© LAWFORD DAVIES DENOON LTD 2010

ISCT Conference | 20 May 2011

Negotiating the Regulatory and IP Hurdles

James Lawford Davies & Alex Denoon

Overview

• hESC therapies are likely to face continuous scrutiny on

morality grounds

• In EU, this results in a more complex regulatory landscape

• Recent controversies re funding, IP and regulatory issues

• Detailed consideration of regulatory framework and protections

is merited

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Approaches to regulation (1)

1. Prohibitions or restrictions:

• Germany‟s 1990 Embryo Protection Act and Stem Cell Act of

2002 (as amended in 2008)

• Italy‟s Law 40/2004

2. Regulation or licensing:

• Victoria‟s Infertility Treatment Act 1995 (Australia)

• UK‟s Human Fertilisation and Embryology Act 1990 (as

amended)

3. Guidance or self-regulation:

• China‟s 2003 joint MoH and MoST Ethical Guiding Principles for

hES cell research

4. No regulation

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Approaches to regulation (2)

“The only workable approach found has been the policy of

federal neutrality, whereby the federal government does not

prohibit embryo research, but also does not officially condone

it, encourage it, or support it with public funds”

(President‟s Council on Bioethics, 2003)

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Common rationales

• Public health and safety

• Welfare of the child and family considerations

• The status of the human embryo

• Regulation stems partly from consensus that embryos have

special status

• No consensus as to how that status defined or protected

• Inevitable compromise - unless research prohibited

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UK Regulation

• Human Fertilisation and

Embryology Authority (HFEA)

• Human Tissue Authority (HTA)

• Medicines and Healthcare

products Regulatory Agency

(MHRA)

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UK regulation

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Common rationales

• Public health and safety

• Welfare of the child and family considerations

• The status of the human embryo

• Regulation stems partly from consensus that embryos have

special status

• No consensus as to how that status defined or protected

• Inevitable compromise - unless research prohibited

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Brüstle v Greenpeace (1)

• In 1997, Oliver Brüstle filed a patent for Neural Precursor Stem

Cells, Methods for the Production and Use in neural defects

• Cells derived from blastocyst

• Greenpeace argued that patent invalid because it breached

the morality criteria in Article 6(2)(c) of the Biotech Directive:

• “uses of human embryos for industrial or commercial

purposes” are unpatentable

• German national proceedings

• Referral to ECJ from German court in January 2010

• Oral proceedings 12 January 2011

• Advocate General‟s Opinion 10 March 2011

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Brüstle v Greenpeace (2)

• Greenpeace partially successful at first instance but on appeal,

Federal Patent Court stayed the action and referred questions

on the meaning of Article 6(2)(c) to the CJEU:

1. meaning and scope of “embryo”

2. meaning and scope of exclusion of “industrial and commercial

uses”

3. exclusion by virtue of upstream uses or “necessary” prior

human embryo destruction

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Brüstle v Greenpeace (3)

• The AG issued his Opinion on 10 March 2011 stating that

inventions that necessitated the destruction of an embryo were

unpatentable on morality grounds

• 117. Furthermore, I consider that an invention must be

excluded from patentability, in accordance with that provision,

where the application of the technical process for which the

patent is filed necessitates the prior destruction of human

embryos or their use as base material, even if the description

of that process does not contain any reference to the use of

human embryos.

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Brüstle: reaction

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Practical Ramifications

• If the CJEU adopts the Opinion, hESC patents will be vulnerable if theywere derived in a manner that resulted in the destruction of the embryo

• The wording in the decision may be very narrow – wait and see

• Regardless, in the short term the practical consequences may be morelimited than some commentators have suggested:

• Possible to obtain similar patents in other jurisdictions

• Australia, Canada, China, India, NZ, Singapore and the US

• Possible to obtain patents for other elements of the therapies or thedelivery of therapies

• “Regulatory IP” such as orphan drug designation will be applicable formany products

• Data exclusivity would provide some protection for 8 + 2 years afterMarketing Authorisation

• Extremely difficult to obtain a Marketing Authorisation for a biosimilar hESC

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15 years of Effective Protection

• The legislative compromise to reward new medicines appears

designed to deliver an effective 15 years of effective protection

• Patent Law: 20 year patent with 5-year SPC extension

• Regulatory: Data exclusivity (8+2+1 in EU) and Orphan Drug

Designation

• Bolar provisions to accelerate generics after expiry of initial period

• Biosimilars have proved to be challenging for generics

companies and regulators alike

• For biologics, the adage is that “the product is the process”

