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CORPORATE OVERVIEW
iBio is a biotechnology company focused on commercializing their proprietary
technologies and product candidates as well as providing product development and
manufacturing services to clients and collaborators. The Company’s technologies
constitute a proprietary, transformative platform for development and production of
biologics in hydroponically grown green plants.
Stated simply, iBio’s technologies harness the natural protein production
capability that plants use to sustain their own growth, and direct it instead to
produce proteins for a range of applications including for vaccines and
biopharmaceuticals. Through this methodology, the Company can produce a wide
assortment of products at greatly reduced manufacturing costs.
The Company’s technologies can be used to produce a wide array of biologics and
also to create and produce proprietary derivatives of preexisting products with
improved properties. The Company has used its technologies and its collaborative
relationships to demonstrate the applicability of its technologies to a diverse range
of product candidates including products against fibrotic diseases, vaccines, enzyme
replacements, monoclonal antibodies, and recombinant versions of marketed
products that are currently derived from human blood plasma.
In addition to the broad array of biological products that can be produced with the
Company’s technologies we believe their technologies offer other advantages that
are not available with conventional manufacturing systems. These anticipated
advantages include reduced production time and lower operating costs. Additionally,
it is expected that the capex for a plant based manufacturing facility will be
dramatically lower than a comparable facility using conventional manufacturing
processes.
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BUSINESS STRATEGY
The near-term focus of iBio is to realize two key objectives: (1) the establishment
of additional business arrangements pursuant to which commercial, government
and not-for-profit licensees will utilize the Company’s technologies in connection
with the development and manufacturing of therapeutic proteins and vaccine
products; and (2) the further development of select product candidates based
upon or enhanced by their technology platforms. These objectives are the core
components of their strategy to commercialize the proprietary technologies they
have been developed and validated.
The Company’s strategy to engage in partnering and out-licensing of their
technologies seeks to preserve the opportunity for iBio to share in the successful
development and commercialization of product candidates by licensees while
enhancing their own capital and financial resources for development, alone or
through commercial alliances with others, of high-potential product candidates
based upon their technologies. In addition to financial resources they may receive in
connection with the license of their technologies, we believe that successful
development by third party licensees of iBio technology-enhanced product
candidates will further validate their technologies, increase awareness of the
advantages that may be realized by the use of such platforms and promote broader
adoption of their technologies by additional third parties.
The advancement of iBio technology-enhanced product candidates is a key element
of their strategy. We believe that selecting and developing products which
individually have substantial commercial value and are representative of classes of
pharmaceuticals that can be successfully produced using their technology platforms
will allow them to maximize the near and longer term value of their technologies
while exploiting individual product opportunities. To realize this result, the
Company is currently internally advancing through preclinical IND enabling studies
a proprietary recombinant protein we call IBIO-CFB03 for treatment of idiopathic
pulmonary fibrosis, systemic sclerosis, and potentially other fibrotic diseases.
iBio intends to perform their contract manufacturing through their 70% owned
subsidiary, iBio CMO LLC (“iBio CMO”). On January 13, 2016, the Company
entered into a contract manufacturing joint venture with an affiliate of Eastern
Capital Limited. The Eastern Affiliate contributed $15 million in cash for a 30%
interest in iBio CMO. The Company retained a 70% interest in iBio CMO and
contributed a royalty bearing license which grants iBio CMO a non-exclusive license
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to use their proprietary technologies for research purposes and an exclusive U.S.
license for manufacturing purposes. We retained the exclusive right to grant product
licenses to those who wish to sell or distribute products made using their technology.
iBio CMO’s operations take place in Bryan, Texas in a facility controlled by another
affiliate of Eastern as sublandlord. The facility is a Class A life sciences building on
the campus of Texas A&M University, designed and equipped for plant-made
manufacture of biopharmaceuticals. iBio CMO was granted a 34-year sublease for
the facility. Commercial operations commenced in January 2016. iBio CMO
operates on the basis of three parallel lines of business: (1) Development and
manufacturing of third party products; (2) Development and production of iBio’s
proprietary product(s) for treatment of fibrotic diseases; and (3) Commercial
technology transfer services.
