Title:    

Managing  Intellectual  Property  to  Promote  Pre-­‐Competitive   Research:  The  Mouse  as  a  Model  for  Constructing  a  Robust   Research  Commons  

Author:     Tania  Bubela,  Paul  N  Schofield,  Camille  D  Ryan,  Rhiannon  Adams,   David  Einhorn   EAP  Date  (approved  for  print):  31/10/2012   DOI:  10.5778/JLIS.2012.22.Bubela.1  

 

 

 

Note to users: Articles in the ‘Epubs ahead of print’ (EAP) section are peer reviewed accepted articles to be published in this journal. Please be aware that although EAPs do not have all bibliographic details available yet, they can be cited using the year of online publication and the Digital Object Identifier (DOI) as follows: Author(s), ‘Article Title’, Journal (Year), DOI, EAP (pg #). The EAP page number will be retained in the bottom margin of the printed version of this article when it is collated in a print issue. Collated print versions of the article will contain an additional volumetric page number. Both page citations will be relevant, but any EAP reference must continue to be preceded by the letters EAP. ISSN-0729-1485 Copyright © 2012 University of Tasmania All rights reserved. Subject to the law of copyright no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise, without the permission of the owner of the copyright. All enquiries seeking permission to reproduce any part of this publication should be addressed in the first instance to: The Editor, Journal of Law, Information and Science, Private Bag 89, Hobart, Tasmania 7001, Australia. editor@jlisjournal.org

 

http://www.jlisjournal.org/

Managing Intellectual Property to Promote PreCompetitive Research: The Mouse as a Model for Constructing a Robust Research Commons
TANIA BUBELA, PAUL N SCHOFIELD, CAMILLE D RYAN, RHIANNON ADAMS, DAVID EINHORN* 1 Introduction

New models for research and innovation are emerging in the life sciences, with emphasis placed on collaboration and partnership between a variety of stakeholders, including academia, government, industry and nongovernmental organizations.1 At the same time, a deluge of biological data is being generated around the world, primarily due to the advent of highthroughput technologies such as next-generation sequencing, RNAseq, and array based gene expression analysis.2 More recently population genetics and systematic phenotype analysis of model organisms3 such as the mouse and zebrafish have begun to generate large volumes of complex and multi-layered data, while a similar explosion is occurring in the availability of bioresources fundamental to biomedical research, such as mutant mouse strains. The latter is due in part to a coordinated high-throughput community project, the International Knockout Mouse Consortium (IKMC),4 which is generating and

                                                                                                               
*

Tania Bubela has a PhD (Biology, University of Sydney, Australia) and JD (University of Alberta, Canada) and is an Associate Professor in the Department of Public Health Sciences, School of Public Health, University of Alberta, Canada; Dr Paul Schofield has a DPhil in Biochemistry from the University of Oxford, is Reader in Biomedical Informatics in the Department of Physiology Development and Neuroscience, University of Cambridge, United Kingdom; Dr Cami Ryan is with the Department of Bioresource Policy, Business and Economics College of Agriculture and Bioresources, University of Saskatchewan, Canada; Rhiannon Adams is an intellectual property lawyer with Parlee McLaws LLP, Edmonton, Alberta, Canada; and David Einhorn is house counsel for The Jackson Laboratory, Bar Harbor, Maine, USA. Tania Bubela, Garret A FitzGerald and E Richard Gold, “Recalibrating Intellectual Property Rights to Enhance Translational Research Collaborations” (2012) 4 Science Translational Medicine 122cm3. Julian Parkhill, Ewan Birney and Paul Kersey, “Genomic Infrastructure after the Deluge” (2010) 11 Genome Biology 402. Information

1

2

3

Steve D M Brown and Mark W Moore, “Towards an Encyclopaedia of Mammalian Gene Function: The International Mouse Phenotyping Consortium” (2012) 5 Disease Models & Mechanisms 289; Zebrafish Mutation Project, Wellcome Trust Sanger Institute (2012) <http://www.sanger.ac.uk/Projects/D_rerio/zmp/>. Francis S Collins, Janet Rossant and Wolfgang Wurst, “A Mouse for all Reasons” (2007) 128 Cell 9; William C Skarnes et al, “A Conditional Knockout Resource for the Genome-Wide Study of Mouse Gene Function” (2011) 474 Nature 337.

4

EAP 1

Journal of Law, Information and Science

Vol 22(1) 2012  

distributing gametes, mouse embryonic stem (mES) cells and vectors for knockouts of the majority of protein-coding genes in the mouse genome. As a result, the traditional modes of sharing data and bioresources are no longer adequate to the scale or nature of the task required.5 Funding agencies, but more centrally the investigators themselves,6 have realised that great added value is to be obtained by sharing data and resources. This realisation has resulted in shifts in policy and investigator behaviour towards a collaborative and integrative model for basic and translational research.7 To support such large-scale, distributed research efforts, research communities have established institutions and infrastructure for the sharing of data and resources. For example, the infrastructure for archiving and sharing mouse strains has seen a dramatic expansion in recent years in addition to sharing of nucleic acid and protein sequence data; particularly their annotations.8 These, for some time, have been made available through the International Nucleotide Sequence Database Collaboration9 and integrative databases such as ENSEMBL,10 Mouse genome Informatics (MGI)11 and Mouse Genome Database (MGD),12 the value of which have increased hugely with the proliferation of gene-associated data. The first international mouse repository, The Jackson Laboratory (JAX), assumed the role in the 1930s and centralises distribution of over 5000 mouse strains.13 JAX was followed by new repositories, which include the National Institutes of Health (NIH) funded Regional Mutant Mouse14 repositories and

                                                                                                               
5 6

Parkhill, Birney and Kersey, above n 2. Robert W Williams, “Herding Cats: The Sociology of Data Integration” (2009) 3 Frontiers in Neuroscience 154. Dawn Field et al, “Megascience. ‘Omics data sharing’” (2009) 326 Science 234; Mark Harvey and Andrew McMeekin, Public or Private Economies of Knowledge? Turbulence in the Biological Sciences (Edward Elgar, 2007). Paul N Schofield et al, “Post-Publication Sharing of Data and Tools” (2009) 461 Nature 171. International Nucleotide Sequence Database Collaboration (2012) <http://www.insdc.org>. Ensembl Genome Browser (2012) <http://uswest.ensembl.org/index.html>. MGI-Mouse Genome Informatics (2012) <http://www.informatics.jax.org>. Mouse Genome Database (MGD) (2012) <http://www.nih.gov/science/models/mouse/resources/mgd.html>; Judith A Blake et al, “The Mouse Genome Database (MGD): Premier Model Organism Resource for Mammalian Genomics and Genetics” (2011) 39(Database Issue) Nucleic Acids Research D842. The Jackson Laboratory (2012) <www.jax.org>. Mutant Mouse Regional Resource Centers (MMRRC) (2012)

