DECLARATION OF VENKATESH L. MURTHY, M.D., Ph.D.
`
`I, VenkateshL. Murthy, declare as follows:
`
`1.
`
`I have been retained by Jubilant DraxImage,Inc. ("Jubilant") to offer
`
`the instant declaration.
`
`I understand that Jubilant is petitioning the United States
`
`Patent and TradeinarkOffice for interpartes review of patents related to rubidium-
`
`82 elution systems.
`
`I have been retained by Jubilant to explain, in this declaration,
`
`medical uses of rubidium-82 and standard medical procedures therefor.
`
`I have not
`
`been asked to analyze or provide legal opinions regarding any patent.
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`I am a board-certifiedphysician in internalmedicine and cardiovascular
`
`2.
`
`disease and an associate professor at the University of Michigan in its Department
`
`of Radiology, Divisions of Nuclear Medicine and CardiothoracicRadiology, and
`
`Departmentof Internal Medicine, Division of CardiovascularMedicine.
`
`3.
`
`I
`
`received a B.S.
`
`in Biology and a M.S.
`
`in Chemistry from the
`
`Massachusetts Institute of Technology in 1996.
`
`I received a Ph.D. in Biophysics
`
`and Biophysical Chemistry from Johns Hopkins School of Medicine in 2001 and a
`
`M.D. from Johns Hopkins School of Medicine in 2004.
`
`I completedmy Internal
`
`Medicine Internship at Johns Hopkins Bayview Medical Center in 2005.
`
`In 2006, I
`
`completed one year of Radiology Residency at
`
`the Mallinckrodt
`
`Institute of
`
`A X EXHIBITMn/
`Deponent
`
`Date
`tr
`WWW.DEPOBOOKPRODUCTSCOM
`
`JUBILANT EXHIBIT 1017
`Jubilant v. Bracco IPR2018-01448
`
`Bracco Ex. 2017
`Jubilant v. Bracco
`IPR2018-01449
`
`

`

`Radiology at Barnes-Jewish Hospital. In 2008,
`
`I completedmy Internal Medicine
`
`Residency at Johns Hopkins Bayview Medical Center. Between2008 and 2012,
`
`I
`
`completed a CardiovascularMedicine Fellowship and a CardiovascularImaging
`
`Fellowship at Brigham & Woman'sHospital. I hold a Level 3 certification from the
`
`Certification Board in Nuclear Cardiology, a Level 2 Compreherisive certification
`
`from the National Board of Echocardiography, and have completedLevel 3 training
`
`in CardiovascularMRI.
`
`I am a Fellow of the American Collegeof Cardiology, the
`
`AmericanHeart Association, and the American Society of Nuclear Cardiology.
`
`4.
`
`At the University of Michigan, between 2012 and 2017,
`
`I served as
`
`a
`
`Clinical AssistantProfessor in the Departmentof Radiology's Division of Nuclear
`
`Medicine and CardiothoracicRadiology, and the Departmentof Internal Medicine's
`
`Division of CardiovascularMedicine. Since 2017,
`
`I have served as
`
`a Clinical
`
`Associate Professor in Departmentof Radiology's Division of Nuclear Medicine
`
`and CardiothoracicRadiology, and the Departmentof Internal Medicine's Division
`
`of CardiovascularMedicine. Since 2016,
`
`I also have served as
`
`the Director of
`
`Cardiac PET Research at the Frankel CardiovascularCenter.
`
`I am a member of the
`
`American College of Cardiology (2008), the Society of CardiovascularMagnetic
`
`Resonance (2006),
`
`the American Society of Nuclear Cardiology (2010),.
`
`the
`
`American Heart Association (2010), and the Society of Nuclear Medicine and
`
`Molecular Imaging (2010).
`
`I serve as a reviewer, editor, or board member of more
`
`Page 2 of 17
`
`

`

`than four dozen peer-reviewedjournals in the areas of cardiology, nuclear medicine,
`
`and related topics.
`
`I am an author of 96 peer-reviewedarticles, many of which I was
`
`the lead author.
`
`I am an author of several articles related to rubidium-82 elution
`
`systems,
`
`including:
`
`(cid:127) Boyden, et al., "Risk stratification with myocardial perfusion Rb-82
`positron emission tomography," Curr. Cardiovasc. Imaging Rep. v. 7,
`pp. 9266 (2014);
`(cid:127) Moody, et al., "Limitations of 82Rb weight-adjusteddosing accuracy
`at low doses," J Nuclear Cardiology, v. 24, pp. 1395-1401 (2017); and
`Lee, et al., "Optimization of temporal sampling for 82Rb myocardial
`blood flow quantification," J. Nuclear Cardiology, v. 24, pp. 1517-29
`(2017).
`
`(cid:127)
`
`5.
`
`I have personal experience working with rubidium-82 elution systems.
`
`I first started working with rubidium-82 elution systems during mygt Brigham &
`
`Woman's Hospital, which began in July 2008. There, I trained in the use of such
`
`systems, particularly the Cardiogen-82®Infusion System, discussed below. As part
`
`of my training, I
`
`reviewed journal articles describing medical applications of
`
`rubidium-82, and product documentation,describing operating procedures of the
`
`Cardiogen-82®Infusion System, as it existed in 2008. Also, I received training from
`
`faculty at Brigham & Woman's Hospital regarding such procedures. Thus, I am
`
`familiar with prevailing medical practices in 2008 generally and as
`
`they apply to
`
`rubidium-82 elution systems.
`
`Page 3 of 17
`
`

