Overview of CombiFlash Product Line Teledyne Isco Confidential

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

Teledyne Isco Confidential 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

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

Teledyne Isco Confidential Pricing 68-5230-021 CombiFlash Rf+ UV $30,327 68-5230-022 CombiFlash Rf+ UV/Vis $31,269 68-5230-031 CombiFlash Rf+ UV MS Ready $31,587 68-5230-032 CombiFlash Rf+ UV/Vis MS Ready $32,529   68-5230-023 CombiFlash Rf Lumen UV $45,930 68-5230-024 CombiFlash Rf Lumen UV/Vis $47,236 68-5230-033 CombiFlash Rf Lumen UV MS Ready $47,190 685230-034 CombiFlash Rf Lumen UV/Vis MS Ready $48,496 68-5230-041 CombiFlash Rf PurIon UV $98,286 68-5230-042 CombiFlash Rf PurIon UV/Vis $99,167 68-5230-043 CombiFlash Rf PurIon UV with ELSD $118,462 68-5230-044 CombiFlash Rf PurIon UV/Vis with ELSD $119,348 Teledyne Isco Confidential

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

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

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

Teledyne Isco Confidential 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

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

Teledyne Isco Confidential 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

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

Teledyne Isco Confidential 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

Teledyne Isco Confidential 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

Teledyne Isco Confidential What is different about Advion’s expression Compact 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

Teledyne Isco Confidential 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

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

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

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

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

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

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

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

Teledyne Isco Confidential MS Settings Teledyne Isco Confidential

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

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

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

Teledyne Isco Confidential MS Tab Options Teledyne Isco Confidential

Teledyne Isco Confidential Manual Control Teledyne Isco Confidential

Teledyne Isco Confidential Real Time Run Display Teledyne Isco Confidential

Past Peak MS Display in Real Time Teledyne Isco Confidential

Teledyne Isco Confidential

Teledyne Isco Confidential Post Run MS Teledyne Isco Confidential

CombiFlash Rf+ PurIon Specifications Dimensions (W x H x D) CombiFlash PurIon Mass Detector: cm Fluid Interface cm 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

Teledyne Isco Confidential Typical Messages Teledyne Isco Confidential

Teledyne Isco Confidential Typical Messages Teledyne Isco Confidential

Going from Standby to Operate Teledyne Isco Confidential

Going from Operate to Standby Teledyne Isco Confidential

Teledyne Isco Confidential

Teledyne Isco Confidential 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

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

Teledyne Isco Confidential Biotage Claims 1 Biotage TIsco Streamlined Workflow Isolera 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

Teledyne Isco Confidential Biotage Claims 2 Biotage TIsco Tailored Technology Isolera 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

Teledyne Isco Confidential Biotage Claims 3 Biotage TIsco Intelligent Integration Seamless 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

Teledyne Isco Confidential Biotage Claims 4 TIsco Biotage 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

Biotage Dalton Specifications Dimensions (W x H x D) Isolera™ Dalton Mass Detector: 35.5 x 56 x 25 cm Isolera™ Dalton Nanolink: 35.4 x 52.5 x 21 cm Isolera™ Dalton system: 85 x 59 x 62 cm Weight Isolera™ Dalton Mass Detector: 32 kg Isolera™ Dalton Nanolink: 10 kg Isolera™: 35 kg Isolera™ Dalton system: 77 kg Mass Analyzer Miniaturized single quadrupole Ionization Source Chip based electrospray ionization Detection Range m/z 80–800 Mass Accuracy ± m/z 0.5 in full scan in a temperature controlled environment, ±3 °C Mass Resolution m/z 0.7 ±0.1 FWHM in full scan in a temperature controlled environment, ±3 °C Sampling Adjustment Automatic Start-up Time 30 minutes* Vacuum Pumps Fully integrated Control Interface Isolera™ Spektra User Serviceable Parts Spraychip® (chip based ESI source) Vac-chip™ (micro engineered atmospheric pressure interface) Compatible Systems Isolera™ Spektra Flash Chromatography systems Gas Requirement  2–6 bar N2 Gas Consumption  2.5 L/min Power Requirement 100–240 V AC; 50–60 Hz Teledyne Isco Confidential

Biotage Dalton Ordering Information Part Number Description ISO-DALT-NLINK    Isolera™ Dalton Nanolink ISO-DALT-DET Isolera™ Dalton Mass Detector  SER-DALT-IN  Isolera™ Dalton Installation SER-DALT-SAP Service Agreement - Priority - Isolera™ Dalton  413712 Mass Detector Vac-chip 100 (1pcs.) 413711 Mass Detector Spraychip 200 (1pcs.) 413874 Masscape SW for Personal Computer Teledyne Isco Confidential

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

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

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

Interchim Specifications Ion Source: APCI (ESI as option, easy switch)  API: orthogonal ion sampling from heated capillary – allows for small single turbo pump (Patents pending) Flow rate range: 10 µL/min to 500 µL/min  Polarity: +ve and –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  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 injection at 100 µL/min) 100:1 S/N (RMS) with SIM of m/z 609.28 Scan sensitivity: 100 pg Reserpine (FIA - 5µL injection at 100 µL/min) 100:1 S/N (RMS) with full-scan acquisition of m/z 100 to m/z 1200 Accuracy: +/- 0.1 m/z units over entire acquisition range Stability: +/- 0.1 m/z units 12 hours in temperature controlled environment (21 +/- 3°C) Teledyne Isco Confidential

Competitive Position Against Interchim TIsco Interchim Standard with ESI, APCI optional Control through PeakTrak Integrated Fluid Interface Should have a price advantage over Interchim Local service support SIMPLE! Standard with APCI, ESI optional Don’t know how controlled – most likely through a Window’s task screen Screen shots on website show Advion control software No description of fluid interface – believe it to be modular Specifications are just a repeat of the Advion specs Teledyne Isco Confidential

Teledyne Isco Confidential

Teledyne Isco Confidential

Teledyne Isco Confidential

Teledyne Isco Confidential

Teledyne Isco Confidential

Agela Cheetah system coupled with cMS We are highly thankful to all our customers who visited our Booth and shown their interest in our products . We will surely address the queries/address of our privileged customers through our Indian office and look forward for business patronage with Indian customers. This was announced at a trade show in India in December 2012. No further information has been seen since. Focus is reportedly on interfacing with their Flexa HPLC system Teledyne Isco Confidential

Accessories/Upgrades Part Number   List Price  68-5237-050 PurIon Including Fluid Interface $68,484 68-5237-081 Fluid Interface $18,543  68-5237-051 CombiFlash Rf Upgrade including PurIon $70,146 APCI Ionization Probe Option Roughing Pump Vent Kit Demo Kit for MS Teledyne Isco Confidential

Teledyne Isco Confidential Roughing Pump Vent Kit Teledyne Isco Confidential

Wednesday August 28 Agenda   Group 1 Group 2 800 AM Lab III Lecture III Operation CombiFlash Rf + Details CombiFlash Rf 150 1000 AM Break 1030 AM Lab IV Lecture IV Torrent Columns and Column Plan Troubleshooting 1200 PM Lunch 130 PM 230 PM 300 PM Teledyne Isco Confidential

Key Markets Pharmaceutical Drug Discovery Agricultural Chemistry Petrochemicals Natural Products Foods and Flavors Teledyne Isco Confidential