`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, M.D.
`Case IPR2014-00111
`
`
`
`PERCUTANEOUS AORTIC VALVE
`
`PROPOSAL/PROTOCOL
`
`l. GOALS:
`
`The main940mm ofthis pilot study18 to demonstrate the
`
`"1:"
`
`1:3.
`
`feasibility ofpercutaneously placed aortic valve. Thisstudyisw
`designedteshewthatsuehadeweeeaabeplaeedwhhoutthe
`.112 1%;
`needfeeasternotomynrmrcuiatorybypass
`A
`x
`1,
`.
`/
`//
`<;~/ ///g/( Zj/t‘: 1/1 14/
`(59:3 // #161? //.///7
`[31:
`ZZ/L’5
`I”) /
`/(/ (K/7 :Z f’,’
`,4? 1/
`A AAA/pA AA)“ Us/(I
`1‘9 / (7 vc: //)/. /
`3’0 <1
`cz x:
`1.11% {A
`CAI-:A
`II HYPOTHESES.
`\/1)1
`MICE H Z
`(57 f“
`K:- // fl/
`1 K ”dz/11’5”
`1.We speculate that we can disperse the forces that are? ”A A’
`.1, 1,,
`required to seat an artificial aortic valve utilizing stent. 1,1,111- ,1.11
`technology.
`WW“. A ’ A
`2. We speculate that this procedure can be done safely and H"A”
`effectively utilizing percutaneous technologies.
`1121;:/
`3. We speculate that the ascending aorta can withstand a [AK I11,1,/12r//5/1,
`stented structure without dissection or rupture.
`1W 11;, 111.111
`
`. 4 W3 SPSCUIate that the intraluminal valves can properly 11.1 K1141”. .1.
`\MJBEEELQBfllihin a stented system
`11111 Z , 1, 1,1, 1
`\
`71:) I451? /Z 4)
`[KI11/1/1/ZJ/t‘
`1W“ A7””“7701
`/
`Ill. Equipment and Supplies
`IfWW
`1. We propose that we use 10 pigs to place the percutaneous
`devices and to derive the needed data. This would require AAAA A Ifl
`the facilities to house and provide upkeep. Our
`VA A IVII
`veterinarian facilities have these capabilities. Moreover,
`”11“.
`1/1..)
`the facility has a catheterization laboratory which can be
`Al A A b A
`1/ 14> 111 ./ Hi 6
`utilized with proper funding to derive the primary set of
`(2‘1”)
`//1// K (17/
`data. ‘The collaborators and I will perform the procedures
`WW (A?)
`f? a‘ /
`and interpretation necessary to publish our series. There
`a /1 ~-/ 1 1.1.1,;
`will be a need for computers and software for the analysis.
` ‘1/“5//3(//
`2. We will be making the valves and stents at the Universityw
`of Missouri unless it is found that we have neither the
`yo ti“ 5'2/17" 417/! ,
`1
`C)
`1
`1:
`1W:\ -~
`1
`7
`’7:
`"A
`.3 /
`1 (”L/u tit-Aui“ {/3”" AAAA A] WWA
`[Zea/WM W" VA“ A) A‘AAA”Z3
`3% A33.
`(“I/WA (A U [:5
`111w 71v / “A/ A AA
`C/ B
`
`y,
`[5 "MAW/1
`
`.’
`
`.
`
`1' [2/71/119/
`eff (,// r“ (7‘1
`
`1952/ .
`
`1/?) ;//‘3/l/l/
`
`
`
`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 10 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. Excitingly, 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,
`de'bulking 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 well as catheterization personnel, The
`
`NORRED EXHIBIT 2138 - Page 2
`NORRED EXHIBIT 2138 - Pag 2
`
`232%a:
`
`
`
`engineering department will need partial funding for post-‘-
`doctoral candidates to help in the development of the
`valve. As well, the cardiology department and I 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 effon including the
`collaborative efforts of representatives from the
`Cardiology, Biophysics, Chemical Engineering,
`Engineering, 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 placement 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
`
`NORRED EXHIBIT 2138 - Page { "
`NORRED EXHIBIT 2138 - Page 3
`
`
`
`
`
`This timeline 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
`
`3
`
`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 hernodynamic equipment
`within the catheterization lab will be utilized to provide
`information as to the effect of deployment upon. the pig’s
`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 the activation of. the
`coagulation cascade. Cardiac enzymes will be
`periodically drawn to assess for microembolization or
`delayed trauma upon the cardiac circulation. Finally, the
`
`NORRED EXHIBIT 2138 - Page 45/} -.
`NORRED EXHIBIT 2138 - Page 4
`
`'1”:/
`
`«
`
`
`
`pigs will be sacrificed alter these data have beers. collected,
`and tissue sections from the ascending aorta, heart, brain,
`lungs, kidneys, spleen and liver will be taken to assess for
`structural alterations which ma 3/ be related to the
`pereutaneou sly delivered valves.
`
`Vll. FUTURE DiRECl‘lONS
`
`l. From this pilot study we will have the information needed
`to pursue more ambitious projects which will lead ultimately
`to trials in humans with iaoperahle aortic stemsis, From
`census data. there were approximately 50 million Americans
`over the age of 65,, Among this population there is an annual
`incidence of 2 to 9%, depending upon age, of aortic steaosis°
`This eoal‘l mean that a3 high as 35 millioa elderly perstms
`could suffer from this disease.
`[Axillflng those who are older,
`especially over ’75, they are less likely to be operative
`candidates. This could represent a tremendous amount of
`patieets who could he helped by this procedure. For the
`investor, this could represent a tremendous previously
`untapped market, which could lead to substantial profits,
`For the physician, more importantly, it could lead to
`definitive treatment where previously there were lcw options
`besides palliation.
`V) N
`(I N 47' NW: L:
`
`[2,
`
`A V
`
`’7 /
`
`/, 5/: V L 3/ 6
`l
`521/04, t
`27 (2A2, A [2, 113;
`:9
`__N
`flap
`l/rlLUc; *7
`fl
`2) M A 7 (:42 IA z, 6
`”5) fl N , M “1.,
`:3
`U
`C /~\« B“ 65"”
`C a) {x},
`:60 V7 w A {2, L:
`(7/)
`5) P /<’ a a,’ 5"!) 0/9 5
`{iii}, 1/ pegs 11 I? ‘/
`
`(a s3 ‘7‘
`
`7’)
`
`A
`
`,7,
`
`flax/Mn 1/
`
`,, 12
`
`, x
`A ( a 1:?" ‘2 ,‘:>
`
`g; (SH-'1')
`3»
`.
`,.
`
`/ f
`(W M / 1/ 2
`0137' 1-/ 1L1 E 13 2
`39/03 4 M [‘7’
`{LNGC ([(lJ/g’é
`
`/
`é 10 >
`
`‘
`
`4);
`if a \ >\\
`
`NORRED EXHIBIT 2138 - Page 5
`NORRED EXHIBIT 2138 - Page 5
`
`