Hot Issues in Patenting
Antibodies
6th Annual Antibody Therapeutics
Conference
IBC Life Sciences
San Diego, CA
December 9-11, 2008
Moderator: Timothy J. Shea, Jr. – Director
Sterne, Kessler, Goldstein & Fox P.L.L.C.
Panelists:
Michael Braunagel, Ph.D., Director, Strategic
Alliances and Licensing, Affitech AS
Diana Hamlet-Cox, Ph.D., J.D., Vice President
and Chief Patent Counsel, Medarex, Inc.
Bernd Hutter, Ph.D., Associate Director & Team
Leader IP, MorphoSys AG
Diane Wilcock, Ph.D., Director, Intellectual
Property, Xoma (US) LLC;
Jennifer A. Zarutskie, Ph.D., J.D., Director of
Intellectual Property, Patent Counsel, Dyax Corp.
Introduction
• Therapeutic antibodies have come of age
• Fastest-growing segment of pharmaceutical industry
– Growing at rate of 30% per year
• 2007 revenues of approximately $26 billion
• Five of the six biopharma R&D collaborations valued at
>$1B in 2007 focused on antibody technologies
• As antibody technology as evolved, so has the legal
landscape
• Strategies for patenting pioneering antibody technologies
of yesterday are not necessarily applicable today
2
Introduction
• Our panel of experienced in-house
IP experts will address four hot
topics in antibody patenting:
– Patentability issues
• Obviousness after KSR
• Written description/enablement
– Freedom-to-Operate issues
– Antibodies as biosimilars
– Patent life-cycle management
3
Patentability Issues - Basics
• Antibodies must meet same standards for
patentability as other inventions:
– Antibody must be novel
• i.e., not disclosed in single prior art reference
– Antibody must be nonobvious
• i.e., cannot be obvious modification of what is
already publicly known in field
– Application must describe antibody with sufficient
specificity
• Enough to show that inventors had “possession”
of full scope of what is claimed as invention
– Application must enable how to make and use
antibody
– Application must teach best mode known to
inventors of making/using invention (US only)
• Nonobviousness and written description have become
the most difficult hurdles in antibody patenting
4
Patentability Issues - Obviousness
• The bar for showing that an antibody is
nonobvious has been raised in the U.S.
– Now closer to EP standard (inventive step)
• KSR Int’l v. Teleflex Inc. (S. Ct. 2007)
– Rejected “rigid approach” of Fed. Cir. (i.e. TSM test)
as inconsistent with more “expansive and flexible”
analysis set forth in S. Ct. precedent
– “The combination of familiar elements according to
known methods is likely to be obvious when it does
no more than yield predictable results”
– “obvious to try” may be enough (in some cases)
– Made easier for examiners to shift burden to applicant
to show invention not obvious
5
Patentability Issues - Obviousness
• Ex parte Kubin (BPAI 2007)
– Decided one month after KSR
– Currently on appeal to Fed. Cir.
– Calls into question Fed. Cir. ruling in In re Deuel
• But cannot overrule since Board decision
– Deuel (Fed. Cir. 1995)
• Claims to sequence for gene not prima facie obvious over prior
art teaching of method of gene cloning, together with reference
disclosing partial amino acid sequence for protein even where
motivation to obtain sequence existed
• “Obvious to try” not standard
• Applied chemical standard for structural obviousness
– Kubin
• Board cited KSR for proposition that “obvious to try” can be
enough to establish prima facie case
• Cited advances in state of art since Deuel
• Affirmed rejection
– Motivation to sequence existed
– Methodologies available
– Reasonable expectation of achieving success
6
Patentability Issues – Obviousness
• PTO Training Guidelines
– Issued post-KSR
– Set forth acceptable “rationales” to support rejection
– Rationale D (particularly applicable to antibody
technologies)–
• Applying a known technique to a known product ready
for improvement to yield predictable results
• Dilemma
– Many of pioneering antibody technologies have
become mainstream
•
•
•
•
Humanization
Phage display
Transgenic mice
Fc engineering?
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Patentability Issues - Obviousness
• Hypothetical I
– Mouse antibody A to human antigen X was
known. Company took A, humanized it to
produce AJ then engineered the Fc region to
produce AK which has dramatically increased
effector function (e.g., ADCC). General
techniques for humanizing and Fc
engineering are known in art. Ab claimed in
terms of VH and VL sequences, which are
novel.
– Obvious???
