by

Claire Baldockcbaldock@boult.com

© Boult Wade Tennant 2011

Securing patent protection for therapeutic antibodies in Europe

AIPPI Forum 2011 - HyderabadPharma Workshop 3 - 14 Oct 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) Antibody often considered novel if antigen is

novel but not always

1. “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 subject-matter 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 c-Met 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

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 Functional Definition I

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.

T1466/05 – Appeal board

“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 Functional Definition II

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

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

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.

Appeal board (cont)

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).

Structural Definitions

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)

Medical uses of antibodies

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

But not always - 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

T0018/09

“ 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.

Appeal board

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

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

T0601/05 (cont)

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 target2. 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

In summary

by

Claire Baldockcbaldock@boult.com

© Boult Wade Tennant 2011

Securing patent protection for therapeutic antibodies in Europe

AIPPI Forum 2011 - HyderabadPharma Workshop 3 - 14 Oct 2011