Editor-in-Chief
Janice M. Reichert
Volume 3 • Issue 3 • May/June 2011
Volu me 3 I ssu e 3
M ay /J u n e 2011
E ditor - i n -C hi e f
J a n ice M. R e ich e rt
About the cover
Natural immunoglobulins, like Swiss
Army(TM) multipurpose knives, are an
integrated tool box contained within
a single unit. Increasing knowledge
of antibody structure and activity
now allows researchers to isolate
novel antibodies from designed
libraries, engineer primary antibodies
on a more rational basis and extend
the potency of these molecular
tools. Several articles in this issue of
mAbs (Igawa et al. pp. 243–52, Villa
et al. pp. 264–72, Dong et al. pp.
273–88, Fitzgerald and Lugovskoy
pp. 299–309) discuss new approaches
designed to yield novel antibodies
with desirable pharmaceutical
properties.
221
EDITORIAL
The amazing, multipurpose antibody
Alain Beck and Janice M. Reichert
223
MEETING REPORT
Next generation and biosimilar monoclonal antibodies: Essential considerations
toward regulatory acceptance in Europe; February 3–4, 2011, Freiburg, Germany
Janice M. Reichert
241
COMMENTARY
Regulatory pathways in the European Union
Manuela Kohler
243
REVIEWS
Engineering the variable region of therapeutic IgG antibodies
Tomoyuki Igawa, Hiroyuki Tsunoda, Taichi Kuramochi, Zenjiro Sampei, Shinya Ishii
and Kunihiro Hattori
253
Fragmentation of monoclonal antibodies
Josef Vlasak and Roxana Ionescu
264
REPORTS
A novel synthetic naïve human antibody library allows the isolation
of antibodies against a new epitope of oncofetal fibronectin
Alessandra Villa, Valeria Lovato, Emil Bujak, Sarah Wulhfard, Nadine Pasche and Dario Neri
273
A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor
and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity
Jianying Dong, Arlene Sereno, Dikran Aivazian, Emma Langley, Brian R. Miller, William B. Snyder, Eric Chan, Matt Cantele, Ronald Morena, Ingrid B.J.K. Joseph, Antonio Boccia, Cyrus Virata,
James Gamez, Grace Yco, Michael Favis, Xiufeng Wu, Christilyn P. Graff, Qin Wang, Ellen Rohde, Rachel Rennard, Lisa Berquist, Flora Huang, Ying Zhang, Sharon X. Gao, Steffan N. Ho,
Stephen J. Demarest, Mitchell E. Reff, Kandasamy Hariharan and Scott M. Glaser
289
Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab
in preclinical study
Ningyan Zhang, Liming Liu, Calin Dan Dumitru,Nga Rewa Houston Cummings, Michael Cukan, Youwei Jiang, Yuan Li, Fang Li, Teresa Mitchell, Muralidhar R. Mallem, Yangsi Ou, Rohan N. Patel, Kim Vo, Hui Wang, Irina Burnina, Byung-Kwon Choi, Hans Huber, Terrance A. Stadheim
and Dongxing Zha
299
PERSPECTIVES
Rational engineering of antibody therapeutics targeting multiple ­oncogene pathways
Jonathan Fitzgerald and Alexey Lugovskoy
310
Intellectual property protection: Strategies for future antibody inventions
Ulrich Storz
318
POINT-OF-VIEW
Biosimilars 2.0: Guiding principles for a global “patients first” standard
Joseph Miletich, Geoffrey Eich, Gustavo Grampp and Barbara Mounho
326
EDITOR’S CORNER
2011 upcoming meetings
Janice M. Reichert
Print ISSN: 1942-0862; Online ISSN: 1942-0870
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EDITORIAL BOARD
Gregory P. Adams
Fox Chase Cancer Center
Raffit Hassan
National Cancer Institute
Andreas Plückthun
University of Zurich
Nasimul Ahsan
W.G “Bill” Hefner VA
Medical Center
Mitchell Ho
National Institutes of Health
Leonard Presta
Merck & Co., Inc.
P. Mark Hogarth
Burnet Institute
Vijay Ramakrishnan
Pikamab, Inc.
James S. Huston
The Antibody Society
Mitsuo Satoh
Kyowa Hakko Kirin
Roy Jefferis
University of Birmingham
Christian K. Schneider
Paul-Ehrlich-Institut, Federal Agency
for Sera and Vaccines
Ashraf Amanullah
Genentech, Inc.
Laurent P. Audoly
Pieris AG
Joseph P. Balthasar
University of New York at Buffalo
Richard Begent
University College London
Detlev Biniszkiewicz
Novartis Institutes for BioMedical
Research
Sally Bolmer
Human Genome Sciences, Inc.
Pavel V. Bondarenko
Amgen
Arindam Bose
Pfizer
Andrew Bradbury
Los Alamos National
Laboratory
John C. Byrd
The Ohio State University
Paul J. Carter
Genentech
Ravi J. Chari
ImmunoGen, Inc.
Michel Chartrain
Merck & Co., Inc.
Mike Clark
Cambridge University
Raphael Clynes
Columbia University
Nathalie Corvaïa
Centre d’Immunologie Pierre Fabre
Graeme Currie
Regeneron Pharmaceuticals
John R. Desjarlais
Xencor, Inc.
