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ACTIVITY REPORT
2009
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CONTENTS
Cellectis in a Nutshell
Word rom the CEO
Activity and Markets
Our Strategic Goals
Product Porolio
1999 2009: 10 YEARS IN PICTURES
2009 HIGHLIGHTS
Scientic Updates
Intellectual Property
New Contracts and Partnership Agreements
COMPANY
Governance
Subsidiaries
Human Resources and Communications
FINANCIAL STATEMENTS
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INNOVATION
ITS IN OUR DNA
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CELLECTIS IN A NUTSHELL
Cellectis is a pioneer in the feld o genome engineering.The company designs and markets meganucleases
innovative tools that enable targeted modifcations
to DNA with three primary aims: understanding,
production and treatment. These meganucleases are
applied in the research, biomanuacturing, agrobio-
technology and therapeutic sectors.To date, Cellectis has established more than 50 agree-
ments with pharmaceutical laboratories, seed producers
and biotech companies across the world, and has
ormed over 20 academic research partnerships.
Cellectis was ounded in 1999 by scientists Dr. AndrChoulika and Dr. David Sourdive with an exclusive
technology license rom the Institut Pasteur. Rodney
Rothstein o Columbia University chairs the companys
Scientifc Advisory Board, composed o internationally
renowned scientists.
Since 2007, Cellectis has been listed on the NYSE-
Euronext Alternext market in Paris and has secured
over70 million in unding since inception.
While pursuing an aggressive plan or growth, the
company has maintained a low cash burn because
o increasing revenue streams rom product sales,production and partnering, and licensing activities.
Worldwide pioneer in genome engineering
Established in 1999, listed on the
NYSE-Euronext Alternext market
in Paris since 2007
Operating Revenues 2009: 12.1 M
(80% rom international revenues)
Sta: 85 including 32 PhDs
3 afliates:Cellectis bioresearch,Cellectis genome surgery, Ectycell
Applications: research and biomanuac-
turing, agrobiotechnology, human health
Main technologies: meganuclease-based
genome engineering, meganuclease
engineering
IP portolio: 60 patents granted plus
over 200 pending
Location: Paris area
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6 l Cellectis l Activity Report 2009 l
In 2009, Cellectis celebrated 10 years o sustained growth in research, development,
application and marketing o meganucleases, the sequence-specifc enzymes that
are the basis o our business. These DNA scissors induce cut and paste o DNA
sequences at very specifc locations in living cells, oering powerul applications
and potential in the felds o human therapeutics, agriculture and biouels, among
others. The genome engineering technology based on meganucleases that we have
developed can potentially be applied to any living organism. During my years in
research, I recognized that changing the specifcity o these enzymes allowing
them to target desired sites precisely would make a tremendous tool or genome
surgery and an excellent basis or a company.
As we look orward to accomplishing uture goals, this 10-year anniversary is an
opportunity to take stock o what we have achieved. We have initiated and led the
eld o genome engineering internationally, thanks to unwavering dedication to our
initial vision. We have grown rom three enthusiastic scientists in the Institut Pasteurs
incubator to a company o almost 90 today. And because o our strong growth over
the years, we are now in a position not only to expand organically but also throughacquisition.
We ounded the company in December 1999, but when I look back, Cellectis actually
had its beginnings more than a decade earlier. In the late 80s, a research team at In-
stitut Pasteur, which I was honored to be part o, discovered meganucleases, enzymes
that promote DNA transer inSaccharomyces cerevisiae (bakers yeast). Shortly there-
ater, I began working on retroviruses and DNA recombination in mice. When we
began experimenting with meganucleases in mammalian cells, we incorporated the
recognition site o a meganuclease we were working on into a retrovirus. We thentried these DNA scissors out on inected cells. Suddenly the retrovirus disappeared.
We could remove the virus rom a cell, which was a total paradigm shit at the time in
terms o our way o thinking about antivirals.
The adventure that is Cellectis began at the end o 1999. In 2000, the Institut Pasteur
agreed to sign exclusive licenses with us or six amilies o patents relating to ho-
mologous recombination and meganucleases. That year we also won a competition
sponsored by the French Higher Education and Research Ministry, meant to help inthe development o technologically innovative companies.
Dr Andr Choulika
WORD FROM THE CEO
It all began with ordinary bakers yeast
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There were many milestones in the progress o our young company. We raised sub-
stantial venture capital in 2002, despite a dicult nancial environment. In 2004, we
moved to our current headquarters. That year also marked our rst major research
breakthrough we discovered a way to generate meganucleases on an industrial
scale, a crucial step to successully commercializing our technology. In January 2007,
Cellectis announced an initial public oering on the NYSE-Euronext Alternext market
in Paris. We raised24.4 million, and the IPO was more than six times oversubscribed.
Throughout this initial period, industry leaders such as Merck, Glaxo SmithKline, Shire,
BASF Plant Science and Limagrain had the oresight to see the potential o our tech-
nology. Our revenues have been growing steadily rom year to year.
This brings us to our 10th anniversary year, during which we had several major ac-
complishments. Our subsidiary, Cellectis bioresearch, which markets research and pro-
duction kits, launched ve new products. Cellectis genome surgery, our therapeutic
subsidiary, obtained consistent saety data supporting the potential o meganucleases
in human medicine. We ounded a new subsidiary, Ectycell, dedicated to the industrial
applications o stem cells. We completed a capital increase o 22 million. And wesigned our largest deal yet, a research, development and commercial agreement with
the agriculture biotechnology leader Monsanto.
For these successes, and those throughout Cellectis history, we must above all credit
the unwavering commitment o our sta, which has been the key success actor or
Cellectis. At all levels, in all departments rom research to accounting to the Board
o Directors Cellectis employees have exhibited strong loyalty and dedication, or
which we will continue to be thankul as we ace challenges in the uture. And as
we orge ahead in our role as industry innovators, well also try to remember howwe turned something small and ordinary, bakers yeast, into an extraordinary tool or
improving human health and well being in the coming decades.
Andr Choulika,Chie Executive Ofcer
Cellectis leads the eld
o genome engineering
internationally, thanks to
unwavering dedication
to our initial vision.
