Policy ForumIntellectual Property

Intellectual Property Landscape of the Human Genome

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Science  14 Oct 2005:
Vol. 310, Issue 5746, pp. 239-240
DOI: 10.1126/science.1120014

Gene patents [HN1] are the subject of considerable debate and yet, like the term “gene” itself, the definition of what constitutes a gene patent is fuzzy (1). Nonetheless, gene patents that seem to cause the most controversy are those claiming human protein-encoding nucleotide sequences [HN2]. This category is the subject of our analysis of the patent landscape of the human genome (2).

Critics describe the growth in gene sequence patents as an intellectual property (IP) “land grab” over a finite number of human genes (3, 4). They suggest that overly broad patents might block follow-on research (5). Alternatively, gene IP rights may become highly fragmented and cause an anticommons effect, imposing high costs on future innovators and underuse of genomic resources (6). Both situations, critics argue, would increase the costs of genetic diagnostics, slow the development of new medicines, stifle academic research, and discourage investment in downstream R&D (7-11).

In contrast, the classic argument in support of gene patenting is that strong IP protection provides incentives crucial to downstream investment (12, 13) and the disclosure of inventions. Patents are also regarded as the cornerstone of vibrant markets for ideas (14) and central to the biotech boom of the 1980s and 1990s (15) [HN3].

Policy-makers are hampered by the lack of empirical data on the extent of gene patenting. Most analyses have relied on anecdotal evidence (11, 16-18) and empirical analyses have been hindered by (i) limited (and poorly defined) coverage of DNA sequence patents (17, 19); (ii) difficulty separating patents that claim gene sequences per se from those merely disclosing DNA sequences (20-22); and (iii) distinguishing patents on the human genome from those on other species (23) [HN4].

Our detailed map was developed using bioinformatics methods to compare nucleotide sequences claimed in U.S. patents to the human genome. Specifically, this map is based on a BLAST [HN5] (24) homology search linking nucleotide sequences disclosed and claimed in granted U.S. utility patents to the set of protein-encoding messenger RNA transcripts contained in the National Center for Biotechnology Information (NCBI) RefSeq (25) and Gene (26) databases [HN6]. This method allows us to map gene-oriented IP rights to specific physical loci on the human genome (27) (see figure, right). Our approach is highly specific in its identification of patents that actually claim human nucleotide sequences. However, by limiting the search to patents using the canonical “SEQ ID NO” claim language we do not consider claims on genes defined through amino acid sequences. (See table S1 for a sensitivity analysis.)

Physical mapping of patent activity on chromosome 20, divided into 300-kb segments.

Each horizontal bar represents a unique patent claiming a gene sequence located in that region. Orange represents the number of unique patent families in a region (28). Labels show the loci of highly patented genes (see table S1).

Our results reveal that nearly 20% of human genes are explicitly claimed as U.S. IP. This represents 4382 of the 23,688 of genes in the NCBI's gene database at the time of writing (see figure, right). These genes are claimed in 4270 patents within 3050 patent families (28). Although this number is low compared with prior reports, a distinction should be made between sequences that are explicitly claimed and those that are merely disclosed, which outnumber claimed sequences roughly 10:1. The 4270 patents are owned by 1156 different assignees (with no adjustments for mergers and acquisition activity, subsidiaries, or spelling variations). Roughly 63% are assigned to private firms (see figure, above). Of the top ten gene patent assignees, nine are U.S.-based, including the University of California, Isis Pharmaceuticals, the former SmithKline Beecham, and Human Genome Sciences. The top patent assignee is Incyte Pharmaceuticals/Incyte Genomics, whose IP rights cover 2000 human genes, mainly for use as probes on DNA microarrays. [HN7]

Although large expanses of the genome are unpatented, some genes have up to 20 patents asserting rights to various gene uses and manifestations including diagnostic uses, single nucleotide polymorphisms (SNPs), cell lines, and constructs containing the gene. The distribution of gene patents was nonuniform (see figure, page 240, top right): Specific regions of the genome are “hot spots” of heavy patent activity, usually with a one-gene-many-patents scenario (see figure, below). Although less common, there were cases in which a single patent claims many genes, typically as complementary DNA probes used on a microarray (see figure, p. 240, bottom).