`

`6.
`
`I have participatedin approximately3,000 to 4,000 rubidium-82patient
`
`elutions over my career. Since 2012,
`
`I have been responsible for training new
`
`physicians in rubidium-82 elutions and supervising the
`
`rubidium-82 elution
`
`procedures at
`
`the University of Michigan. The University of Michigan, where I am
`
`employed, purchased rubidium-82 generators
`
`for
`
`the Bracco CardioGen-82
`
`rubidium-82 elution system for over ten years, from 2007 to 2017. As such,
`
`I have
`
`first-hand knowledge about
`
`the day-to-day operation of rubidium-82 elution
`
`systems,
`
`including
`
`the
`
`accepted
`
`practices
`
`for
`
`infusion
`
`of
`
`various
`
`radiopharmaceuticalagents for use in Positron EmissionTomographyand the use of
`
`rubidium-82 as one such radiopharmaceutical.
`
`7.
`
`My curriculum vitae, which is attached hereto as Exhibit A, contains a
`
`more detailed descriptionof my background.
`
`8.
`
`I am being compensated at my usual consulting rate of $500 per hour
`
`for my technical analysis in this matter. My compensation is not contingentupon
`
`the results of my work.
`
`II.
`
`OVERVIEW
`
`9.
`
`I was asked to provide an overview of the clinical and institutional use
`
`of rubidium-82, and specifically, to explain the medical procedures
`
`used with
`
`rubidium-82 chloride infusion systems as they existed prior to June 2008.
`
`Page 4 of 17
`
`

`

`10.
`
`At a high level, rubidium-82 elutÍon systems are employedin Positron
`
`Emission Tomography (commonly, "PET") systems,
`
`a type of nuclear molecular
`
`imaging system. A rubidium-82 eluate is infused into a patient's body, where it
`
`is
`
`absorbed by cardiac tissue. The rubidium-82 eluate generates positrons as it decays,
`
`which annihilate with electrons and emit
`
`a pair of photons in opposite directions.
`
`The photons are captured by iniaging equipment,a PET scanner, and an estimate of
`
`the location of the rubidiuml82 can be generated therefrom. Two-dimensional
`
`and/or three-dimensionalimages of the absorption of rubidium-82 into cardiac tissue
`
`may be generated from the PET scans.
`
`11.
`
`Below,
`
`I provide an overview of nuclear
`
`imaging generally, an
`
`introduction to rubidium-82 elutionprotocolsand attendantrisks, and an explanation
`
`of medical procedures performed in 2008 to manage some of those risks.
`
`In this
`
`discussion, I refer to several publicationsthat describe these issues,
`
`follows:
`
`as
`
`perfusion
`infusion system for
`(cid:127) Klein,
`cardiac
`82RB
`"Precise
`measurement using: 3D positron emission tomography", Ottawa-
`CarletonInstitute for Electrical and ComputerEngineering (Feb. 2005)
`("Klein");
`(cid:127) Chatal, et al., "Story of rubidium-82 and advantages for myocardial
`perfusion PET Imaging," Frontiers in Medicine, v. 2, art. 65, pp. 1-7
`(Sept. 11, 2015) ("Chatal");
`"Manufacture of Strontium-82/Rubidium-82
`(cid:127) Alvarez-Diez, et al.,
`Generators and Quality Control of Rubidium-82 Chloride for
`Myocardial Perfusion Imaging in Patients using Positon Emission
`Tomography," Applied Radiation and Isotopes, v.
`50, pp. 1015-23
`(1999) ("Alvarez-Diez");
`
`Page 5 of 17
`
`