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ACTIVITY AND MARKETS
Since its ounding, Cellectis has sublicensed its intellectualproperty portolio based on meganucleases and
homologous recombination, originally licensed rom the
Institut Pasteur, but urther complemented by Cellectis
proprietary patents.
The technologies designed and implemented by Cellectis are applicable to all DNA types (hu-
man, animal, plant, viral and bacterial) and all genes o interest. They can unlock or restoreDNAs potential and are thereore open to a broad range o applications:
Human health: the replacement o a deective gene by a unctional gene (monogenic dis-
eases such as muscular dystrophy or hemophilia), the suppression o persistent viral DNA (HIV,
hepatitis B or herpes viruses) and the creation o stem cell lines with particular characteris-
tics. Cellectis is particularly involved in the research and development o therapeutic solutions
in cooperation with AFM (the French Muscular Dystrophy Association), the Necker-Enants
Malades Hospital and the Vision Institute.
Agrobiotechnology: the improvement o certain properties o plant crops through the re-
placement, addition or suppression o genes o interest or the modulation o their expression.
Five o the worlds leading seed producers BASF, Bayer Cropsciences, Pioneer, Limagrain and
Monsanto already use Cellectis technologies.
Research and biomanuacturing: through its subsidiary Cellectis bioresearch, the company
markets its cGPS (cellular Genome Positioning System) and cGPS Custom amilies o kits or
the in vitro modication o cell lines.
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The main biotechnology tools developed by Cellectis are based on the properties o mega-
nucleases, natural molecular scissors that can cut DNA at a highly precise site specic to eachmeganuclease. Once the cut has been made, it is possible to remove, integrate or substitute
a portion o the DNA with the same high degree o precision. Cellectis has exclusive usage
rights to nine Institut Pasteur amilies o granted or pending patents relating to the technolo-
gies underpinning this mechanism, in particular homologous recombination. Cellectis currently
holds about 60 granted patents, its complete portolio comprising over 260 patents granted or
pending, including the rights linked to Vectocell, a technology platorm acquired in 2009 by
Cellectis (see p24).
Each year, Cellectis designs and produces dozens o meganucleases with modied specic-ity, tailor-made or researchers and engineers in state-unded and private laboratories and or
clients in industry. These enable controlled, rapid, sae and reproducible modications o the
targeted portion o DNA. These collaborations, along with an active technology outlicensing
program and a rapidly expanding line o commercial research kits, have led to steady revenue
growth or the company. Cellectis expects to launch tens o new commercial research products
in 2010 and aims to reach sustainable protability in 2011 or 2012.
Any industry that dealswith living organisms be
they animals, plants or
microorganisms is potentially
a Cellectis market.Marc Le Bozec, CFO
DNA cut with incredibletarget specicity andDNA repair/insertion
Cut
Meganuclease
Human genome size:6.4 billion bases
(G, A, T, C).
Paste
2500nm
ChromosomeCell
The frst in vivocut and paste
Meganucleases are DNA scissors that cut DNA at a unique target site, creating an opening toallow sequence deletion, insertion and/or repair.
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Today we are proud to have established a business model that will continue to support us in
the coming decades as we pursue our role as innovators in the eld. Inherent to our strategic
mission are several types o challenges.
Maximizing Technology and Creating Innovation
The frst part o our fnancial strategy is to maximize our existing technology, based on the Institut
Pasteur technologies exclusively licensed to us, or optimal nancial return. In this respect, we
look to license access to our engineering platorm and homologous recombination patents and
maximize the monetization o our intellectual property.
In order to grow, we are simultaneously working to create, develop and commercialize new
products, such as the six innovative turnkey research kits we put on the market through oursubsidiary Cellectis bioresearch since 2008.
Our ocus as we grow will be to increase the value o our technology when and where it can
be useully applied. We thereore aim not only to enable others to create desired products, but
also to identiy and create them ourselves, establishing subsidiaries in select areas ranging rom
healthcare to academic research.
Pursuing Excellence in Diverse Fields
Cellectis strategy is to selectively diversiy its technology across dierent markets, leading
to short, medium and long-term revenue generation.
Capitalizing on current technologies
Our aim is to set the industry standard in DNA recombination through our research tools.
We thereore market our technologies to industry and academia. We want to be where
innovation begins.
OUR STRATEGIC GOALS
A single-minded ocus has driven us throughout ourhistory: to create a genome engineering market leader.
Although this sounds straightorward, this business model
did not exist when we ounded Cellectis 10 years ago.
Scientic data are led and protected.
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Building solid partnerships
The rapidly growing agrobiotechnology sector is investing heavily in technologies to gen-erate plant species or human consumption that are easy to grow, environmentally sae
and have high added-value or the consumers compared to classical plants. Our targeted
technology is perectly suited to these needs.
Investing in the uture
The development o human therapeutics to cure genetic or viral diseases is an exciting eld that
holds perhaps the highest growth potential or Cellectis though there still is a lot o work to
accomplish. This research necessitates a signicant investment o both time and capital, but we
are now beginning to obtain results and proos o concept sustaining the incredible potential oour technology in the eld o molecular medicine.
Upstream Research
Cellectis has succeeded in capitalizing on its leadership position. It is vital to strengthen this
position by investing in upstream genome engineering research, however. Our researchers are
leading us to urther advances in our knowledge o meganucleases the current basis o our
technology.
In addition to cutting-edge research, a critical area o growth or Cellectis will be combining
meganucleases with other technologies, mainly in the eld o vectorization, to be able to bring
the meganucleases in vivo to the cells where they are needed.
Strong Growth with an Eye on the Future
Our overall nancial strategy is to build a strong equity base. To do so, we need to achieve
strong internal and external growth. In the last two years, we have created three subsidiaries, each
dedicated to a specic market, while exploring several other promising avenues or growth.
External growth is the key component o our long-term strategy. It is largely or this reason that
we raised 22 million in capital in October 2009. We actively seek to develop organically and
acquire companies that will complement our technology and help speed up our development.
