in the united states patentandtrademark office€¦ · nj 228940468v4 atty. dock. no. 103248.037100...

NJ 228940468v4

Atty. Dock. No. 103248.037100

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE In re: Mimedx Group Inc. :

: Case No. TO BE ASSIGNED Patent No.: 8,372,437 B2 :

: Issued: February 12, 2013 :

: For: Placental Tissue Grafts : X

MAIL STOP PATENT BOARD Patent Trial and Appeal Board United States Patent and Trademark Office P.O. Box 1450 Alexandria, VA 22313-1450

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,372,437

Sir:

Pursuant to 35 USC §311 et seq. and 37 CFR §42.1 et seq., Musculoskeletal

Transplant Foundation (“Petitioner”) hereby petitions for an inter partes review of

U.S. Patent No. 8,372,437 B2 (“the ‘437 Pat.”). Petitioner respectfully submits that

Claims 1 and 2 of this patent are unpatentable under Pre-AIA 35 USC §§102 and

103 in view of the prior art references discussed herein. This Petition clearly

demonstrates that there is a reasonable likelihood that Petitioner will prevail with

respect to at least one of these claims. Accordingly, it is respectfully requested that

the Board institute an inter partes review of the ‘437 Pat. pursuant to 37 CFR

§42.108.

I hereby certify that this correspondence is being transmitted via the U.S. Patent and Trademark Office electronic filing system (PRPS) to the USPTO on February 2, 2015. /John K. Kim/

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TABLE OF CONTENTS

TABLE OF CONTENTS ............................................................................................ i PETITIONER’S EXHIBIT LIST ............................................................................. iv I. Introduction ...................................................................................................... 1 II. Mandatory Notices Under 37 CFR §42.8 ........................................................ 1

A. Real Parties-In-Interest .......................................................................... 1 B. Related Matters ...................................................................................... 1 C. Lead/Back-up Counsel under 37 CFR §42.8(b)(3) ............................... 2 D. Required Fees ........................................................................................ 2 E. Standing Under 37 CFR §42.104 .......................................................... 2

III. Subject Matter Of The ‘437 Pat. ...................................................................... 2 IV. Independent Claim of the ‘437 Pat. ................................................................. 3 V. Claim Construction Under 37 CFR §42.104(b)(3) .......................................... 3

A. ‘437 Pat. Claim Terms........................................................................... 3 B. Claim Construction Analyses of Product-by-Process Claim ................ 6

VI. The Related ‘494 Patent .................................................................................. 7 VII. Background of the Alleged Invention In the ‘437 Patent ................................ 8 VIII. Priority Claim & Prior Art Status Of The References Discussed

Herein ............................................................................................................. 10 IX. Level and Person of Ordinary Skill in the Art ............................................... 12 X. Unpatentability Of Claim 1 Of The ‘437 Pat. ............................................... 12

A. Claim 1 is Unpatentable Over Klen .................................................... 12

(1) Claim 1 Is Anticipated By Klen ................................................ 12

(a) Elm. A .................................................................................. 13 (b) Elm. B .................................................................................. 13 (c) Elm. C .................................................................................. 19 (d) Elm. D ................................................................................. 19 (e) Elm. E .................................................................................. 21 (f) Elm. F ................................................................................... 23 (g) The “consisting of” Language ............................................. 23 (h) Conclusion ........................................................................... 24

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(2) Claim 1 Is Obvious Over Klen In View Of Shimazaki (“Shim.”) ................................................................................... 24

(3) Claim 1 Is Obvious Over Klen In View Of Sulner or Shenaq ....................................................................................... 26

(a) Sulner ................................................................................... 26 (b) Shenaq ................................................................................. 27

B. Claim 1 is Obvious Over Vishwakarma In View of Sulner or Shenaq ................................................................................................. 28

1. Elm. A (“a dehydrated, laminated tissue graft … produced by a process consisting of”) ............................ 28

2. Elm. B (“isolating an intact amnion layer”) ................... 28 3. Elm. C (“isolating the chorion layer”) ............................ 30 4. Elm. D (“washing and substantially cleaning the

amnion layer and the chorion layer”) ............................. 31 5. Elm. E (“laminating the amnion layer and the

chorion layer together”) .................................................. 33 6. Elm. F (“dehydrating the laminated graft …”) ............... 34 7. The “chorion layer” limitation of Elms. D and E ........... 34

a) Sulner .................................................................... 35 b) Shenaq .................................................................. 38

8. The “consisting of” Language ........................................ 38 9. Conclusion ...................................................................... 39

C. Claim 1 is Obvious Over Tseng In View of Sulner or Shenaq ........... 39


2. Elm. B (“isolating an intact amnion layer”) ................... 40 3. Elm. C (“isolating a chorion layer”) ............................... 43 4. Elm. D (“washing and substantially cleaning the


chorion layer together”) .................................................. 46 6. Elm. F (“dehydrating the laminated graft …”) ............... 47 7. The “chorion layer” limitation of Elm. E ....................... 49

a) Sulner .................................................................... 50

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b) Shenaq .................................................................. 51

8. The “consisting of” Language ........................................ 51 9. Conclusion ...................................................................... 52

D. Claim 1 is Obvious Over Ward In View of Sulner or Shenaq ............ 52


2. Elm. B (“isolating an intact amnion layer”) ................... 53 3. Elm. C (“isolating a chorion layer”) ............................... 55 4. Elm. D (“washing and substantially cleaning the


chorion layer together”) .................................................. 57

a) Sulner .................................................................... 57 b) Shenaq .................................................................. 58

6. Elm. F (“dehydrating the laminated graft …”) ............... 58 7. The “consisting of” Language ........................................ 59 8. Conclusion ...................................................................... 59

XI. Claim 2 is Unpatentable Over The Prior Art ................................................ 59 XII. Conclusion ..................................................................................................... 60

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PETITIONER’S EXHIBIT LIST

Exhibit No. Exhibit Description Abbreviation Ex. 1001 U.S. Patent No. 8,372,437 to Daniel et al. the ‘437

Patent Ex. 1002 United States Patent and Trademark Office

(“USPTO”) file wrapper for the ‘437 Patent ‘437 Patent File Wrapper

Ex. 1003 Complaint filed in MiMedx Group Inc. v. Liventa Bioscience, Inc. et al., Civil Action No. Case 1:14-cv-01178-RWS (“Related Litigation”)

N/A

Ex. 1004 Joint Claim Construction Statement filed in the Related Litigation.