7

8

9

10 11 12

13 14

EAP  2    

Managing Intellectual Property to Promote Pre-Competitive Research  

the Knockout Mouse Project (KOMP) Repository15 in the USA, the European Mutant Mouse Archive (EMMA)16 network in Europe, the Canadian Mouse Mutant Repository (CMMR) in Canada,17 and the Riken Bioresource Centre in Japan.18 The scale of these repositories is enormous; for example, EMMA alone has archived more than 2000 strains of mice since 2002 and now services 550 requests per year. All repositories now face the challenges of global integration, addressed through the International Mouse Strain Resource (IMSR)19 and importantly that of capacity, which will soon be reached. The theme linking these endeavours in data and bioresource sharing is the concept of “the commons”. For example, the 2009 Rome Agenda20 was the result of an international multi-stakeholder meeting to discuss mouse research infrastructure. The Agenda comprises a series of recommendations targeted at a diversity of actors from funders and journals to researchers, research institutions and resource managers. It calls for the promotion of a “mouse research commons” for mouse resources (such as gametes, mES cells and mutant mouse models for human disease) and data. Similarly, Einhorn and Heimes describe the role of JAX as creating a mouse academic research commons.21 Here we explore the term “commons” in the context of bioresources for studying mouse models of human disease.22 The concept of the “commons” recognises that not all of the barriers to building shared research resources are technological, which include the complexities of constructing a conditional knockout resource, bioinformatics, or supporting information and communication technologies. Instead, the economic, legal, cultural and

                                                                                                                                                                                                                                                                       
<http://www.mmrrc.org>; Franziska B Grieder, “Mutant Mouse Regional Resource Center Program: A Resource for Distribution of Mouse Models for Biomedical Research” (2002) 52 Comparative Medicine 203.
15 16

Knockout Mouse Project (KOMP) Repository (2012) <www.komp.org>. The European Mutant Mouse Archive (EMMA) (2012) <www.emmanet.org>; Phil Wilkinson et al, “EMMA – Mouse Mutant Resources for the International Scientific Community” (2011) 38 (Database Issue) Nucleic Acids Research D570. Canadian Mouse Mutant Repository (CMMR) (2012) <http://www.cmmr.ca>. RIKEN BioResource Center <http://www.brc.riken.jp/inf/en/index.shtml>; Atsushi Yoshiki et al, “The Mouse Resources at the RIKEN BioResource Center” (2009) 58 Experimental Animals 85. International Mouse Strain Resource (IMSR) <http://www.findmice.org>; Janan T Eppig and Mark Strivens, “Finding a Mouse: The International Mouse Strain Resource (IMSR)” (1999) 15 Trends in Genetics 81. Schofield et al, above n 8. David Einhorn and Rita Heimes, “Creating a Mouse Academic Research Commons” (2009) 27 Nature Biotechnology 890. J P Sundberg, J M Ward and P Schofield, “Where’s the Mouse Info?” (2009) 46 Veterinary Pathology 1241.

17 18

19

20 21

22

 

EAP 3

Journal of Law, Information and Science

Vol 22(1) 2012  

behavioural aspects of sharing resources also need to be taken into account.23 Indeed, the movement in many research communities towards shared resources has been the result of collective action initiated by the researchers themselves.24 In analysing the mouse research commons, we further rely on an empirical study involving a detailed patent landscape25 and semistructured interviews with 48 experts internationally (resource producers, managers, funders, and biomedical researchers that utilise mouse models of human disease). We begin here with an overview of the need for research commons and their centrality in biomedical research policy.

2

The Centrality of Research Commons in Biomedical Research Policy

Publicly funded research institutions are under increasing pressure to demonstrate the relevance of their work.26 In biomedicine, as in other sciences, universities operate under the dual mandates of knowledge generation as a public good and the commercialisation or translation of research outputs. This latter trend towards a market orientation in research-intensive universities, supported by governments and funders began post World War II and accelerated alongside the rise of the biotechnology sector from the early 1980s.27 The result is conflicting attitudes and policies regarding commercialisation and the value of industry linkages as universities focus on intellectual property rights (IPRs) over research outputs.28 The latter is mediated by technology transfer or industry-liaison offices (TTOs) centred in most research-intensive universities.29

                                                                                                               
23

Peter Dawyndt, Tom Dedeurwaerdere and Jean Swings, “Contributions of Bioinformatics and Intellectual Property Rights in Sharing Biological Information” (2006) 58 International Social Science Journal 249. Charlotte Hess and Elinor Ostrom, “A Framework for Analysing Microbiological Commons” (2006) 58 International Social Science Journal 335. the

24

25

Tania Bubela, “Grand Challenges for Evidence and Health Policy: Metrics and Indicators in Complex Systems” in Robert P Kouri, Catherine Régis (eds), Les grandsdéfis en droit et politiques de la santé/Grand challenges in health law and policy (Thomson Reuters, 2010) 55. Rebecca M Henderson, Adam Jaffe and Manuel Trajtenberg, “Universities as a Source of Commercial Technology: A Detailed Analysis of University Patenting, 1965-1988” (1998) 80 Review of Economics and Statistics 119; Jason Owen-Smith and Walter W Powell, “The Expanding Role of University Patenting in the Life Sciences: Assessing the Importance of Experience and Connectivity” (2003) 32 Research Policy 1695. Elizabeth Popp Berman, Creating the Market University: How Academic Science Became an Economic Engine (Princeton University Press, 2012). Timothy Caulfield, Shawn H E Harmon and Yann Joly, “Open Science versus Commercialization: a Modern Research Conflict?” (2012) 4(17) Genome Medicine 1. Tania M Bubela and Timothy Caulfield, “Role and Reality: Technology Transfer at Canadian Universities” (2010) 28 Trends in Biotechnology 447.

26

27

28

29

EAP  4    

Managing Intellectual Property to Promote Pre-Competitive Research  

Evidence indicates that the pressure to undertake commercialisation or translation has increased over the past decade,30 resulting in a shift of community norms as researchers navigate industry-oriented funding priorities and performance metrics. Traditional incentive structures in science, such as quantity and quality of research publications, have been augmented with number of invention disclosures, patent applications and patents.31 Public research dollars have shifted from supporting discovery research to applied research, often with explicit requirements for industry partnership or co-funding.32 The result is an increase in secrecy and data withholding, contrary to the norms of open science,33 and a decrease in the degree of collaboration in highly innovative fields that require multi-sectoral collaborations incubated within an academic research setting, such as stem cell research. 34 The innovation literature recognises that research breakthroughs, especially those that involve platform technologies, induce multiple and largely unpredictable follow-on research paths.35 The development of innovative research tools raise the level of knowledge essential for product development for the public and private sectors. Examples include the Polymerase Chain Reaction (PCR) that enables the amplification of DNA, methods for DNA sequencing, molecular engineering, and the focus of this paper, genetically modified animal models of human disease. Given that the dominant market for research tools and platforms developed through public funds is other publicly-funded research institutions, commercially-motivated management of research tools and platforms has the negative impact of limiting follow-on research. High-profile examples of lack of access to essential research have led to a community backlash and a call for a more open research environment and a plethora of policies from funding agencies targeting the sharing of data and materials for research.36 Mouse model research provides several high-profile examples of community and institutional responses to research tool access problems. Ironically, the access problems were largely created by the patenting and licensing actions of

                                                                                                               
30 31 32 33

Ibid; Caulfield, Harmon and Joly, above n 28. Bubela, FitzGerald and Gold, above n 1. Berman, above n 27. John P Walsh, Charlene Cho and Wesley M Cohen, “View from the Bench: Patents and Material Transfers” (2005) 309 Science 2002. Tania Bubela et al, “Commercialization and Collaboration: Competing Policies in Publicly-Funded Stem Cell Research” (2010) 7 Cell Stem Cell 25. Fiona Murray, “The Oncomouse that Roared: Hybrid Exchange Strategies as a Source of Distinction at the Boundary of Overlapping Institutions” (2010) 116 American Journal of Sociology 341; Philippe Aghion et al, “Innovation and Open Science: The Public and Private Sectors in the Process of Innovation: Theory and Evidence from the Mouse Genetics Revolution” (2010) 100 American Economic Review: Papers & Proceedings 153. For a review see Caulfield, Harmon and Joly, above n 28.

