Download Is Totipotency of a Human Cell a Sufficient Reason to Exclude Its

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, Marstallstra␤e
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
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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
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CONFLICTS
The authors indicate no potential conflicts of interest.
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