NORRED EXHIBIT 2142 - Page 1
`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, M.D.
`Case IPR2014-00111
`
`
`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, M.D.
`Case IPR2014-00111
`
`
`
`The aortic valve directs the flow of blood from the
`
`left ventricle into the systemic circulation through the
`
`aortic artery.
`
`It accomplishes this function by opening
`
`during the contraction of the left ventricle and closing
`
`when the left ventricle relaxes.
`
`In a normally functioning valve,
`
`three leaflet—
`
`shaped cusps open widely to allow the unimpeded
`
`transference of blood, and then close tightly, not
`
`allowing any blood back into the left ventricle.
`
`Significant restriction to blood flow is called stenosis,
`
`and blood leakage back into the left ventricle is called
`
`regurgitation.
`
`The aortic valve is a tricuspid structure. Each cusp
`
`folds up toward the aorta during the contraction phase
`
`and then folds back against the others in the relaxation
`
`phase.
`
`[Figure 1 show a picture] However, it is
`
`important
`
`to understand that the structure of the aortic
`
`valve is complex, with integral relationships beyond its
`
`three—leaflet valve structure.
`
`For instance, each
`
`leaflet sits directly opposite an out pouching of the
`
`NORRED EXHIBIT 2142 - Page 2
`NORRED EXHIBIT 2142 - Page 2
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`
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`(if. ‘3 3
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`proximal aorta. This dilated segment, called the sinus
`
`of valsalva,
`
`is part of an anatomic relationship that
`
`assists the repetitive opening and closing of the valve
`
`while minimizing the stress on any point within this
`
`valvular apparatus. Further,
`
`the proximal portion of the
`
`aortic valve is highly elastic, which allows it to dilate
`
`during the contraction phase of the left ventricle.
`
`Moreover,
`
`these valvular structures are integrally
`
`related to the coronary arteries, which supply blood
`
`sapglyjto the heart.
`
`These arteries, as represented in
`
`Figure 2, are located within 2 of the three sinuses
`
`Thus, each component plays a vital role in the function
`
`and durability of the valve.
`
`The first components of the aortic valve I would
`
`like to discuss are the leaflets.
`
`As stated,
`
`the number of leaflets within a normal
`
`aortic valve is three. Any congenital variation in the
`
`number of leaflets causes significant problems with
`
`function. When there are less than three valves,
`
`the
`
`valve undergoes rapid stenosis and restriction. An
`
`NORRED EXHIBIT 2142 - Page 3
`NORRED EXHIBIT 2142 - Page 3
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`
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`individual with a unicusped valve rarely survives beyond
`
`the first year of life. Among individuals with congenital
`
`alterations in the valve number,
`
`the most frequently
`
`encountered is a bicuspid aortic valve.
`
`Individuals with
`
`this variationévin valve number
`
`can survive into
`
`adulthood. However,
`
`this valve combination becomes more
`
`and more stenotic and regurgitant by the 4th and 5th
`
`decade, which usually results in the need for surgical
`
`replacement.
`
`(See figures 3 and {1; Rarely, an individual
`
`with a quadricusped valve will survive into adulthood.
`
`‘\
`
`This alteration in design also results in marked
`
`stenosis.
`
`The anatomy of a normal aortic valve (three cusps,
`
`(gfginues, aortic arteries) permits the dispersion of
`
`pressure over a larger surface area in the structure.
`
`This dispersion resists the exhaustion of any one
`
`component of the valve. Moreover,
`
`the curvature of the
`
`cusp structure allows the leaflet to reverse curvature.
`
`/AE ability needed in order to fold and allow the maximum
`
`opening diameter during contraction. Finally,
`
`a curved
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`NORRED EXHIBIT 2142 - Page 4
`NORRED EXHIBIT 2142 - Page 4
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`design allows a redundancy in the coaptation area of the
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`leaflets.
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`The area of coaptation is the valve edge that
`
`must meet and close in order to prevent regurgitation.
`
`Hence, both the number of leaflets and their overall
`
`shape is important
`
`in the function and durability of the
`
`valve.
`
`As mentioned earlier,
`
`the valve leaflets have a
`
`direct relationship to the sinuses of valsalva.
`
`The
`
`sinus diameter is almost
`
`twice that of the aorta.
`
`This
`
`cavity plays an important role in the mechanism of valve
`
`closure.
`
`[referenced Mano Thubrikar]
`
`An oblique section
`
`through the leaflet—sinus assembly shows this remarkable
`
`relationship.
`
`(See Figure 4). This section reveals that
`
`the sinus and leaflet form a circle when the valve is in
`
`a closed position.
