Stem Cells: Patents and Related Legal Issues
STEM CELLS: PATENTS AND RELATED LEGAL ISSUES
Introduction
Although the existence of stem cells was speculated for some time, it was only in the 1990s that the first stem cells were isolated. As of May 2002, 2000 patents relating to stem cell technology were filed, about a third of them have issued. Of the applications involving embryonic stem cell one quarter have been granted.
In the field of embryonic stem cells, the leading breakthroughs came from scientists such as James A. Thomson from the University of Wisconsin, John D. Gearhart at Johns Hopkins School of Medicine, and Austin G. Smith and Peter S. Mountford at the University of Edinburgh. Thomson was the first to isolate primate embryonic stem cells, more particularly human embryonic stem cells and to develop a method for isolating the same. Gearhart was the first to isolate and develop human embryonic pluripotent germ cell lines. Smith and Mountford developed methods for the preparation of transgenic animals. Each of these institutions has patented their technologies, and has granted exclusive commercial licenses in certain fields to or entered into collaborative partnerships with Geron Corporation.
Due to their ability to regenerate and develop into various cell types, stem cells have great therapeutic potential in areas of transplantation, regeneration (e.g. spinal cord and other nervous system disorders), autoimmune conditions, cancers and in conditions such as Parkinson's, Alzheimer's, and Multiple Sclerosis.
However, very few technologies in the life sciences are without controversy. Although, the technology can have many uncontroversial benefits, it can also be used for purposes that evoke public concern such as human cloning. The source of stem cells from humans, especially embryonic stem cells, is especially controversial, and some have argued that such technologies should not be patented. But as Justice Ian Binnie in the minority decision of the Harvard College v. Canada (Commissioner of Patents) stated, "…regulation necessarily follows, rather than precedes, the invention. No doubt most people would agree that nuclear technology requires regulation; yet the regulation could hardly have been anticipated in 1869, decades before Ernest Rutherford, while at McGill University, with Frederick Soddy, first formulated the theory of atomic disintegration. Prescription drugs are regulated, but the regulatory structure for new drug approval is not in the Patent Act. The grant of a patent does not allow the drug to be marketed. Nor should it. Health and safety are not, and never have been, the preoccupation of intellectual property legislation".
Governments around the world are grappling with the idea of how this technology should be best regulated to address moral and ethical concerns while still encouraging research and development.
The object of this paper is to give the reader an overview of the science of stem cells, the cause of the related moral and ethical issues, and the current patent and regulatory framework in Canada, the United States and Europe. As a case study, the relationship between the University of Wisconsin and Geron Corporation will be discussed, as well as its implications on third party embryonic stem cell research.
The Science
Stem cells are cells that can differentiate into other cell types. Their importance to the research and medical fields lie in the fact that they are unspecialized cells that can renew themselves for long periods of time through cell division but under certain conditions they can differentiate into other more specialized cell types.
Among the major issues with stem cells are how undifferentiated or unspecialized they are and how broad a range of different cell types they have a potential to form. Cells that can differentiate into any other cell type are totipotent. A fertilized egg is totipotent. As the fertilized egg divides, additional totipotent cells are created. At day 4-5 after fertilization, the ball of cells organize into an outer layer that will become the placenta and an inner layer called the inner cell mass. The cells of the inner cell mass will form the tissues of the developing body and can differentiate into many if not any other cell types except for those giving rise to the placenta. These cells are pluripotent. Such cells include embryonic stem cells but most recently there is also data to suggest that pluripotent adult stem cells exist. , This would indicate that the adult stem cells can differentiate into more than just the cell type from the tissues from which they are derived. As the pluripotent cells divide further, they become more specialized and give rise to progenitor cells of various cell lines, such as adult blood, skin and neural and gut stem cells. These multipotent or restricted cells can give rise to multiple cell types within an organ. ,
The great potential of stem cells for therapeutic purposes has resulted in an exponential growth in stem cell research. However, supplies are limited. There are thought to be two main sources of stem cells: embryonic stem cells and adult stem cells.
Embryonic stem cells are generally derived from the inner cell mass of 5 to 6 day old embryos called blastocysts. As such, embryonic stem cells can be derived from embryos that develop from eggs fertilized in vitro and then donated for research purposes. They can also be derived from human fetuses from terminated pregnancies by isolating the region that would have become the ovary or testis, and subsequently culturing the cells to result in a pluripotent cell line. Another source is from somatic cell nuclear transfer into an enucleated host oocyte that is cultured until the internal cell mass forms and the cells are propagated as noted above. Yet another source is to activate development of an unfertilized egg until formation of the inner cell mass, at which point the embryonic stem cells can be isolated and propagated as desired.
