Montreal 2017

Harnessing the power of nature to

address global challenges

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Our world is facing many sustainability challenges

Limited resources, a changing environment, the evolution of disease and a continuous growth in population…

… but what if we could harness the power of nature to solve these global challenges

Sources: Center for Disease Control; United Nations; United Network for Organ Sharing; U.S. Energy Information Administration

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Illumina led the genome reading revolution, SGI will lead writing

Reading DNA

Inexpensive

access to

massive

amounts of

genomic data

Notes: 1 Cost of sequencing a human genome — NHGRI; 2 Cost of synthesizing one gene per base pair (curve is illustrative and represents estimate) – Rob Carlson (synthesis.cc)

$0.001

$10

$1

$0.1

$0.01

Moore’s Law2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Reading: Gene sequencing 1

$1B

Writing: Gene synthesis 2

$100M

$10M

$1M

$100K

$10K

$1K $0.00001

$0.0001

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Nature’s DNA-based operating system controls life

Transcription Translation

DNA RNA RNA Protein

DNAThe genome is the operating

system of life

mRNA ProteinControls the function of life

● Messengers

● Antibodies

● Enzymes

● Transporters

● Structure

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The next chapter in genomics — Writing genomic information

Reading

genomic

information

Designing

and building

biological

systems

Better, cheaper, faster

IMPROVE EXISTING PRODUCTS

Novel solutions

CREATE AND COMMERCIALIZE NEW PRODUCTS

Vaccines

Biologics

Bio-based chemicals

Nutritional supplements

Sustainable fuels

Insect resistant crops

Transplantable organs

DNA assembly instruments

Targeted medicines

Novel reagents

SGI is translating genomic understanding into sustainable solutions

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Synthetic Genomics Inc. and a history of “world’s first” innovations

2010

Company founded

in 2005

20152005

First genome

transplanted

First bacterial

genome synthesized

Isothermal DNA assembly

First synthetic cell created 1

Synthetic flu

vaccine

Automated DNA, RNA, and

protein production

Genome transplant across

multiple cell platforms

First minimal

cell 1

= Direct commercial opportunities

= Platform technologies enabling future applied products

Engineered phage

Notes: 1 Done in collaboration with JCVI

J. Craig Venter, Ph.D.

Chairman, Co-Chief

Science Officer

Hamilton O. Smith, M.D.

Co-Chief Science Officer

The Nobel Prize in Physiology or Medicine 1978

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syn3.0

minimal cell

Genome design

principles

Minimization

rules

Defragmentation

rules

Gene

function

Selected SGI “world’s firsts” 2007: Synthesis of bacterial genome

2010: Synthetic cell

2016: Minimal cell

World’s first science lays the foundation for rational genome writing

syn3.0 has 531 thousand

base pairs of DNA

syn1.0

syn3.0

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Integrated bioinformatics and visualization platform

SGI’s core technology enables sophisticated genome writing at scale

Access to

biological diversity

Select advantaged

organismDesign in silico Precisely cut DNA Build DNA

Precisely insert

DNATest for function

1 2 3 4 5 6 7

Viral Heterotrophic Phototrophic MammalianBio

log

ical co

mp

lexit

y

11 kb

60 Mb

245 Mb

2.7 Gb

Part

ners

hip

s

Synthetic

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Writing genomes to address sustainability challenges from industrial to healthExisting strategic partnerships with an increasing focus on health care applications

Algal protein

Omega-3

oils

Renewable

chemicals

Bio-based

intermediates

Plant

protection /

enhancement

Algal

biodiesel

Flu

vaccines

Biologics

Organ

transplant

Immuno-

therapy

RNA platform

Dietary

supplements

Food

ingredients

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Sustainable omega-3 nutritional oil

Programmable vaccine development

Engineered pigs as organ donors for humans

Novel production systems for biologics

“Printing” biology and changing medicine manufacturing

Examples of Synthetic Genomics technology in action

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Providing sustainable, cost-effective nutritional oil

