective and paints a different picture of the effect of these patents on genetic testing worldwide. This empirical evidence could assist in ensuring that reforms are targeted in the areas most in need of intervention. It could also be used as a basis for a more detailed analysis into differences in patent laws and practices between countries. Although genetic diagnostic tests for HNPCC and FVL were, before the expiry of the European patents, subject to the broadest global patent protection, their licensing and enforcement strategies have not been subject to criticism. This suggests that patentees have the option of adopting profitable business strategies that rely on patent protection but do not interfere with broad provision of tests. In context, then, it seems unlikely that DNA sequence and method patents will suffer an absolute Darwinian fate30. Indeed, innovative medical treatments such as Herceptin (trastu-
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zumab) and the human papilloma virus (HPV) vaccine are also underpinned by patent claims to uses of naturally occurring amino acids and nucleotide sequences45,46. Nevertheless, an evolution of some sort is occurring, both in the types of patent claims that are eligible and the types of business strategies that are sustainable. Sherkow and Scott47 argue that “litigation and ever-evolving technological and business landscapes are killing monopoly-priced, single-gene sequencing” epitomized in Myriad’s business model. They emphasize that sequencing technology and patents on that technology, not on genes, are driving genetic diagnostic testing businesses now47. The focus of academic and policy debate should shift to the pressing matters associated with this next wave of biotechnology patents as well as proprietary databases of genetic test information48. Note: Any Supplementary Information and Source Data files are available in the online version of the paper (doi:10.1038/nbt.3182). ACKNOWLEDGMENTS We are grateful to G. Van Overwalle, T. Bubela and S. Chandraskharan for helpful feedback on drafts of this manuscript. This project was funded by the Australian Research Council Discovery Grant DP0985077, 2009–2013 to D.N. author CONTRIBUTIONS J.L. and D.N. designed the study. J.L. and T.W. performed patent searches. T.W. and J.L. created the figures. D.N., J.L. and T.W. wrote the manuscript. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Cho, M.K. et al. J. Mol. Diagn. 5, 3–8 (2003). 2. Carbone, J. et al. Nat. Biotechnol. 28, 784–791 (2010). 3. Cook-Deegan, R., Chandrasekharan, S. & Angrist, M. Nature 458, 405–406 (2009). 4. US Secretary’s Advisory Committee on Genetics, Health and Society. Gene patents and licensing practices and their impact on patient access to genetic tests (SACGHS, Bethesda, Maryland) http://oba.od.nih.gov/SACGHS/sacghs_documents.html#GHSDOC_011 (2010). 5. Hawkins, N. Genet. Med. 13, 320–324 (2011). 6. Caulfield, T. et al. Nat. Biotechnol. 24, 1091–1094 (2006). 7. Gaisser, S. et al. Nature 458, 407–408 (2009). 8. Nicol, D. Community Genet. 8, 228–234 (2005). 9. Nicol, D. & Liddicoat, J. Aust. Health Rev. 37, 281–285 (2013). 10. Jensen, K. & Murray, F. Science 310, 239–240 (2005). 11. Schauinger, S. The human gene patent report http://hgpr. org/finalHGPR.pdf (2012). 12. Holman, C.M. 80 UMKC L. Rev. 563 (2012). http:// dx.doi.org/10.2139/ssrn.2001574 13. Holman, C.M. Nat. Biotechnol. 30, 1054–1058 (2012). 14. Pressman, L. Life Sciences Law & Industry Report 6, 329 (2012). 15. Rosenfeld, J.A. & Mason, C.E. Genome Med. 5, 27 (2013). 16. Van Zimmerman, E. et al. in Breast Cancer Gene Research and Medical Practices (eds. Gibbon, S. et al.) (2014). 17. Association for Molecular Pathology v. Myriad Genetics, Inc. 133 S Ct 3027 (2013). 18. Gold, E.R. & Cook-Deegan, R. Sci. Transl. Med. 5, 192ed9 (2013). 19. Noonan, K.E. Game over for Myriad—update. Patent
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Docs http://www.patentdocs.org/2015/02/game-overfor-myriad-update.html (16 February 2015). 20. McKernan, K.J. et al. Nat. Biotechnol. 31, 884–887 (2013). 21. Graff, G.D. et al. Nat. Biotechnol. 31, 404–410 (2013). 22. Mayo Collaborative Services v. Prometheus Laboratories Inc. 132 S Ct 1289 (2012). 23. Alice Corporation Pty Ltd v. CLS Bank International 134 S Ct 1537 (2014). 24. Haanes, E.J. & Cànaves, J.M. Nat. Biotechnol. 30, 758–760 (2012). 25. D’Arcy v. Myriad Genetics Inc. [2014] FCFCA 115. 26. Matthijs, G. et al. Nat. Biotechnol. 31, 704–710 (2013). 27. Jefferson, O.A. et al. Nat. Biotechnol. 31, 1086–1093 (2013). 28. Hopkins, M.M. et al. Nat. Biotechnol. 25, 185–187 (2007). 29. Kers, J.G. et al. Eur. J. Hum. Genet. 22, 1155–1159 (2014). 30. Huys, I. et al. Nat. Rev. Genet. 13, 441–448 (2012).