Adult stem cells are present within some adult tissues and can theoretically be derived therefrom, such as from skin biopsies and the bone marrow. , In another example neuronal stem cells could be obtained from adult brain tissue during surgical treatment or potentially from cadavers.
Once a source of stem cells is obtained, the question then becomes how to best maintain them in their undifferentiated state and how to control there differentiation into desired cell types. Examples of how this can be done include the activation or inhibition of the expression of specific genes and control of the cell culture environment (the presence or absence of certain factors such as hormones, cytokines, etc.., and possibly other conditions such as pH, temperature, cell concentration, etc…). For instance, to maintain embryonic stem cells in their pluripotent state, it has been found that they must express the extrinsic transcription factor Oct4 and receive the extrinsic signal from cytokine leukemia inhibitory factor (LIF). Withdrawal of LIF from the culture media results in the aggregation of embryonic stem cells to form embryoid bodies where they differentiate into various cell types. The presence of certain factors within the culture media can direct the differentiation of these cells into certain cell types.
One of the reasons stem cell research has become one of the most recognized areas in medicine is their potential use in regenerative and reparative medicine. For example, stem cells could supply replacement cells for degenerative diseases or for the treatment of traumatic injuries. Stem cells can be used for the endless supply of nerve cells for the treatment of Parkinson's disease or spinal cord injury, pancreatic islet cells to treat diabetes, blood cells to treat anemia and muscle cells to treat muscular dystrophy. Transplantation can be done with unmodified or genetically modified stem cells or differentiated cells derived therefrom.
Other applications include the identification and diagnosis of certain medical conditions. As many of our more serious medical conditions, such as cancer and birth defects, are due to abnormal cell specialization and cell division, a study of stem cells may assist in our knowledge of how these conditions develop and how to treat them. In another aspect stem cell research can assist in drug development and drug screening. The testing of the safety and efficacy of drugs in cell lines of different types would not replace clinical trials but can streamline it.
Ethical Issues
There are a number of contentious ethical issues that relate to stem cell research. These issues include but are not limited to the use of an embryo, especially a human embryo as a source of cells. There are also concerns that stem cell research will lead to the comodification of human reproductive tissue and the coercion of donors. Another area of concern is the experimental use of stem cells to create chimeras (hybrid human and non-human entities) and human clones. The patenting (or ownership) of human cells or technology derived therefrom is also an issue for many. Governments are playing catch-up with the new technology to study the implications of these emerging issues and to decide on whether additional legislative and regulatory provisions are required. The legislative and regulatory framework in Canada, the United States and Europe is briefly reviewed below.
Patenting And The Regulation Of Stem Cell Technology
A patent provides the patent holder the right to exclude others from exploiting the invention in a particular jurisdiction for a particular length of time. However, this exclusive right is not an unregulated right to actively exploit the invention. The right is subject to other laws within the jurisdiction that may prohibit certain activities. Although there is much uniformity between the patent laws of various jurisdictions, there are differences, especially when it comes to subject matter related to the life sciences. Therefore what may be patentable in the United States may or may not be patentable in Canada or Europe. Generally, for an invention to be patentable it must be new, non-obvious, have economic utility and be of a subject matter that is permitted to be patented under the laws of the respective country.
The subject matter of the technologies that arise from the field of stem cell research include but are not necessarily limited to the following:
Method of isolating and detecting stem cells
Isolated stem cells
Method of proliferating stem cells
Method of differentiating stem cells, method of obtaining certain cell types from stem cells and maintaining them as a source of such cells
Isolated differentiated cells
Genetically modified stem cells and cells derived therefrom and methods of making same
Applications for any and all of the above, including research/diagnostic tools, therapeutic tools for the treatment of certain medical conditions and diseases, aesthetic implications, cloning of cells, cloning of organisms.
A discussion of how the above subject matter is dealt with by the patent laws in Canada, Europe and the United States follows. The lack of patentability of certain inventions may deter research and development in a particular jurisdiction. In addition, the development of inventions in this field may also be limited by various regulatory restrictions on the source of stem cells and type of research that can be conducted.
