Intellectual property rights in genetics and genomics.

The purpose of this RFA is to encourage the study of the role of laws and policies regarding intellectual property rights to genetics and genomics research and development, and the effect of such laws and policies on progress in these fields and on commercialization, drug development, health care delivery, and the public health.

Since its inception, the Human Genome Project has attempted to follow a policy of free and open access to genetic and genomic data e.g., National Human Genome Research institute (NHGRI) Policy Regarding Intellectual Property of Human Genomic Sequence (April 9, 1996), http://www.genome.gov/ 10000926; NHGRI Policy on Human Genomic Sequence Data (Dec. 21, 2000), http://www. genome.gov/10000910. The National institutes of Health (NIH) policy recognizes the appropriateness of intellectual property protections for discoveries that are associated with useful products, but promotes the free dissemination of research tools whenever possible, especially when the prospect of commercial gain is remote (Report of the National Institutes of Health (NIH) Working Group on Research Tools, http:// www.nih.gov/news/researchtoolsl).

Over the past three decades, however, many patents have been granted on gene sequences and other types of basic information derived from genetic sequence. For some, this has generated apprehension that gene patents are being granted too broadly or freely, especially for foundational tools. The concern is that the too-liberal issuance of such patent rights, especially when coupled with exclusive licensing practices, will result in the imposition of reach-through restrictions or excessive fees, and inhibit investigators from conducting additional research with these tools. This, it is feared, will ultimately be to the detriment of advances in medical research and to public health.

In January 2001, partly in response to a letter from the NIH urging the implementation of stricter criteria for the issuance of biotechnology patents, the U.S. Patent and Trademark Office revised its guidelines to patent examiners regarding patents on DNA sequence and sequence-derived intellectual property, effectively "raising the bar" on utility standards in this area [U.S. Patent and Trademark Office, Utility Examination Guidelines, Fed Reg 66(4) (January 5, 2001)]. However, questions remain about whether this revision raised the "bar" high enough to serve the public interest. An example of the potential problem is the recent acquisition and aggressive pursuit by Genetic Technologies Limited (GTG), an Australian company, of exceptionally broad global patent protection covering the use of information to derive risks of disease in all non-coding regions of the genome [see Nature (2003) 423:105]. While this is perhaps an extreme example (and the validity of GTG's patents has not yet been tested in the courts), other controversial cases can also be cited (e.g., the Myriad Genetics BRCA1 patent, the University of Miami Canavan disease patent, the CCR5 HIV co-receptor gene patent). Such cases are increasingly leading genetics and genomics researchers, business entities, health care providers, and consumers to question how the balance between providing intellectual property protection and fostering biomedical innovation can best be attained.

Issues regarding the appropriate scope of protection for intellectual property rights in genetics and genomics research and development will only increase in complexity as progress in these fields continues. For example, large-scale proteomics efforts [such as protein biomarker discovery projects, the NIGMS Protein Structure Initiative (http://www.nigms.nih.gov/psi/) and initiatives to characterize protein-protein interactions] will generate new types of potentially patentable information, and with this information, new intellectual property challenges. Such challenges will also arise in several areas of research being emphasized under the new NIH Roadmap Initiative (http://nihroadmap. nih.gov/). For example, in the "chemical genomics" area, questions will arise about whether patents should be filed on the compounds that will be discovered or whether to place such compounds in the public domain, and about how pricing should be determined should a compound discovered through this process end up as a drug. In the bioinformatics and computational biology area, questions will arise about how best to promote the widespread distribution of new software to be developed (e.g., using an open source model of licensing or some other model).

Anticipating the growing need to confront questions of this type, the NHGRI has identified addressing intellectual property issues as one of the "Grand Challenges" for the future of genomics. Specifically, the Institute's document "A Vision for the Future of Genomics Research," [Nature (2003) 422:835-847], also available at: http://www.genome.gov/11006873), called for "the development of policy options in the area of intellectual property that will facilitate the widespread use of genetic and genomic information in both research and clinical settings." To be maximally informed and effective, however, the development of such policy options must be based on a solid and broad-based body of theoretic and empiric data. While a number of studies already conducted or now underway provide a good preliminary foundation on which to build, there is a clear need for additional research and scholarship in this area.