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Are the gene-patent storm clouds dissipating? A global snapshot Johnathon Liddicoat, Tess Whitton & Dianne Nicol
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In genetic diagnostics testing, what are the boundaries of the global patent problem, and is there a real risk that patents and licensing practices could impede access to tests?
M
uch has been written about the perceived and possible impediments posed by DNA sequence and associated method-of-use patents to the provision of genetic diagnostic testing services. These issues have recently soared into public consciousness owing to the protracted litigation concerning patents held by Myriad Genetics for genes associated with breast and ovarian cancer (BRCA1 and BRCA2) and entry into the debate of high-profile campaigners such as the actress Angelina Jolie. Surveys and case studies in the United States have provided useful empirical evidence on the negative effects of sequence and method patents and, more particularly, associated licensing practices, on the provision of genetic diagnostic services1–3. In 2010, the US Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS) completed an in-depth report on genetics diagnostic tests and patents that indicated that the true impact of DNA and method patents had not yet been fully felt. The committee noted that “a near perfect storm is developing at the confluence of clinical practice and patent law”4. One difficulty in predicting patent-based issues in the global context is that the evidence base from which to make this determination is focused largely on the situation in the United States. Surveys and interviews undertaken in other jurisdictions suggest that, so far, the global impact has been less profound5–9. A further difficulty is the lack of information on the number of relevant patents and their scope, even in the United States, where the patent landscape has been most intenJohnathon Liddicoat, Tess Whitton and Dianne Nicol are at the Centre for Law and Genetics, Faculty of Law, University of Tasmania, Hobart, Tasmania, Australia. e-mail: [email protected]
sively studied. A much-cited 2005 study by Jensen and Murray10 used bioinformatics techniques to determine the extent of patenting of the human genome by comparing gene sequences that were included in United States patents with publicly available human genome sequence information. The authors concluded: “Our results reveal that nearly 20% of human genes are explicitly claimed as US IP”10. However, closer analysis of the patent claims suggests that the Jensen-Murray results may overestimate the percentage of human genes subject to patent claims, because not all of the sequences referred to therein were explicitly claimed11–13. Further, many of those that were claimed were partial gene sequences14. Yet others have argued that, because claims to partial sequences are nonspecific, 41–100% of all human genes could be targeted if relevant patents were enforced in the United States15. Regardless, the potential for existing patents to contribute to any incipient patent storm outside the United States is largely unknown. Has the risk of a gene-patent storm dissipated? For almost two decades, Myriad enforced its patent rights related to testing for susceptibility to familial breast cancers by requiring that all testing in the United States be performed in its own laboratories2. This has limited both the options for women who want to be tested and the ability of laboratories to provide the tests. Myriad has not been the only company that has employed a business strategy that preserves exclusivity in the diagnostic testing marketplace. Others include Athena Diagnostics and PGxHealth2. The activities of this small number of companies, primarily in the United States, have triggered extensive academic commentary, law-reform inquiries and court challenges, in the United States and in other
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jurisdictions16. Myriad’s patents were challenged in the US Supreme Court on the basis that they failed to satisfy the threshold requirement of patentable subject matter. The court in Association for Molecular Pathology v. Myriad17 decided that isolated gene sequences that are identical to the naturally occurring form are not patentable subject matter. That decision has been described as a “surgical strike” on “cowboy business models”18. After the decision, Myriad initially continued to pursue US competitors for patent infringement, but these legal challenges now appear to have been settled out of court19. Whether this means that the storm clouds have now dissipated remains to be tested. The Myriad decision needs to be viewed in context. First, it relates only to isolated gene sequences that are identical to those in nature. The US Supreme Court specifically upheld the validity of claims to human-made DNA that is complementary to the messenger RNA translated from naturally occurring gene sequences. It is unclear whether other human interventions, such