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EMBRYONIC STEM CELLS Commentary: Is Totipotency of a Human Cell a Sufficient Reason to Exclude Its Patentability Under the European Law? KATJA TRILLER VRTOVEC,a BOJAN VRTOVECb a Max Planck Institute for Intellectual Property, Competition and Tax Law, München, Germany; bLjubljana University Medical Center, Ljubljana, Slovenia Key Words. Embryonic stem cells • Totipotent stem cells • Patents • Bioethics ABSTRACT This article argues that totipotent character of human totipotent cells— defined as the capacity of a cell “to differentiate into all somatic lineages (ectoderm, mesoderm, endoderm), the germ line and extra-embryonic tissues such as the placenta”—is not a sufficient reason to exclude their patentability on the basis of Article 5(1) of the Directive 98/44/EC on the Legal Protection of Biotechnological Inventions (Biopatent Directive), which maintains that “the human body, at the various stages of its formation and development, [. . .] cannot constitute patentable inventions.” Since human totipotent cells have both the potential to generate an entire new organism or to generate only different tissues or organs of an organism, they simultaneously fit the definition of the unpatentable human body at the earliest stage of its formation as well as of an element of the human body, which “may constitute a patentable invention” pursuant to Article 5(2) of the Biopatent Directive, whether that element is isolated from the human body or otherwise produced by means of a technical process. Therefore, this article suggests that, when evaluating patentability of human totipotent cells, they should be further evaluated according to their location and their method of derivation (i.e., whether human totipotent cells are located in the human body, whether they are isolated from the human body, or whether they are produced otherwise by means of a technical process). STEM CELLS 2007;25:3026 –3028 Disclosure of potential conflicts of interest is found at the end of this article. INTRODUCTION The European Patent Office (EPO) defines totipotency as the capability of the cell “to differentiate into all somatic lineages (ectoderm, mesoderm, endoderm), the germ line and extraembryonic tissues such as the placenta” [1]. Totipotent cells thus retain the capacity to form an entire organism and produce a new individual unaided [2]. The EPO further specifies pluripotent cells as cells that are able “to differentiate into cells of at least two or three somatic lineages (ectoderm, mesoderm, endoderm)” [1]. Pluripotent cells are hence unable to form all the different types of cell of which the organism is composed; however, their differentiation potential is nevertheless broader than multipotent cells like those of the hematopoietic system [2]. The only human cells that have so far been shown to possess a totipotent character are blastomeres from early cleavage stages of an embryo [2]. Single blastomeres can be used for the derivation of pluripotent human embryonic stem cell lines (human ESC lines). Human ESC lines have no potential to generate a new and entire organism, especially not under in vitro conditions where they are derived [2]. Although the term embryo may seem clear in scientific terminology [3], legal documents do not use it in a consistent manner or may even lack any definition. In some national laws (e.g., the U.K.) it is used to describe any cell with the totipotent differentiation potential, regardless of its method of creation [4], whereas in other countries (e.g., Germany) it includes fertilized totipotent cells (e.g., a zygote) but not totipotent cells created by other scientific techniques [5]. To date, the EPO has not defined the scope of the term embryo [6]. Because legal documents are lacking a uniform legal terminology, this article will use the clear descriptive term totipotent cells, which in this context refers to any cell with the broadest developmental potential. According to the European Commission, “[human] totipotent stem cells should not be patentable, on grounds of human dignity” [7]. The Commission based its conclusion on the fact that “each [totipotent] cell could develop into a human being on its own and under Article 5(1) of the [Directive 98/44/EC on the Legal Protection of Biotechnological Inventions (Biopatent Directive) [8]] the human body at the various stages of its formation and development cannot constitute a patentable invention” [7]. The same position on the nonpatentability of human totipotent cells was taken by the UK Patent Office, which stated that “human totipotent cells have the potential to develop into an entire human body. In view of this potential, such cells are not patentable because the human body at the various stages of its formation and development is excluded from patentability [. . .]