Antibodies and the EPO An Industry Perspective Andrew Smith, Assistant General Patent Counsel.

Antibodies and the EPO

An Industry Perspective

Andrew Smith, Assistant General Patent Counsel

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Köhler and Milstein (1975) discovered method of making monoclonal antibodies: “Such cultures could be valuable for medical and industrial use.”

11 years later (1986) first monoclonal antibody approved

30 more Mabs approved between 1994 and 2012

~50 Mabs enter the clinic every year

~500 Mabs in various phases of clinical development

Average time in clinical trials prior to regulatory approval is ~7.5 yr

Copyright © 2012 Eli Lilly and Company

Antibodies are big business

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Therapeutic antibody development involves multiple risks

Less than 10% of antibodies that enter clinical development are approved Total cost of development becoming unsustainable

- 2 billion U.S.D. includes cost associated with attrition- Unclear whether costs for a single product will ever be recouped

- Royalty stacking- Tailored therapy

- Partnering and risk mitigation strategies required


Antibodies are risky business

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Solid exclusivity and freedom-to-operate advice from patent attorneys in major market jurisdictions is essential to allow effective business planning

A patent system that supports and promotes this enormous investment in medical innovation is imperative . . .


Antibodies are risky business

Initial technology based on injecting an antigen into a rabbit or mouse and “collecting” antibodies

- Product-by-process claims given the “pool” of antibodies could not be described any other way- Focus on antibodies as “research tools” not as “therapeutics” or “diagnostics”- Practice eventually evolved into claiming an entire class or genus of antibodies characterized by their ability to bind an antigen – free beer!

Antibody engineering involved characterizing the relevant structure of the antibody and making it more human-like

- Significant innovation occurs today for any antibody in clinical studies- Completely unpredictable and potentially not even possible to “invent” an antibody with the same structure as a claimed structurally-defined antibody, even if using the same starting materials

5Copyright © 2012 Eli Lilly and Company

Law has lost pace with science

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S -

S

S - SS

- S

S - S

S - S

CONSTANT

J

VARIABLE

VL CDR1

S - S

S - S

J

VARIABLE

VH CDR1

S S

D

VH CDR2

VH CDR3

VL CDR2

VL CDR3

S - S

S - S

S - S

CONSTA

NT

J

VARIA

BLE

VLCDR1

S - S

S - S

J

VARIA

BLE

VHCDR1

S S

D

VHCDR2VHCDR3

VL CDR2VL CDR3

S SS SS S

Heavy Chain

Light Chain

CO

NS

TAN

T

CO

NS

TAN

TF(ab)2 fragment

Fab’ fragment

Fc

CH

O

CH

O

IgG Structure and Function

VL Domain

CL Domain

Hinge Region

CH1 Domain

CH2 Domain

CH3 Domain

VH Domain

FcgR Binding C

ON

STA

NT

CO

NS

TAN

T

CONSTA

NTCONSTANT


Structure Responsible for Function

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Antibodies are not structurally similar in the regions responsible for their biological function.

Significant diversity in amino acid sequence occurs in the three hypervariable regions on the light and heavy chains (CDRs), and also to some extent in the “framework.”

CDR grafting generally results in a loss of function

Single amino acid changes in the CDRs and Framework often have dramatic effects on function

See e.g., Roberts et al. (1987) Nature 328:731-734; Riechmann et al. (1988) Nature 332:323-327; Tempest et al., (1991) Bio/Technology 9:266-271; Co et al. (1991) PNAS 88:

2869-2873


Structure v. Function

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Human Engineered Ab


Does current EPO practice . . .

• Acknowledge the enormous investment and innovation associated with novel Ab development?

• Provide a basis from which exclusivity advice can allow effective business planning?

• Threaten future development of Ab therapeutics?

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Antibodies at the EPO


EPO overview: predictability v surprising effect

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S Hoekstra, Director Biotechnology at EPO, from DCP Seminar, Gent, 18 Nov 2011


Small Organic Molecule


Peptide


Antibody


‘routine methods’ and ‘unexpected properties’

T735/00

“The case law in this field acknowledges inventive step if and when there is evidence that claimed monoclonal antibody prepared by routine methods shows unexpected properties (cf decision T645/02)”

“If, however, there are no unexpected effects achieved with a further monoclonal antibody compared with a monoclonal antibody with essentially the same properties as desired the case law denies inventive step”

“the preparation of monoclonal antibodies was a matter of routine experiment.” …”the search as such for monoclonal antibodies, given that the problem to be solved is an alternative, is not inventive either because there is an incentive in this art to look for useful antibodies.”

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Reasons for the Decision: 26


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Nature Biotechnology, Nils Lonberg, Sept 2005

EPO ‘routine methods’ approach

The ‘routine method’ assessment to be determined retrospectively at some future date... brings inherent uncertainty to Ab patentability…! With the passage of time all Ab development will be routine, lack of inventive step will be insurmountable…


Drafting: ‘unexpected properties’

Where ‘unexpected properties’ are apparent at filing – still prepare for:

(i) the prior art Ab reference that was missed…

(ii) prior art Ab is a partial functional overlap / data not directly comparable.

Suggestion:

Build in flexibility for re-formulating the problem by emphasizing the desirability of further properties (even if no data at filing):

antigen specificity, epitope binding, affinity/binding (Kon, Koff, Kd), neutralizing titre (Ki), clearance rate, mechanism of action, Ab stability, catalytic activity, immunogenicity.

