Download Commentary: Isolated Stem Cells—Patentable as Cultural Artifacts?

EMBRYONIC STEM CELLS
Commentary: Isolated Stem Cells—Patentable as Cultural Artifacts?
MATS G. HANSSON,a GERT HELGESSON,a RICHARD WESSMAN,b RUDOLF JAENISCHc
a
Centre for Bioethics at Karolinska Institutet and Uppsala University, Department of Public Health and Caring
Sciences, Uppsala Science Park, Uppsala, Sweden; bDepartment of Law, Uppsala University, Uppsala, Sweden;
c
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology,
Cambridge, Massachusetts, USA
Key Words. Stem cells • Patent • Ethics
ABSTRACT
This article argues that an isolated embryonic stem cell
basically represents a cultural artifact that has no equivalent to cells of the embryo, and that it is likely that the
isolation of adult stem cells has a similar consequence. An
isolated stem cell could thus be distinguished as something other than the stem cell existing as part of a human
body. Since isolation of stem cells implies modification,
product patents should, where the results carry enough
novelty, inventive step, and potential for industrial application, as a matter of principle be a viable option for
patent authorities. Questions of morality, which may affect the patentability, should also be viewed in light of the
distinction between isolated result and body part. At the
same time, it is essential that patent authorities do not
accept broad patent claims that will be detrimental to
research. STEM CELLS 2007;25:1507–1510
Disclosure of potential conflicts of interest is found at the end of this article.
INTRODUCTION
Recently, the European Patent Office (EPO) rejected an application from the Wisconsin Alumni Research Foundation
(WARF) for a patent on five stem cell lines. Previously, in the
“Edinburgh case,” regarding a patent involving genetic markers
used to identify stem cells, the EPO review panel came to the
conclusion that any claims involving human embryonic stem
cells (hESC) violated the European Patent Convention. Both
cases are pending appeal [1, 2]. Cases such as these touch upon
several difficult questions, not least the morality of stem cell
research in general and stem cell patents in particular. In order
to further the discussion in these matters, it is important to have
a clear understanding of the underlying biological facts.
Biological facts are rarely transferable to moral arguments.
However, ethical opinions and policy-making in relevant areas
should be consistent with such facts. According to paragraph 7
of Directive 98/44/EC on the legal protection of biotechnical
inventions, the European Group on Ethics in Science and New
Technologies to the European Commission (EGE) evaluates
ethical aspects of biotechnology. The EGE has evaluated the
ethical aspects of patenting inventions involving human stem
cells [3]. They argue that isolated stem cells, which have not
been modified, do not, as products, fulfill the legal requirements
to be seen as patentable. In its second report to the Council and
European Parliament, the European Commission concludes that
it would be premature to come to a definitive conclusion with
regard to patentability of inventions relating to stem cells [4].
This article argues that, since isolation of stem cells implies
modification, product patents may in some cases be a viable
option for patent authorities. Furthermore, the modification in
question should be taken into consideration in the assessment of
applications to patent a particular method or use involving stem
cells or stem cell technology.
THE EPIGENETIC STATE OF THE GENOME
AND ADAPTATION TO GROWTH IN
TISSUE CULTURE
EGE claims that one should distinguish among: (a) “stem cells
freshly derived from an organ or tissue which have not yet been
subjected to any modification and which are capable of being
propagated as stem cell lines,” (b) “unmodified stem cell lines
which refer to cultured lines of cells which have been propagated originally from freshly derived stem cells and which have
not been modified in any other way. . . ,” and (c) “modified stem
cell lines which refer to cultured lines of cells, propagated from
stem cells or stem cell lines, which have been modified either by
genetic manipulation, or by treatment that causes the cells to
differentiate in a particular way” [3]. Only the last kind of cells
may be patented as products, according to EGE.
