Antibody Patenting Issues – US and EP
Joint Educational Session
Biotechnology Committee and IP Practice in Europe Committee
2012 Annual Meeting
Friday, October 26, 2012
Thurgood Marshall Ballroom
3:40-5:55 PM
Moderator: Jim Kelley, Eli Lilly and Company
These panelists presented a “Tale of Two Continents.” However, unlike Charles Dickens’ tale,
the present situations for patenting antibodies on these two continents is certainly not “the best of
times.” An audience of 150-175 practitioners remained engaged well beyond the scheduled
stopping time of 5:30.
Table of Contents
Table of Contents .......................................................................................................................................... 1
Patenting Antibodies in Europe .................................................................................................................... 1
Written Description & Antibodies................................................................................................................. 7
Patenting Antibodies in Europe
3:40-4:40
Panelists:
Dr. Andreas Huebel of Michalski Hüttermann & Partner, Germany
Louise Holliday of D. Young & Co., LLP, UK
Andrew G. Smith, Eli Lilly & Company, UK
Dr. Huebel described the EPO’s approach to assessing inventive step for antibodies. He began
by describing the general “problem-solution” approach that the EPO uses for inventive step,
which involves:
1. determining the closest prior art;
2. determining the difference between the claimed invention and the closest prior art in
terms of features;
3. identifying the technical effect resulting from the distinguishing features;
4. formulating the objective technical problem that the claimed invention solves;
5. determining the differences between the claimed invention and the prior art; and
6. assessing whether there is any teaching in the prior art as a whole that would (not simply
could, but would) have prompted the skilled person, faced with the objective technical
problem, to modify or adapt the closest prior art while taking account of that teaching,
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thereby arriving at something falling within the terms of the claims, and thus achieving
what the invention achieves.
7. If so, the claimed invention lacks an inventive step and is not patentable in Europe.
He noted that the “technical problem” does not necessarily imply that the technical solution is a
technical improvement over the prior art. Thus, in general, the problem could be simply to seek
an alternative to a known device or process which provides the same or similar effects or is more
cost-effective.
However, Dr. Huebel next noted that the EPO does not usually consider a new antibody that has
the same or similar effect as a known antibody to be an inventive alternative. This is completely
the opposite of how the EPO handles claims to other compositions of matter. Dr. Huebel took
the audience through some counter-examples for small molecules. He used slides from the EPO
to illustrate that the EPO considers that since most of an antibody’s structure is known (i.e., the
framework and constant regions), one antibody “looks” essentially like every other antibody
structurally. The CDRs are responsible for unique binding properties of an antibody, yet the
CDRs constitute a small portion of the overall structure.
The EPO’s rationale for treating one type of molecule differently from another type of molecule
include the office’s view that with antibodies, nature does it for you, that is, once you have a
method to produce one type of antibody, the skilled artisan knows that by routine techniques
he/she will succeed to produce other antibodies with equivalent functional properties, albeit
different structure. By contrast, for small molecules, the skilled artisan – not nature and not
using routine techniques – has to envisage specific structural changes within the molecule,
usually without an expectation to succeed unless the prior art guides him/her to expectations.
On the other hand, the EPO reward early discoveries with broad reach-through claims that are all
functionally and not structurally limited. If antigen A is novel, then an antibody against antigen
A is usually considered to be novel AND inventive, provided that antigen A is well defined in
the application. A generic antibody against a known target is not inventive. The provision of a
novel antibody against a known antigen involves an inventive step only if the antibody shows
unexpected properties or if it was unexpected that such an antibody could be produced at all.
These approaches are all contrary to EPO’s practice for other compositions of matter and they
are causing significant challenges to obtaining meaningful protection for diagnostic and
therapeutic antibodies in Europe.
Dr. Huebel finished by challenging the EPO’s approach with a set of questions: What is an
unexpected property of a new antibody [unexpected property is not required]? Is it really nature
doing it for us [often, not much or nothing]? Is the basic nucleus of small molecules equivalent
to the backbone or to the CDRs of Abs [probably not, but this is somewhat analogous and it does
not destroy the possibility of obtaining protection on structurally very similar molecules]? Is it
appropriate to consider routine techniques in assessing inventive step of a product defined by its
structure [no]? Is the unpredictability of CDR sequences sufficiently considered [no]?