JCCS

Ex. 1005 Exhibit D to Joint Claim Construction Statement: MiMedx’s Proposed Claim Constructions and Supporting Evidence for the ‘437 Patent.

MiMedx’s PCC

Ex. 1006 Expert Declaration of Rebecca N. Baergen. Baergen Dec. Ex. 1007 U.S. Patent No. 8,709,494 to Daniel et al. The ‘494

Patent Ex. 1008 United States Patent and Trademark Office

(“USPTO”) file wrapper for the ‘494 Patent. ‘494 Patent File Wrapper

Ex. 1009 Parry et al., 1998, New England J. Med., 338(10) 663-670

Parry

Ex. 1010 Expert Declaration of Dr. Helen N. Jones Jones Dec. Ex. 1011 U.S. Patent No. 6,152,142 to Tseng Tseng Ex. 1012 Vishwakarma et al., Amniotic Arthroplasty for

Tuberculosis of the Hip, J. Bone & Joint Surgery 68-B(1), 68-74 (1986)

Vish.

Ex. 1013 Klen, Preparation of chorion and/or amnion grafts used in burns, Transactions of the Third International Congress on Research in Burns, held in Prague, Sept. 20-25, 1970, Matter et al., eds., pp. 289-292 (1971)

Klen

Ex. 1014 Ward et al., The healing of chronic venous leg ulcers with prepared human amnion, British Journal of Plastic Surgery, 42, 463-467 (1989)

Ward

Ex. 1015 U.S. Patent Publication No. 2007/0038298 A1 to Sulner

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Sulner et al. Ex. 1016 International Publication No. WO 93/10722 to

Shenaq et al. Shenaq

Ex. 1017 Dua et al., Amniotic membrane transplantation, Br. J. Ophthalmol., 83:748-752 (1999)

Dua-99

Ex. 1018 U.S. Patent Publication No. 2003/0187515 A1 to Hariri et al.

Hariri-03

Ex. 1019

U.S. Provisional Patent Application Serial No. 60/838,467 filed August 17, 2006

‘467 Provisional Application

Ex. 1020 Image from “Placenta McGraw-Hill Online Learning Test”, McGraw-Hill Companies, available at http://www .mhhe.com/cgi-in/netquiz_get.pl? qfooter=/usr /web/home/mhhe/biosci/genbio/ maderbiology7/student/olc/art_quizzes/0565fq. htm&afooter=/usr/w eb/home/mhhe/ biosci /genbio/maderbiology7/student/olc/art_quizzes/05 65fa.htm&test=/usr/web/home/mhhe/biosci/genbi o/maderbiology7/student/olc/art_quizzes/0565q .txt&ans wers=/usr/web/ home/mhhe/biosci/ genbio/maderbiology7/student/olc/art_quizzes/056 5a.txt

McGraw-Hill Image

Ex. 1021 Japanese Patent Publication No. 2001-161353 to Shimazaki, et al.

JP Language Shimazaki

Ex. 1022 English Translation of Japanese Patent Publication No. 2001-161353 to Shimazaki, et al. and corresponding Translation Certification

Shim.

Ex. 1023 Chinese Patent Publication No. CN1757717A to Wei He

CN Language Wei He

Ex. 1024 English Translation of Chinese Patent Publication No. CN1757717A to Wei He and corresponding Translation Certification

Wei

Ex. 1025 U.S. Provisional Patent Application Serial No. 60/696,167 filed June 29, 2006

Sulner Provisional Application

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Ex. 1026 Farazdaghi et al., Electron Microscopy of Human Amniotic Membrane, Advances in Tissue Banking, Vol. 5: The Scientific Basis of Tissue Transplantation, Phillips et al., eds., 149-171 (2001)

Farazdaghi

Ex. 1027 Oxlund et al., Biomechanical analysis of human chorioamniotic membranes, European Journal of Obstetrics and Gynecology and Reproductive Biology, Vol. 34, No. 3, pp. 247-255 (March 1990)

Oxlund

Ex. 1028 Burgos, H., Angiogenic and growth factors in human amnio-chorion and placenta, Eur. J. of Clin. Invest., Vol. 13, pp. 289-296 (December 1982)

Burgos

Ex. 1029 International Publication No. WO 2007/010305 to Dua et al.

Dua-07

Ex. 1030 Douglas, Homografts of Fetal Membranes as a Covering for Large Wounds – Especially Those from Burns, Journal of Tennessee State Medical Association, 45:6, 230-235 (June 1952)

Douglas

Ex. 1031 Dioguardi et al., Skin Substitutes in Burn Treatment – Our Experience, Annals of the Medit. Burns Club, 3:4, 1-7 (December 1990)

Dioguardi

Ex. 1032 Dino et al., Human Amnion: The Establishment of an Amnion Bank and its Practical Applications in Surgery, The Journal of The Philippine Medical Association, Vol. 42, No. 7, 357-366 (July 1966)

Dino

Ex. 1033 Robson et al., Amniotic Membranes as a Temporary Wound Dressing, Surgery, Gynecology & Obstetrics, Vol. 136, pp. 904-906 (June 1973)

Robson

Ex. 1034 U.S. Patent Publication No. 2004/0048796 A1 to Hariri et al.