`
`Furthermore, it is angulated to a
`
`degree as to allow pressure
`
`transduction along the
`
`entire surface of this unit. All this suggests that the
`
`shape of the leaflet—sinus assembly is important
`
`in
`
`determining how stresses are developed within the valve.
`
`This relationship also allows the valve leaflets to close
`
`NORRED EXHIBIT 2142 - Page 5
`NORRED EXHIBIT 2142 - Page 5
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`
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`without straining the aortic valve, as has been
`
`suggested. Finally,
`
`this relationship of the sinuses and
`
`KS‘
`valve allowkfor the efficient flow of blood in the
`
`coronary ostia.
`
`Another structure,
`
`the aortic root, has been
`
`observed to expand during ventricular contraction.
`
`The
`
`dilatation of this structure
`
`ipredicted by Poisselles'
`
`law, which describes the relationship of resistance to
`
`vessel diameter,
`
`length an fluid viscosity)‘
`
`reduces
`
`tension, which in turn reduces resistance to flow.
`
`This
`
`phenomenon also allows for complete opening of the aortic
`
`valve.
`
`Interestingly, when the cusps open, a circular
`
`dimension is maintained that is at least the same
`
`diameter as before contraction. Moreover+iitmi33haswbeen
`CIA/x}
`”MMWWH”wibemevenmlargerwthanntheweriginalfiorifieefigi
` @.W
`
`(Medical Engineering & Physics 19(8): 696—710,l997).
`
`This behavior reduces circumferential stress on the valve
`
`and generates a reduced Reynolds shear stress number
`
`(the
`
`number used to evaluate the amount of stress in a
`
`confined fluid system).
`
`In a similar manner,
`
`the inner
`
`NORRED EXHIBIT 2142 - Page 6
`NORRED EXHIBIT 2142 - Page 6
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`lining of the cusp of the valve,
`
`the lamina
`
`ventricularis, extends into the ventricular myocardium
`
`when the valve is in an open position.
`
`A confluence of
`
`fibers at the base, called the fibrous coronet,
`
`is a
`
`%
`
`WW
`
`distinct structure separating the elastic fibers abovq3(§%wmw
`
`and the myocardium below. However,
`
`this structure is not
`
`static.
`
`It is a very dynamic structure, which bends and
`
`molds to the forces exerted from the ventricular
`
`myocardium (Cardiovascular Research, 22,7,1988)(Journal
`
`of Biomechanics33 (6): 653—658, 2000 June).
`
`In a fashion
`
`similar to the aortic root,
`
`this structure allows the
`
`valvular apparatus to open with the least amount of
`
`strain.
`
`The coronary arteries arise within or above the
`
`€93
`The blood flow to the heart occurs
`sinus of valsalva.
`c5) (vi/14s
`jog
`,
`,\
`r
`.
`,
`Q [fl
`.
`.
`d M ‘L 1
`AI E1
`mostiywwhenmthe ventricle rela%es. At this timfir
`the
`cusps of the aortic valve are closed, andfi/stmentioned,
`
`the diastolic forces of the blood against the valve are
`
`
`
`dispersed along the valve and adjacent sinus.
`
`The
`
`opening, or ostia, of the coronary arteries, when located
`
`NORRED EXHIBIT 2142 - Page 7
`NORRED EXHIBIT 2142 - Page 7
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`near the apex and middle of the sinuses, allows for least
`
`turbulent, most
`
`laminar flow characteristics.
`
`(This
`
`optimal location will be important to keep in mind when
`
`designing a replacement valve because this relationship
`
`promotes the greatest amount of flow with the least
`
`amount of resistance.)
`
`In disease states where these
`
`relationships are lost, it has been proposed that this
`
`loss could increase stress at the coronary ostia.
`Aortic Valve CRC presiy.
`
`[Eie
`L
`
`These integral relationships are not only seen in
`
`the gross anatomy of the valvular apparatus. The
`
`microanatomy shows the integral nature of these
`
`structures as well.
`
`The amount of elastin shown by
`
`staining methods is in a higher concentration %%:i/
`anywhere else in the bodya/i American Journal of
`
`Pathology 445 (7): 1931). This concentration allows a
`
`greater amount of dilatation of the structures in this
`
`area. Further, scanning electron micrographs have shown
`
`the unique arrangement of collagen in the valves, which
`471
`«.
`
`permits the unique reversal of curvaturewwwhioh is vital
`
`NORRED EXHIBIT 2142 - Page 8
`NORRED EXHIBIT 2142 - Page 8
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`in the function of the valve.
`
`(See Figure 6).
`
`(Anatomic
`
`Embryology 172(61): 1985).
`
`The fibers are unusually
`
`small and arranged in sheets with unique distances
`
`between each strand.