However, the only “unmodified” human stem cells are those
still present in the human body or embryo. Embryonic stem (ES)
cells are isolated from in vitro fertilized (IVF) embryos that
have been cultured in vitro up to the blastocyst stage. If used for
infertility treatment, such embryos are transplanted into the
uterus of a woman. If used for the derivation of an ES cell line,
the blastocysts are explanted into a special culture medium and
cultured in vitro for an extended period of time, generating a
novel cell type that is not part of the blastocyst. Already, the act
of placing a cell into a culture medium implies modification,
Correspondence: Mats G. Hansson, Th.D., B.A., Centre for Bioethics at Karolinska Institutet and Uppsala University, Department of Public
Health and Caring Sciences, Uppsala Science Park, SE-751 85 Uppsala, Sweden. Telephone: ⫹46186113576 Fax: ⫹4618506404; e-mail:
[email protected] Received November 1, 2006; accepted for publication February 18, 2007; first published online in STEM
CELLS EXPRESS March 8, 2007; available online without subscription through the open access option. ©AlphaMed Press 1066-5099/2007/
$30.00/0 doi:10.1634/stemcells.2006-0684
STEM CELLS 2007;25:1507–1510 www.StemCells.com
1508
hence even a “freshly derived” stem cell has been subjected to
modification. The main reason is that isolation of ES cells
selects for in vitro survival and proliferation of cells under
adverse culture conditions [5]. Thus, the isolation process does
not select for pluripotency, just for survival, with pluripotency
being a useful side product of the procedure. The result of
adaptation to tissue culture is the outgrowth of cells that have no
equivalent to cells in the embryo. One consequence of this
isolation procedure is that chromatin configurations are different, as are methylation of genes and other epigenetic characteristics [6]. For example, the chromosomes inherited from the
mother are epigenetically different from the chromosomes inherited from the father. These differences are established during
gametogenesis and are crucial for the correct expression of
genes such as imprinted genes. Disturbance of methylation
differences between the two alleles of imprinted genes results in
loss of imprinting and abnormal development [7]. In normal
embryogenesis, the epigenetic differences of the two parental
genomes persist, but when placed into a different environment,
as in isolation of ES cells, or when the parental genomes of the
somatic cells are exposed to the egg cytoplasm, as in somatic
cell nuclear transfer, the “epigenetic memory” of the genomes
will be erased [5]. The process of ES cell derivation inevitably
leads to epigenetic instability [6] and tends to equalize the
methylation differences between the parental genomes. This can
be manifested in the loss of imprinting (LOI) for genes such as
Igf2 that occurs readily in mouse [6] but less frequently in
human ES cells [8]. Thus, an ES cell basically represents a
cultural artifact that has no equivalent to cells of the embryo. It
is worth emphasizing that epigenetic changes are, in principle,
reversible in contrast to genetic alterations. However, it would
not appear possible to reverse the multiple stochastic epigenetic
abnormalities created by in vitro culture of cells to the “normal”
epigenetic state that is the consequence of gametogenesis and in
vivo development. Similarly, the isolation of adult stem cells
requires a stringent selection for proliferation and adaptation to
growth in tissue culture and, thus, produces cells that have no
counterpart in the normal animal [9, 10].
The brief in vitro culture of explanted mouse embryos has
been shown to lead to LOI of sensitive genes such as Igf2 in the
blastocyst [11] and to gene expression abnormalities after in
utero implantation of the cultured embryos [12]. Although LOI
has not been investigated in cultured human embryos, the significantly higher incidence of Beckwith-Wiedemann syndrome
in IVF babies [13, 14], an imprinting disorder caused by LOI of
Igf2 and other imprinted genes, raises the prospect that the brief
in vitro culture of human embryos as part of the infertility
treatment may cause epigenetic abnormalities [15]. Does this
imply that the act of explanting and culturing an IVF embryo
creates a “patentable artifact” as defined above? We believe not
and give the following reason. Although the in vitro culture of
a human embryo can cause some stochastic epigenetic alterations in the embryo’s genome, the cells in the embryo remain
competent to generate a baby, although with an increased risk of
imprinting disorder. In contrast, the process of ES cell derivation creates a novel cell type that is not present and is not part
of the normal blastocyst and that has vastly different molecular
and biological characteristics from the cells in the embryo. For
example, the global DNA methylation level in the blastocyst is
highly reduced as compared with somatic cells [16], whereas
that of ES cells is as high as in somatic cells [17]. Although ES
cells can contribute to normal development when introduced
into a host embryo, they do not have the potential to generate an
organism in contrast to the blastocyst from which they were
derived. Thus, the derivation of ES cells is a process that leads
to a novel cell type with novel characteristics that neither exist
in the embryo nor in the fetus.
Stem Cell Patents
An isolated stem cell should then be distinguished as something other than the stem cell still existing as part of a human
body. This opens a possibility for legal consideration of patenting the method for manipulating the growth conditions but also
for patenting an isolated stem cell as a unique result of modifying the cell by placing it in an appropriate medium.
