1. UPDATE
LEGAL/REGULATOR
Y CELL THERAPY
AND COMBINATION
PRODUCTS
VIC Congress – Cell Therapy Manufacturing Erik Vollebregt
6 December 2012 www.axonadvocaten.nl

2. Introduction
• Scope of ATMP regulation re cell therapy in CAT classification decisions
• Developments in patent law

3. CAT Classification round-up
• CAT publishes classification decisions since 1-7-2011
• Two step approach assessment methodology cell therapies:
1. Definition of medicinal product under 2001/83
• Presentation criterion (claim)
• Function criterion (function)
2. Definition of ATMP under 1394/2007
• contains or consists of engineered cells or tissues, and
• substantially manipulated
• not same essential function in recipient as in
donor
• presented with a view to regenerating, repairing or
replacing a human tissue

4. ATMP definition seen otherwise
ATMP Regulation‘s scope requires that cells making up the product
1. are human;
2. are viable;
3. fall within one of three categories of ATMPs
• Tissue Engineered Products (TEPs)
• Gene Therapy Products; or
• Somatic Cell-Based Therapies;
4. are generated industrially manufactured or manufactured by a method
involving an industrial process (2001/83 requirement); and
5. are placed on the market (2001/83 requirement – as opposed to
hospital exemption)

5. CAT Classification round-up
Until recently: CAT classification position on ATMP was always ―yes‖
Recently CAT said ―no ATMP‖ to
• cosmetic fillers (autologous cells of Stromal Vascular Fraction (SVF) of
adipose tissue and cryopreserved purified autologous collagen in PBS.)
• solution for intra-venous injection suspension of oncolytic adenovirus for
treatment of colorectal cancer
• suspension containing human islets of Langerhans, autologous or
allogeneic

6. CAT Classification: cosmetic fillers
• cosmetic fillers (autologous cells of Stromal Vascular Fraction (SVF) of
adipose tissue and cryopreserved purified autologous collagen in PBS)
• is medicinal product
• but not engineered cells
• cells are viable but not substantially manipulated
• the essential function of cells is considered to be the same as
in the donor‘s fat tissue

7. CAT Classification: treatment of
colorectal cancer
• Not cell therapy
• chimeric adenovirus obtained by a process of bio-selection
• mechanism of action is through the direct infection and replicating-lysing
properties of the virus
• not through the action of any recombinant nucleic acid sequence
or to the product of genetic expression of this sequence
• So: no ATMP – no exclusion of other categories?

8. CAT Classification: islets of
Langerhans
No ATMP because:
No engineered cells
• product is derived from pancreatic tissue by a number of steps that do
not constitute substantial manipulation
• manipulation of the tissue does not alter the biological characteristics
and physiological functions relevant for the intended clinical use
• no change in the biological characteristics of the islets: the cells of the
islets do not divide and phenotype and function of the cells contained in
the product are not changed
Same essential function
• same essential function in the recipient and the donor, i.e. pancreatic
function
• CAT explicitly excludes gene therapy product option

9. Combination ATMPs
‗Combined advanced therapy medicinal product‘ means an advanced
therapy medicinal product that fulfils the following conditions:
— it must incorporate, as an integral part of the product, one or more
medical devices within the meaning of Article 1(2)(a) of Directive
93/42/EEC or one or more active implantable medical devices within the
meaning of Article 1(2)(c) of Directive 90/385/EEC,
and
— its cellular or tissue part must contain viable cells or tissues,
or
— its cellular or tissue part containing non-viable cells or tissues must be
liable to act upon the human body with action that can be considered as
primary to that of the devices referred to.

