WO 2011/109433
`
`PCT/US2011/026741
`
`38.
`
`The method of Claim 33, wherein the section of tissue comprises an ultimate
`
`tensile strength of greater than about 25 MegaPascals.
`
`39.
`
`The method of Claim 33, wherein the section of tissue comprises a treated
`
`pericardium tissue.
`
`40.
`
`(a)
`
`(b)
`
`A method of preparing a section of tissue for medical use, comprising:
`
`contacting the section of tissue with distilled water;
`
`contacting the section of tissue with isopropyl alcohol for a pre-fixation period of
`
`time of not less than about 3 days; and
`
`( c)
`
`contacting the section of tissue with one of
`
`(i)
`
`(ii)
`
`a formalin solution, or
`
`a glutaraldehyde solution
`
`5
`
`10
`
`for a fixation period of time of not less than about 3 days; and
`
`(d)
`
`contacting the section of tissue with isopropyl alcohol for a post-fixation period
`
`of time of not less than about 3 days;
`
`15
`
`wherein step (b) occurs sometime after step (a), wherein step ( c) occurs sometime after
`
`step (b), and wherein step (d) occurs sometime after step (c).
`
`41.
`
`The method of Claim 40, wherein for step ( c):
`
`if the formalin solution is used, then the formalin solution comprises a concentration of
`
`about 1 - 37.5% formalin; and
`
`20
`
`if the glutaraldehyde solution is used, then the glutaraldehyde solution comprises a
`
`concentration of about 0.1 - 25% glutaraldehyde.
`
`42.
`
`The method of Claim 40, wherein for step (c):
`
`if the formalin solution is used, then the formalin solution comprises a concentration of
`
`about 8-12% formalin; and
`
`25
`
`if the glutaraldehyde solution is used, then the glutaraldehyde solution comprises a
`
`concentration of about 0.1-0.5% glutaraldehyde.
`
`43.
`
`The method of Claim 40, wherein the section of tissue comprises a treated
`
`pericardium tissue.
`
`18
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1551 of 2039
`
`

`

`WO 2011/109433
`
`PCT/US2011/026741
`
`1/5
`
`~100
`
`TISSUE PREPARATION
`
`r - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -~
`I
`I
`I
`I .,,..,,.
`1
`1
`I
`I
`
`~--------------- 1 ---------------- I
`
`DRY!NG
`
`, /
`
`END
`
`200
`
`.,,..,,. 300
`
`FIG. 1
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1552 of 2039
`
`

`

`WO 2011/109433
`
`PCT/US2011/026741
`
`2/5
`
`PERICARDIUM TISSUE HARVESTED
`
`204
`
`208
`
`TISSUE IS CLEANED AND DECELLULARIZED BY
`RINSING AND SEPARATING TISSUE WITH
`DISTILLED WATER
`
`200
`
`,,,✓ 220
`
`r - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 7 ,,,,,,
`(
`,,,
`:
`I I,.,.,,,
`
`TiONAL ADDITIONAL REMOVAL OF LIPIDS
`OP
`1
`100% GLYCEROL PRETREATMENT
`:
`I
`______________ T ______________ I
`
`r'f
`l _ _ _ _ _ _ _ _ _ _ _ _ _ _ t ______________
`I
`: ,.,.,,,,,,228
`r'i
`:
`LIGHT ENERGY EXPOSURE
`L--------------- J ______________ J
`I _____________________________ I
`
`224
`
`I
`I
`
`I
`
`1
`
`SECONDARY CLEANING
`
`RINSING VVITH DISTILLED \NATER
`
`RINSING WITH 25% ISOPROPYL ALCOHOL
`
`232
`
`236
`
`240
`
`244
`
`RINSING \NITH DISTILLED \NATER
`
`FIG. 2A
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1553 of 2039
`
`