Louise Holliday next presented a very thorough examination of the types of antibody-related
claims that the EPO grant, including providing a quantitative examination by type of claims. A
chart presented the results of her thorough study of the claims that the EPO has granted over the
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last few years. She noted that all claim types are granted to some extent in recent years,
including those with primarily structural limitations. However, she noted that these are difficult
to obtain because of inventive step challenges.
She pointed out the seeming inconsistencies with the EPO’s approaches. For example, the
EPO’s deciding that a claim to an antibody defined by its target is really not a reach through
claim. Also, the EPO’s “obvious to try” approach to considering inventive step for antibodies
was illustrated and critiqued. If the function known or was suggested to be desirable, and there
were routine ways of generating antibodies with that function, and the scale of any
improvements would have been predictable, then the antibody claim would be considered to lack
an inventive step.
She finally provided some guidance as to which features of an antibody might possibly be
credited with providing an unexpected technical effect – including stability, epitope, specificity,
neutralizing titer, mechanism of action. That being said, she laid out the prior case law on
demonstrating an unexpected technical effect and came to the conclusion spontaneously that the
EPO is not following its own precedents, which included that it is acceptable to provide an
alternative solution to a known problem (T92/92, T495/91), that for an inventive step to be
present, it is not necessary to show improvement – substantial or gradual – over the prior art
(T583/93) and that for chemical inventions “providing the public with a useful choice” suffices.
Finally, Andy Smith gave an industrial perspective. Historically, the first therapeutic antibody
was approved merely 11 years after Kohler and Milstein’s breakthrough on monoclonal antibody
production in 1975. Thirty more therapeutic antibodies were approved between 1994 and 2012,
~50 enter the clinic every year, ~500 are in various phases of clinical development. Therapeutic
antibodies predominate in the biological market. However, the costs of developing drugs is skyrocketing. The EPO’s “double whammy” of granting broad functional claims to early entrants
who many not even have any antibodies and no claims to later entrants who actually have
antibodies in the clinic is causing much concern. There is a significant difference in incentives
to invest $2B+ in developing an antibody product between the present situation, which involves
relying solely on regulatory exclusivity of 10 years and having significant freedom to operate
risks vs. relying on narrow but longer-lived patent on the antibody product for up to 15 years
from market authorization and not having freedom to operate risks and expenses from earlier,
broad, functionally-defined claims.
Mr. Smith made the case that EPO law on inventive step for antibodies has not kept up with the
science. The office is seemingly in a time warp. While decades ago, the initial technology was
based on injecting an antigen into an animal and the harvesting polyclonal antibodies, now
significant engineering is required. This is not unlike the structure-activity studies that go on for
small molecules. The office seems stuck in an era in which antibodies could not be described
structurally without undue burden and when the focus of antibodies was simply as research tools,
not as diagnostics or therapeutics. Today, by contrast, an antibody for diagnostic or therapeutic
purposes is derived by an arduous, lengthy process that relies on “nature” little or not at all.
To emphasize certain points about predictability, he pointed to several references (old) for the
propositions that antibodies are not structurally similar in the regions responsible for their
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biological function, that 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,” that CDR grafting generally results in a loss of function, and that 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. He
thus concluded that finding a suitable diagnostic or therapeutic antibody is analogous to finding a
needle in a haystack, just like one thinks of discovering a therapeutic small molecule. He
contrasted this view with that of the EPO, which is that finding antibodies is like finding a needle
in a stack of needles! See below.
Mr. Smith discussed the case T735/00, which dealt with “routine methods” and “unexpected
properties” concluded that with the EPO’s approach eventually all antibody development will be
considered by the EPO to be routine and lack of inventive step will be insurmountable. From
that case, he provided the following quotations:
“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)”
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“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.”
Turning then to T645/02 for contrast, he discussed the following passage from the
reasons for the decision (at 7):
“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, in that case, saw “elements of surprise” in the provision of a monoclonal antibody as
produced by the deposited hybridoma. Similarly, for contrast with T735/00, he also discussed
T418/07, in which the Board noted that the application of known techniques would likely result
in antibodies with different antigen binding sites compared with those claimed:
“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.”
