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Overview of CombiFlash Product Line

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  1. Overview of CombiFlash Product Line Teledyne Isco Confidential

  2. Agenda • Overview • Product Availability Dates • Pricing • Phase out of Current Products • Detailed Description of CombiFlash Rf+ PurIon Teledyne Isco Confidential

  3. Overview • CombiFlash Rf 150 • CombiFlash Rf+ • CombiFlash Rf+ Lumen • CombiFlash Rf+ PurIon • CombiFlash Rf Torrent • RediSep Rf and RediSep Rf Gold media • Foxy R1, R2, and Retriever 500 Fraction Collectors • 340 CF ELSD Teledyne Isco Confidential

  4. Product Availability Dates • CombiFlash Rf+ • CombiFlash Rf+ Lumen • CombiFlash Rf+ PurIon • Available for customer shipment by October 31st • CE Mark by October 31st Teledyne Isco Confidential

  5. Pricing Teledyne Isco Confidential

  6. Phase Out of Current Products • Rf 200 and Rf 200i modules will be shipped until the end of December • 68-5230-006, 68-5230-008, 68-5230-010, and 68-5230-011 • Can be quoted until the end of October with a validity of 30 days • No orders will be accepted after the end of November • No shipments will occur after December 31, 2013 Teledyne Isco Confidential

  7. Introducing the CombiFlash Rf+ PurIon A Fully Integrated Flash Chromatography – Mass Spectrometer System Teledyne Isco Confidential

  8. Topics • The Question • Partner • How Does it Work • Functions • Control • Competition • Accessories Teledyne Isco Confidential

  9. The Question • Why use an MS connected in real time to a Flash system? • Molecular weight and limited structural information. • The ‘ultimate’ in selectivity. • Visibility of co-eluting contaminants • Mass confirmation of collected fractions to avoid offline TLCs, workup and core lab LC-MS assays. • Characterization of isomeric mixtures. Teledyne Isco Confidential

  10. Mass Spec vs. other Flash detectors • UV – provides a linear response to the concentration of an analyte as long as it absorbs at the available detector UV wavelengths. • Response varies by compound/wavelength • Not all compounds can be detected • Not selective • ELSD measures light scattered from semi- and non-volatile particles that have been dried of mobile phase through evaporation. • More universal than UV • More consistent response than UV since does not have absorption coefficient • Non-linear response • Still not selective • Mass Spectrometry • Applicable to a broad range of organic compounds • As well as providing chromatographic data it identifies the compound by confirming its mass (no advantage if only using TIC!) • Mass spectrometry has a broad range of utility but is not a universal detector Teledyne Isco Confidential

  11. Partner • Advion selected over 2 years ago as the MS vendor to work with • Other companies considered included Microsaic • Advion development was most advanced and product was closer to market than others • Advion willing to drive toward our cost point target Teledyne Isco Confidential

  12. Advion Global Headquarters Ithaca, New York A Leader of Mass Spec and Microfluidic Systems based upon decades of LC/MS expertise Teledyne Isco Confidential

  13. The pioneer and leader in nano/micro fluidic ionization sources, flow radiochemistry, and compact mass spectrometry systems. Expression™ CMS A compact mass spectrometer for organic chemists, giving them direct access to mass measurement at all steps of solution phase synthetic routes TriVersa NanoMate® An automated chip-based nanoelectrospray ion source for high performance/high resolution mass spectrometers. The most versatile sample introduction technique for mass spectrometry. Chip-Mate An affordable chip-based nanoelectrospray LC/MS ion source with unique spray-sensing capabilities for maximum robustness NanoTek® A microfluidic flow synthesis system for clinical radiochemistry Until 2012, Advion was North America’s largest LC/MS/MS CRO (sold to Quintiles) Teledyne Isco Confidential

  14. New product ideas driven by customer requirements, CRO intelligence and synthetic chemistry industry experience • Advion’s CRO included 58 LC/MS/MS serving small molecule analytical Discovery to Phase 4 • Advion Scientific Founder’s Cornell research group was the inventor of Ion Spray • Group headed by Dr. Jack Henion • Advion is an expert in Ion Sources and applying them to their best advantage for a variety of applications • Advion CEO, David Patteson, former CEO of Biotage AB Teledyne Isco Confidential

  15. What is different about Advion’s expressionCompact MS? • Developed by small molecule, peptide and natural product MS experts & chemists for chemists • A fresh new perspective and an alternative to traditional MS products • Designed for In-Hood use • Fast answers in space-restricted labs • Does not compromise performance requirements or budgets • High Performance, Compact, Affordable Mass Spec Detector for the chemist Teledyne Isco Confidential