34

35

36

 

EAP 5

Journal of Law, Information and Science

Vol 22(1) 2012  

publicly-funded research institutions. Several excellent papers by Fiona Murray and colleagues detail the history of these cases: knockout mouse technology, the OncoMouse, and Cre-lox.37 What follows is a brief overview of the key facts that galvanised the mouse model research community to become highly pro-active in institutionalising data and materials sharing, discussed in the following sections of this paper. Such activity was facilitated by strong leadership, with Dr Harold Varmus, a leading mouse model researcher at the helm of the National Institutes of Health (NIH) in the United States.38 Genetically modified mice, the most common type known as knockout mice, are the quintessential biomedical research tool. In their simplest form, knockout mice lack one or both copies of a specific gene and therefore produce reduced levels of the protein the gene encodes or none at all. Knockin mice carry engineered copies of genes which may be still functional but altered in some way, for example carrying a human coding sequence, replacing one or both of the endogenous copies. Knockout mice and knockout mouse embryonic stem cell lines allow biomedical researchers to study gene function and some knockout mice and cell lines are models for human genetic diseases, including some cancers and diseases with a more complex etiology including a genetic contribution. Examples of the latter include many cardio-vascular diseases and diabetes. Marking the importance of knockout mice as a research tool, the 2007 Nobel Prize in physiology or medicine was awarded to Dr Mario R Capecchi, Sir Martin J Evans and Dr Oliver Smithies for their early work on knockout mice. The University of Utah, home to Dr Capecchi, received a patent over the technology but never sought to enforce that patent against internal use by academic researchers and knockout mice were made broadly available at marginal cost though JAX.39 The OncoMouse, genetically modified to have a predisposition towards cancer, was developed and patented by researchers at Harvard University and licensed exclusively to DuPont, which provided the research funding. The OncoMouse is most well-known for the legal controversy it spurred in expanding patentable subject-matter to mammals in most jurisdictions.40 However, for the research community, the greatest controversy arose initially

                                                                                                               
37

Murray, above n 35; Aghion, above n 35; Fiona Murray et al, “Of Mice and Academics: Examining the Effect of Openness on Innovation” (Working Paper No 14819, National Bureau of Economic Research, 2009). Harold Varmus, The Art and Politics of Science (W W Norton & Company, 1st ed, 2009). Murray et al, above n 37. Harvard College v Canada (Commissioner of Patents) [2002] SCC 76; T19/90 HARVARD/Onco-mouse [1990] EPOR 501; T315/03 HARVARD/Transgenic Animal (2004), [2005] EPOR 31.

38

39 40

EAP  6    

Managing Intellectual Property to Promote Pre-Competitive Research  

from the breadth of the patent covering the OncoMouse technology41 and later in DuPont’s restrictive licensing policies that interfered with emerging community norms about sharing bioresources. The development of OncoMouse technology proceeded in the early 1980s in a number of research laboratories. Making such transgenic mice42 and using other techniques to make knockout and knockin mice was technically complex and required highly skilled personnel. The community struggled with how to share these genetically altered mice and to develop terms of exchange, but “scientists in the mouse community explicitly referred to their long tradition of openly sharing research mice, asking for little more than acknowledgment in future publications,”43 enabled by large publicly-funded mouse facilities such as JAX. However, genetically altered mice were more complex and costly to produce than spontaneous or experimentally induced mutant strains and were physiologically fragile, making them difficult to share in large numbers, especially from the few production laboratories. The laboratories, instead “traded skills in building an oncomouse rather than the mice themselves.”44 Thus, by the late 1980s: the appropriate norms of exchange remained in flux in academia, with some calling for internationally acceptable and consistent guidelines to remedy the difficulty scientists were having in establishing their own exchange practices. Scientists recognized that one of the prerequisites for more extensive mouse exchange was breeding efficiency — it was costly to establish a communal resource unless breeding was straightforward. ... In early 1989, discussions opened with JAX regarding the breeding, exchange, and standardization of oncomice. At precisely this moment, DuPont appeared with the oncomouse patent, and scientific life changed dramatically for the entire mouse genetics community.45 The DuPont licensing terms for the OncoMouse, distributed via the supplier Charles River Labs, placed limits on the informal exchange of mice (no third party distribution, including of novel lines derived from oncomice, made in individual laboratories), required annual disclosure to DuPont of published and unpublished findings using the mice, and imposed reach-through rights on future discoveries made using the OncoMouse. These rights gave DuPont “a percentage share in any sales or proceeds from a product or process

                                                                                                               
41

The dominant claim of US patent 4,736,866 granted on April 12, 1988 stated: “A transgenic non-human mammal all of whose germ cells and somatic cells contain a recombinant activated oncogenes sequence introduced into said mammal, or an ancestor of said mammal, at an embryonic stage.” A gene has been inserted into the genome of the mouse. Murray, above n 35, 358. Ibid 360. Ibid 361.

42 43 44 45

 

EAP 7

Journal of Law, Information and Science

Vol 22(1) 2012  

developed using an OncoMouse, even though the mice would not be incorporated into the end product.”46 The response from the scientific community to these onerous terms, which were contrary to the norms of the community, especially researcher autonomy in follow-on research, was overwhelmingly negative. The community response spanned the spectrum of acquiescence to civil disobedience in ignoring the underlying patent claims, to formal institutional resistance. The latter resulted in a formal compromise brokered by the NIH in 1999, after four years of negotiations. DuPont and the NIH signed a memorandum of understanding (MOU) allowing researchers to exchange OncoMice among not-for-profit researchers, including those developed in independent research laboratories, so long as they had a simple conditions-ofuse agreement in place, which no longer included reporting requirements and reach-through rights. The MOU enabled JAX and other public repositories to distribute OncoMouse lines, making them widely accessible to the academic research community. Unlike OncoMouse, which originated in a Harvard laboratory, the powerful cre-lox technology for understanding gene function had its origins in the life sciences division of DuPont. The technology enables specific genes to be turned on or off at differing developmental stages or in specific tissues. DuPont therefore strictly controlled access to cre-lox mice from the outset until the NIH negotiated an MOU in July 1998 to allow JAX or universities to distribute and share cre-lox mice with a simple, standardised conditions–ofuse agreement.47 The previous three cases provide an excellent resource for examining the impact of openness on follow-on research. The analysis by Fiona Murray and colleagues shows that openness (knockout mice as well as OncoMouse and cre-lox technology following their respective MOUs) not only encourages a greater quantity of follow-on research, measured through citations, but also enables new researchers to enter the field and the opening of novel research directions, measured through new authors, institutional affiliations and keywords in follow-on citations.48 Murray’s research clearly demonstrates the importance of developing institutional mechanisms to enable the development, distribution and sharing of research tools, the goal of the research commons. Such developments counteract many of the challenges associated with increasing IPRs over upstream research outputs — namely (i) the anticommons effect49 where downstream innovation is hampered by the high

                                                                                                               
46 47 48 49

Ibid 362. Murray et al, above n 37. Ibid. Michael A Heller and Rebecca S Eisenberg, “Can Patents Deter Innovation? The Anticommons in Biomedical Research” (1998) 280 Science 698.

EAP  8    

Managing Intellectual Property to Promote Pre-Competitive Research  

transaction costs necessary to negotiate permission to use and aggregate proprietary technologies; (ii) blocking patents over key technologies such as cre-lox; and (iii) overly aggressive licensing strategies which hamper access to novel technologies and compensate the patent holder through reach-through rights beyond what may be considered their fair contribution to technological development. Indeed, the DuPont licenses were motivating factors in newer more sophisticated licensing strategies by publicly funded institutions that eschew exclusive licenses over research tools and/or retain rights for noncommercial research purposes.50 Some more enlightened TTOs have also ceased seeking IPRs over mouse models, acknowledging their importance as research tools and that licensing fees in this context are simply a research tax on sister institutions.

