DECLARATION OF ANDY ADLER, PH.D.
`
`I, Dr. Andy Adler, based on my personal knowledge and information, hereby declare as
`follows:
`
`1.
`I am a Canada Research Professor in biomedical engineering in Systems and
`Computer Engineering at Carleton University in Ottawa, Canada, where I have been employed
`since 2006. I taught and performed research at the University of Ottawa between 2002 – 2006.
`As part of my position at the University of Ottawa, I supervised student research.
`
`2.
`With Dr. Robert deKemp as my co-supervisor, I supervised Ran Klein’s research and
`the resulting thesis, Precise 82Rb Infusion System for Cardiac Perfusion Measurement Using 3D
`Positron Emission Tomography (“Klein Thesis”). The Klein Thesis is an Ottawa-Carleton
`Institute for Electrical and Computer Engineering School of Information Technology and
`Engineering (Electrical & Computer Engineering) thesis submitted to the Faculty of Engineering
`at the University of Ottawa in 2005.
`
`3.
`I maintained a website for my professional matters while working at the University of
`Ottawa and, later, at Carleton University. While at the University of Ottawa, my website was
`located at http://www.site.uottawa.ca/~adler. When I moved to Carleton University, I relocated
`my professional website to a new location at http://www.sce.carleton.ca/faculty/adler.
`
`4.
`I published the Klein Thesis on my professional webpage at the University of Ottawa
`initially in April 2005. I removed the Klein Thesis from my webpage in November 2005 but
`republished it on my professional webpage at the University of Ottawa in the early summer of
`2006.
` When I relocated my professional website
`to
`the University of Carleton
`(http://www.sce.carleton.ca/faculty/adler) later in the summer of 2006, I republished the Klein
`Thesis at this new Internet location.
`
`5.
`The Klein Thesis has been accessible to the public from my professional webpage
`continuously since at least 2006, first, at the University of Ottawa (http://www.site.uottawa.ca/-
`~adler) and, later, at Carleton University (http://www.sce.carleton.ca/faculty/adler).
`
`JUBILANT EXHIBIT 1020
`Jubilant v. Bracco, IPR-01449
`
`

`

`Adler Declaration
`
`6.
`While I worked at the University of Ottawa, I regularly updated my professional
`website to keep it current, and I posted information related to the research that I supervised on a
`“Students” page, which was publicly available. This includes making available to the public
`copies of the publications that resulted from the research that I supervised, such as the Klein
`Thesis.
`
`7.
`Attachment A to this Declaration is a true and accurate copy of the Klein Thesis as I
`published it on my professional website at the University of Ottawa in April 2005 and, later, in
`2006.
`
`8.
`During the time when my professional website was maintained on the University of
`Ottawa website (http://www.site.uottawa.ca/~adler), it was available to be indexed and locatable
`through Internet search engines. The Wayback Machine, for example, indicates that its crawler
`system captured my professional website at http://www.site.uottawa.ca/~adler several times
`between 2002-2006.
`
`9.
`Attachment B is a copy of the “Students” page from my professional website as
`captured by
`the Wayback Machine
`from
`the University of Ottawa website
`(http://www.site.uottawa.ca/~adler) on July 3, 2006. Attachment B is a true and accurate copy of
`the “Students” page from my professional website as it existed on July 3, 2006.
`
`10.
`Attachment B identifies the Klein Thesis with a hyperlink. The hyperlink provided
`the means for members of the public to download the Klein Thesis from my professional website
`on the University of Ottawa website.
`
`11.
`As mentioned, I changed employment from the University of Ottawa to Carleton
`University in the summer of 2006, and I relocated my professional website to a website
`(http://www.sce.carleton.ca/faculty/adler/) at Carleton University. Initially, I republished all
`content from my professional website, including the Klein thesis as it existed on the University
`of Ottawa’s website, to its new location on the Carleton University website. I have continued to
`supplement my professional website since 2006.
`
`12.
`captured
`
`Attachment C is a copy of the “Students” page from my professional website as
`by
`the Wayback Machine
`from
`the Carleton University website
`
`
`
`Page 2 of 3
`
`