`
`In theory,
`
`this would give a
`
`greater amount of tensile strength while allowing
`
`continued flexibility.
`
`As always, nature has selected
`
`the most efficient machinery, and we have only to
`
`discover the reasons why.
`
`11. Aortic Valve Dynamics and Physics
`
`The aortic valve is not a static structure andwis
`_”‘\
`better~underet¢odWinWawdynamicwstatem FullLEnderstanding
`
`@% this structure requires understanding the dynamics and
`
`physics of the opening and closing of the valve:
`
`the
`
`motion of the various parts,
`
`the design of the valve in
`
`vitro and the hydrodynamics of the valve.
`
`The valve's ultimate function is to allow fluid
`
`transfer from the ventricle to the systemic circulation.
`
`In order to do this efficiently, it minimizes shear
`
`stress, resistance to flow and tensile forces. The
`
`NORRED EXHIBIT 2142 - Page 9
`NORRED EXHIBIT 2142 - Page 9
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`opening and closing of the aortic valve depends upon
`
`differential pressures,
`
`flow velocity characteristics
`
`and, as mentioned earlier,
`
`the unique anatomic
`
`relationship between the valves and the sinuses of
`
`
`valsalva.
`M
`‘has been developed by Bellhouse et al.
`
`The most comprehensive model of this process
`
`In this model,
`
`the
`
`flow of fluid through the aortic valve was studied by
`
`injecting dye within the flow of fluid.
`
`Some of the
`
`MR»
`
`pertinent observations incorporated in this model were as
`
`follows:
`
`1) The valve opens rapidly, and as the leaflets
`
`move into the sinuses, vortices form between the leaflet
`
`and the sinus walls; 2) The flow enters the sinus at the
`
`sinus ridge, curls back along the sinus wall and leaflet
`
`and flows then back into the main stream; 3) During the
`
`end of systole,
`
`the vorticeal motion createdwduring
`
`contraction forces the valves back toward a closed
`
`position.
`
`These observations are important because they
`
`show that absolute pressure differences created between
`
`the aorta and ventricle are not the source of initial
`
`closure of the aortic valve .
`
`In fact, it would be
`
`NORRED EXHIBIT 2142 - Page 10
`NORRED EXHIBIT 2142 - Page 10
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`
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`detrimental to valve stress if these forces dictated
`
`closure of the aortic valve. For example,
`
`if two objects
`
`are separated and a set amount of force is applied to
`
`each,
`
`increasing the distance between them would produce
`
`greater velocity and the momentum at impact would be
`
`greater. Therefore, if the leaflets are closed or near
`
`closure as contraction is coming to an end,
`
`then the
`
`force used for coaptation would be less. Less force per
`
`cycle equates to greater longevity of the valve.
`
`This phenomenon would affect the design for
`
`prosthetic valves.
`
`The cusps and the relationship of
`
`closure for prosthetic valves must
`
`incorporate passive
`
`closure during systole in order to lengthen the life span
`
`of any such device.
`
`To understand how to do this, we must explore The
`
`theory of laminar flow as it relates to aortic valve
`
`function.
`
`Laminar flow is predicted by
`’,/
`
`which incorporates the laws asfidescribed by Outsell and
`
`PM.
`!Reynolds number,
`A
`
`Bernoulli.
`
`In general,
`
`the lower the Reynolds number,
`
`the more likely that flow will be laminar.
`
`The equation
`
`NORRED EXHIBIT 2142 - Page 11
`NORRED EXHIBIT 2142 - Page 11
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`
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`that describes the Reynolds number
`
`in the aorta is as
`
`follows:
`
`Ua/v = Reynolds number
`
`That is U, which equals the velocity of bloodfiand a,
`
`which represents the radius of the aortic valve,
`
`is
`
`inversely related to the viscosity of blood.
`
`As
`
`the
`
`velocity increases or the viscosity decreases,
`
`the
`
`tendency towards turbulent flow also increases.
`( L4,g}
`IV“
`”v iJCW
`the behavior of the system is.als£u
`, , .w’“ ”.7W
`
`Moreover,
`
`predicted bywthemratemefwa-eeeleratienwefiWtmeflmflfiflfixM%
`LAL 2&2 [4/9W/
`
`described by the Strouhal numberj:whichlpredigtgéfggx OJ
`'oharaéte¥i§ifi£fifi¥fif“firuyrve w”lln a system where
`
`awkwy
`
`viscosity, velocity and radius vary slightly,
`GP iiu Elm;
`acceleration or decelerationApredicts laminar versus non
`
`
`laminar flow. When looked at in this perspective, it is
`
`the rate of
`
`easy to see the relevance of this information to valve
`
`function. Only a small pressure difference is required
`
`to open the native aortic valve. Maintaining a small
`
`NORRED EXHIBIT 2142 - Page 12
`NORRED EXHIBIT 2142 - Page 12
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`pressure difference minimizes acceleration to flow.