4.1.1 Patent Law
In Canada, the Patent Act gives the patent holder an exclusive right to make, use and sell the invention encompassed within the scope of the claims of a patent. A patent will only be granted for categories of inventions defined in the Patent Act. The subject matter of the invention must fall within the definition of invention in section 2 of the Act, which is any new, non-obvious and useful "art, process, machine, manufacture or composition of matter". The invention must also not fall within any of the exclusions specified in subsection 27(8) of the Patent Act: "no patent shall be granted for any mere scientific principle or abstract theorem." Laws of nature and other mere discoveries are encompassed within the scope of this exclusion. If the invention meets the requirements then the Commissioner of Patents must grant a patent unless the applicant is not by law entitled to be granted a patent.
In the recently decided Harvard College v. Canada (Commissioner of Patents) the majority of the Supreme Court of Canada held that higher life forms, such as genetically modified organisms, plants and seeds, did not come under the definition of "composition of matter" in the Patent Act and was thus not patentable subject matter. In that decision the Court expressly stated that its decision would not interfere with the status quo established in prior decisions of Re Application of Abitibi Co. and Pioneer HiBred and the Commissioner's decision of Harvard Mouse that stated that lower life forms, such as microorganisms, yeasts, moulds, fungi, bacteria, actinomyocetes, unicellular algae, cell lines, viruses or protozoa are patentable. The Court further did not interfere with the prior Commissioner's decision that process claims for the manufacture of the genetically modified mouse were patentable. Further it should be noted that methods of medical treatment are not patentable in Canada. However "use" claims of compounds or devices for the treatment of a medical condition are patentable. The decision in Harvard College, is also important as the Court expressly did not adopt the United States interpretation of "composition of matter" as established in Diamond v. Chakrabarty that is "anything under the sun that is made by man".
A search of the Canadian patent database on January 26, 2003 with the search term "stem cell" revealed 685 patents and patent applications of which 35 were issued patents. From a review of these patents and the case law, it would appear that as long as the novelty, obviousness and utility requirements are met, isolated stem cells, new cell lines, methods of isolating, identifying, proliferating, differentiating and using them would be patentable but the "method of medical treatment" and "higher life form" would not. Of the 35 Canadian patents, sample claims include the following:
1. A use of an effective quantity of interleukin -1 (IL-1) in conjunction with an effective quantity of a colony stimulating factor for inducing proliferation and differentiation of hemopoietic stem cells in a mammal.
Canadian Patent No. 1290688, to Immunex Corporation, issued October 15, 1991
1. A composition for use in enhancing the production of white blood cells, including neutrophils, from stem cells which comprises an effective amount of recombinant colony stimulating factor-1 (CSF-1) as an active ingredient in admixture with at least one pharmaceutically acceptable excipient.
Canadian Patent No. 1322158 to Cetus Corporation
1. A cell composition consisting essentially of a viable, substantially homogenous cell population of stem cells from an identical genetic or congenic source having the phenotype Thy-l10Lin-Sca-l+', and a medium appropriate for storage, proliferation, or differentiation of said stem cells.
Canadian Patent No. 1340607 to The Board of Trustees of the Leland Stanford Junior University
4.1.2 Legislation, Regulations and Guidelines
Certain recommendations and legislation are currently being considered by Parliament.
The Canadian Biotechnology Advisory Committee (CBAC) prepared a final report in June 2002 on "Patenting of Higher Life Forms and Related Issues" in which they recommended that "human bodies at all stages of development" should not be patentable. CBAC explains that this recommendation only applies to entire human bodies such as zygotes to an adult body but does not include nucleotide sequences, gametes, stem and other cells, or organs that remain patentable.
Bill C-13
As of Janaury 26, 2003, there is no law regulating human cloning or the acquisition and use of embryonic stem cells. However, Bill C-13, "An Act Respecting Assisted Human Reproduction" is currently before Parliament. If it passes, the Bill will regulate the use of embryos for research. The Bill passed its First Reading in the House of Commons on October 9, 2002. This Bill was not specifically designed to regulate stem cell research, but rather to regulate reproductive technologies. There are, however, a number of sections in this Bill, which will affect stem cell research.
The Bill sets up two types of activities: (1) prohibited activities and (2) controlled activities.
Prohibited Activities
The prohibited activities under this Bill include the creation of human clones; the creation of an in vitro embryo for any purpose other than creating a human being or for improving assisted reproduction procedures; the maintenance of an embryo outside a woman after 14 developmental days; the alteration of the germ line of a human being or in vitro embryo; the transplantation of non-human gametes into a human being; the creation of chimeras; the purchase or sale of gametes or embryos; and the use human reproductive material without the requisite consent of the donor. A contravention of one of the prohibited activities is a criminal offence. It should be noted that the 14-day cut off period for maintenance of an embryo outside a woman is based on the fact that at about 14 days after fertilization, the cells of a human embryo lose their ability to form other embryos and acquire individuality.
