Pharma workshop III: the patenting of stem cells
Patenting of stem cells
• Speakers:
– John Livingstone, Finnegan, USA
– Clara Sattler de Sousa e Brito, LIERMANN-CASTELL,
Germany
– Francis Sung-Ho Han, Korea
• Moderator:
– Thomas Bouvet, Véron & Associés, France
• Summary:
– Introducing the Basics of Stem Cell Research
– European situation: CJEU C-34/10, Brüstle vs.
Greenpeace
– US situation
– Korean situation
Agenda
• Introducing the Basics of Stem Cell Research
– What is a stem cell?
– Types of stem cells
– Science of stem cells
– Potential uses of stem cells
– Patentable subject matter in the United States
What is a stem cell?
• Cell with the potential to
develop into many
different cell types
• In many tissues, stem cells
serve as an internal repair
system to replenish or
replace damaged cells
Stem Cell Characteristics
A stem cell has the following characteristics:
Unspecialized
Self-regeneration
through cell division
Can become
specialized under
certain conditions
Science of Stem Cells
• Unspecialized
‒ no tissue-specific structures
‒ an unspecialized cell can eventually produce specialized cells
• Self-regeneration through cell division
‒ normal cells, such as blood cells, do not self-replicate
‒ stem cells replicate many times on their own
‒ can ultimately yield millions of undifferentiated cells over time
• Can become specialized
‒ process is called differentiation
‒ controlling differentiation potentially allows doctors to create cell types
useful for various medical treatments
Types of Stem Cells
1. Embryonic Stem Cells (ESCs)
• Stem cells that exist in an embryo, i.e. a spermfertilized egg
‒
Totipotent
‒
Cells from early embryos
Up to about 6 days after fertilization
These cells can differentiate into ANY cell type
Pluripotent
Cells extracted later, from about 6 days to 8 weeks
These cells can differentiate into almost any kind of cell,
except supporting tissue (e.g. a placenta)
Types of Stem Cells (cont.)
2. Adult or Somatic Stem Cells
•
Stem cells found in various areas of adult tissue
‒
‒
unlike ESCs, only some adult stem cells can differentiate
adult stem cells typically only generate cell types of the tissue
from which they are found (e.g., brain, skin, etc.)
3. Induced Pluripotent Stem Cells (IPSCs)
•
Adult stem cells that are genetically “reprogrammed” to
regain some of the properties of embryonic stem cells
(+)
appear to regain pluripotent characteristics; patient
specific; appear to avoid ethical concerns
(—)
shorter life span; patient specific; lower efficiency;
potential for harboring adult cell profiles (intrinsic
epigenetic variability)
Potential Uses
• Mitigate disease
– insulin making beta cells to treat diabetes
• Generate replacement tissues
– use of skin stem cells to generate dermal layers to treat burn
victims
• High throughput screening for new drugs
• Study of tissue dynamics
• Some conditions currently being researched:
‒ spinal cord injury, multiple sclerosis, cardiovascular disease,
Parkinson’s disease, Alzheimer’s disease, and many others
Europe as a community of values
Europe as a community of values
The case: Brüstle vs. Greenpeace
Patent DE 197 56 864 C1
neural precursor cells derived from human embryonic stem cells,
methods to produce them and uses thereof for the therapy of neural
defects
1997
Filed, granted and published
2004
Greenpeace: action for invalidity that draws on ordre public and morality to German Patent
Court
2006
GPC declares partially invalid insofar as the patent covers cells derived from human
embryonic stem cells
2007
Revision at the German Federal Court of Justice
2009
Referral to ECJ
2011
ECJ decision
2012
Decision of GFCJ
Derivation and cultivation of embryonic stem
cells
stemcells.nih.gov
Art. 6 EU-Biotechnology Directive
(1) Inventions shall be considered unpatentable where
their commercial exploitation would be contrary to
ordre public or morality; however, exploitation shall not
be deemed to be so contrary merely because it is
prohibited by law or regulation.
(2) On the basis of paragraph 1, the following, in particular,
shall be considered unpatentable:
a) processes for cloning human beings
b) processes for modifying the germ line genetic
identity of human beings;
c) uses of human embryos for industrial or
commercial purposes
History of the Biotechnology Directive
1988 first attempt to regulate
1995 failure
1998 directive 98/44/EC
U.S.Pat.No. 5,843,780
filed 1996
U.S.Pat.No. 6,200,806
filed 1998
Thomson et al., Science
282, 1145-1147, 1998.