BMP7, an osteogenic factor, and CDKN2A, a tumor suppressor gene, [HN8] were the most highly patented genes in the genome [their sequences were each claimed in 20 patents (table S2)]. The patents on CDKN2A are distributed between nine different assignees and, collectively, claim all three splice variants of the gene. Nearly all of these patents are directed toward diagnostic applications. In contrast, the patents on BMP7 are for the use of BMP7 proteins in implants to stimulate bone growth. However, a number are directed towards more speculative utilities, such as drug-screening probes, which suggests a strategy of “science-based” rather than “disease-based” patenting.

Unsurprisingly, other heavily patented genes tended to have relevance to human health and diseases: e.g., BRCA1 (breast cancer), PIK3R5 (diabetes), and LEPR (obesity) [HN9]. Of the 291 cancer genes reviewed by Futreal et. al. [HN10] (29), 131 are patented—significantly more than expected for a random sample of genes (P = 1.2−32 based on binomial distribution). Moreover, these genes contain a higher number of patents per gene than expected by chance (P = 9.4−11 based on a chi-squared test) (30).

Patent and gene ownership characteristics.

(A) and (B) Distribution of gene patent assignees “public” includes governments, schools, universities, research institutions, and hospitals. (A) Ownership breakdown for the 4270 human gene patents. Fractional ownership is based on the number of assignees on a single patent or the number of patents on a gene. (B) “Ownership” breakdown of the genes in the human genome. (C) The fragmentation of gene ownership by the Herfindahl index, rounded to the nearest 1000. (31). (The 3002 genes with an index of 10,000 are not shown; those for 8000 to 9000 would not be visible on the graph.) The assignee names were used as listed on the patents by the European Patent Office. As such, the Herfindahl indices are likely to overestimate the “true” fragmentation because they do not reflect assignee name changes, mergers, acquisitions, splits, partnerships, or other events that usually lead to a consolidation of IP rights.

Of the 4000+ patented genes, at least 3000 have only a single IP rights holder. For the remainder, we examined whether IP ownership was fragmented by constructing a measure based on the Herfindahl index [HN11] (31) (see figure, top right; part C). The two genes with the most fragmented ownership were PSEN2 [HN12], the amyloid precursor protein (8 assignees for 9 patents), and BRCA1, the early onset breast cancer gene (12 assignees for 14 patents). Such fragmentation raises the possibility that innovators may incur considerable costs securing access to genes via structuring complex licensing agreements.

Global characteristics of the patent map.

(Left) Distribution of genes by the number of times they are patented. (Right) Distribution of patents by the number of unique genes they claim.

Our analysis suggests a number of avenues for further research: It would be valuable to examine whether current practice in patent examination has allowed multiple conflicting patents on the same gene. In addition, genes with multiple patents and IP owners provide a valuable context in which to explore the variety of arrangements used to facilitate or block access to gene-based research and the impact of these arrangements on future innovators. Finally, whereas our study includes only protein-coding genes, future studies should characterize the nature and extent of the rapidly growing IP surrounding non-protein coding components of the human genome, such as microRNAs, ribozymes, and cis-regulatory elements.

Supporting Online Material www.sciencemag.org/cgi/content/full/310/5746/239/DC1

HyperNotes Related Resources on the World Wide Web

General Hypernotes

Web Collections, References, and Resource Lists

The Google Directory provides links to Internet resources on intellectual property.

Academic Info provides links to Internet resources on intellectual property.

T. G. Field, Franklin Pierce Law Center, Concord, NH, offers a U.S. intellectual property resource page. A section on intellectual property and health is included.

The ExPASy Life Sciences Directory is provided by the Swiss Institute of Bioinformatics.

Links related to the human genome and other scientific resources are provided by Science's Functional Genomics Web site.

GeneCards, provided by the Weizmann Institute of Science in association with XenneX, is a database of human genes, their products, and their involvement in diseases, with links provided to other genome databases and resources.

The DNA Patent Database, maintained at the Kennedy Institute of Ethics, Georgetown University, Washington, DC, is a searchable collection of U.S. DNA-based patents and patent applications.

Online Texts and Lecture Notes

The Human Genome is a presentation by the Wellcome Trust.

The National Center for Biotechnology Information (NCBI), a resource for molecular biology information from the U.S. National Library of Medicine and the National Institutes of Health, offers a science primer and an overview of human genome resources.

The NCBI's Online Mendelian Inheritance in Man (OMIM) is a reference source on human genes and genetic disorders.

DNAPatent.com offers introductions to patent law for non-lawyers and genetic engineering for non-scientists.

The United States Patent and Trademark Office (USPTO) offers a resource page on patents.

BitLaw is a resource on technology law provided by Beck & Tysver, P.L.L.C.