`

`WO 2011/109433
`
`PCT/US2011/026741
`
`3/5
`
`0
`1
`
`~248
`
`FlXATION FOR COLLAGEN CROSS-LINKING
`(ONE OF THE FOLLOVV!NG)
`
`IMMERSION IN 1-37 .5% FORrv1AUN
`
`OR
`
`1Ml\•1ERSION lN 100% GLYCEROL
`
`OR
`
`IMMERSION lN 0:1 - 25% GLUTARALDEHYDE
`
`200
`
`v--
`---r--- 248 a
`
`248 b
`
`248 C
`
`IMMERSION IN 0.1-25'% GLUTARALDEHYDE (FILTERED --L-------248
`--L----- 24
`
`OR
`
`TO UMIT OL!GOMERIC CONTENT)
`
`OR
`
`IMMERSION IN ONE OF 248a, 248c, or 248d
`\NITH AMINO ACID ENRICHMENT
`
`ALCOHOL POST-FIXATION TREATMENT:
`
`RINSING IN DISTILLED WATER
`
`25%!SOPROPYLALCOHOL
`
`I
`
`I
`
`RINSING WITH DISTILLED WATER
`
`i
`•
`•
`
`---
`
`~
`
`d
`
`Be
`
`~252
`
`L-------256
`
`L-,-- 260
`
`r
`-----
`r ---
`
`~264
`
`~
`
`FIG. 28
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1554 of 2039
`
`

`

`WO 2011/109433
`
`PCT/US2011/026741
`
`4/5
`
`TISSUE IS DRIED
`
`TISSUE IS PLACED ON FLAT SURFACE
`
`304
`
`300
`
`V
`
`8
`/ 3 0
`
`V
`
`3 12
`TENSION AND/OR COMPRESSION LOAD ISv ~
`APPLIED TO TISSUE
`
`y
`
`TISSUE IS DRIED IN DARK CONDITIONS
`
`314
`~
`
`V
`
`FIG. 3
`
`, ,
`TISSUE INSPECTION
`AND
`ORIENTATION OF FIBER DIRECTION
`
`316
`
`V
`
`, ,
`---------------- ---------------- I
`I
`1--.,,.
`OPTIONAL SIZING OF TISSUE SHEET
`I
`I
`
`.,,. 320
`
`.,,..,,.
`
`TISSUE
`
`~ ,
`400
`
`F!G.4
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1555 of 2039
`
`

`

`WO 2011/109433
`
`PCT/US2011/026741
`
`Stress-Strain Curves of Wet Tissue
`50 r----,-----,-..;.......--r-;.._,.;.;......--y, _ _ _ -r-_ _ ---r' _ _ ___,..
`
`30
`
`if)
`if)
`w
`0:::
`~ to
`
`0
`
`~10.___ _ _ _ _ _ _ ....._ _ _ ......._ _ _ ___. ......... _ _ ..J.-_ _ --1 _ _ ~
`-0.2
`0
`0:3
`R1
`0.6
`-tl7
`0.4
`
`STRAIN
`Stress-strain curves in wet or hydrated state of five samples. Each curve corresponds
`to a separate sample.
`
`FIG. 5
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1556 of 2039
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) \-Vorld Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`9 September 2011 (09.09.2011)
`
`PCT
`
`1111111111111111 IIIIII IIIII 111111111111111 II Ill lllll 111111111111111 IIIII IIII IIIIIII IIII IIII IIII
`
`(10) International Publication Number
`WO 2011/109450 A2
`
`(51) International Patent Classification: Not classified
`
`(21) International Application Number:
`PCT/US201 li026763
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`1 March2011 (01.03.2011)
`
`English
`
`English
`
`(30) Priority Data:
`61/309,109
`13/038,361
`
`us
`us
`(71) Applicant (for all designated States except US): COLIB(cid:173)
`RI HEART VALVE LLC [US/US]; 2150 W. 6th Ave,
`Suite M, Broomfield, CO 80020 (US).
`
`1 March 2010 (01.03.2010)
`1 March2011 (01.03.2011)
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): FISH, R., David
`[US/US]; 6349 Vanderbilt Street, Houston, TX 77005
`
`(US). PANIAGUA, David [CR/US]; 3813 Dnunmond
`Street, Houston, TX 77025 (US).
`
`(74) Agent: YASKANIN, Mark, L.; Holme Roberts & Owen
`LLP, 1700 Lincoh1 Street, Suite 4100, Denver, CO 80203
`(US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, M.A, MD,
`ME, MG, MK, MN, J'vIW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for eve1y
`kind o_f regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`
`[Continued on next page]
`
`-
`;;;;;;;;;;;;;;;
`
`(54) Title: PERCUTANEOUSLY DELIVERABLE HEART VAL VE AND METHODS ASSOCIATED THEREWITH
`
`AA
`
`(57) Abstract: A prosthetic heart valve implantable by catheter
`without surgery includes a substantially "dry" membrane or tissue
`material. In at least one embodiment, the tissue is folded in a dry
`state to form a tissue leaflet assembly that is then attached to a
`frame to form an implantable prosthetic heart valve. Alternatively,
`one or more tissue leaflets are operatively associated with a frame
`to form an implantable prosthetic heart valve. The implantable
`prosthetic heart valve is subsequently pre-mounted on an integrat(cid:173)
`ed catlieter delivery system. The catheter delivery system that in(cid:173)
`cludes the implantable prosthetic heart valve is then packaged and
`transported while the tissue remains dry. The implantable pros(cid:173)
`thetic heart valve, while remaining substantially dry, can then be
`implanted into the receiving patient.
`
`;;;;;;;;;;;;;;; -
`-;;;;;;;;;;;;;;;
`;;;;;;;;;;;;;;; -
`
`;;;;;;;;;;;;;;;
`
`;;;;;;;;;;;;;;;
`
`1300
`
`1000
`
`-;
`
`;;;;;;;;;;;;;;
`;;;;;;;;;;;;;;;
`;;;;;;;;;;;;;;;
`
`FIG.13
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1557 of 2039
`
`

