Transcript Smith.Antibodies and the EPO - An Industry Perspectivex

Antibodies and the EPO
An Industry Perspective
Andrew Smith, Assistant General Patent Counsel
Antibodies are big business
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
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Antibodies are risky business
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
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Antibodies are risky business
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 . . .
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Law has lost pace with science
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
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Structure Responsible for Function
IgG Structure and Function
VH Domain
VL Domain
CH1 Domain
CHO
SS
CH2 Domain
F(ab)2 fragment
SS
CONSTANT
Hinge Region
CONSTANT
SS
SS
SS
CL Domain
CHO
Fab’ fragment
CONSTANT
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SS
CONSTANT
CH3 Domain
SS
FcgR Binding
Fc
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Structure v. Function
 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
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Human Engineered Ab
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Antibodies at the EPO
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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EPO overview: predictability v surprising effect
S Hoekstra, Director Biotechnology at EPO, from DCP Seminar, Gent, 18 Nov 2011
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Small Organic Molecule
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Peptide
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Antibody
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‘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.”
Reasons for the Decision: 26
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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…
Nature Biotechnology, Nils Lonberg, Sept 2005
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Drafting: ‘unexpected properties’
Where ‘unexpected properties’ are apparent at filing – still prepare for:
(i)
(ii)
the prior art Ab reference that was missed…
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,
neutralizing titre (Ki),
Ab stability,
epitope binding,
clearance rate,
catalytic activity,
affinity/binding (Kon, Koff, Kd),
mechanism of action,
immunogenicity.
Data for comparison on property undisclosed in the art can be later generated…
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“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.”
Reasons for the Decision: 26
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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.”
Reasons for the Decision: 7
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.”
Reasons for the Decision: 34
The Board notes that the application of known techniques would likely
result in antibodies with different antigen binding sites to those
claimed
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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,
neutralizing titre (Ki),
Ab stability,
epitope binding,
clearance rate,
catalytic activity,
affinity/binding (Kon, Koff, Kd),
mechanism of action,
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?
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Prosecution: No ‘unexpected properties’
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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Typical optimization of humanized Ab lead
Immunogenicity
Specific antibody sequence
Biological Function
- Specificity
- Affinity
- Kinetics
- Agonist or antagonist
Effector Functions
Developability
- Physical stability
- Chemical stability
- Solubility
- Expression
- Purification
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Antibody
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Typical optimization of small molecule
Toxicity
Specific chemical structure
Biological Function
- Specificity
- Affinity
- Potency
- Agonist or antagonist
Metabolic Stability
Developability
- Physical stability
- Chemical stability
- Solubility
- Manufacturing costs
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Small Organic Molecule
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EPO: chemical structure/function
T643/96
N
The patent claim was
directed, inter alia, to a
compound of formula:
Closest prior art:
O
X
Y
z
Closest prior art thus
including a 1, 3, 4
oxadiazole nucleus of
formula:
N N
O
useful in the treatment of
dementia
wherein one of X, Y or Z is an
oxygen atom and the other two
are nitrogen atoms,
for the treatment of, inter alia,
pre-senile and senile dementia.
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Chemical IS case law: structure/function
T643/96
“When deciding on inventive step in relation to pharmacologically
active compounds, what is essential is not whether a particular substructure 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).
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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?
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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.
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