8
Patentability Issues - Obviousness
• Hypothetical II
– Full-length human antigen “X” has been
characterized and is known to be a receptor
for an apoptotic pathway. Company used
phage display to generate novel Ab “A.”
Epitope mapping shows A is first Ab known
to bind particular epitope. In vitro assays
show Ab is agonistic and induces apoptosis
in target cells. Claimed in terms of CDR
sequences, epitope and function.
– Obvious???
9
Patentability Issues - Obviousness
• Ways to Defeat Obviousness Rejections Generally
– Show no reasonable expectation of success to produce
claimed antibody/method of use (i.e. not predictable)
– Show claimed antibody/method of use has unexpected
results
• Anticipating the rejection (Filing Strategies)
– Counsel and scientists must work together to characterize
Abs as much as possible before filing (Must be interactive)
• Epitope mapping
• Functional properties
– Include in vivo data as early as possible
– Follow up with clinical observations (often unpredictable)
– Benchmark your Ab against prior art Abs to identify superior
features
• Rebutting the rejection (Prosecution Strategies)
– Work with scientists to design experiments to include in
expert declarations
10
Recently Granted US Antibody
Patents
30%
25%
20%
15%
10%
5%
0%
Novel Ag Ab Seqlimited
Hybma
Epitope
Diag
Function
Other
Type
US patents granted from 1 Aug – 1 Nov 2008 with “antibod*” in title. N=120
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Examples Of Recently Granted
Epitope Claims
• An isolated monoclonal antibody specific to CYP24
wherein the antibody binds specifically to the CYP24
epitope C-QRLEIKPWKAYRDYRKE-NH2 (SEQ. ID. NO.
2).
• A method of making an antibody that specifically binds to
cytochrome P450 CYP1B1, the method comprising
raising the antibody using a peptide consisting of an
amino acid sequence ….. or an antigenic fragment
thereof.
• A monoclonal anti-CD80 antibody or CD80-binding
fragment thereof, wherein the antibody has the same
epitopic specificity as an antibody selected from the
group consisting of: …..
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Examples Of Recently Granted
Functional Claims
•
An isolated human antibody or antigen binding fragment thereof
that specifically binds properdin, wherein said antibody inhibits
oligomerization of a properdin monomer.
•
A host cell expressing a monoclonal antibody or fragment
thereof that binds specifically to human CD80 antigen and
inhibits the binding of the CD80 antigen to CD28 without
inhibiting the binding of the CD80 antigen to CTLA-4.
•
A method of treating rheumatoid arthritis in a human comprising
administering to the human an effective TNFT-inhibiting amount
of an anti-TNFT antibody or antigen-binding fragment thereof,
said antibody comprising a human constant region, wherein
said antibody or antigen-binding fragment (i) competitively
inhibits binding of A2 (ATCC Accession No. PTA-7045) to
human tumor necrosis factor TNFT, and (ii) binds to human
TNFT with an affinity of at least 1×108 liter/mole, measured as
an association constant (Ka).
13
Patentability Issues – Written Description/
Enablement
• Written description – application must show applicant has
“possession” of full scope of invention claimed
– WD has become primary battleground in Ab patenting (and
biotech patenting generally)
• Genus claim vs. species claim
– Species claim protects specific Ab
• E.g. Ab claimed in terms of specific VH and VL sequences
• Generally easier to design around
– Since changes to sequence can take outside of scope of claim
(assuming not “equivalent”)
– Genus claim protects specific Ab and others with like
structure and/or function
• E.g., Ab claimed in terms of epitope it binds to and function
• Generally more desirable since much broader and therefore
more difficult to design around
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Patentability Issues – Written Description/
Enablement
•
•
Issue: What is required in application to support generic or
subgeneric claims?
Rule:
– “A genus can be described by disclosing: (1) a representative
number of species in that genus; OR (2) its ‘relevant identifying
characteristics,’ such as ‘ complete or partial structure, other
physical and/or chemical properties, functional characteristics when
coupled with a known or disclosed correlation between function and
structure, or some combination of such characteristics.” In re
Alonso (Fed. Cir. October 30, 2008)
– Alonso
• Generic claim to method of treating neurofibrosarcoma in a
human by administering a therapeutically effective amount of a
mAb idiotypic to the neurofibrosarcoma (not lim. to spec. mAb)
• Application disclosed one mAb
• Court found one mAb not representative of “densely populated
genus”
• “The specification teaches nothing about the structure, epitope
characterization, binding affinity, specificity, or pharmacological
properties common to the large family of antibodies implicated
by the method.”