as the addition of methylated nucleotides, would be sufficient to cross the subject-matter threshold20. Second, there is continuing uncertainty about the patentability of methods that use gene sequences for diagnostic purposes21. In the earlier US Supreme Court case of Mayo Collaborative Services v. Prometheus Labs22, the court held that a method of comparing and analyzing rates of drug metabolism in the human body through comparison with reference data failed to satisfy the patentable subject-matter requirement on the basis that it amounted to patenting a law of nature. The Court subsequently reaffirmed Mayo in June 2014 in Alice Corp. Pty. Ltd. v. CLS Bank International23, establishing a two-step test to determine eligibility. The first question is 347
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pat e n t s whether the patent claims are directed toward patent-ineligible matter—for example, laws of nature, abstract ideas or natural phenomena. If so, the next step is to assess whether something additional is claimed to ensure that the patent does not amount to a claim on the prohibited content itself, such as a narrow application of the principle or use in a machine with a specific purpose. The implications of these decisions for diagnostic method claims are, at present, unclear24. Third, the decision in Myriad, as well as those in Mayo and Alice, is directly applicable only in the United States. The more recent decision of the Full Court of the Federal Court of Australia in D’Arcy v. Myriad Genetics25, although now on appeal to the High Court of Australia, illustrates the point that other countries are not bound to follow US law. The court in D’Arcy decided that isolated sequences claimed in the Australian patent, broadly equivalent to one of the BRCA patents in Myriad, were patentable subject matter. In Europe, Myriad’s BRCA patent portfolio was subject to a series of more narrow legal challenges relating to specific technical problems with particular patents in the early 2000s (ref. 26). Although the narrow grounds for these challenges meant that the decisions did not profoundly affect laws relating to gene patenting more generally, they “arguably kick-start[ed] the worldwide discussion of their legal and ethical validity”26. Last, Myriad and other patent holders have had limited success enforcing their patents in countries outside the United States. In Europe, for example, providers of diagnostic tests have, of late, largely been able to ignore intellectual property issues. It was reported in 2009 that there was little evidence that patents had harmed health care in Europe7. Although the authors expressed concern that the situation could change in the subsequent five years, the study has not been replicated and there have been no other reports of significant patent enforcement actions against European test providers to date. The reasons for the lower-than-expected impact of gene patents on genetic testing in Europe have not been
definitively elucidated. This may be attributable to many factors—including, on one hand, lack of interest in pursuing a licensing deal on the part of patentees, or, on the other hand, lack of knowledge, willful blindness or ignoring of patent protection on the part of the test providers5,7—in addition to the nature of the patents themselves. For these reasons, it seems premature to conclude that Myriad and other US cases have on their own brought to an end the gene-patent controversy in the global context. There was a well-reported surge in filings for patents claiming DNA sequences, methods and other DNArelated products in the 1990s (refs. 11,21,27). Analysis of patterns in filing activity in later years indicates that the surge has not continued11,21,28,29. Moreover, many of the applications filed in the 1990s were not pursued to examination, and others that were granted were allowed to lapse11,21,27,28. Other commentators predict an inevitable extinction—a “Darwinian fate”—for gene patents30. Hopkins et al. confirmed that there is a “wide divergence in numbers of granted patents between the US and other regions”28. However, the actual numbers and types of valid sequence and method patents currently in force, both in the United States and globally, are largely unknown. The difference in impact of gene patents between countries is also not yet clear30. One way of providing a more accurate picture of the impact of individual patent claims on genetic diagnostic testing is to undertake a manual claim-by-claim analysis rather than to rely on bioinformatics tools. This approach was adopted by Huys et al. for patents claiming rights linked to the 22 most commonly undertaken genetic diagnostic tests31. The researchers found that 15 of those tests had the potential to be ‘blocked’ by patents in the United States or Europe31 (Box 1). A blocking claim was classified as one that, using native laws of interpretation, would be almost impossible to circumvent if best-practice guidelines were followed in performing the required test. Of the 35 patents identified as having claims that were blocking, 24 had been granted in the