MARKET OPPORTUNITY = $7.5 BILLION IN 2021 1

Sources: 1 Researchandmarkets 2015

Omega-3 DHA

oil

=Essential fat that

supports brain, eyes,

heart health

CONVENTIONAL SOURCE: FISH OIL

NOVEL SOURCE: MICROALGAL OIL

Highly omega-3 DHA-

producing algae

• Biodiscovery

• Isolation

• Domestication

• Evolution of natural strains

• Process development

● Controlled and sustainable production

● Vegetarian source

● No contamination or fish allergen

Affected by over-fishing

and El Nińo

Maybe contaminated with

heavy metals

May contain fish

allergen

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Directed evolution resulting in improved DHA productivity, titer and product quality

24.6% 30.4%39.5% 43.8%

0%

20%

40%

60%

80%

100%

WH5554 NH5783 NH6181 NH6329

%FAME

DHA DPA Palmitate Myristate Other

DH

A P

rod

uc

tivit

y g

L-1

hr-1

DH

A T

ite

r g

L-1

WT isolate

Strain 1

Strain 2

Strain 3

Strain 4

WT isolate

Strain 1

Strain 2

Strain 3

Strain 4

WT isolate

Strain 1

Strain 2

Strain 1 Strain 2 Strain 4 Strain 3

• Improved DHA Productivity

• DHA titer (5X improvement)

• Product quality (1.8X DHA/FAME improvement

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Faster development of flu vaccineMore rapid outbreak response, higher precision

Identify flu

virus strainsCreate safe strain Inject into eggs (random

results)

Harvest, purify & screen

for the right antigen

Vaccine seed

produced

MARKET SIZE = $4 BILLION 1

CONVENTIONAL METHODOLOGY

SYNTHETIC VACCINE SEED POWERED BY SGI TECHNOLOGY

Antigen

35

days

5

days

Synthetic DNA containing

desired traits

Transfected into mammalian

cells

Vaccine seed produced• Genome sequence

• Data analytics

• Bio-design tools

• Scaled genetic assembly / synthesis

• Genome editing

Sources: 1 CSL in GEN 10/14

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Emerging RNA platform data confirms the potential of SGI’s novel approach

Multigenic and tunable

Consistent protein expression

0

0.5

1

1.5

2

2.5

3

3.5

4

Q1 2016 Q2 2016 Alphavirus

0 1 2 3 4

NSP Protein15’ 3’AA…A

NSP Protein15’ 3’AA…A

Protein2

NSP Protein15’ 3’AA…A

Protein2 Protein3

Mono

Bi

Tri

0 1 2 3 4

NSP Protein35’ 3’AA…A

Mono

Tri

NSP Protein15’ 3’AA…A

Protein2 Protein3

102 103 104 105 106

102 103 104 105 106

High levels of protein expression Platform with increased safety and efficacy

Re

lati

ve

un

its

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The challenge

“SGI-inside” to enable pig-to-human organ transplantation

Source: 1https://optn.transplant.hrsa.gov/

0

20,000

40,000

60,000

80,000

100,000

120,000

Nu

mb

er

of

org

an

s

2003 2009 2015

U.S. organ demand, transplants and donors1

In 2015, organ demand

exceeded supply by ~90,000 organs

● SGI engineers pig cell to be implanted at United

Therapeutics to grow into organ donor pig

● Leveraging SGI expertise:

‒ Cell engineering

‒ World’s highest quality porcine genome

‒ In vitro functional assays

‒ Multiple simultaneous transgene insertions

● United Therapeutics to sell universally transplantable

organs from pigs

● Milestones and royalties on all pig-organs for SGI

United Therapeutics partnership

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SGI cell engineering to enable

transplantable pig organs

Core mechanisms and SGI

proprietary tools

SGI genome engineering drives rapid progress of transplant program

● Tools

● Inflammation

● Autoimmunity

● Immune

regulation

● Tolerance

UNDERSTAND THE BIOLOGY

● Deep

sequencing

● Bioinformatics

● Gene editing

● Landing pad

● Deletion/insertion

● DNA synthesis

● Analytical

chemistry

APPLY THE TOOLBOX

SGI

engineered

porcine

cellModified

pigs

KIDNEY HEARTLUNG

LIVERPANCREAS

Program timeline

● 2014: Program launch - lung

● 2015: Expansion to kidney

● 2016: First engineered pigs born

● 2017: Transplantation animal

trials planned

● 2020: First in humans planned

● Milestones and royalties on all

pig organs for SGI

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SGI’s novel hosts to displace legacy systems producing >$320B of therapeutics