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Patentability Issues – Written Description/
Enablement
• Broad generic claims are possible
– If first to fully characterize a novel antigen
(Noelle claim)
• E.g., “An antibody that specifically binds antigen
X.”
• But truly novel antigens increasingly rare
• Subgenus claims (the battleground)
– Structure-function correlation is key
• But how much???
– What is “representative number of species”?
– Do you need all CDRs described? VH and VL? Is
VH CDR3 enough? Can the “structure” come from
the antigen (e.g., epitope?)
– What is needed to show function? Is in vivo data
needed?
16
Patentability Issues – Written Description/
Enablement
• Novel Antigens: Still A Low Threshold
For Broad Antibody Claims
• Broad claims are still being granted for
antibodies to novel targets even where
no antibody was actually made.
• For example US 7,442,772
– Granted October 2008
– Claim 1. An isolated antibody that binds to
the polypeptide shown in FIG. 32 (SEQ ID
NO:83)
– Made functional predictions based on
homology
– Provided prophetic examples
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Sequence-Limited Claims;
Recent Examples
•
V regions
– An immunologically active chimeric anti-CD20 antibody, wherein the
antibody comprises a light chain variable region comprising the amino
acid sequence shown as residues 23 to 128 of SEQ ID NO: 4 and a
heavy chain variable region comprising the amino acid sequence
shown as residues 20 to 140 of SEQ ID NO: 6
•
6 CDRs
– A purified polynucleotide which encodes a human antibody, wherein
the antibody comprises:
• a VHCDR1 region comprising an amino acid sequence as set
forth in SEQ ID NO:355;
• a VHCDR2 region comprising an amino acid sequence…;
• a VHCDR3 region comprising an amino acid sequence…;
• a VLCDR1 region comprising an amino acid sequence…;
• a VLCDR2 region comprising an amino acid sequence…; and
• a VLCDR3 region comprising an amino acid sequence….
• <6 CDRs
– An isolated human antibody or a fragment thereof, which comprises
at least three complementarity determining regions (CDRs), wherein
one of the at least three CDRs has the sequence of SEQ ID NO:51
and which antibody or fragment thereof specifically binds to an
aspartyl (asparaginyl) X-hydroxylase (AAH).
18
Patentability Issues – Written Description/
Enablement
• Anticipating the rejection
– Application should provide as many
exemplary Abs in genus as possible
• Extra support for commercially relevant leads
– Include information about the target and
target-Ab interaction
• Alonso: epitope characterization, binding
affinity, specificity, pharmacological
properties, etc.
• Data linking structure and function can be
valuable for increasing claim scope
– Identify those antibody residues key for
functional activity
19
Patentability Issues – Written Description/
Enablement
• Enablement (how to make and use)
– Generally easier for application to teach how to make
and use full scope of invention than to show actually
had possession at filing
• Anomaly – possible for application to adequately teach
how to make and use claimed genus, but not
adequately describe it
– Key distinction from WD
• In US, Applicants can use data generated after the filing
date to show application enables claim
– But more difficult in EP and JP
– Do not need to enable later arising technology, but
“nascent technology” requires “specific and useful”
teaching to enable (Chiron v. Genentech (Fed. Cir.
2004)
20
Patentability Issues – The European
Perspective
• Difficult to get claims to Ab if another Ab with similar
properties was known
– Your Ab must have different (preferably superior) features
• Making an Ab against a known target is not innovative
per se
• Generic Ab claims – new gene
– If gene novel and some relevant function determined, can
often get one patent to gene, polypeptide and Ab to same
• Ab claims to known polypeptides
– EPO will require substantial disclosure of Ab structure,
function, properties, etc.
– Some indication of inventiveness required (e.g., higher
affinity, binding to key epitope, special function, etc.)