`

`Adler Declaration
`
`(http://www.sce.carleton.ca/faculty/adler) on September 25, 2006. Attachment C is a true and
`accurate copy of the “Students” page from my professional website as it existed on September
`25, 2006.
`
`13.
`Attachment C identifies the Klein Thesis with a hyperlink. The hyperlink provided
`the means for members of the public to download the Klein Thesis from my professional website
`on the Carleton University website.
`
`14.
`Thus, the Klein Thesis first was made accessible to the public from my professional
`webpage in April, 2005. It was removed and republished on my professional website in summer
`2006, first, at the University of Ottawa (http://www.site.uottawa.ca/~adler) and, later, at Carleton
`University (http://www.sce.carleton.ca/faculty/adler). The Klein Thesis has been available for
`download from my professional website continuously since the early summer of 2006 and no
`later than July 3, 2006.
`
`I declare that all statements made herein of my own knowledge are true and that all
`statements made on information and belief are believed to be true; and further that these
`statements were made with the knowledge that willful false statements and the like so made are
`punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States
`Code.
`
`
`
`Date: __________________
`
`
`
`
`
`
`
`
`
`
`
` _____________________________
`
`Dr. Andy Adler
`
`
`
`
`
`Page 3 of 3
`
`17 August 2018
`
`

`

`Exhibit A
`
`
`
`
`Exhibit A
`
`
`
`
`
`
`
`
`

`

`Andy Adler
`
`Page 1 of 1
`
`uOttawa
`
`Engineering
`
`SITE
`
`Staff
`
`A. Adler
`
`Courses
`ELG 7173 - Topics in Signal Processing II: Medical Imaging
`MCG 4150 - Bioinstrumentation and Biocontrols
`Research:
`Publications
`Presentations
`Students
`Undergraduate Projects
`Research Groups:
`
`VIVA Lab
`SMRLab (Sensing and Modeling Research)
`Biography
`Office Hours(during term)
` 1330−1530 Tuesdays
` 1000−1200 Fridays
`Software (Open Source)
`Octave (download)
`
`Andy Adler
`
`Ph.D.
`Assistant Professor
`
`Andy Adler
`
`School of Information Technology and Engineering (SITE), University of Ottawa
`161 Louis Pasteur
`Ottawa, Ontario, Canada, K1N 6N5
`Tel: (613) 562-5800 ext. 6218, Fax: (613) 562-5175
`Office: Colonel By Hall, A-610
`Email: adler@site.uottawa.ca
`PGP Fingerprint: 8D4E 497F 418D 48D9 1626 C614 0C30 9D2C B728 87D8
`
`Last Updated: $Date: 2005-01-17 17:04:48 -0500 (Mon, 17 Jan 2005) $
`
`http://www.sce.carleton.ca/~adler/webversion2005-04-02/
`
`7/18/2018
`
`

`

`Exhibit B
`
`
`
`
`Exhibit B
`
`
`
`
`
`
`
`
`

`

`Graduate Students
`
`Page 1 of 2
`
`uOttawa
`
`Engineering
`
`SITE
`
`Staff
`
`A. Adler
`
`Students
`
`Graduate Students
`
`Ph.D.
`
`• Brad Graham
`− Project: Compensation for image artefacts in EIT images of lungs
`• Tao Dai
`− Project: TBD
`
`M.A.Sc.
`
`• Richard Youmaran
`− Project: Automatic analysis of ultrasound images of the eye
`• Tatyana Dembinsky
`− Project: Evaluation of Iris Recognition Technology
`• Camille Gomez-Laberge
`− Project: TBD
`
`Information for research group members.
`Alumni
`
`• Yednek Asfaw
`− M.A.Sc. (2005):
`• Ran Klein (Co-supervision with R. DeKemp)
`− M.A.Sc. (2005): Precise 82Rb Infusion System For Cardiac Perfusion Measurement Using 3D Positron
`Emission Tomography
`• Tong Qu (Co-supervision with A. El Saddik)
`− M.A.Sc. (2004): Dynamic Signature Verification System Design Using Stroke Based Feature Extraction
`Algorithm
`• Yi Pan
`− M.Eng. (2004):
`Undergraduate Projects (CEG/SEG/ELG 4905 / CSI 4900)
`Previous Undergraduate Projects
`
`2005
`
`2004
`
`• Roger Messier
`− Project: Web to LCD display gateway
`• Alex Richer
`− Project: Eddy current monitoring technology
`• Maria Gorlatova
`− Project: Calculation of airflow parameters in a novel device for measuring mouse breathing
`• Yevgeniya Yodko, Ozgur Candir, Lengwan Ren
`− Project: Variability in electrode measurements in Electrical Impedance Tomography
`
`2003
`
`• Jamal Abdo
`− Project: Eddy current monitoring Technology Evaluation
`• Payam Abolghasem, Lawrance Santhiyapillai
`− Project: Design and construction of instrumentation amplifiers for ECG/EMG for excercise monitoring
`• Sudhakar Sivapalan
`− Project: Design and construction of instrumentation amplifiers for ECG/EMG for excercise monitoring
`
`http://www.sce.carleton.ca/~adler/webversion2005-04-02/students.html
`
`7/18/2018
`
`