2000 expiration of implementation period
2001 confirmed ECJ
2006 last implementations in Italy and
Louxembourg
Patents on hESC (granted)
Art. 6 II lit. c of the Biotechnology
Directive
In particular, patents shall NOT be granted for:
(c) uses of human embryos for industrial or
commercial purposes
Questions on Referral (1)
1. What is meant by the term “human embryos” in Article
6(2)(c) of Directive 98/44 ...?
a)
Does it include all stages of the development of human life, beginning
with the fertilisation of the ovum, or must further requirements, such as
the attainment of a certain stage of development, be satisfied?
b)
Are the following organisms also included:
– unfertilised human ova into which a cell nucleus from a mature
human cell has been transplanted;
– unfertilised human ova whose division and further development have
been stimulated by parthenogenesis?
c)
Are stem cells obtained from human embryos at the blastocyst stage also
included???
Questions on Referral (2+3)
1.
What is meant by the expression “uses of human embryos for industrial or
commercial purposes”? Does it include any commercial exploitation within
the meaning of Article 6(1) of [Directive 98/44], especially use for the
purposes of scientific research?
1.
Is technical teaching to be considered unpatentable pursuant to
Article 6(2)(c) of the Directive even if the use of human embryos does not
form part of the technical teaching claimed with the patent, but is a
necessary precondition for the application of that teaching
a)
because the patent concerns a product whose production necessitates the
prior destruction of human embryos,
b)
or because the patent concerns a process for which such a product is
needed as base material?
Observations Question 1 –
term „human embryos“?
• GB and SE:
must be left solely to discretion of the member states due to enormous
divergences
• PT and Commission:
must be defined autonomously specifically for EU law
If yes, how?
GB and PT:
„all developmental stages from fertilisation to birth“
SE and Commission:
no definition, but Commission refers to comparative law
• everybody: stem cells are not included in the concept of an embryo since
they are pluripotent only
Observations Question 2 –
“industrial or commercial purposes”?
PT: any commercial exploitation including purposes of scientific
research
Commission: repetitive use for medical, chemical or technical
purposes respectively use for purposes of purchase or sale
SE: not including inventions based on research allowed in a
member state
GB: industrial or commercial purposes do not include scientific
research
Observations Question 3 Technical teaching as claimed vs.
use required?
everybody in unison:
the mere fact that hESCs were originally derived
from fertilized oocytes does not preclude
patentability of inventions that use established
hESCs as a starting point
Judgement Question 1 –
term „human embryos“?
1.
Article 6(2)(c) of Directive 98/44/EC of the European Parliament and of
the Council of 6 July 1998 on the legal protection of biotechnological
inventions must be interpreted as meaning that:
–
any human ovum after fertilisation, any non-fertilised human ovum into
which the cell nucleus from a mature human cell has been transplanted,
and any non-fertilised human ovum whose division and further
development have been stimulated by parthenogenesis constitute a
‘human embryo’;
–
it is for the referring court to ascertain, in the light of scientific
developments, whether a stem cell obtained from a human embryo at the
blastocyst stage constitutes a ‘human embryo’ within the meaning of
Article 6(2)(c) of Directive 98/44.
Judgement Question 2 –
“industrial or commercial purposes”?
2. The exclusion from patentability concerning the use of
human embryos for industrial or commercial purposes set
out in Article 6(2)(c) of Directive 98/44 also covers the use of
human embryos for purposes of scientific research, only use
for therapeutic or diagnostic purposes which is applied to
the human embryo and is useful to it being patentable.
Judgement Question 3 –
technical teaching as claimed vs.
use required?
3.
Article 6(2)(c) of Directive 98/44 excludes an invention from patentability
where the technical teaching which is the subject-matter of the patent
application requires the prior destruction of human embryos or their use as
base material, whatever the stage at which that takes place and even if the
description of the technical teaching claimed does not refer to the use of
human embryos.
Criticism
• economic impact of the judgement:
― patent law is needed to foster innovation
the judgement will slow down the development of new therapies
and lead to a movement of the respective industry and research
away from Europe
• legal reasoning:
― comparative law: against all member states statements and not taking
into account the liberal regulations and practice in several member
states
― fundamental rights: no discussion of relevant case law
doubts about the competency of the ECJ as a super-national court
― ECJ as a non specialized court in IP matters
Consequences
• patent law
― consequences for stem cell patenting
national practice in the member states
EPO
― consequences for other biotechnology and pharmaceutical patents
e.g. fetal cell lines
• consequences abite patent law
― research funding
― reserach regulation?
UKIPO revised practice
– practice notice
•
...where the implementation of an invention requires the use of cells that
originate from a process which requires the destruction of a human
embryo, the invention is not patentable...
•
...where the implementation of the invention requires the use of a
human embryonic stem cell line the establishment of which originally
required the destruction of a human embryo, the invention is not
patentable.