. The Patent Office will therefore not grant patents for human totipotent cells” [9]. An identical view is supported in legal and ethical literature [6, 10, 11]. In practice, five patent applications with claims to human totipotent cells or their derivatives are currently awaiting examination at the EPO [12], and 57 such patent applications are filed worldwide [13]. However, none of the patent-granting processes are bound to be resolved soon, since the EPO has currently suspended the examination of human ESC-related applications until the legal and ethical uncertainties are resolved [6]. Correspondence: Katja Triller Vrtovec, B.L., LL.M., Max Planck Institute for Intellectual Property, Competition and Tax Law, Marstallstrae 8, D-80539 München, Germany. Telephone: ⫹386 41 38 88 27; Fax: ⫹386 13 65 49 75; e-mail: [email protected] Received June 29, 2007; accepted for publication August 21, 2007; first published online in STEM CELLS EXPRESS August 30, 2007. ©AlphaMed Press 1066-5099/2007/$30.00/0 doi: 10.1634/stemcells.2007-0511 STEM CELLS 2007;25:3026 –3028 www.StemCells.com Vrtovec, Vrtovec It appears that the current European position on the nonpatentability of human totipotent cells is based on a notion that equalizes the totipotency of cells with the existing individualized new organism. The latter represents the human body, which “cannot constitute patentable inventions” under Article 5(1) of the Biopatent Directive. None of the cited positions, however, acknowledge the fact that human totipotent cells, besides their natural potential to generate an entire new organism [14], are also able—a potential they share with pluripotent human ESC lines [1]—to generate different tissues or organs of an organism when cultured and differentiated in vitro [15]. Pluripotent character of human ESC lines is namely the reason why human ESC lines represent the main research tool for the regenerative medicine of the 21st century [16]. Because of the unlimited differentiation potential of human totipotent cells, we can also equalize the totipotency of cells with an individualized element (cell, tissue, or organ) of the human body. The latter represents an element of the human body, which “may constitute a patentable invention” under Article 5(2) of the Biopatent Directive. Since human totipotent cells thus simultaneously fit the definition of the unpatentable human body as well as of a patentable element of the human body, their patentability cannot be excluded merely because of their totipotent character. Therefore, the aim of this article is to find an additional characteristic of human totipotent cells that would justify their current unpatentable status under the European law. GENERAL RULE ON THE PATENTABILITY OF BIOLOGICAL MATERIAL UNDER ARTICLE 3(2) OF THE BIOPATENT DIRECTIVE Article 2(1)(a) of the Biopatent Directive defines biological material as “any material containing genetic information and capable of reproducing itself or being reproduced in a biological system.” According to Article 3(2) of the Biopatent Directive, biological material may be the subject of an invention if it is isolated from its natural environment or produced by means of a technical process, even if it previously occurred in nature. Biological material in general is thus patentable if it is located outside its natural environment (i.e., in an in vitro setting). Biological material is not patentable if it is located in its natural environment (i.e., in an in vivo setting). Since human totipotent cells contain genetic information and are capable of reproducing themselves in a biological system, they fit the definition of biological material. Consequently, patentability of human totipotent cells should be investigated with regard to their position in their natural environment (i.e., their location inside or outside the human body). PATENTABILITY OF HUMAN TOTIPOTENT CELLS LOCATED IN THE HUMAN BODY UNDER ARTICLE 5(1) OF THE BIOPATENT DIRECTIVE Human totipotent cells located in a human body (i.e., a fertilized oocyte in a woman’s fallopian tube) can differentiate into an entire human body, which normally results in the birth of a new human being. By the natural course of development and without any in vitro manipulations, human totipotent cells located in the human body do not differentiate into a particular element of the www.StemCells.com 3027 human body (i.e., into different tissues or organs of an organism). Therefore, human totipotent cells located in a human body can only represent a human body at the earliest stage of its formation and development, which “cannot constitute patentable inventions” under Article 5(1) of the Biopatent Directive. PATENTABILITY OF HUMAN TOTIPOTENT CELLS LOCATED OUTSIDE THE HUMAN BODY UNDER ARTICLE 5(2) OF THE BIOPATENT DIRECTIVE Human totipotent cells located outside the human body, regardless of their way of derivation (e.g., a zygote explanted from a