3

Understanding the Research Commons

An academic research commons is a set of resources available to all researchers on terms that encourage efficiency, equitable use and sustainability that is managed by groups of varying sizes and interests.51 Understanding the formation and sustainability of such commons may be aided by the seminal research of Nobel Laureate, Elinor Ostrom, and colleagues who have developed an analytical framework52 to understand the development of institutions to manage the commons. Their work on natural resource commons recognised the importance of intermediate institutions in solving problems of overuse of the commons. Institutions may be formal or informal and are best understood as the set of human-constructed constraints and opportunities within which specific courses of action may be chosen; the set then shapes the consequences of those choices.53 Ostrom and colleagues realised that shared natural resources are often sustainable through collective action, without private property rights and with minimal or no state regulation. The framework includes understanding the nature of the resource, the attributes of the community, the rules in use and how collective decisions

                                                                                                               
50

Examples of these policies may be found in licensing guidelines such as those promulgated by the Association of University Technology Managers (AUTM): In the Public Interest: Nine Points to Consider in Licensing University Technology (2007) AUTM <https://www.autm.net/Nine_Points_to_Consider.htm> (“AUTM Nine Points”); and the Organisation for Economic Co-operation and Development (OECD) Guidelines for the Licensing of Genetic Inventions (2006) OECD <http://www.oecd.org/dataoecd/39/38/36198812.pdf> (“OECD gene licensing guidelines”). Hess and Ostrom, above n 24. The Institutional Analysis and Development (IAD) Framework was developed by Nobel Laureate, Eilnor Ostrom to synthesize over two decades of research on collective action and natural resource commons. A complete synthesis of this seminal work may be found in Elinor Ostrom, Understanding Institutional Diversity (Princeton University Press, 2005). Ibid.

51 52

53

 

EAP 9

Journal of Law, Information and Science

Vol 22(1) 2012  

and individual behaviour lead to outcomes that can then be evaluated.54 It enables comparisons and an understanding of the success or failure of diverse types of commons based on the specific context. There are, however, a number of differences between natural resource and research commons. First, while the primary problem with natural resource commons is over-use, the main issue facing research commons is under-use.55 Second, the value of a research commons is enhanced as more people use the resource — known as a “network effect”.56 Third, research commons are potentially global rather than local in scope, although mainly still located and servicing researchers in developed countries. Thus, a global research commons must be managed to facilitate not only use, but also re-contribution from the user community, creating a feedback loop between withdrawal, value-added research, and deposit.57 Here, we focus on some of the key issues identified by Ostrom as indicative of a robust and sustainable commons. These include: an identifiable community with a degree of cultural homogeneity; well-designed rules that meet the needs of the community and the resource; some ability for active participation in the development of rules by the community such as in discussions that lead to the IKMC or the Rome Agenda;58 appropriate incentive structures; and appropriate and enforced sanctions for non-compliance.59 We discuss the degree to which divergence from the ideal negatively impacts commons creation. We conclude with considering how rules and practices may be formulated to take into account structural and cultural limitations that operate as impediments to research commons.

4

Implications of a Heterogeneous Community

In contrast to Ostrom’s ideal of cultural homogeneity, the international research community comprises researchers, research institutions and their TTOs, private and public repositories, high-throughput resource generators, industry, funders, and other policy makers that produce, manage, fund and/or utilise mouse models as research tools in understanding basic biology and human disease. The actors involved are heterogeneous representing both public and private sectors. This leads to a fragmented and complex community with conflicting values. The conflict arises largely because the

                                                                                                               
54 55 56

Ibid. Schofield et al, above n 8. Tom Dedeurwaerdere, “Self-Governance and International Regulation of the Global Microbial Commons: Introduction to the Special Issue on the Microbial Commons” (2010) 4 International Journal of the Commons 390. Paul N Schofield et al, “Sustaining the Data and Bioresource Commons” (2010) 330 Science 592. Schofield et al, above n 8. Hess and Ostrom, above n 24; Ostrom, above n 52.

57

58 59

EAP  10    

Managing Intellectual Property to Promote Pre-Competitive Research  

impetus for collective action to build research commons has been a direct response to the trend, discussed above, towards the privatisation of scientific information, resources, and research methods through the seeking and enforcement of IPRs. The greatest implication of this clash of values for the creation of a research commons is the potential for loss of trust between, and even within, classes of user-producers. While strong leadership and a more homogeneous culture may enable the construction of a resource, the building of the resource does not equate to the establishment of a research commons, whereby the user community is integrated by both using and adding value to the commons, supported by incentives from research institutions and funders.

4.1 Producer Perspectives
Our interviews with scientists involved in the formation of the IKMC and its constituents indicated that international high-throughput resource production came about through the efforts of a collaborative network of key individuals who jointly sought funding. These individuals either had prior research relationships or knew each other by reputation through publication outputs. As explained by one interviewee: We all knew each other, we all trusted each other, respect each other and respect each other’s ideas so that when we came together to propose the program, we really brought together a bunch of ideas, synthesized them into what I think is the best possible approach to this project. The core group that came together to advocate, seek funding and then construct the resource was committed to the concept of a shared community research platform and an open access60 model for research tools.61 The core group also emphasised the importance of strong leadership in developing a co-ordinated, multi-national, high-throughput pipeline model: So when, when you’re in a project that is so interdependent you need to sort of set up the supply chain. Yeah, you need to manage it

                                                                                                               
60

The goal of open access is to create norms to facilitate access to knowledge and collaboration. Its IP strategy or mechanism involves collaborators and funders creating clear rules on how knowledge is produced and used and enforcing those rules. It does not necessarily rely on IPRs. It is most used for research tools and data and an example is the Structural Genomics Consortium. Aled M Edwards et al, “Open Access Chemical and Clinical Probes to Support Drug Discovery” (2009) 5 Nature Chemical Biology 436; Bubela, FitzGerald and Gold above n 1. This echoed the policy of the most influential funders of the IKMC, the NIH and the Wellcome Trust. However, leading members of the mouse model research community found a meeting of the minds with then NIH Director Dr Harold Varmus, himself a mouse researcher, in developing the long-standing NIH policy on sharing biomaterials. National Institutes of Health, “Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources” (1999) 64 Federal Register 72090 <http://grants.nih.gov/grants/intell-property_64FR72090.pdf>.