• Cost of developing a competing biologic can be large

• Products often delivered by infusion so healthcare

professionals are route to market (note the insulin market)

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Some Terminology

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Expression Meaning

Reference

Medicinal

Product (RMP)

The innovative medicine that has undergone full preclinical and

clinical studies (10+ years) to assess quality, safety and efficacy

Generic Can be approved without pre-clinical or clinical data if it has the

same:

• qualitative and quantitative composition in active substances;

and

• pharmaceutical form

as the Reference Medicinal Product

Biosimilar A generic where the medicine is a biopharmaceutical

Exclusivity for Reference Medicinal Product

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What is Protected Impact

8 yrs Data Exclusivity period

for RMP

No generic product can be approved using the

data used to approve the RMP

+2 Marketing exclusivity

period for RMP

Generic product can seek an MA by referring

to the RMP. However, the generic cannot be

marketed

+1 Marketing exclusivity

period for RMP

As above, if a new therapeutic indication for

the RMP approved in the first 8 years and it

has a significant clinical benefit

Orphan Drug Designation - 10 yrs exclusivity

• Orphan Drug intended for the diagnosis, prevention or

treatment of a life-threatening or chronically debilitating

condition affecting not more than 5 in 10,000 persons

• For 10 years after designation, no EU regulator shall accept

another application for an MA, or grant or extend an MA for the

same therapeutic indication, in respect of a similar medicinal

product

• Orphan Drug Designation can deliver 10 years of market

exclusivity

• This can be extended by 2 years for paediatric indications

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Generic vs Biosimilar

Generic Biosimilar

Characteristics Simple, small & stable Complex, large & less stable

Characterisatio

n

Relatively easy Relatively difficult

Manufacturing

Process

Chemical process;

Easy to produce

identical copies

Biological substances with complex

biological process;

Challenging to reproduce similar copies

Procedure

requires

Bioequivalence Comparability studies to demonstrate

similarity

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Biosimilar Applications

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• Biosimilars approved for:

• Somatropin (growth hormone) by Sandoz and BioPartners

• Epoetin alfa by Medice Arzneimittel, Sandoz and Hexal

• Epoetin zeta by Hospira and Stada

• Filgastrim (G-CSF) by CT Arzneimittel and Ratiopharm and

Teva

• However,

•Alpheon‟s application for a interferon alfa 2a refused in June

2006

•Marvel‟s applications for three insulin products (rapid,

intermediate and long) withdrawn in January 2008

•BioPartners‟ application for interferon beta 1a withdrawn in

May 2009

Molecular Complexity and Generics

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Aspirin180 Daltons

✓ Insulin 5,700 Daltons

✓

EPO34,000 Daltons

✓MAb

150,000 Daltons

?

Factor VII250,000 Daltons

✗HeLa cell ≈2x1015 Daltons

Will there ever be a Biosimilar hESC product?

• High barriers to entry for a biosimilar of a hESC product

• A hESC product could be considered a biosimilar (not a generic)

• Unlikely that a biosimilar cell-based therapy would be approved

under the existing framework

• Product-specific guidelines for biosimilars generally require

appropriate validated surrogate end points for clinical studies.

These may not exist.

• Pharmacodynamics and pharmacokinetics are extremely difficult to

measurable where the cell itself is the API

• It may even be challenging to identify the mode of action of a

hESC medicinal product

• Preclinical and clinical trials needed to establish comparability

• Ownership of and access to the cell line itself will be crucial

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Creation of hESC lines in the UK - UKSCB

• Creation of an hESC line requires a licence from the HFEA.

• The research must:

• Increase knowledge about the development of embryos,

• Increase knowledge about serious disease, or

• Enable such knowledge to be applied in developing treatments for serious

disease.

• To minimise the embryos used, every hESC line derived in the UK must

be deposited in the UK Stem Cell Bank, which researchers can access

The UKSCB established to provide a repository of human

embryonic, foetal and adult stem cell lines as part of the

UK governance for the research use of human embryos

Provides quality controlled stocks of these cells that

researchers worldwide can rely on to facilitate research

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Concluding remarks

• Complex regulatory landscape

• Legal and political challenges should be anticipated

• But, based on experience to date:

• Challenges likely to be targeted rather than industry-wide, eg:

• WARF

• Brüstle

• NIH Decision

• Geron‟s clinical hold

• Shirley v Sibelius

• „Work-arounds‟ likely

• Careful planning therefore essential

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Legal Information

• The information in this presentation is provided for information purposes only.