`
`Thus,
`
`laminar flow is more likely.
`
`The deceleration
`
`phase is naturally a gradual process; however, as stated
`
`éflmfluvt.
`above, it is the relationship between the sinuses and the
`
`cusps that allows this deceleration to occur without an
`
`abrupt pressure drop.
`
`When laminar flow is produced,
`
`the resistance to flow, wall stress, shear stress and
`
`Afli;
`circumferential stress iswreduced. This reduction
`
`decreases cardiac work and increases the longevity of the
`
`valvular apparatus. Ultimately,
`
`a design to replace a
`
`diseased aortic valve must incorporate many if not all of
`
`these relationships.
`
`III. Aortic Stenosis
`
`fl
`
`Aortic stenosis is the condition )of restriction to
`Kw
`
`the ejection of blood from the left ventricle to the
`
`systemic circulation at the aortic valve level.
`
`If the
`
`aortic valve cusps do not open, or there is failure of
`
`the valvular apparatus,
`
`then a pressure gradient
`
`develops.
`
`In order to overcome this pressure
`
`NORRED EXHIBIT 2142 - Page 13
`NORRED EXHIBIT 2142 - Page 13
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`difference,
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`the left ventricle begins to hypertrophy.
`
`Over a period of time,
`
`this process produces pressure
`
`overload on the left ventricle, which produces dramatic
`
`clinical symptoms.
`
`In the most severe form, it is fatal
`
`unless treated. The incidence of aortic stenosis varies
`
`considerably.
`
`In epidemiological studies,
`
`the incidence
`
`is between 2
`
`to 4% of the general population.
`
`In the early 20th century,
`
`the most common etiology
`
`of aortic stenosis was rheumatic fever. This
`
`streptococcal infection produces inflammatory changes in
`
`the aortic valve.
`
`Interestingly,
`
`these
`
`changes affect
`
`the coaptation surface to a greater degree than the other
`
`structures of the aortic valve. Affecting the coaptation
`
`points results in fusion of cusps. This fusion results
`
`in a restriction to the opening of the cusps.
`
`A pressure
`
`difference develops as well as non—laminar flow. Once
`
`
`
`this cycle develops, valve deterioration and W.MMMMMW;E7‘‘‘‘‘‘‘
`
`calcification increases. Unfortunately, post infectious
`
`aortic stenosis can result in rapid progression to severe
`
`aortic stenosis.
`
`Of the total cases of aortic stenosis
`
`NORRED EXHIBIT 2142 - Page 14
`NORRED EXHIBIT 2142 - Page 14
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`in the 1940's, reportedly 52% were the result of
`
`rheumatic fever. Currently,
`
`less than 9% of the cases of
`
`aortic stenosis are poéfginflammatory.
`
`The second most common cause of aortic stenosis is a
`
`bicuspid aortic valve. This has remained relatively
`
`constant throughout
`
`the decades.
`
`It accounts for 33 to
`
`40% of the total cases of aortic stenosis.
`
`This
`
`condition affects most parameters of aortic function
`
`because the optimal anatomic relationship between the
`
`sinuses, arteries and the valve cusp is lost.
`
`Further,
`
`the opening and closing characteristics of the valve are
`
`altered, which in turn alters the acceleration and
`
`deceleration of flow.
`
`As a result, non—laminar flow
`
`characteristics are developed.
`
`Because of the altered
`
`anatomy, a bicuspid aortic valve cannot easily reverse
`
`curvature.
`
`Due to this limitation,
`
`the bicuspid aortic
`
`valve has increased stress at the base.
`
`It is at this
`
`point where morphologic changes first appear. However,
`
`this valve is usually survived into adulthood..Currently,
`
`the most common cause of aortic stenosis is degenerative
`
`NORRED EXHIBIT 2142 - Page 15
`NORRED EXHIBIT 2142 - Page 15
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`
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`aortic stenosis.
`
`By the 7th decade,
`
`the normal aortic
`
`valve can undergo degenerative changes.
`
`The
`
`characteristic that defines these changes is increased
`
`calcium deposition along the body of the cusps.
`
`Predominantly the calcification is located at the bases
`
`of the cusp and on the aortic side.
`
`When enough calcium
`
`is deposited as to restrict flow,
`
`then there will be a
`
`variable amount of fusion along the coaptation surface.
