Pioneering the Development of Safe and Effective Non-Viral Vectors and Processes for Human Gene Therapy and DNA Vaccination.

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1 Pioneering the Development of Safe and Effective Non-Viral Vectors and Processes for Human Gene Therapy and DNA Vaccination. Founded 1999, Clague Hodgson, Ph.D. Chief Scientific Officer, VP, R&D, Jim Williams, Ph.D. (2002) Director of Process Development: Aaron Carnes, B.Sc.Ch. (2000) Funding to Date: Grants $3.4 M; Revenue $9.5 M; Angels $1.5 M US Patents and Patent Applications: ~20 Preclinical/Clinical Products Made so Far: >200 Phase I Clinical Trials completed so far: 4 HyperGRO TM Fermentation Licensed cgmp Facilities: 5 RNA-OUT Antibiotic-free Selection Vector Technology Licensees: 7 Nature Technology Corportation 4701 Innovation Drive Lincoln, NE Phone: (402) (natx) Fax: (402) support@natx.com

2 Plasmid DNA Manufacturing: HyperGRO Leading Fermentation Process 2.6 g/l DNA yield HIGHLIGHTS Generic low metabolic burden process Toxic/unstable plasmid production Highest yields Licensed to 5 cgmp CMOs

3 Antibiotic-Free RNA-OUT Marker Selection

4 Improved Expression: in vitro NTC8 series RNA-OUT Vectors Out-Perform Industry Standards gwiz (VR1012) and pvax1 in vitro

5 Improved Expression: in vivo NTC8 series RNA-OUT Vectors Out-Perform Industry Standards gwiz (VR1012) and pvax1 in vivo 5 µg museap plasmids delivered by IM EP to 5 BALB/C mice/group on day 0. pvax1 museap was below limit of detection at all timepoints

6 Vector Retrofit to RNA-OUT Antibiotic free Selection Improves Expression

7 Antibiotic-Free RNA-OUT Marker Vector Retrofit Replace antibiotic selection markers such as AmpR and KanR in existing vector with Sucrose Selection Advantages Removes antibiotic selection (regulatory compliance) Improved transgene Expression Clinically tested Small size (150bp) Increased potency Perfect for: Lenti Vectors Retroviral vectors Helper plasmids Sleeping Beauty Therapeutic plasmids for in vivo or ex vivo gene therapy DNA vaccines mrna vectors CAR-T cell therapies All viral vectors currently using antibiotic resistance markers

8 High Yield Manufacture Three cgmp facilities have successfully utilized NTC s HyperGRO TM fermentation process for high yield manufacture of NTC s RNA-OUT Vectors

9 Nanoplasmid TM platform Safe and Effective Vectors for DNA Vaccination and Gene Therapy

10 Nanoplasmid TM Antibiotic-Free RNA-OUT Marker selection and propagation

11 NTC 9 Series Nanoplasmid TM Size Comparison Nanoplasmid vectors are smaller than already minimal NTC8685 vectors, which are smaller than gwiz. Increased Expression Smaller Size Antibiotic Free, RNA-OUT Selectable Marker Regulatory Compliant Scalable Manufacturing with HyperGRO

12 Improved in vivo Expression NTC s Nanoplasmid TM RNA-OUT Vectors Out-Perform Industry Standard NTC8 series RNA-OUT vectors in vivo Intramuscular and Intradermal Nanoplasmid vectors have dramatically higher in vivo expression than NTC8685, gwiz and pvax1. Nanoplasmid vectors include NTC8685 vector generation advantages, with the additional advantage of a reduced bacterial backbone, reducing size and improving expression.

13 Improved Expression Level & Duration NTC s Nanoplasmid TM RNA-OUT Vectors Out-Perform Industry Standard NTC8 series RNA-OUT vectors and minicircle vectors in vivo Intradermal- CMV Promoter Liver- RSV Promoter Reduced Spacer Region (<500 bp) increases transgene expression level & duration: - Multiple tissues (improved expression in skin, muscle, liver, salivary gland, etc) - Multiple promoters (improved expression with CMV, EF1, RSV, haat, etc, promoters)

14 Improved Immunogenicity NTC s Nanoplasmid TM RNA-OUT Vectors Out-Perform Industry Standard NTC8 series RNA-OUT vectors in vivo Needle free intradermal immunization

15 Improved Safety and Regulatory Compliance Nanoplasmid vectors have antibiotic-free selection and R6K mini origin of replication: they are replicationincompatible with native organisms. They can only replicate within the specialized E. coli host strain used for manufacture.

16 High Yield Manufacture High yield manufacture of NTC s Nanoplasmid TM Vectors in designer host strains compatible with HyperGRO TM fermentation process NTC9 series Nanoplasmid TM vector growth and plasmid yield profile of a 10L HyperGRO TM fed-batch fermentation using C slow ramp temperature induction. Final Nanoplasmid TM yield was 1147 mg/l

17 Three Pronged Business Strategy: Creating valuable IP enabling gene-based drugs Providing design, development and manufacturing of gene-based medicines to industry partners Technology transfer and licensing HyperGRO TM plasmid fermentation process - 5 licensed CMOs NTC8 series RNA-OUT vectors - 7 licensed vector users Nanoplasmid TM vectors - >20 Biotech/Pharma companies evaluating

18 Plasmid Production Platform: Intellectual Property

19 High Expression Level/Duration Vector Platform: Intellectual Property

20 NTC8 series RNA-OUT vector Phase I Clinical Trials: 4 Immunological Studies Completed: no serious adverse events: -Efficacy Herpes simplex virus II therapeutic vaccine, Admedus Vaccines + 19/20 patients showed T cell responses ++ Cytomegalovirus, EBV, Adenovirus (in bone marrow transplants, Baylor) 80% clinical responses Allergic tolerization vs. Japanese red cedar pollen, Immunomic Therapeutics, Inc. + Phase 1A and Phase 1B completed % patient conversion from skin test positive to negative Phase 2 IND submitted + No safety issues in multiple preclinical toxicology studies ++ Clinical cgmp vector manufactured at CMOs using HyperGRO TM process

21 NTC9 series RNA-OUT Nanoplasmid TM vectors Next Generation Platform US Patent Applications for Nanoplasmid TM compositions and production: 3 Preclinical Nanoplasmid TM Products Made so Far: >100 Biotech/Pharma companies currently evaluating Nanoplasmid TM platform : >20 Nanoplasmid TM Application areas DNA Vaccination (e.g. EP or Needle Free Delivery for cancer, infectious diseases, etc) Adoptive Immunotherapy (e.g. CAR-targeted T cell for hematological malignancies, etc) Passive Immunotherapy (e.g. in vivo production of therapeutic antibodies, etc) Allergy Immunotherapy (e.g. peanut, pollen, animal dander, etc) Regenerative Medicine (e.g. Wound Healing, Burns, etc) Gene Replacement Therapies (e.g. growth factors, synthetic biological drugs, etc) Type II diabetes (e.g. diabetic ulcers, peripheral arterial disease, peripheral neuropathy) Anti-inflammatory cytokine gene therapy (e.g. Type 1 diabetes or Rheumatoid Arthritis autoimmmune disease therapy, etc) induced Pluripotent Stem Cell Reprogramming (e.g. Stem Cell Therapies) Gene silencing therapeutics (e.g. shrna gene therapies, microrna mimics, antagonists and targeted therapies,, aptamers, lncrnas, etc) mrna editing (e.g. splice switching antisense oligos - Duchene's Muscular Dystrophy, etc) Orphan Drugs (e.g. hugt1a1 gene replacement therapy for Crigler-Najjar syndrome) Personalized Medicines