Box 1 Definitions of blocking patent, simple patent family and extended patent family ‘Blocking’ claims, and therefore blocking patents, are defined as patents with claims that have been interpreted to be almost impossible to circumvent if best-practice guidelines are followed in performing the test31. A ‘simple patent family’ consists of patents that have exactly the same priority or combination of priority documents34. An ‘extended patent family’ consists of patents that share, directly or indirectly, at least one priority document. It includes patents that have the same scope but lack a common priority document34.
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United States and 11 in Europe. Nearly half of the claims analyzed were labeled as difficult to circumvent, around one-third were easy to circumvent and 15% were labeled as almost impossible to circumvent. Method claims were generally found to be more difficult to circumvent than sequence claims. Patent-search process Scope. We mapped the global landscape for patents based on the 35 patents identified as problematic in the study by Huys et al 31. Our study diverges from that analysis in one way. As noted earlier, the authors linked these patents to 15 of the 22 most common genetic diagnostic tests. In so doing, they treated spinocerebellar ataxia types 1 and 6 as a single disease. As these diseases are linked to mutations in two different genes and have relatively distinct phenotypes, we treated them as separate diseases, bringing the total number of common genetic tests to 23 (refs. 32,33). Patent identification. Using the European and US patent numbers provided by Huys et al.31, we used two methods to examine the extent of global protection: the first using the European Patent Office (EPO) list of ‘simple’ family patents; the second using the EPO list of ‘extended’ family patents34 (Box 1). Simple patent families were used to provide a conservative estimate of whether a familial patent exists in other countries. Extended patent families were primarily used to capture all possible familial patents. The aim of this study was not to undertake a specific claim-by-claim analysis for each patent in each jurisdiction, but rather to identify general trends in global patenting and patent maintenance for families of the patents identified by Huys et al.31 as having claims that are almost impossible to circumvent using bestpractice guidelines for genetic testing. For this reason, the results presented here should not been seen as representing a freedom-tooperate analysis. Legal status. The legal status of each patent, including all applications and European designations, was initially obtained from the EPO, then cross-referenced against each country’s patent office database. Any discrepancy between the EPO and the country’s patent office was resolved in preference of the latter. The databases were accessed between 1 and 3 December 2013. Where the status could not be determined from an individual country’s patent office, either because of inaccessible patent data (e.g., Monaco Patent Office) or because the date of patent lapse was not present (e.g., Austrian Patent Office, Japan Patent Office), reliance was placed solely on information
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pat e n t s
Table 1 Number of genetic diagnostics tests with at least one potentially blocking patent per country
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Country
Applied for or designated (extended family)
Applied for or designated (simple family)
In force (extended family)
In force (simple family)
United States
15
14
13
13
Canada
12
10
9
8
Japan
13
8
9
7
UK
13
11
5
5
France
12
10
5
5
Germany
12
10
5
5
Liechtenstein
12
10
4
4
Switzerland
12
10
4
4
Luxembourg
10
9
4
4
Australia
12
8
4
2
Italy
12
10
3
3
The Netherlands
11
10
3
3
Spain
11
10
3
3
Belgium
10
9
3
3
Ireland
9
8
3
3
Austria
11
10
2
2
Denmark
11
10
2
2
Greece
9
8
2
2
Portugal
8
8
2
2
New Zealand
4
4
2
2
Sweden
11
10
1
1
Monaco
8
7
1
1
Finland
6
6
1
1
Hungary
1
1
1
1
South Korea
1
1
1
1
South Africa
1
0
1
0
China
2
2
0
0
Cyprus
2
2
0
0
Brazil
1
1
0
0
Czech Republic
1
1
0
0
Israel
1
1
0
0
Mexico
1
1
0
0
Norway
1
1
0
0
Poland
1
1
0
0
Russia
1
1
0
0
provided by the EPO. If an English language version of the website or search was not supported, we relied on translations performed by Google Chrome. Where neither the country’s patent office website nor the EPO showed the relevant information (e.g., lapse date or fee payments), we contacted the patent office directly (see Supplementary Table 1 for the location of resources used for each jurisdiction). Granted patents were recorded only if they were in force as of 3 December 2013. Applications or designations were recorded if they had been made at any time. Table 1 shows the number of genetic diagnostic tests that are exposed to simple and extended families of the patents identified by Huys et al.31 as almost impossible to circumvent for each country.