Dimiter S. Dimitrov
National Institutes of Health
Donald L. Drakeman
Advent Venture Partners
Denny Kraichely
Johnson & Johnson/Centocor
Gaurav Laroia
MSD Pharmaceuticals Pvt. Ltd.
Marie-Paule Lefranc
Université Montpellier II
Nils Lonberg
Bristol–Myers Squibb/Medarex
Henry Lowman
CytomX Therapeutics, Inc.
James D. Marks
University of California
at San Francisco
John L. Marquardt, Jr.
Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP
R.A. Mashelkar
National Chemical Laboratory
Richard Mason
BTG group
Kiran Mazumdar Shaw
Biocon Limited
John McCafferty
Cambridge University
Sherie Morrison
University of California
at Los Angeles
Jan Mueller-Berghaus
Paul-Ehrlich-Institut, Federal Agency
for Sera and Vaccines
Bilikallahalli K. Muralidhara
Pfizer
Dario Neri
Swiss Federal Institute
of Technology
Jane Osbourn
MedImmune, Inc.
Stefan Dübel
Technische Universität Braunschweig
Gilles Paintaud
University of Tours–
François Rabelais
Martin Glennie
University of Southampton
Paul Parren
Genmab
Iqbal S. Grewal
ImmuGene
Ira Pastan
National Institutes of Health
Yajun Guo
PLA General Hospital Cancer Center
André Pèlegrin
Institut de Recherche en Cancérologie
de Montpellier
Sherif Hanala
Bio-Rad Laboratories
Jamie Scott
Simon Fraser University
Marjorie A. Shapiro
US Food and Drug Administration
David Shen
Teva Pharamceuticals
Arne Skerra
Technische Universitaet Muenchen
William R. Strohl
J&J Biotechnology Center
of Excellence
Shanmuuga Sundaram
ImClone Systems
Jean-Luc Teillaud
Centre de Recherche des Cordeliers/
INSERM
Jan ter Meulen
Merck & Co., Inc.
Pablo Umaña
Glycart Biotechnology AG
(Roche Group)
Jan van de Winkel
Genmab
E. Sally Ward
University of Texas–Southwestern
Hervé Watier
Universite Francois-Rabelais de Tours
and CNRS
Louis M. Weiner
Georgetown University Medical
Center
Gregory Winter
MRC Laboratory of Molecular
Biology
K. Dane Wittrup
Massachusetts Institute of Technology
Clive R. Wood
Bayer Schering Pharma AG
Jenny M. Woof
University of Dundee Medical School
Herren Wu
MedImmune, Inc.
Thierry Wurch
Pierre Fabre
Bodi Zhang
Tufts University
PERSPECTIVE
mAbs 3:3, 310-317; May/June 2011; © 2011 Landes Bioscience
Intellectual property protection
Strategies for future antibody inventions
Ulrich Storz
Senior Partner with Michalski Huettermann Patent Attorneys; Duesseldorf, Germany
I
n the last decade, therapeutic antibodies have become one of the most
commercially successful classes of biopharmaceutic drugs. Major drug manufacturers who have successfully managed
to occupy this new market, as well as
biotechnology firms, some of which have
experienced a quick growth and are now
on par with the former, owe part of their
success to suitable intellectual property
(IP) strategies. This article provides
an overview of the current thinking on
antibody-related patents, and discusses
strategies for protecting the antibody
products of the future.
Introduction
Key words: antibody, mimetics, patent,
inventive, intellectual property
Submitted: 02/28/11
Accepted: 03/18/11
DOI: 10.4161/mabs.3.3.15530
Correspondence to: Ulrich Storz;
Email: st@mhpatent.de
310
Patent protection for most of the antibodies with large global markets will
expire within the next three to seven
years, thus exposing the respective drugs
to competition by biosimilar manufacturers (Table 1). To protect their market leadership, numerous companies are therefore
in a process of developing or already have
on the market, second generation antibodies. An invention for which patent
protection is sought has to pass particular
tests, which are, among others, the novelty requirement, the inventive step/nonobviousness requirement and the written
description and enablement requirement.1
These requirements are, however, not
absolute, but subject to constant changes.
The Moving Target
Antibody engineering and design underwent substantial advancements in the
past 20 years, including development of
mAbs
recombinant chimerization and humanization techniques and the creation of
libraries, display methods and affinity
maturation approaches. However, in a
global knowledge society, a method that
was cutting-edge technology yesterday
may be an industry standard today, particularly with respect to technical disciplines
that are strongly influenced by academic
research, as is the case with therapeutic
antibodies.
This situation is reflected in the increasing scrutiny patent authorities exhibit with
respect to antibody-related patent applications. The hurdles are steadily set higher
or, as the European Patent Office (EPO)
puts it, “the bars are raised.”
Patent protection plays a crucial role in
the pharmaceutical industry because of its
reliance on rapidly changing technology.
Because of high upfront disbursements for
research and lengthy clinical development
and approval procedures (with the respective outcomes by no means predictable),
the industry depends on efficient patent
protection to assure a sufficient return
of investment. This phenomenon can
be summed up in the phrase “no patent
equals no product”. To ensure that the
scientific development of new antibody
drugs will continue in the future, it is thus
important to co-develop suitable patent
strategies.