`

`11
`
`(July
`
`(cid:127)
`
`III.
`
`(cid:127) Bracco CardioGen-82®Infusion System User's Guide, Rev.
`3, 2007) ("Infusion Manual");
`(cid:127) Bracco CardioGen-82® Rubidium Rb 82 Generator, Rev. 43-8200
`(May 2000) ("GeneratorManual"); and
`the Use of Bar Code Technology in
`Implementation Guide for
`Healthcare, HIMSS (2003) ("HIMSS").
`HISTORY OF DEVELOPMENT AND USE OF RUBIDIUM-82 IN
`MEDICAL DIAGNOSTIC IMAGING
`Overview of Nuclear Molecular Imaging and Positron Emission
`Tomography
`Nuclear molecular imaging has been a leading medical diagnostic tool
`
`A.
`
`12.
`
`for decades, allowing clinicians to image physiological distribution of specific
`
`moleculeswithin the body in a non-invasivemanner. Klein at 4, Chatal at 1.
`
`In this
`
`process,
`
`a compound labeled with a radioactive isotope (a "tracer") is
`
`introduced
`
`into a patient, usually by injection, and the tracer's location is later imaged using a
`
`scanner that is sensitiveto radiation emitted by the tracer. Klein at 4.
`
`13.
`
`Different radioactive tracers are designed to concentrate in different
`
`locations in a patient's body by participating in the biochemicalprocesses
`
`at those
`
`locations. Klein at 4. Over time, the radioactivelabel
`
`in the tracer decays, resulting
`
`in the emission of radiation, which can be imaged.
`
`Id. As the tracer interacts with
`
`the body, the concentrations of the tracer in those locations varies over time.
`
`Id.
`
`14. When imaging a patient, tissues that contain high concentrations of a
`
`tracer will radiate strongly compared to other tissues. A scanner that is capable of
`
`Page 6 of 17
`
`

`

`detecting the radiation will measure the radiation and reconstruct
`
`tomographic
`
`images (two-dimensional slices or sections) of the location of interest. Klein at 4.
`
`Because of the imeasureable change over time,
`
`the resulting images reflect
`
`the
`
`i
`
`biochemical and physiological processes within the body,
`
`as opposed to the
`
`anatomical images produced by other techniques such
`
`as conventional x-ray
`
`computedtomography(CT) and magnetic resonance imaging (MRI).
`
`Id.
`
`15.
`
`Radioactive material, in a closed system, experiences an exponential
`
`decrease in observed activity as time progresses. The rate of decay is a characteristic
`
`property of each radioactiveisotope. Klein at 4. The average time required for the
`
`activity to reach half of its original activity is referred to as
`
`the "half-life" of the
`
`isotope, expressed as "Tii2," and can vary from split seconds to years.
`
`Id.
`
`16.
`
`The half-life of a
`
`tracer dictates how much time can pass between
`
`productionof the tracer and the PET scan itself. Klein at 7. Tradeoffsexist between
`
`short half-lives, which reduce patient and practitioner radiation exposure and
`
`decrease the turnaroundtime between scans, and longer half-lives, which increase
`
`the usable window of the tracor and the options availablefor producing the tracer.
`
`Klein at 7, Chatal at 1, 4.
`
`B.
`
`Medical Uses of Rubidium-82
`17. Medical applicationsofrubidium-82 first were uncovered in the 1950's
`
`when it was discovered that biological behavior of rubidium was comparable to
`
`Page 7 of 17
`
`

`

`potassium, and that its myocardialmuscle uptake was proportional to blood flow in
`
`coronary arteries. Chatal at 1. Thus, rubidium-82 can be used to image blood flow
`
`to cardiac tissue.
`
`18.
`
`Preclinical studies were performed through the 1980s, primarily on
`
`dogs. Chatal at
`
`1.
`
`In the 1980s, clinical studies wëre performed on hundreds of
`
`patients.
`
`Id. They demonstratedgood diagnostic accuracy of rubidium-82 PET
`
`techniques, and superior performance to another technique, called technetium-
`
`99m/SPECT. Id.
`
`19.
`
`In 1989, the U.S. Food and Drug Administration ("FDA") approved a
`
`strontium-82/rubidium-82 generator, called the CardioGen-82®, for clinical use.
`
`Klein at 7, Chatal at
`
`1. Following FDA approvalin 1989, the CardioGen-82®was
`
`released to market and was utilized by many medical imaging centers and research
`
`centers to generate rubidium-82 for patient infusion. Klein at 7, Chatal at 1. Thus,
`
`rubidium-82 elutions were in medical use for almost 20 years prior to 2008 and
`
`standard medical protocols were developedaround the CardioGen-82® Infusion
`
`System.
`
`20.
`
`As noted,
`
`rubidium-82 can be used to image blood. flow to cardiac
`
`tissue. Klein at 4. PET images will reflect the rubidium-82 uptake within the cardiac
`
`tissue, and inconsistencies in uptake can reflect cardiac impairments.Id. Thus, PET
`
`Page 8 of 17
`
`