Patent applications or designations and patents currently in force were recorded for each country. Countries without relevant applications or designations were not recorded. Figure 1 shows the total number of countries that have relevant patent applications or designations and patents currently in force by disease. Variability in global strategies for patent protection Figure 1 and Supplementary Figure 1 illustrate that in most countries there is a wide divergence between the number of genetic diagnostic tests that would be affected if all applications or designations had been granted and remained on foot, and the number that could be affected by patents currently in force.
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There are many reasons for this disparity: the applications may never have been examined or may have been rejected, and the patents that were granted may have been allowed to lapse or simply expired. In general, less than half of all patent applications make it to expiry, irrespective of the nature of the underlying technology. For example, empirical data in the United States show that around 85% of patent applications are granted; of those granted, around half lapse for failure to pay maintenance fees35,36. Given the speculative nature of genetic technologies, it would not be surprising to see a similar rate of attrition. Table 1 and Figure 1 also illustrate differences between countries in the numbers of genetic diagnostic tests linked with problematic patent applications and with patents currently in force. Again, this result is not altogether unexpected. Although international agreements provide efficient means for filing and prosecuting patents in multiple countries, patentees must still nominate the countries in which they seek protection and pay filing, examination and maintenance fees in each. Moreover, though the international agreements specify basic requirements for patentable inventions, the specific details of what is and is not patentable can vary significantly between countries. Even though this may result in only small differences in the language of claims between jurisdictions, these differences may be sufficient to make it uneconomic for patent holders to maintain their patents in some jurisdictions. Thus, applicants will routinely make strategic decisions about where to file and where to request examination. As a matter of good business practice, they will continually review their patent portfolios for cost effectiveness. It has been reported that many gene patents have been abandoned in Europe and the United States21,27. Table 1 shows that abandonment is prevalent in European countries. In Austria and Denmark, for example, of the 11 genetic tests associated with relevant extended family patent applications or designations, only two currently have active extended family patents (cf US, with 13 of the 15 genetic tests associated with a patent application having an in force patent). Various strategies have been adopted for filing and maintenance of patents relevant to common genetic diagnostic tests (Fig. 1). In some instances, applications were filed in only a small number of countries (e.g., Rett syndrome, factor II thrombophilia, cystic fibrosis and myotonic dystrophy), and in others there were mass applications or designations in multiple countries but selective maintenance (e.g., for hemochromatosis, GJB2-related 349
pat e n t s 30
Granted and in effect
Designated
Applied for
25
20
15
10
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Fragile X syndrome (Gr)
Fragile X syndrome (Ap)
Charcot-Marie-Tooth type 1A (Gr)
Charcot-Marie-Tooth type 1A (Ap)
Familial adenomatous polyposis (Gr)
Rett syndrome (Gr)
Familial adenomatous polyposis (Ap)
Rett syndrome (Ap)
Factor II thrombophilia (Gr)
Cystic fibrosis (Gr)
Factor II thrombophilia (Ap)
Cystic fibrosis (Ap)
Myotonic dystrophy (Gr)
Myotonic dystrophy (AP)
GJB2-related hereditary hearing loss and deafness (Gr)
Spinocerebellar ataxia - SCA6 (Gr)
GJB2-related hereditary hearing loss and deafness (Ap)
Spinocerebellar ataxia - SCA1 (Gr)
Spinocerebellar ataxia - SCA6 (Ap)
Haemochromatosis (Gr)
Spinocerebellar ataxia - SCA1 (Ap)
Friedreich ataxia (Gr)
Haemochromatosis (Ap)
Friedreich ataxia (Ap)
Spinal musuclar atropy (Gr)
Spinal musuclar atropy (Ap)
Hereditary breast/ovarian cancer (Gr)
Hereditary breast/ovarian cancer (Ap)
Hereditary nonpolyposis colon cancer (Gr)
Factor V Leiden thrombophilia (Gr)
Hereditary nonpolyposis colon cancer (Ap)
© 2015 Nature America, Inc. All rights reserved.
