Transcript Claire Baldock

AIPPI Forum 2011 - Hyderabad
Pharma Workshop 3 - 14 Oct 2011
Securing patent protection for
therapeutic antibodies in Europe
by
Claire Baldock
[email protected]
© Boult Wade Tennant 2011
Patentability requirements – same as
any other Biotech invention

Novelty (Art. 54 EPC)

Inventive step (Art. 56 EPC)

Sufficiency (Art. 83 EPC)

Clarity/support (Art. 84 EPC)

Industrial application (Art. 57 EPC)
Hierarchy of antibody claims
1.
Antibodies to a new target protein
2.
New antibodies to a known protein
3.
New use of antibodies to a known protein
1. Antibody to a new protein

If a protein is found novel and inventive, and is
capable of industrial application, patentability of
antibodies to that protein tends to follow

Broad antibody claims can be obtained, even if
no antibody has actually been made at the
filing date (e.g. T0604/04, T0019/08)

Accepted form of reach-through claim.
“Antibody that binds to antigen X”.
Novelty (Article 54EPC)

1.


Antibody often considered novel if antigen is
novel but not always
“Antibody that binds (novel antigen X)” can be
anticipated by antibodies that bind a related
known antigen which has epitopes in common
with antigen X
Example – a mouse version of a human
protein
Not avoided by claiming antibody has
specificity for antigen X
What is meant by “specificity”?
T 189/01 – Yeda Research (IFN-beta 2/Il-6R)
15. An antibody against IFN-β2/Il-6R soluble
extracellular fragment which specifically
recognises said fragment ….
(Para. 14) “The notion of specificity does not exclude that
an antibody may cross-react with other polypeptides than
that against which it has been raised. This is because the
cross-reaction is in fact not a feature of the antibody, but
much more a feature of the antigenic epitope… which can
be present on several different molecules.”
Disclaiming cross-reacting antibodies
Disclaimer
“… an amendment to a claim resulting in
incorporation therein of a “negative” technical
feature, typically excluding from a general feature
specific embodiments or areas.”
Antibody example
“Antibody which immunoreacts with antigen X but
not antigen Y.”
G0002/10 – 30 August 2011
1.

“… the overriding principle for any amendment to
be allowable under Article 123(2) is that the
subject matter of an amended claim must be at
least implicitly disclosed to the skilled person,
using common general knowledge, in the
application are filed. As has also been set out in
the foregoing, that applies equally to the subjectmatter of a claim, the scope of which is determined
by a disclaimer.”
If antibody with functional profile “binds X but not
Y” was not originally disclosed, allowed claims of
this type may be invalid under G02/10
New antibody to a known antigen


Presumption that it is routine to generate an
antibody to a known antigen (see T0431/96)
Thus claim “Antibody which binds known antigen
X” generally not inventive

Antibodies need to be defined by other specific
technical or functional features conferring a
particular technical effect