The World Intellectual Property Organization of the United Nations provides an introduction to intellectual property.

The Biotechnology Information Organization offers a primer on genome and genetic research, patent protection, and 21st century medicine.

The National Human Genome Research Institute (NHGRI) offers a resource page on commercialization and patenting. A presentation about the Human Genome Project and lecture notes (in PDF format) for a course titled “Current topics in genome analysis 2005” are provided.

The Institute on Biotechnology and the Human Future maintains a resource page on gene patents.

The Science, Technology and Innovation Program, Harvard University, provides links to Internet resources and background papers on biotechnology and intellectual property rights.

D. Popp, Department of Public Administration, Syracuse University, provides lecture notes for a course on the economics of science and technology.

K. A. Marrs, Department of Biology, Indiana University-Purdue University Indianapolis, offers resources for a course on biotechnology.

General Reports and Articles

A Patent System for the 21st Century is a 2004 report available from the National Academies Press. An appendix titled “A patent primer” is included.

W. W. Fisher, Harvard Law School, makes available an essay titled “Theories of intellectual property.”

The Nuffield Council on Bioethics makes available in PDF format a 2002 discussion paper titled “The ethics of patenting DNA” (8).

The Australia Law Reform Commission makes available a 2003 issue paper titled “Gene patenting and human health,” as well as the 2004 final report titled “Genes and ingenuity.”

The 11 March 2005 issue of Science had a Policy Forum by J. Paradise, L. Andrews, and T. Holbrook titled “Patents on human genes: An analysis of scope and claims.”

J. P. Walsh, Department of Sociology, University of Illinois at Chicago, makes available in PDF format a 2003 book chapter by J. P. Walsh, W. M. Cohen, and A. Arora titled “Patenting and licensing of research tools and biomedical innovation.”

Darby & Darby makes available a March 2001 article by P. Fehlner titled “A new ‘biohazard’ for patent applicants: Broad biotechnology patent claims.”

S. Scotchmer, Economics Department, University of California, Berkeley, makes available in PDF format a 1991 article titled “Standing on the shoulders of giants: Cumulative research and the patent law” (5) and other publications on intellectual property.

Numbered Hypernotes

1. Gene patents. Wikipedia has articles on patents and genes. Cornell University Law School's Legal Information Institute provides an introduction to patent law. The Human Genome Project Information Web site offers a resource page on genetics and patenting. The American Medical Association offers a resource page on gene patenting; a link to the 2001 USPTO gene patent guidelines (7) is provided. AG BioTech InfoNet makes available a September 2000 Nature Biotechnology article by J. Grisham titled “New rules for gene patents.” The online Duke Law & Technology Review makes available a 28 February 2001 article titled “The fate of gene patents under the new utility guidelines.” The Bio-IT World Web site makes available a November 2002 special feature on gene patenting. The April 2002 issue of Bryn Mawr S&T had an article by J. A. Di Grazio titled “Patenting human genes.” The USPTO's Manual of Patent Examining Procedure includes a biotechnology section.

2. Nucleotide and nucleotide sequence are defined in a presentation on nucleic acids made available by Geneticengineering.org. Genome News Network provides introductions to genes, DNA and sequencing. S. M. Carr, Department of Biology, Memorial University of Newfoundland, provides an illustration of DNA nucleotides for a course on the principles of genetics. U. Melcher's Molecular Genetics includes a section on nucleotide sequencing.

3. Gene patenting pros and cons. The Stakeholder Dialogue Process on the Issues of Intellectual Property Rights in Biotechnology Web site, maintained by the Wissenschaftszentrum Berlin für Sozialforschung, makes available a working group report on the argumentation regarding patents on genes. The 1 May 1998 issue of Science had a Review by M. A. Heller and R. S. Eisenberg titled “Can patents deter innovation? The anticommons in biomedical research” (6) and a Policy commentary by J. J. Doll titled “The patenting of DNA” (13); comments are available on the Web. Law.com offers a Gene Patent Debate: “Why we hate gene patents” by B. A. Caulfield and “Why we need gene patents” by L. Bendekgey and D. H. Cox. The Bio-IT World Web site makes available a November 2002 article by S. Meyer titled “Are gene patents in the public interest?” The Guardian makes available a 15 November 2000 article by J. Meeks titled “The race to buy life.” The October 2002 issue of Nature Reviews Genetics had an article by L. B. Andrews titled “Genes and patent policy: Rethinking intellectual property rights” (10). The December 2002 issue of Nature Biotechnology had an article by S. M. Thomas, M. M. Hopkins, and M. Brady titled “Shares in the human genome—The future of patenting DNA” (11). S. Stern, Kellogg School of Management, Northwestern University, makes available in PDF format a 2000 article by J. S. Cans and S. Stern titled “Incumbency and R&D incentives: Licensing the gale of creative destruction” (14). The Institute on Biotechnology and the Human Future maintains a collection of links to organizational position statements on gene patenting.