0
Factor V Leiden thrombophilia (Ap)
5
Figure 1 Number of countries with at least one extended patent family application or designation, by disease. Ap, application (which also includes European patent designations); Gr, granted and in effect on 3 December 2013. Created using extended patent family data and ordered by patents in effect. Data on protection by simple patent family are presented in Supplementary Figure 1.
hearing loss and deafness and spinocerebellar ataxia). Other applicants chose to file and maintain patents in a large number of countries (especially those relating to factor V Leiden (FVL), but also for hereditary nonpolyposis colon cancer (HNPCC), hereditary breast and ovarian cancer (BRCA) and Friedreich ataxia (FRDA)). Patent term expiry, which is currently 20 years from the filing date, must also be taken into consideration when interpreting the results (although it should be noted that the rules relating to expiry changed for some countries in the mid-1990s). In the intervening period between the study by Huys et al.31 and the current study, US patent protection relating to Charcot-Marie-Tooth neuropathy type 1A expired (US 5306616), as did European patent protection relating to fragile X (EP 0580621) and familial adenomatous polyposis (EP 0569527). In the time between collection of the patent data for this study and publication, European patent protection for HNPCC (EP 0760867) and for FVL (EP 350
0690991, EP 0696325) has expired. Looking to the future, European patents for BRCA are due to expire later in 2015 (EP 0699754, 0705902, 0705903), and for FRDA in 2017 (EP 0885309). Accordingly, the patent landscape will continue to change over the next few years. A match between global patent protection and enforcement strategies? Before conducting this study, we expected that more aggressive enforcement strategies would be underpinned by greater patent protection on a global scale. To this end, we expected that the BRCA tests would be subject to the broadest global patent protection. Our results show that this expectation has played out to some extent (Fig. 1), with patent applications or designations relating to BRCA tests being filed in the second-highest number of countries (26, compared with 28 for FVL). However, the relevant BRCA patents have been maintained in only 12 (46%) of those countries. As a consequence, at the time that the data for this study were collected, the tests for FVL and HNPCC
were subject to broader global patent protection than is BRCA. Myriad may have let patent protection in some countries lapse because it was not in their interests, on the basis that “Myriad’s sole-provider model has not worked in jurisdictions outside of the United States”37. In contrast, patents relating to HNPCC tests, which were, until expiry of the European patents, subject to broader global patent protection than was BRCA, were nonexclusively licensed37. In the case of FVL, global patent protection is near the end of its life cycle and has already expired in some jurisdictions. However, at the time that data were collected for this study, it was still protected in 25 of the 28 countries in which applications were filed (89%), strongly suggesting that it had some value to the patentees. However, this test has largely gone un-noticed in commentary on business models and patents affecting diagnostic tests1,4,6. There is only one recorded instance in the United States of laboratories not supplying the FVL test because of a patent1. There is also a recorded instance of enforcement in France, where the exclusive licensee of the European patents was successful in proving infringement by a competitor producing diagnostics tests38. It has been suggested that a number of commercial kits have been made available for FVL testing without a license from the patentee or its exclusive licensee39. A recently published recommendation on best practices for testing for FVL and related diseases, which provides guidelines for in-house testing, makes no mention of concerns about patent enforcement40, further suggesting that this patent is not unduly impeding the provision of FVL tests. This is a little surprising, not only because the patent has been maintained globally, but also because FVL is one of the most common genetic disorders, with approximately 3–8% of general European and US populations heterozygous for the associated mutation41. Thus, it does not necessarily follow that maintaining patent protection globally is tied to a sole provider or aggressive enforcement business strategy. In some instances, patent protection is used to generate nonexclusive licensing fees for in-house use or provide a revenue stream through royalty payments from commercial test kits. Alternatively, claims that could otherwise be detrimental to other diagnostic providers may instead be used as part of a broader strategy to develop and commercialize further inventions, such as other biochemical tests, research tools and therapies13. Potential blocking of genetic diagnostics tests: a global problem? The United States, Canada and Japan have