61

 

EAP 11

Journal of Law, Information and Science

Vol 22(1) 2012  

… you have to get together every once in a while. You have to be able to communicate. We need to start being able to build trust, and then that causes an open sharing. Even faced with technological and management difficulties, these individuals demonstrated significant dedication to the task: So it’s been a really big shift to go into this high-through-put culture and you know, like anything in life, there are parts you like and there are parts you don’t like … What keeps me going in the tough moments is that I am really committed to providing these resources democratically. Industry involvement in the project62 was facilitated by individuals who had moved between the project’s main publicly-funded production facilities, academia, and the private sector during their careers. Such a career trajectory underscores the difficulties inherent is separating basic researchers from more applied researchers. Many of the individuals involved embodied a descriptor that is often ascribed to modern-day research institutions — the blurring of boundaries between public and private, between basic and commercial research. Some indicated that this was beneficial to building trust relationships with the industry partners on the project: [H]aving spent time in industry, … it’s easier to know where they’re coming from so when you need to explain your position or when you need to explain how to get things done — you have this sort of credibility and that helps an awful lot in getting deals done. It also helped to allay fears of the academic partners. Nevertheless, some academic participants indicated their frustration at industry culture that limited participation in the open, frank discussion required to develop the project, especially the use of specific proprietary technologies required to build the resource: [Some researchers in industry] would come [to conferences] and actually talk in depth of the science and answer the questions … [Others] who we knew in another life as well … had been ordered not to interact so they had a very chilling effect on the entire discourse. The researchers also noted the tension between institutional policies directed at building open access community resources and a commercialisation ethos built on a strong foundation of IPRs and/or close collaboration or partnership with industry. This tension is illustrated in the following quotes: “So, if I was interested in commercialising it then I think I would work in a company and I think if you want to make money go to a company but for an academic researcher it’s kind of inappropriate.” Another stated: “Well, I'm a great

                                                                                                               
62

The biotechnology company, Regeneron was part of KOMP. From Regeneron’s perspective, the KOMP/EuCOMM/NorCOMM resources are pre-competitive.

EAP  12    

Managing Intellectual Property to Promote Pre-Competitive Research  

believer in the whole open access thing. Which is why I’ve been emphasising things like, once the publication is out there, give it away. So, to me that’s the side I’m going to err on. I think that the commercialisation aspect I think can become an impediment.” On industry collaboration and funding, another stated: “So, I realised that if you deal with a company, it’s a two edged sword — yes they might be able to give you the funding but, number two, they’ll place restrictions on what you produce and academics won’t benefit. So, that turned me off completely from commercialising this sort of basic technology and I think it’s a bad idea for anybody, for any scientist, to patent basic technologies and give away exclusive rights to it. It has to be done the right way with non-exclusive rights and academics can still use it.” Others commented on IPRs as impediments to research: “We’re in a world now where we’re talking a lot about open access to things because this whole concept of IP has matured to a level where it has become a big enough issue in a broad way that it really does affect the ability to do research, so it’s discussed much more now than it used to be. And, the short answer is by and large it interferes.” The latter was especially true in gaining access to proprietary platform technologies required to build the resource, including postivie/negative selection, isogenic DNA and recombineering technologies.

4.2 User Perspectives
The user community was generally supportive of the need for the resource, considering mouse models “as an essential component of investigative research for … genetic diseases.” Another stated: “I think the power of the mouse model is phenomenal in biology. … [The resource’s] power is that it makes it possible for just about anybody to have a model of whatever they’re looking for. They don’t need to have the skills in their own laboratory.” Potential users were excited about the possibilities for the resource to open up new areas of research: “And, there are a lot of genes in that resource now that aren’t of interest but as soon as the connections are made between the function, suddenly all kinds of new genes become interesting to people. Especially now with microarrays, genome wide proteomics, this sort of thing. People are starting to make connections to genes that you’ve never heard of before and oh, look, I can make a mouse from this resource.” Others commented on the efficiencies to be gained in a community resource rather than duplicating research resources in multiple laboratories to create model organisms. This also has ethical implications for animal welfare. Centralising resource production focussed on gametes and mES cells ensures that the minimum number of live-knockout mice are generated, distributed by the repositories and used by the community. However, the user community did not unequivocally endorse this publicly funded effort to construct a community resource and raised concerns pertinent to the issue of whether the resource would catalyse the intended commons environment where users were integrated into knowledge production. Some had trust issues, particularly with the quality control of the resource and the establishment of the new, untested IKMC repositories. However, more significantly, some indicated mistrust of potential “freeriders”, especially related to deposit of resources. Free-riders appropriate

 

EAP 13

Journal of Law, Information and Science

Vol 22(1) 2012  

value from a resource without contributing value back. This fear arose in two contexts: first, scientific competition (eg, the fear of being beaten to a key finding or publication); and second, a fear of industry using and generating value from the contributed resource (eg, a mouse model) without adequate compensation. This last concern was shared by TTOs and research institutions.63 The final concern was that the considerable funds to build the community resource were directed away from hypothesis-driven research. In other words, community projects compete for limited research funds with investigator-driven research.

5

Do Current Rules Facilitate a Robust Research Commons?

The free-rider concern may be addressed through appropriate rules. Rules may be defined as “shared normative understandings of what a participant in a position must, must not, or may do … backed by at least a minimal sanctioning ability for noncompliance.”64 The rules in use may comprise a combination of formal laws such as those governing IP, regulatory approval processes, and animal welfare. Others may be constitutional in that they determine who has the authority to make rules and laws in specific areas or settings. However, the rules also encompass funder or research institution policies and guidelines, contractual arrangements (eg, material transfer agreements (MTAs) and other licensing arrangements, collaborative research agreements, memoranda of understanding), and even informal rules, community norms and practices such as citation, other attribution, reciprocity and sharing, and form and timing of publication. At the national level, IP laws set the stage for what may or may not be appropriated from the commons. These laws are the least amenable to change, indeed, from the perspective of the user-producers, these laws form the backdrop against which specific policies and community norms are formulated. More important than the specifics of the laws is some degree of certainty in their operation; some degree of certainty enables the community to structure relationships within a predictable legal framework. In other words, since commons are largely created from the ground up, by communities of researcher themselves, commons may operate in spite of laws that enable and policies that incentivise commercialisation of research outputs.65 In a practical sense, the market for research tools directs that the bulk of tools be placed within the commons because these are largely generated using public research funds and the market is predominantly made

                                                                                                               
63 64

Bubela and Caulfield, above n 29. Elinor Ostrom and Charlotte Hess, “A Framework for Analyzing the Knowledge Commons” in Charlotte Hess and Elinor Ostrom (eds), Understanding Knowledge as a Commons: From Theory to Practice (MIT Press, 2007) 41. Dianne Nicol, “Implications of DNA Patenting: Reviewing the Evidence” (2011) 21(1) Journal of Law, Information and Science 1; Rochelle Cooper Dreyfuss, “Implications of the DNA Patenting Dispute: A US Response to Dianne Nicol” (2012) 22(1) Journal of Law Information and Science.

65

EAP  14    

Managing Intellectual Property to Promote Pre-Competitive Research  

up of publicly-funded researchers. Commercialising research tools makes limited sense from a social perspective because charging a premium for such tools is, in essence, a research tax within the same community, with public research dollars flowing from one institution to another.66 The interviewees clearly stated the non-utility of appropriating mouse-related research tools through patenting: “So, as far as IP on mouse models, unless it’s something really unique and something you can track efficiently, I don’t think that mouse models have a lot of IP value.”67 Another stated: “The answer is the user just isn’t going to generate a massive amount of income out of these things. And, I think there was, in the early days of this, in the early 90’s in particular, there was this naive view that everything was a gold mine and the government really pushed very hard … to promote the generation of intellectual property. And, I think what happens is that a lot of junk was turned into IP.” In addition, even where IPRs exist, it is common for researchers to simply ignore it: “But, I don’t think I’ve ever been really blocked by IP issues. Because like most researchers when it comes down it, we ignore them.” At the more tractable level of the resource itself, the rules developed to manage the international mouse commons need to incentivise contributions to the commons, use of the commons, and activities that add value to the commons (eg, rules that encourage the deposit of a new mouse model to a repository, encourage researchers to access mouse resources from an established repository, and that encourage the addition of data such as phenotype data to add value to the resource). Given the heterogeneity of the community and the resource, rules to manage the commons must address both proprietary (generally covered by patents) and non-proprietary materials.68 Most funding agencies have developed policies and guidelines for

                                                                                                               
66

Some more enlightened TTOs have recognised the limited value in patenting research tools and the University of British Columbia, for example, has a general policy not to patent mouse models of human disease (Angus Livingstone, personal communication). One example of a truly unique and commercially successful mouse research tool has been developed by Regeneron, a United States based biotechnology company, which has developed and licensed a knockout mouse and embryonic stem cell platforms for identifying therapeutic human antibodies. The platform has been non-exclusively licensed to AstraZeneca for $120 million dollars over six years. Regeneron Pharmaceuticals <www.regeneron.com> (Regeneron’s technology is known as VelocImmune and its goal is to enhance the discovery of human monoclonal antibodies with therapeutic application. The three inter-related technologies are known as VelociGene, VelociMouse and VelocImmune. The first is used to create genetic modifications in a mouse in a precise and high-throughput manner and produces mouse embryonic stem cells determining the function of the gene; the second allows the generation of mammalian models from ES cells and the last provides antibodies for the targets identified in the mammalian models that have potential therapeutic benefit). Einhorn and Heimes, above n 21; Ostrom, above n 52.