4. Difficulties with gene patenting data. The 14 February 2003 issue of Science had a Policy Forum by J. P. Walsh, A. Arora, and W. M. Cohen titled “Working through the patent problem” (18). The July 2003 issue of Nature Biotechnology had an article by M. Stott and J. Valentine titled “Impact of gene patenting on R&D and commerce” (17). The February 2004 issue of Nature Biotechnology had an article by G. Dufresne and M. Duval titled “Genetic sequences: How are they patented?” (20). The December 2002 issue of Nature Biotechnology had an article by G. Dufresne et al. titled “Patent searches for genetic sequences: how to retrieve relevant records from patented sequence databases” (23).

5. BLAST (Basic Local Alignment Search Tool). NCBI provides a resource page on BLAST; an overview is available. The NCBI Handbook has a section on BLAST.

6. NCBI RefSeq and Gene databases. The NCBI's Reference Sequence (RefSeq) collection aims to provide a comprehensive, integrated, non-redundant set of sequences, including genomic DNA, transcript (RNA), and protein products, for major research organisms. Entrez Gene is a searchable database of genes, from RefSeq genomes, and defined by sequence and/or located in the NCBI Map Viewer. The January 2005 database issue of Nucleic Acids Research had an article by K. D. Pruitt, T. Tatusova, and D. R. Maglott titled “NCBI Reference Sequence (RefSeq): A curated non-redundant sequence database of genomes, transcripts and proteins” (25) and an article by D. Maglott, J. Ostell, K. D. Pruitt, and T. Tatusova titled “Entrez Gene: Gene-centered information at NCBI” (26).

7. Top gene-patent assignees. Wired magazine makes available a June 2000 profile of Incyte Genomics. The 13 February 2004 issue of Science had a ScienceScope item about Incyte. Human Genome Sciences lists its patents. Isis Pharmaceuticals provides a Web page on intellectual property. GlaxoSmithKline provides a statement on gene patenting. The University of California Office of Technology Transfer makes available in PDF format the 2004 Annual Report of the technology transfer program and a database of patented technologies available for licensing that includes a biotechnology category. The 25 April 2000 issue of the San Francisco Chronicle had an article by T. Abate titled “Call it the gene rush—Patent stakes run high.” The 7 February 1997 issue of Science had a News article by E. Marshall titled “Companies rush to patent DNA.” The 16 February 2001 issue had a News Focus article by D. Malakoff titled “Will a smaller genome complicate the patent chase?” The 20 September 2002 issue had a News Focus article by T. Gura titled “After the gold rush: Gene firms reinvent themselves.”

8. BMP7 and CDKN2A. The GeneCards database has entries for BMP7 and CDKN2A. OMIM has entries for BMP7 and CDKN2A.

9. BRCA1, PIK3R5, and LEPR. The GeneCards database has entries for BRCA1, PIK3R5, and LEPR. OMIM has entries for BRCA1 and LEPR. The 12 December 1997 issue of Science had a News & Comment article by E. Marshall titled “The battle over BRCA1 goes to court; BRCA2 may be next.” The 8 June 2001 issue had a News of the Week article by M. Balter titled “Transatlantic war over BRCA1 patent.” The 25 June 2005 issue had a News of the Week article by E. Marshall titled “BRCA2 claim faces new challenge.”

10. Futreal's review. The Wellcome Trust Sanger Institute provides an information page on the cancer gene census project and makes available in PDF format the March 2004 review article by P. A. Futreal et al. titled “A census of human cancer genes” (29).

11. Herfindahl Index. Herfindahl Index is defined in the Specialinvestor Financial Dictionary. H index is defined in the Online Glossary of Research Economics. An article on the Herfindahl Index is included in Wikipedia.

12. An entry for PSEN2 is included in GeneCards. OMIM has an entry for PSEN2.

13. Kyle Jensen is in the Department of Chemical Engineering and Fiona Murray is in the Sloan School of Management, Massachusetts Institute of Technology.

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