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pat e n t s the highest numbers of common genetic tests susceptible to patent enforcement (Table 1). However, since the US Supreme Court decision in Myriad, the risk that genetic diagnostic test providers could face enforcement actions has diminished considerably. In Canada, the Children’s Hospital of Eastern Ontario has begun a court case challenging the validity of patents related to long QT syndrome. Once decided, this case may, like Myriad, have broader implications for enforcement of patents against providers of genetic diagnostic tests. At the other end, nine countries have no relevant extended family patents currently in force (Table 1). Of the remainder, 23 countries have relevant extended family patents associated with common genetic tests, and in 16 of these countries, three or fewer genetic tests are susceptible to potentially blocking clams. Before conducting this study, we hypothesized that more tests would be susceptible to patent enforcement in countries with higher spending on health care per capita and higher numbers of in-force patents across all technologies. The countries with the most patents in Table 1 generally conform to these expectations. However, on the basis of healthcare spending, Norway and Denmark are notable exceptions. Data from the Organization for Economic Co-operation and Development (OECD) on global health spending per capita for 2011 (at 2005 purchasing power parity rates)42, show that Norway is second on the total health spending list, after the United States, yet our study has identified no genetic diagnostic tests with potentially blocking patent claims in that country. Denmark is ninth on the list and has two. This may highlight difficulties in patent examination and/or enforcement in those jurisdictions, low levels of genetic diagnostic testing or a combination of factors. Data presented in a report by the European Union Committee of Experts on Rare Diseases provides evidence that the number of different genes for which tests are available within jurisdiction varies widely between European countries. Interestingly, there is some indication of a correlation between the number of different genetic tests and number of active patents. The report provides data from a 2011 survey, which shows that genetic testing was available for 139 genes in Denmark and 110 in Norway, compared with 1,449 in Germany and 1,129 in France43. According to 2013 World Intellectual Property Organization (WIPO) patent statistics, China currently has the third-largest number of patents in force, and South Korea, the fourth-largest44. Yet no extended patent
family members relevant to genetic diagnostic tests were identified in China and only one in South Korea. This may be explained by the fact that many of the patents for the diseases listed are relatively old, and both countries have only recently emerged as jurisdictions with large numbers of patents44. Conclusions The clearest outcome from this study is that the risk that blocking patent claims could impede access to a broad range of common genetic tests is a distinctly North American problem (with some parallels in Japan). This is not particularly surprising in light of the fact that the United States has the highest numbers of patents in force and pending applications in the world44. According to WIPO data, the United States has approximately four times as many inforce patents compared to Germany, 23 times as many as Mexico and 33 times as many as Italy. Decisions of the US Supreme Court are resolving some of the issues associated with problematic patents, but, as noted above, there are still many uncertainties. To date there has not been the same level of judicial scrutiny in Canada and Japan; as such, further investigation of the patent and genetic diagnostic testing landscapes is warranted in those