`

`WO 2011/109450 A2 1111111111111111 IIIIII IIIII 111111111111111 II Ill lllll 111111111111111 IIIII IIII IIIIIII IIII IIII IIII
`
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Published:
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`L V, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`without international search report and to be republished
`upon receipt of that report (Rule 48.2(g))
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1558 of 2039
`
`

`

`WO 2011/109450
`PCT/US2011/026763
`PERCUTANEOUSLY DELIVERABLE HEART VALVE AND METHODS
`
`ASSOCIATED THEREWITH
`
`FIELD
`
`The present invention relates to the field of medical devices, and more particularly, to a
`
`5
`
`percutaneously deliverable heart valve and a method of making a percutaneously deliverable
`
`heart valve.
`
`BACKGROUND
`Heart valve disease is a common degenerative condition that compromises physiologic
`
`function and causes limiting symptoms and threat to life in millions of patients all over the
`
`10 world. There are various underlying causes, but malfunction of heart valves is ultimately
`
`expressed as insufficient conduction of blood through the plane of the valve due to narrowing of
`
`the anatomic pathway (stenosis), or as incompetent closure that allows blood to return back
`
`through the valve again, thereby reducing the effective forward conduction of blood through the
`
`valve (insufficiency or regurgitation). These hemodynamic states lead to 1) deficiency of
`
`15
`
`cardiac output and 2) adverse loads on the pumping chambers of the heart, both of which in tum
`
`lead to functional compromise of the patient and often premature death unless effectively
`
`corrected.
`
`Definitive corrective treatment of heart valve disease is conventionally performed by
`
`open-chest surgical techniques, wherein the valve is manipulated, repaired, or replaced with a
`
`20
`
`prosthetic valve under direct vision. Heart valve surgery is performed in hundreds of thousands
`
`of cases yearly world-wide, but carries a high burden of cost, morbidity, and mortality,
`
`especially in susceptible patients who may be elderly or otherwise physiologically compromised
`
`by collateral disease. Further, the costs and resource requirements of the surgical enterprise
`
`restrict the availability of heart valve replacement to many more patients all over the world.
`
`25
`
`In pursuit of alternatives to heart valve surgery, over the last ten years a number of
`
`development programs have brought percutaneous, trans-catheter implantation of prosthetic
`
`heart valves into commercial use in the European Union (EU) and into pivotal clinical trials in
`
`the United States of America. Initial clinical experience in the EU was directed toward patients
`
`who had critical aortic valve stenosis, but were deemed to be at unacceptably high risk for open-
`
`30
`
`heart surgical valve replacement. In several thousand such cases, utilizing both balloon(cid:173)
`
`expandable and self-expanding designs in two separate programs, percutaneous heart valve
`
`replacement (PHVR) was shown to be feasible and possibly competitive with surgery in selected
`
`patients with 12-18 month mortality rates of about 25%. Grube E., et al., Progress and Current
`
`Status of Percutaneous Aortic Valve Replacement: Results of Three Device Generations of the
`
`35
`
`Core Valve Revalving System, Circ. Cardiovasc Intervent. 2008;1 :167-175.
`
`- 1 -
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1559 of 2039
`
`