Proprietary iBio technologies have been used to advance development of certain
products that have been commercially infeasible to develop with conventional
technologies such as Chinese hamster ovary cell systems and microbial fermentation
methods. They can be used to create and operate manufacturing facilities at
substantially lower capital and operating costs. These include development and
manufacture of both vaccine and therapeutic product candidates. iBio CMO plans to
promote commercial collaborations with third parties on the basis of these
technology advantages and to work with customers to achieve laboratory scale
technical milestones that can form the basis of longer-term manufacturing business
arrangements. iBio itself will be a client of iBio CMO for further IND advancement
of its proprietary products beginning with IBIO-CFB03 for the treatment of a range
of fibrotic diseases. iBio will work with iBio CMO on the production of IBIO-
CFB03 for clinical trials and, with clinical success, for commercial launch.
Due to the lower capital and operating cost requirements for pharmaceutical
production via iBio technology versus legacy methods, certain corporations and
governments that have not already established manufacturing capacity for biologic
products are client prospects for both development and for commercial technology
transfer services to enable autonomous manufacturing in the market being served.
For example, in Brazil, iBio has been collaborating with the Oswaldo Cruz
Foundation (Fiocruz) to develop a recombinant yellow fever vaccine based on iBio
technology. iBio’s contract with Fiocruz provides for commercial technology
transfer services as the product candidates enters human clinical trials. Over time,
iBio expects to work closely with iBio CMO to provide such technology transfer
services for a variety of both commercial and government clients.
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MANAGEMENT TEAM
ROBERT B. KAY
Executive Chairman and Chief Executive Officer
Mr. Kay is an accomplished business strategist and senior manager with extensive
M&A, JV, and international licensing experience. Mr. Kay was a founder and senior
partner of the New York law firm of Kay Collyer & Boose LLP, with a particular
focus on cross-border mergers and acquisitions and joint ventures. Previously, Mr.
Kay served as a director for Genesys S.A. (West Corporation French subsidiary). He
received his B.A. from Cornell University's College of Arts & Sciences and his J.D.
from New York University Law School.
ROBERT L. ERWIN
President
Mr. Erwin previously led Large Scale Biology Corporation from its founding in
1988 through 2003, including a successful initial public offering in 2000, and
continued as non-executive Chairman until 2006. Mr. Erwin recently served as
Managing Director of Bio-Strategic Directors LLC providing consulting services to
the life sciences industry. He served as Chairman of Icon Genetics AG from 1999
until its acquisition by a subsidiary of Bayer AG in 2006. He is currently Chairman
of Novici Biotech, a private biotechnology company and a Director of Resolve
Therapeutics LLC. Mr. Erwin's non-profit work focuses on applying scientific
advances to clinical medicine, especially in the field of oncology. He is co-founder
and President of the Marti Nelson Cancer Foundation, and a member of the Cancer
Policy Forum of the Institute of Medicine. Mr. Erwin received his B.S. degree with
Honors in Zoology and an M.S. degree in Genetics from Louisiana State University.
TERENCE E. RYAN, PHD
Chief Scientific Officer
Dr. Ryan is a pharmaceutical and biotech research leader who is highly
accomplished in recombinant protein expression, and also has a record of innovation
in cell biology, proteomics, and systems biology. His distinguished 20-year career
includes working for such industry leaders as Wyeth (Pfizer) Research,
GlaxoSmithKline, Celera Genomics, and Regeneron Pharmaceuticals. Dr. Ryan
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holds an MS and PhD in Microbiology from Rutgers University, and received his
AB in Biology from Princeton University.
DOUGLAS C. HICKS
Senior Vice President, Business Development & Strategy
Douglas Hicks is the Vice-President, Business Development for iBio, Inc. Mr. Hicks
has over fifteen years of operational, financial, and administrative experience within
both small and large businesses. He has primarily focused on business development,
corporate planning, and strategy execution within the biotechnology,
pharmaceutical, and private equity segments. Prior to joining iBio in 2010, Mr.
Hicks was with Clearview Projects, Inc., a strategic advisory firm which provides
business development, product alliance, and strategic advice to the pharmaceutical
and biotechnology industry. Mr. Hicks joined Clearview when the firm was formed
in 2001 and has held various roles of increased responsibility over his 10 year tenure
with the firm, most recently as Executive Director of Business Development and
Strategic Analysis. While at Clearview, he participated in over thirty-five strategic
transactions across various therapeutic areas. Before joining Clearview, Mr. Hicks
was a consultant at Bristol-Myers Squibb. Mr. Hicks received his MBA from The
Pennsylvania State University, with a focus on finance and strategy.