`

`Graduate Students
`
`Page 2 of 2
`
`• Patrick Hunter
`− Project: Face detection using the red-eye effect.
`
`2002
`
`• Sheila Duan, Yuan Chen
`− Project: Control system for Rubidium-82 tracer infusion for PET scanning.
`• Marie-Ange Janvier
`− Project: Finite Element Modeling of intra-venous tracer infusion for Electrical Impedance Tomography
`• Yednekachew Asfaw, Bryan Chen
`− Project: Face detection using infrared imaging and the red-eye effect.
`• Richard Chungphaisan
`− Project: Calculation of airflow parameters in a novel device for measuring mouse breathing
`
`Last Updated: $Date: 2005-04-02 09:10:42 -0500 (Sat, 02 Apr 2005) $
`
`http://www.sce.carleton.ca/~adler/webversion2005-04-02/students.html
`
`7/18/2018
`
`

`

`
`
`
`Exhibit C
`
`
`
`Exhibit C
`
`
`
`

`

`
`
`
`PRECISE 82RB INFUSION SYSTEM FOR CARDIAC PERFUSION MEASUREMENT
`USING 3D POSITRON EMISSION TOMOGRAPHY
`
`
`
`by
`
`
`
`Ran Klein B.A.Sc
`
`
`
`
`
`
`
`A thesis submitted to the
`
`Faculty of Graduate and Postdoctoral Studies
`
`in partial fulfillment of the requirements for the degree of
`
`
`
`
`Master of Applied Science
`
`in Electrical and Computer Engineering
`
`
`
`
`
`
`
`
`Ottawa-Carleton Institute for Electrical and Computer Engineering
`School of Information Technology and Engineering (Electrical & Computer Engineering)
`
`
`Faculty of Engineering
`University of Ottawa
`
`
`February, 2005
`
`©2005, Ran Klein, Ottawa, Canada
`
`
`
`
`
`
`
`

`

`82Rb Elution System Control
`
`Ran Klein, University of Ottawa
`
`Credits
`
`I wish to extend my gratitude to Robert deKemp and Andy Adler for guiding me
`through this project. Their mentoring, support, and friendship have made this a memorable
`experience.
`
`ii
`
`

`

`82Rb Elution System Control
`
`
`
`
`Ran Klein, University of Ottawa
`
`Abstract
`Introduction: Quantitative myocardial perfusion measurements using positron
`emission tomography (PET) can be improved by introducing diagnostic tracers at a constant
`rate of activity. 82Rb can be produced cost effectively by eluting a 82Sr/82Rb generator with
`saline; however, it exhibits an undesirable, but reproducible, activity rate variation.
`Previously, a threshold-comparison algorithm controlled saline flow through either generator
`or bypass line using an on/off valve, to simulate constant-activity elutions. Methods: In this
`work a mechanical system and control software is developed to control tracer infusion. The
`valve is cycled at 5Hz and its duty-cycle controlled by a predictive-corrective algorithm in
`order to reduce measurable activity rate fluctuations. Results: Precision increases (RMS
`error improves from >40% to ~14%) as does the range of relative activities that can be eluted
`from the generator. Conclusion: The proposed method demonstrates superior precision and
`flexibility. However, further tests must be conducted to ensure that the precision of the
`system does not deteriorate over time.
`
`
`
`Key Words: Rubidium-82, 82Sr/82Rb generator, cardiac, perfusion, positron emission
`tomography, PET, predictive control.
`
`
`
`iii
`
`