67

68

 

EAP 15

Journal of Law, Information and Science

Vol 22(1) 2012  

the deposit of publications and associated data into public databases69 and some, such as the NIH have guidelines on sharing bioresources.70 In addition, organisations such as Science Commons71 promote the data and bioresource sharing, and both the NIH and Science Commons have provided tools or legal templates to enable that sharing under the least restrictive terms possible.72 Repositories such as JAX facilitate resource sharing through simplified processes backed by rules designed for that task.73 JAX facilitates a research commons through negotiated agreements with donors of new mouse strains that protect academics from having to sign MTAs or licenses. JAX distributes the mice pursuant to those agreements to academic and not-for-profit researchers for both patented and unpatented mice using a simple notification that the mice be used for research purposes and may not be sold or transferred to third parties without permission. Mice are distributed to industry or for commercial use if permitted by the donor via MTAs or licenses negotiated at arms’ length between the donor and industry recipient. In this way, JAX ensures that donors accept a research commons approach for academics in return for JAX acting as a bridge between donors and industry.74 Other repositories, however, require complex MTAs for all classes of user before resources may be distributed. Our interviews indicated an important point relating to rules. While there may be adequate rules in place to incentivise the commons, some members of the heterogeneous community may not interpret and use those rules in a manner that facilitates the creation and maintenance of a research commons. For example, the institutional uses of MTAs are of great concern to the community and significantly delay access to resources, increase transaction costs as MTAs often require institutional signing authority, and serve a disincentive to the transfer of bioresources.75 MTAs are simply permissions to use proprietary or non-proprietary materials that are in the control of the provider. MTAs exist over a spectrum from simple conditions of use76 to

                                                                                                               
69

See John Whitfield, “Open Access Comes of Age: Publishing Model Enters Phase of Slower but Steady Growth” (2011) 474 Nature 428; Richard Van Noorden, “Key Questions in the UK’s Shift to Open-Access Research” on Nature News Blog (2012) <http://blogs.nature.com/news/2012/05/key-questions-in-the-uks-shift-to-openaccess-research.html>. Field et al, above n 7; National Institutes of Health, above n 61. Creative Commons Science <creativecommons.org/science>. See Caulfield, Harmon and Joly, above n 28 for a summary of sharing policies in key jurisdictions — US, Canada, UK and Australia. Einhorn and Heimes, above n 21. Ibid. Schofield et al, above n 8. The Canadian Mouse Mutant Repository Terms of Use are as follows: “Users of the Site (“you”) are granted a limited license to use (display or print) the Information for personal non-commercial use only, provided the Information is not modified

70 71 72

73 74 75 76

EAP  16    

Managing Intellectual Property to Promote Pre-Competitive Research  

onerous licenses with reach-through rights.77 Many organisations, including the OECD78 and the Association of University Technology Managers (AUTM)79 have established guidelines for the use of licenses to facilitate the transfer and use of research tools. Unfortunately, widespread implementation is lacking. Researchers were generally dissatisfied with their institutional TTOs or similar research offices that manage MTAs: “The TTO was, number one, very unrealistic, and secondly, they were really greedy in trying to milk a major pharmaceutical company for the maximum amount of money they could possibly do. The net effect is that in the end they killed the project, at least killed any opportunity for the company to fund it.” This commercialisation culture of the TTOs permeated the negotiation of what should, for efficiency, be simple negotiations over the exchange of research tools: “The university is very aggressive about [MTAs], what they write out, what they start with is in my opinion not something I would sign. And it is almost always challenged by the recipient university and almost always we have a back and forth process that can go on for months… So I find it extremely inefficient, rude in the sense that they seem to start at a level at that they know they cannot maintain, but they are just wanting to get all that they can get, and if the other university will sign it, then well that’s terrific.” Indeed, not one of our 43 interviewees had a positive view of TTOs or other institutional contract managers contrary to their supposed role as exchange

                                                                                                                                                                                                                                                                       
and all copyright and other proprietary notices are retained. Any other use is strictly prohibited without our prior permission and the permission of the applicable rights holders.” Terms of Use (2004) Canadian Mouse Mutant Repository (CMMR) <http://www.cmmr.ca/terms.html>. The Jackson Laboratory (JAX) Conditions of Use are as follows: “MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services.” General Terms and Conditions (2012) JAX <http://jaxmice.jax.org/cou/index.html>.
77

Eucomm’s MTA is more onerous and complex. It restricts use to non-commercial use, including distribution to a for-profit entity. If mice are created from the distributed ES cells, these are required to be deposited in a public repository for cryopreservation. However, onward distribution to third parties may only be for non-commercial purposes, using the EuCOMM MTA “in substantive form”. With respect to any modifications performed by recipients, additional conditions attach, constituting reach-through. Recipients may release modifications to non-profit organisations for non-commercial use. In addition, with respect to any IP rights on any modifications, the Recipient shall “grant to the Originator a non-exclusive, worldwide, royalty-free, sub-licensable, fully paid-up license to use such IPR for non-commercial and teaching purposes.” This extends a “retention-of-rights” clause to an unenforceable extreme. Eucomm Product Ordering and MTA, Eucomm <http://www.helmholtzmuenchen.de/fileadmin/MTA/EUCOMM_Product_Ordering_and_MTA.pdf>. OECD, above n 50. Association of University Technology Managers, above n 50.

78 79

 

EAP 17

Journal of Law, Information and Science

Vol 22(1) 2012  

facilitator within the research commons. Instead, they found TTOs to be resistance points to the free-flow of bioresources: “Not anything that’s totally prevented us from doing our research, but over the years it’s getting harder and harder and harder the IP issues because all the MTA’s;” “[IP] hasn’t prevented us from doing research, but it slows you down [yeah] and it costs a lot of money in all the lawyer’s fees. Basically in my opinion it’s mostly a huge waste of money.” In addition, the legal stacking of MTAs on research components causes problems for follow-on research resulting in derivative outputs that may amalgamate multiple components. Paradoxically, the complexity of the background IP and MTAs becomes a disincentive for commercialisation of outputs that may be closer towards practical application: “Most of these things it’s not like that, it’s just somehow their institution wants to project way into the future and five steps of derivation down the road and so I can’t keep track of all the MTAs... And, I just feel like basically the process squashes any incentive to [commercialise research].” In conclusion: “My experience with MTAs is rarely are they easy.”