With his experience in chemical patenting, Mr. Smith saw very close analogies between small
molecule discovery work and antibody discovery work. He also described how the law of
inventive step for small molecules should apply to antibodies as well, pointing out that:
 antibodies in the prior art are typically structurally very different;
 common general knowledge was that single amino acid changes to antibody variable
region causes loss of functionality;
 essential technical features responsible for an antibody’s technical effect, i.e. binding
function, are the specific CDRs and that therefore an inventive step assessment should
examine CDRs;
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


the person skilled in the art would not know or reasonably predict the impact structural
differences to prior art would have on antibody function;
data may be available to support the unpredictability of structural changes specific to the
claimed antibody; and
there is usually no reasonable expectation of engineering an antibody with the specific
CDR sequences in the claim starting from the structure of the prior art Ab.
Despite the significant inventive step hurdles that the EPO is putting in the way of patenting
diagnostic and therapeutic antibodies, he suggested that patent drafters build in flexibility for
reformulating the problem by emphasizing the desirability of including mention of properties
that would be important for diagnostic or therapeutic antibodies (even if no data exist at filing)
for antigen specificity, epitope binding, affinity/binding (Kon, Koff, Kd), neutralizing titre (Ki),
clearance rate, mechanism of action, and stability. Data for comparison with the art can be later
generated. Furthermore, the drafter should provide other evidence that may be pertinent to
inventive step, such as that routine methods would not suffice to prepare the equivalent antibody
of the prior art, that the discovery path to the structurally-claimed antibodies was tortuous and
involved deliberate planning and choices by the inventors, and that there were many failures
along the way, especially if there is evidence that particular amino acid changes resulted in
terrible or astonishing antibodies.
For patent prosecutors, he provided a few cases that might be helpful in case structural claims are
rejected for not having provided unexpected properties, including T32/85 (where the skilled
person can only establish by trial and error whether or not his particular choice of numerous
parameters will provide a satisfactory result, this amounts to an undue burden), T399/05;
T123/06; and 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); and 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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Written Description & Antibodies
4:40-5:55 PM
Panelists:
Amy E. Hamilton, Eli Lilly & Company, Indianapolis
Chris Holman, University of Missouri–Kansas City School of Law
Hans Sauer, Biotechnology Industry Organization, Washington DC
Kristi L. R. Sawert, US Patent & Trademark Office, Washington DC
A recording of the session will eventually be made available.
A list of general cases culminating with Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed.
Cir. 2010) (en banc) (cert. denied) was mentioned, as well as the involvement of Lilly in three of them.
Specific mention was made of cases that more specifically involve written description for antibodies,
including Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc., Case No. 09-11340-FDS (D. Mass.
Sep. 25, 2012), Centocor Ortho Biotech, Inc. v. Abbott Labs., No. 10-1144, (Fed. Cir. Feb. 23, 2011)
(cert. denied). In re Alonso, 545 F.3d 1015 (Fed. Cir. 2008), Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir.
2005), and Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004). Lilly’s involvement as amicus in the
Centocor v. Abbott and Noelle v. Lederman appeals was mentioned. The existence of the USPTO’s
Written Description Guidelines and the separate Training Examples was mentioned. Finally, reference
was made in full disclosure about an article that the moderator had authored in 2005 relating to written
description for antibodies The “Anti”-Written Description Requirement? Antibodies, Example 16, The
Guidelines, and Noelle v. Lederman, 87 J. Pat. & Trademark Off. Soc’y 705 (2005)).
The moderator then addressed questions in several categories to the panel and the panelists answered
them and discussed them.
Category: Impact of Broad Functional Claiming
•
Antibodies can be claimed broadly and functionally.
•
What are the ramifications to patients, the public, companies, universities, start-ups, and the
industry in granting functionally-defined broad antibody claims?
•
Describe the importance of antibody therapies to patients. Does one antibody suffice for all
patients? Give examples. Compare and contrast with small molecule therapeutics.
•
How likely is patent litigation for antibody products?
•
How likely is it that a drug developer could face multiple patent infringement suits from the
holders of functionally-defined antibody claims of overlapping scopes?
