Nanotechnology-Enabled Biopacemakers

1. Nanotechnology-Enabled Biopacemakers Presentation to RUSNANO October 2009

2. Agenda Introduction to Biopace, LLC Advantages of 3rd generation pacemakers Product development plan Investment perspective

3. Biopace, LLC Biopace, LLC aspires to develop and market 3rd generation pacemakers based on nanotechnology-encapsulated stem cells The clinically relevant advantages of this approach hold the promise to replace electronic cardiac pacemakers � a $4B market Moreover, pacing opportunities exist in multiple other indications, including pain, movement disorders, bladder and weight control While focusing initially on cardiac pacemakers, Biopace intends to diversify to become a leading, indication-diversified pacemaker company Biopace will have the option to spin out or develop the stem cell-coated nanofibers and nanoscaffolds for clinical use and quantum dots for diagnostic and research purposes

4. Scientific Founders Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics Director of Center for Molecular Therapeutics, Columbia University Leading Professor of Physiology and Biophysics, Director of Institute of Molecular Cardiology, Stony Brook University Professor, Thomas D. Cabot Associate Professor of Applied Science, Harvard University Professor, Associate Dean of Graduate Affairs, Columbia University Professor, Chairman of Physiology and Biophysics, Stony Brook University Assistant Professor, Worcester Polytechnic Institute

5. Cardiac Pacemaker Sales to Grow to $4B+ by 2008

6. Number of Potential Therapeutic Applications Exist Beyond Cardiac Pacing

7. Broad Scope Of Potential Therapeutic Applications Of Stem Cell-Coated Nano Materials

8. Agenda Introduction to Biopace, LLC Advantages of 3rd generation pacemakers Product development plan Investment perspective

9. Electronic Pacemakers Have A Number Of Drawbacks Not responsive to the autonomic nervous system � to the demands of exercise and emotion Require monitoring and maintenance, including periodic battery and/or electrode replacement Lead implantation site and wires can compromise cardiac output and cause congestive heart failure and �pacemaker syndrome� Problems with infection, interference from other electromagnetic devices Not optimal for pediatric patients due to continuing heart growth

10. Thin film Prevents hMSCs From Spreading Beyond the Film

11. hMSCs were seeded on both sides of the scaffold and then stained for Cx43 (green). Schematic drawing on right shows the approximate location of cells relative to scaffold. Other studies showed that hMSCs do not migrate through the scaffold. Inset on top right is scanning electron micrograph of electrospun polyurethane. The fibers shown here are on the order of 500-1,000 nm (certainly closer to 1,000 nm), however, we are currently making them smaller. I hope to have an SEM image in the next week or two.hMSCs were seeded on both sides of the scaffold and then stained for Cx43 (green). Schematic drawing on right shows the approximate location of cells relative to scaffold. Other studies showed that hMSCs do not migrate through the scaffold. Inset on top right is scanning electron micrograph of electrospun polyurethane. The fibers shown here are on the order of 500-1,000 nm (certainly closer to 1,000 nm), however, we are currently making them smaller. I hope to have an SEM image in the next week or two.

12. Agenda Introduction to Biopace, LLC Advantages of 3rd generation pacemakers Product development plan Investment perspective

13. Development Plan

14. Agenda Introduction to Biopace, LLC Advantages of 3rd generation pacemakers Product development plan Investment perspective

15. Establishment & Maturation of Medtronic 1949 Medtronic founded as a device repair shop 1956 Silicon transistor enables development of cardiac pacemaker 1957 1st generation wearable external pacemaker for patients recovering from open-heart surgery Plastic box with controls for pacing, leads passed through skin & powered by mercury batteries 1960 Medtronic licensed the 2nd generation implantable pacemaker from VA Hospital in Buffalo Received orders for 50 of the $375 implantable units that year 1963 Medtronic sold an average of 100 pacemakers per month ~20% of its total sales coming from outside the United States 1966 Medtronic licenses minimally invasive implantable pacemakers from VA Hospital, Buffalo, dramatically expanded the market 1967 Medtronic introduces "on-demand" pacemaker, expanded market 1972 First Lithium-iodide cell powered pacemaker, expanded market 1972 Hermetically sealed titanium case is used for implantable pacemaker, expanded market Takeaways: Multiple technologies must converge to develop a product � Columbia, Stony Brook, Harvard and Worcester pool technologies, namely ion channels and their delivery, use of stem cells, dissemination of ion current in tissue and encapsulation of stem cells in situ, to develop a biological pacemaker Initial market was small comprised patients recovering from surgery but quickly grew to 300,000 units implanted annually in the US only. We intend to initially administer tandem pacemaker but expect to enjoy the historical growth It took 14 years to move the wearable pacemaker from a lab to a clinic. We have benefited from 7 years of support from the NIH and 5 years from Boston Scientific. We believe that we will reach clinic within 4-5 yearsTakeaways: Multiple technologies must converge to develop a product � Columbia, Stony Brook, Harvard and Worcester pool technologies, namely ion channels and their delivery, use of stem cells, dissemination of ion current in tissue and encapsulation of stem cells in situ, to develop a biological pacemaker Initial market was small comprised patients recovering from surgery but quickly grew to 300,000 units implanted annually in the US only. We intend to initially administer tandem pacemaker but expect to enjoy the historical growth It took 14 years to move the wearable pacemaker from a lab to a clinic. We have benefited from 7 years of support from the NIH and 5 years from Boston Scientific. We believe that we will reach clinic within 4-5 years