Inventive Step/Non-Obviousness
Probably due to the rapid technological
progress in the antibody industry, arguments that were accepted in support of
sufficient inventiveness in the past now
may be rejected by the patent authorities
Volume 3 Issue 3
PERSPECTIVE
PERSPECTIVE
as falling under the routine of a skilled
artisan. In view of the fact that technologies for the production of a human antibody against every conceivable target are
now state of the art (consider, e.g., native
antibody libraries and phage display),
the mere provision of a human antibody
against a target the clinical implications
of which are known would have difficulties to meet the inventive step/non-obviousness requirement. In other words, the
antibody industry is, in some way, a victim
of its own success.
In order to anticipate obvious objections during patent prosecution, applicants
should add to their applications fall-back
positions, like sequences describing the
specific antibody in great detail and/or
experimental data with respect to particular binding properties, aggregation behavior, blood clearance, cross-reactivity and
the like. Such data can often be used as a
last resort to obtain patent protection for
the actual antibody. Further, most of these
data may also be used to meet the written
description and enablement requirement
(see below). A look into pertinent databases, like the board of appeal decisions
database of the EPO2, shows that patent
applications related to therapeutic antibodies have rarely been rejected for lack of
inventive step/obviousness alone. One reason for this might be that applicants seem
zo provide sufficient data that can be used
as fall-back positions.
Written Description
and Enablement Requirement
The enablement requirement, which is
common to both European and US patent
law, strives to ensure that a skilled person
can reproduce the subject matter of the
invention without undue burden. One
example is usually sufficient to provide
enablement, as long as no evidence exists
that embodiments falling under the scope
of the patent are not enabled. In case such
evidence exists, the patent examiner may
decide to narrow the scope of the claims to
the very embodiment for which enabling
data have been presented.
One example for the increasing scrutiny with respect to sufficient enablement
is given in EPO decision T0601/05,3
which is related to a first generation patent
claiming human monoclonal antibodies
(mAbs) that bind to human tumor necrosis factor (TNF)α. The only method for
the production of the claimed antibodies
disclosed in the patent was the hybridoma technique developed by Köhler and
Milstein in the 1970s.4 However, the
board held that the hybridoma technique
would not be suited to prepare high affinity antibodies against TNFα because
human peripheral blood cells cannot
provide a route to high affinity, neutralizing antibodies against self-antigens, but
only to low affinity antibodies. Because
the claim language encompassed both,
the claim was found to be not sufficiently
enabled by the specification.
An example for the ambiguous positions patent authorities have taken with
respect to the enablement requirement is
EP939804 assigned to Human Genome
Sciences (HGS). Said patent comprises
claims related to an antibody that binds
specifically to Neutrokine-α, which is a
member of the TNFα superfamily and was
discovered by HGS on the basis of bioinformatic investigations alone. Regarding
therapeutic implications, the patent comprised no experimental data, only tissue distribution data of Neutrokine-α
mRNA. It was thus alleged that HGS had
postulated a potential therapeutic use only
on the basis of the known relationship to
TNF. In decision T0018/09,5 the EPO
judged, however, that the tissue distribution data suffice to provide a valid basis for
an industrial application and may be used
to develop appropriate means and methods
for diagnosis and treatment and, therefore,
maintained the patent in slightly amended
form. A year before the UK High Court
found the patent invalid for lack of industrial applicability, insufficiency and obviousness, said decision having effect for the
UK only. This decision was confirmed by
the UK Court of Appeal recently in decision Eli Lilly and Company vs. Human
Genome Sciences.6
In addition to the enablement requirement, US law also provides a written
description requirement in order to ensure
that the inventor had, at the filing date,
full possession of the entire claimed subject
matter. In Centocor Ortho Biotech, Inc.
vs. Abbott Laboratories,7 Centocor sued
Abbott for patent infringement by selling
adalimumab (Humira®). Basis for the
legal action was Centocor’s US7070775,
which relates to human antibodies to
human TNFα. The ‘775 patent is a continuation in part (CIP) of an earlier application by Centocor, which was related to
chimeric antibodies. However, said earlier patent predated a patent by Abbott
related to similar subject matter. The case
has generated broad public interest due
to a record verdict in the first instance
under which Abbott was sentenced to pay
$1.67 billion in damages. On appeal,
the decision was fully reversed by the US
Court of Appeals for the Federal Circuit
(CAFC) only for lack of written description. The CAFC considered that most
claims of the ‘775 patent lacked written
description, because the specification did
not describe the claimed human antibody,
nor an antibody with a human variable
region, and concluded that “the scope of
Centocor’s right to exclude cannot overreach the scope of its contribution to the
field of art as described in the patent specification.” The claims on which Abbott
had been sued were thus declared invalid.
The written description requirement
was recently confirmed in the CAFC decision Ariad vs. Eli Lilly,8 related to Ariad’s
US6410516. The patent, which dealt with
transcription factor NFκB and methods
of reducing or altering its activity without indicating how this could actually
be done, was found invalid for failure to
meet the written description requirement.