`

`WO 2011/109450
`
`PCT/US2011/026763
`
`The application of PHVR thus far has been challenged by the technical difficulties of the
`
`implantation sequence-especially in the aortic valve position. The technique for available
`
`devices is limited by the large caliber of the devices and their delivery catheters; often, if it can
`
`be done at all in some smaller arteries, open surgical exposure and management of the femoral
`
`5
`
`artery is required to insert the 18 -24 French (6 - 8 mm diameter) systems, and their bulkiness
`
`inside the central arteries can threaten the safety of the delivery sequence. Further, access site
`
`bleeding complications form a significant part of the adverse events of the procedures.
`
`Typically, the current PHV designs comprise a biological membrane forming the
`
`operating leaflets of the valve, attached within a metal frame, that is then collapsed onto a
`
`10
`
`delivery catheter or balloon, and then constrained within an outer sheath. After an initial
`
`dilation of the diseased valve with a large balloon, this assembly is then advanced to the plane of
`
`the valve and deployed by self-expansion or by balloon expansion.
`
`The effective caliber of the valve delivery system is determined by the total bulk of each
`
`coaxially mounted component. The bulk of the PHV itself is determined by the diameter of the
`
`15
`
`frame and by the thickness, stiffness, and particular arrangement of the inner membrane forming
`
`the operating leaflets of the valve. The characteristic thickness of current PHV membranes is
`
`thus a limiting factor in the ultimate delivery profile of the PHV. Such characteristic membrane
`
`thickness is, in tum, a result of the methods by which it is processed and ultimately delivered for
`
`use. Typically, glutaraldehyde fixation (for protein cross-linking) of animal tissue is employed
`
`20
`
`to produce suitable biological membranes for incorporation. Requirements for strength and
`
`durability have determined the most useful ranges for tissue thickness and cross-linking while
`
`typically imposing countervailing stiffness and brittleness. Subsequent hydration in suitable
`
`solutions improves these characteristics, but the hydrated membrane by this means also gains
`
`thickness.
`
`25
`
`One of the evident requirements for a PHV design is that the valve functions with a high
`
`degree of competence immediately on deployment, since the patient's hemodynamic survival
`
`depends on it. To this end, in part, like surgical valve prostheses, current PHV designs are
`
`completed, transported, and delivered for use in a hydrated state in a jar of solution. In use,
`
`commercially available surgical and percutaneously implanted bioprosthetic heart valves are
`
`30
`
`rinsed and prepared before use in a "wet" state. More particularly, commercially available
`
`prosthetic heart valves are rinsed, crimped, and mounted in the catheterization lab. Accordingly,
`
`problems with current commercially available prosthetic heart valves include the time, cost and
`
`variability associated with the necessity to rinse, crimp, and mount the valve in the
`
`catheterization lab. That is, current mounting of prosthetic heart valves in the catheterization lab
`
`35
`
`imposes one or more of delay, cost, technical burdens and possible errors. Avoiding one or
`
`- 2 -
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1560 of 2039
`
`