In 2004, the Board on Science Technology and Economic Policy (STEP Board) and the Science, Technology, and Law Program of the National Academies of Sciences convened a committee on Intellectual Property in Genomic and Protein Research and Innovation (the "NAS Committee"). The NAS Committee's charge is to review the patenting and licensing of human genetic material and proteins and their implications for biomedical research, therapeutic and diagnostic products, and medical practice. The NAS Committee is expected to release its report in the Summer of 2005, but there will clearly be a need for other, more in depth, examinations and analyses of these issues, by investigators from a broad range of disciplines.

To assist in addressing this need, the NHGRI proposes a new initiative to encourage the study of the role of laws and policies regarding intellectual property rights in genetics and genomics research and development, and the effect of such laws and policies on progress in these fields and on commercialization, drug development, health care delivery, and public health. The initiative is designed to support rigorous, carefully focused legal, statistical, economic, political science, historical, and other social scientific investigations, both theoretical and empirical.

As used in this RFA, the term "genetics and genomics" includes genomics (broadly defined to include both nucleic acid and protein products of large-scale analyses of the human and other genomes and methods for identifying and analyzing them) and human molecular genetics. The term is not, however, meant to include all of biotechnology, although the line between genomics and biotechnology is frequently hard to define. For example, the term "genetics and genomics subject matter" includes the following: (1) Both individual elements of data and comprehensive databases or other resources regarding genes and gene fragments; gene regulatory sequences; ESTs; SNPs; haplotypes; proteins and protein structures; protein-protein interactions; cellular pathways; computational models of the cell; gene expression profiling (microarrays); small molecules; and mouse (or other animal) knockouts. (2) The relationships between diseases or traits and genes, SNPs, haplotypes, or proteins; the relationships among genotype, environment, and phenotype (e.g., in large databases); and the use of such information in diagnostics. (3) Fundamental tools or methods for the production or analysis of data or databases of the types listed above, the bioinformatics software to probe the databases, and the algorithms that the software elaborates. The term "genetics and genomics subject matter" as used in this initiative does not, however, include such subject matter as biomedical devices, engineered tissues, stem cells, large-scale cell culture, whole organism cloning, or individual treatment applications.