We want to be whereinnovation begins.David Sourdive, Executive VP,
Corporate Development
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PRODUCT PORTFOLIO
The purpose o the modifcation can be to
Understand the function of a given gene
Manufacture tools for research and development
Create biological products, such as therapeutic proteins or antibodies Improve the characteristics of certain plant species
Treat the cause of diseases resulting from a disruption in genetic
programming or rom a persistent viral inection
Our product portolio includes projects developed by Cellectis and our subsidiaries as well as
collaborative projects, particularly in the eld o agrobiotechnology. Cellectis devotes a large
part o its internal research eorts to therapeutic projects, which carry a greater risk but oer
high added-value in the long term.
Research and production tools using our meganucleases or academic and industrial research
laboratories are our other area o ocus. These have a short development cycle, they should
thus generate revenue in the short term and provide broad visibility or the Cellectis brand
worldwide.
Meganuclease Kits
Cellectis bioresearch has created the industry standard in targeted gene integration: cellular
Genome Positioning Systems (cGPS) and cGPS Custom, so named because the kits bring
the users choice DNA directly to a very specifc genomic address. To date, Cellectis bioresearch
has a total o six kits on the market fve o which were launched in 2009, a particularly
successul year.
The value o our precise system over more conventional random integration is that the results
obtained are ully predictable a single copy o the gene o interest will be integrated at the
same place in the genome every time and are thereore reproducible. This is not the case
with classical transection, which inserts a gene at random in the genome. Our systems also
result in stable integration, which is not the case or cells produced by random integration. The
cGPS and cGPS Custom kits also oer speed a process that once might have taken six to 18months may now take as little as our weeks.
Cellectis commercializes
products, not services.
We chose this route because
it has greater commercial
potential and it helps brand
Cellectis more broadly as best
in class and a game changing
technology provider.
Marc Le Bozec, CFO
Cellectis products are designed or targeted gene modi-cation. Their purpose is to modiy the DNA in a living cell,
or the benet o human health and wellness, with three
primary aims: understanding, production and treatment.
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The application o the kits is threeold:
1. Biological production: integration o a gene into a cell allows it to express a protein o interestsuch as a biodrug, or enables the engineering o post-translational pathways
2. Drug screening: modiying a cell line to express a receptor specic o a disorder, or example,
allow drug candidates to be screened
3. Functional genomics: comparison o two genes, identication o the role o a specic gene or
o genes are made possible, as well as the stable expression o shRNA or research purposes
Each cGPS kit contains a vectorized meganuclease and an engineered mammalian cell line
with a pre-integrated meganuclease recognition site, enabling 10 experiments:
cGPS CHO-K1: this kit is for using CHO cells to express therapeutic targets and for gene
unction studies
cGPS CHO-K1 Duo: enables targeted integration at two distinct genomic sites in CHO cells,
ideal or expressing multimeric proteins and establishing inducible expression systems
cGPS CHO-S Cemax: the ideal cell line i high titers o proteins are needed
cGPS NIH3T3: this product targets the murine cell line NIH3T3
For clients who wish to work with a particular wild type cell line, they can use cGPS Custom.
These kits contain a meganuclease that Cellectis has engineered to change its recognition site
sequence. Cellectis is constantly expanding the list o cell lines that can be customized in this
way. Products currently available include:
cGPS Custom CHO-K1: the frst engineered meganuclease targeting the original CHO cell line
cGPS Custom HEK293: our rst research kit for use on human cell lines
Meganucleases or Agrobiotechnology
Meganucleases can be engineered or use in any plant species. Cellectis uses its technology
and expertise to provide seed producers with meganucleases to make targeted modications in
plant genomes and develop the next generation o quality crops. The modications that bring
added value to existing plants include gene stacking, gene knock-out, as well as modulation o
gene unction.
One o the kits commercialized by Cellectis bioresearch.
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Therapeutic Products
Cellectis genome surgery is devoted to developing human therapeutic products that use mega-
nucleases as their active component. The companys targets are genetic diseases, such as sickle
cell anemia, muscular dystrophy and severe combined immunodeciency (SCID), as well as
certain viral diseases, such as hepatitis B, AIDS and herpes.
Genetic diseases: In many genetic diseases, such as sickle cell anemia, there is currently no
available therapy to treat the cause o the disease, but only to relieve the symptoms. Among
other projects underway, Cellectis genome surgery is developing meganuclease-based products
in partnership with the French Muscular Dystrophy Association (lAssociation ranaise contreles myopathies or AFM) to address such diseases as sickle cell anemia, beta thalassaemia and
Duchenne and Becker muscular dystrophies. The 7.3 million program, unded by AFM, is
working on the potential o a meganuclease-based therapy to correct a mutation that is respon-
sible or an inherited disease.
Viral diseases: In its development o antiviral products, Cellectis genome surgery obtained in
2009 a proo o concept o the eectiveness or anti-HSV (Herpes simplex virus) meganucle-
ases in cells as well as preliminary animal saety data supporting the use o vectorized antiviral
meganucleases. Most antiviral agents block the lie cycle o the virus at a certain stage but they
do not kill it. Meganucleases, acting as DNA clippers, can excise the virus rom cells, thereby
disabling it.
The structure o DNA, the nucleic acid that containsthe genetic inormation.
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1999 2009:
10 YEARS IN PICTURES
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1999 2009: 10 YEARS IN PICTURES
2
000
2
001
Cellectis original home, at the Institut Pasteur.
Cellectis is ounded. First in-licensing. Signature o the rst
licensing agreements.
Tridimensionalmodeling o a meganucleasecoupled to DNA.
The team in 2000.
The rst robots arrive.1
999
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2
002
2
003
Establishment o the Scientic Advisory Board,
chaired by Pro Franois Jacob.
Engineering o the rst synthetic
hybrid meganuclease.
Pro Franois Jacob, recipient o the Nobel Prize inMedicine in 1965, currently Honorary Chairmano the Scientic Advisory Board.
Team discussions take place at every opportunity.
The Parc Biocitech.
The Fleming building,Cellectis headquarters.
The number oweekly screeningtests increases.
The frst screen-ing tests ormeganucleases.
A new stepin screening.
2
004
Cellectis moves to Romainville
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Cellectis holds its
initial public oering.
First publication showing
the in vivo eectiveness
o meganucleases.
First custom meganuclease
engineered in the laboratory.2
005
2
006
2
007
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High-throughput screening.
The Cellectis team today.