The decision fuels fears that the written
description requirement discriminates
against universities and start up ventures
that have their emphasis in basic research.
These entities are under constant pressure to secure their results at the earliest
possible date, and to the broadest possible
extent, in order to publish them or present them to potential licensees. A requirement for additional data in the future will
increase the financial burden for these
small or non-commercial entities.
Novelty
Contrary to increasing requirements as
to inventive step/non-obviousness and to
written description and enablement, the
relevant authorities have lowered hurdles
with respect to the novelty requirement.
www.landesbioscience.commAbs
311
Table 1. Commercially most successful therapeutic antibodies and their key patents
Antibody INN
(Trade name)
Company
Key indication
Key patent
Expiry
Rituximab (Rituxan)
Genentech
Non-Hodgkin lymphoma
US5736137
April 7, 2015
Bevacizumab
(Avastin)
Genentech
Colon cancer
US7060269
August 6, 2017
(+ 697 days patent term adjustment)
Trastuzumab
(Herceptin)
Genentech
Breast cancer
US6719971
June 18, 2019
Adalimumab
(Humira)
Abbott
Rheumatoid arthritis
US6090382
February 9, 2016
US6509015
February 9, 2016
Cetuximab (Erbitux)
ImClone
Colon cancer
US6217866
April 17, 2018
Palivizumab (Synagis)
MedImmune
Respiratory syncytial virus
­infection in newborns
US5824307
October 20, 2015
Infliximab (Remicade)
Johnson& Johnson
Rheumatoid arthritis
US7276239
February 2, 2010
Note: The phrase “key patent“ refers to only one member of a patent family that exists for the product. INN, international non-proprietary name
Table 2. Selected key patents protecting anti-TNFα antibodies
Key patent
Assignee
Main claim
Priority
US5654407
Bayer
A composition comprising human monoclonal antibodies that bind specifically to human tumor
necrosis factor α.
March 5, 1993
US6090382
Abbott
An isolated human antibody (..) that dissociates from human TNFα with a Kd of 1 x 10 -8 M or less (..)
February 9,
1996
US7012135
UCB
An antibody molecule having specificity for human TNF[alpha], comprising the light chain region
hTNF40-gL1 (SEQ ID NO:8) and the heavy chain variable region gh3hTNF40.4 (SEQ ID NO:11).
June 6, 2000
Recent case law with respect to small molecules has strengthened the concept of
selection inventions, which is established
granting practice at the EPO already and
which stipulates that the disclosure of a
chemical class does not necessarily anticipate the novelty of an individual compound
falling within this class (so called “genusspecies anticipation,” according to which a
species anticipates the genus, whereas the
genus does not anticipate a species).
This means, for example, that, despite
the fact that the racemate of a given structure is prior art, a patent related to only
one enantiomer of said racemate may be
considered novel, and thus patentable in
case the inventive step requirement is met
as well (e.g., due to difficult resolution of
the racemate). This view has been consented by courts in the UK, Germany and
the US with respect to the (+)-enantiomer
of Citalopram (decisions Generics UK vs.
Daichi,9 BGH Escitalopram10 and Forest
Labs., Inc. vs. Ivax Pharm., Inc.).11
In another example, courts in all three
countries agreed that a given compound,
which falls within the scope of a general
formula disclosed in the prior art, can be
considered novel if it is not mentioned
explicitly in the latter, but only by means
312
of a Markush group in which some substituents are designated as R1-RX. Courts in
UK, Germany and the US came to similar
results in cases related to the antipsychotic
olanzapine (decisions Dr. Reddy’s vs. Eli
Lilly,12 BGH Olanzapin13 and Eli Lilly &
Co. vs. Zenith Goldline Pharm., Inc.).14
Translated to biomolecules, this means
that, e.g., a sequence claim related to a
second generation antibody will be considered novel even if said claimed sequence
is comprised in the similarity interval of a
prior sequence disclosure (e.g., “SEQ ID
No 1 or sequences having a similarity of
>95% with the former”).
Approaches to Protect
Therapeutic Antibody Products
The approaches to protect therapeutic
antibody products have been previously
discussed.15 In short, the respective antibody can be specified by (1) binding a
specific target, (2) having specific binding characteristics against a given target, (3) reference to a specific deposited
cell line or a specific production process
or (4) by having, or being encoded by,
a specific amino acid/DNA sequence
with respect to the whole antibody or to
mAbs
sections therof. Crucial issues for selecting
the right strategy are the scope of protection that can be obtained with a given
claim language, and the prospects of patent allowance by the patent authorities.
Generally, for first generation antibody
patents, a broad claim language could be
used (e.g., by specifying the target only),
thus providing a broad scope of protection, while in second or higher generation
patents the claim language must be more
restrictive (e.g., by specifying the amino
acid/DNA sequence), thus providing only
a narrow scope of protection. Said trend is
illustrated, for example, by the history of
patents protecting anti-TNFα antibodies
(Table 2).