MARK GIANNONE
Chief Financial Officer
Mr. Giannone has been a member of the accounting firm of Bosco Giannone LLC
since its formation in 1999. His prior experience included employment as a senior
accountant at Kenneth Leventhal & Co. (acquired by Ernst &Young LLP) and as a
tax manager at BDO Seidman, a lecturer in various continuing education programs
for the New York State Society of Certified Public Accountants and New York
University.
WAYNE P. FITZMAURICE, PH.D.
Vice President, Intellectual Property
Dr. Fitzmaurice has extensive experience in plant biotechnology research, and is a
USPTO certified Patent Agent. He led research teams at Biosource Technologies
(later Large Scale Biology Corp.) for 15 years from 1992 to 2007 ultimately holding
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the position of Senior Director of Plant Biology and Pharmaceutical Development.
He is a founding partner of Novici Biotech, and functions as their Senior Director of
Intellectual Property. With Novici he is on key patents as both an inventor and a
prosecuting patent agent. He also acted as an independent consultant in
biotechnology intellectual property for several corporations. Dr. Fitzmaurice
received a Ph.D. in Biochemistry from The Johns Hopkins University, and did
postdoctoral research at the University of Wisconsin-Madison and North Carolina
State University.
BOARD OF DIRECTORS
ROBERT B. KAY
Executive Chairman and Chief Executive Officer
Mr. Kay is an accomplished business strategist and senior manager with extensive
M&A, JV, and international licensing experience. Mr. Kay was a founder and senior
partner of the New York law firm of Kay Collyer & Boose LLP, with a particular
focus on cross-border mergers and acquisitions and joint ventures. Previously, Mr.
Kay served as a director for Genesys S.A. (West Corporation French subsidiary). He
received his B.A. from Cornell University's College of Arts & Sciences and his J.D.
from New York University Law School.
GLENN CHANG
Director
Mr. Chang is Director, Executive Vice President and Chief Financial Officer of First
American International Bank of Brooklyn, N.Y. Prior to the founding of the Bank in
1999, he spent almost 20 years at Citibank as Vice President. Mr. Chang is a
Certified Public Accountant.
ARTHUR Y. ELLIOTT, PHD
Director
Dr. Elliott is a distinguished infectious disease and vaccine manufacturing and
licensing expert whose career includes 16 years with Merck & Co., serving
ultimately as Executive Director of Biological Operations, Merck Manufacturing
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Division, responsible for the bulk manufacture, testing, release and registration of
all biological products sold. Dr. Elliott continues to serve as Senior Program
Manager for the Antigen Sparing Project for the United States Department of Health
and Human Services in the Avian Influenza Pandemic Preparedness Program in
Washington, D.C., (since 2006), and is a member of the American Association for
Advancement of Science, American Society for Microbiology, and American Tissue
Culture Association. Dr. Elliott holds a PhD in Virology from Purdue University,
and an M.S. in Microbiology and a B.A. in Biology from North Texas State
University.
GENERAL JAMES T. HILL, USA (RET.)
Director
At the time of his retirement from active duty, General Hill was the Commander of
the United States Southern Command, reporting directly to the President and the
Secretary of Defense. As such he led all U.S. military forces and operations in
Central America, South America and the Caribbean, and worked directly with U.S.
Ambassadors, foreign heads of state, key Washington decision-makers, foreign
senior military and civilian leaders, developing and executing United States policy.
General Hill is President of The JT Hill Group, a consulting firm and serves on the
boards of Fraunhofer USA, Inc and The Protective Group, providers of personnel
protective equipment.
JOHN D. MCKEY, JR.
Director
Mr. McKey has served as of counsel at McCarthy, Summers, Bobko, Wood, Sawyer
& Perry, P.A. in Stuart, Florida since 2003, and previously was a partner from 1987
through 2003. From 1977 to 1987 Mr. McKey was a partner at Gunster Yoakley in
Palm Beach, Florida. Mr. McKey received his B.B.A at the University of Georgia
and his J.D. from the University of Florida College of Law.
PHILIP K. RUSSELL, M .D.