Inception o
Cellectis bioresearch and
Cellectis genome surgery.
Cellectis bioresearch
launches its rst
meganuclease kits.
Cellectis is granted its 58th patent.
Inception o Ectycell.
Cellectis Wall o Patents, displaying some o the 58 patents granted to the company.
2
008
2
009
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2009 HIGHLIGHTS
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SCIENTIFIC UPDATES
Ten years ago, Cellectis was
established to industrialize
the design and develop-
ment o an articial system
or using the ull power
o genome engineering to
modiy any genomeprecisely at any location.
This system involved the combination o two
undamental technologies developed at theInstitut Pasteur, meganucleases (proteins that
cut DNA precisely at dened sites in vivo)
and homologous recombination (a naturally
occurring process whereby DNA can be
precisely replaced).
Individually, these two technologies have
limited applications. The low targeting e-
ciency o homologous recombination restrictsits use to a small number o species (such as
mice or yeast) and to academic research.
At the same time, the small number o natu-
ral or engineered meganucleases available
could cut DNA at only a ew predened
sequences, so the challenge was to indus-
trialize the production o meganucleases to
target a larger number o DNA sequences.
Thereore, using its capacity to create new
meganucleases with new and chosen recog-nition sites, Cellectis developed the rst-ever
technology or industrial scale, targeted in
vivo genome engineering using meganucle-
ases, which makes it possible to cut DNA
at any desired, predened site in a given
genome.
Today, Cellectis is a world leader in targeted
genome engineering, with a growing,diversied product portolio, cutting-edge
technology (validated by numerous scientic
publications, including ve in 2009) and a
strong intellectual property strategy.
The Mechanism o Meganucleases
There are numerous actors that can alter
the DNA o a cells genome, such as X-rays,
chemical products, certain enzymes and
even ordinary processes in the lie o any
cell (cell division, DNA replication). The
cells o all living species have a nely tuned
mechanism that enables them to repair
these alterations in the genome with the
aim o preserving its integrity.
Cellectis technologies are based on this
undamental mechanism that is common
to all living species. The cells endogenous
maintenance and repair system can be
used judiciously to introduce targeted
modifcations, in a precise and rational way.
Meganucleases are among the tools that
organisms use to repair DNA. They are a
particular class o endonucleases or DNA
scissors, capable o cutting a chromosomeat a specic site in a living cell. In nature,
meganucleases come rom single-cell
organisms such as bacteria, yeast, algae
and some plant organelles.
Meganucleases perorm cut-and-paste-
type operations at the site o their target
sequence. Meganucleases have a long re-
cognition site o 12 to over 32 base pairs,
which would potentially occur only once in a
genome. This is the key to their precision.This high degree o specifcity is what gives
meganucleases the potential to be the
ultimate tools or precise genome surgery
in living cells and organisms. Cellectis has
harnessed the power o meganucleases by
developing a unique method o redefning
the amino acids that play a role in DNA
recognition. We analyze the target DNA
sequence in which the modication is to
take place and select the preerred locali-zation o the target sites.
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Major Breakthroughs
Thanks to its protein-
engineering platorm,
which in 2009 increased
its production capacity
to almost 100 new mega-
nucleases per year, Cellectisis targeting very diverse
applications, rom antivirals
to crop improvement and
rom research and produc-
tion tools to therapeutic
molecules. Some o the
highlights rom a year that
saw the ruition o many
o our research projects are
described here.
Production Time Signicantly Reduced
Over the past ve years, Cellectis has built
an archive o more than 20,000 well-
characterized meganucleases the Omega-
base which Cellectis researchers have
used to generate signicant improvements
in the manuacture o new meganucleases.
By constantly improving its meganuclease
engineering processes, Cellectis made abreakthrough in 2009 in the eciency o
its technology platorm. This has resulted in
a reduction in the time required to produce
a new meganuclease, rom nine to three
months, in a large number o cases. Improve-
ments have resulted in an increase in capac-
ity while urther raising quality standards.
We created a milestone o 96 engineered
meganucleases in 2009, surpassing ourtarget o 20 set at the beginning o the year.
The 40th meganuclease was delivered to
the French Muscular Dystrophy Association
(lAssociation ranaise contre les myopa-
thies), the rst step toward what could be
a new class o drugs to ght Duchenne
muscular dystrophy.
Conrming the Power o Meganucleases
as Viral Clippers
In 2009, our R&D team obtained the rst
data strongly supporting the proo o
concept o the antiviral power o meganucle-
ases. In addition to correcting mutations
responsible or inherited disease, we can, or
viral diseases, introduce a meganuclease to
clear the cell o a virus. This method is called
virus clipping. Most antiviral agents cur-rently available block the lie cycle o a virus
at one stage during DNA or RNA synthesis,
or virus adsorption or instance but do
not kill it. Our researchers have shown that
meganucleases can directly destroy a virus by
removing it rom the genome o an organism.
A Look at the Meganuclease Portolio
Cellectis produces meganucleases or a broadvariety o targets o interest. During the
course o 2009, the product portolio was
expanded with many new meganucleases
and ve new cGPS kits, or a total o six kits
on the market (see p13). Today, Cellectis has
meganucleases that target the human ge-
nome, as well as that o the mouse, hamster,
plant, sh and several viruses.
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Spotlight on Two o Our Scientic
Publications
In 2009, Cellectis published, among others,
two papers in peer-reviewed scientic
journals detailing research that could aid in
the treatment o severe combined immuno-
deciency (SCID), an extreme orm o
heritable immunodeciency. SCID patients
oten die very early because o their
susceptibility to inectious diseases.
In July, Cellectis announced the publication
o Ecient Targeting o a SCID Gene by an
Engineered Single Chain Homing Endonucle-
ase in Nucleic Acids Research. This paper
is the rst to report the induction o gene
targeting in an endogenous gene by an en-
gineered meganuclease. The targeted region
was within the human RAG-1 gene, whose
inactivation results in SCID. Meganuclease-induced gene targeting could be achieved
in up to 6% o the treated cells, a level
compatible with therapeutic applications.
Further studies will be conducted with these
meganucleases in order to correct mutations
in patient cell lines and, potentially, to cure
SCID patients.