`

`WO 2011/109450
`
`PCT/US2011/026763
`
`more of these problems would be advantageous. In addition, current "wet" valve designs
`
`impose additional profile on the collapsed valve. The hydrated membrane, while having
`
`desirable and necessary flexibility for reliable operation immediately on deployment, also
`
`imposes a large part of the thickness of the assembled and mounted valve that compromises its
`
`5
`
`deliverability.
`
`Expanding on some of the problems described above, the use of current PHV s in the
`
`catheter lab requires a number of preparatory acts that are potentially troublesome and can
`
`prolong the delivery sequence during a critical phase of the procedure. Since PHVs are
`
`delivered for use "wet" in a preservative solution, they have to be treated prior to insertion with
`
`10
`
`a series of cleansing and hydrating solutions. Once this is completed, the PHV s have to be
`
`mounted on their delivery catheters. Special crimping and mounting tools are needed in the case
`
`of the balloon-expandable Edwards Sapien valve, for example. Accordingly, there is a need to
`
`address the shortcomings discussed above.
`
`SUMMARY
`
`15
`
`It is to be understood that the present invention includes a variety of different versions or
`
`embodiments, and this Summary is not meant to be limiting or all-inclusive. This Summary
`
`provides some general descriptions of some of the embodiments, but may also include some
`
`more specific descriptions of other embodiments.
`
`In at least one embodiment, a substantially "dry" membrane PHV system is provided
`
`20 wherein a tissue material is prepared and folded in a dry state to form a tissue leaflet assembly.
`
`Thereafter, the tissue leaflet assembly is attached to a frame to form an implantable prosthetic
`
`heart valve that is subsequently pre-mounted in an integrated catheter delivery system. The
`
`catheter delivery system that includes the prosthetic heart valve is then packaged and transported
`
`while the tissue leaflet assembly remains substantially dry. The prosthetic heart valve is
`
`25
`
`available for use directly out of its package envelope. Accordingly, it can be inserted into the
`
`body without need of hydration, crimping or mounting tools, or other preparatory acts. That is,
`
`the tissue forming the tissue leaflet assembly of the prosthetic heart valve can be treated and
`
`dried, then while remaining dry, folded into a tissue leaflet assembly. Thereafter, the tissue
`
`leaflet assembly is at least partially rehydrated and then attached within a frame, such as a stent,
`
`30
`
`to form an implantable prosthetic heart valve. The tissue leaflet assembly of the prosthetic heart
`
`valve is then allowed to dry. The prosthetic heart valve can thereafter be subsequently
`
`packaged, delivered, and shipped while the tissue leaflet assembly of the prosthetic heart valve
`
`remains in a dry condition. The prosthetic heart valve can then be implanted into the receiving
`
`patient. Accordingly, the PHV system simplifies arterial insertion, and, as the dry condition also
`
`35
`
`confers lower bulk and profile, procedural manipulation and associated complications may be
`
`- 3 -
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1561 of 2039
`
`