IN LINE WITH EUROPEAN UNION
DIRECTIVE 98/44
Paragraph 2 of Directive 98/44/EC on the legal protection of
biotechnical inventions states that “an element isolated from the
human body . . . may constitute a patentable invention” [18]. In
Recital 21, it is specified that such an element “is not excluded from
patentability since it is, for example, the result of technical processes used to identify, purify and classify it and to reproduce it
outside the human body, techniques which human beings alone are
capable of putting into practice and which nature is incapable of
accomplishing by itself.” We suggest that the isolation and proliferation of a human stem cell constitutes a result of a technical
process (i.e., mastering the dynamics of the chromatin structural
proteins) in the sense of the directive and, accordingly, a research
result that is, in principle, patentable [19].
COMPATIBLE WITH STRONG VIEWS
POTENTIALITY
ON
There is today no international consensus on the moral status of
human embryonic stem cells, and there are different policies for
patenting among national patent offices that reflect a wide
diversity of moral cultures [20 –22]. This is illustrated in a recent
review of European patent laws [23]. In Germany, one is not
allowed to extract hESC from embryos, and research on imported pluripotent hESC is permitted only if the cells originate
from culture lines established before January 1, 2002 [24, 25].
The U.K. Patent Office has declared that patents will not be
granted for any processes for obtaining stem cells from human
embryos or for totipotent cells. However, pluripotent hESC are
regarded as patentable [23]. The EPO has so far excluded
patents detailing the process of extracting stem cells from a
human blastocyst as well as patents relying on already established cell lines [18]. As reflected by the patents granted by the
United States Patent and Trademark Office (USPTO), none of
these patents are excluded in the United States [26, 27].
The legal argumentation for different national patent policies is complex. However, there seems to be one moral consideration that is common to the policies excluding patentability of
hESC. Patentability implies, according to this view, research on
embryos or variants thereof that carry the potential of developing into a mature human being, and is therefore wrong. An
associated argument is that the research involves destruction of
embryos carrying such a potentiality, but we will not go into this
aspect here, acknowledging for the sake of the argument that
there are embryos that really are “spare” in the sense that they
are extra numerous embryos created through IVF and would be
destroyed anyway [28].
The potentiality of an entity and its moral implications has
been an issue regarding the ethics of embryo research for some
time [29]. According to a weak view of potentiality, possibility
and probability are seen as necessary conditions for potentiality.
The embryo must, according to this view, have a real physical
possibility of developing into a mature human being (e.g.,
through implantation and favorable development conditions),
and this development must be probable. If these necessary
Hansson, Helgesson, Wessman et al.
1509
conditions are not fulfilled, the embryo does not carry more
potentiality and, therefore, not more moral weight than a sperm
and an egg taken together but kept apart in two different Petri
dishes. The underlying moral considerations of the referred
patent policies seem, however, to be based on another view,
where the potentiality of an entity refers to its intrinsic qualities.
We call this the strong view of potentiality. The potentiality of
the embryo denotes, according to this view, the inherent capacity or potency to develop into a mature human being. As such,
it is worthy of moral consideration or protection, even if external
conditions are lacking in order to make this development probable or even possible.
As argued above, the derivation of ES cells is a process that
leads to a novel cell type with novel intrinsic qualities that do
not exist in the embryo. The derivation process is, furthermore,
not reversible. The ES cells do not carry any potentiality, not
even in the strong sense, and should therefore be, in principle,
patentable. Based on the weak view on potentiality, patentability
of hESC should not be controversial. Taking the diversity of
moral cultures into consideration, it may be seen as an advantage of our proposal that ES cells may be patentable and policy
makers can still honor strong views on the potentiality of a
human embryo.
NOT NECESSARILY LEADING
PATENTS
TO
BROAD
EGE argues that a right to patent “unmodified” stem cells
implies too broad patents, since several technological applications may be derived from one original achievement. This is an
important concern that was also expressed when genes were
proposed as patentable. That this concern should not be taken
lightly is evident when we look at how the WARF patents were
handled by USPTO. As described by Loring and Campbell,
USPTO issued a broad patent on December 1, 1998, claiming
primate (including human) ES cells and on March 13, 2001, a
second patent focusing on hESC [26]. Provided that the scope of
these patents is not changed when challenged in a court of law,
they seem to give WARF far-reaching possibilities to hinder
both academic researchers and biotechnology companies from
making, using, selling, offering for sale, or importing hESC
covered by the claims until 2015. The origins of the cell lines
were two nonhuman species of primates, but the claim granted
covered a larger group of primates, including humans. hESC
made in another country become subject to U.S. patent law if
they are imported into the United States. According to Loring
and Campbell, “WARF requires a license agreement for distribution of any [human embryonic stem] cell lines in the United
States” [26], and they are charging both academic and commercially based researchers large fees for a license.