Higher generation antibody patents
claim, in most cases, a sequence, at least
with respect to one or more complementarity determining regions. In such case, the
inventive step/non-obviousness requirement is met more easily, because according
to well-established lines of argumentation,
the skilled person would very unlikely find
any incentive in the prior art to arrive at a
specific sequence, at least if such sequence
has not merely been isolated from nature,
but is the subject of, e.g, an affinity maturation process. Further, the enablement/
Volume 3 Issue 3
Table 3. 2nd generation antibodies and their key patents
Second generation mAb INN
(Trade name, Company)
Target
First generation mAb INN
(Trade name, Company)
Alleged improvement
Key patent
Ofatumumab (Arzerra,
GlaxoSmithKline)
CD20
Rituximab (Rituxan,
Genentech)
Humanized
US7850962
GA101 (Roche)
CD20
Rituximab (Rituxan,
Genentech)
Glycoengineered for better ADCC
EP1692182
Golimumab (Simponi,
Centocor)
Tumor necrosis
factor α
Adalimumab (Humira,
Abbbott)
Unclear (Centocor advertises better
dosing frequency, but patent claims
specific affinity to tumor necrosis
factor α)
US7070775
Respiratory
syncytial virus
Palivizumab (Synagis,
Medimmune)
Higher target affinity (50–70 fold)
US740851
Motavizumab (Medimmune)
­
ADCC, antibody-dependent cell-mediated cytotoxicity; CD, cluster of differentiation; INN, international non-proprietary name
Table 4. Selected therapeutic antibodies against new targets
Company
Drug name
Target
Key patent
Ganymed
GT468
Placental protein PLAC1
EP2166021
Merrimack
MM-111
Human epidermal growth factor
receptor (HER)2 + HER3
US7332580
LPath
Sphingomab
Sphingosine-1-phosphate
US7829674
disclosure hurdle is passed more easily
because a given sequence is fully disclosed
and enabled by merely mentioning it in
the claims or the specification.
Admittedly, the scope of protection
of such claim language is quite narrow, although to date it is still unclear
whether or not such claim types enjoy a
scope of equivalence and, if so, to what
extent. Further, if such patent protects
an approved antibody therapeutic, third
parties wanting to put a follow-on biological (also called “biosimilar”) on the market cannot simply substitute one or more
amino acid residues to avoid a potential
patent infringement. Under the respective
draft guidelines recently published by the
European Medicines Agency (EMA),16
and subject to public consultation until
May 31, 2011, the resulting antibody
would most probably no longer qualify as
a biosimilar, as amino acid sequence identity is considered to be a conditio sine qua
non to obtain antibody biosimilar status.17
Antibody Evolution
In view of expiring patent protection for
first generation antibody therapeutics,
major drug makers and biotechnology
firms are currently in a process of developing second generation variants of their or
their competitors’ antibodies. Generally,
the improvements that eventually give rise
to a patent allowance have been achieved
by use of methods that are now considered to belong to the standard toolbox of
antibody engineering, i.e., humanization,
affinity maturation and glycoengineering
techniques (Table 3).
New Targets
While cellular signalling processes are
well-understood, new potential targets
for antibody therapy are still being discovered. Today, about 100 such targets
are addressed by approved biopharmaceuticals,18 but the spectrum of soluble
proteins or membrane receptors that represent potential therapeutic targets should
be much higher. Although the evaluation
of a new target and the subsequent development of a respective antibody are costly
endeavors, recent advancements in antibody technology may accelerate the validation of new targets, in particular those
relevent to cancer, autoimmune diseases,
infectious diseases and neurodegenerative
diseases.
Filing a patent application for an antibody against a new target is, usually, a safe
bet. In case a patent application describes,
and claims, a new protein that may play a
physiological role in the human body, it is
common to also draft a claim related to a
theoretical antibody against said protein,
i.e., an antibody which has not actually
been manufactured. Such type of claim
is routinely granted in the case when the
target protein is novel and substantially
defined, even if the applicant has not
produced such an antibody or provides
no data or enablement related to such
antibody (see, for example, US decision
Noelle vs. Lederman19 or EPO technical
board decision T0542/95).20
In both cases, the rationale behind this
position was that the provision and correct
specification, of a novel protein X enables
a skilled person to produce an antibody
against said protein. Therefore, it is considered a fair reward for the applicant of
protein X to be granted a claim related to
a theoretical antibody against said protein.
However, publication of limited data
for a protein that is part of a cellular signalling process does not automatically
compromise the inventive step/nonobviousness of a patent claim related to
an antibody against such protein. This is
because it may remain unclear whether or
not said moiety is involved in a pathogenic
process and, if so, whether underexpression or overexpression, or expression of a
dysfunctional or misfunctional product, is
responsible for the pathologic condition,
or if the moiety is causative for, or a consequence of, said pathologic condition.
Ganymed (Mainz, Germany) developed a series of antibodies against newly
found antigens that are specific for different types of cancer. The physiological
role of these antigens is not fully clear.
However, it seems that the respective antibodies are not meant to interfere in cellular signalling processes, as is the case, for
www.landesbioscience.commAbs
313
example, in anti VEGF therapy. The idea
is rather to evoke antibody-dependent cellmediated cytotoxicity responses against
the respective cells.
LPath (San Diego, CA) has pursued
a different concept. The company developed a mAb against a non-protein target,
i.e., the sphingolipd sphingosine-1-phosphate, which is a tumor growth factor.