  16. Specifications for CMS – not PurIon • Ion Source: ESI with APCI option (switchable with minimal effort) • API: Patented orthogonal ion sampling from heated capillary – allows very high performance with a single small turbo pump • Flow rate range: 10 µL/min to 500 µL/min (1 ml/min with APCI using high organic) • Polarity: +ve or –ve ion in sequential analyses • m/z Range: m/z 10 to m/z 1,200 • Acquisition rate: 5,000 m/z units sec1 (compatible with UPLC) • Resolution: 0.5-0.7 m/z units (FWHM) at 1000 m/z units sec1 over entire acquisition range • SIM sensitivity: 10 pg Reserpine (FIA - 5µL sample injection volume at 100 µL/min) 100:1 S/N (RMS) with SIM of m/z 609.28 • Accuracy:  0.1 m/z units over entire acquisition range Teledyne Isco Confidential

  17. Components making up a CombiFlash Rf+ PurIon • CombiFlash Rf+ • CombiFlash PurIon Detector Module • Fluid Interface • Roughing Pump Teledyne Isco Confidential

  18. Fluid Interface Flow Diagram Pulse damper Pressure Transducer To Mass Spec Splitter Valve Prime valve Back pressure 40 psi To Rf port D From Rf port C Pump head Teledyne Isco Confidential

  19. Method Development to Ion Source From Fluid Interface 2 µm Filter Method Development Inject Valve Ion Source Teledyne Isco Confidential

  20. Under the Cover View Prime Valve Pressure Transducer Carrier Pump Pulse Damper Back Pressure Regulator MRA (Splitter Valve) Teledyne Isco Confidential

  21. Front and Back Panels of Fluid Interface Power Cables for MS and Rf Prime Valve Carrier Pump USB to Rf MRA USB from front of MS USB to back of MS AC Power Cord Teledyne Isco Confidential

  22. Functions/Options • Target Mass or Mass Range Detection • ESI or APCI • Positive or Negative Ionization • Pre-purification verification • Reaction Monitoring Teledyne Isco Confidential

  23. Control • Single point control via PeakTrak • User does not have access to all operating parameters • Goal was to keep operation SIMPLE Teledyne Isco Confidential

  24. MS Settings Teledyne Isco Confidential

  25. Method Development Screen • Pre-purification Verification • Reaction Monitoring • Flow Injection Analysis Teledyne Isco Confidential

  26. Flow Injection or Reaction Monitoring 200 µL/min to ESI/APCI Mass Spectrometer CombiFlash Rf+ Return to UV Column 10 - 200 mL/min Gradient Isocratic make up Pump Rheodyne Mass Rate Attenuator (MRA) 200 µL/min Methanol with 0.1% Formic Acid Teledyne Isco Confidential

  27. Manual Injection Valve Injection Port Drain Tube To Ion Source Scan Mass Position From Fluid Interface Inject Sample Position 5 µl volume tubing Teledyne Isco Confidential

  28. MS Tab Options Teledyne Isco Confidential

  29. Manual Control Teledyne Isco Confidential

  30. Real Time Run Display Teledyne Isco Confidential

  31. Past Peak MS Display in Real Time Teledyne Isco Confidential

  32. Teledyne Isco Confidential

  33. Post Run MS Teledyne Isco Confidential

  34. CombiFlash Rf+ PurIon Specifications Dimensions (W x H x D) CombiFlash PurIonMass Detector: cm Fluid Interfacecm CombiFlash Rf+ PurIon system:cm Roughing Pump: Weight CombiFlash PurIon Mass Detector: kg Fluid Interface: kg CombiFlash Rf+: kg Roughing Pump: CombiFlash Rf+ PurIon system: kg Mass Analyzer Single quadrupole Ionization Source Electrospray ionization (Optional Atmospheric Chemical Ionization) Detection Range m/z 50 – 1200 Mass Accuracy ± m/z 0.5 in full scan in a temperature controlled environment, ±3 °C Mass Resolution m/z ± 1 Sampling Adjustment Automatic Start-up Time 30 minutes after roughing pump reaching full vacuum Vacuum Pumps Integrated Turbo pump, external roughing pump Control Interface PeakTrak Compatible Systems CombiFlash Rf+ and CombiFlash Rf+ Lumen (Mass Ready) Systems Upgraded CombiFlash Rf200 Systems Gas Requirement 4.5 - 9 bar N2 Gas Consumption 4 L/min Power Requirement 100–240 V AC; 50–60 Hz Teledyne Isco Confidential