`
`The incidence of aortic stenosis reaches as high as 12%
`
`in octogenarians. This population accounts for 51% of
`
`the current cases of aortic stenosis.
`
`The factors that
`
`promote aortic stenosis in a normal valve are the same as
`
`thosea/Ghich contribute to athersclerosis in arteries
`{Eejm 19%5].
`Thus, degenerative aortic stenosis hasMy?
`become the most prevalent etiologyfif/Elinically,
`symptomatic aortic stenosis not onfy has disabling
`
`symptoms, but also a high mortality.
`cmflmwjt,
`
`.Currantly aortic
`
`stenosis isAgraded aécording to the calculated aortic
`valve area/dgaée Figure7).
`As represented in the table/\5
`
`severe aortic stenosis occurs when the valve area is less
`
`NORRED EXHIBIT 2142 - Page 16
`NORRED EXHIBIT 2142 - Page 16
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`
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`a
`
`than l.0cm2(AVA index of <0.6cm2/m2). The most frequent
`
`V
`
`symptom is angina pectoris occurring in up to 70% of
`
`I
`these cases. This is followed by syncope or presyncope.
`
`Once aortic stenosis becomes symptomatic,
`
`the 2~year
`
`mortality can be as high as 50% {Eraunwal
`
`l9ZE}.
`
`The
`
`10—year survival is a dismal 10%.
`
`In conclusion, aortic
`
`stenosis can produce severe life—limiting symptoms and
`
`ultimately is fatal.
`
`IV. Aortic Regurgitation
`
`W"
`v§qurtic regurgitation is the condition of leaked backflow
`W
`of blood from the aortaito the left ventricle.
`
`This
`
`regurgitation results in a decreased effective cardiac
`
`output.
`
`results in an increased volume of work on.the left
`
`In turn,
`.
`
`.
`
`longstanding aortic regurgitation
`0,.
`
`ventricle.
`
`In time,
`
`the left ventricle begins to dilate.
`
`Unlike aortic stenosis,
`
`this condition can be well
`
`tolerated for many years. However, once the left
`
`ventricle begins to dilate and lose its contractility, it
`
`NORRED EXHIBIT 2142 - Page 17
`NORRED EXHIBIT 2142 - Page 17
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`
`
`w-
`becomes rapidly symptomatic. EThe most common symptoms
`
`result from heart failuri:(/fi/fitiologically, aortic
`regurgitation and stenosis iiiiiare very similar. The most
`
`common etiology of aortic regurgitation has been
`
`rheumatic fever.
`
`However,
`
`just as in stenosis,
`
`this
`
`incidence has decreased as the incidence of rheumatic
`
`fever has decreased. Logically whenever there is
`
`stenosis,
`
`there can be increase circumferential stress
`
`placed upon the proximal aortic root. It is this stress
`
`that promotes aortic root dilatation in certain patients.
`
`Moreover,
`
`a dilatation of the aortic root can separate
`
`the cusps of the aortic valve and create regurgitation.
`
`Thus, senile aortic stenosis, bicuspid aortic valves and
`
`distinctly rheumatic aortic valves have a propensity to
`
`leak.
`
`However,
`
`there are other unique entities, which
`
`promote aortic regurgitation.
`
`For example, Marfan's
`
`syndrome is defined by defective collagen deposition.
`
`This deficiency manifests as dilatation of the aortic
`
`root at a very young age, and tragically can result in
`
`NORRED EXHIBIT 2142 - Page 18
`NORRED EXHIBIT 2142 - Page 18
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`
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`the dissection of the aorta. More commonly,
`
`the aorta
`
`can become dilated in response to systemic hypertension.
`
`In a certain portion of patients, aortic dilatation with
`
`concomitant aortic regurgitation is the only
`
`manifestation of their hypertension.
`
`Thus,
`
`there are
`
`distincfi different causes for aortic regurgitation in
`l\
`
`the presence of a structurally normal aortic valve.
`
`Severe aortic regurgitation has a poor prognosis.
`
`Eremwthewwork by Goldschlager et al
`
`C
`
`'
`
`" ‘s found that the
`
`gefljmfi
`
`survival of aortic regurgitation is about 50% at 8years
`
`therapafls
`(54): 1973). With maximum medical
`(Am. J. Med.
`it still has a poor prognosis.
`Even among asymptomatic
`
`patients,
`
`there is a decrease in the max V02 as measured
`
`with a standard cardiopulmonary exercise test. Moreover,
`
`many patients who undergo surgical replacement
`
`of the
`
`native valve for aortic regurgitation report an increase
`
`level of functioning that they didn't realize they had
`
`lost.
`
`In fact, although more weéggt§lerated, aortic
`
`valve regurgitation is a serious disease, which is
`
`S
`limitingwee a patient's lifestyle as well as life span.