LPath claims that this drug has a direct
effect on angiogenesis in addition to a
direct effect on tumor cells themselves,
i.e., inhibition of metastasis, tumor cell
growth and apoptosis, and thus combines
effects of some marketed antibodies.
Merrimack (Cambridge, MA) is
developing MM-111, which is an IgGlike bispecific antibody whereby, unlike
natural antibodies, one arm binds the
human epidermal growth factor receptor
2 (HER2) and a second arm binds the
HER3 receptor. It is claimed that the antibody uses the HER2 target to block the
HER3 pathway, as it appears that HER3
signalling is an important therapeutic target in HER2-positive cancers.21 Table 4
summarizes the above examples.
New Antibody Formats
Strictly speaking, when first introduced,
formats such as chimerized antibodies,
humanized antibodies, antigen binding
fragments (Fab) and single chain variable
fragments were considered new antibody
formats, and were (or still are) subject to
patent protection. The basic concept of
rearranging and recombining different
components of IgGs was further pursued
in the last decade. Potential advantages
of new antibody formats compared to
full-size molecules depend on the respective nature of the format and encompass,
for example, lack of glycosylation, lack
of disulfide bridges, reduced molecular
weight, better stability and serum half life,
better tissue penetration, lower immunogenicity, straightforward transfer from
animal trials to humans, suitability for
oral administration, expression advantages
(e.g., expression in E. coli or yeast instead
of Chinese hamster ovary cells), higher
efficiency and ease of selection/screening.
These advantages can be referred to to
meet the inventive step/non-obviousness
requirement in first generation patents
314
claiming the respective antibody formats
or their technology. Relevant patents on
major advancements in this field are listed
in Table 5.
In most cases, companies have first
established, and protected, the basic
enabling technologies related to the new
format as such. In a subsequent step,
specific drug candidates are developed,
thereby forming the subject of respective
patent applications.
One example resulting from a new
antibody format is Symphogen’s (Lyngby,
Denmark) Sym004, which is a recombinant IgG1 antibody product consisting of two antibodies targeting distinct
non-overlapping epitopes in epidermal
growth factor receptor (EGFR) extracellular domain III and which may, one day,
compete with JmClone’s Cetuximab. In
comparison to the latter, Sym004 is said
to induce removal of the receptor from
the cancer cell surface, leading to more
pronounced cancer growth inhibition.
The product is undergoing evaluation in
a clinical Phase 1 study [NCT01117428]
of patients with advanced solid tumors,
and is pursued, among others, under
the European Patent application
EP2132229A1 and related patent family
members. The basis for upcoming inventive step/non-obviousness considerations
will probably be advantageous binding
properties compared to prior art products
(e.g., Cetuximab) due to the polyclonality of the product.
Another example is Philogen’s
(Sovicille, Italy) L19-TNFα, which consists of the human antibody L19, which
targets the extradomain B of fibronectin,
fused to human TNF. In this construct,
the L19 domain provides vascular targeting of the TNF domain to the site of disease, where the latter exerts its antitumor
activity. The product is said to have superior anti-carcinogenic effect. Respective
experimental data put the corresponding
patent application ready for grant by the
EPO, and the product candidate is now
protected under EP1257297B1.
Yet another example is ATN-103,
which is an anti-TNF Nanobody ® developed by Ablynx (Ghent, Belgium) that
is currently undergoing evaluation in
clinical studies as a treatment for rheumatoid arthritis. ATN-103 targets the same
mAbs
antigen as the marketed antibody drugs
Adalimumab (Humira®), Infliximab
(Remicade®), Golimumab (Simponi®)
and Certolizumab pegol (Cimzia®), as
well as the fusion protein Etanercept
(Enbrel®) and is said to have a variety of
advantages related to administration and
pharmacokinetics, which are currently
used as a basis for inventive step/non-obviousness argumentation in the patent prosecution of European Patent Application
EP1558647A1.
Antibody Mimetics
Proteins not belonging to the immunglobulin family and even non-proteins
such as aptamers or synthetic polymers,
have also been suggested as alternatives to
antibodies.22 One reason for the increasing interest in these so-called “alternative
scaffolds,” or “antibody mimetics,” is the
barrier to entry into the field created by
existing antibody IP. As with new antibody formats, potential advantages of
new antibody mimetics depend on their
respective structural characteristics. These
specific advantages may be used as a basis
for patentability, i.e., in order to meet the
requirements towards novelty and inventive step/non-obviousness. An overview
of some selected approaches is shown in
Table 6. Some product candidates derived
from these approaches have already
entered the clinical phase, while others are
still in the preclinical phase.
Companies have in most cases first
established and protected the basic scaffold technologies, and have then started
to develop specific drug candidates, i.e.,
scaffold-based products that bind a given
target. The approach has the risk that
the respective patent applications meant
to protect these products may not be
considered as inventive/non-obvious by
the respective authorities. The rationale
behind such considerations is that both
(1) the respective scaffold and its implicit
advantages and (2) the respective target
and its clinical implications were already
known to the skilled person at the priority date of said second-generation patent application. The mere combination
of a known scaffold and a known target,
although novel, may thus be considered
obvious to the skilled person.