Hariri-04

Ex. 1035 Rinastiti et al., Histological evaluation of rabbit gingival wound healing transplanted with human amniotic membrane, Int. J. Oral Maxillogac. Surg., Vol. 35, pp. 247-251 (September 2005)

Rinastiti

Ex. 1036 U.S. Patent Publication No. 2006/0153928 A1 to Kinoshita-06

vii NJ 228940468v4

Kinoshita et al. Ex. 1037 International Publication No. WO2007/013331

A1 to Kinoshita et al. JP Language Kinoshita-07

Ex. 1038 English Translation of International Publication No. WO2007/013331 A1 to Kinoshita et al. and corresponding Translation Certification

Kinoshita-07

Ex. 1039 Ishino et al., Amniotic Membrane as a Carrier for Cultivated Human Corneal Endothelial Cell Transplantation, IOVS, Vol. 45, No. 3, pp. 800-806 (March 2004)

Ishino

Ex. 1040 International Publication No. WO 2005/075002 to Taguchi et al.

JP Language Taguchi

Ex. 1041 English Translation of International Publication No. WO 2005/075002 to Taguchi et al. and corresponding Translation Certification

Taguchi

Ex. 1042 International Publication No. WO 2005/007835 to Wang

Wang

Ex. 1043 Ohno-Matsui, In vitro and in vivo characterization of iris pigment epithelial cells cultured on amniotic membranes, Molecular Vision, Vol. 12, pp. 1022-1032 (August 2006)

Matsui

Ex. 1044 Hanada et al., Multilayered Amniotic Membrane Transplantation for Severe Ulceration of the Cornea and Sclera, American J. of Ophthalmol., Vol. 131, No. 3, pp. 324-331 (March 2001)

Hanada

Ex. 1045 Lee et al., Amniotic Membrane Transplantation for Persistent Epithelial Defects With Ulceration, Amniotic Membrane Transplantation, Vol. 123, No. 3, pp. 303-312 (March 1997)

Lee

Ex. 1046 Toda et al., The Potential of Amniotic Membrane/Amnion-Derived Cells for Regeneration of Various Tissues, J. Pharmacol. Sci., Vol. 105, pp. 215-218 (June 2007)

Toda

Petition for Inter Partes Review of U.S. Patent No. 8,372,437

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I. Introduction: Petitioner petitions for an inter partes review with respect to

Claims 1 and 2 of U.S. Patent No. 8,372,437 (“the ‘437 Pat.") (see Ex. 1001 & its

file history at Ex. 1002), which are unpatentable under Pre-AIA 35 USC §§102(b)

and/or 103(a) and should therefore be cancelled. This Petition demonstrates that

there is a reasonable likelihood that Petitioner will prevail with respect to at least

one of these claims. 35 USC §314(a).

II. Mandatory Notices Under 37 CFR §42.8

A. Real Parties-In-Interest: The real parties-in- interest are the Petitioner (i.e.,

Musculoskeletal Transplant Foundation, “Petitioner”), Liventa Bioscience, Inc. and

Medline Industries, Inc.

B. Related Matters: The ‘437 Pat. is involved in MiMedx Group Inc. v.

Liventa Bioscience, Inc. et al., Case No. 1:14-CV-01178-MHC (N.D. Ga.)

(“Related Litigation”), filed by MiMedx Group Inc. (“P. Owner”). Ex. 1003. The

‘437 Pat. is related to: US Pat. Nos. 8709494 (“the ‘494 Pat.”); 8597687 (“the ‘687

Pat.”); 8623421; 8460715; and 8460716; and US Appln. Nos. 14/222510 and

14/285573. Petitioner is also filing an IPR Petition for P. Owner’s US Pat. No.

8323701. The ‘494 and ‘687 Pats. are also involved in MiMedx Group Inc. v.

Tissue Transplant Technology Ltd. (d/b/a Bone Bank Allograft) and Human

Biologics of Texas Ltd., Case No. 1:14-CV-719-HLH (W.D. Tx.), and Defendants

in that litigation independently filed IPR Petitions for ‘494 and ‘687 Pats.


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C. Lead/Back-up Counsel under 37 CFR §42.8(b)(3): Petitioner appoints

Ralph W. Selitto, Jr., Reg. No. 26,996, as lead counsel, and John K. Kim, Reg. No.

37,002, and Eric E. Bleich, Reg. No. 47,430, as back-up counsel. A Power of

Attorney is filed herewith. Petitioner may be served electronically at

[email protected], [email protected] and [email protected], and by postal

mail and hand delivery at Greenberg Traurig, LLP, Attn: Ralph W. Selitto, Jr., 200

Park Avenue, Florham Park, NJ 07932. The attorneys of record may be contacted

at 973-443-3550, while their facsimile number is 973-295-1309.

D. Required Fees: The Board is authorized to charge $23,000, or any

additional fees associated with this Petition, to Deposit Account No. 501561.

E. Standing Under 37 CFR §42.104: Petitioner certifies that the ‘437 Pat. is

available for inter partes review and that Petitioner (and the real parties in interest)

are not barred or estopped from requesting an inter partes review challenging the

patent claims on the grounds identified in the Petition.

III. Subject Matter Of The ‘437 Pat.

The ‘437 Pat. discloses a tissue graft derived from amnion and chorion that

are separated from placenta and methods of preparing and preserving same. Ex.