Controlled Activities
Activities, which are defined as controlled activities may only be carried out in accordance with the regulations and the obtaining of a license. Controlled activities include altering or manipulating any human reproductive material for the purpose of creating an embryo; altering, manipulating, treating or using an in vitro embryo; storing, transferring, destroying, importing or exporting any human gamete or in vitro embryo; or reimbursing expenditures incurred by donors or surrogate mothers. A contravention of one of these controlled activities is a criminal offence.
Affect on Stem Cell Research
This Bill affects access by a researcher to in vitro embryos for research purposes. Pursuant to this Bill, in vitro embryos can only be created for two purposes: (1) reproduction purposes and (2) research directed to improve assisted reproduction procedures. The creation of in vitro embryos for research, other than the limited exception to improve assisted reproduction procedures, is a prohibited activity. Thus a researcher cannot simply create an in vitro embryo as a source to supply stem cells. If in vitro embryos are created for reproduction purposes and they are no longer required for reproduction, then they can be donated to research with written consent from the embryo donor. Thus a researcher is able to obtain in vitro embryos for research, but only if the in vitro embryos were created for reproduction, no longer required for reproduction and donated to research with consent.
In addition to influencing access to in vitro embryos, the Bill also affects the kinds of research that can be conducted using in vitro embryos. The alteration, manipulation, treatment or making use of an in vitro embryo is a controlled activity. Thus any research which uses in vitro embryos must comply with the regulations and the researcher must have a license. The Agency, which is responsible for issuing licenses for controlled activities, would be the Assisted Human Reproduction Agency of Canada, an agency that would be newly established under this Bill. The Bill states that licenses for research on in vitro embryos may be issued only if the Agency is satisfied the use of such embryos is necessary for the purpose of the proposed research. This Bill governs the use of in vitro embryos for research and establishes the test which needs to be satisfied before the research is permitted. This Bill does not govern the further steps in research such as the use of the cell lines derived from in vitro embryos.
Research Funding Guidelines
As mentioned above, at the moment there is no law that regulates stem cell research or the use of in vitro embryos. However there are voluntary guidelines that regulate research on human reproductive material. The Tri-Council Policy Statement sets out a number of guiding principles to govern research that involves human subjects including respect for human dignity, respect for free & informed consent, respect for vulnerable persons, and respect for privacy & confidentiality. The guideline applies to all researchers and institutes that receive funding from one of the following funding agencies: (1) Canadian Institutes of Health Research; (2) Social Sciences and Humanities Research Council; and (3) Natural Sciences and Engineering Research Council.
An extension was made to the Tri-Council Policy Statement in March 2002 to encompass stem cell research. This guideline is entitled: "Human Pluripotent Stem Cell Research: Guidelines for CIHR-Funded Research." This Guideline encompasses all forms of stem cell research. It states that the Canadian Institutes of Health Research will not fund the creation of embryos for research purposes or cloning. In addition, consistent with the proposed Bill discussed above, researchers can have access to embryos, but only if they were created for reproduction purposes and no longer needed, and were donated to research with consent.
Difference Between Current Guidelines and Proposed Bill
Stem cell research is currently regulated by voluntary guidelines set by the Canadian Institutes of Health Research. It applies to all researchers and research institutes which receive federal funding from this agency. If the guidelines are contravened, then the researcher or research institute will lose their funding. Private research is not regulated by this mechanism.
Proposed Bill C-13 will regulate not just federally funded research, but all research using in vitro embryos. Failure to obey this mechanism of regulation is a criminal offence, which may result in fines and/or jail time.
4.2 - Europe
4.2.1 Patent Law
The European Patent Convention sets up a unified system of procedures and standards for examining a patent application for contracting states.
The European Patent Convention establishes a number of statutory requirements for patentability including novelty, inventive step and industrial application. The European Patent Convention also sets out a couple of express exclusions to patentability. Pursuant to Article 53(a) there is an exception to patentability for inventions that violate "ordre public" or morality. Under Article 53(b) there is a prohibition on patents for biological methods for the production of animals and plants. In addition, under Article 52(4) there is a prohibition for the patenting of medical treatments, however "use" claims for the use of a substance in the preparation of a medication for the treatment of a medical condition, are acceptable.
Unlike the patent system established by the European Patent Convention, the patent system in the United States does not have such express exclusions to patentability within their Patent Act. In Canada, the patent system does have some express exclusions to patentability, however none are as broad as the exception in Europe against inventions that violate "ordre public" or morality.