10. Combination ATMPs
No public classification summaries
However, classified as ATMP:
• Allogeneic human fibroblasts cultured onto a biodegradable matrix
• Hollow fiber cartridges populated with the C3A cells to be used with
ancillary support equipment
• Autologous osteoprogenitor cells, isolated from bone marrow and
expanded in vitro, incorporated, as an integral part, with 3D
biodegradable scaffold
• Autologous cultured chondrocytes integrated in a scaffold

11. New Medical Devices Regulation:
scrutiny
Scrutiny procedure motivated by political decision to increase supervision
of conformity assessment of high risk devices
• New MDCG will have the right to ‗call‘ up files from notified bodies
• Procedure is not really well defined
• It‘s the thing that the industry is most sceptical about in the proposed
MDR

12. New Medical Devices Regulation:
scrutiny
Scope
• Class III devices; and
• Other devices than class III, for a predefined period
Other devices if justified only by one or more of the following criteria:
(a) the novelty of the device or of the technology on which it is based and
the significant clinical or public health impact thereof;
(b) an adverse change in the risk-benefit profile of a specific category or
group of devices due to scientifically valid health concerns in respect of
components or source material or in respect of the impact on health in
case of failure;
(c) an increased rate of serious incidents reported in respect of a specific
category or group of devices;
(d) significant discrepancies in the conformity assessments carried out by
different notified bodies on substantially similar devices;
(e) public health concerns regarding a specific category or group of devices
or the technology on which they are based.

13. Brüstle
ECJ October 18, 2011
Article 6 Biotech Directive:
Inventions are unpatentable where their commercial exploitation would be
contrary to ordre public or morality;
Unpatentable (e.g.):
(a) [process cloning humans];
(b) [process for modifying germ line identity];
(c) uses of human embryos for industrial or commercial purposes;
(d) […]

14. Brüstle
• Brüstle had applied for patent on isolated and purified precursor cells
derived from human embryonic stem cells with the potential to develop
into neuronal cells as treatment for Parkinson‘s disease
• Brüstle used human blastocysts which had to be killed for deriving the
embryonic stem cells
• Questions asked by German court of appeal:
• What is an embryo?
• Does scientific research fall under ―industrial or commercial
purposes?
• what if the use of embryos is not in patent itself but a requisite for the
applicability of the invention?

15. Brüstle ECJ
ECJ:
• An embyro includes all cells that are capable of developing into a human
being and includes:
• Fertilized cells from day one as long as they are totipotent;
• Non fertilized cells where a nuclear of a human cell is implanted
and stimulated to develop;
• Parthenogenesis
• Pluripotent cells are not an embryo (not capable of developing into a
human being) but: if the invention requires prior destruction of a human
embryo (even long time prior to invention), it is not patentable.
• Brüstle method: the blastocyst needed to be destroyed by
obtaining the embryonic stem cells so not patentable.

16. Brüstle ECJ
ECJ:
• Use of embryo‘s for scientific research purposes is also form of industrial
and commercial application (already filing a patent is such form)
• Interpretation of Biotech Directive is binding on all member states
And then?
• Induced pluripotent cells derived from adult cells are allowed. But:
techniques could advance to induce totipotent cells
• Using embryonic pluripotent stem cells without killing embryo (but patent
application should express that a technique is used that does not kill
embryo)
• Banking on other forms of protection (know how, data exclusivity)

17. Brüstle German Supreme Court
Brüstle at Karlsruhe German Supreme Court 27 November 2012
(X ZR 58/07)
• research methods that involve the use of stem cells gathered from
human embryos destroyed in the process cannot be patented
HOWEVER
• patents can be issued for stem cell research methods where the embryo
from which the cells are collected is not destroyed or
OR
• where the stem cells are collected from embryos that are not capable of
further development

18. Brüstle nationally
Implications?
• Limitation of scope if ECJ Brüstle judgment but for Germany only
• Today it is possible to produce replacement cells from the bone marrow
cells of adults or from cord blood
• Do we still need human embryos as a source of stem cells?

19. Thanks for your attention
Erik Vollebregt
Axon Lawyers
Piet Heinkade 183
1019 HC Amsterdam
T +31 88 650 6500
F +31 88 650 6555
M +31 6 47 180 683
E erik.vollebregt@axonlawyers.com
@meddevlegal READ MY BLOG:
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