6

Incentives

Despite the existence of repositories and the existence of policies, guidelines, and legal tools that facilitate a research commons, only an estimated 35 per cent of mouse strains are made available in repositories.80 This is, in part, due to lack of adequate incentives for both the producers of the resource, and for user-contributors. Part of the problem is the tenure and promotion incentives in universities, where a premium is placed on high-impact publications and patents. Resource production may be considered a community service that does not lead to high-impact research outputs, which places this activity in conflict with the demands of the academy. This tension was noted by interviewees: “So I think that tension exists, absolutely, and it seems we were talking about tenure decisions, that’s a place where this sort of things are often discussed. I think you don’t get the same kind of value for resource based papers, as you do as hypothesised papers.” Another stated: “Resource based science, is a different kind of science, has a different kind of value, and at some point doesn’t have the same creativity as hypothesis-driven research. I think that it has the creativity, absolutely, when it first starts, but it can eventually become turning a crank. And whether you are doing hypothesis based research, or resource based research, if you have slipped into turning a crank, then that is not as valuable.” Indeed, some researchers were actively discouraged from acting as producers: “[I] was basically told that I have to stop doing so much of this stuff that’s for the greater good of the community and I need to start concentrating on my own science… A lot of people are very, very, very much self-serving when it comes to their advancing their science, but I feel that through efforts to build community that that makes me a better citizen and that makes me more appreciated by the community and so, so I’ll give you now, beyond this point.”

                                                                                                               
80

Schofield et al, above n 8.

EAP  18    

Managing Intellectual Property to Promote Pre-Competitive Research  

In commenting on the limitations of current value structures, one interviewee made the interesting observation that publication-based science is of lesser social value because it rarely leads to direct impacts, either in terms of products of social value or in terms of tangible resources that can enable the research enterprise: “It’s Darwinian I would say. It’s this publications based system which I don’t like anymore and in fact you can … find some very brilliant people who publish very little because they’ve been busy actually working on these sort of large scale projects or applications or they’re just... or it’s not their thing — they know they’re not going the academic track and very often, what happens is that what’s published is actually very deceptive. People publish because it’s a dead end. Pharmaceutical companies are the classics to that way — anything that they publish means that it’s a dead end and they are trying to get something out of it.” To rectify the lack of incentives to contribute to the research commons, a number of actions may be taken, including insistence by journals and funders that bioresources be deposited in an identified repository within a specific timeframe following publication; funders should cover the costs of that deposition.81 Deposition policies should be clearly articulated and should not be difficult to implement since many journals already have similar policies with respect to data. Another incentive is attribution for the resource developer. Publications should acknowledge the original source of bioresources. A tracking system for use of bioresources should be developed and then used by funders and research institutions to assess research impact in the same way as publications, publication citations, and patents.

7

Disincentives and Sanctioning

Significant disincentives to using and depositing in repositories are concerns related to the quality of the resource, negotiating MTAs, and fear of patent litigation.82 These are real concerns; JAX, for example, faced two sets of litigation related to patented mice and genes in the past five years.83 In the first instance, JAX was sued in 2008 by the Central Institute for Experimental Animals (CIEA), a Kawasaki, Japan–based non-profit for distributing a mouse model for grafting human tissue.84 Both JAX and the Japanese research group separately developed these immunodeficient mice through cross-breeding. JAX did not patent its mouse, whereas CIEA did. On 1 June 2010, a US District Court judge ruled in a summary judgement that the Jackson

                                                                                                               
81 82 83 84

Ibid. Emily Waltz, “Lawsuit Rocks Jackson” (2010) 28 Nature Biotechnology 768. Ibid. Alison Abbott, “Mouse Patent Sparks ‘Uncivil’ Spat” (2009) 459 Nature 620; The Central Institute for Experimental Animals v The Jackson Laboratory, No. C–08–05568 (RMW), 2010 WL 520726 (ND Cal, Feb 8, 2010).

 

EAP 19

Journal of Law, Information and Science

Vol 22(1) 2012  

Laboratory had not infringed CIEA’s patent.85 As explained by Waltz what ultimately swayed the judge to side with Jackson was that the CIEA, in its patent application, described the mouse very narrowly in terms of its source, and that based on the International Guidelines for Nomenclature of Mouse and Rat Strains,86 the two strains, separately inbred over many generations and at multiple locations, could not be considered the same mice. In addition, the judge found that the two strains were not functionally equivalent. CIEA insisted that it brought the suit, not based on a financial motivation, but to ensure that CIEA research contributions were appropriately acknowledged in the use and distribution of these important research tools, but interestingly CIEA never once communicated with JAX about any concerns, including that of attribution, before it filed its lawsuit. In the second instance, JAX was sued by the Alzheimer’s Institute of America (AIA), a non-practising entity and assignee of patents that cover a mouse model of early-onset Alzheimer’s Disease, which was developed based on a genetic link to Alzheimer’s known as the Swedish Mutation.87 AIA sued JAX for patent infringement for distributing 22 Alzheimer’s mouse lines to the research community that AIA claimed, and JAX disputed, were covered by its patents.88 AIA dropped the suit against JAX after NIH Director Francis Collins stepped in to grant JAX a special determination that JAX, which had multiple grants and contracts from the NIH to distribute mice, could freely use in that distribution any invention patented in the United States, effectively shielding JAX from these kinds of lawsuits and substituting the federal government in the event a patentee still wished to pursue claims of infringement.89 This legal tool of the US Federal Government to immunise Federal Contractors from patent infringement suits is a powerful one, and enhanced JAX’s position supporting federal protection for a mouse research commons. The legal tool, known as “Authorization and Consent”, has most commonly be used for

                                                                                                               
85

The Central Institute for Experimental Animals v The Jackson Laboratory, 726 F Supp 2d 1045 (ND Cal, 2010). International Committee on Standardized Genetic Nomenclature for Mice, Guidelines for Nomenclature of Mouse and Rat Strains (2006) Mouse Genome Informatics (MGI) <http://www.informatics.jax.org/mgihome/nomen/strains.shtml>. Erica Check Hayden, Lawsuit Dismissal Removes Cloud over Alzheimer’s Research (2011) Nature News Blog <http://blogs.nature.com/news/2011/08/lawsuit_dismissal_removes_clou.html> While the AIA has dropped its infringement suit against JAX, litigation against the other defendants continues. In March 2005, AIA filed against the Mayo Clinic. In December 2009 it filed against the Oklahoma Medical Research Foundation and Comentis and against Pfizer in June 2009. The JAX litigation was part of a suit filed in February 2010 against Elan Pharmaceuticals, Eli Lilly, Anaspec, Immunobiological Laboratories, Invitrogen and Phoenix Pharmaceuticals. In November 2010, AIA filed against the University of Pennsylvania and Avid Radiopharmaceuticals. Authorization and Consent, 48 CFR § 52.227-1-3 (1995).