In August, work conducted by a team romthe French National Institute or Health and
Medical Research (INSERM unit U768) and
Cellectis was detailed in the paper Reduced
Immunoglobulin Class Switch Recombina-
tion in the Absence o Artemis, published in
Blood. The Artemis gene is involved in the
repair o double-strand DNA breaks; muta-
tions in this gene are responsible or SCID.The INSERM and Cellectis researchers bred
lines o mice in order to study the disease.
The results conrmed that Artemis is in-
volved in the maturation o B and T lympho-
cytes, and in immunoglobulin, the crucial
components o the adaptive immune system.
This work will make it possible to test new
approaches or treating SCID, particularly
using meganucleases.
Advances in Therapeutic Programs
Pharmacokinetic and toxicity experiments
have been conducted with I-CreI and with
anti HBV (hepatitis B virus) meganucleases
vectorized with AAV8. No acute toxicity
was detected with the I-CreI protein. There
seems to be a moderate immune responseagainst the AAV vector but it is still too early
at this point to make conclusions about
the toxicity o the vectorized protein itsel.
Publications in 2009
S. Grizot, J.C. Epinat, S. Thomas, A. Duclert,
S.Rolland, F. Pques and P. Duchateau
Generation o Redesigned Homing
Endonucleases Comprising DNA-Binding
Domains Derived From Two Dierent
Scaolds
Nucleic Acids Research, Advance Access,
published online December 21, 2009
P. Rivera-Munoz, P. Soulas-Sprauel,
G. Le Guyader, V. Abramowski, S. Bruneau,
A. Fischer, F. Pques and J.P. de Villartay
Reduced Immunoglobulin Class Switch
Recombination in the Absence of Artemis
Blood, 2009 Oct 22, 114 (17): 3601-3609
R. Galetto, P. Duchateau and F. Pques
Targeted Approaches for Gene
Therapy and the Emergence of EngineeredMeganucleases
Expert Opinion on Biological Therapy,
October 2009, 9 (10): 1289-1303
S. Grizot, J. Smith, F. Daboussi, J. Prieto,
P. Redondo, N. Merino, M. Villate,
S. Thomas, L. Lemaire, G. Montoya,
F.J. Blanco, F. Pques and P. Duchateau
Efcient Targeting o a SCID Gene
by an Engineered Single Chain HomingEndonuclease
Nucleic Acids Research, 2009, 37 (16):
5405-5419
J.P. Cabaniols, L. Mathis and C. Delenda
Targeted Gene Modifcations in Drug
Discovery and Development
Current Opinion in Pharmacology, 2009,
9 (5): 657-663
l Cellectis l Activity Report 200 9 l 23
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24 l Cellectis l Activity Report 2009 l
One o our companys oremost assets is the
strong position o its intellectual propertyestate. The Institut Pasteur patent amilies
covering the use o homologous recombina-
tion and the use o endonucleases rom the
meganuclease amily to induce DNA recom-
bination ormed the initial basis o Cellectis
ounding. We have also since developed a
healthy proprietary portolio.
Cellectis patents all into three broad catego-
ries patents on general principles, patents
on specic meganucleases and applications,
and patents covering the manuacturing o
modied meganucleases.
At the end o 2009, Cellectis owned the
rights to 53 patent amilies, including 58
patents granted and over 200 patent appli-
cations. In 2009 alone, Cellectis was granted
our new patents and led 15 new patentapplications.
Our strategy involves building up an intel-
lectual property portolio that protects our
products, their applications and the corre-
sponding body o technological knowledge.
INPI Innovation Award
In December 2009, Cellectis was honored to
receive the Paris Ile-de-France Region Inno-
vation Award conerred by the French Patent
and Trademark Oce (Institut national de la
proprit industrielle or INPI).
INPIs annual awards honor small and
medium-sized companies whose success can
be attributed to their pro-innovation policies.
These rms use a comprehensive intellec-
tual property strategy to leverage business
growth.
Vectocell
When Cellectis acquired Vectocell intracel-
lular delivery technology in September 2009,
it expanded its intellectual property portolio
by an additional nine patent amilies.
Vectocell technology is a peptide technol-
ogy that can carry proteins and other com-
ponents inside the cells. It was developed
rom internalizing human antibodies and
can be used to optimize the ecacy o drug
candidates. Its ability to provide an entry into
any chosen mammalian cell type, including
humans, with no detectable immunogenicitygives it a broad spectrum o applications.
Cellectis envisions that the use o this tech-
nology in tandem with meganucleases
will make it a valuable property in biothera-
peutics and or many other applications.
INTELLECTUAL PROPERTY
Evolution o Cellectis IP portolio
Number o patents granted
In 2009, in addition to its 58 granted patents, Cellectiscomplete portolio comprises over 200 pending patents.
Andr Choulika, CEO, and Michle Paquier,IP Manager, receive the INPI Innovation Award.
60
50
40
30
20
10
0
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
24 l Cellectis l Activity Report 2009 l
NEW CONTRACTS AND PARTNERSHIP AGREEMENTS
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l Cellectis l Activity Report 200 9 l 25
Monsanto
In September 2009, Cellectis announced a
landmark deal with Monsanto. The nonex-
clusive research and commercial agreement
or Cellectis proprietary meganuclease-
based technology includes a 3 million
upront payment, a 1 million equity invest-
ment and ees payable to Cellectis or each
meganuclease developed or Monsanto.
In addition, Cellectis is eligible to receive
milestone payments at multiple development
stages (worth over100 million) as well as
royalties on certain traits commercialized by
Monsanto.
This agreement with Monsanto, a leader
in agrobiotechnology, could allow Cellectis
genome engineering technology to be put
to use in developing the next generationo quality crops. In addition, it oers the
opportunity or Cellectis technology to be
used by the largest discovery engine in the
agricultural eld. The scope o the agree-
ment stands as recognition that the industry
leader believes in Cellectis approach.
Other Agreements
In May, Cellectis signed a nonexclusive
licensing agreement with the pharmaceutical
group Servier or the use o Cellectis modi-
ed cell lines or high-throughput screening.
This contract ormalized a well-established
research relationship between the two com-
panies and should accelerate the develop-
ment o high perormance screening tools or
innovative drug targets.