Although the European Patent Convention unifies the procedures and standards for examining a patent application, the interpretation and enforcement of a patent is left to each individual nation. In 1998, the European Union issued Directive 98/44/EC as a method of unifying the legal protection of biotechnological inventions within member states. This Directive provides patent law protection for biotechnological inventions, and sets up a number of express exclusions to patentability. These exclusions include patenting animal and plant varieties and inventions whose commercial exploitation would be contrary to "ordre public" or morality. In addition, the human body and its gene sequences are excluded from patent protection, unless the gene sequence is isolated from the human body. Further, patents on processes for modifying the germ line genetic identity of human beings, processes for cloning human beings and uses of human embryos for industrial or commercial purposes are prohibited on the ground that such processes are contrary to "ordre public" and morality.
This Directive was a response to the University of Edinburgh's Patent No. EP 0695351, which was issued in 1999 by the European Patent Office and entitled: "Isolation, Selection and Propagation of Animal Transgenic Stem Cells." , The patent was challenged through opposition procedures in the European Patent Office because the claims extended to a method of somatic cell nuclear transfer in "animals" which included humans. Critics held that this patent encompassed human cloning and the creation of transgenic animals, including humans. The opponents argued that the patent contravened Article 53(a) of the European Patent Convention and Article 6(1) of the European Union Biotechnology Directive, which prohibits the patenting of inventions that are contrary to "ordre public" or morality. The University of Edinburgh amended the patent claims to no longer cover human or animal embryonic stem cells, but it still covers modified human and animal non-embryonic stem cells. On July 24, 2002 the Opposition Board upheld the amended claims and confirmed the rejection of human embryonic stem cell embodiments of the invention as being contrary to morality (Rule 23d(c) & Article 53(a) of the EPC) and not patentable before the EPO A subset of the allowed independent claims can be found in Appendix 'A' hereto.
4.2.2 Legislation, Regulations and Guidelines
Restrictions on stem cell research and development in Europe varies from country by country. For instance in England, the regulations are slightly more liberal than those proposed in Canadian Bill C-13. In England and Sweden, the creation of embryos for research purposes is permitted, but research on human embryos is only permitted on embryos up to 14 days old. As of June 2001, reproductive cloning is prevented by the National laws of Austria, Denmark, Finland, France, Germany, Italy, Norway, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Stem cell research is permitted by the National laws in Denmark, Finland France, Italy, Spain, the United Kingdom. Research on aborted foetuses is permitted in Denmark, Finland, France, Germany, Italy, Spain, Sweden and the United Kingdom. Research on human embryos is permitted in Denmark, Finland, Hungary, Spain, Sweden and the United Kingdom. Research on human embryos is not permitted in France, Germany, Italy, or Norway. Many of the other countries do not have express laws dealing with these issues.
4.3 - United States
4.3.1 Patent Law
Similar to the law in Canada, a patent granted by the United States gives the holder of the patent the right to exclude others from making, using or selling the invention. The patent does not give the holder the right to actually make, use or sell the invention if there is other law that would prohibit such activity.
In order for an invention to be patentable, it must fall within one of the four statutory classes of subject matter: process, machine, manufacture or composition of matter. In addition, the invention must have utility. This means that the invention must be operable and have practical use. Other requirements for patentability include novelty and non-obviousness.
Patent law in the United States allows the patenting of "anything under the sun that is made by man," as long as the requirements for patentability are satisfied. The United States Patent and Trademark Office rarely consider arguments against patentability based on public policy and morality grounds. Stem cells and related research are considered patentable subject matter as long as the other requirements of patentability are met. Several patents have issued with claims directed to processes of creating stem cells, to the stem cells themselves and to methods which use stem cells. Although higher life forms, such as genetically modified mice are patentable, it has been argued that Congress did not intend to allow patents on humans per se and that granting patents on people would violate the 13th Amendment to the Constitution abolishing slavery. This was the position taken by the United States Patent and Trademark Office in a 1987 notice. This did not extend to claims to a process for human cloning. However, there was proposed legislation ("Human Cloning Prohibition Act of 2001) to prohibit the act of both replicative and therapeutic cloning which if enacted would obviously impact on the development of such inventions in the United States.
4.3.2 Legislation, Regulations and Guidelines
Similar to the current Canadian system, there are no comprehensive laws in the United States that govern stem cell or embryo research. The laws that do exist regulate only government funded research and not private research. In addition to the Federal regulations discussed below, each State has different laws with regard to the use of human embryos in State funded research. However, some State laws are non-existent.