– Tendency by EPO to limit to specific CDRs
• Even where invention was more directed to function
21
Patentability Issues – The European
Perspective
• Other key differences EP vs. US
– First-to-file (EP) vs. first to invent (US)
– Grace period (US) vs. absolute novelty (EP)
– Opposition (EP) vs. Reexamination (US)
– Best mode in US, not in Europe
– IDS requirement in U.S., not in Europe
22
FTO Fundamentals
• Patentability Z freedom to operate (FTO)
– Patent is only a grant of the right to exclude
others from making, using, or selling the
patented invention
– Patent does not give patent owner the
affirmative right to do anything
• No affirmative right to make, use, sell own
invention
– KEY: A company can receive a patent for its
technology and still be blocked from
practicing that technology by a broader
(dominant) patent
23
FTO Fundamentals
• Dominant patents vs. subordinate
patents
– Example:
• Company A may receive a patent to a
specific anti-CD20 humanized antibody, but
may be blocked from making, using or selling
that antibody by Company B’s patent to basic
humanization technology and Company C’s
patent broadly directed to any recombinant
antibody that binds CD20.
– Holder of subordinate patent may need
license under each dominant patent to
practice its own technology!
24
FTO Fundamentals
• BUT – subordinate patent can still
have value
– If subordinate patent is directed to
improvement in the technology that is
considered essential or particularly
advantageous
• Example: PDL’s Queen patents on
humanization technology
• Valuable subordinate/improvement
patent can be tool to clear FTO
(e.g., through cross-license)
25
The FTO Search
• Focus is on what is claimed, not just what is disclosed in
application
– Claims often much broader (c.f. Alonso)
• Best to search issued patents and published applications
– Published applications show what is coming and can give
rise to provisional rights
• Caveats
– No guarantee that all relevant patents will be identified
• Delay in U.S. between filing and publication
• Some applications never publish before issuance
– No guarantee that pending applications will issue with
published claims
• Often filed with extremely broad claims that have little chance
of issuing
• Moving target
26
Strategies for Clearing FTO
•
Noninfringement/Design Around Analysis
– Determine whether claims actually cover contemplated
commercialization activity
– Consider alternatives that will avoid claims (i.e., “design around”)
– Carefully review prosecution history
• Prosecution history can be roadmap to design-around
strategies
– Limitation on doctrine of equivalents (Festo)
•
Invalidity Analysis
– Consider whether claims anticipated by or obvious over prior art
• Broad claims more difficult to obtain now (but not impossible –
see Noelle)
– Consider whether claimed subject matter adequately described and
enabled
• As discussed above, important considerations for Ab
technologies
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Strategies for Clearing FTO
• Practical Analysis
– What is stage of your technology? Will
patent be expired by time you go to market?
– While older targets may have better FTO,
your own patent protection is likely to be
narrower
– Impact of Seagate (Fed. Cir. 2007)
• Eased affirmative duty of potential infringers to
exercise due care
• Opinions of counsel not per se required, but
authoritative, outside opinion still valued by inhouse counsel
• Increased value in proactive FTO analyses
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Strategies for Clearing FTO
• Consider applicability of FDA Safe Harbor Exemption (35
U.S.C. 271(e)(1))
– European equivalent is “Bolar exemption”
– U.S. statute exempts from infringement uses of patented
inventions for purposes reasonably related to generating
information for FDA approval
– Merck case (US Supreme Court) construed exemption very
broadly
– Impact on research tools in Ab space?
• Recently Fed. Cir. placed limits on exemption in Proveris
– Found defendant’s optical spray analyzer used by customers to
generate data on drugs for FDA submissions infringed claims to
system and method for characterizing aerosol sprays
– Exemption not available where OSA itself not subject to premarket approval and defendant not seeking FDA approval
• Question: What does this mean for Ab discovery technologies
such as phage display and transgenic mice?
• Question: How will courts analyze an antigen claim under this
analysis?
– Antigen could hypothetically be a drug itself, but likely isn’t. When
is that determination made?
29
Strategies for Clearing FTO
• Reexamination (hot area)
– Faster and much less costly than litigation
• Similar to oppositions in Europe
– Limited to patents and publications
– Must have “substantial new question of
patentability”
• Easier to show in view of KSR
– Easier burden of proof compared to litigation
– >90% of reexam requests are granted by
PTO
– >70% of reexams – claims canceled or
changed
• can extinguish past damages if in litigation
– Notable Ab reexam – Cabilly II (Genentech)
– Claims finally rejected (decision on appeal)
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Strategies for Clearing FTO
• Licensing
– Consider whether taking license is
desirable/possible
• Particularly if noninfringement/design
around/invalidity positions uncertain
– License more likely to be granted where
patent holder is not competitor and does not
plan to exploit technology in your intended
field of use
– BUT – must keep in mind royalty stacking
problem (particularly in antibody space)
• Allow for need for possible licenses in future
31
Strategies for Clearing FTO
• Licensing
– Antibody Humanization
• Winter patents
• Queen patents
– Phage Display industry
– Example of where subordinate patent is as
valuable or more valuable than dominant
patent
32
Strategies for Clearing FTO
• Offshoring
– Must consider 35 U.S.C. 271(g)
• Importation of product made abroad by
process patented in US can be infringing
even where no patent in country where
product made
– But see Kinik
• 271(g) defenses not available in ITC
exclusionary actions!