`

`scans can indicate abnormalities in blood flow to cardiac tissue and can lead to
`
`diagnoses of cardiac conditions.
`
`C.
`
`21.
`
`Generating Rubidium-82
`Rubidium-82 can be generated at relatively low cost using a strontium-
`
`82/rubidium-82generator which produces rubidium-82 as a byproductof strontium-
`
`82 decay. Chatal at 4, Klein at 7-8. As strontium-82 decays within a strontium-
`
`82/rubidium-82 generator, it generates rubidium-82 which remains bound to the
`
`substrate.
`
`Id.. When a saline solution, such as 019% NaCl saline,
`
`is flushedthrough
`
`the strontium-82/rubidium-82;generator, the rubidium-82 is displaced from the
`
`substrate by sodium (Na) and the rubidium-82 (82Rb) is eluted in the form of 82RbCl
`
`(eluate) that can be infused into a patient.
`
`Id.
`
`22.
`
`Rubidium-82 has a relatively short half-life of 76 seconds, which is
`
`shorter than other tracers comthonly used for medicál imaging. Chatal at 4; Klein at
`
`7. For example,the technetium-99mused in the competitive SPECT technique has
`
`a half-life of 6 hours.
`
`Id. Because of rubidium-82's short half-life, its effective
`
`radiation dose to patients and window of potential exposure to medical staff can be
`
`lower than for other tracers that have longer half-lives.
`
`23.
`
`Strontium-82, a
`
`required ingredient in a strontium-82/rubidium-82
`
`generator, has a relatively long half-life of 25.5 days. Klein at 8. As a byproductof
`
`the strontium-82production, strontium-85 (Tl/2=64.8 days)
`
`is also produced.
`
`Id.
`
`Page 9 of 17;
`
`

`

`Although the strontium-85is not beneficialfor rubidium-82production,it
`
`is difficult
`
`to separate from strontium-82 and thus it
`
`is present
`
`in each batch of strontium-82
`
`created by a manufacturer.
`
`Id.
`
`24.
`
`Because of the strontium-82'srelatively long half-life, there is no need
`
`to produce the strontium-82 at
`
`a scanning site.
`
`:Klein at
`
`8.
`
`The strontium-
`
`82/rubidium-82generator may be inanufactured at one location, then transported to
`
`a scanning site where it would generate rubidium-82 for infusion into a patient.
`
`Thus, use of a strontium-82/rubidium-82 generator permits use of PET scans at a
`
`medicalfacility without incurring the expense of a cyclotron or other equipmentthat
`
`would be required to generate radioactive material on site. Rubidium-82, on the
`
`other hand, with its short 76 second half-life, must be produced at the scanning site
`
`using a generator. Chatal at 1, 4; Klein at 7.
`
`25.
`
`Prior
`
`to 2008,
`
`the CardioGen-82® Infusion System was
`
`a self-
`
`contained system that accepted a replaceable strontium-82/rubidium-82generator.
`
`The strontium-82/rubidium-82 generator typically would be replaced every one to
`
`two months. As with many other medical systems,
`
`the CardioGen-82®Infusion
`
`System was provided as wheeled cart
`
`that permitted the CardioGen-82®Infusion
`
`System to be movedabout in a hospitalenvironment. The CardioGen-82®Infusion
`
`System also contained tubing circuits that were intended to be replaced every time
`
`Page 10 of 17
`
`

`

`the strontium-82/rubidium-82 generator was
`
`replaced.
`
`Alvarez-Diez at 1020;
`
`Infusion Manual at 1; Klein at 19-25.
`
`D.
`
`26.
`
`Risks Associated with strontium-82/rubidium-82 Generators,
`Including Strontium Breakthrough, and Controls Therefor
`The use of strontium-82/rubidium-82generator systems and the related
`
`infusion systemd presents certaiñ risks. First, the strontium-82material contained in
`
`the strontium-82/rubidium-82generator, the strontium-85material contained in the
`
`strontium-82/rubidium-82 generator,
`
`and
`
`the
`
`rubidium-82 eluate
`
`generated
`
`therefrom all are radioactive.
`
`It
`
`is extremely important to minimize radiation
`
`exposure and to shield patients and medical personnel from inadvertentradiation
`
`exposure at all times. For this reason, all rubidium-82 elution systems,
`
`including the
`
`CardioGen-82® Infusion System and predlinical systems described in academic
`
`literature, possess extensivesliielding. Generator Manual, p. 5; Klein at 8.
`
`27.
`
`Another risk associated with the use of strontium-82/rubidium-82
`
`generators to pröduce rubidium-82 eluate for infusion is the possibility of strontium
`
`"breakthrough."Klein at 9. As saline is flushed throughthe strontium-82/rubidium-
`
`82 generator, some strontium (either strontium-82 or strontium-85) appears in the
`
`eluate.
`
`Id.
`
`In high enough quantities, these compounds have adverse health effects
`
`because strontium is absorbed in bone, which surrounds bone marrow, and can cause
`
`increased risks of cancer.
`
`Id.
`
`Page 11 of 17
`
`