`

`WO 2011/109450
`
`PCT/US2011/026763
`
`reduced if not eliminated. In addition, one or more embodiments of the present invention widen
`
`the candidacy of patients with smaller arteries for the PHY procedure. As an added advantage,
`
`at least one embodiment of the present invention allows the implantation to take place under
`
`shorten elapsed times at the most critical phase of the procedure.
`
`5
`
`In at least one embodiment, a membrane PHV system is provided wherein a tissue
`
`material is prepared and folded in a dry state to form a tissue leaflet assembly, and further
`
`wherein the tissue leaflet assembly is thereafter at least partially hydrated and attached to a
`
`frame that is subsequently pre-mounted in an integrated catheter delivery system.
`
`In at least one embodiment, a membrane PHV system is provided wherein a tissue
`
`10 material is prepared and folded in a dry state to form a tissue leaflet assembly, and further
`
`wherein the tissue leaflet assembly is at least partially hydrated and attached to a frame to form
`
`the prosthetic heart valve. Thereafter, the prosthetic heart valve is allowed to dry and
`
`subsequently pre-mounted in an integrated catheter delivery system after which the tissue leaflet
`
`assembly of the prosthetic heart valve remains dry, and wherein the system is then associated
`
`15 with a package for shipment while the tissue leaflet assembly remains dry.
`
`In at least one embodiment, a membrane PHV system is provided wherein a tissue
`
`material is prepared and then folded in a dry state to form a tissue leaflet assembly, and further
`
`wherein the tissue leaflet assembly is at least partially hydrated and attached to a frame to form
`
`the prosthetic heart valve. Thereafter, the prosthetic heart valve is allowed to dry and
`
`20
`
`subsequently pre-mounted in an integrated catheter delivery system after which the tissue leaflet
`
`assembly of the prosthetic heart valve is then at least partially hydrated and associated with a
`
`package for shipment.
`
`In at least one embodiment, an article adapted for trans-catheter delivery into a patient is
`
`provided, comprising: a prosthetic heart valve further comprising a treated tissue attached to a
`
`25
`
`frame, wherein the treated tissue comprises a thickness of about 50 to 500 micrometers and an
`
`ultimate tensile strength of greater than about 15 MegaPascals when at a water content of less
`
`than about 50% by weight of the section of treated tissue. Here it is noted that the tensile
`
`strength of the treated tissue described herein is higher than the tensile strength of other known
`
`prepared tissues, whether hydrated or dry. In at least one embodiment, the water content of the
`
`30
`
`treated tissue is less than about 40% by weight of the treated tissue. In at least one embodiment,
`
`the ultimate tensile strength is greater than about 20 MegaPascals. In at least one embodiment,
`
`the treated tissue does not include a matrix that has been exposed to a polymer infiltrate. In at
`
`least one embodiment the treated tissue comprises a treated pericardium tissue.
`
`In at least one embodiment, the method further comprises exposing the section of tissue
`
`35
`
`to light energy for an exposure duration, the exposure duration extending until there is no further
`
`- 4 -
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1562 of 2039
`
`

`

`WO 2011/109450
`
`PCT/US2011/026763
`
`visible separation of lipid droplets from an exposed surface of the section of tissue. In at least
`
`one embodiment, the light energy is at least equivalent to exposing the section of tissue to a 25-
`
`100 watt light source, and more preferably, a 50 watt incandescent light source with a flat
`
`radiant face situated at a distance of about 10 centimeters from the exposed surface for about 15
`
`5 minutes. In at least one embodiment, the method further comprises: ( d) rinsing the section of
`
`tissue with distilled water and isopropyl alcohol for a post-fixation period of time of not less
`
`than about 7 days; wherein step ( d) occurs after step ( c ).
`
`In at least one embodiment, an article adapted for implantation in a patient is provided,
`
`comprising: a prosthetic heart valve further comprising a treated tissue attached to a frame,
`
`10 wherein the treated tissue comprises a water content of less than about 60% by weight of the
`
`treated tissue. In at least one embodiment, the treated tissue comprises a section of pericardium
`
`tissue having an ultimate tensile strength of greater than about 12 MegaPascals. In at least one
`
`embodiment, the section of treated tissue comprises a thickness of between about 50 to 300
`
`micrometers. In at least one embodiment, the water content of the treated tissue is less than
`
`15
`
`about 40% by weight of the treated tissue.
`
`As used herein, the term "dry" ( or "substantially dry") when referring to the state of the
`
`tissue that forms the heart valve of the percutaneous heart valve means a moisture content less
`
`than the water moisture content of the tissue when the tissue is allowed to fully rehydrate in the
`
`body of a patient. Typically, pericardium tissue treated in accordance with one or more
`
`20
`
`embodiments described herein is about 70% by weight water when fully hydrated. Drying to a
`
`constitution of less than 40% by weight of water usefully alters the handling properties for
`
`purposes of folding and sewing the tissue. As those skilled in the art will appreciate, the
`
`moisture content of the tissue may vary when dry. For example, the moisture content of the
`
`tissue when being folded and dry may be different than the moisture content of the tissue when
`
`25
`
`dry and being shipped in a premounted state within a catheter delivery system.
`
`Advantageously, at least one embodiment of the one or more present inventions is
`
`directed to a prosthetic heart valve that is mounted onto a valve delivery system and stored in a
`
`sterile package. Accordingly, in at least one embodiment, an assembly is provided, comprising:
`
`a prosthetic heart valve including:
`
`30
`
`a frame; and
`
`a tissue leaflet assembly attached to the frame;
`
`a percutaneously insertable valve delivery mechanism, wherein the prosthetic heart valve
`
`is releasably mounted onto the percutaneously insertable valve delivery mechanism; and
`
`sterile packaging containing the prosthetic heart valve releasably mounted onto the
`
`35
`
`percutaneously insertable valve delivery mechanism.
`
`- 5 -
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1563 of 2039
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`

