October 24, 2012

1. Paradigm A University of Michigan non-profit company to facilitate next generation clinical sequencing and clinical trials October 24, 2012 Robert Penny M.D. Ph.D. CEO, Paradigm David Mallery J.D., MBA President, Paradigm Joe Paulauskis Ph.D. COO, Paradigm

2. Mission: • Revolutionize the treatment and prevention of cancer and complex diseases by rigorously developing and applying post-genome science to advances in human health • Expression Project for Oncology • Building the research foundation • The Molecular Profiling Institute • Target Now • TCGA • Biospecimen acquisition, banking and management for the largest cancer research project to date • (65 million in NUH contracts)

3. Paradigm & Molecular Profiling Institute Patient Care Theranostics Paradigm & Molecular Profiling Institute PCDx & Target Now TBAC PCDx & Target Now Tissue Banking & Analysis Center Clinical Application PCDx & Target Now TBAC Research TGen, Harvard, Stanford, GSK, BMS, Wyeth, Research Research Discover TCGA, expO, Clinical Trials TCGA expO,TBAC Database Characterization TCGA, expO, TBAC databases and biorepositories

4. expO Benefits • New Treatments • Diagnostic tests • Prognostic tools • Patents • Publications • Medical & Scientific presentations • Public release of evolving database • New Proprietary IP • Genotyping • Haplotyping • Methylation Proteomics CGH Improved clinical management of cancer patients Clinical Annotation Data Expression Array Data Public Data Open Competition IRB-approved Protocols (as necessary) TCGA Specimen Repository Pharma Members IRB-approved Proprietary Protocols (as necessary)

5. IGC’s Tissue Network Virginia Piper Cancer Institute, MN Community Hospitals of Indianapolis, IN St. Francis Hospital, IN St. Vincent Hospital, IN IGC Headquarters Trinity, MI St. FrancisTulsa, OK Inova Fairfax, VA ScottsdaleHealthCare, AZ U of A Tucson, AZ Rex Hospital, NC Texas HealthDallas, TX Lee Memorial, FL 7 ExpO / TCGA Sites 4 TCGA Sites Trinity MFHTyler, TX U TN Cancer Inst., TN 3 Low Volume - Withdrew

6. TCGA Biospecimen Core Resource Pilot Project TCGA Biospecimen Core Resource Full Project TCGA Tissue Source Site Network Full Project

8. The Cancer Genome Atlas(TCGA) Sponsored by the National Cancer Institute and the National Human Genome Research Institute, the National Institutes of Health Human Cancer Biospecimen Core Resource The major requirement for The Cancer Genome Atlas Pilot Project is the development of a Single, Centralized Human Cancer Biospecimen Core Resource (BCR). The BCR will oversee the acquisition of appropriately consented, standardized and rigorously collected biospecimens (patient cancer samples etc…), transport and preservation of samples and patient information to the BCR. An independent categorization and quality assurance check on these samples will occur prior to the isolation of analytes (DNA and RNA) to be distributed to the Sequencing and Characterization Centers. Samples will be de-identified with removal of patient privateinformation. Medical Centers Established Tissue Banks TSS Networks IGC Genome Sequencing Centers Building on the technologies that were used to complete the Human Genome Project, high-throughput genome sequencing centers will identify the mutations in DNA associated with specific types of cancer. Cancer Genome Characterization Centers Several characterization technologies will be used to analyze the copy number, methylation, miRNA and expression changes associated with cancer. Data Management, Bioinformatics and Computational Analysis The information that is generated by The Cancer Genome Atlas network will be centrally managed and entered into public databases as it becomes available, allowing scientists to access the information during the course of this project. Scientists will analyze the complete set of genetic and clinical data produced by The Cancer Genome Atlas network to develop a comprehensive Web-based resource which will be available to the scientific community. This resource will describe the genetic “fingerprints” of specific cancer types and will be known as The Cancer Genome Atlas. Researchers will evaluate the information contained in The Cancer Genome Atlas to determine how it can be used to speed up advances in cancer diagnosis, treatment, and prevention.

9. Pathway Analysis in GBM EGFR ERBB2 PDGFRA MET mutation in 7% amplification In 13% amplification in 4% mutation, amplification in 45% mutation, homozygous deletion in 17% mutation, homozygous deletion in 36% NF-1 RAS PI-3KClass I PTEN mutation in 2% mutation in 15% AKT amplification in 2% RTK/RAS/PI-3Ksignaling network 86% Proliferation Survival Translation FOXO mutation in 2% P53signaling86% CDKN2A (P16/INK4A) CDKN2B CDKN2C Activated oncogenes homozygous deletion in 51% homozygous deletion in 47% homozygous deletion in 2% homozygousdeletion in 49% CDKN2A (ARF) amplification in 17% amplification in 1% CDK4 CCND2 CDK6 amplification in 14% MDM2 amplification in 2% MDM4 RB1 amplification in 6% homozygous deletion, mutation in 11% TP53 RB signaling77% mutation, homozygous deletion in 35% G1/S progression Senescence Apoptosis

10. Cancer’s road map is now being formed

11. Target Now • Late Stage Cancer Patients • Profile Patients for Potential Rx Targets • Prospective Trial: Complete • DNA microarray • Immunohistochemistry • Sequencing • FISH • Other

13. Vitamin D receptor elevated, Rx Calcitriol • PDGFR (Platelet derived growth factor receptor) elevated • Rx • Inhibitor molecules • Gleevec • SU112248 • BAY43-9006

14. Results of the Prospective Trial in Late Stage Cancer • 106 Patients • PFS ratio of ≥1.3 • Deteriorating health of the patients was a significant cause of drop • out from the trial • Ratios for patient’s tumor type ≥ 1.3 PFS included: • colorectal 4/11 (36%), breast 8/18 (44%), ovarian 1/5 (20%), mostly • rare tumor types 5/32 (16%). • Conclusion: When using an endpoint of patient as their own control, • use of molecular profiling can provide clinical benefit in 26% of • patients who are treated according to MP results. Diagnosis 1st recurrence 2nd recurrence Outcome MPbx

15. CEO Robert Penny, M.D., Ph.D. • Founded 6 successful medical diagnostic companies • Secured over $65 million in NIH contracts over 5 years • Developed the leading revenue genomics test in Oncology today • Built one of the first clinically annotated gene expression databases • Leadership role The Cancer Genome Atlas project • Venture capital and medical diagnostic company • Experienced scientist • Co-founded 3 biotech companies • Leadership TCGA • Pfizer Global Head of Pharmacogenomics • Leadership TCGA President David Mallery, J.D., M.B.A. COO Joe Paulauskis, Ph.D.

16. Specimen analysis, coupled with pathology expertise, state-of-the-art bioinformatics interpretation and personalized customer service that: • Benefits patients by providing the most advanced information available for cancer treatment • Benefits clinicians by providing accurate, validated diagnostic, prognostic and therapeutic information • Benefits UMHS by • establishing UMHS as a national leader in personalized medicine • attracting additional patients • enhancing UMHS ability to conduct clinical trials • creating a new revenue source for UMHS

18. Pathologist & Oncologist Reviewed Tumor Biopsy (FFPE) Informed Consent Patient Delivery Sequencing • Clinical Trial Eligible • Actionable Results Analysis 3–4 Day Turnaround Laser Cryo Enrichment & Or oncologist ordered

19. Millions of papers interrogated Bench Tens of thousands of articles identified Test ID and development Thousands of articles evaluated Division of dedicated professional staff Real-time evidence report with weekly updates Thousands of articles reviewed and graded Bedside Thousands of rules developed Hundreds of articles cited