`

`28.
`
`Various guidelines have been promulgated by different regulatory
`
`agencies relatingto guidelinesfor strontiumexposure. By no later than 2005, Health
`
`Canada guidelines dictated that strontium-82 and strontium-85 breakthroughnot
`
`exceed 20 BqlMBq and 200 Bq/MBq respectivelyof the eluted rubidium-82activity.
`
`Klein at 9. Since at
`
`least as early as the 1990s,
`
`the U.S. Pharmacopeia has
`
`included
`
`radionucleic purity specifications for rubidium chloride injections.
`
`JDGØ at 1392.
`
`USP 23 specifies a maximum strontium-82 activity in rubidium-82 eluate (after 1
`
`hour of standing) of 0.02 kBq per MBq of rubidium-82 and a maximum strontium-
`
`85 activity of 0.2 kBq per MBq of rubidium-82,the same as Health Canada.
`
`Id. The
`
`Cardiogen-82®was approved by the FDA with the same limits. Generator Manual
`
`at 1.
`
`Id
`
`"When eluted at a rate of 50 mL/minute, each generator eluate at
`the
`end of elution should not contain more than 0.02 microcurie of
`strontium Sr 82 and not more than 0.2 microcurie of strontium Sr 85
`per millicurie of rubidium chloride Rb 82 injection, and not more than
`1 microgram of tin per mL of eluate."
`
`29.
`
`In order to minimize the risks associated with strontium breakthrough,
`
`daily breakthroughtests were required to be performed before patientelutionscould
`
`occur. These breakthroughtests tested a sample of eluate generated by an strontium-
`
`82/rubidium-82generator using a radiationdetector (or dose calibrator) to quantify
`
`Page 12 of 17
`
`

`

`any strontium in the eluate before human use. Klein at 18, Generator Manual at 9;
`
`Infusion Manual at 31.
`
`30.
`
`Prior to 2008, daily breakthroughtests for the CardioGen-82®Infusion
`
`System required a multistep manual process,
`
`follows:
`
`as
`
`a.
`
`flushing the geileratorwith, for example, 50mL of saline at a rate of 50
`
`mL/rnin, and collecting a test sample of the eluate;
`
`b. mensuring radiation activity of the test sample quickly after elution;
`
`c. allowing the test sample to stand for approximately60 minutes;
`
`d. measuring radiation activity of the test sample after the 60 minute
`
`standing period concludes.
`
`Generator Manual at
`
`10.
`
`- During the 60-minute period between the first
`
`measurement of radiation activity and the second measurement of radiation activity,
`
`radiation activity of the rubidium-82 decays to a negligible level. The activity that
`
`remains at
`
`the end of the 60-minute period reflects activity of the strontium-82 and
`
`the strontium-85. An operator calculates the strontium-82 and strontium-85
`
`breakthroughvalues from the recorded measurements and times and compares them
`
`to designated limits. Id.
`
`31.
`
`Once strontium breakthroughin a strontium-82/rubidium-82generator
`
`exceeds regulatory limits, it cannot be stopped or reversed. The generator must be
`
`Page 13 of 17
`
`

`

`replaced with a new strontium-82/rubidium-82generator before patientelutionsmay
`
`resume. By 2008,
`
`it was a standard medical practice to suspend all patient elutions
`
`when a strontium breakthrough event
`
`is detected, pending replacement of
`
`the
`
`strontium-82/rubidium-82generator. For example, the CardioGen-82user manuals
`
`make clear
`
`that patient infusion procedures are not to be performed unless the
`
`generator passes the daily strontiumbreakthroughtest:
`
`PATIENT ADMINISTRATION MAY BE PERFORMED ONLY
`AFTER SUCCESSFULCOMPLETION OF DAILY CALIBRATION,
`SR-82/85 BREAKTHROUGH PROCEDURES,AND FIRST WASH
`(ELUTION) DISPOSAL USING SAME SETTINGS AS SEEN ON
`SR-82/85 BREAKTHROUGH SHEETPAGE.
`
`Infusion Manual at 31.
`
`32.
`
`Thus, by 2008,
`
`it was a standard medical practice to perform strontium
`
`breakthroughtests by hand on a daily basis prior to the first patient inftision of the
`
`day.
`
`It was also standard medical practice to disqualify a strontium-82/rubidium-82
`
`generator from further use if the generator failed a strontium breakthroughtest, and
`
`the amountof strontiumpresent in a test sample of eluate exceeded regulatorylimits.
`
`33. Moreover, by 2008,
`
`it was a standard medical practice to create written
`
`records of all medical procedures performed on patients, and to create written
`
`records of all procedures performed to setup, calibrate, and approve medical
`
`equipment for daily patient use. The CardioGen-82® Infusion System was no
`
`Page 14 of 17
`
`