Director
Major General (ret.) Philip K. Russell, M.D. served in the U.S. Army Medical Corps
from 1959 to 1990, pursuing a career in infectious disease and tropical medicine
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research. Following his military service, Dr. Russell joined the faculty of Johns
Hopkins University's School of Hygiene and Public Health and worked closely with
the World Health Organization as special advisor to the Children's Vaccine
Initiative. He was founding board member of the International AIDS Vaccine
Initiative, and is an advisor to the Bill and Melinda Gates Foundation. He has served
on numerous advisory boards of national and international agencies, including the
Centers for Disease Control, National Institutes of Health, and the Institute of
Medicine. He is the past Chairman of the Albert B. Sabin Vaccine Institute.
SEYMOUR FLUG
Director
Mr. Flug was Chairman of the Board and CEO of Diners Club International and a
managing Director of Citibank. Prior to that, he was Senior Vice President of Hess
Oil Company. He began his career as a CPA with the accounting firm of Deloitte &
Touche.
TECHNOLOGY
THE IBIO TECHNOLOGY IS A UNIQUE PLANT-BASED PLATFORM THAT
ACCELERATES THE DEVELOPMENT AND MANUFACTURING OF HIGH LEVELS OF
TARGET PROTEIN
❖ iBio scientists engineer vectors containing the target sequence within a viral replicon
❖ The vector is transferred to an AGROBACTERIUM host that efficiently introduces
target DNA to the plant cell nucleus.
❖ The viral replicon directs the production of large amounts of target-specific messenger
RNA in plant cells, which is translated into protein by the plant’s own machinery for
several days.
❖ Once the plants have been infiltrated with agrobacteria, the viral sequences of the launch
vectors, along with the cloned target sequences, are massively amplified through the
action of virally encoded enzymes.
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Translation of these recombinant viral vector mRNAs can result in the accumulation of
gram quantities of target protein per kilogram of fresh plant tissue in less than a week.
❖ The plants accumulate high levels of target protein in their leaf and stem tissue.
This expression of recombinant protein is termed “transient” expression because the
target gene sequence is expressed as protein for a fixed period of time, and the foreign
genes are not incorporated into the plant chromosome to result in the creation of
transgenic plants.
❖ The plant biomass is harvested, homogenized, and clarified to produce an extract
containing the protein of interest.
Proteins are further purified as required using conventional separation and
chromatography steps widely used in the biopharmaceutical industry.
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FAST DEVELOPMENT AND PRODUCTION
The iBio Technology dramatically speeds up drug development and production.
Due to entire plants not being required to be genetically modified, accelerated production and
development is possible. By using non-GMO plants as manufacturing platform, the iBio
Technology process eliminates the months or years needed by technologies using mammalian
cells to find a high-producing, stable cell clone that can be expanded into the trillions of daughter
cells required for manufacturing useful amounts of a drug.
USING THE IBIO TECHNOLOGY, A NOVEL PROTEIN PRODUCT CAN BE
PRODUCED AT FACTORY SCALE IN UNDER A MONTH
Once a desired gene is cloned into the iBio Technology vectors, it is introduced into the leaves of
the plants by automated vacuum infiltration technology. Over the next 4-7 days, special features
of the proprietary vectors ensure the gene spreads to every cell in the stems and leaves where the
desired protein is expressed at extremely high levels.
FLEXIBLE TECHNOLOGY ALLOWS FOR AGILE PRODUCTION
Since the growth of plants and introduction of the iBio Technology vectors is the same
regardless of the desired product, a facility using the iBio Technology system can easily produce
multiple proteins in the same facility without physical reconfiguration.
BIOTHERAPEUTICS
TREATING FIBROTIC DISEASES WITH IBIO-CFB03
iBio’s proprietary therapeutic product, IBIO-CFB03, is intended to treat systemic scleroderma,
idiopathic pulmonary fibrosis (IPF), and other fibrotic diseases.
iBio has produced the active pharmaceutical ingredient using its patented iBio Technology and
has made the clinical development of this promising product a key priority.
COLLABORATING WITH DR. CAROL FEGHALI-BOSTWICK AT THE MEDICAL
UNIVERSITY OF SOUTH CAROLINA
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Data published in 2012 by Dr. Feghali-Bostwick demonstrates that specific endostatin-derived
peptides are useful for both in inhibition and reversal of fibrosis in preclinical mouse models of
fibrosis as well as in human skin.