Technical effect must be across the range claimed
(T0939/92)
Some examples
Functional
 Binding affinity
 Binding specificity
 Binding a defined
epitope (amino acid
sequence)
 Blocking the binding of
a specific antibody to
its epitope
 New biological
function
Structural
 Specific amino acid
sequences
 One or more CDR
sequences
 V-region sequences
 Structurally modified
Fc region
 Specific glycoforms
 Specific isotypes
 Fragments
Binding affinity
EP 2004693 (pending)
1.
An isolated human or humanized antibody or
functional fragment thereof comprising an
antigen-binding region that is specific for
target protein c-Met, wherein the antibody or
functional fragment thereof binds to human cMet with a KD at or below 4.6 pM
Binding specificity
T1466/05
1.
An antibody reactive with the pyridinoline in
peptide-linked pyridinoline but not with free
pyridinoline which is useful in an assay to
indicate bone resorption
Binding an epitope
EP-B-1606317 (July 2010)
5. A monoclonal antibody that specifically binds to an antigenic epitope of a human IL-22RA
polypeptide having the amino acid sequence of SEQ ID NO:3, wherein said antigenic
epitope is selected from the group of:
(a) an epitope consisting of the amino add sequence of SEQ ID NO:3 from amino acid
number 41 (Lys) to amino acid number 47 (Asp); (b) an epitope consisting of the amino acid
sequence of SEQ ID NO:3 from amino acid 41 (Lys) to amino acid number 62 (Cys); (c) an
epitope consisting of the amino acid sequence of SEQ ID NO:3 from amino acid number 84
(Ala) to amino acid number 97 (Ser); and (d) an epitope consisting of the amino acid
sequence of SEQ ID NO:3 from amino acid number 93 (Thr) to amino acid number 120
(Met);
wherein the antibody reduces or neutralizes the activity of a human IL-22 polypeptide
having the amino acid sequence of SEQ ID NO:6.
Competing with a defined antibody
EP-B-1734995 (July 2010)
1.
A chimeric or humanized monoclonal antibody
(mAb) that competes with antibody L2G7 produced
by hybridoma ATCC No.:PTA-5162 for binding to
Hepatocyte Growth Factor (HGF), and which
neutralizes HGF and inhibits growth of a human
tumor xenograft in a mouse as a single agent.
New biological function
T617/07
Granted claims EP-B-1181318:
1.
Monoclonal antibody, synthetic and
biotechnological derivatives thereof, able to
recognise and bind the high affinity tyrosine
kinase receptor of NGF (Nerve Growth
Factor), named TrkA, and act as an
antagonist for the binding of NGF to TrkA
T1466/05 Functional Definition I
1.
“An antibody reactive with the pyridinoline in
peptide-linked pyridinoline and not free pyridinoline
which is useful in an assay to indicate bone
resorption”

Single antibody made and deposited with the
required activity

Question was whether the claim was enabled
across the range
T1466/05 – Appeal board

Appeal Board held that contrary to the arguments of the
applicant the availability of the deposited antibody was not
enough assistance to produce further antibodies of the same
function. The claim was not limited to antibodies with the
same CDRs as the deposited antibody

The epitope on the antigen to which an antibody would have
to bind to provide the required discrimination between free
and linked pyridinoline was not identified. Therefore,
preparing and screening for the appropriate antibodies would
be a matter of pure chance

Additional experimentation going beyond the average effort
necessary in the field on monoclonal antibodies was an
undue burden. The claim is insufficient.
T0617/07 Functional Definition II
“Use of a monoclonal antibody, synthetic and
biotechnological derivatives thereof, able to recognise
and bind the high affinity tyrosine kinase receptor of
NGF, named TrkA and act as antagonist for the
binding of NGF to TrkA, and which prevents the
functional activation of TrkA by NGF, in the
manufacture of a pharmacological composition for
treatment of neurological pathologies comprised within
the following group: chronic pain and acute pain.”
T0617/07 (cont)


Decision of the OD 31 Jan 2007
Claim 1 – term “antagonist for the binding of
NGF to TrkA” given broad interpretation

Any antibody that blocks binding of NGF to
TrkA, regardless of whether it antagonises or
agonises TrkA receptor

Claim lacks novelty over prior art antibody
which blocks binding of NGF to TrkA; P
amends to make clear that antibody must also
inhibit activity of the natural ligand
T0617/07 (cont)

A single antibody was disclosed, MNAC13,
which was shown to have the functional
property

Question also arose whether the specification
allowed the making of further antibodies with
the same activity without undue burden
Appeal board

Specification provided a very detailed protocol of
how MNAC13 had been produced which differed
from standard protocols for set out in the prior art
for these antibodies

Different groups of mice immunized with cells
expressing TrkA and their sera tested for ability to
inhibit binding of NGF to TrkA. Only splenocytes of
mice whose sera showed greatest inhibition were
used for fusion with myeloma cells.
Appeal board (cont)

