Gala s Gene Product Expression (GPEx ) Platform

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1 Gala Biotech A Company with Gene Insertion and Manufacturing Technologies for the Next Generation of Gene Expression and Biologics Production Gala s Gene Product Expression (GPEx ) Platform Rapid creation of stable, high yielding mammalian cell lines Applicable to a wide variety of cell types Scaleable from µg to kg Patent protected/proprietary Manufacturing and support services from cdna to the clinic and beyond

2 Gala s Gene Product Expression (GPEx ) Platform A New Operating System for Mammalian Cells Mammalian Cell Integrase Reverse Transcriptase Single copy of gene at any one genomic location Increased expression level per copy of gene inserted Genes inserted covalently Ideal for multigenic gene expression applications Faster path to stable cell lines Targets open matrix scaffold attachment regions of genome Patent protected/proprietary RNA genome Replication Incompetent Retrovector Gala s Gene Product Expression (GPEx ) Platform General Retrovector Construction Single Gene Expression Promoter LTR Ψ Gene LTR Basic Retrovector System Includes: Appropriate Promoter RNA Transport Elements RNA Stabilization Elements Optimized IRES Sequnece Promoter Subunit 1 IRES Subunit 2 Stoichiometric & Multigenic Expression

3 Gala s Gene Product Expression (GPEx ) Platform Single Protein Unique Advantage of Multigenic Expression Stoichiometric Production Polycistronic Message Independent Expression of Multiple Proteins Gene 1 Gene 1 Gene 2 Gene 1 Gene 2 Recombinant Protein Monoclonal Antibody Protein + Processing Enzyme Receptor + Secreted Surrogate Gala s Gene Product Expression (GPEx ) Platform GPEx is an Iterative Process Increasing Gene Copy/Expression Levels Cell Infection Protein for Analysis Retrovector Cell Population Clonal Selection Master Cell Bank Candidate Cell Growth Cell Line Analysis

4 Gala s Gene Product Expression (GPEx ) Platform Unique Advantage of Speed 6-8 Weeks for Vector Initial Production (VIP) 8-10 Weeks for Packaging Cell Line (PCL) Weeks for Production Cell Line cdna Vector ~2 Weeks after DNA cloning Packaging Line Production Cell Line MCB Candidate Expression Evaluation Product 4-6 months for 2 cycles (VIP and PCL) of multiple (4-5x) infections/transductions to create stable Master Cell Bank candidate Gala s Gene Product Expression (GPEx ) Platform Gala s Typical mab Project Flow Chart with GPEx - VIP Only Clone Variable Regions of Heavy and Light Chain Genes into Gala s backbone vectors (Week 1-3) Make Vector (Week 3) Perform 3-5x Vector Initial Production (VIP) Infection (Week 3) Perform Clonal Selection and Initial Protein Analysis (Week 4) Deliver Media from a Pooled Population of Cells (Week 10) Deliver Media from a Clonal Cell Line and Bank the Clonal Line (Weeks 12-13)

5 Gala s Parallel Processes in Therapeutic Protein Development Discovery & Screening Pre-Clinical Clinical Trials Market Vector Design, Packaging Cell Line, Vector production Embryo Transfer GPEx (Mammalian Cell Culture) µgs to kgs Transgametic (Transgenic Cattle) kgs to tons Summary of GPEx Expression Experience Fully humanized, full size tetrameric mab Murine monoclonal Fab +/- epitope tag (5 gram production runs at >95% purity) SC humanized Ab SC humanized Ab-IL2 fusion HBsAg CBD-fusion protein GPCR, GFP, GH, protease inhibitor Several proprietary proteins from collaborators (including IgG1, IgG2, IgG4 antibodies) and therapeutic proteins

6 Summary of GPEx Advantages Technology Advantages Speed, yield, stability Choice of mammalian lines Multigenic expression Manufacturing Advantages Patent protected/proprietary Solid regulatory path/fda opinion Manufacturing options Pay as you go terms Working with Gala GPEx Feasibility Study Partner provides cdna to Gala Gala uses GPEx to obtain initial quantities of protein for confirmatory/ functional studies Reinfection can be used to increase expression levels Cell line can be out-licensed or Gala/Cardinal can begin manufacturing activities Gala has many flexible deal structures!