Regulation of Research using Embryos
There is regulation of research using embryos at the Federal level. This law only applies to federally funded research and prohibits federal funds being used for "research that involves the creation of a human embryo or in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury… greater than that allowed for research on fetuses in utero." This regulation does not specifically apply to research on stem cell lines, but only on the use of human embryos in research. As such it does have implications on stem cell research.
Regulation of Research using Fetuses
There is also Federal regulation of research that uses human fetuses. Under this law government funded research that uses fetal tissue is allowed in transplantation studies for therapeutic purposes provided that the fetal tissue is from aborted or stillborn fetuses and the researcher obtains the requisite consent. The definition of fetal tissue in this regulation is broad enough to include both cells and tissues and thus will likely encompass stem cells derived from fetuses. This regulation does not deal with research per se and only deals with "transplantation" of stem cells derived from fetal tissue into human tissue.
Regulation of Stem Cell Research
Federally funded stem cell research is regulated thorough funding guidelines introduced by President Bush on August 9, 2001. Under these guidelines Federal funds will be provided for research using "stem cells derived from embryos existing as of August 9, 2001, that were derived with the informed consent of the donors, from excess embryos created solely for reproductive purposes and without any financial inducements to the donors. The government has stated that are approximately 64 stem cell lines worldwide that reportedly meet these guidelines and has created an NIH Stem Cell Registry listing the acceptable cell lines". However this number is being disputed as many cell lines listed on the NIH registry of stem cells are not available or do not exist.
Under the guidelines, federal agencies will not provide funding for research involving "(1) the derivation or use of stem cell lines derived from newly destroyed embryos (after August 9, 2001); (2) the creation of any human embryos for research purposes; or (3) cloning of human embryos for any purposes". In addition to the new guidelines, a President's Council on Bioethics was established to study stem cells and embryo research as well as other issues. In conjunction with the new guidelines, the President affirmed its commitment to fund research involving "stem cells from other sources, e. g., umbilical cord, placenta, adult and animal tissues".
There are a number of problems that have been reported with these guidelines. First, critics are concerned that the number of stem cell lines predicted to actually satisfy the requirements of this guideline has been overestimated. Third, these guidelines only apply to federally funded research, and not to privately funded research. Therefore stem cell research funded by private sources is not regulated. Although concerns have been expressed on the availability of some of the cell lines that are covered by patents , the Federal government has established agreements with some of the patent owners to ensure availability of the cell lines to federally funded researchers. These agreements, include those with WiCell Research Institute, Inc. for the Wisconsin Alumni Research Foundation of the University of Wisconsin – Madison (WARF), patents developed by Dr. Thomson (US Patents 5,843,780; 6,200,806 and Application No. 09/522,030 and related foreign rights). The agreement dated September 5, 2001 provides for the availability of WARF's cell lines to federally funded researchers for a nominal transmittal fee not exceeding $5000.00. Similar agreements were entered into with BresaGen, Inc. dated April 24, 2002, The Regents of the University of California, dated April 26, 2002 and ES Cell International Pte. Ltd. dated April 5, 2002. It is interesting to note that the cell lines covered in the three latter agreements were dominated by the prior WARF patents. These agreements account for four of the eleven parties that have been identified to have ownership rights in the 64 stem cell lines identified on the registry. The full list of the parties and number of cell lines are as follows: BresaGen, Inc., Athens, Georgia (4); CyThera, Inc., San Diego, California (9); ES Cell International, Melbourne, Australia (6); Geron, Inc., Menlo Park, California (7); Göteborg University, Göteborg, Sweden (19); Karolinska Institute, Stockholm, Sweden (6); National Centre for Biological Sciences/ Tata Institute of Fundamental Research, Bangalore, India (3); Reliance Life Sciences, Mumbai, India (7); Technion University, Haifa, Israel (4); University of California, San Francisco, California (2); Wisconsin Alumni Research Foundation, Madison, Wisconsin (5).
Independent of the NIH agreement, WiCell/WARF appear to be committed to make their cell lines available to academic researchers as further detailed below.
Wisconsin Alumni Research FOUNDATION Versus Geron Corporation
5.1 - Original Agreement
Geron obtained a worldwide exclusive license, in 1999, from the Wisconsin Alumni Research Foundation for the embryonic stem cell technology developed by Dr. Thomson for isolated primate embryonic stem cells. This research is the subject of certain patents as noted previously in this paper. The license granted Geron the exclusive right to six cell types for therapeutic and diagnostic products, and entitlements to commericalize certain research products based on these cell types. The six cell types were heptatocytes, myocytes, neural cells, pancreatic islet cells, hematopoietic cells and osteoblasts. Under the agreement Geron also obtained a first option to negotiate an exclusive license for additional cell types. A copy of the option provision (section 2C of the agreement) is reproduced in Appendix B hereto.