In June, following a successful research
program, the international cooperative group
Limagrain exercised its option or a nonex-
clusive commercial license to use the I-Scel
meganuclease to develop its agricultural
products.
Also in June, Cellectis bioresearch signed a
license agreement with the biomanuacturingorganization Celonic AG or its patented
CEMAX technology, which will allow
Cellectis bioresearch to use CEMAX or
the development o its commercial products.
By optimizing it, Cellectis bioresearch has
already used the technology in one o its
production kits launched in November 2009,
cGPS CHO-S Cemax.
In December, Cellectis bioresearch and
tebu-bio, which supplies and distributes
biological research reagents in Europe,
decided to join orces or the distribution o
Cellectis bioresearchs research kits. Cellectis
bioresearch will be responsible or the design
and production o the targeted integration
kits rom its cGPS and cGPS Custom lines.
tebu-bio will be responsible or distributing
these kits to research laboratories across
Europe. tebu-bio will have exclusive distribu-
tion rights or the major European marketswhere it has a physical presence. This
partnership will oer Cellectis bioresearch a
oothold in the academic research market,
a major target in terms o the number o
potential users.
In December, BASF Plant Science broad-
ened its license to use Cellectis mega-
nuclease technology. Under a nonexclusive
license, BASF Plant Science will use mega-
nucleases engineered by Cellectis to make
targeted modications o plant genomes.
Finally, in December, Bayer HealthCare,
the healthcare subgroup o Bayer, acquired
a license to use Cellectis patent amily
WO9011354 covering homologous recom-
bination aimed at introducing new eatures
into the genome. This global license includesthe use o the Institut Pasteur technology
relating to homologous recombination to
obtain and utilize certain transgenic animals
in pharmaceutical research, in all countries,
including Japan.
NEW CONTRACTS AND PARTNERSHIP AGREEMENTS
l Cellectis l Activity Report 200 9 l 25
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COMPANY
GOVERNANCE
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l Cellectis l Activity Report 200 9 l 27
GOVERNANCE
Dirk Pollet, PhD,
Chie Business Ofcer
David J.D. Sourdive, PhD,
Executive Vice President,
Corporate Development
Frdric Pques, PhD,
Chie Scientifc Ofcer
Andr Choulika, PhD,
Chie Executive Ofcer
Marc Le Bozec,
Chie Financial Ofcer
Sylvie Delassus, PhD,
Senior Vice President,
Corporate Communication
Executive Committee
The Executive Committee is composed othe senior-level management o Cellectis,
which implements the companys strategy
and directs its day-to-day operations. (photo)
Board o Directors
The Board o Directors determines the
company strategy and oversees Cellectis ac-
tivities. Members o the Board o Directors
serve or a term o three years; the Chair-
man convenes meetings when it is deemed
necessary or desirable. In 2009, the Board o
Directors met seven times.
On December 31, 2009:
Christian Policard, Chairman
Martin Bitsch, MD
Andr Choulika, PhD,Chie Executive Ofcer, Cellectis
Alain Godard
Roger J. Hajjar, MD.,
Kaminvest Holding Representative
Ray Kazandjian
Richard C. Mulligan, PhD
David J.D. Sourdive, PhD, Executive VicePresident, Corporate Development, Cellectis
Pascale Altier, Observer, The Institut Pasteur
Representative
During 2009, AGF Private Equity decided
to resign as a member o Cellectis Board o
Directors. We would like to warmly thank
Dr. Thierry Laugel as its representative or his
dedication and the wonderul job he did while
he held this position. We very much appreci-
ated working with him during these past years.
Scientifc Advisory Board
The Scientic Advisory Board, set up in2002, is composed o eight active members,
appointed or one year and meets twice a
year. Its mission is to outline Cellectis broad
scientic orientations. It presents Cellectis
management team with methods and strat-
egies to achieve the companys technological
goals. It evaluates the work achieved
during the year and the results obtained.
On December 31, 2009:
Pro. Franois Jacob, Honorary Chairman,
MD, Collge de France, Paris, France
Pro. Rodney J. Rothstein, PhD, Chairman,
Columbia University, New York, United
States
Pro. Frederick W. Alt, PhD, Howard Hughes
Medical Institute, Chevy Chase, UnitedStates; Harvard Medical School, Boston,
United States
Pro. Bernard Dujon, PhD, Universit Pierre
et Marie Curie (Paris VI) - Institut Pasteur,
Paris, France
Pro. Alain Fischer, MD, Hpital Necker -
Enants Malades, Paris, France
Pro. James E. Haber, PhD, BrandeisUniversity, Waltham, United States
Pro. Denis Pompon, PhD, Center o Mo-
lecular Genetics, Gi-sur-Yvette, France
Pro. Jos-Alain Sahel, MD, Hpital des
Quinze-Vingts, Paris, France
Pro. Luis Serrano, PhD, Center or
Genomic Regulation, Barcelona, Spain
Executive Committee, rom let to right:
SUBSIDIARIES
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28 l Cellectis l Activity Report 2009 l
Cellectis genome surgery
Cellectis genome surgery is dedicated to the development o innovative therapeutic approaches
using meganucleases to treat genetic diseases, cancers and persistent viral inections.
Cellectis genome surgery seeks to treat patients suering rom serious diseases resistant to
conventional treatment. Its prospective therapy targets the very DNA sequence responsible or
the disease. This DNA sequence may be o congenital origin (in the case o genetic disease) or
acquired (in the case o a viral inection or a cancer).
The mission o this subsidiary is to ulll unmet medical needs, giving patients new hope. The
genome surgery approach aims to attack the cause o a disease and cure the patient, rather
than merely treat its symptoms.
In 2009, Cellectis genome surgery took important steps orward, establishing preliminary data
supporting a proo o concept or the antiviral power o meganucleases against HIV, hepatitis
B or herpes viruses, or example.
Since its establishment in June 2008, Cellectis genome surgery has worked together with its
partners academic research groups and clinicians all over the world to transorm its research
into an eective medical treatment.
SUBSIDIARIES
In the last two years, Cellectis has established three
subsidiaries. Their mission is to develop the applications
o our technology each in a given market sector. The
core activity o the company research and development
o the technology, the meganuclease platorm and
the database, as well as intellectual property remain the
central activities o Cellectis.