Board felt this protocol to be “more sophisticated”
than those shown in the art of record in that it
enriched the pool of antibodies likely to have
capability to prevent activation of the TrkA receptor.
Therefore, there was not an undue burden in
making other antibodies falling within the claim if
following the protocol provided. Claim sufficient.
Structural Definitions
EP-B-1423431 (June 2010)
1.
An anti-VLA-1 antibody or antigen-binding fragment thereof whose
light chain complementarity determining regions are defined by
amino acid residues 24 to 33, 49 to 55, and 88 to 96 of SEQ ID
NO : 1, and whose heavy chain complementarity determining
regions are defined by amino acid residues 31 to 35, 50 to 65, and
98 to 107 of SEQ ID NO: 2.

Quite specific but variation can be built in as with normal amino
acid sequence claims, eg % identity, % homology, hybridising etc.

There are conventions for CDR numbering in a sequence, eg
Kabat, Chothia etc. Absence of identification of the convention
applied in the disclosure may lead to lack of clarity (Article 84).
Medical uses of antibodies

A pharmaceutical or diagnostic composition
comprising an antibody which binds antigen X and a
pharmaceutically acceptable exipient

Antibody which binds to antigen X for use in treating
disease Y

For sufficiency to be recognised there must be
sufficient data to the avail that the antibody affects
the target and the target is linked to the disease
(T0609/02)
But not always - T0018/09


Subject matter – New member of the TNF ligand
super family of proteins – Neutokine α
No functional data present and large list of possible
function and uses, some of them conflicting, given
on the basis of the known function of related
molecules
T0018/09
13. An isolated antibody or portion thereof that binds
specifically to
g)
the full length Neutrokine α polypeptide (amino acid
sequence of residues 1 to 285 of SEQ ID NO 2); or
h)
the extracellular domain of the Neutrokine α
polypeptide (amino acid sequence 73 to 285 of SEQ ID
NO 2
18. A pharmaceutical composition comprising……….the
antibody of claim 13 etc
19. A diagnostic composition comprising………the antibody
of claim 13 etc
Appeal board
“ Whereas the use of antibodies in the preparation of a
pharmaceutical or diagnostic compositions may imply the
identification of a condition or disease wherein that protein is
involved (which is also true for the compositions themselves), the
screening and selection of antibodies that may be prima facie of
relevance for the treatment and/or detection of that condition or
disease does not pose any actual technical problem since
(activity) assays related to or associated with , that condition or
disease may readily be available to the skilled person even
though other criteria, such as (low) immunogenicity, (high)
specificity and pharmaceutical suitability may be required for a
later selection of the most appropriate antibodies.”
Claims 13, 18 and 19 all sufficiently disclosed.
T0601/05
1.
“A pharmaceutical composition containing a human
monoclonal antibody that binds to human tumor
necrosis factor alpha”

The uniform opinion at the priority date was that
antibodies useful for the treatment of TNF-related
disorders should have a high affinity to soluble TNF
and should be capable of neutralising its activity

Claim 1 covered antibodies for use as a
pharmaceutical, whatever their affinity for TNF
T0601/05 (cont)

The patent disclosed a method for producing the
antibodies from human cells which would only be
capable of making low affinity antibodies

Thus, a whole class of compounds falling within
claim 1 could not be produced on the basis of the
teaching in the patent. This was the very class
aimed at by the scientific community

Claim found insufficient

Presumption in T0018/09 rebuttable
In summary

Applicants have found many innovative and successful ways to
claim antibodies both by structure and function

Downfalls can be:
1.
Lack of novelty over antibodies which cross-react with the
claimed target
2.
The making of a single antibody with the claimed
functional properties not sufficient to support a broader
claim to any antibody with those same functional
properties if the generation of other antibodies would be
“pure change”
3.
Exception to 2. above seems to exist in cases where
antibody is against a new and inventive antigen
AIPPI Forum 2011 - Hyderabad
Pharma Workshop 3 - 14 Oct 2011
Securing patent protection for
therapeutic antibodies in Europe
by
Claire Baldock
[email protected]
© Boult Wade Tennant 2011