Volume 3 Issue 3
Table 5. Selected new antibody formats and their key patents
Company
Technology
Enzon
Polyalkylene oxide-modified scFv
Technology name/candidate drug
Key technology patent
US7150872
Macrogenics
Diabodies
US2007004909
CAT
Diabodies (scFv2, potentially bispecific)
US5837242
Micromet
Bispecific scFv2 directed against target antigen
and CD3 on T cells
Affimed
Affimed
Unilever
Camelid Antibodies (CH2-CH3-VHH)2
“BITE”
US7235641
Diabody-Diabody dimers
“TandAbs”
US2005089519
scFv-Diabody-scFv
“Flexibodies”
US2005079170
US6838254
Ablynx
Camelid VHH
“Nanobodies” ATN-103 (anti-TNF)
US2003088074
Domantis/GSK
Variable regions of heavy (VH) or light (VL) chain
(“Domain Antibodies”)
“dAb”
US2006280734
Scancell
Tumor epitopes on a IgG structure
with unchanged FC domain
“Immunobody”
US2004146505
Hybritech/Liliy
Trifunctional antibodies (Fab-Fab-Fab, maleimide linkers)
Trion Pharma
Trifunctional IgG, Fc binds accessory cells, Fabs bind CD3
and tumor Antigen
“Triomab”
US6551592
Affitech
Antibodies with T cell epitopes between ß-strands of
constant domains, and new V-regions specific for antigen
presenting cells
“Troybodies”
US6294654
Affitech
Antibody fragments that cross-link antigen and antibody
effector molecules
“Pepbodies”
US2004101905
Vaccibody AS
Bivalent homodimers, each chain consisting of scFv targeting unit specific for antigen presenting cells
“Vaccibody”
US2004253238
Planet Biotechnology
IgA (two IgG structures joined by a J chain and a secretory
component), expressed in a plant host, secretory component replaced by a protection protein
“SIgA plAntibodies”
US6303341
Trubion
Variable regions of heavy (VH) and light (VL) chain + Fc
(small modular immunopharmaceuticals)
“SMIP”
US2008227958
Haptogen/Pfizer
Homodimeric heavy chain complex found in immunized
nurse or dogfish sharks, lacking light chains
Novel Antigen Receptor (“NAR“)
US2005043519
AdAlta
Recombinant shark antibody domain library
“IgNAR”
US2009148438
Xencor
Altered Fc region to enhance affinity for Fcgamma
receptors, thus enhancing ADCC
“XmAB”
US20080181890
Arana
New world primate framework + non-new world primate
CDR
“syn-humanisation”
US2008095767
City of Hope
Dimerized construct comprising CH3 + VL + VH
“minibody”
US5837821
Seattle Genetics
Antibody-drug conjugate technology
with enzyme-cleavable linkers
Epitomics
Humanized rabbit antibodies
with increased target ­affinity
“RabMAbs”
US2005033031
CH2 and CH3 domains with two identical antigen binding
sites engineered into the CH3 domains
“Fcab“ (antigen binding Fc)
US2009298195
IgG with two additional binding sites engineered
into the CH3 domains
“mAb²“
US2009298195
Polyclonal antibody mixtures obtained by simultaneous
expression; antibodies bind to different regions of the
same antigen or multiple antigens
“Sympress“ Sym004 (anti-EGFR)
EP2152872
IgG4 antibodies with hinge region removed
(no ­interaction with immune system)
“UniBody“
WO2010063785
Human bispecific mAbs
“DuoBody“
US2010105874
F-Star
Symphogen
Genmab
US5273743
WO2009117531
ADCC, antibody-dependent cell-mediated cytotoxicity; CDR, complementarity-determining region; EGFR, epidermal growth factor receptor; mAbs,
monoclonal antibodies; PlGF, placental growth factor; scFv, single chain variable fragment; TNF, tumor necrosis factor; VEGF, vascular endothelial
growth factor; VEGFR, vascular endothelial growth factor receptor.
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315
Table 5 (continued). Selected new antibody formats and their key patents
Company
Technology
Technology name/candidate drug
Key technology patent
Regeneron
Fusion peptides consisting of the extracellular domain of
protein receptor and an Fc domain
VEGF trap extracellular segments
of VEGFR1 and 2 and an Fc; binds
VEGF-A and PlGF
US7087411
Philogen
Fusion proteins for targeted delivery of bioactive molecules to vascular sites of disease
“Vascular Targeting“ L19-TNFα
US2010316602
ADCC, antibody-dependent cell-mediated cytotoxicity; CDR, complementarity-determining region; EGFR, epidermal growth factor receptor; mAbs,
monoclonal antibodies; PlGF, placental growth factor; scFv, single chain variable fragment; TNF, tumor necrosis factor; VEGF, vascular endothelial
growth factor; VEGFR, vascular endothelial growth factor receptor.