1001 at 1:14-18. The method includes separating a chorion layer from an amnion

layer, cleaning the layers, laminating the layers together to form the graft, and

dehydrating the graft. Id. at 2:42-3:56.


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IV. Independent Claim of the ‘437 Pat.

The sole independent claim of the ‘437 Pat. is a product-by-process claim,

and is reproduced in the following chart. The claim elements are referenced below

by their corresponding letters (i.e., Elms. A-F), which are provided in the left

column of the chart.

Claim 1

A A dehydrated, laminated tissue graft, wherein the tissue graft is produced by a process consisting of:

B isolating an intact amnion layer;

C isolating a chorion layer;

D washing and substantially cleaning the amnion layer and the chorion layer;

E laminating the amnion layer and the chorion layer together; and

F dehydrating the laminated graft to produce the dehydrated, laminated tissue graft.

V. Claim Construction Under 37 CFR §42.104(b)(3)

A. ‘437 Pat. Claim Terms: Claim Under 37 CFR §42.100(b), the terms of

the claims of the ‘437 Pat. are construed under the “broadest reasonable

interpretation” standard. In the parties’ Joint Claim Construction Statement

(“JCCS”) filed in the Related Litigation, P. Owner has advanced the following

proposed constructions for the ‘437 Pat. (see Exs. 1004-1006 which includes (1)

the JCCS; (2) MiMedx’s Proposed Claim Constructions and Supporting Evidence

for the ‘437 Patent, and (3) an Expert Declaration of Rebecca N. Baergen, MD,


4 NJ 228940468v4

respectively):

• “washing and substantially cleaning the amnion layer and the chorion

layer” in Claim 1: This step is directed to reducing the amount of blood clots and

other extraneous tissue found in the native amnion and chorion layer (see

Ex.1004);

• “intact amnion layer” in Claim 1: Amnion layer separated from native

chorion layer which retains a sufficient number of cells to support the desired

purpose of the tissue graft (see id.);

• “isolating a chorion layer” in Claim 1: Separating the chorion layer

from native amnion (see id.);

• “isolating an … amnion layer” in Claim 1: Separating the amnion layer

from native chorion (see id.);

With the exception of the terms “isolating a chorion layer” and “isolating

an . . . amnion layer,” which Petitioner and P. Owner agreed in the Related

Litigation should be construed as set forth above, Petitioner states that P. Owner’s

proposed constructions of the above claim terms are inconsistent with the

principles of claim construction dictated by the Federal Circuit in Phillips v. AWH

Corp., 415 F.3d 1303 (Fed. Cir. 2005), and thus P. Owner’s proposed constructions

should not be adopted in the Related Litigation. However, pursuant to 37 CFR

§42.140(b)(3), Petitioner states that P. Owner’s construction of the claims for


5 NJ 228940468v4

purposes of litigation should be considered as within the scope of the Office’s

“broadest reasonable interpretation” standard for purposes of this IPR Petition, and

the prior art references discussed below render Claims 1 and 2 unpatentable in

view of P. Owner’s own interpretation of the scope of the claims. See Sap Am., Inc.

v. Versata Dev. Group, Inc., Case CBM2012-00001, Paper 70, at *7 (P.T.A.B.

June 11, 2013) (“There are . . . two claim construction standards: the Office’s

[broadest reasonable interpretation] construction and the district court standard set

forth in Phillips v. AWH. see also Motorola Mobility, LLC v. Arnouse, Case

IPR2012-00001, Paper 21, at *6 (P.T.A.B. Feb. 12, 2013) (finding that Petitioner’s

identification of “the claim constructions made in the concurrent litigation”

satisfied 37 CFR §42.140(b)(3)).

P. Owner did not construe the term “laminating the amnion layer and the

chorion layer together” (Elm. E of Claim 1) in the Related Litigation, or even

proffer a specific definition of the term “laminate” in the specification of the ‘437

Pat. Petitioner therefore submits that the term “laminating the amnion layer and the

chorion layer together” should be construed, for purposes of this IPR Petition only,

according to the Office’s “broadest reasonable interpretation” standard. A person

of ordinary skill in the art would construe “laminating the amnion layer and the

chorion layer together” as combining the isolated amnion layer and the isolated


6 NJ 228940468v4

chorion layer in a stacked configuration (i.e., one on top of another).1 Ex. 1010 ¶22.

The ‘437 Pat. supports this construction, as it discloses grafts “comprised of …

multiple layers of a combination of amnion and chorion” and “laminated

amnion and chorion combined tissue grafts” (emphasis added). Ex. 1001 at Abst.,

2:33-36, and 10:20-24. The ‘437 Patent also discloses “mounting one or more

additional layers of chorion tissue or amniotic layer … to create … laminated

placental tissue grafts having a thickness and strength greater than a single

layer of placental membrane tissue graft” (emphasis added). Id. at 3:28-34.

Petitioner’s proposed construction is believed to be within the scope of the Office’s

“broadest reasonable interpretation” standard for purposes of this IPR Petition.

B. Claim Construction Analyses of Product-by-Process Claim: Claim

1 is a product-by-process claim. As such, Petitioner has conducted two claim

construction analyses. In the first analysis, both the structural features and process

steps recited in Claim 1 have been treated as elements of the claim, and both types

of elements will be compared to the structural features and process steps disclosed

in the prior art discussed hereinafter.

In the second analysis, the process steps of Claim 1 have been read out of

the claim, because when “the product in [a] product-by-process claim is the same 1 While using this definition of “laminating,” Petitioner is not bound to rely on

same for the purpose of the Related Litigation.