•
Do broad antibody patents inhibit the development of competing and possibly better products?
Category: Exception? Comparison with other therapeutic molecules
•
Antibodies can be claimed functionally and broadly while such is generally not the case for other
types of therapeutic molecules.
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•
Are antibodies treated specially?
•
What justifies special treatment for some therapeutic molecules over others?
•
Should therapeutic antibodies be shielded from competition by broad functionally-defined claims
when competition in other areas of other types of therapeutic molecules is robust and generally
beneficial?
Category: Law
•
What is the law of written description for genus claims?
•
Is it firmly settled, or is there uncertainty about it?
•
What does this law mean for antibody claims?
Category: Abbott v. Centocor (IL12 Abs)
•
Centocor’s STELARA® (anti-IL12; psoriasis)
–
$281 million in H1 2012; ~$500 million in 2013
•
Suits in August 2009 after Abbott prevailed in interference.
•
Abbott’s briakinumab
–
•
6,914,128,
–
•
U.S. and European regulatory applications withdrawn in January, 2011.
29. A neutralizing isolated human antibody, or antigen-binding portion thereof that
binds to human IL-12 and disassociates from human IL-12 with a Koff rate constant of
1×10-2 s-1 or less, as determined by surface plasmon resonance.
7,504,485
–
1. A pharmaceutical composition comprising an isolated human antibody, or antigenbinding portion thereof, which is capable of binding to an epitope of the p40 subunit of
IL-12, and further comprising an additional agent.
–
11. The composition of any one of claims 1-4, wherein the antibody, or the antigen
binding portion thereof, dissociates from the p40 subunit of IL-12 with a Kd of 1×10-10 or
less or a Koff of 1×10-3 s-1 or less, as determined by surface plasmon resonance.
•
More than 300 variants of a parental Ab were described by sequence and by binding affinity.
•
Bind to an epitope located on the p40 subunit of IL-12.
•
Very many fell within functional claim limits.
•
Invalid:
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•
–
Enablement
–
Obvious
–
Written Description
STELARA® is in the VH5 family, but all of Abbott’s Abs are in the VH3 family.
–
Centocor: The asserted claims, all of which defined a genus of antibodies based on their
ability to bind and neutralize IL-12, were invalid because the patent did not disclose
enough examples within each VH family to support the genus claims.
•
STELARA® is in the kappa family, but all of Abbott Abs are in the lambda family.
•
STELARA® and Abbott’s Abs bind at different places.
•
The dozens of contacts between STELARA® and IL-12 are all different than the dozens of
contacts that [Abbott’s Ab] makes with IL-12; not contact is the same at a chemical and structural
level.
•
The amino acid sequence of STELARA® and [Abbott’s Abs] are about 50% different.
•
The only antibody sequences described in the Abbott patents are in [a single] lineage and there is
only about a 10% difference among the sequences.
Category: Genus Claims
•
Is there any way for a specification to comply with the WDR for a functionally-claimed genus of
antibodies? If so, how?
–
Representative Number of Species?
–
Identifying Structural Characteristics?
–
Structure-Function Correlation?
•
What number of representative species might suffice when the diversity of structures within the
genus is not known?
•
What number or diversity of structures might have sufficed in Abbott v. Centocor?
•
What are the identifying structural characteristics of a functionally-defined antibody?
•
Is there a structure – function relationship between variable region functions and the structure of
variable regions? If so, how does one describe that?
Category: Scope
•
What are the perceived and real risks for narrow vs. broad antibody claims?
•
What scope is sufficient?
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•
What scope might be justified under the facts of Abbott v. Centocor (IL12 Abs)?
Category: Pick your poison, obviousness (no claims) or written description (narrow claims)
•
What are the roles of predictability in obviousness and written description?
•
Once a target is disclosed, aren’t all functionally-defined antibody claims involving that target
obvious under KSR?
–
•
“When there is a design need or market pressure to solve a problem and there are a finite
number of identified, predictable solutions, a person of ordinary skill has good reason to
pursue the known options within his or her technical grasp.” KSR Int'l Co. v. Teleflex
Inc., 550 U.S. 398, 421 (2007). “If this leads to the anticipated success, it is likely the
product not of innovation but of ordinary skill and common sense.” Id.