86

87

88

89

EAP  20    

Managing Intellectual Property to Promote Pre-Competitive Research  

large defence contracts,90 and its use in the context of protecting the distribution of research mice is unprecedented. Given its effect, other international jurisdictions may consider implementing similar powers. These two lawsuits against a not-for-profit repository are notable for their rarity. Given the large number of patents over mouse research tools, if these had significant value, more significant levels of litigation might be expected. Our patent landscape identified 2,373 patents to 2007 claiming a nucleotide sequence, a mouse, a mES line, or a method for making a genetically modified mouse.91 A total of 952 mouse genes were claimed, identified through a blast analysis of claimed sequences.92 Most of these patents are still active and maintained. The patent landscape was illuminating. It indicated that public sector universities held the greatest proportion of “low value” granted, inforce patents over mouse and mammalian DNA. Broader DNA patents not limited to any organism were predominantly claimed by pharmaceutical companies. Mouse and mammalian cell lines were predominantly claimed by pharmaceutical companies and mice were equally claimed by government agencies, public universities, and pharmaceutical companies. The majority of patents in each category also claimed a method and about a third of mouse and mammalian DNA patents cited a government funding source, compared to only between 10 and 20 per cent for the broad DNA patents, cell lines and mice. As a result, the Rome Agenda recommended that mouse models generated using public funds should be patented only under exceptional circumstances, and if so then licensed with minimal constraints on academic use.93 The lack of litigation is one indicator of the low value inherent in patenting mouse-related research tools.94 Of greater concern, however, are the broad methods patents — over a hundred — that covered most of the methods required to create a large-scale knockout resource. Indeed, these methods patents were identified by interviewees from the three resource projects as problematic, especially since many are held or exclusively licensed by academics to biotechnology companies. Further, the opacity of the patent landscape may be problematic

                                                                                                               
90

For more information on the operation of the Authorization and Consent clause of the Federal Acquisition Regulations (ibid) see: Lionel Marks Lavenue, “Patent Infringement against the United States and Government Contractors under 28 U.S.C. section 1498 in the United States Court of Federal Claims” (1995) 2 Journal of Intellectual Property Law 389. Bubela, above n 25. Kyle Jensen and Fiona Murray, “Intellectual Property Landscape of the Human Genome” (2005) 310 Science 239. Schofield et al, above n 8. Note that patent enforcement and ensuing litigation are highly costly in terms of monitoring, human resources and money. For an individual, an institution, or a firm, especially with large patent portfolios, it is generally only economical to enforce the most valuable patents. Indeed, litigation is one metric used to assess patent value. John R Allison et al, “Valuable Patents” (2004) 92 Georgetown Law Journal 435.

91 92

93 94

 

EAP 21

Journal of Law, Information and Science

Vol 22(1) 2012  

when constructing a community resource of genetically altered mice, against a backdrop of gene, mouse and process patents. As one interviewee stated: “It’s very murky, people turn up patents you couldn’t believe existed and it’s just almost a surreal aspect to the randomness of it all … it’s not necessarily anything that you’d think would be important but we have to obviously in a large scale project worry about it.” Resolving the background IP issues takes time and energy away from resource building and research: “So I think commercializing basic technologies… that are so useful for applying to almost any sort of problem – you find that you have these roadblocks and hurdles to progress and people are threatening you and you have to put a lot of energy into resolving those issues and, you know, I just don’t like this side of science; this commercialization of basic technologies.” The backdrop of IP also complicates the types of users of the resource. For example, broad methods patents such as for microinjection used to create bioresources dissuade depositors and their research institutions from contributing to repositories for fear of patent litigation. Methods patents were identified by interviewees as barriers for high-throughput production facilities and the ability of associated resources to distribute, especially to commercial users. As one interviewee stated: “Ideally it should be open to industry as well, which it may be difficult.” However, the background IPRs and possible claims of infringement are problematic for industry: “It’s come up in our discussions every once and a while whether our resource will be used by industry. Again, I can’t comment on things going on, but obviously in industry people are not just buying the technology, they are buying the protection for the technology as well.” In response to this problem, funding agencies could require grant awards to stipulate that any exclusive licensing by grantees include a research exemption carved out for academic and non-profit institutions. This would address the public policy concern and ensure full benefit and use of research tools and technologies developed using public or philanthropic funding as well as enhancing the research commons. However, similar recommendations have been made for several decades without much impact, largely because of the difficulty in defining the scope of a research exemption where a clear boundary of basic versus applied research does not exist. Therefore funding agencies, and potentially “gatekeeper” journals, need to develop systems to enforce existing policies and guidelines that promote the commons and sanction non-compliance in real terms. Such sanctions could include withholding of future funding for non-compliance with stated data and materials management plans or delays in publication until deposit is made, as is currently applied to genomics sequence data.95

                                                                                                               
95

For withholding future funding for non-compliance see Caulfield, Harmon and Joly, above n 28. The journal Science requires that the “appropriate data sets (including microarray data, protein or DNA sequences, atomic coordinates or electron microscopy maps for macromolecular structures, and climate data) must be deposited in an approved database, and an accession number or a specific

EAP  22    

Managing Intellectual Property to Promote Pre-Competitive Research  

Unfortunately, some of the perverse incentives for patenting of research tools, which hinder the creation and maintenance of a research commons, derive, ironically, from funders for whom patents have become a metric for research impact. Academic institutions through their TTOs also value patenting and licensing activities, which have become the main metrics of success for a TTO96 and increasingly for the evaluation of research faculty. At the same time, it is widely recognised that most patents are without value and most TTOs in developed countries do not generate enough revenue to sustain their own operations.97 It is therefore imperative for the construction of a robust research commons that will extract the greatest value from publicly funded research that funders of research institutions align incentives and metrics with the goals of resource sharing and collaboration.

8

Conclusions

In conclusion, this article has applied a commons framework to help the model organism community structure institutions and rules to facilitate bioresource sharing. Rather than focussing on formal IPRs and legislative reform of the patent system, including debates on patentable subject matter, we have focussed on the attempts by one community to operationalise softlaw and norms to achieve a research commons. While policies and guidelines are a step in the right direction and will likely influence community norms towards the sharing of bioresources, they will not have the maximum desired effect without more thought given to enforcement. Currently, enforcement of existing policies for resource deposition is highly variable98 and accordingly some of the answers must lie with funders and journals who may insist on compliance with sharing policies. Community sanctioning and disapprobation of free-riders has not proven sufficient and needs to be backed by enforcement from funders, journals and research institutions. In addition, parts of the community, particularly research institutions and their TTOs or research contracts offices act as significant impediments to a viable research commons. These institutions need to re-evaluate their patenting and licensing practices in light of existing best-practice guidelines and the needs of the community as a whole. A simple financial calculation should indicate that the return on public investment in the development of research tools is best served when these are made available to the research community and not appropriated. The cost of patenting far exceeds any returns from license fees in this domain in the vast

                                                                                                                                                                                                                                                                       
access address must be included in the published paper” as part of its submission policy. General Information for Authors, Science <http://www.sciencemag.org/site/feature/contribinfo/prep/gen_info.xhtml>.
96 97

Bubela and Caulfield, above n 29. Stuart MacDonald, “When Means become Ends: Considering the Impact of Patent Strategy on Innovation” (2004) 16 Information Economics and Politics 135. Schofield et al, above n 8.

98

 

EAP 23

Journal of Law, Information and Science

Vol 22(1) 2012  

majority of cases, while the implications of patenting and exclusive licensing have significant negative consequences for research as a social enterprise.99 A combination of existing community norms, rule development, incentive structures, and adequate enforcement will all contribute to adaptable institutions to manage a bioresource commons ready to respond to changing technologies and research environments. The model organism communities have excelled at grass-roots-up organisation and innovation and the movement to implement a true science commons based on community norms has gathered considerable momentum. Influencing the other actors in the game, the funding agencies, research institutions, TTOs and journals is the next major challenge.

Acknowledgments
We would like to thank Edna Einsiedel and David Hik for comments on the manuscript, as well as research assistance from Noelle Orton. Amir Reshef edited the final manuscript and completed the footnotes. TB and CR acknowledge support from Genome Canada and Genome Prairie (NorCOMM I and NorCOMM II projects). PNS acknowledges support from the European Commission Framework 6 Contract number LSHG-CT-2006-037811, CASIMIR.

                                                                                                               
99

Murray, above n 37.

EAP  24    

Sign up to vote on this title
UsefulNot useful