7 NJ 228940468v4

as or obvious from a product of the prior art, the claim is unpatentable even though

the prior product was made by a different process” (emphasis added). In re

Thorpe, 777 F.2d 695, 698, (Fed. Cir. 1985). This second analysis is referred to

hereinafter as “the Thorpe analysis.” Petitioner has considered the related ‘494

Patent in conducting the Thorpe analysis of Claim 1, as further discussed below.

VI. The Related ‘494 Patent

Claim 1 of P. Owner’s related ‘494 Pat., which was filed as a continuation of

the ‘437 Pat., is reproduced below to facilitate consideration and discussion:

1. A dehydrated, laminated tissue graft consisting essentially of

one or more washed and/or substantially cleaned amnion layers and

one or more washed and/or substantially cleaned chorion layers,

wherein at least one of the amnion layers contains its fibroblast cell

layer, and further wherein the amnion layer and the chorion layer are

directly laminated to each other. See ‘494 Pat. (Ex. 1007 at 11:32-38).

Claim 1 of the ‘494 Patent is a “product” claim directed to the same

dehydrated, laminated tissue graft as is recited in the product-by-process Claim 1

of the ‘437 Patent. In fact, during prosecution of the ‘494 Patent, the Examiner

(i.e., the same Examiner as in the ‘437 Pat.) issued a nonstatutory double patenting

rejection of pending Claim 21 (which corresponds to Claim 1 of the ‘494 Pat.) as

being anticipated by or obvious in view of Claim 1 of the ‘437 Pat. See ‘494 Patent

File Wrapper (Ex. 1008, 77-78). The Examiner noted that “patent claim 1 [of the


8 NJ 228940468v4

‘437 Pat.] defines a tissue graft via the process of production[, and that the]

patented tissue graft consists of one layer of intact amnion and one layer of

chorion, each washed and/or substantially cleaned, which are laminated together

and the tissue graft is dehydrated” (emphasis added). Id. The Thorpe analysis of

Claim 1 (i.e., presented below in Sec. X.) is based on the Examiner’s foregoing

description of the patented tissue graft (hereinafter “PT Graft”) as constituting the

structure implied by the process steps of Claim 1. The elements of the PT Graft are

reproduced in the following chart, and are referenced below by their corresponding

letters (i.e., Elms. U-Z), which are provided in the left column of the chart.

PT Graft

U patented tissue graft consists of

V one layer of intact amnion;

W one layer of chorion;

X each washed and/or substantially cleaned;

Y which are laminated together; and

Z the tissue graft is dehydrated.

Rather than argue against the nonstatutory double patenting rejection, P.

Owner filed a Terminal Disclaimer based on the ‘437 Pat., thereby acquiescing to

the Examiner’s characterization of Claim 1 of the ‘437 Pat. Id. at 48-49, 52.

VII. Background of the Alleged Invention In the ‘437 Patent

The human placenta includes two membranes: the amnion and the chorion,


9 NJ 228940468v4

see Parry (Ex. 1009, 1), which are sometimes referred to in the art as the amniotic

and chorionic membranes, respectively. Ex. 1010 ¶26.

As the innermost membrane of the placenta, the amnion is in contact with

the amniotic fluid and the fetus. The chorion is the outer-most membrane of the

placenta and is therefore in contact with the maternal tissues of the uterus (i.e., the

maternal decidua). Id., ¶28. An intermediate/spongy layer is located between the

amnion and chorion, and absorbs physical stresses by permitting the amnion to

slide along the chorion without disrupting the firm adherence of the chorion to the

maternal decidua (i.e., the uterine wall). Ex. 1009, 1-2.

As acknowledged by the ‘437 Pat., human placental membranes have been

used in various surgical procedures since the early 1900s. Ex. 1001 1:21-23. Such

surgical procedures included the treatment of a variety of conditions including

corneal injuries, burns, peripheral nerve injuries, chronic ulcers of the leg and skin

wounds. See, e.g., Exs. 1011-17, 1021-24, 1030, 1032-33, 1035-36, 1038-39 and

1041-44.

Historically, placental membranes were recovered and processed within the

hospital where they would be used. They were minimally manipulated and used as

transplants rather than as commercial medical products (see, e.g., Exs. 1012, 1013,

1032, 1033). For example, the amnion did not undergo any steps to decellularize it.

It was therefore well-known to retain an intact amnion prior to the date of alleged


10 NJ 228940468v4

invention. Ex. 1010 ¶31.

Methods of separating of amnion and chorion from one another (which

occurs through the spongy layer intermediate the amnion and chorion) for the

purposes of using these membranes as graft materials was also well-known in the

prior art (see, e.g., Exs. 1011-1013, 1016, 1023-24). Ex. 1010 ¶32.

Washing and cleaning the placental membranes to remove blood clots and

other extraneous tissue was also well-known prior to the date of alleged invention

(see, e.g., Exs. 1012-10), and could include the use of antibiotic solutions to

control bioburden. (see, e.g., Exs. 1012, 1017). Ex. 1010 ¶¶34-35.

Methods for combining (i.e., stacking one on top another) multiple layers of

amnion and/or chorion to form multi-layered (i.e., laminated) tissue grafts were

also well-known prior to the date of alleged invention (see, e.g., Exs. 1013, 1015,

1016, 1018, 1034). Ex. 1010 ¶36.

Methods for preserving tissue grafts were also well known prior to the date

of alleged invention, and included dehydration (including, e.g., air drying and

lyophilization). (see, e.g., Exs. 1012-16), Ex. 1010 ¶37.

Since the tissue graft and process claimed in the ‘437 Patent were already

known in the prior art, Claims 1 and 2 are unpatentable over the prior art.

VIII. Priority Claim & Prior Art Status Of The References Discussed Herein

The ‘437 Pat. matured from U.S. Patent Application Serial No. 11/840728


11 NJ 228940468v4

(“‘728 Appln.”) filed 8/17/07, and claimed the benefit under §119(e) of U.S.