33
Patent Life Cycle Management for Abs
• The Dilemma
– The cost to develop a drug or biologic and it bring to
market is hundreds of millions of $$$
– Patent protection for the basic NCE or protein is
generally sought very early in the R&D process
– Due to the extensive regulatory review period,
significant patent term has been lost by the time the
product goes to market
– Traditional NCE strategies may not be available and
claims may be harder to get given that Abs are single
class of structurally similar molecules
34
Patent Life Cycle Management for Abs
• Strategic use of patents to
maintain product exclusivity and
revenue stream over life of
blockbuster drug or biologic
• Involves obtaining additional
patents that extend protection
beyond the original patents
covering the NCE or biologic per
se
35
Patent Life Cycle Management for Abs
• Strategies
– Develop/access newly patented platforms
• to make second generation products (e.g.
improved ADCC, half-life, etc.)
– Manage filings
• To limit extent to which own earlier filings limit
ability to protect later innovations
• Multiple provisional filings in US within priority
year are not uncommon
– Consider filing on clinical applications
• Disease specific
• Route of admin., pharm. Formulations, timing and
sequence of coadmin. Therapies
• Mechanisms?
– What to keep as trade secrets?
36
Antibodies as Biosimilars
• Biosimilar Legislation is Coming in US
– No longer a matter of if, but when
– Proposed legislation is stalled but will regain momentum
with new administration
• Competition likely to come from big pharma/large
biotechs as much as usual generics
– experience with clinical trials will be key advantage
• But is development of biosimilar mAbs even possible with
current technology?
– Pros:
• structure, and safety and efficacy profiles generally well
established, readily available potency assays
– Cons:
• small structural changes can have major functional
significance, efficacy and safety highly specific
• Myozyme – same manufacturer needs FDA approval to add
second plant to make same exact product (Genzyme need
separate BLA.)
37
Antibodies as Biosimilars
• What will framework look like?
– Very different from ANDAs
– Some clinical trials will likely be required
– FDA will look to EMEA for guidance
• Develop regulatory framework cautiously
– Biosimilarity Z interchangeability
• Interchangeability is the “holy grail” since would
allow doctor to substitute biosimilar for brand
– but FDA says technology not there yet for Abs
• Most biosimilars will be follow-ons, but not truly
interchangeable
38
Antibodies as Biosimilars
• BLA for Biosimilar Requirements (House bill)
–
Applicant must demonstrate that:
• Product is “biosimilar” to a reference product
• Product and reference product utilize the same
mechanism of action for the condition of use
• Condition of use has been previously approved for
reference product
• Route of administration, dosage form and strength are
same as reference product
• Facility meets standards to assure safety, purity and
potency
– Data exclusivity is key battleground
• BIO advocates 14 years
• To extent possible, avoid limiting value of regulatory
data protection by disclosing too many details about
how to make/test product
39
Antibodies as Biosimilars
• European perspective
– “Similar biological medicinal products”
– Legal framework exists; regulatory
framework is developing
– “biosimilars” approved to date by EMEA
• Omnitrope (Sandoz)(2006)(first biosimilar
approved by EMEA)
• Valtropin (Biopartners)(2006)
• Binocrit (Sandoz)(2007)
• Epoetin alfa (Hexal)(2007)
• Abseamed (Medice Arzneimittel Pütter)(2007)
40
Antibodies as Biosimilars
• EMEA Core Principles
– Biological medicinal products are much more difficult
to characterize than small molecules
• Broad spectrum of complexity across biological
products
– standard generic approach for small molecules is
“scientifically not appropriate” for biologicals
– Patient safety is paramount
– Case-by-case basis and dictated by the science
– The toxological and clinical profile of the biosimilar
“shall be provided”
– A well-defined regulatory framework can only be
developed over time based on experience and
increased scientific knowledge
– Patients and physicians must be informed in the event
of the substitution of an original product by a similar
biological product
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Hot Topics in Patenting Antibodies
Thank You
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