`

`different. For example,the CardioGen-82®Infusion System user manual contained
`
`a "CARDIOGEN® Rb-82 Generator Sr-82 Breakthrough Log Sheet"
`
`in which
`
`operators compiled data regarding results of the:daily strontium breakthroughtests
`
`performed on individual generators.
`
`Infusion Manual at 38. The CardioGen-82®
`
`Infusion System:usermanualalso contained an "Rb-82 Infusion System Calibration
`
`Log Sheet"
`
`in which operators logged generator performance data obtained from
`
`calibration infusions and calibration factors computed from that data.
`
`Infusion
`
`Manual at 37. The BreakthroughLog Sheet and the CalibrationLog Sheet both were
`
`designed to be restarted for each generator received from the manufacturer, which
`
`identified its "GeneratorLot Number." Id., at 37-38.
`
`IV.
`
`STANDARD INFORMATION TECHNOLOGY PRACTICES IN
`MEDICAL FACILITIES
`it was a standard medical practice to employ information
`
`By 2008,
`
`34.
`
`technologysystems to track patients, medical devices and medicines within medical
`
`facilities. See generally, HIMSS. For example,patients commonly were assigned
`
`bar-coded bracelets upon admissionto a facility and their paper charts were given
`
`labels with the same bar coding. HIMSS, at 5-6.
`
`In this manner, when medicines
`
`were administeredto a patient, the patient's bar code would be scanned to generate
`
`a record of the event. See, HIMSS, at 6, 21. Moreover, when medical personnel
`
`I
`
`Page 15 of 17
`
`

`

`needed to review a patient's medical file,
`
`the same bar code would be scanned to
`
`retrieve the patient's file.
`
`35. Medical devices and medicines also were assigned bar codes. HIMSS
`
`at
`
`ix, 6. By 2008,
`
`it was common use bar codes to trackAtt a variety of healthcare
`
`assets including patient records, medications,
`
`reusable and disposable medical
`
`devices, blood and tissue specimens, and movablemedical equipment. See, HIMSS,
`
`at 6, 21; see also,
`
`id. at Ch. 3-5. When medical personnel would retrieve medical
`
`devices from inventory at
`
`a facility,
`
`they would track their use by scanning the
`
`devices' bar codes,
`
`as well as bar codes on a patient's file or
`
`identification band.
`
`Similarly, medicines were assigned bar codes, which would be scanned upon
`
`retrieval from the pharmacy and administrationto patients. Bar codes could contain
`
`a variety of information, including product identifiers, medication type, lot numbers,
`
`or patient data.
`
`I am not aware that the CardioGen-82®Infusion System had such
`
`capabilities,however.
`
`V.
`
`DECLARATION IN LIEU OF OATH
`In signing this declaration, I realize that this declaration will be filed as
`
`36.
`
`evidence in a contested case before the Patent Trial and Appeal Board of the United
`
`States Patent and TrademarkOffice.
`
`37.
`
`I am aware that willfully false statements and the like made by me in
`
`connection with this declarationare punishableby fine or imprisonment,or both (18
`
`Page 16 of 17
`
`

`

`U.S.C. § 1001) and may jeopardizethe validity of the Petition. All statementsherein
`
`made by me of my own knowledgeare true and all statements made on information
`
`and belief are believed to be true.
`
`I declare under penalty of perjury that
`
`the
`
`foregoing is true and correct.
`
`nkatesh L. Murthy, M.D., Ph. D.
`
`Page 17 of 17
`
`