EPO- Change of practice
adopted Guidelines for Examination
Regarding the term "uses of human embryos" in Rule 28(c) EPC:
A claim directed to a product, which at the filing date of the
application could be exclusively obtained by a method which
necessarily involved the destruction of human embryos from which the
said product is derived is excluded from patentability under Rule 28(c),
even if said method is not part of the claim (see G 2/06).
The point in time at which such destruction
takes place is irrelevant.
The 4 scenarios for embryo use:
direct
destructive
method
indirect
product
method
product
(established hES)
NO R 28 (c)
NO G 2/06
NO following C-34/10
Guidelines 2012, G-II,5.3 (iii)
nondestructive
method
product
NO R 28 (c)
(established hES)
NO as G 2/06
method
product
YES indirect non-destructive; III,2-3
effective date on or after
10th january 2008
Patentability of products for hEC culture
PATENT
???
Culture media, supports or apparatuses "suitable for" use with human embryonic cells,
or even "specifically designed" for this purpose, are not per se excluded from
patentability.
Their production normally does not require the use of human embryos.
Patentability of iPS
PATENT
???
sigmaaldrich.com
EP 1 859 055 - Cellartis
• a kit for use in real time PCR to assess the state of hBS cell (human
blastocyst-derived stem cell) differentiations
• OD holds that:
two conditions to be met:
— use of human embryos
„Even if the the hBS cells are established cell lines these cell lines have
been generated from human embryos at some point in time.“ under
referral to C-34/10
— use is industrial and commercial
„industrial and commercial context“ even if there is an intention to use
for further research
therefore application of R. 28 (c) EPC
• currently under appeal
Conflict with Art. 27 II TRIPS
• as an exemption from Art. 27 I TRIPS, members may exclude
from patentability inventions, the prevention within their
territory of the commercial exploitation of which is necessary
to protect ordre public or morality
• commercial exploitation must thus not be allowed
• either revise the judgement or rephrase the Biotechnology Directive
• or pressure of de facto harmonisation of research/biomedical regulation
Research funding – horizon 2020
•
•
•
launch in 2014 - 2012
€80 billion budget
proposed support for research and innovation under Horizon 2020 will:
― strengthen the EU’s position in science
― strengthen industrial leadership in innovation
― tackle societal challenges by helping to bridge the gap between research and the
market - market-driven approach
― breaking down barriers to create a genuine single market for knowledge, research
and innovation
Horizon 2020 – Article 16
3. The following fields of research shall not be financed:
(a) research activity aiming at human cloning for reproductive purposes;
(b) research activity intended to modify the genetic heritage of human beings
which could make such changes heritable;
(c) research activities intended to create human embryos solely for the purpose
of research or for the purpose of stem cell procurement, including by means of
somatic cell nuclear transfer.
4. ... no funding shall be granted for research activities that are prohibited in all the
member states. No activity shall be funded in a member state where such
activity is forbidden.
Legal Affairs Committee of the
European Parliament
Vote on September 18, 2012:
• several changes inter alia addition of new exemptions in Article 16:
(ca) research which involves the destruction of human embryos;
(cb) research using human embryonic stem cells.
• only funding of research on other types of human stem cells may be
financed
Next steps to Horizon 2020
European Parliament and European Council finalise Horizon 2020 until the end of 2013
parliamentary committees for industry and research, and for environment and public health, in the next
weeks
Parliament’s plenary in November
3. United States situation
Patentable Subject Matter ─
United States
• “Anything under the sun that is made by man.”
–
•
•
•
•
•
•
•
•
•
Diamond v. Chakrabarty, 447 U.S. 303 (1979)
Isolation Techniques
Extraction Techniques
Proliferation Techniques (growth factors/culture systems)
Differentiation Factors/Methods
Delivery techniques
Reprogramming viruses
Methods of de-differentiation
Antibodies for identification
And the list goes on …
Examples (recent publications)
• Methods and Compositions for Increasing Production of Induced
Pluripotent Stem Cells (IPSCS), US2012/0252122 A1, October 4, 2012, U.S.