16. Medtronic�s Portfolio Has Grown From Pacemakers To Electronic Stimulators For Number Of Indications Cardiac Pacemakers For Slow Heartbeat Adapta Pacemaker EnRhythm Pacemaker CareLink Remote Monitoring Network Neurostimulators � Movement Disorders Dystonia Soletra Neurostimulator Access Review Patient Controller (Soletra) Essential Tremor Activa PC Activa RC Soletra Neurostimulator DBS Patient Programmer Access Review Patient Controller (Soletra) Parkinson's Disease Activa PC Activa RC Soletra Neurostimulator Kinetra Neurostimulator DBS Patient Programmer Access Patient Controller (Kinetra) Access Review Patient Controller (Soletra) Gastric Electrical Stimulation For Gastroparesis Enterra Neurostimulator Neurostimulators � Bladder Control Overactive Bladder Neurostimulators Neurostimulators � Pain Conditions Chronic Back and Leg Pain PrimeAdvanced Neurostimulator RestoreAdvanced Neurostimulator RestoreUltra Neurostimulator MyStim Patient Programmer Complex Regional Pain Syndrome PrimeAdvanced Neurostimulator RestoreAdvanced Neurostimulator RestoreUltra Neurostimulator MyStim Patient Programmer Painful Neuropathy PrimeAdvanced Neurostimulator RestoreAdvanced Neurostimulator RestoreUltra Neurostimulator MyStim Patient Programmer

17. Biopace, LLC Achievements and Expectations Achievements� 1998 First biological pacemaker engineered in petri dish 2003 First hMSCs loaded with pacemaker gene and first hMSCs cultured on a fiber 2004 First tandem pacemaker successfully tested in a canine Expectations� 2010 Biopace, LLC is incorporated, achieves proof of principle in vivo 2014 Expecting First tandem pacemaker in a nanofilm to enter clinical development in patients with complete heart block 2015 Wireless transmission of pacing will point to reliability and safety of nanotechnology-encapsulated biological pacemaker ? this will expand marketshare 2016 Expecting MIZDRAV to approve Phase III studies; concurrent capitalization will permit diversification to other pacemaker indications Takeaways: Multiple technologies must converge to develop a product � Columbia, Stony Brook, Harvard and Worcester pool technologies, namely ion channels and their delivery, use of stem cells, dissemination of ion current in tissue and encapsulation of stem cells in situ, to develop a biological pacemaker Initial market was small comprised patients recovering from surgery but quickly grew to 300,000 units implanted annually in the US only. We intend to initially administer tandem pacemaker but expect to enjoy the historical growth It took 14 years to move the wearable pacemaker from a lab to a clinic. We have benefited from 7 years of support from the NIH and 5 years from Boston Scientific. We believe that we will reach clinic within 4-5 yearsTakeaways: Multiple technologies must converge to develop a product � Columbia, Stony Brook, Harvard and Worcester pool technologies, namely ion channels and their delivery, use of stem cells, dissemination of ion current in tissue and encapsulation of stem cells in situ, to develop a biological pacemaker Initial market was small comprised patients recovering from surgery but quickly grew to 300,000 units implanted annually in the US only. We intend to initially administer tandem pacemaker but expect to enjoy the historical growth It took 14 years to move the wearable pacemaker from a lab to a clinic. We have benefited from 7 years of support from the NIH and 5 years from Boston Scientific. We believe that we will reach clinic within 4-5 years

18. Thank youJerry M. Kokoshka, Ph.D.Senior Associate DirectorColumbia Technology VenturesPH 1535 East630 West 168th StreetNew York, NY 10032jk2108@Columbia.edu

19. Financials / Budgets

21. Nanofilm-Encapsulated Stem Cell Pacemaker Represents A Revolutionary New Approach

22. Key Deliverables And Risks