The information is not exhaustive. While every endeavour is made to ensure

that the information is correct at the time of publication, the legal position may

change as a result of matters including new legislative developments, new

case law, local implementation variations or other developments. The

information does not take into account the specifics of any person's position

and may be wholly inappropriate for your particular circumstances. The

information is not intended to be legal advice, cannot be relied on as legal

advice and should not be a substitute for legal advice.

• Unless otherwise stated, the information is limited to the position in England

and Wales.

• Copyright: Lawford Davies Denoon Ltd retains copyright in the material and all

rights are reserved. None of the information may be copied (whether in whole

or in part).

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© LAWFORD DAVIES DENOON LTD 2010

Thank youLawford Davies Denoon14A Clerkenwell Green

London EC1R 0DP020 3441 0908

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EU Regulation: ATMP

• Single EU marketing authorisation procedure for ATMPs

• Specific pre-clinical and clinical requirements and

• Specific “detailed” guidelines on GMP

• Committee for Advanced Therapies within EMEA to provide

scientific advice on ATMPs (at least two members with medical

device expertise)

• Post-authorisation monitoring via pharmacovigilance and risk

management

• Incentives for SMEs

• Consistent with Australia, Canada and USA

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Overview of EU Regulation

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EU Regulatory Framework: Overview

Blood

2002/98/EC

Human Tissues and

Cells

2004/23/EC

Other materials

Clinical Trials

2001/20/EC

Medicinal Products

2001/83/EC

726/2004

GMP

2003/94/EC

Annex I

2003/63/ECATMP

Regulation

Amendments

2004/27/EC,

2004/24/EC and

2002/98/EC

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EU Regulation: Tissues and Cells (1)

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EU Regulation: Tissues and Cells (2)

• Preamble:

This Directive should apply to tissues and cells including

haematopoietic peripheral blood, umbilical-cord (blood) and bone-

marrow stem cells, reproductive cells (eggs, sperm), foetal tissues

and cells and adult and embryonic stem cells.

• Article 2:

This Directive shall apply to the donation, procurement, testing,

processing, preservation, storage and distribution of human tissues

and cells intended for human applications and of manufactured

products derived from human tissues and cells intended for human

applications.

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EU Regulation: Tissues and Cells (3)

• Article 2 contd:

This Directive shall not apply to:

(a) tissues and cells used as an autologous graft

within the same surgical procedure;

(b) blood and blood components as defined by

Directive 2002/98/EC;

(c) organs or parts of organs if it is their function to

be used for the same purpose as the entire organ in

the human body.

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EU Regulation: ATMP (1)

ATMP Regulation Bridges the Gap

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Medical

Devices

93/42/EEC

Medicinal

Products

2001/83/EC

Regulation

on Advanced

Therapies 1394/2007

Advanced Therapies

Legislative Framework

Science

Medical

DevicesTissue

EngineeringCell Therapy Gene Therapy Biotech Pharmaceuticals

CAT Specific expertise

CHMP Expertise

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EU Regulation: ATMP (3)

• Article 2 – Definitions:

a) "Advanced therapy medicinal product" means any of the

following medicinal products for human use:

• a gene therapy medicinal product as defined in Part IV of

Annex I to Directive 2001/83/EC;

• a somatic cell therapy medicinal product as defined in Part IV

of Annex I to Directive 2001/83/EC,

• a tissue engineered product as defined in point (b).

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EU Regulation: ATMP (4)

• Article 2 contd:

b) "Tissue engineered product" means a product that:

• contains or consists of engineered cells or tissues,

and

• is presented as having properties for, or is used in or

administered to human beings with a view to regenerating,

repairing or replacing a human tissue. A tissue engineered

product may contain cells or tissues of human or animal origin,

or both. The cells or tissues may be viable or non-viable. It

may also contain additional substances, such as cellular

products, bio-molecules, bio-materials, chemical substances,

scaffolds or matrices.

EU Regulation: ATMP (5)

• Article 2 contd:

c) Cells or tissues shall be considered "engineered" if they

fulfil at least one of the following conditions:

• the cells or tissues have been subject to substantial

manipulation, so that biological characteristics, physiological

functions or structural properties relevant for the intended

regeneration, repair or replacement are achieved. The

manipulations listed in Annex I, in particular, shall not be

considered as substantial manipulations;

• the cells or tissues are not intended to be used for the same

essential function or functions in the recipient as in the donor.

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