`
`NORRED EXHIBIT 2142 - Page 19
`NORRED EXHIBIT 2142 - Page 19
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`V. Surgical Therapy
`
`For patients suffering from aortic regurgitation or
`, V FL] Wu
`.W
`the best therapy to date is surgicall
`,
`”QB/JQW
`\
`
`aortic stenosis,
`
`There is no questioning the benefit of surgical vs.
`
`medical management for these conditions.
`
`The 5—year
`
`survival for medical treatment @hl&?:f symptomatic aortic
`
`stenosis is 20% vs.
`
`\
`80% with a standard valve
`
`replacement.
`
`The natural history of the valve has been
`
`well characterized by the work of Braunwald et al
`
`
`
`
`1973. Unfortunately, aortic valve replacement carrie
`
`
`.,,,,,,
`'
`v I
`‘
`
`certain surgical morbidity and mortality.“ortic valve
`
`in
`
`,.
`
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`5%
`
`‘ ’
`
`
`
`replacement may be among the most invasive surgeries. It
`
`requires access to the native valve, which necessitates a
`
`sternotomy. Also,
`
`the heart must be stopped and placed
`
`on a bypass pump.
`
`Further,
`
`the ascending aorta is cross—
`
`clamped at a position proximal
`
`to the great vessels.
`
`The
`
`native valve is then excised, and depending upon the
`
`condition of the aortic root, it may be excised also.
`
`NORRED EXHIBIT 2142 - Page 20
`NORRED EXHIBIT 2142 - Page 20
`
`
`
`Then thafmechanicalor biomechanical valv€>is
`
`‘6’”
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`
`sutured
`
`into place.
`
`Although this is a life—saving procedure
`
`for those patients suffering from these disorders,
`
`the
`
`surgery is not without significant risk of mortality and
`
`morbidity.
`
`The risks of the surgery can be classified into
`
`immediate and long—term risks.
`
`The immediate risks of
`
`the surgery involve the mechanics of the valve
`
`replacement procedure.
`
`In accessing the heart,
`
`the
`
`sternum is split in two by a reciprocating saw. Given
`
`that this is a central point of attachment for the chest
`
`cavity, it must withstand considerable force.
`
`The
`
`s?ernum currently is wired back into place with a series
`
`.
`.
`C3
`or interrupted suture w1re from the cranial end to the
`
`dorsal end.
`
`infection.
`
`mew
`
`-
`
`fifkmw
`
`The difficultyliswin wound&:jhiscence and
`
`pry/V“
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`W" 517» m0
`The patients whomare at risk include
`W
`
`diabetics,
`
`the immunosuppressed and the elderly. Wound
`
`dehiscence or infection can be mild and readily amendable
`
`to simple wound care techniques. Or,
`
`these can be so
`
`severe as to lead to death or significant morbidity.
`
`The
`
`NORRED EXHIBIT 2142 - Page 21
`NORRED EXHIBIT 2142 - Page 21
`
`
`
`incidence is reported to be as low as l
`
`in 200 in low
`
`risk groups, and as high as 10 in 100 in high—risk
`
`groups.
`
`Among»the immediate risks is a significant decrease
`
`in cerebral function.
`
`Thembypasswpumpwallewthhewsurgeon
`
`tomeperateWTn“awcontfoIIedwfashionttovachievewgeed
`
`results.
`
`It is becoming more and more apparent that this
`W
`There is an
`in and of itself promotes&dysfunction.
`immediate risk of major stroke reported to be I
`to 3%.
`
`However,
`
`among those patients without recognizable
`
`strokes,
`
`there are still reported deficits in cognitive
`
`function. When this cognitive dysfunction is measuri in
`
`In one series, up
`terms of IQ point§\it can be dramatic.
`2
`to 60% of patienuxundergoing bypass surgery had an
`5
`immediate drop in their IQ scores by 20 points. This can
`
`be dramatically recognized by family and friends whewafe
`
`B
`.
`likelywtowrepert.a distinct drop in mental alertness.
`
`Thus even in a technically successful surgery,
`,;\k
`
`there can
`
`be a substantial drop in cognitive function.
`
`NORRED EXHIBIT 2142 - Page 22
`NORRED EXHIBIT 2142 - Page 22
`
`
`
`ZThe long—term risks are also serious and include
`
`thromboembolism and valve
`
`infectious endocarditis,
`
`dysfunctionffj
`,
`“wwaiigwméhflfiflpmjquQN /W$GAC@£:[
`
`VI. The Study Objectives and Stages
`
`The objective of this study is to demonstrate the
`
`feasibility of a percutaneously placed aortic valve as
`
`reflected in the testing of/l4 hypotheses. We speculate
`
`that the following assertions can be demonstrated to be
`
`the case:
`
`1. A cross~linked nitinol expandable stent can be
`
`annealed to a biological valve (see appendix).