`

`Exhibit A
`Exhibit A
`
`

`

`Venkatesh L. Murthy, M.D., Ph.D.
`Associate Professor
`University of Michigan
`Internal Medicine, Division of Cardiovascular Medicine
`Department
`of
`Department of Radiology, Divisions of Nuclear Medicine and Cardiothoracic Radiology
`1338 Cardiovascular Center
`1500 E. Medical Center Drive, SPC 5873
`Ann Arbor, MI 48109
`Tel: (734) 936-5387 Fax: (734) 232-3246
`vimurthy@med.umich.edu
`
`9/1996-5/2004
`
`7/2004-6/2005
`7/2005-6/2006
`
`EDUCATION AND TRAINING
`9/1993-6/1996
`Massachusetts Institute of Technology, Bachelor of Science (Biology) &
`Master of Science (Chemistry)
`Johns Hopkins School of Medicine, Doctor of Medicine (awarded 5/2004)
`& Doctor of Philosophy (Biophysics and Biophysical Chemistry, awarded
`2/2001), NIH Medical Scientist Training Program
`Johns Hopkins Bayview Medical Center, Medicine Internship
`Mallinckrodt Institute of Radiology, Barnes-Jewish Hospital, Radiology
`Residency
`Johns Hopkins Bayview Medical Center, Medicine Residency
`Brigham & Women's Hospital, Cardiovascular Medicine Fellowship
`Harvard School of Public Health: Program in Clinical Effectiveness
`Brigham & Women's Hospital, Cardiovascular Imaging Fellowship
`Brigham & Women's Center for Clinical Investigation: Advanced
`Biostatistics for Medical Researchers .
`Harvard University Catalyst Program: Certificate in Applied Biostatistics
`Brigham & Women's Hospital: Current Clinical Practice of Non-Invasive
`Vascular Diagnostic Imaging
`
`7/2006-6/2008
`7/2008-6/2011
`7/2010-8/2010
`7/2010-8/2012
`5/2011
`
`9/2011-6/2012
`5/2012
`
`CERTIFICATION AND LICENSURE
`8/2008 -12/2018
`Internal Medicine
`American Board of Internal Medicine,
`11/2011-12/2021
`American Board of Medicine, Cardiovascular Diseases
`Drug Enforcement Administration, controlled Substances Registration
`1/2008-1/2017
`Massachusetts Board of Registration in Medicine, Medical License
`5/2008-3/2013
`Massachusetts Controlled Substances Practitioner
`5/2008-5/2014
`Michigan Medical License
`7/2012 -· 1/2019
`7/2012-1/2019
`Michigan Controlled Substances License
`2 Comprehensive
`7/2012-6/2022
`National Board of Echocardiography, Level
`1/2013-3/2023
`Certification Board in Nuclear Cardiology, Level
`
`3
`
`Curriculum Vitae: Venkatesh L. Murthy
`
`8 June 2018
`
`1of 34
`
`

`

`7/2012-Present
`2/2014- Present
`9/2014- Present
`
`Cardiovascular MRI, Level
`Fellow of the American College of Cardiology
`Fellow of the American Society of Nuclear Cardiology
`
`3
`
`9/2017-Present
`
`9/2012-9/2017
`
`9/2012-9/2017
`
`ACADEMic, ADMINISTRATIVEAND CLINICAL APPOINTMENTS
`Clinical Associate Professor, Division of Cardiovascular Medicine,
`9/2017-Present
`Department of Internal Medicine (Primary)
`Clinical Associate Professor, Divisions of Nuclear Medicine and
`Cardiothoracic Radiology, Department of Radiology (Secondary)
`Clinical Assistant Professor, Division of Cardiovascular Medicine,
`Department of Internal Medicine (Primary)
`Clinical Assistant Professor, Divisions of Nuclear Medicine and
`Cardiothoracic Radiology, Department of Radiology (Secondary)
`Director of Cardiac PET Research, Frankel Cardiovascular Center
`
`6/2016-Present
`
`RESEARCH INTERESTS
`
`EMERGING NON-INVASIVE IVIETHODS FOR CARDIOMETABOLIC RISK ASSESSMENT
`imaging (PET and CT) and
`I am investigating a number of exciting new tools including the use of
`to non-invasively
`serum biomarkers (ultrasensitive protein assays, microRNAs and metabolites)
`evaluate coronary vascular dysfunction, cardiovascular inflammation and autonomic
`dysfunction and their relationships with adiposity, obesity and cardiometabo ic outcomes
`and heart failure.
`including metabolic syndrome, diabetes, renal failure, coronary heart disease
`
`EFFECTS OF ACCREDITATION,TRAINING AND CERTIFICATION ON QUALITY OUTCOMES IN
`CARDIAC IMAGING
`financial and
`Accreditation is now mandatory in many imaging areas but requires substantial
`time expenditures. We are utilizing Medicare data to evaluate the relationship between
`accreditation on patient-centered quality outcomes including revascularization. Similar
`approaches are also being used to investigate the effects of provider and staff training and
`certification.
`
`EARLY EFFECTS OF CHEST IRRADIATION ON CARDIAc STRUCTURE AND FUNCTI0N
`Together with colleagues in radiation oncology, we are investigating the effects of radiation
`function, myocardial edema,:myocardial
`fibrosis and early
`therapy on coronary vasomotor
`markers of systolic dysfunction.
`
`GRANTS
`
`PRESENT AND ACTIVE
`5/15/2014-4/30/2019 PO1CA059827 (PI: Theodore Lawrence)
`therapy
`Optimization of high dose conformal
`
`Curriculum Vitae: Venkatesh L Murthy
`
`8 June 2018
`
`2 of 34
`
`