● 3x faster doubling time than E. coli

● Inexpensive minimal and defined media

A proprietary system for research and production

● Compatible with protocols developed for E. coli

● Potential for secretion of functional complex proteins

● Path to 10x productivity and high

quality

● Greatly reduce deployment of at-

risk infrastructure investments

● Inexpensive minimal and defined

media

● Facile engineering and post-

translational modifications

● Genuine antibody display or

secretion

An end-to-end biologics platform

CHO / mammalian

~42%

E. Coli~29%

Yeast~17%

Misc. ~9%

Human~4%

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Superior Vmax attributes drive productivity multiples over E. coli

Key features E. coli Vmax Achieved improvement and key benefits

Doubling

time

● 20-30 min ● <10 min 2-3x ● Faster completion of experiments

● Shorter run time for commercial production

Growth ● Optimal at 37°C,

slow at room

temp

● Optimal at 30°C with fast

growth at room tempFlexibility ● Seamless switch from E.coli to Vmax

● Potentially omit the need for temperature controlled

shaker

Biomass ● 8-10 optical

density

● >14 optical density 1.5-1.75x ● Faster and more cost-effective production

● Nearly twice the biomass per unit of medium

Protein

expression

● Limited ● Soluble protein from 2 of

3 E.coli incompatible

targets

● 2x more protein with

E.coli compatible target

2-3x ● Better success rate for difficult to express protein

● Production of high yield, soluble, and stable

recombinant proteins

Cloning ● Culture ready in

~14-16 hours

● Culture ready in ~6

hours2-3x ● Single day cloning procedure

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Vmax™ performs better than E. coli in making intracellular biologics

0 1.6 2.6 3.6 4.6 5.6 10 0 3.6 4.6 5.6 10Hours into fermentation:

induced induced

0

20

40

60

80

100

0 1.6 2.6 3.6 4.6 5.6 10

Time (hrs)

Wet

Ce

ll W

eigh

t (g

/L)

0

20

40

60

80

100

0 3.6 4.6 5.6 10

Time (hrs)

Tota

l Pro

tein

Fermenter

Vmax E. coli

• More biomass in less time

• Higher product yield

0

2

4

6

8

10

12

14

16

0 100 200 300 400 500

OD

600

Time (min)

Vmax

E. coli NEB Turbo

E. coli BL21(DE3)

E. coli EPI300

Cultured at 37°C (shake flask)

Shake Flask

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Purification: protein A versus cation exchangeCmax™ process is highly productive

Alternative eukaryote for biologics production

● Minimal media used for growth

● Robust host- Limited cell lysis during fermentation

Fermentation

Supernatants

25KDa

50KDa

Hc

Lc

Protein A

Mixed mode cation

exchange

5.0 4.75 4.5 4.25

pH

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Revolutionizing research and enabling precision medicine

● Automated production of DNA, genes, mRNA, and protein to accelerate discovery

● Production of gene panels, CRISPR guides, and variant libraries

● Automated, scalable, and controllable commercial biological production

‒ mRNA therapeutics (e.g. via SGI replicon RNA system)

‒ Therapeutic proteins (e.g. via expression in SGI host systems)

● Specialized production of medicines on demand at point-of-care

‒ Vaccines

‒ mRNA therapeutics

BioXp™ 3200

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SGI is building the integrated synthetic biology platform of the future

Transform Vmax cGMP Processing

DNAProtein

DNA BiologicsAt any scale

Automation Time reduction Scale

“Print” DNA

Cost $

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SGI is building the integrated synthetic biology platform of the future

Transcription Translation

DNA RNA RNA Protein

DNA mRNA ProteinAt any scale

Today: BioXp™ 3200“Print” custom DNA

2019: DBC ”Print” DNA, RNA and protein

Automated cloning of DNA operating system into SGI production hosts (e.g. Cmax or Vmax) or other hosts

“Print” DNA Printable RNA vaccines

SGI replicon RNA Therapeutics, enzymes

and diverse protein

libraries

Immuno-antibodies

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Peer reviewed technology

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Imagine a world