Some examples of appropriate topic areas, with examples of specific research questions for each area, are listed below. Investigators are welcome to propose research in one or more of these topic areas, or in similar areas. Investigators should not be constrained by the specific research questions included on this list. The focus of the research, however, should remain on intellectual property rights to genetics and genomics-related subject matter, and should not be so broad as to encompass other major areas of biotechnology. (1) Types of Intellectual Property Rights and Related Policy Implications. What types of intellectual property rights to genetics and genomics-related subject matter are being, or should be, sought, obtained, or refused? What types of entities are seeking, obtaining, or being refused, intellectual property rights in this field? What are, or should be, the standards for novelty, non-obviousness, and utility in this field? What is, or should be, the breadth of the claims in this field? Do intellectual property rights to genetics and genomics-related subject matter benefit the public when there is no identifiable product? What has been the effect of intellectual property, rights in this field on research in the private sector? What are the mechanisms, existing or proposed as well as legal or business custom, for protecting information contained in databases generally, and what are the policy implications of allowing or refusing protection for genomic and genetic databases, whether through intellectual property or sui generis protection? What is, or should be, the role of patents, copyrights, trade secrets, and sui generis intellectual property, rights for various data types? How do the laws governing patents, copyrights, trade secrets, and sui generis intellectual property rights act as an incentive, a disincentive, or a neutral factor in determining the planning, content, and progress of genetics and genomics research and development programs? (2) Ownership and Assignment of Intellectual Property Rights and Related Policy Implications. What are, or should be, the mechanisms for exploiting intellectual property rights to genetics and genomics-related subject matter? How frequently are, or should, such rights be assigned (e.g., sold, or licensed exclusively or non-exclusively to third parties)? What are, or should be, the usual mechanisms of such assignments? Who are, or should be, the usual parties to such assignments? To what extent would genetics and genomics subject matter be treated differently if the corresponding intellectual property rights were not assigned? What are, or should be, the practices of biotechnology and pharmaceutical companies regarding the sharing of commercially valuable data? What are, or should be, the practices of universities regarding the sharing of commercially valuable data (government funded and non-government funded)? How have universities interpreted the Bayh-Dole Act, and what has been the impact of Bayh-Dole on genetics and genomics research? Are, or should, assignments in this field under Bayh-Dole typically be pursuant to employment contract or policies, or the result of arms-length negotiations? What is the practical impact of restrictions or limitations on the ownership of intellectual property rights imposed by government funding agencies (such as "Declaration of Exceptional Circumstances")? How will the mechanisms of assignment of intellectual property rights, and restrictions on such assignment, likely affect genetics and genomics subject matter in the future? (3) Licensing Practices and Related Policy Implications. What are the categories of genetics and genomics subject matter for which intellectual property rights are licensed or may be licensed in the future? What are the relative numbers of intellectual property rights involving genetics and genomics subject matter that are subject to licensing arrangements? What are the terms of such licenses (including exclusivity versus non-exclusivity, royalty rates, fields of use restrictions, etc.), and who are the parties to such agreements? What are the structures for such licensing arrangements (e.g., cross-licensing, block or blanket licenses, compulsory licenses, etc.)? What are the structures and operation of patent pools? How are end user license agreements (EULAs) attached to the sale of research tools being used, and how broad are their "reach-through" provisions? To what extent might the genetics and genomics subject matter be differently treated if the corresponding intellectual property rights were not licensed or were not disclosed and treated as a trade secret? How are the planning, content, and progress of genetics and genomics research and development programs affected by refusals to license or offers to license on unacceptable terms? How does the way in which genetics and genomics subject matter is licensed affect the prospects for commercialization? What is the effect of being required to obtain multiple licenses to conduct some types of research or clinical tests? Does an open source model of licensing genomic software tools increase the usefulness of the tools and improve their acceptance in the research community? Are intellectual property rights involving genetics and genomics subject matter to which licensing arrangements pertain more or less likely to be involved in infringement litigation? What would be the policy implications of limiting exclusive licenses in the field of genetics and genomics to therapeutics and vaccines (i.e., excluding diagnostics)? (4) Enforcement and Related Policy Implications. What are the categories of genetics and genomics subject matter for which the intellectual property rights have been involved in administrative or judicial action? What legal issues have been raised in such lawsuits, and who have been the parties to such lawsuits? What has been the resolution of such cases (e.g., dismissal, settlement, administrative action, trial verdict or judgment, appellate judgment, remedies and relief awarded, etc.)? What are the relative numbers of intellectual property rights involving genetics and genomics subject matter that have been filed in various forums? What are the numbers of intellectual property rights involving genetics and genomics subject matter that have been challenged but that do not actually reach litigation? How frequently are cease and desist letters issued, and how do universities or companies respond to them? How have the planning, content, and progress of genetics and genomics research and development programs been affected by threat, actual or perceived, of infringement litigation? What strategies are employed to allocate the risk of, to prepare for, or to defend against, infringement litigation? What impact has Madey v. Duke, 64 USPQ2d 1737, 307 F.3d 1351 (Fed Cir 2002), cert. Denied, 156 L.3d. 656 (2003), interpreting the experimental use (research) exemption to patent infringement in the context, had in the context of academic research? What would be the policy implications of formalizing a research exemption in the patent law? (5) International Issues and Related Policy Implications. What are the categories of genetics and genomics subject matter for which intellectual property rights have been or may be sought both in the United States and abroad? How does the operation of intellectual property rights involving genetics and genomics subject matter differ in the United States from other countries (e.g., what are the differences in the criteria for patentability applied in the U.S. and by other major patent offices, such as in Europe and Japan)? What mechanisms of procurement, ownership, licensing, and enforcement (or restrictions on these activities) exist only in other countries, and what are the advantages and disadvantages of such? How are international treaty obligations likely to affect the laws and customs in the United States governing intellectual property rights to genetics and genomics related subject matter? How do territorial and jurisdictional limitations on intellectual property rights affect the planning, content, and progress of genetics and genomics research and development programs? (6) Overarching Issues. Has the planning, content, and progress of genetics and genomics research and development programs been enhanced, or conversely chilled, by intellectual property rights? Have intellectual property rights positively or negatively affected the quantity and quality of the publication of scientific advances involving genetics and genomics, or the timing of data release and publication? What are the legal and practical implications for unfettered research activities (e.g., the significance of a bona fide research use exemption to patent infringement, a fair use defense to copyright infringement, a reverse engineering exception to trade secret misappropriation, etc.)? Are existing mechanisms of protection of intellectual property rights to genetics and genomics related subject matter adequate or inadequate to the task of striking the proper balance between intellectual property rights and open access to devices, methods, products and data involved in genetics and genomics research and development? How have intellectual property rights to genetics and genomics-related subject marter positively or negatively affected public access to health care (e.g., accelerated or delayed the commercial availability of diagnostics or treatments, increased or decreased their cost, etc.)?