Table 6. Selected antibody mimetics and their key patents
Company
Scaffold protein
Technology name
Size
Example drug
Key technology patent
Molecular Partners
Ankyrin repeat proteins
“DARPins”
10–19 kDa
MP0112 (Anti-VEGF)
US7417130
Borean Pharma
C-Type Lectins
“Tetranectins“
Affibody
A-domain proteins of
S. aureus
“Affibodies”
BioRexis/Pfizer
Transferrin
“Transbodies”
Pieris Proteolab
Lipocalins
“Anticalin”
Adnexus/Bristol Myers
Squibb
10th type III domain
of fibronectin
“AdNectins”
(Monobodies)
Dyax
Scil Proteins GmbH
US2004132094
6 kDa
ABY-025 (Anti-HER2)
US5831012
US2004023334
20 kDa
PRS-050
US7250297
10 kDa
Angiocept (CT-322;
anti- VEGFR2)
US6818418
Kunitz domain protease
inhibitors
6 kD
Ecallantide (antiKallikrein)
US2004209243
Ubiquitin derived binders
10 kDa
SPVF2801-30 (antiEDB)
Gamma Crystallin
derived binders
“Affilin”
US7838629
20 kDa
Selecore/Nascacell
Cysteine knots or knottins
“Microbodies“
US7186524
General Hospital/
Genetics Institute
Thioredoxin A scaffold
“Peptide aptamers”
US6004746
Archemix
Nucleic acid aptamers
Catalyst Biosciences
Target specific proteases
obtained by directed
evolution
“Alterases”
US2004146938
Mosbach/Lund University
Artificial Antibodies
produced by molecular
imprinting of polymers
“Plastic antibodies”
US2004157209
Phylogica
Peptide libraries
from bacterial genomes
“Phylomers“
US6994982
NextBiomed
SH-3 domains
Pegaptanib (antiVEGF); ARC1779 (antivWillebrandt)
US5475096
US6794144
Gliknik
Antibody-mimetics
“Stradobody”
Avidia/Amgen
“A domains” of membrane
receptors stabilized
by disulfide bonds and Ca2+
“Avimers“
“Maxibodies“
Evogenix/Cephalon
CTLA4-based compounds
“Evibody”
Covagen
Fyn SH3
“Fynomers“
US2010239633
9–18 kDa
US7803907
7 kDa
US2010119446
US7166697
CTLA, Cytotoxic T-Lymphocyte Antigen; EDB, extracellular domain B; HER, human epidermal growth factor receptor; kDa, kilo Dalton; VEGF, vascular
endothelial growth factor.
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mAbs
Volume 3 Issue 3
Therefore, to obtain patent protection
for such products, advantageous properties of the product, or, ideally, an unexpected synergism between the scaffold
and the target, should be disclosed in the
patent, in order to be at hand as fallback
position or as basis for a respective argumentation with respect to meet the inventive step/non-obviousness requirement.
Molecular Partners (Schlieren, Switzerland) has developed an ankyrin-based
drug for the treatment for age-related
macular degeneration (MP0112), which
targets vascular endothelial growth factor
(VEGF) A and, thus, would compete, if
approved, with the marketed Fab fragment
ranibizumab (Lucentis®). MP0112, which
is pursued under the international patent
application WO2010060748A1, is said to
have a higher target affinity than the former. In the respective claims, a minimum
Kd of less than 10 -7 M is claimed, the latter being the basis for upcoming inventive
step/non-obviousness considerations in
the respective prosecution proceedings.
Another example is PRS-050 by Pieris
AG (Freising, Germany). Clinical trials for
this drug, which is a PEGylated Anticalin®,
were initiated in 2010. PRS-050 binds and
neutralizes human and murine VEGF with
picomolar affinity, and is said to be used
as a drug for treating solid tumors. Pieris
claims that, compared to other anti-VEGF
antibodies, PRS-050 exhibits better tissue
penetration and, consequently, can infiltrate tumors much easier, and has a shorter
half-life which supports VEGF removal
from the body. Further, Pieris claims that
the drug does not aggregate. The drug is
currently protected under EP2046820 B1
and related patents.
Scil proteins (Halle, Germany) has in
its pipeline proprietary ubiquitin-based
drug candidates called Affilin® therapeutics. The lead candidate SPVF2801-30 is
in preclinical development. SPVF2801-30
is a fusion protein comprising a heterodimeric Affilin®, plus a specific cytokine.
Despite systemic advantages of their proprietary ubiquitin-based Affilin® therapeutics, Scil provides data supporting
superior target affinity and specificity of
the claimed drug. Patent protection is currently pursued under PCT application No
PCT/EP2010/069665.
Conclusion
The quick advancements of antibody
technologies require a steady adaptation
of patent strategies, to ensure that future
products will still be protected by IP rights.
While requirements as to inventive step/
non-obviousness and written description
and enablement seem to be on the rise, the
hurdles with respect to the novelty requirement have been lowered. Companies and
research institutions which are involved
in the development of new therapeutic
antibody products should develop an adequate IP expertise or seek expert advice, to
account for these developments, in order
to be able to protect their investments for
research and development.
Disclaimer
The information provided herein reflect
the personal views and considerations of
the author. They do not represent legal
counsel and should not be attributed to
Michalski • Hüttermann & Partner Patent
Attorneys or to any of its clients. Patent
numbers and patent lifetimes have been
verified with utmost care, but no liability
is taken for their correctness.
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