`

`82Rb Elution System Control
`
`
`
`
`Ran Klein, University of Ottawa
`
`Table of Contents
`
`........................................................................................................................................................ii
`Credits
`.......................................................................................................................................................iii
`Abstract
`Table of Contents..................................................................................................................................................iv
`Table of Figures....................................................................................................................................................vi
`Table of Tables ...................................................................................................................................................viii
`List of Acronyms..................................................................................................................................................ix
`List of Variables .................................................................................................................................................... x
`Introduction
`........................................................................................................................................................ 1
`Chapter 1:
`Introduction to Molecular Imaging and Dynamic PET................................................................... 4
`1.1 Positron Emission Tomography ................................................................................................................ 4
`1.2 82Sr/82Rb Generator – a Cost-effective Tracer Source............................................................................... 7
`Sr Breakthrough............................................................................................................................................. 9
`1.3 82Rb Elution Profiles ............................................................................................................................... 10
`1.4 Constant-Activity Elution for Quantitative Perfusion Measurement in the Left Ventricle of the Heart . 11
`1.5 Quantitative Perfusion Measurements Using 82Rb.................................................................................. 14
`Chapter 2: The Second Generation 82Rb Infuser – a starting point................................................................. 16
`2.1 The Daily Protocol and Elution Types .................................................................................................... 17
`2.2 Hardware Description ............................................................................................................................. 19
`2.3 Prototype Performance............................................................................................................................ 25
`2.4 Further Development of the 82Rb Elution System (RbES)...................................................................... 26
`Chapter 3:
`System Design and Conceptual Understanding ............................................................................ 28
`3.1 Requirements........................................................................................................................................... 28
`Functional Requirements............................................................................................................................. 28
`Non-Functional Requirements..................................................................................................................... 29
`Other Requirements..................................................................................................................................... 30
`3.2 Initial Design Considerations .................................................................................................................. 32
`Safety........................................................................................................................................................... 32
`Process Monitoring...................................................................................................................................... 33
`Hardware Modifications .............................................................................................................................. 34
`Software packages ....................................................................................................................................... 36
`3.3 Flow Hardware Layout Justification ....................................................................................................... 39
`Pump Speed Variation ................................................................................................................................. 40
`Bypass Ratio Control................................................................................................................................... 41
`3.4 Design of Physical Processes .................................................................................................................. 43
`Run sequence............................................................................................................................................... 44
`Calibration ................................................................................................................................................... 45
`Breakthrough Activity Measurement........................................................................................................... 50
`Elution Tests................................................................................................................................................ 52
`3.5 Software Design...................................................................................................................................... 53
`Pre-Run Stage and the GUI-Sequence......................................................................................................... 53
`Post-Run Stage ............................................................................................................................................ 55
`Real-Time Sequence.................................................................................................................................... 56
`Physical Sequence ....................................................................................................................................... 58
`3.6 Error Detection........................................................................................................................................ 64
`Pressure Errors............................................................................................................................................. 66
`Pump Communication and Operation Errors............................................................................................... 66
`Computer Resources.................................................................................................................................... 67
`Positron Detector Errors .............................................................................................................................. 67
`
`
`
`iv
`
`

`

`82Rb Elution System Control
`
`
`
`
`Ran Klein, University of Ottawa
`
`Dose Calibrator Communication Errors ...................................................................................................... 67
`Maintenance................................................................................................................................................. 67
`Software Errors............................................................................................................................................ 68
`Warnings...................................................................................................................................................... 68
`Outlier Highlighting .................................................................................................................................... 68
`3.7 System Refinement ................................................................................................................................. 69
`Dose Calibrator Spike Removal Algorithm................................................................................................. 69
`3.8 Summary ................................................................................................................................................. 70
`Chapter 4: Elution Profile Control.................................................................................................................. 71
`4.1 Threshold Comparison Algorithm with Auto-tuning Hysteresis Correction (HC-TC) ........................... 73
`4.2 Variable Flow Control............................................................................................................................. 74
`Cycling Valve Control................................................................................................................................. 74
`Transient State Control................................................................................................................................ 74
`Implementation of the Variable Flow Control............................................................................................. 75
`Valve Response Measurements ................................................................................................................... 76
`Modeling of Valve Response....................................................................................................................... 79
`PWM Valve Life Span................................................................................................................................. 80
`4.3 Variable Flow Control Algorithms.......................................................................................................... 81
`PID Control.................................................................................................................................................. 82
`Forgetful PID Controller.............................................................................................................................. 85
`Predictive Control........................................................................................................................................ 85
`Predictive Corrective Control ...................................................................................................................... 88
`Initial Error Removal................................................................................................................................... 89
`Setting the Saline Flow Rate........................................................................................................................ 90
`Automatic Parameter Tuning....................................................................................................................... 91
`Summary...................................................................................................................................................... 96
`Chapter 5: Testing and Characterization......................................................................................................... 98
`5.1 Safety Testing.......................................................................................................................................... 98
`The Worst Case Scenario............................................................................................................................. 99
`5.2 Test Cases.............................................................................................................................................. 100
`User Interface Testing................................................................................................................................ 102
`Functional Testing ..................................................................................................................................... 102
`Error Handling Testing.............................................................................................................................. 103
`5.3 Testing in a Routine Clinical Setting..................................................................................................... 103
`Computer Crash Issue................................................................................................................................ 104
`5.4 Calibration Characterization.................................................................................................................. 106
`Calibration Constant vs. Flow Rate ........................................................................................................... 107
`Summary of Calibration Analysis.............................................................................................................. 109
`5.5 Analysis of the Self-Tuning Model....................................................................................................... 110
`Variation in Valve Model Parameters with Requested Elution Parameters............................................... 112
`Analysis of Tuned Valve Response........................................................................................................... 114
`5.6 Elution Tests.......................................................................................................................................... 116
`Range of Relative Activities as a Function of Elution Duration................................................................ 120
`5.7 Generator Life Span .............................................................................................................................. 121
`Breakthrough Sr Activity........................................................................................................................... 122
`Activity Curves.......................................................................................................................................... 123
`5.8 Benefits of 82Rb Constant-Activity Elutions ......................................................................................... 124
`Comparison of 82Rb and 13N-ammonia for Measurement of Perfusion in 3D PET ................................... 124
`Optimized Perfusion Measurements.......................................................................................................... 126
`5.9 Critical Analysis and Future work......................................................................................................... 127
`Chapter 6: Conclusion .................................................................................................................................. 130
`List of References.............................................................................................................................................. 133
`Appendix A: Test Cases ................................................................................................................................... 137
`
`
`
`v
`
`