`

`WO 2011/109450
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`PCT/US2011/026763
`
`In at least one embodiment, the percutaneously insertable valve delivery mechanism
`
`comprises a balloon catheter. In at least one embodiment, the balloon catheter is a 12 to 14
`
`French balloon catheter. In at least one embodiment, the balloon catheter is less than about 12
`
`French. In at least one embodiment, the balloon catheter is between about 5 to 12 French. In at
`
`5
`
`least one embodiment, the percutaneously insertable valve delivery mechanism comprises a
`
`mandrel. In at least one embodiment, tissue forming the tissue leaflet assembly within the sterile
`
`packaging is at least one of hydrated and not substantially dry. In at least one embodiment,
`
`tissue forming the tissue leaflet assembly within the sterile packaging is substantially dry. In at
`
`least one embodiment, the frame comprises a stent. In at least one embodiment, tissue forming
`
`10
`
`the tissue leaflet assembly comprises treated pericardium tissue.
`
`At least one embodiment of the one or more present inventions includes a prosthetic
`
`heart valve for implantation in a patient. Accordingly, a pre-packaged percutaneous, trans(cid:173)
`
`catheter deliverable prosthetic heart valve ready for implantation in a patient is provided,
`
`compnsmg:
`
`15
`
`a frame; and,
`
`a tissue leaflet assembly attached to the frame, the tissue leaflet assembly comprising a
`
`substantially dry tissue.
`
`In at least one embodiment, the substantially dry tissue comprises treated pericardium
`
`tissue. In at least one embodiment, the frame and tissue leaflet assembly attached thereto are
`
`20
`
`operably associated with a 12 to 14 French balloon catheter. In at least one embodiment, the
`
`frame and tissue leaflet assembly attached thereto are operably associated with a balloon
`
`catheter having a size of less than about 12 French. In at least one embodiment, the frame and
`
`tissue leaflet assembly attached thereto are operably associated with a balloon catheter having a
`
`size of between about 5 to 12 French. In at least one embodiment, the substantially dry tissue
`
`25
`
`comprises a water moisture content of less than about 40% by weight of the substantially dry
`
`tissue.
`
`In at least another embodiment, an assembly for use with a patient is provided,
`
`compnsmg:
`
`a sealed sterile package containing a delivery system for percutaneously deploying a
`
`30
`
`heart valve in the patient, the heart valve including:
`
`a frame releasably mounted on the delivery system within the sealed sterile package; and
`
`a tissue leaflet assembly attached to the frame.
`
`In at least one embodiment, the tissue leaflet assembly comprises pericardium tissue.
`
`In at least one embodiment, a method is provided, comprising:
`
`35
`
`partially compressing and mounting a prosthetic heart valve upon a delivery catheter, the
`
`- 6 -
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1564 of 2039
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`