A major goal of this initiative is to help expand the research base necessary to inform the future development of policy options regarding intellectual property in the contexts of genetics and genomics research and development. In this sense, the proposed development of policy options by applicants to this initiative is not required, but is encouraged when feasible. Investigators may propose to examine existing databases related to biotechnology and intellectual property rights or to gather new empirical data. However, proposals that are primarily dependent on data mining efforts should identify and incorporate innovative analytical methodologies to interpret the data.

Although applications for proposals to examine issues regarding intellectual property, genetics, and genomics in the specific context of differing cultures and belief systems are beyond the scope of this initiative, the NHGRI encourages research on these topics as part of its regular research program in the area of Ethical, Legal, and Social Implications (ELSI). Applicants interested in conducting research on such topics are strongly encouraged to consider submitting R01 or R03 applications under one of the appropriate standing NHGRI PAs for the ELSI Program. See http://grants.nih.gov/grantslguidc/pa-files/PA-04-050.html (R01 Program Announcement); http:// grants.nih.gov/grants/guide/pa-files/PA-04-051.html (R03 Program Announcement).

This RFA will use NIH R01 and R03 award mechanisms. Applicants are solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The earliest anticipated award date is 15 July 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as new investigator-initiated applications using the standard receipt dates for new applications described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/ modular/modular.htm).

Annual meetings of investigators will be held. This will facilitate the sharing of information, encourage collaboration, reduce possible duplication of effort, and promote more rapid dissemination of research findings. The initial meeting will take place shortly after the awards are made. Funds for travel to these meetings for up to two investigators per year should be included in the requested budget.

Prospective applicants are asked to submit a letter of intent that includes the following information: descriptive title of the proposed research; name, address, and telephone number of" the Principal Investigator; names of other key personnel; participating institutions; number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows Institute Center (IC) staff to estimate the potential review workload and plan the review.

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for federal grants or cooperative agreements. The DUNS number can be obtained by calling 866-705-5711 or through the website at http://www.dunandbradstreet. com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/ grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, 301-435-0714, e-mail: [e-mail].

The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih. gov/grants/funding/phs398/label-bk.pdf.

The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a new application. That is, the application for the RFA must not include an introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Letters of intent are due 21 October 2004, with applications due 18 November 2004. The earliest anticipated start date is 15 July 2005.

Contact: Jean E. McEwen, NHGRI, Division of Extramural Research, Ethical, Legal, and Social Implications Program, 5635 Fishers Lane, Suite 4076, MSC 9305, Bethesda, MD 20892-9305 USA, until 28 June 2004: 301-402-4997, after 28 June 2004: 301-496-7531, fax: [phone], e-mail [e-mail]; Rudy O. Pozzatti, NHGRI, Scientific Review Branch, 5635 Fishers Lane, Suite 4076, MSC 9306, Bethesda, MD 20892-9306 USA, 301-402-0838, fax: [phone], e-mail: [e-mail].

Reference: RFA No. RFA-HG-04-004