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; Products and Services $10.2 M; Licensing/Royalties $7.3 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 NTC Value Propositions Nanoplasmid technology transfection and expression performance similar to viral vectors with much less immunogenic risk The HyperGRO process allows for industry leading scalability of plasmids, increasing yield while simultaneously decreasing costs RNA-OUT is a smaller, safer selection marker, which has been tested in clinical trials and improves overall expression up to 4x Potential game-changing approach to DNA vaccine and gene therapy 2

3 Plasmid yield (mg/l) HyperGRO: Industry Leading Scalability of Plasmid Vectors Proprietary fed-batch bacterial fermentation process Produces up to 10x the yield of typical processes Dramatically improves the scalability of plasmid production compared with traditional techniques Results in the production of more usable, high quality plasmid for gene therapy and DNA vaccine purposes, without increased cost Licensed to 5 cgmp CMOs Shake flask Typical fermentation proceses HyperGRO 3

4 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 4

5 Antibiotic-Free RNA-OUT Marker vector 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 5

6 Nanoplasmid TM platform Safe and Effective Vectors for DNA Vaccination and Gene Therapy 6

7 Three Pronged Business Strategy Creating valuable IP enabling gene-based drugs - 8 Granted US Patents - 12 Pending US Patent Applications Providing design, development and manufacturing of gene-based medicines to industry partners Technology transfer and licensing HyperGRO TM plasmid fermentation process - 5 licensed CMOs NTC RNA-OUT Marker vectors - 7 licensed vector users Nanoplasmid TM vectors - >20 Biotech/Pharma companies evaluating 7

8 Plasmid Production Platform: Intellectual Property Granted US Patent 8

9 High Expression Level/Duration Vector Platform: Intellectual Property Granted US Patent 9

10 Licensed Applications Licensed applications of NTC technologies: DNA vaccines for infectious diseases including HPV, Epstein Barr virus, herpes simplex, CMV, adenovirus, immune tolerance and veterinary applications Gene therapy vectors for dermatology, wound healing, ophthalmology RNA-OUT markers for increased expression and improved safety for nucleic acid based vectors, and for therapeutic viral vector production Plasmid expression and copy number enhancers for improved performance and reduced cost Fermentation media, strains, and processes for improved plasmid DNA vector production Nanoplasmid TM, NTC s new platform technology, remains exclusive and has not been licensed despite significant interest from existing partners and new parties Current licensed applications validate NTC s key intellectual properties and position its technology to be the industry standard in gene therapy 10

11 NTC 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 Potential 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 11

12 Summary / Conclusions Effective Plasmid Gene Therapy Solution With An Emphasis On Safety Transfection rates to enable replacement of viral vectors, without the immunogenic risks Selection markers are antibiotic-free, and improve target gene expression several-fold Industry Leading Scalability HyperGRO an industry leading bacterial fermentation process Results in significantly more plasmid produced compared to competitors Robust scalability results in decreased cost of production Stable, Versatile Gene Therapy Solution Can be used with a variety of delivery devices or mechanisms Can support viral vector production processes due to its robust scalability of gene product Proven Safety And Effectiveness Through Clinical Trials 4 Phase I trials completed successfully Proven safety profile in all four Phase I trials Safety and effectiveness demonstrated in multiple clinical areas, including allergy, infectious disease, and chimeric antigen-t cell therapy NTC technologies provide a stable, massively scalable and robust platform for developing clinical gene therapies 12