5.2 - Dispute
A dispute arose between Geron and the Wisconsin Alumni Research Foundation when Geron attempted to exercise its option for additional cell types. The Wisconsin Alumni Research Foundation denied Geron's right to these additional cell types. While Geron's position was that WARF, under the Agreement did not have the discretion to exhaust Geron's option rights and to deny Geron's request to the additional rights. In August, 2001, the Wisconsin Alumni Research Foundation applied to the Federal District Court in Madison to interpret the original license agreement.
5.3 - Settlement
On January 8, 2002 Geron and Wisconsin Alumni Research Foundation reached a settlement to the lawsuit surrounding their original licensing agreement. The parties entered into a new licensing agreement for the commercialization of the embryonic stem cell technology. Under the new license Geron negotiated exclusive rights to develop therapeutic and diagnostic products from the neural cells, cardiomyocytes and pancreatic islet cells developed from the human embryonic stem cell technology. In addition, Geron obtained non-exclusive rights to develop therapeutic and diagnostic products from the hematopoietic, chondrocyte and osteoblast cells developed from the human embryonic stem cell technology. In the settlement Geron also obtained a non-exclusive right to develop research products using the hepatocytes, neural cells, hematopoietic cells, osteoblasts, pancreatic islets and myocytes.
The new licensing arrangement also provides access to the patented stem cell materials to governmental, academic and non-profit researchers without royalties or fees. A third party for-profit company does not have free access to the patented stem cell materials and has to negotiate a collaboration or license directly with Geron and/or WARF as the case may be.
5.4 - Third Party Impact
A lag in stem cell research was reported a year after President Bush altered the Federal funding guidelines directed at stem cell research. The guideline limits Federal funding on research involving stem cells to stem cell lines existing as of August 9, 2001. Unfortunately a number of the existing stem cell lines approved for research were not in good shape to be transported to researchers. In addition, access to some of the approved stem cell lines was limited because of patent rights, such as the patents held by the University of Wisconsin and licensed to Geron.
Non-profit researchers and academic scientists were given free access to the stem cell lines controlled by Geron and the University of Wisconsin in the negotiated settlement agreement between these two parties. As a result, government, academic and non-profit researchers have access to these stem cells, and can continue research on these stem cells without jeopardizing their access to federal funding.
Third party for-profit companies can only have access to the Geron-controlled stem cell lines through collaboration or licensing arrangements with Geron.
5.5 - Implications in Canada
The WARF inventions are pending patent applications in Canada. They have not yet been allowed. A copy of the independent claims currently pending in Canada are attached hereto at Appendix C. Although only granted patents can be enforced against third parties, once issued, compensation can be obtained by WARF for infringement occurring from the date of publication of the patent application. The agreements between the NIH and WiCell only apply to US Federally funded researchers and do not extend to researchers funded by other sources. However, WiCell is committed to making their cell lines available to government, academic and non-profit researchers throughout the world and have established reasonable provisions to ensure that this occurs.
Conclusion
Although stem cell research raises religious, moral and ethical concerns, it has far reaching potential for beneficial applications. Governments are trying to address and balance these benefits with the concerns of their respective societies through legislation and regulations.
The current patent environment in Canada and the United States (although more so in the United States) is fairly favourable to granting patent rights in most areas of stem cell research while Europe has much more restrictive provisions. In contrast, it is interesting to note that while the United States has taken the most expansive position with regard to the granting of patents arising from stem cell research, it has taken one of the more restrictive positions with regard to funding of this research. The opposite is true in certain European countries such as the United Kingdom.
Although the current range of stem cell research activities that can be conducted by commercial entities is quite open in the US, Canada and certain parts of Europe, they are faced with having to negotiate license agreements from current patent holders of dominating technology.
Government, academic and non-profit researchers have more access to materials from certain patent holders, however, the scope of their research may be limited, in certain jurisdictions, such as in the United States, depending on their funding source.
If Bill C-13 passes, all researchers in Canada will be subject to the provisions thereof irrespective of funding source or commercial status.
With regard to the traditional general concern by the academic community that patents can hinder certain research activities, the Geron/WARF settlement is a refreshing look at how academic research and scientific development can be maintained while still promoting the commercial interests of the parties.