Provisional Patent Application Serial No. 60/838467 (“‘467 Prov. Appln.”) filed

8/17/06.

The ‘467 Prov. Appln. fails to disclose all of the features recited in Claim 1

of the ‘437 Pat. (e.g., the steps of laminating an amnion layer and a chorion layer

together, and washing and substantially cleaning a chorion layer. In fact, the ‘467

Prov. Appln. teaches that the chorion layer “can be discarded in the appropriate

biohazardous waste receptacle” (emphasis added) after it is separated from the

amnion layer, as well as “gently scrub[bing] the chorion away from the amnion”

(emphasis added). Id. 1019, 18, 22. Because the ‘467 Prov. Appln. does not

provide written support for the tissue graft recited in Claim 1, the ‘437 Pat. is not

entitled to the benefit of the 8/17/06 filing date of the ‘467 Prov. Appln. Ex. 1010

¶45-46. Thus, the earliest possible filing date to which the claims of the ‘437

Patent are entitled is 8/17/07, the filing date of the ‘728 Appln. Id.

All references discussed herein, with the exception of Sulner, were

published more than one year prior to 8/17/07, and therefore qualify as

incontestable prior art under §102(b). Sulner was filed prior to 8/17/07, and thus

constitutes prior art, at least, under §102(e).

Once a patent challenger comes forward with invalidating prior art, the

burden of production shifts to the patentee to show that “it is not prior art because


12 NJ 228940468v4

the asserted claim is entitled to the benefit of an earlier filing date”. Research Corp.

Techs. v. Microsoft Corp., 627 F.3d 859, 870 (Fed. Cir. 2010). Thus, Petitioner

reserves the right to challenge the ‘437 Pat.’s priority claim should P. Owner

attempt to antedate or otherwise disqualify any of the references as prior art.

IX. Level and Person of Ordinary Skill in the Art : Petitioner submits that

persons of ordinary skill in the art (“POSA”) of the ‘437 Patent during the 2006-

2007 time frame covering 8/17/06 and 8/17/07 would possess an advanced degree

(i.e., a Masters or Doctorate degree) in a biomedical science such as physiology,

biochemistry, biology, cell biology, or a medical science degree in pathology or

medicine, and knowledge of tissue processing methods. Ex. 1010 ¶14. A POSA as

of the 2006-2007 timeframe would also have at least two years of experience in

and/or knowledge of the processing of tissues for clinical and/or research use. Id.

X. Unpatentability Of Claim 1 Of The ‘437 Pat.

A. Claim 1 is Unpatentable Over Klen

(1) Claim 1 Is Anticipated By Klen

Klen (not cited in the ‘437 Pat.) discloses amnion grafts, chorion grafts and

combined amnion-chorion grafts, and a process for producing such grafts that

includes cutting, cleaning and drying steps (“the Klen process”). Ex. 1013, 4-5.

The Klen process includes all of the elements recited in Claim 1 (i.e., the process

steps) and only those elements (hereinafter “Elms.”), thereby anticipating Claim 1,


13 NJ 228940468v4

as discussed in greater detail below.

(a) Elm. A: Klen discloses a combined amnion-chorion graft that is dried,

id., and therefore teaches a dehydrated,

laminated tissue graft, as recited in Claim 1. See

Sec. X.A.(1)(g) below for “consisting of” and

Thorpe analysis discussions. (b) Elm. B: The

Klen process includes Elm. B: “isolating an

intact amnion layer.” Klen teaches amnion

grafts made from amnion only, and chorion grafts made from chorion only. Id., 4.

In order to make amnion-only or chorion-only grafts, amnion and chorion must be

separated from another, i.e., isolated, as discussed below. Ex. 1010 ¶50, 69.

The Klen process is discussed below, after a prefatory discussion of

the placenta, which is illustrated in FIG. 12 with the amnion, chorion, umbilical

cord and embryo in utero. While the term “placenta” may be used more broadly to

include the amnion and chorion, here it is being used to specifically identify the

vascularized structure that develops from the chorion frondosum and the decidua

basalis. At/before birth, the amnion and chorion are punctured to permit egress of

2 Illustration from “Placenta McGraw-Hill Online Learning Test” Website,

McGraw-Hill Companies. Ex. 1020.


14 NJ 228940468v4

the developed embryo/infant, and thereafter constitute substantially planar layers

that overlie each other (with an intermediate spongy layer, as discussed below) and

the placenta when placed on a flat surface. Ex. 1010 ¶¶52-54.

Turning now to the following disclosure of the Klen process, its steps

have been given reference numbers (i.e., 1-6) in brackets that correspond to

schematic figures (i.e., FIGS. 2-6) that illustrate such steps, with the exception of

Step 1, which has not been illustrated.

“At the beginning of the preparation the umbilical cord is tied to

prevent bleeding [1]. As the placenta is usually situated excentrically,

we put it with the side where the umbilical cord is attached on a

bottom of the basin in order to have a good survey about the

dimensions of the membranes [2]. At the site of the smallest distance

between the margin of the placenta and membranes, we cut these

radially, to the umbilical cord [3]. Then the amnion is cut circularly

following the border of the chorion [4], and the chorion again along

the margin of the placenta which enables us to gain the largest grafts

[6]. Some time ago we preserved the complete amnion from the

surface of the chorion and placenta.” Ex. 1013, 4.

Steps 2-6 and their respective figures are discussed below.


15 NJ 228940468v4

STEP 2/FIG. 2: Klen discloses how the amnion and

chorion (A and C, respectively) and placenta (P) are put in a

basin (not shown) “with the side where the umbilical cord [U]

is attached [i.e., the amnion side] on the bottom of the basin …

to have a good survey about the dimensions of the membranes.” Id. As shown in

FIG. 2, this placement causes the chorion C to face upwards.