`111
`2.Fhe flow characteristics produced by this uniquely
`
`designed device will perform in a similar fashion to
`
`that of other bioprosthetic valves.
`
`3. The strain relationships will be proportionate to
`
`the native valve structure.
`
`4. The flexible base will allow more even dispersion
`
`of
`
`“INN
`
`.
`.
`flexion strain.
`
`NORRED EXHIBIT 2142 - Page 23
`NORRED EXHIBIT 2142 - Page 23
`
`
`
`5. The interface of the stent aorta will be
`
`sufficient
`
`to maintain the valve in the proper position
`
`for function in—vivo.
`
`6. The stent/valve can be inserted percutaneously.
`
`7. The ascending aorta can accommodate a stented
`
`valve
`
`structure without rupture or significant dissection.
`
`8. The ascending aorta and coronary arteries can be
`
`visualized with existing techniques.
`
`9. With detailed visualization ,the stent/valve will
`
`be
`
`place as to avoid obstructing the native valve
`
`function.
`
`10. The stent/valve combination will not
`
`significantly
`
`obstruct coronary flow.
`
`11. A biotome can be directed across the interatrial
`
`septum into the left ventricle.
`
`12. Once a properly designed catheter is inserted
`
`into
`
`the left ventricle ,
`
`the native valve can be
`
`excised in
`
`a controlled manner.
`
`NORRED EXHIBIT 2142 - Page 24
`NORRED EXHIBIT 2142 - Page 24
`
`
`
`13. An animal would survive the placement of a
`
`percutaneous valve.
`
`14. The stented aortic valve in vivo will have a gradient
`@‘
`
`of
`
`less than lOEnmhg.
`
`Our belief is that a properly designed valve can be
`
`placed nonsurgically without
`
`the assistance of a bypass
`
`pump and mimic the function of a native valve. The tasks
`
`of the study will be divided into 4 related stages:
`
`flow
`
`modeling, valve modification, catheter design and in—vivo
`
`experiments. These stages are discussed in detail in the
`
`following protocol
`
`Protocol
`
`Flow Modeling
`
`The initial experiments will be performed to assess
`
`the valvular function in a flow model.
`
`As listed in
`
`equipment and supplies,
`
`the systems used include a
`
`simulated flow model and devices used to measure the
`,1
`
`pressure and resistance/yfifiée adjacent picture). The
`
`models are static and therefore limit the assessment.
`
`NORRED EXHIBIT 2142 - Page 25
`NORRED EXHIBIT 2142 - Page 25
`
`
`
`However,
`
`important stress and strain relationships can be
`
`obtained. <Ege valve will be initially placed by hand in
`
`the model systemi) The basic measurements will be
`
`derived, and from these measurements, we will publish our
`
`first data on the experimental valve.
`
`The timeline for these experiments is expected to be
`
`4
`
`to 6 weeks.
`
`The preparation for these experiments will
`
`take up the bulk of our project time. During this time,
`
`several mock runs will be used to modify the devices in
`
`
`
`order to obtain the most accurate hemodynamic
`
`
`
`information. Once we have accurate information concerning
`
`laminar flow characteristics, Reynolds number and strain
`
`relationships, we will begin to practice for in—vivo
`
`
`
`experiments.
`
`
`Two types of flow systems have been developed, each
`
`with set points of measurements embedded at certain
`
` distances from the valve.
`
`One uses ultrasound sensors
`
`and the other laser sensors.
`
`In the pulsed laser system,
`
`the lasers are set at perpendicular angles to measure
`
`differential velocities.
`
`Further,
`
`these velocities can
`
`NORRED EXHIBIT 2142 - Page 26
`NORRED EXHIBIT 2142 - Page 26
`
`
`
`measure shear stresses along the systolic flow and
`
`regurgitant flow.
`
`The flow systems allow high~speed photographs
`
`to be
`
`taken to demonstrate the function of early closure in
`
`relationship with sinuses
`
`(Annals of Biomedical
`
`Engineering. Vol. 26).
`
`Thus,
`
`the flow model measurements
`
`coupled with functional data will be reported. MWWngfiy
`
`The final phase of these experiments will help
`
`prepare for a more successful attempt at in—vivo
`placement of the experimental valve;ngith current
`
`”WM“
`
`WW...
`
`:?:f:?