inventors
• Agents for Promoting Tissue Regeneration by Recruiting Bone Marrow
Mesenchymal Stem Cells and/or Pluripotent Stem Cells Into Blood,
US2012/0251510 A1, October 4, 2012, Japanese inventors
• Pluripotent Stem Cells Obtained from Dental Pulp, US2012/0251504 A1,
October 4, 2012, Spanish inventors
• Adult Stem Cell Derived Conditioned Medium and/or Adult Stem Cells for
Use in the Therapeutic Treatment of a Tumor Disease, US2012/0251489
A1, October 4, 2012, Italian inventors
• Transformed Human Pluripotent Stem Cells and Associated Methods,
US2012/0252697 A1, October 4, 2012, Canadian Inventors
• Stem Cell Targeting, US2012/0253017 A1, October 4, 2012, U.S. inventors
Examples (issued patents)
• WARF Patents (5,843,780, 6,200,806, 7,029,913)
• Methods of Increasing Platelet and Hematopoietic
Stem Cell Production, 8,283,313
• Induced Pluripotent Stem Cells Produced with Oct3/4,
Klf4 and Sox2, 8,278,104
• Cardiac Muscle Repair or Regeneration Using Bone
Marrow-Derived Stem Cells, 8,158,120
• Methods of Isolation, Expansion and Differentiation
of Fetal Stem Cells From Chronic Villus, Amniotic
Fluid, and Placenta and Therapeutic Uses Thereof,
8,021,876
U.S. Stem Cell Issues
• Historically, no issues regarding patentable subject
matter
• Primary issues revolve around:
– Political and ethical controversy
– Funding: Bush v. Obama v. Romney (?)
•
•
•
•
shifts research costs
difficult for start-ups
proof of concept
potentially hampers development
– Value inflection points
• timelines differ from new chemical entity development
U.S. Response to Brüstle
• Enforcement of existing patents?
• Therapeutic issues
– Reliance on regulatory framework
– Pioneering work may move to Europe
• Non-therapeutic issues
– High throughput screens may move to Europe
– Low cost development and FTO
• This industry is still an art
– Trade secrets and know how
4. The Korean situation
Korean situation
• Active clinical developments including the use of adult stem cells(ASC)
and cells differentiated from embryonic stem cells(ESC): ASC>ESC Korea
Food and Drug Administrations’ approval of marketing of 3 ASC products
in 2011 and 2012
• Recent developments using genes and stem cell derivatives such as
cellular lysate, supernatant etc., and induced pluripotent stem cells(iPS)
• Widening gaps among (1) patents, (2) regulatory affairs-related issues
regarding the clinical developments and (3) commercial value of
pharmaceutical products based upon stem cells or their derivatives
• More systematic supports from Korean government while window for
survival of commercial developers of stem cell-pharmaceutical products
narrowing deepening the understanding of importance of IP in the
emerging pharmaceutical field
No exclusion of patentability of
stem cell-related inventions in Korea
• KIPO applies the same statutory patentability requirements
applied to other types of patents.
• Requirement of “The Biotechnology-Related Invention
Examination Guidelines”
“An invention in the field of genetic engineering that is likely to
contravene public order or good morals or to injure public health
shall not be granted a patent under Article 32 of the Korean Patent
Law.
“Such an invention includes (i) an invention likely to destroy an
ecosystem or cause environmental pollution, (ii) an invention likely
to cause harm to a human being or to impair human dignity, (iii) an
invention relating to a transgenic organism not excluding a human
being and (iv) an invention regarding activities or research outcome
prohibited under the Korean Bioethics and Safety Act.”
Subject matters of
stem cell-related patents in Korea
Examples of granted patents regarding ASC, ESC, iPS etc.
- Patent No. 100494265:
Composition for treatment of articular cartilage damage
- Patent No. 101114800:
Composition comprising mesenchymal stem cells or culture solution
of mesenchymal stem cells for the prevention or treatment of neural
diseases
- Patent No. 101135636:
Method for producing mesenchymal stem cells from human
pluripotent stem cells and mesenchymal stem cells produced by
thereof
- Patent No. 100826597:
Monoclonal antibody specific to cell surface protein of human
embryonic stem cell
- Patent No. 100985832:
Method for culturing human embryonic stem cells
- Patent No. 1066773:
Method for isolation of inner cell mass and method of preparation of
embryonic stem cell lines using inner cell mass isolated by the same
- Patent No. 1010100:
Method of manufacturing embryonic stem cell being introduced
gene using nano particles
Alternative to the use of stem cells
Better understanding of mechanisms of actions(MOA)
underlying the therapeutic outcomes of stem cell
pharmaceuticals would lead to the use of alternatives such as
endogenous or exogenous stem cell stimulators, therapeutic
proteins or genes related to MOA without involving the direct
use of stem cells.
For example, use of induced pluripotent stem cells(iPS) may
avoid the ethical concerns and limited donor-accessibility
which are the main issues in using embryonic stem cells.
Possible consequences
of the European exclusion
of patentability of stem cells
European exclusion could hinder research on stem
cells, especially on embryonic stem cells. As a result,
filing of patent applications on the alternative
approaches may increase. Clearer picture will
emerge as various key national patent’s office clarify
their official positions on stem cell patents.