`

`Role: Co-I on sub-project examining cardiac toxicity from lung radiation
`therapy
`1/1/2017 -12/31/2018 Hope Foundation (PI: Laurence H. Baker)
`Sarcoma survivorship
`Role: Co-I
`4/1/2017 -3/31/2019 Singulex (PI: Venkatesh Murthy)
`Coronary flow reserve PET biomarker study
`Role: PI
`4/1/2017 -3/31/2022 1RO1HL136685-01 (PI: Venkatesh Murthy and Ravi Shah)
`Molecular markers of early cardiometabolic health transitions in the
`CARDIA study
`Role: PI with Ravi Shah (multiple PI plan)
`Imaging (PI: Venkatesh Murthy)
`1/1/2018 -12/31/2018 Siemens Molecular
`Advanced reconstruction and collimation for cardiac molecular imaging
`Role: Pl
`7/1/2018 -6/30/2023 RO1AGO59729 (PI: Venkatesh Murthy, Anne Newman and Ravi Shah)
`Implications of metabolism on healthy aging in African and Caucasian
`Americans:
`the Health ABC study
`Role: PI with Anne Newman & Ravi Shah (multiple PI plan)
`Percentile score of 2%,
`Impact score of 17
`
`PREVIOUS
`7/1/2014-6/30/2017 2014 Mitzi & William Blahd,
`IVID, Pilot Research Grant
`Molecular irnaging of inflammation in cardiac sarcoidosis
`Role: PI
`10/1/2014-9/31/2017 Breast Cancer Research Fund (PI: Lori Pierce)
`Biomarkers and cardiac MRI as early indicators of cardiac exposure
`following breast radiotherapy
`Role: Primary Co-I
`7/1/2016-6/30/2017 Frankel Cardiovascular Center Micro Grants (PI: Venkatesh Murthy, Roma
`Gianchandani and James Corbett)
`Use of continuous glucose sensors
`myocardial viability testing
`Role: Pl
`1/1/2015-6/30/2017 Intersocietal Accreditation Commission Research Award
`testing in Medicare
`lAC accreditation and the performänce of stress
`beneficiaries
`Role: PI
`4/1/2014-3/31/2017 Stuart and Barbara Padnos Breast Cancer Research Funds
`Cardiac MRI for evaluation of radiation-induced card¡otoxicity in breast
`cancer patients
`Role: Co-PI with Reshma
`Jagsi
`11/1/2012-10/31/2016 Gilead IN-US 259-0160 (PI: Marcelo Di Carli)
`
`to improve throughput and safety of
`
`Curriculum Vitae: Venkatesh L. Murthy
`
`8 June 2018
`
`3 of 34
`
`

`

`Effects of ranolazine on myocardial blood flow in symptomatic patients
`with diabetes and suspected or known coronary arterý disease
`Role: Consultant
`2/1/2015-1/31/2016 Michigan Translational Research and Commercialization Program
`18F-Hydroxyphenethylguanidinesfor PET quantification of cardiac
`sympathetic nerve density in patients with ischemic cardiomyopathy
`undergoing ICD implantation
`Role: Co-PI with David Raffel
`9/1/2014-8/31/2015 Michigan Translational Research and Commercialization for Life Sciences
`Kickstart Award (PI: David Raffel)
`Clinical translation of 18F-hydroxyphenethylguanidines
`cardiac nerve density
`Role: Primary Co-I
`7/1/2014-6/30/2015 Radiology/Nuclear Medicine Seed Grants for Advancing Clinical Use of
`PET Radiopharmaceuticals
`Clinical translation of 18-F-labeled hydroxyphenethylguanidinesfor
`quantification of regional cardiac sympathetic nerve density with PET
`Role: Co-I with PI David Raffel
`Brigham & Women's Cardiovascular Leadership Council Award (Pl: Usha
`Tedrow) Development of advanced tools for image guided
`electrophysiologyinterventions
`Institutes of Health T32 HLO94301 (PI: Marcelo Di Carli)
`National
`Noninvasive Cardiovascular Imaging Research Training Program
`Institutes of Health T32 GMOO7309 (PI: Stephen
`National
`Desiderio/Robert Siliciano) Medical Scientist Training Program
`
`7/2011-6/2013
`
`7/2010 -6/2012
`
`9/1996 -4/2004
`
`for quantifying
`
`1993
`
`1994
`
`1995
`
`1996-2004
`
`HONORS AND AWARDS
`National Merit Scholarship Finalist
`1993
`New York State Governor's Excellence Award
`Massachusetts Institute of Technology, Robert A. Boit Writing Prize
`American Chemical Society, Jarnes Flack Norris & Theodore William
`Richards Undergraduate Research Scholarship
`Institutes of Health, Medical Scientist Training Program
`National
`Fellowship
`Johns Hopkins School of Medicine, Hans J. Prochaska Research Award
`American Society of Nuclear Cardiology/Astellas Scientific Sessions Travel
`Award
`Society of Nuclear Medicine, Cardiovascular Council Young Investigator
`Award First Place
`Society of Nuclear Medicine, Young Professionals Conimittee First Place
`Prize
`
`2001
`
`2010
`
`2011
`
`2011
`
`Curriculum Vitae: Venkatesh L. Murthy
`
`8 June 2018
`
`4 of 34
`
`

`

`2011
`
`2011
`
`2011
`
`2