Genome surgery aims
to attack the cause o a disease
and cure the patient rather than
merely treat its symptoms.Frdric Pques, CSO
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l Cellectis l Activity Report 200 9 l 29
Cellectis bioresearch
Established in 2008, Cellectis bioresearch develops and markets research and production kits
that make genome engineering accessible to biological researchers and companies worldwide.
It oers turnkey solutions, enabling biologists to design their daily work tools with control and
precision, such as cell lines with the eatures o a healthy or diseased organ or tissue.
Cellectis bioresearch commercializes ready-to-use products, designed to attract rst adopters o
the technology with their ease o use.
The kits are a simple and eective means o using Cellectis meganuclease-based technologies,
as they all contain a cell line and a meganuclease. The kits enable a gene to be integrated into
a very precise area o a genome. In 2009, Cellectis launched ve kits and plans to multiply that
number in 2010. The long-term objective is to make the kits universally accepted and used,
integrated as standard genome engineering tools.
The technology has already succeeded in penetrating the industrial market. The current chal-
lenge is to place Cellectis bioresearch products in the majority o the worlds genetic research
laboratories, enabling researchers, technicians and engineers to benet rom meganuclease
technology.
Ectycell
Ectycell was established in September 2009 to research and commercialize industrial uses o
stem cells. The initial goals are to develop:
Tools for generating induced pluripotent stem cells from adult cells
Robust, reproducible differentiation of stem cells
Cell libraries for testing drug candidates
Stem cells can divide or sel-renew indenitely, or dierentiate into many distinct cell types.
They are believed to have the potential to revolutionize medical research and care.
Cellectis core technologies can potentially have a major impact on the stem cell eld. Ectycell is
tackling such key issues as reducing the high attrition rate in drug development by using early-
stage assays that better predict a molecules eect on the organism as a whole or on a genetical-
ly diverse population. Ectycell may also open new paths or regenerative medicine especially
or pathologies like Alzheimers and Parkinsons diseases.
HUMAN RESOURCES AND COMMUNICATIONS
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30 l Cellectis l Activity Report 2009 l
The majority o Cellectis employees work in the companys corporate headquarters in the ParcBiocitech, located near Paris. The state-o-the-art acil ities occupy about 5 ,000 m2 in two buil-
dings, including 3, 700 m2 o lab space. For the purposes o some partnerships, employees are
occasionally assigned to work at academic laboratories.
Cellectis Employees: Our Chie Asset
A large number o employees have been working at the company or a long time, some o
them since its establishment. Almost hal o the frst 30 employees hired at Cellectis are still
with us today.
Two words characterize the Cellectis employee: creative and versatile. Its not the technology
that drives us, but its application. We have and need people who are able to evolve their think-
ing along with the developing technology.
The Team Vision
The team is united by a common goal and vision to improve human health and wellness
through genome engineering. This creates an atmosphere where there is a ree exchange o
ideas. Cellectis osters this team spirit through biannual seminars or all employees and weeklygeneral meetings, where the most recent scientic advances are discussed, as well as many
inormal events.
At the same time, we have a very ambitious recruitment objective: we want to be at the cutting
edge. About 85% o our sta come rom a scientic background. A high proportion o Cellectis
employees have at least a masters degree, 32 members o our sta hold a PhD.
Since our ounding as a startup company with only a hand-
ul o employees (eight by the end o 2000) to end o 2009
with a ull sta o 85, we have ostered an open, nurturing
atmosphere inused with a pioneering spirit. As we continue
to expand, we aim at keeping this pioneering spirit while
providing the best, most efcient work environment possible.
79%
80%
5%
3%
13%63%
25%
18%
Scientic Departments
Business Development
Administration
15%
Sta breakdown by categories
The percentage o people employed inthe scientic departments has increasedin the last three years.
2009
2008
2007
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l Cellectis l Activity Report 200 9 l 31
Making Technological Innovation Happen
Thanks to the innovation, enthusiasm and commitment o our sta, Cellectis has succeeded in
making signicant technological advances in biotechnology, always remaining at the oreront
o its eld.
To encourage the generation o new ideas, we provide many opportunities or our sta to have
discussions with their peers, both in-house and at exterior events. Cellectis employees regularly
attend scientic meetings and seminars, business conventions and nancial conerences. The
agenda o these events is available on our website www.cellectis.com.
Communicating with Our Stakeholders
Besides communicating within the scientic community, we also want to share our enthusiasm
or what we do and communicate it to our various stakeholders. For this purpose, we created a
Communications department in 2009.
By proessionalizing our eorts in this area, we will be better able to explain our work to inves-
tors, industrial partners and the nancial community as well as to other research scientists. An
improved understanding o our activities by our stakeholders will help us, in turn, to carry out
our work within productive partnerships.
The team is united by a
common goal and
vision to improve humanhealth and wellness through
genome engineering.Delphine Jay,Director o Human Resources
Total Female
Number o Employees
00 01 02 03 04 05 06 07 07 08 09
100
80
60
40
20
0
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32 l Cellectis l Activity Report 2009 l
FINANCIAL
STATEMENTS
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l Cellectis l Activity Report 200 9 l 33
1
6
2 3
4
5
1. Free foat 43%
2. Corporate Partners 3% (Regeneron, Monsanto)
3. Institut Pasteur 4%
4. Founders & Management 20%
5. Bus Angel 8%
6. Venture Capitals 22%
Shareholders Breakdown as o Decembre 31, 2009
Share Prices and Capital Structure in 2009
2009
15
12
9
6
2010Apr Jul Oct
100
200
300
0
Share Price Evolution In millions o
100 million market capitalizat ion. About 10,000 share average volume. NYSE-Euronext ACLS.PA
Share Volume Evolution in thousands o shares
FINANCIAL STATEMENTS
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34 l Cellectis l Activity Report 2009 l
Figures in thousands o euros December 31, 2009 December 31, 2008
Net intangible assets 16 17
Gross values 2 878 3 177
Depreciation, amortization and impairement losses (1 990) (1 741)
Net tangible assets 888 1436
Investment in other equity 0 0
Other non-current nancial assets 231 230
Non-current fnancial assets 231 230
Deerred tax assets 10 438 7 365
Total non-current assets 11573 9048
inventories 118 121
Trade receivables 1 761 722
Current tax assets 3 082 2 891
Other current assets 1 622 2 074
Cash & cash equivalents 45 595 28 723
Total current assets 52178 34531
TOTAL ASSETS 63751 43579
Balance Sheet Assets
Net tangible assets gures refect a nancing policy to use leasing extensively. The company
operates a large pool o robots representing an initial value o over6 million but this has been
ully nanced over a three-year period by two banks (BNP Paribas and DLL).