The trade-off. What is truly better for “biotech?”
Category: The Antibody Exception?
•
Is there an exception to the law of written description for antibodies?
•
Does the PTO actually examine antibody applications for compliance with the written description
requirement?
•
If there is no exception,
–
Why do so many think that there is an exception?
–
Explain the apparent lack of conformance among the Guidelines and the Law on the one
hand and Example 13 and PTO practice on the other.
–
Why are so many antibody claims functional rather than structural?
–
Competitive binding
–
E.g., 7,595,378, claim 4. (4. An isolated human monoclonal antibody which binds to
human EGFR, competes with antibody 225, but does not compete with antibody 528.)
–
E.g., 7,579,000, claim 1. (1. An anticoagulant antibody that binds with greater affinity to
the factor VIIa/tissue factor (FVIIa/TF) complex than to tissue factor (TF) alone, wherein
the antibody does not compete for binding to TF with FVII and FX and wherein the
antibody comprises the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:3.)
–
E.g., 7,537,761, claim 1. (1. An isolated antibody or antigen-binding fragment thereof
that can compete with a monoclonal antibody expressed by a hybridoma from the group
of [5 deposited hybridomas] for binding to the polypeptides of SEQ ID NO:2 or SEQ ID
NO:3
–
Epitope defined by competitive binding
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•
–
E.g., 8,138,316, claim 2 (A monoclonal antibody that competes for the epitope that binds
the monoclonal antibody of claim 1 on feline pancreatic lipase.)
–
E.g., 7,595,378, claim 3 (3. An isolated monoclonal antibody which binds an epitope on
human EGFR recognized by an antibody comprising heavy and light chain variable
regions comprising the amino acid sequences set forth in SEQ ID NOs: 2 and 4,
respectively.)
–
Epitope defined by antigen sequence
–
E.g., 8,030,454, claim 2 (2. A monoclonal anti-human sonic hedgehog antibody that
binds human sonic hedgehog at an epitope contained within the region of the protein
having the amino acid sequence of amino acids 75-96 of SEQ ID NO: 16.
–
Neutralization
–
8,252,906 4. The antibody of claim 1, wherein the antibody competes with antibody scFv
E317, scFv E425, or scFv Y571 for binding to the gD of HSV-1 and HSV-2, and is able
to neutralize HSV-1 and HSV-2 with substantially equivalent potency.
–
7,910,707 5. An isolated neutralizing anti-IFN-.alpha. antibody that binds to human IFN.alpha.1, IFN-.alpha.2, IFN-.alpha.4, IFN-.alpha.5, IFN-.alpha.8, IFN-.alpha.10 and IFN.alpha.21, wherein said antibody is capable of inhibiting at least 60% of anti-viral activity
in a heterogenous collection of IFN-.alpha. subtypes produced by activated leukocytes,
wherein the collection comprises human IFN-.alpha.1, IFN-.alpha.2, IFN-.alpha.4, IFN.alpha.5, IFN-.alpha.8, IFN-.alpha.10 and IFN-.alpha.21.
What is the evidence for and against the proposition in Example 13 that
–
“[i]t does not appear that persons of skill in the art consider knowledge of the amino acid
sequence of variable regions critical for purposes of assessing possession of an
antibody?”
•
Which art? Which persons? What level of skill? Which antibody?
•
“While our precedent suggests that written description for certain antibody claims can be satisfied
by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly
characterized antigens where creation of the claimed antibodies is routine.” Centocor v. Abbott,
CAFC, February 23, 2011 slip op. at 19.
•
So, is the exception limited to claims that merely require binding to a newly-discovered, wellcharacterized antigen, as opposed to say more specific functions like neutralizing, binding with
particular strength, or binding to a specific “epitope?”
•
Does the exception extend to all functional limitations in antibody claims?
•
Are there justifications for the exception? If so, what are they?
•
Can the Office change its approach without being made to change by the courts?
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•
What about the changes made in the examples in 2008?
•
When considering changing, what about the settled expectations of the patenting community?
•
Considering Ariad and Centocor, and now Abbott, are the expectations of the patenting
community settled?
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