Transcript Holliday.EPO.Claim.Types.Antibodies

Patenting Antibodies in Europe
Claim types and their associated
inventive step issues
Louise Holliday
[email protected]
Types of antibody claims

Functional
◦ Binding to target antigen or epitope
◦ Activity – qualitative or quantitative

Structural
◦ CDRs, VH/VL or whole antibody sequence

Source
◦ Obtainable from a deposited hybridoma
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Target

“An antibody capable of binding specifically to X”
Example
EP 07013470
1. An isolated antibody
that specifically binds
to a p51 protein
comprising the amino
acid sequence of SEQ
ID No. 1
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Epitope

“An antibody capable
of binding specifically
to the epitope of
SEQ ID NO:1”
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Qualitative activity

“An antibody which specifically binds to
X but not to Y”

“An antibody capable of binding X and
inhibiting the binding of X to XR”

“An antibody which binds X and induces
apoptosis of nucleated blood cells”
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Quantitative activity

An antibody capable of binding to X, which has an
affinity constant for X between 0.1 and 10 nM

An antibody which has at least 5 times higher
binding activity for X than antibody Y

An antibody which causes at least 50% more lysis
of target cells relative to the reference polyclonal
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Sequence

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
Whole Ab
CDRs
VH + VL
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Deposit
1.
An antibody which is produced by the deposited
cell line having ATCC No. PTA-1234.
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Claim types – Ab patents granted 2008
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Inventive step
Definition by
sequence
Definition by
function
Definition by
target
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Definition by target
New target
If target is novel and
inventive,
so is antibody to target
Known target
If target is known,
considered obvious to
make antibody to
target
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Reach through claims
1. New receptor identified
2. Method for screening for agonist using receptor
3. Agonists identified using method
EPO/USPTO/JPO
“one would have no knowledge beforehand as to whether of not any
given compound…would fall within the scope of what is claimed. It
would require undue experimentation (be an undue burden) to
randomly screen undefined compounds for the claimed activity”
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Definition by target

Is that not also true for antibody claims?
◦ New target (X)
◦ An antibody capable of binding specifically to protein X
 “binding specifically” often not defined
 Isn’t it likely that some Abs out there will cross-react? If so
claim should lack novelty.
 If target X is highly similar to other known targets (eg another
GPCR) is there anything inventive about an antibody to it?
 Should they have to show that it is possible to make an
antibody which does not cross-react?
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Definition by function
If there is a known antibody to the same
target, it is obvious to use known
techniques to improve properties of
antibody
“known techniques” –
e.g. chimerization,
humanization, affinity
maturation, Fc
engineering
“improved property”e.g immunogenicity,
affinity and efficacy
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Definition by function

Key question:
◦ Would it have been obvious to try to generate an
antibody having the claimed activity with a
reasonable expectation of success using known
techniques?
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Obvious to try?
Was the function
known/suggested
as being
desirable?
no
yes
Are there
routine ways to
generate/select
antibodies
having that
function?
yes
no
no
Is the scale of
improvement
predictable?
yes
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Obvious to try?
Quantitative
definition
Molecular
function
Physiological
effect
Epitope
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Case study

Claim 1: originally defined by target
• A human monoclonal antibody of the IgG isotype, which
specifically binds to the A2 domain of FVIII.
Prior art: Human scFv which
binds the A2 domain of FVIII
(made by phage display)
Ab of invention inhibited procoagulant activity of FVIII
more than scFv of prior art
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Case study

Amended claim to specify quantitative activity
◦ “inhibits up to 99% of the pro-coagulant activity of FVIII at a concentration
of 0.1 μg/ml”
Not allowed

Amended claim to specify epitope
◦ “the epitope of said antibody comprises the amino acid residues between
positions 484 and 508 of FVIII”
Allowed


Did not have to show prior art scFv did not bind this epitope
Did not have to demonstrate that binding this epitope was
associated with high inhibitory activity (ie, did not have to
demonstrate any technical advantage associated with binding this
epitope)
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Definition by sequence/source
Whole Ab
VH/VL
CDR Sequences
Deposit
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Definition by sequence/source
Question
Is the new
antibody a “mere
alternative” to a
known antibody?
Question
Or does it
provide an
unexpected
technical effect?
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Unexpected technical effect (UTE)

For example
Antigen
specificity
Clearance
rate
Affinity
/binding
(Kon, Koff,
Kd)
Epitope
binding
Catalytic
activity
Immunogenicity
Mechanism
of action
Ab stability
Neutralising
Titre (Ki)
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Definition by sequence/source




Why do you need to demonstrate a UTE?
Acceptable to provide an alternative solution to a
known problem (T92/92, T495/91)
For an inventive step to be present, it is not
necessary to show improvement – substantial or
gradual – over the prior art (T583/93)
c/f chemical inventions: “providing the public with
a useful choice”
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Broadening out from the specific
sequence

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
Variant sequence
having X% identity
Variant sequences
having one or more
amino acid mutations
Definition by key
residues in CDRs
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Sequence variants

EPO: the particular affinity of a given, classical antibody
is the result of the precise 3D structure of its entire
antigen binding region, which in turn relies on the
cooperative effect of the 3 CDRs and 4 FR regions per
VH and per VL domain. Replacement of amino acids
within said domains is expected to result in a
disturbance of the 3D structure and thus in (at least
partial) disturbance of the antibody’s functionality/affinity.
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Definition by sequence

CDR variants
◦ Have to convince examiner that all variants within the scope of the
claim have or would have the desired activity
◦ May need to experimentally verify that specific variants retain activity
Example
EP 07013470
1. An isolated human antibody, which has the following
characteristics:
b) a light chain CDR3 domain comprising the amino
acid sequence of SEQ ID NO:3, or modified from
SEQ ID NO:3 by a single alanine substitution at
position 1, 4, 5, 7 or 8;
c) a heavy chain CDR3 domain comprising the
amino acid sequence of SEQ ID NO:4, or
modified from SEQ ID NO:4 by a single alanine
substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11
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Definition by sequence

VH/VL variants
◦ Do all antibodies within the scope of the claim “solve the problem”
of the invention?
◦ May be able to use variant language (e.g. % identity) in
combination with a functional definition
Example
EP Application No. 037219555
1. An antibody or fragment thereof comprising an
amino acid sequence that is at least 85% identical to
a VH domain...wherein said antibody or fragment
thereof specifically binds a CK-B4 polypeptide and
inhibits or abolishes the ability of a CK-B4
polypeptide to induce calcium flux of a cell
expressing CCR6.
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Conclusion

There are various different types of patent claim
which may be used for antibodies

Each is associated with a particular type of inventive
step objection

The EPO position varies between surprisingly
lenient and surprisingly harsh depending on the type
of claim

Where possible it is good to include multiple claim
types and fall back positions to provide flexibility for
amendment and argumentation during prosecution
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