`
`software available fromwfiemryweorporation, we will have
`
`the data necessary to begin modification of the valve
`
`system before our in—vivo attempts. This software can
`
`help deduce strain relationships in a computer model.
`
`Differing values can be used to assess the effects that
`
`variations in different geometric configurations alter
`
`
`
`the function.
`
`These detailed in-vitro experiments will
`
`save valuable time and resources in pre—experimental
`
`troubleshooting.
`
`NORRED EXHIBIT 2142 - Page 27
`NORRED EXHIBIT 2142 - Page 27
`
`
`
`Valve modification
`
`The valve/stent combination has reached a point in
`
`design and development where successful modification
`
`depends on experimentation.
`(ihe initial design has
`several areas that may(neiiv:::i::§atiofi;)
`W (/7 )The most obviou;{is the stent arrangement.
`
`WWX
`
`5
`
`4
`
`For
`
`maximum compression, it has been proposed that an
`
`interlaced series of nitinol wire would be favorable.
`
`This may hold to be true; however,
`
`reinforcement at the
`
`base may be necessary for more stability. Further,
`
`careful consideration of the sinuses may necessitate a
`
`more direct modeling system.
`
`It is possible that for
`
`each individual aortic roobkthe normal variance may
`\
`
`preclude a onqgsizegfiitaggll approach.
`B C C: ;m I” W
`~£®rvex§mple,
`
`.
`the placement of the coronary ostium
`
`varies significantly among individualsi
`
`Itwseenmwlogical
`
`that~a system that avoids directly obstructing the
`
`coronaries would be preferable. Differing designs can be
`L/VWW
`
`employed to exactly set the relationship of an opening in
`
`the stented structure./ Precise knowledge of the angle
`
`NORRED EXHIBIT 2142 - Page 28
`NORRED EXHIBIT 2142 - Page 28
`
`
`
`between the coronaries,
`
`the depth of the sinuses,
`
`the
`
`size of the cusps directly opposite the ostia and the
`
`
`degree in which the stentcd segments contour the ostia
`
`may be needed for the most effective percutaneously
`
`replaced valve:]hith the placement of the valve, it is
`
`crucial to allow enough distance between the native valve
`
`and the coronaries. Thus,
`
`there are several
`
`considerations in the modification of this valvular
`
`model.
`
`I have made several prototypes and find
`
`considerable variability in the interface of the stent
`
`and valve. Whether this variability will be important
`
`in
`
`the overall function of the valve is unknown at this
`
`army
`
`“
`
`differing techniques of harvesting biological
`
`valves can have a dramatic impact on their function.
`
`When a valve is harvested and placed in formalin, it
`
`undergoes an amount of swelling from cellular death and
`
`necrosis, which can increase the thickness of the valve.
`
`Increasing the thickness of the valve can be detrimental
`
`to the placement by inhibiting the flow of blood into the
`
`NORRED EXHIBIT 2142 - Page 29
`NORRED EXHIBIT 2142 - Page 29
`
`
`
`coronary ostia. Similarly, cellular death affects valve
`
`longevity and function negatively .
`
`These factors
`
`necessitate experimentation with differing techniques of
`
`preservation in our initial valve development.
`
`We will
`
`try simple formalin preserved valves as well as
`
`cryopreserved valves. Differing buffering solutions may
`
`also be evaluated if found necessary.
`
`Furthermore, our initial experience reveals the
`”(l/W
`
`meticulous nature of the annealing process.
`‘i—WAWWWWMM
`the entire valvular apparatus can
`
`suture is disrupted,
`
`If a single
`
`tear. Diligent work and documentation
`
`of the most
`
`effective way to anneal
`
`the two components of the valve
`
`is necessary. Fortunately, much of this work has begun
`
`and many lessons have been learned, but more time and
`
`”4WSFw
`resources willmneedwtofibe devoted to this line of
`
`modification.
`
`An estimate of one 40—hour week dedicated
`
`to this endeavor is realistic.
`
`Another potential problem with a nonsurgically
`
`placed valve is perivalvular leak.
`
`If the edges of the
`
`valve begin to lift and form a low resistance channel,
`
`NORRED EXHIBIT 2142 - Page 30
`NORRED EXHIBIT 2142 - Page 30
`
`
`
`the valve may begin to develop torque upon itself, which
`
`may ultimately lead to valvular dysfunction and even
`
`failure.
`
`In addressing this hypothetical problem, it has
`
`been proposed to use a rim of perivalvular
`
`tissue to act
`
`as a counter valve, which seals itself hydrostatically
`
`and prevents or limits perivalvular leak.
`
`The in—vitro
`
`flow model will be invaluable in assessing this
`
`possibility. We will use the time at the end of the flow
`
`modeling to adjust for this po
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