• WHAT IS ORGAN FIBROSIS?
• WHAT IS SYSTEMIC SCLERODERMA?
• WHAT IS IPF?
IBIO TECHNOLOGY BENEFIT: MONOCLONAL ANTIBODIES
Monoclonal antibodies are usually manufactured in engineered mouse or hamster cells, but they
can be manufactured at a significantly lower cost in whole plants using the iBio Technology.
Production of monoclonal antibodies in plants results in high yields of biologically active
antibody without contaminating animal cell products. In addition to antibody therapies for
chronic disease, monoclonal antibodies have been developed to treat infectious diseases.
The iBio Technology expression platform has produced a monoclonal antibody that protects
against respiratory anthrax in a non-human primate model, as well as an anti-influenza
neuraminidase monoclonal antibody that is active against Tamiflu™-resistant virus strains.
IBIO TECHNOLOGY BENEFIT: REPLACEMENT PROTEINS FROM HUMAN BLOOD
Many proteins have been purified from human blood or plasma to compensate for genetic defects
in individuals who cannot make these proteins for themselves. As was seen in the case of
hemophilia, patients receiving replacement proteins purified from blood or plasma run the risk of
infection from viruses or other pathogens found in blood. Because of this risk, clotting factors for
hemophiliacs are now supplied as recombinant proteins manufactured from engineered animal
cells; however, there are still several genetic diseases for which the current source of
replacement protein therapy continues to use human blood or plasma as the starting material.
Production of these replacement proteins using the iBio Technology would remove this risk of
disease transmission, since the technology uses no animal cells or animal products, and there is
no risk of transmission of viruses to patients from plant material.
IBIO TECHNOLOGY BENEFIT: ENZYME REPLACEMENT THERAPY
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The iBio Technology plant expression system can dramatically lower the cost of important
recombinant proteins used in enzyme replacement therapy for certain genetic disorders, putting
these life-saving treatments in easier reach of patients. In addition, supply disruptions resulting
from problems with complex cell-based manufacturing methods, such as the recent shortages of
some replacement therapies caused by viral contamination of the recombinant protein
manufacturing process, would be obviated by the adoption of iBio’s plant expression technology.
Human viral pathogens cannot replicate in plant cells, and no human or animal components are
used in the iBio Technology process, providing an additional product safety and production
reliability margin.
VACCINES
IBIO TECHNOLOGY IS THE MANUFACTURING PLATFORM OF CHOICE WHEN
RAPID RESPONSE TO PANDEMIC THREATS IS PARAMOUNT
Vaccines are increasingly being developed from recombinant proteins representing highly
immunogenic proteins of the natural pathogen. In contrast to earlier vaccine technologies which
used killed or weakened pathogens to stimulate an immune response, the newer "subunit"
vaccines offer an improved safety profile, as well as the potential for a significantly simplified
manufacturing and quality process. The iBio Technology delivers the improved safety and
manufacturing profile demonstrated with subunit vaccines, but unlike competitor technologies,
iBio's extremely rapid gene sequence-to-manufacturing timeline (as little as one month) makes
the iBio Technology the manufacturing platform of choice when rapid response to pandemic
threats is paramount.
Hookworms are parasitic nematodes that cause anemia and child development complications in
infected individuals, most commonly in tropical and subtropical environments. iBio Technology
is being used to produce a vaccine antigen to an enzyme found in the gut of the hookworm.
Antibodies to this gut enzyme block its action, which normally acts to break down hemoglobin in
the blood as a source of iron for the hookworm. When this gut enzyme is blocked, the hookworm
dies, allowing infected patients to resume a healthier life. The antigenic form of this hookworm
gut enzyme has proven to be impossible to manufacture efficiently using bacterial, yeast, or
animal cell expression systems. However, commercially useful amounts of the antigen can be
manufactured using the iBio Technology plant expression technology, and development of a
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vaccine in partnership with the Sabin Vaccine Research Institute is proceeding towards human
safety and efficacy studies.
IBIO TECHNOLOGY OFFERS A BREADTH OF APPLICATION THAT IS UNMATCHED
The iBio Technology expression platform has been used to manufacture vaccine candidates that
represent a broad range of viral, bacterial and parasitic threats to human health. The technology
has been used to successfully produce vaccine components that could not be manufactured using
bacterial, yeast or animal cell expression systems, demonstrating a breadth of application that is
unmatched.