  35. TypicalMessages Teledyne Isco Confidential

  36. Typical Messages Teledyne Isco Confidential

  37. Going from Standby to Operate Teledyne Isco Confidential

  38. Going from Operate to Standby Teledyne Isco Confidential

  39. Teledyne Isco Confidential

  40. Competition • Biotage Isolera Dalton - Introduced September 2012 – Active demos and reported sales • Interchim - Introduced January 2012 – Demo at University of Boston in March • Agela - Introduced November 2012 – No known activity Teledyne Isco Confidential

  41. Biotage Isolera Dalton Flash Chromatography with Integrated Mass Identification Be sure you have your target compound the moment your purification is complete. Isolera™ Dalton integrates the Biotage approach to flash chromatography with true compound identification using mass detection. For the first time, Flash chemists can automatically collect targeted mass fractions of their compounds on a flash system. Isolera™ Dalton is nothing less than a fully-fledged mass identifier system specifically designed to plug seamlessly into the Isolera™ family. Provided by a company with over twenty years’ experience in Flash chromatography, Isolera Dalton represents the most advanced and innovative purification system available, designed by people who understand Flash purification and the needs of the synthetic chemist. Teledyne Isco Confidential

  42. Biotage Claims 1 Biotage TIsco • Streamlined WorkflowIsolera Dalton brings mass detection to flash chromatography. This system identifies compounds by mass in real time during Flash separation, leading to greater confidence in purification and a significant saving in time and money. This combination of identification and purification removes complex off-line analytical steps from the workflow, vastly increasing throughput and putting the entire purification and analysis in the hands of the chemist. • Reactor content can be injected directly to identify target masses, which then are transferred directly to the Flash method for mass targeted purification. Teledyne Isco Confidential

  43. Biotage Claims 2 Biotage TIsco Tailored TechnologyIsolera Dalton automates and takes the hard work out of the compound identification and purification, perfect for chemists whose priorities lie more towards the chemistry than small details of running the analysis. Minimal user intervention required makes it available to chemists unfamiliar with mass detection or those whose priorities lie in compound synthesis rather than analysis. Isolera™ Dalton Mass Detector uses a chip-based electrospray system with a miniaturized quadrupole and internal vacuum pumps, allowing the system to easily fit in a fume hood, and is capable of handling both normal and reverse-phase samples with ease.  PurIon system is not miniaturized and requires an external roughing pump – reduces the possibility of plugging Teledyne Isco Confidential

  44. Biotage Claims 3 Biotage TIsco Intelligent IntegrationSeamless interaction between a flash system and a mass detector requires advanced technology and fine tuning. This is all taken care of by the Isolera™ Dalton Nanolink interface, an intelligent sampling device that at any given moment provides Isolera Dalton Mass Detector with the exact amount of sample required, and dynamically adjusts to the solvent effluent flow rate employed in the Flash system. Isolera™ Spektra software with its graphic user interface provides a straightforward controlling environment, giving easy access to the process The Fluid Interface provides control of carrier solvent and switching valve Teledyne Isco Confidential

  45. Biotage Claims 4 Biotage TIsco • Compound identification by mass during purification and by direct injection • Fully automated integration of Flash purification and mass detection via the Isolera™ Dalton Nanolink • Automatically accommodates different flash flow rates • Simple wizard-based approach to method development • Compact system with miniaturized mass detector, easily fits inside a fume hood with no external pumps Requires an external roughing pump – Biotage does not since they do no offer the option of APCI probe Teledyne Isco Confidential

  46. Biotage Dalton Specifications Teledyne Isco Confidential

  47. Biotage Dalton Ordering Information Teledyne Isco Confidential

  48. Biotage Dalton Pricing Information • Syngenta in Switzerland early 2013 – verbally told 80K • University of New Orleans at Spring ACS $110k • Flyer in Japan in June $100k • BMS in July $115K • Anonymous inquiry $115k for complete system $100k for upgrade to existing system Teledyne Isco Confidential

  49. Competitive Position Against Biotage TIsco Biotage Will stress internal vacuum pump only • Need external pump so user can choose/switch between ESI and APCI interfaces Teledyne Isco Confidential

  50. Interchim puriFlash MS • Mass triggered fraction collection from normal & reverse phase flash chromatography & prep-LC • Mass & Purity confirmation of flash fractions • 100% confidence • Real-time reaction monitoring of batch reactions • The hood-based puriFlash MS reduces the burden on open-access platforms Teledyne Isco Confidential