jurisdictions. Our results provide evidence that the likelihood that the specific set of patents identified by Huys et al.31 could impede genetic testing on a global scale is remote, because many of those patents are not currently in force in countries other than the United States. On this basis, we argue that it would be unwise to extrapolate concerns about the overreach of gene patents and licensing practices from the United States to other jurisdictions. In context, this study puts the hype associated with DNA sequence and method patents into perspective and paints a different picture of the effect of these patents on genetic testing worldwide. This empirical evidence could assist in ensuring that reforms are targeted in the areas most in need of intervention. It could also be used as a basis for a more detailed analysis into differences in patent laws and practices between countries. Although genetic diagnostic tests for HNPCC and FVL were, before the expiry of the European patents, subject to the broadest global patent protection, their licensing and enforcement strategies have not been subject to criticism. This suggests that patentees have the option of adopting profitable business strategies that rely on patent protection but do not interfere with broad provision of tests. In context, then, it seems unlikely that DNA sequence and method patents will suffer an absolute Darwinian fate30. Indeed, innovative medical treatments such as Herceptin (trastu-
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zumab) and the human papilloma virus (HPV) vaccine are also underpinned by patent claims to uses of naturally occurring amino acids and nucleotide sequences45,46. Nevertheless, an evolution of some sort is occurring, both in the types of patent claims that are eligible and the types of business strategies that are sustainable. Sherkow and Scott47 argue that “litigation and ever-evolving technological and business landscapes are killing monopoly-priced, single-gene sequencing” epitomized in Myriad’s business model. They emphasize that sequencing technology and patents on that technology, not on genes, are driving genetic diagnostic testing businesses now47. The focus of academic and policy debate should shift to the pressing matters associated with this next wave of biotechnology patents as well as proprietary databases of genetic test information48. Note: Any Supplementary Information and Source Data files are available in the online version of the paper (doi:10.1038/nbt.3182). ACKNOWLEDGMENTS We are grateful to G. Van Overwalle, T. Bubela and S. Chandraskharan for helpful feedback on drafts of this manuscript. This project was funded by the Australian Research Council Discovery Grant DP0985077, 2009–2013 to D.N. author CONTRIBUTIONS J.L. and D.N. designed the study. J.L. and T.W. performed patent searches. T.W. and J.L. created the figures. D.N., J.L. and T.W. wrote the manuscript. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Cho, M.K. et al. J. Mol. Diagn. 5, 3–8 (2003). 2. Carbone, J. et al. Nat. Biotechnol. 28, 784–791 (2010). 3. Cook-Deegan, R., Chandrasekharan, S. & Angrist, M. Nature 458, 405–406 (2009). 4. US Secretary’s Advisory Committee on Genetics, Health and Society. Gene patents and licensing practices and their impact on patient access to genetic tests (SACGHS, Bethesda, Maryland) http://oba.od.nih.gov/SACGHS/sacghs_documents.html#GHSDOC_011 (2010). 5. Hawkins, N. Genet. Med. 13, 320–324 (2011). 6. Caulfield, T. et al. Nat. Biotechnol. 24, 1091–1094 (2006). 7. Gaisser, S. et al. Nature 458, 407–408 (2009). 8. Nicol, D. Community Genet. 8, 228–234 (2005). 9. Nicol, D. & Liddicoat, J. Aust. Health Rev. 37, 281–285 (2013). 10. Jensen, K. & Murray, F. Science 310, 239–240 (2005). 11. Schauinger, S. The human gene patent report http://hgpr. org/finalHGPR.pdf (2012). 12. Holman, C.M. 80 UMKC L. Rev. 563 (2012). http:// dx.doi.org/10.2139/ssrn.2001574 13. Holman, C.M. Nat. Biotechnol. 30, 1054–1058 (2012). 14. Pressman, L. Life Sciences Law & Industry Report 6, 329 (2012). 15. Rosenfeld, J.A. & Mason, C.E. Genome Med. 5, 27 (2013). 16. Van Zimmerman, E. et al. in Breast Cancer Gene Research and Medical Practices (eds. Gibbon, S. et al.) (2014). 17. Association for Molecular Pathology v. Myriad Genetics, Inc. 133 S Ct 3027 (2013). 18. Gold, E.R. & Cook-Deegan, R. Sci. Transl. Med. 5, 192ed9 (2013). 19. Noonan, K.E. Game over for Myriad—update. Patent
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