Each of these vaccines is available to be licensed from iBio along with the iBio Technology
manufacturing platform, providing a turnkey entry into vaccine development and manufacturing.
• YELLOW FEVER • INFLUENZA
• MALARIA
• HOOKWORM
• HUMAN PAPILLOMA VIRUS
• BACTERIAL PATHOGENS
IBIOMODULATOR
IBIOMODULATOR IMPROVES EFFECTIVENESS OF A VACCINE AGAINST
HPV16
The E7 transforming gene of human papilloma virus has been implicated in the maintenance of
HPV in keratinous tissues and their oncogenic transformation in cervical cancers. Fusions of E7
and a less-transforming mutant form (E7GGG) were made in the lichenase surface loop and
compared with native, unfused E7 and E7GGG as vaccines. Since there is no cell culture or
animal model of HPV infection, E7-transformed mouse TC-1 cells serve as a surrogate tumor
model for HPV infections and cancers.
Vaccines (+/-adjuvant) were evaluated for their ability to prevent implantation and growth of
TC-1 tumors (prophylaxis), and for their ability to induce immunity that reduces existing TC-1
tumors and extends survival.
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Fusion of iBiomodulator with the E7GGG or E7 antigens completely prevented the
establishment of E7 expressing TC-1 cell tumors in mice, showing that an effective prophylactic
vaccine for HPV-16 can be produced in plants. In addition, the E7 antigens fused to
ibioModulator completely protected mice from prior administration of HPV tumorigenic cells,
indicating that therapeutic vaccination could provide a treatment option for already-established
cervical tumors. In both prophylactic and therapeutic mode, E7 antigens administered without
being fused to iBioModulator failed to completely protect the mice from tumors and tumor-
related death.
IBIOMODULATOR IMPROVES ANTIBODY TITERS AND EXTENDS
PROTECTION IN VACCINES
In a transmission-blocking vaccine for malaria, fusion of iBioModulator with the Pfs25 antigen
of Plasmodium falciparum resulted in a 10-fold increase in antigen-specific IgG when compared
to native (unfused) Pfs25. In addition, in the standard oocyte membrane-feeding assay for
transmission blocking antibodies, fusion of Pfs25 with iBioModulator reduced the dose of
vaccine required for complete transmission-blocking activity five-fold, and provided longer
protection after immunization.
IBIO-CFB03
PROPRIETARY FIBROSIS DRUG THAT HAS BREAKTHROUGH POTENTIAL.
iBio, in collaboration with Dr. Carol Feghali-Bostwick of the Medical University of South
Carolina, is developing a proprietary therapeutic product for the treatment of systemic
scleroderma with potential application to idiopathic pulmonary fibrosis (IPF) and other fibrotic
diseases.
PRECLINICAL DATA FOR IBIO-CFB03 INDICATES ABILITY TO STOP OR EVEN
REVERSE FIBROSIS
Data published in 2012 by Dr. Feghali-Bostwick demonstrate that specific endostatin-derived
peptides are useful for both inhibition and reversal of fibrosis in preclinical mouse models of
fibrosis, as well as in human skin.
iBio has produced the active pharmaceutical ingredient using its patented iBio Technology and
has made the clinical development of this promising product a key priority.
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MARKET NEED
WHAT IS SYSTEMIC SCLERODERMA?
Systemic Scleroderma is a disorder that affects
connective tissue of skin and internal organs as well
as the walls of blood vessels. Early diagnosis and
individualized therapy can be helpful, but treatment
of systemic scleroderma is limited to symptom
management. No currently-approved drug has been
proven to arrest the underlying process or processes
that drive progression of the disease.
KEY FIGURES
123,000 - 245,000
PREVALENCE OF SYSTEMIC
SCLERODERMA IN US & EU
European Respiratory Review, 2012
__________________________________________________________________________
WHAT IS IDIOPATHIC PULMONARY
FIBROSIS (IPF)?
Idiopathic pulmonary fibrosis is a life-shortening
lung disease with a rapidly progressing negative
impact on quality of life leading to death within an
average of three to five years after diagnosis
KEY FIGURES
44-88K PREVALENCE OF IPF IN US
~188K PREVALENCE OF IPF IN EU
European Rrespiratory Review, 2012
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