Data for comparison on property undisclosed in the art can be later generated…


“routine methods” and ‘unexpected properties’

T735/00

“The case law in this field acknowledges inventive step if and when there is evidence that claimed monoclonal antibody prepared by routine methods shows unexpected properties (cf decision T645/02)”

“If, however, there are no unexpected effects achieved with a further monoclonal antibody compared with a monoclonal antibody with essentially the same properties as desired the case law denies inventive step”

“the preparation of monoclonal antibodies was a matter of routine experiment.” …”the search as such for monoclonal antibodies, given that the problem to be solved is an alternative, is not inventive either because there is an incentive in this art to look for useful antibodies.”

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No ‘unexpected properties’ for the Ab ?

T645/02

“There is no doubt that the skilled person, having knowledge of the relevant state of the art, will make use of the classical fusion method for producing monoclonal antibodies in order to solve the problem underlying the application. This method, which when using the particular immunogen without any doubt allows the production of various monoclonal antibodies directed against this immunogen, allows no assessment of the prospect of success regarding the isolation of one particular monoclonal antibody with precisely defined properties.”

The Board saw “elements of surprise” in the provision of a monoclonal antibody as produced by the deposited hybridoma



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No ‘unexpected properties’ for the Ab ?

T418/07

“The relevant question to be answered in the context of the assessment of inventive step is whether the skilled person, having possession and knowledge of the murine MAK195 antibody and its specific properties, would find sufficient guidance in the prior art to have the comfort of a reasonable expectation that the identification of a human antibody falling within the scope of the independent claims would be successful.”

The Board notes that the application of known techniques would likely result in antibodies with different antigen binding sites to those claimed



Drafting: No ‘unexpected properties’

Suggestion:

Build in flexibility for re-formulating the problem by emphasizing the desirability of further properties (even if no data at filing):

antigen specificity, epitope binding, affinity/binding (Kon, Koff, Kd), neutralizing titre (Ki), clearance rate, mechanism of action, Ab stability, catalytic activity, immunogenicity.

Data for comparison on property undisclosed in the art can be later generated…

Other Evidence:

• Routine methods are not enough to prepare the equivalent Ab of the prior art?

• Evidence of uncertainty in the development process; is success dependent on a chance event?

• Evidence of amino acid substitutions leading to failed attempts?


Prosecution: No ‘unexpected properties’

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Case law that could assist rebuttal of ‘routine method’ argument:

T32/85– Where the skilled person can only establish by trial and error whether

of not his particular choice of numerous parameters will provide a satisfactory result, this amounts to an undue burden.

T399/05; T123/06; T1063/06– Use of trial and error, even if via routine experimentation amounts to

an undue burden, i.e. invitation to perform a research program

T727/95– Relying on chance events for reproducibility amounts to undue

burden in the absence of evidence that such chance events occur and can be identified frequently enough to guarantee success


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Specific antibody sequence

Immunogenicity

Biological Function- Specificity- Affinity- Kinetics- Agonist or antagonist

Effector Functions

Developability- Physical stability- Chemical stability- Solubility- Expression- Purification

Typical optimization of humanized Ab lead


Antibody


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Specific chemical structure

Toxicity

Biological Function- Specificity- Affinity- Potency- Agonist or antagonist

Metabolic Stability

Developability- Physical stability- Chemical stability- Solubility- Manufacturing costs

Typical optimization of small molecule


Small Organic Molecule


EPO: chemical structure/function

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N

O

X Y

z

N N

O

useful in the treatment of dementia

The patent claim was directed, inter alia, to a compound of formula:

Closest prior art:wherein one of X, Y or Z is an oxygen atom and the other two are nitrogen atoms,

Closest prior art thus including a 1, 3, 4 oxadiazole nucleus of formula:

for the treatment of, inter alia, pre-senile and senile dementia.

T643/96


Chemical IS case law: structure/function

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T643/96

“When deciding on inventive step in relation to pharmacologically active compounds, what is essential is not whether a particular sub-structure of a chemical compound is replaced by another known isosteric one, but whether information was available on the impact of such a replacement on the pharmacological activity profile of the (group of) specific compound(s) concerned.”

The Board held PSA would not have expected replacement of N atom by a C atom would retain anti-dementia activity.

(T643/96 reaffirmed by T467/94, T156/95).


Chemical case law – applied to Abs

• Prior art Ab typically structurally very different

• CGK evidence of single amino acid changes to Ab variable region causing

loss of Ab functionality

• Essential technical features responsible for technical effect, i.e. binding

function, are specific CDRs; inventive step assessment should examine these

• PSA would not know /reasonably predict the impact structural differences to

prior art would have on Ab function

• Data may be available to support the unpredictability of structural changes

specific to the claimed Ab

• Is there a reasonable expectation of engineering an Ab with claim specific

CDR sequences starting from the structure of the prior art Ab?


Comments:

• Current EPO practice applies a different standard to IS assessment of Abs versus small molecule chemicals – is this justified?

• Patent exclusivity for novel structurally defined Abs, deemed functionally equivalent of prior art Ab appears very difficult...

• ‘Routine method’ approach to inventive step introduces uncertainty to exclusivity strategy planning; ultimately all Abs will lack inventive step…?

• EPO practice undermining patent law principle of rewarding innovation

• Should the innovator wait for unexpected properties from the clinic? – open label studies… confidentiality… SME options, securing finance…?

• Return on innovator investment may have to rely on DPE…

• Patient populations unlikely to be uniformly suited to single Ab treatment; functional equivalent Abs entering the clinic are essential for alternative treatment options - current EPO practice deters investing here.


Antibodies and the EPO An Industry Perspective Andrew Smith, Assistant General Patent Counsel.

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Transcript of Antibodies and the EPO An Industry Perspective Andrew Smith, Assistant General Patent Counsel.