woman’s fallopian tube or a totipotent cell created in vitro by somatic cell nuclear transfer [SCNT] technique [17]), do not have the capability to differentiate into an entire human body on their own when left in an in vitro setting. It has not been shown that individual isolated blastomeres have the capacity to generate a complete organism in most mammalian species [15]. In addition, with recent technological advances, it is possible to generate human ESC lines from “nonviable” triploid zygotes, which cannot develop to term because they contain an extra set of haploid chromosomes, or from abnormal nuclear transfer blastocysts, which cannot implant into the uterus [6]. Therefore, human totipotent cells located outside the human body cannot be qualified as a human body at the earliest stage of its formation and development and should not be excluded from patentability solely on the basis of Article 5(1) of the Biopatent Directive. ETHICAL CONSIDERATIONS THAT MAY PRECLUDE PATENTABILITY OF HUMAN TOTIPOTENT CELLS LOCATED OUTSIDE THE HUMAN BODY UNDER ARTICLE 6 OF THE BIOPATENT DIRECTIVE Article 6(1) of the Biopatent Directive states that “inventions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality [. . . ].” Particular activities that are considered unpatentable include “processes for cloning human beings” under Article 6(2)(a) of the Biopatent Directive and “uses of human embryos for industrial or commercial purposes” under Article 6(2)(c) of the Biopatent Directive. Human totipotent cells located outside the human body could nevertheless be considered unpatentable due to ethical considerations depending on their method of derivation. Human totipotent cells located in vitro may either be produced by a natural process of fertilization or by other “techniques which human beings alone are capable of putting into practice and which nature is incapable of accomplishing by itself [e.g., SCNT technique, altered nuclear transfer]” as defined in Recital 21 of the Biopatent Directive. Isolation of a fertilized human totipotent cell (i.e., a zygote) from the human body for the purpose of culturing it in vitro should clearly be qualified as an unpatentable use of human embryos for industrial or commercial purposes. Patentability of human totipotent cells derived by artificial techniques and their derivative human ESC lines largely depends on the EPO’s interpretation of the word “embryo.” Patentability of these “cultural artifacts” [18] could only be threatened by ethical considerations when a broad interpretation of the word embryo (i.e., Patentability of Human Totipotent Cells 3028 including any cell with the totipotent differentiation potential, regardless of its method of creation) is used. It should also be noted that implantation of SCNT derived human totipotent cells to the female uterus could be considered an unpatentable process for cloning human beings. According to Recital 41 of the Biopatent Directive, the latter “may be defined as any process, including techniques of embryo splitting, designed to create a human being with the same nuclear genetic information as another living or deceased human being.” CONCLUSION In summary, current unpatentable status of human totipotent cells under the European law is not justified either by their totipotent character or by their location in a human body but rather by their method of derivation. The exclusion from patentability should obviously be justifiable for human totipotent cells that are created by natural process of fertilization whether located inside the human body or isolated from the human body. Conversely, the exclusion from patentability is probably not justifiable for human totipotent cells that are produced outside the human body by other “techniques which human beings alone are capable of putting into practice and which nature is incapable of accomplishing by itself” [8]. ACKNOWLEDGMENTS This work was prepared with the support of the Max Planck Institute for Intellectual Property, Competition and Tax Law, München, Germany, during the research at the Institute. DISCLOSURE 10 2 3 4 5 6 7 8 9 European Patent Office. Note under C12N5/06 of the European Patent Classification. Available at: http://v3.espacenet.com/eclasrch?ECLA⫽/ espacenet/ecla/c12n/c12n5.htm?q⫽5– 06b2p. Accessed April 14, 2007. Lanza R, Gearhart J, Hogan B et al. Essentials of Stem Cell Biology. 1st ed. Burlington, MA: Elsevier Academic Press, 2005:1–548. Wernig M, Meissner A, Foreman R et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007;448: 318 –324. House of Lords. Regina v. Secretary of State for Health (Respondent) ex parte Quintavalle (on behalf of Prof-Life Alliance) (Appellant). Session 2002-03; March 13, 2003; [2003] UKHL 13. Embryonenschutzgesetz (EschG). In der Fassung der Bekanntmachung vom 13. Dezember 1990; BGBl. I S. 2747. 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