Ex. 1010 ¶55.

STEP 3/FIG. 3: The placenta P and membranes A, C

are turned over (i.e., flipped over from the position of FIG. 2)

so that the amnion A and umbilical cord U face upwards to provide access to the

amnion A. Id. ¶56. Klen discloses that “at the site [S] of the smallest distance

between the margin of the placenta [P] and membranes [A, C], we cut these

radially, to the umbilical cord [U]” Ex. 1013, 4. As shown in FIG. 3, the radial cut

(RC) is made in the amnion A along the entire distance between the

aforementioned site S and umbilical cord U. The radial cut RC is also made in the

chorion C, but only to where it fuses to the placenta P (not shown), as cutting the

placenta P would cause excessive bleeding and complicate the preparation process,

and is therefore avoided. Ex. 1010 ¶56. However, the chorion C may alternatively

be cut through into the placenta P, i.e., along the entire distance between the site S

and umbilical cord U.


16 NJ 228940468v4

STEP 4/FIG. 4: Klen discloses that “the amnion [A]

is cut circularly following the border of the chorion [C].”

Ex. 1013, 4. With the amnion A still facing upwards, a first

circular cut C1 is made in the amnion A, along the border

of the chorion C, i.e., where it fuses to the placenta P. The

first cut C1 is made to separate the amnion A from the placenta P. Ex. 1010 ¶57.

STEP 5/FIG. 5: The placenta P and membranes A, C

are turned over again (i.e., flipped over from the position

shown in FIG. 4) so that the chorion C and placenta P face

upwards and are therefore accessible for this step. Id. ¶58.

Klen discloses that “the chorion [C is cut] again along the margin of the placenta

[P],” Ex. 1013, 4, to make the second circular cut C2 therein, as shown. The

second cut C2 is made to separate the chorion C from the placenta P. Two cuts (i.e.,

C1 and C2) are used in view of the thickness of the chorion near the placenta. Ex.

1010 ¶58.

STEP 6/FIG. 6: Klen discloses that cuts C1 and

C2 “enable us to gain the largest grafts.” Cuts C1 and

C2 thereby permit the placenta P and umbilical cord U

to be separated from the amnion A and chorion C, to

produce a band-like graft with the amnion A still attached to the chorion C, as


17 NJ 228940468v4

shown in FIG. 6. Ex. 1010 ¶54.

Klen then discloses that “[s]ome time ago we had preserved the complete

amnion from the surface of the chorion” (emphasis added). Ex. 1013, 4. This

disclosure refers to a known process in which the complete amnion is preserved

(i.e., separated from) from the chorion. In fact, since Klen’s amnion-only and

chorion-only grafts can only be made by separating the amnion and chorion from

another, a POSA would understand that Klen’s process includes the previously

known step of separating amnion from chorion. Ex. 1010 ¶¶60, 71. Thus, Klen

discloses the step of isolating an amnion layer, as construed by P. Owner.

Klen’s disclosure of having “preserved the complete amnion …” also

teaches the “intact amnion layer” of Elm. B, as the word “complete” means that

nothing has been removed from the amnion. Thus, Klen discloses the step of

isolating an amnion layer that is intact. Ex. 1010 ¶72.

Under P. Owner’s construction of the claim term, “intact amnion layer,” the

isolated amnion layer needs only to retain “a sufficient number of cells to support

the desired purpose of the tissue graft.” To the extent that P. Owner’s construction

means that the amnion layer is intact even if some cells are removed during

processing (i.e., the amnion layer contains fewer cells than a native amnion) see Ex.

1006 ¶¶133-141), Klen discloses such an intact amnion layer. Indeed, Klen teaches

that the “complete amnion” is “preserved,” which necessarily means that it retains


18 NJ 228940468v4

“a sufficient number of cells to support the desired purpose of the tissue graft.”

Further, Klen discloses no steps of decellularizing the amnion. For instance,

the washing, cutting and drying steps disclosed in Klen would not cause a

relatively large number of cells to be removed from the amnion (i.e., relative to the

total number of cells therein). Ex. 1010 ¶74. Rather, the effective removal of a

relatively large number of cells from the amnion would require mechanical (e.g.,

scraping) and/or chemical methods (e.g., detergent, enzymatic). Id.

Notwithstanding the fact that Klen discloses no steps of decellularizing the amnion,

a relatively small number of the cells could be removed from the amnion by one or

more of the steps of the Klen process (e.g., washing, which could remove some

loose cells from the surface of the epithelial layer). Nevertheless, a large majority,

if not substantially all, of the cells of the amnion would be retained therein after

completion of the Klen process, certainly enough to constitute “a sufficient number

of cells to support the desired purpose of the tissue graft.” Id. ¶75. This is evident

when the Klen process is compared to the aggressive cleaning steps disclosed in

the ‘437 Pat., which include: (i) massaging the placenta in hyperisotonic saline to

remove blood clots; (ii) using a cell scraper, blunt instrument, finger or gauze to

further remove blood clots and debris from the separated amnion; and (iii)

agitating the separated amnion for 30-90 minutes in hypertonic solution. Ex. 1001,

5:67–7:7. In other words, if the amnion undergoing the aggressive cleaning steps


19 NJ 228940468v4

of the ‘437 Pat. retains a sufficient number of cells to support the desired purpose

of the tissue graft, then amnion submerged/washed in saline according to Klen

must also retain a sufficient number of cells. Ex. 1010 ¶75. In view of the above

discussion, Klen discloses Elm. B of Claim 1 (i.e., the step of isolating an intact

amnion layer), as such element has been construed by P. Owner. For the same

reasons, Klen also discloses Elm. V of the PT Graft discussed above in Sec. VI.

under the Thorpe analysis.

