Patenting Antibodies in Europe

1
Patenting Antibodies in Europe

• Claim types and their associated inventive step
  issues

Louise Holliday lch_at_dyoung.co.uk
2
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

3
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
4
Epitope

• An antibody capable of binding specifically to
  the epitope of SEQ ID NO1

5
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

6
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

7
Sequence

• Whole Ab
• CDRs
• VH VL

8
Deposit

• An antibody which is produced by the deposited
  cell line having ATCC No. PTA-1234.

9
Claim types Ab patents granted 2008
10
Inventive step
11
Definition by target
12
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 compoundwould 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

13
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
• Isnt 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?

14
Definition by function
15
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?

16
Obvious to try?
no
Was the function known/suggested as being
desirable?
yes
no
Are there routine ways to generate/select
antibodies having that function?
no
yes
Is the scale of improvement predictable?
yes
17
Obvious to try?
Quantitative definition
Molecular function
Physiological effect
Epitope
18
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 pro-coagulant activity of FVIII more
than scFv of prior art
19
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)

20
Definition by sequence/source
21
Definition by sequence/source
22
Unexpected technical effect (UTE)

• For example

23
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

24
Broadening out from the specific sequence

• Variant sequence having X identity
• Variant sequences having one or more amino acid
  mutations
• Definition by key residues in CDRs

25
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 antibodys
  functionality/affinity.

26
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
• An isolated human antibody, which has the
  following characteristics
• a light chain CDR3 domain comprising the amino
  acid sequence of SEQ ID NO3, or modified from
  SEQ ID NO3 by a single alanine substitution at
  position 1, 4, 5, 7 or 8
• a heavy chain CDR3 domain comprising the amino
  acid sequence of SEQ ID NO4, or modified from
  SEQ ID NO4 by a single alanine substitution at
  position 2, 3, 4, 5, 6, 8, 9, 10 or 11

27
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
•  

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.
Example
28
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