Pharma workshop III: the 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

Patenting of stem cells

• Summary:

– Introducing the Basics of Stem Cell Research

– European situation: CJEU C-34/10, Brüstle vs.

Greenpeace

– US situation

– Korean situation

• 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

Agenda

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

A stem cell has the following characteristics:

Unspecialized

Stem Cell Characteristics

Can become

specialized under

certain conditions

Self-regeneration

through cell division

• 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

Science of Stem Cells

1. Embryonic Stem Cells (ESCs)

• Stem cells that exist in an embryo, i.e. a sperm-

fertilized 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

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)

Types of Stem Cells (cont.)

• 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

Potential Uses

Europe as a community of values

Europe as a community of values

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

Filed, granted and published

Greenpeace: action for invalidity that draws on ordre public and morality to German Patent

Court

GPC declares partially invalid insofar as the patent covers cells derived from human

embryonic stem cells

Revision at the German Federal Court of Justice

Referral to ECJ

ECJ decision

Decision of GFCJ

The case: Brüstle vs. Greenpeace

1997

2004

2006

2007

2009

2011

2012

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

� 2000 expiration of implementation period

� 2001 confirmed ECJ

� 2006 last implementations in Italy and

Louxembourg

Thomson et al., Science

282, 1145-1147, 1998.

U.S.Pat.No. 5,843,780

filed 1996

U.S.Pat.No. 6,200,806

filed 1998

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?

• 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 1 –

term „human embryos“?

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.

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.

EPO- Change of practice

adopted Guidelines for Examination

The 4 scenarios for embryo use:

direct indirect

non-

destructive

method product

(established hES)

method product

method productdestructive methodproduct

(established hES)

NO R 28 (c) NO G 2/06 NO following C-34/10

Guidelines 2012, G-II,5.3 (iii)

NO R 28 (c) NO as G 2/06 YES indirect non-destructive; III,2-3

effective date on or after

10th january 2008

Patentability of products for hEC culture

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.

PATENT

???

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

• 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

• 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

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

� 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

Next steps to Horizon 2020

3. United States situation

• “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 …

Patentable Subject Matter ─

United States

• 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 (recent publications)

• 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

Examples (issued patents)

• 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. Stem Cell Issues

• 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

U.S. Response to Brüstle

4. The 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

Korean situation

• 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.”

No exclusion of patentability of

stem cell-related inventions 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

Subject matters of

stem cell-related patents in Korea

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.

Alternative to the use 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.

Possible consequences

of the European exclusion

of patentability of stem cells