Deerred tax assets relate to accumulated losses, which can be indenitely deducted rom earn-
ing beore tax.
The cash position at the end o the period has improved by almost 60% compared to the end
o 2008 (45.6 million compared to 28.7 million).
Financial items are presented
according to IFRS
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l Cellectis l Activity Report 200 9 l 35
Equity was strengthened at the end o fscal year 2009, amounting to over 51 million on
December 31, 2009, compared to 33 million on December 31, 2008.
The company has a limited amount o debt (1.8 million at the end o 2009). This debt rep-
resents a set o reimbursable advances granted by the French government innovation agency
OSEO. These advances are to be reimbursed only i a series o ongoing research programs reach
commercial success.
The total current liabilities increased by less than 20% between the end o 2008 and the end
o 2009, demonstrating managements ability to grow the company while managing cash e-
ectively.
Balance Sheet Liabilities
Figures in thousands o euros December 31, 2009 December 31, 2008
Share capital 582 479
Share premium and reserves 54 375 32 583
Net income/ loss o the year (3 852) 123
Equity 51105 33185
Retirement benet obligation 42 32
Other nancial liabilities 1 826 1 304
Total non-current liabilities 1868 1336
Short term provisions 71 88
Trade payables 4 731 5 372
Other current liabilities 5 975 3 598
Total current liabilities 10778 9058
TOTAL EQUITY & LIABILITIES 63751 43579
Financial items are presented
according to IFRS
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36 l Cellectis l Activity Report 2009 l
Total operating revenues increased by about 14% between 2008 and 2009. Importantly, 2009
revenues were impacted signifcantly by several deals (Limagrain, Monsanto, Bayer Healthcare,
BASF Plant Science) and existing contracts, whereas 2008 revenues were driven primarily by asingle contract (over7 million rom Regeneron Pharmaceuticals) representing nearly 70% o
total operating revenues.
Total operating expenses increased almost 50% between 2008 and 2009, rising rom 14 mil-
lion to20.8 million. Approximately2.5 million in expenses related to preclinical activities that
were outsourced, including pre-GMP batch manuacturing and GLP preclinical testing. About
2.5 million was attributable to expenses and success ees relating to intellectual property mon-
etization.
The headcount went rom 68 at the end o 2008 to 85 at the end o 2009, resulting in a 30%increase in personnel expenses.
Proft & Loss
Figures in thousands o euros2009
12 months2008
12 months
Sales 11 951 10 600
Other revenues 136 10
Total operating revenues 12 088 10 610
Purchases consumed (1 623) (1 111)
Personnel costs (5 564) (4 298)
Other operating expenses (12 425) (8 149)
Tax (870) (222)
Amortization (342) (348)
Provisions 0 60
Total operating Expenses (20 825) (14 068)
Current operating income/loss (8 737) (3 458)
Other non-current income & expenses (683) 0
Operating income/loss (9 420) (3 458)
Cash & cash equivalent income 1 248 812
Cost o fnancing, gross (6) (10)
Cost o fnancing, net 1 242 802
Other fnancial income & expenses 0 v 0
Income tax 4 327 2 779
Net operating income/loss (3 852) 123
NET INCOME OF THE YEAR (3 852) 123
Financial items are presented
according to IFRS
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l Cellectis l Activity Report 200 9 l 37
Operating activities consumed approximately 5 million in 2009, compared to a 1.4 million
generation in 2008. This refects a signicant eort by the company to accelerate the develop-
ment o meganuclease-based products downstream in the value chain: preclinical activities and
research kit development were a primary ocus o Cellectis investments in 2009.
Overall Cellectis strengthened its cash position by almost 17 million year on year, increasing
rom 28.7 million at the end o 2008 to 45.6 million at the end o 2009.
Cash Flow Statement
Figures in thousands o euros 2009 2008
Net income/ loss o the year (3852) 123
Change in amortizations & provisions 257 288
Change in taxes payable (3 073) (882)
Change in other operating assets and liabilities 289 202
Change in working capital 1 459 1 707
Net cash provided (used) by operating activities (4920) 1432
Acquisition o intangible assets (18) (21)
Acquisition o tangible assets (480) (555)
Acquisition o nancial assets (1) (236)
Net income orm sale o tangible assets 720 0
Net cash provided (used) by investing activities 221 (812)
Repayment o long-term borrowings (268) (157)
Proceeds rom issuance o common stock 21 839 3 063
NET CASH PROVIDED (USED) BY FINANCING ACTIVITIES 21571 2906
Change in cash & cash equivalents 16872 3526
Opening cash and cash equivalents 28 723 25 197
Closing cash and cash equivalents 45 595 28 723
CHANGE IN CASH & CASH EQUIVALENTS 16872 3526
Financial items are presented
according to IFRS
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Cellectis
Contact:Cellectis102 avenue Gaston Roussel93230 RomainvilleFranceTel: +33 (0)1 41 83 99 [email protected]
Photo copyright:Cdric PorchezInstitut Pasteur(Jean Pierre Dacbert/Cabinet Dacbert)
Ramon MartinezCellectisKarim DaherBiocitechiStockphotoGetty ImagesMichle Paquier
Graphic Designer:Valentina Herrmann
Redaction and layout support:Avec des Mots
Printer:GraphiCentre
This report was printed with vegetal inkson PEFC certied paper
Cellectis makes available on its website(www.cellectis.com) the legal and nancialinormation, including in particular it sannual accounts and semi-annual report,required to be made available to thepublicpursuant to article 221-1 o the rules o
the French Autorit des marchs nanciersand article 4 o the rules o the Alternextmarket o NYSE Euronext Paris.
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MADE BY CELLECTIS
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