`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, M.D.
`Case IPR2014-00395
`
`
`
`PERCUTANEOUS AORTIC VALVE
`
`PROPOSAUPROTOCOL
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`l. GOALS:
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`The main oigective ofthis pilot study is to demonstrate the
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`feasibility of/percutaneously placed aortic valve. This*study~is-~
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`Ill. Equipment and Supplies
`1. We propose that we use 10 pigs to place the percutaneous
`devices and to derive the needed data. This would require
`the facilities to house and provide upkeep. Our
`veterinarian facilities have these capabilities. Moreover,
`the facility has a catheterization laboratory which can be
`utilized with proper funding to derive the primary set of
`data. ‘The collaborators and 1? will perform the procedures
`and interpretation necessary to publish our series. There
`will be a need for computers and software for the analysis.
`2. We will be making the valves and stents at the Universityw
`of Missouri unless it is found that we have neither the
`exper”ti§g;Wn;gi:.MejquiprneWntLThus far we have found our
`...........................Ilvaiiéliféiiiical engineering
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`Therefore, much of the expense will logically be in the
`development of the prototypes. The materials will
`include, but will not be limited, to different polymers,
`metals, and ceramics to initiate in a fluid model the exact
`valves we will pursue in the animal models. We estimate
`that the first l0 weeks of research will be the construction
`
`of adequate prototypes.
`. It is invaluable to have adequate visualization of the aortic
`valve for the successful completion of this project, and in
`pursuit of this visualization we will utilize to an extent not
`previously utilized, echocardiography. We will place, as
`will be discussed in the procedures section, 3 echoprobes
`for the adequate visualization of the aortic valve. These
`will be placed in the esophagus, the right atrium, and
`transcutaneously. Also, an intravascular "ultrasound will
`be utilized in the data acquisition portion of the study.
`This could represent a substantial portion of our budget in
`securing these devices.
`. We will also be developing and modifying known
`catheters and peripheral equipment as seen necessary for
`the successful completion of this project. , this
`may lead to a multitude of novel devices, which will be
`needed to visualize and deliver the stent/valve. Further,
`
`there will. be the need for novel debulking devices to
`percutaneously (please see submitted background material
`for further explanation) remove the native aortic valve
`structure sufficiently to relieve the stenosis. This may
`require testing on a delivery device for precise biotome
`resection, percutaneous ultrasound and laser debulking
`and new more effective balloon valvuloplasty. However,
`debulking devices would not be necessary in this protocol
`because the pigs would not have aortic stenosis.
`. Finally, staff will be instrumental in the timely completion
`of this project. These will include maintenance staff for
`the pigs as wel.l as catheterization personnel. The
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`NORRED EXHIBIT 2238 - Page 2
`NORRED EXHIBIT 2238 - Pag 2
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`engineering department will need partial funding for post-
`doctoral candidates to help in the development of the
`valve. As well, the cardiology department and 1 will need
`secretarial support to help in the clerical and
`organizational demands placed upon a rigorous study
`protocol. This staff is fortunately available with a high
`level of experience within. this institution and would only
`need allocation of said monies to properly establish their
`work roles.
`
`IV.
`
`COLLABORATION
`
`_ This project will be a multidiscipline effort including the
`collaborative efforts of representatives from the
`Cardiology, Biophysics, Chemical Engineering,
`En.gineering, Pathology and Veterinary departments.
`Representatives from each department have, to date, been
`utilized in a peripheral manner to gain more knowledge
`and insight to bring about the project to its issuance. This
`working relationship will be needed to successfully
`complete this project.
`
`PROCEDURES
`
`. The project can be roughly divided into 3 phases. The
`first phase will be the successful assembly of working
`prototypes with subsequent fluid model testing. The
`second phase will be the placelnent of the devices into the
`pigs with subsequent data acquisition. The final stage will
`be the analysis of the data with subsequent conclusions.
`TIMELINE:
`
`1. PHASE 1
`
`2. PHASE 2
`
`3. PHASE 3
`
`8 TO 10 WEEKS
`
`1 TO 2 WEEKS
`
`6 TO 8 WEEKS
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`NORRED EXHIBIT 2238 - Page 3
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`This tirneline may be influenced positively or negatively
`dependent upon initial successes/failures encountered at
`each stage.
`
`VI.
`
`DATA ACQUISITION
`
`.. The most important data will be the initial success of
`placing the device without excess mortality in the pigs.
`Subsequently, we will collect data confirming the valves
`function and durability through a variety of ways. These
`will include the use of the echo devices to precisely
`monitor the fimction of the valve in~vivo under a variety
`of stress conditions. Specifically, we will infuse
`vasopressors and chronotropic chemicals into the pigs to
`provide different rate and pressure situations and assess
`each devices’ tolerance to these conditions. An
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`3
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`intravascular ultrasound device will be utilized to assess
`
`the stent deployment within the ascending aorta, and a
`similar intracardiac echo will assess the coaptation of the
`aortic valves within the native aortic valve structure. This
`
`will provide crucial data as to the devices’ ability to open
`and close without impinging upon vital. structures, namely,
`the coronary arteries. The hemodynamic equipment
`within the catheterization lab will be utilized to provide
`information as to the effect of deployment upon. the pigs
`circulatory system. These measurements will include
`instantaneous gradients across the valve and stent
`combination, along with standard measurements of cardiac
`output and systemic resistance. A hematologic profile
`will be collected from each valve to assess its rheostatic
`
`In addition, fibrin
`effects upon the circulating blood pool.
`assays will be drawn to assess tie activation of the
`coagul.a.ti.on cascade, Cardiac enzzymes will be
`periodically drawn to assess for niicroembolization or
`delayed trauma upon the cardiac circulation.
`l7inal.l.y, the
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`NORRED EXHIBIT 2238 - Page 45/? -
`NORRED EXHIBIT 2238 - Page 4
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`will be S2it;lT'.lfi£:t:3€.Tl, after these data lia.ve been eoll.eeted,,
`and tissue sections from the ascending aorta, heart, lora.in,
`luitgs, l<l(ll'i‘t;f:y’S, srileeri and liver will
`taken to assess for
`structural alterations ‘Wh,lCl1lTl!c1yl)€ related to the
`pereutaneou sly delivered valves.
`
`Vll. FUTURE DlRECl‘.l.0NS
`
`l. From this pilot :-study we will liave the inforrnat;'ion ueetied
`to pursue more ambitious projects which will lead ultimately
`to trials in liumans with irioperelile aortie stenesis. From
`eensus data. there were approximately 5 0 million Ainericans
`over the age of 65, Among this popula.tion tliiere is an annual
`incidence of 2 to 9%, depending upon age, of aortic: stenosis.
`This eo- .lt‘i mean that;
`liigh as 4,5 million eaderly persons
`eould suffer from this disease. Among those who are older,
`especially over 7.5, they are less likely to be ope“ratis/e
`candidates. This could represent a tremendous amount of
`patients who could be lielped by'tl1is preeedure.
`i7or the
`investor, this could represent a tremendous previously
`untapped iriarket, which eeuid lead to substantial };;irotits,
`For the physician, more iinportantly, it could lead to
`del‘iuit’ive treatment; where previotisly t"nere were .?ew optiotis
`besides palliation.
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`NORRED EXHIBIT 2238 - Page 5
`NORRED EXHIBIT 2238 - Page 5