Patenting Antibodies in Europe Claim types and their associated inventive step issues Louise Holliday lch@dyoung.co.uk

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

Target “An antibody capable of binding specifically to X” EP 07013470 Example EP 07013470 1. An isolated antibody that specifically binds to a p51 protein comprising the amino acid sequence of SEQ ID No. 1

Epitope “An antibody capable of binding specifically to the epitope of SEQ ID NO:1”

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”

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

Sequence Whole Ab CDRs VH + VL

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

Claim types – Ab patents granted 2008

Inventive step Definition by sequence Definition by function Definition by target Definition by function Definition by sequence

Definition by target New target Known 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

Reach through claims EPO/USPTO/JPO 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”

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?

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

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?

Obvious to try? no yes no no yes yes 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

Obvious to try? Quantitative definition Molecular function Physiological effect Epitope

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

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)

Definition by sequence/source Whole Ab VH/VL CDR Sequences Deposit

Definition by sequence/source Is the new antibody a “mere alternative” to a known antibody? Question Or does it provide an unexpected technical effect?

Unexpected technical effect (UTE) For example Immunogenicity Antigen specificity Affinity /binding (Kon, Koff, Kd) Mechanism of action Neutralising Titre (Ki) Ab stability Epitope binding Clearance rate Catalytic activity

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”

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

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.

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 NO:3, or modified from SEQ ID NO:3 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 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

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.

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