The fundamental principle of a patent is to protect reasonable commercial claims and inventive achievements as a means
to promote technological development and application of research into different sectors of society. The two WARF patents
seem to have violated this principle by granting claims with an
unreasonable scope leading to a situation that, in fact, may be
detrimental to stem cell research. In analogy to the development
in gene patenting, whether the result in terms of an isolated stem
cell in a specific culture medium or a propagated stem cell line
carries enough novelty, inventive step, and potential for industrial application has to be proven by the researcher. We suggest
that the patent authorities may consider them as objects both for
product and method patents that fulfill, in principle, the legal
requirements for such patents, but that the scope of the patents
must be reasonable and well informed by the scientific develwww.StemCells.com
opment and the foreseen effects of a patent on research and
other commercial interests. In order not to frustrate research that
could advance knowledge regarding the many detailed steps
involved, we suggest as a preliminary guideline that patent
authorities should take a conservative view regarding the scope
of patents with a limitation to the intrinsic qualities of both the
patented ES cells and the patented methodologies (i.e., on its
potentiality in the strong sense described above).
Product and method patents of ES cells and related technologies may be broadly categorized as related to: (a) isolation of
ES cells, (b) derivations of ES cells (through genetic modification or otherwise), (c) methods of culturing ES cells, and (d)
methods of using ES cells (differentiation/transplantation). A
conservative policy would, for example, imply that claims may
be restricted to ES cells deriving from a particular species, and
that the scope of potential differentiation should be restricted to
derivates of one specified tissue only. The patent should only
cover a particular cell line and only specific uses (i.e., differentiation into one specific kind of tissue or a specific kind of
transplantation). If the next step in a process (e.g., derivation) is
an obvious next step without any need for further invention, this
step does not provide the necessary prerequisite for a patent. It
should be observed that these are only examples of what a
conservative view may imply. It should also be noted that there
are two possibilities of limiting patents, on the one hand through
restrictions on the area of patentability and on the other through
determining the extent of protection for the patent. Due account
shall be taken of any element that is equivalent to an element
specified in the claims. The closer determination of scope of
protection and equivalent elements is, however, a question that
must be decided in future infringement trials.
COMMERCIALIZATION
AND
CONSENT
EGE has also put forward two ethical arguments against product
patenting of human stem cells. They argue that isolated stem
cells “are so close to the human body, to the fetus or to the
embryo they have been isolated from, that their patenting may
be considered as a form of commercialization of the human
body” ([3], p.16). However, the concept “close” is not defined
and, as a matter of fact, genes and gene products are already
patentable [30]. The ethical discussion about commercialization
of human body parts is far from settled, but the point in this
context is that what is commercialized is not something “close
to a human body” but a product being a result of an advanced
biotechnical process, a technique which human nature is “incapable of accomplishing by itself.” Similarity with human body
parts has never been a matter of consideration regarding patenting of biotechnical products. Rather, trying to develop something that is close to nature has been a drive in many technological developments.
Secondly, EGE argues in accord with Article 3 of the
Charter of Fundamental Rights and with Recital 26 of the 1998
European Union (EU) Patent Directive, which states that “. . .
the person from whose body the material is taken must have had
an opportunity of expressing free and informed consent thereto
. . . ” [3]. Such consent based on information about the purpose
of research is intrinsic to all regulations of human stem cell
research. However, it should be observed that the right to
withdraw a previously given consent is limited in relation to
stem cell research. The Convention of Biomedicine and Human
Rights grants such a right with regard to all kinds of research
using human tissue [31]. However, this right does not apply
regarding the results of a research study, and since stem cells
placed in a culture medium and being viable are results in this
Stem Cell Patents
1510
sense, the donor has no right to withdraw consent at that point,
requiring that the cells should either be destroyed or made
unidentifiable.
CONCLUSION
An isolated embryonic stem cell represents a cultural artifact
that has no equivalent to cells of the embryo. Isolation of adult
stem cells likely implies the same kind of modification. An
implication of this is that isolated stem cells constitute research
results that, in principle, fulfill the legal requirements of both
product and method patents. In order for patents not to be
detrimental to research and industrial application, it is vital that
patent authorities assume a conservative approach in order to set
a reasonable balance between different interests and limit the
scope of the patents.
ACKNOWLEDGMENTS
We are grateful to Paul Berg, Cahill Professor of Biochemistry,
Emeritus at Stanford University School of Medicine, for helpful
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area from the Knut and Alice Wallenberg’s Foundation (the
national Biobank Program within Wallenberg Consortium North
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DISCLOSURE
OF
POTENTIAL CONFLICTS
OF INTEREST
The authors indicate no potential conflicts of interest.
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