7 Gala s Intellectual Property Estate Know How GPEx Other Gala Filings Vector Design and Production Mammalian Cell Culture Unique work-around of global patents Retroviral Backbone Enhanced backbone constructs Mammary specific promoter Nuclear export & RNA stability tools Replication defective retroviruses Pseudotyping of retrovector Packaging Cell Lines Modified translation element Cell culture promoter Gala filings in process Sponsor is responsible for, and owns, improvements that are product specific Gala is responsible for, and owns, improvements to the retrovector system and cell line engineering/manufacturing Gala s Facility 43,000 sq. ft. multi-purpose facility in Middleton, WI Administration Molecular biology R&D - protein chemistry Embryology Regulatory (QA, QC, etc.) Cell culture & vector production cgmp Biocontainment BSL3 suites (18) Cell based mfg. - Class 100,000 Protein purification - Class 10,000 Support functions - shipping, etc.

8 Manufacturing at Gala: Initial Capabilities & Capacity Research quantities of protein in roller bottles Scale-up for Phase I material in roller bottles or small bioreactors (initially 6 x 2L and 2 x 10L) cgmp manufacturing of Phase I/Phase II material in bioreactors (initially 1 or 2 x 30L and 1 or 2 x 100L) Seamless technology transfer / transition to Cardinal Health in Raleigh, NC, for Phase II/Phase III and commercial-scale cgmp manufacturing Other Cardinal services available that support an integrated genuine gene-to-clinic biopharmaceutical outsourcing capability Potential for single point of project management across all aspects of gene-to-clinic client projects client only deals with one contact Gala s Manufacturing Capabilities: cgmp Suites

9 Gala s Manufacturing Capabilities: Timing I 4 Wash Room 3 5 Wash 2 1 Room Facility Q1 04 Q1 04 Q1 04??? Q1 03 Q1 03 Q1 03 Equipment Q1 05 Q1 04 Q1 04??? Q4 03 Q1 03 Q1 03 Phase4 Phase 3 Phase 5 Phase 2 Phase 1 cgmp Mfg Q3 05 Q2 04??? Q1 04 Q4 03 Phase I/II regulatory compliance Cardinal Health: Support Services Formulation Assay development Release testing Stability testing mab conjugation: toxins and radioisotopes Fill/finish Sales/Marketing/Distribution of final Product Cardinal is adding Phase III/commercial biopharmaceutical manufacturing capability/capacity

10 Cardinal Health s Biotechnology & Sterile Life Sciences Group New 75,000 sq.ft. facility in Raleigh, NC Manufacturing capabilities Vial fill-finish Aseptic vial filling 2cc-100cc Liquid and lyophilized vials Terminal sterilization for liquid vials Bio-processing Fermentation at various scales Ultra-filtration and/or liquid chromatography purification Blending at various scales In operation by end of 2003 Summary of Gala/Cardinal Relationship Cell Line Creation Stable Clonal Cell Line Master Cell Bank Line Gala Biotech Middleton, WI Pilot Scale Development Scale Clinical Scale (Phase I/II) (cgmp) The Gala Biotech / Cardinal Health Advantage Providing Clients with an Integrated Seamless Transition from Gene to Clinic for API Manufacturing Biotechnology & Sterile Life Sciences Group Raleigh, NC Clinical (Phase III) & Commercial Scale (cgmp) Clinical Scale (Phase I/II) (cgmp)

11 Gala s Regulatory Status Gala uses proprietary techniques to enhance nuclear transport, vector yield, and stability Gala has assembled an excellent core regulatory group, including the use of outside consultants and experts in the area of shared biologics manufacturing Gala s practices are designed to meet the regulatory requirements of not only clients, but also various regulatory agencies, e.g. FDA, ICH, etc. Gala is taking a progressive approach to increasing regulatory compliance: GLP now, and cgmp by Q4 03. From recent meeting with the FDA (both CVM and CBER), Gala will be subject to the same standards as any other biologic manufacturer (e.g. validated viral clearance and inactivation in the manufacturing process) Gala s Current Status In excess of 100 technical person years and $23 million invested to develop both technology and a solid IP estate Cardinal is a key strategic partner/investor in Gala with $10 million invested to date Employees = 37, including 16 PhD s GPEx Technology suite fully developed Several feasibility deals nearing completion and now adding more of these, as well as expanding scope of existing deals to cell line licensing and/or cgmp manufacturing New 43,000 square foot facility with 18 BSL3 cell line engineering suites and capacity for 5 cgmp manufacturing suites Expanding to GLP followed by cgmp manufacturing capabilities with multiple manufacturing projects in parallel Gala remains very flexible with respect to how to work with its collaborators