`

`82Rb Elution System Control
`
`
`
`Ran Klein, University of Ottawa
`
`Table of Figures
`Figure 1-1 – Positron emission tomography......................................................................................................... 5
`Figure 1-2 – 82Rb uptake images for measurement of myocardial perfusion. ...................................................... 6
`Figure 1-3 – 82Sr/82Rb decay sequence. ................................................................................................................ 8
`Figure 1-4 – 82Rb activity during recharging of a generator............................................................................... 10
`Figure 1-5 – Generator activity/volume curves with different flow rates and at different times........................ 11
`Figure 1-6 – Dynamic 82Rb imaging of a canine heart. ...................................................................................... 12
`Figure 2-1 – Daily protocol flow chart. .............................................................................................................. 19
`Figure 2-2 – Hardware component diagram of RbES......................................................................................... 19
`Figure 2-3 – Photograph of the assembled RbES and its components................................................................ 24
`Figure 2-4 – Photograph of top cover of the RbES............................................................................................. 24
`Figure 2-5 – Elution of 50% bolus activity within 30 s using a simple threshold comparison algorithm. ......... 25
`Figure 3-1 – Electro-optic level switch operation............................................................................................... 35
`Figure 3-2 – Response of transport of activity through a fixed volume line at a fixed flow rate........................ 40
`Figure 3-3 – Flow control through generator using a bypass line maintains a constant flow rate through all
`other lines. .................................................................................................................................................. 41
`Figure 3-4 – Flow control through the generator using a variable pinch valve on the generator line................. 42
`Figure 3-5 – Flow control through the generator using a double sided pinch valve on the bypass line and
`generator line. ............................................................................................................................................. 43
`Figure 3-6 – Schematic of the activity counter relating some of the factors that contribute to its efficiency
`measure....................................................................................................................................................... 46
`Figure 3-7 – Dose calibrator chamber measurement diagram. ........................................................................... 47
`Figure 3-8 – Sample calibration run results........................................................................................................ 48
`Figure 3-9 – Aperture response of the dose calibrator as a function of distance along the saline line from
`the vial. ....................................................................................................................................................... 49
`Figure 3-10 – Example of a constant-flow test run without (top) and with (bottom) a Gaussian aperture
`correction.................................................................................................................................................... 50
`Figure 3-11 – Opening message screen. ............................................................................................................. 53
`Figure 3-12 – Various screenshots...................................................................................................................... 54
`Figure 3-13 – Sequence, data, and control, flow and structure diagram of software.......................................... 56
`Figure 3-14 – The Hardware_Interface model.................................................................................................... 57
`Figure 3-15 – Flow Chart for all elution types. .................................................................................................. 59
`Figure 3-16 – Inputs to the Physical_Sequence M-file S-Function block. ......................................................... 62
`Figure 3-17 – Calibration results with and without the dose calibrator peak removal algorithm. ...................... 70
`Figure 4-1 – Elution of 50% bolus activity within 30 s using a simple threshold comparison algorithm. ......... 72
`Figure 4-2 – Pulse-width-modulation control of a solenoid valve to simulate a variable pinch valve. .............. 74
`Figure 4-3 – Activity vs. time curves as measured with the generator valve cycling at 15 Hz at various
`generator valve duty-cycles. ....................................................................................................................... 76
`Figure 4-4 – Valve response curves at υvalve = 2, 5, 15, and 100 Hz................................................................... 77
`Figure 4-5 – Elutions at valve flow ratio ≈ 50% produced by cycling the generator valve at 2, 5, and
`15 Hz. ............................