`

`WO 2011/109450
`
`prosthetic heart valve comprising a tissue;
`
`allowing the tissue to at least partially dry;
`
`PCT/US2011/026763
`
`further compressing and mounting the prosthetic heart valve upon the delivery catheter;
`
`and
`
`5
`
`sterilizing and packaging the prosthetic heart valve and delivery catheter.
`
`In at least one embodiment, the method further comprises transporting the sterilized and
`
`packaged prosthetic heart valve and delivery catheter. In at least one embodiment, the tissue
`
`comprises treated pericardium tissue. In at least one embodiment, prior to partially compressing
`
`and mounting the prosthetic heart valve upon the delivery catheter, the tissue is at least one of
`
`10
`
`(a) not substantially dry, and (b) at least partially hydrated.
`
`For the various embodiments described herein, the prosthetic heart valve, including the
`
`tissue leaflet assembly, comprises membrane tissue other than pericardium tissue.
`
`In at least one embodiment, a method is provided, comprising:
`
`attaching pericardium tissue to a frame;
`
`15
`
`partially compressing and mounting the frame, with the tissue attached thereto, upon a
`
`delivery catheter;
`
`allowing the tissue to at least partially dry;
`
`further compressing and mounting the frame, with the tissue attached thereto, upon the
`
`delivery catheter; and
`
`20
`
`sterilizing and packaging the frame and delivery catheter, with the tissue attached
`
`thereto.
`
`In at least one embodiment, prior to partially compressing and mounting the frame, the
`
`tissue is at least one of (a) not substantially dry, and (b) at least partially hydrated. In at least
`
`one embodiment, the method further comprises transporting the sterilized and packaged frame,
`
`25 with the tissue attached thereto, mounted upon the delivery catheter, to a surgical or medical
`
`procedure facility. In at least one embodiment, prior to attaching the tissue to the frame the
`
`tissue is folded to form a tissue leaflet assembly. In at least one embodiment, the tissue leaflet
`
`assembly comprises at least one cuff and at least one pleat.
`
`In at least one embodiment, a method of preparing a percutaneous, trans-catheter
`
`30
`
`prosthetic heart valve is provided, the method comprising:
`
`providing a membrane tissue from an organism;
`
`treating the membrane tissue with at least one chemical to produce a treated membrane
`
`tissue;
`
`drying the treated membrane tissue until it is a substantially dry tissue;
`
`35
`
`attaching the substantially dry tissue in a frame;
`
`- 7 -
`
`Edwards Lifesciences Corporation, et al. Exhibit 1011, p. 1565 of 2039
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`

`

`WO 2011/109450
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`PCT/US2011/026763
`
`rehydrating the substantially dry tissue that is attached within the frame to form a
`
`rehydrated tissue;
`
`collapsing the frame with the rehydrated tissue attached thereto; and
`
`drying the rehydrated tissue within the collapsed frame until it is a substantially dry
`
`5
`
`tissue.
`
`In at least one embodiment the method further comprises compressing and mounting the
`
`frame, with the substantially dry tissue attached thereto, upon a delivery catheter. In at least one
`
`embodiment the method further comprises sterilizing and packaging the frame, with the
`
`substantially dry tissue attached thereto, mounted upon the delivery catheter. In at least one
`
`10
`
`embodiment, the treating comprises sterilizing the frame with the substantially dry tissue
`
`attached thereto with exposure to at least one of ethylene oxide, a proton beam, and gamma
`
`radiation. In at least one embodiment, the method further comprises shipping the sterilized and
`
`packaged frame with the substantially dry tissue attached thereto, mounted upon the delivery
`
`catheter, to a surgery or medical procedure facility. In at least one embodiment, prior to the
`
`15
`
`attaching step the dry tissue is not folded to provide a cuff and/or a pleat. In at least one
`
`embodiment, prior to the attaching step the dry tissue is folded to form a tissue leaflet assembly.
`
`In at least one embodiment, the tissue leaflet assembly comprises at least one cuff and at least
`
`one pleat.
`
`In at least one embodiment, the method of preparing a percutaneous, trans-catheter
`
`20
`
`prosthetic heart valve further comprises implanting the frame with the substantially dry tissue
`
`attached thereto into a patient. In at least one embodiment, the frame comprises a stent. In at
`
`least one embodiment, the method further comprises mounting the frame and the tissue leaflet
`
`assembly attached thereto upon a 12 to 14 French balloon catheter. In at least one embodiment,
`
`the method further comprises mounting the frame and the tissue leaflet assembly attached
`
`25
`
`thereto upon a balloon catheter having a size of less than about 12 French. In at least one
`
`embodiment, the method further comprises mounting the frame and the tissue leaflet assembly
`
`attached thereto upon a balloon catheter having a size of between about 5 to 12 French. In at
`
`least one embodiment, the method