APPENDIX A
Independent Claims allowed in EP0695351, entitled: "Isolation, Selection and Propagation of Transgenic Stem Cells"
1. A method of isolating and/or enriching and/or selectively propagating desired animal stem cells other than embryonic stem cells, which comprises maintaining a source of said cells under culture conditions conducive to cell survival, characterized in that the source of the cells includes stem cells containing a selectable marker which is capable of differential expression in (a) desired stem cells of said source and (b) cells of said source other than the desired stem cells, whereby differential expression of said selectable marker results in preferential isolation and/or survival and/or division of the desired stem cells containing the said selectable marker.
31. An animal cell other than an embryonic stem cell capable of being cultured to form a mixture of cells including desired stem cells and cells other than the desired stem cells, characterized in that all cells in the said mixture of cells contain a selectable marker and in that in the said mixture of cells, under appropriate selective culture conditions, differential expression of the selectable marker in (a) the desired stem cells and (b) cells other than the desired stem cells enables selective survival or growth of the desired stem cells to occur, so as to enable isolation and/or enrichment and/or propagation of desired stem cells.
APPENDIX B
Section 2(c), Option Provision in the Wisconsin Alumni Research Foundation/ Geron Licensing Agreement
WARF hereby grants Geron the first option to negotiate an exclusive license for addition of cell types to the Licensed Field. Geron may exercise its option under this Section 2C by providing WARF with written notice of its desire to add a cell type to the License Field including a Development Plan detailing Geron's plan and timeline for bringing Products to market incorporating the new cell type and by paying WARF an upfront license fee to be negotiated in good faith between the parties factoring in commercially reasonable terms given the advancement of cell therapy in therapeutics an diagnostics and the value added by Geron. The terms of the exclusive license, other than the upfront license fee, shall be identical to the terms set forth in this Agreement, unless otherwise negotiated and agreed to by the parties. If the parties fail to agree on an upfront license fee for an additional cell type, WARF agrees that it will not offer such cell type to any third party on terms more favorable as a whole to such licensee than were offered to Geron hereunder for a period of eighteen (18) months from the date Geron first exercised its option to add a cell type to the Licensed Field. In the context of this Agreement, "terms more favorable as a whole" shall mean that the combination of the commercial terms for example the license fee, royalty rate, milestones, minimum royalties and other fees required as consideration for the rights granted under the license are not more favorable when taken together than the package offered to Geron. The option to add cell types shall expire on March 31, 2001 unless extended for an additional period by written agreement on terms mutually agreeable to the parties.
APPENDIX C
Independent claims currently pending in the Dr. Thomson, Wisconsin Alumni Research Foundation Canadian patent applications
CA 2190528
1. A purified preparation of primate embryonic stem cells which (i) is capable of proliferation in vitro culture for over one year, (ii) maintains a normal karyotype through prolonged culture, (iii) maintains the potential to differentiate to derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) will not differentiate when cultured on a fibroblast feeder layer.
9. A method of isolating a primate embryonic stem cell line, comprising the steps of:
(a) isolating a primate blastocyst;
(b) isolating cells from the inner cell mass of the blastocyte of (a);
(c) plating the inner cell mass cells on embryonic fibroblasts, wherein inner cell massderived cell masses are formed;
(d) dissociating the mass into dissociated cells;
(e) replating the dissociated cells on embryonic feeder cells;
(f) selecting colonies with compact morphologies and cells with high nucleus to cytoplasm ratios and prominent nucleoli; and
(g) culturing the cells of the selected colonies.
CA 2342205
1. A primate embryonic stem cell that is MHC compatible to a selected donor, wherein the cell has been derived by transplantation of cell nucleus from a differentiated cell of the donor to an enucleated primate oocyte.
7. A method for producing the preparation of claim 4, comprising transplanting cell nucleus from a differentiated cell of a primate donor to an enucleated primate oocyte so as to provide embryonic stem cells coding for said donor's major histocompatibility complex.
CA 2390281
1. A method for obtaining human hematopoietic cells, comprising exposing a human embryonic stem cell culture to mammalian hematopoietic stromal cells so as to thereby create human hematopoietic cells.
CA 2400158
1. A method for producing primate embryoid bodies from colonies of primate embryonic stem cells that are adhering to a substrate, the method comprising: removing the adhering colonies of the embryonic stem cells from the substrate in clumps; and then incubating the clumps in a container under conditions in which the clumps are essentially inhibited from attaching to the container and coalesce into embryoid bodies.