(c) Elm. C: The Klen process includes Elm. C: “isolating a chorion

layer.” As discussed immediately above in Sec. X.A.(1)(b), Klen teaches amnion

grafts made from amnion only, as well as chorion grafts made from chorion only.

Id., 4. In order to make Klen’s amnion-only or chorion-only grafts, the amnion and

chorion must be separated, which would include isolating the chorion layer (see

above and Ex. 1010 ¶¶69, 77). Thus, Klen discloses Elm. C of Claim 1 (i.e., the

step of isolating a chorion), as such element has been construed by P. Owner. For

the same reasons, Klen also discloses Elm. W of the PT Graft discussed above in

Sec. VI. under the Thorpe analysis.

(d) Elm. D: The Klen process includes Elm. D: “washing and

substantially cleaning the amnion layer and the chorion layer.” Klen teaches that

“[t]he membranes are submerged into the saline[,] washing away the majority of


20 NJ 228940468v4

blood-clots” (emphasis added) Ex. 1013, 4, which constitutes “washing and

substantially cleaning the amnion layer and the chorion layer.” Ex. 1010 ¶79.

P. Owner’s claim construction requires this step to “reduc[e] the amount of

blood clots and other extraneous tissue found in the native amnion and chorion

layer.” Klen also inherently discloses that at least some of the extraneous tissues

found in the amnion and chorion would be washed away by submerging such

membranes in the saline. According to P. Owner’s expert’s declaration, these

extraneous tissues may include “the remnants of tissue from various pathological

states and/or dead tissue,” Ex. 1006 ¶111, which a POSA would understand to not

only be unsafe and undesirable for inclusion in a tissue graft, but also easily

removed, relative to non-extraneous tissues. Ex. 1010 ¶81. Extraneous tissues

would therefore be necessarily removed from the membranes by submerging them

in the saline and washing the extraneous tissues away from the membranes before

further processing and producing the graft, in the same way that blood clots are

washed away upon submerging the membranes. Ex. 1010 ¶81. Thus, Klen

discloses washing and substantially cleaning the amnion layer and the chorion

layer, as construed by P. Owner.

Should the Board construe Elm. D to require that the washing and

substantially cleaning step removes extraneous tissue including the spongy layer,

Klen satisfies this narrower construction. P. Owner stated during the prosecution of


21 NJ 228940468v4

the ‘437 Pat. that “the intact amnion layer and chorion layer were isolated and

substantially cleaned[, and as] such the tissue graft was substantially free from

blood clots and an intermediate layer (emphasis added) Ex. 1002, 51-52 (see also,

Reasons for Allowance, Ex. 1002, 28-29 and ‘437 Pat., Ex. 1001, 6:42-44). As

discussed above, Klen teaches removing extraneous tissues from the membranes.

A POSA would have known that the spongy layer is unnecessary for certain

medical applications, (see, e.g., Shimazaki (“hereinafter “Shim.”), (0023); Wei

6:7), and hence, extraneous tissue. A POSA would therefore have been motivated

to remove the spongy layer from the amnion and chorion, either based on Klen

alone or combined with Shim. or Wei. Ex. 1021-22, (0023); Ex. 1023-24 6:7). Ex.

1010 ¶82. Thus, regardless of whether the Board adopts P. Owner’s proposed

construction of Elm. D of Claim 1, or a narrower construction, Klen discloses such

element (i.e., the step of washing and substantially cleaning the amnion and

chorion layers). Id. For the same reasons, Klen also discloses Elm. X of the PT

Graft discussed above in Sec. VI. under the Thorpe analysis.

(e) Elm. E: The process for producing the combined amnion-chorion

graft of Klen includes Elm. E: laminating the amnion layer and the chorion layer


22 NJ 228940468v4

together.3 As discussed above in Sec. V., “laminating the amnion layer and the

chorion layer together” has been construed as combining the amnion layer and

chorion layer in a stacked configuration. Indeed, the ‘437 Pat. discloses grafts

“comprised of … multiple layers of a combination of amnion and chorion” and

“laminated amnion and chorion combined tissue grafts” (emphasis added). Ex.

1001, Abst.; 2:33-36; 10:20-24. In the same way, the “combined amnion-chorion

graft” taught by Klen constitutes a disclosure of laminating an amnion layer and a

chorion layer together. Ex. 1010 ¶85. Klen also discloses that the combined

amnion-chorion grafts are “rolled up” prior to being freeze-dried and stored. Ex.

1013, 5. Before rolling up a graft having an amnion layer and a chorion layer, such

layers would necessarily be combined in a stacked configuration (i.e., laminated).

In other words, rolling up a combined amnion-chorion graft requires that the

amnion layer and chorion layer be combined to stack them one on top of another

before the combined graft is rolled up. Ex. 1010 ¶86. Thus, for the above reasons,

Klen discloses Elm. E of Claim 1 (i.e., the step of laminating the amnion layer and 3 To the extent that the Board finds that Klen does not expressly teach the

laminating step, it would have been obvious to perform the laminating step, based

on Klen’s disclosures of (i) separating the amnion and chorion and (ii) a combined

amnion-chorion graft. For the same reasons, Klen also renders obvious Elm. Y of

the PT Graft discussed above in Sec. VI. under the Thorpe analysis.


23 NJ 228940468v4

chorion layer together). For the same reasons, Klen also discloses Elm. Y of the PT

Graft discussed above in Sec. VI. under the Thorpe analysis.

(f) Elm. F: Regarding “dehydrating the laminated graft to produce the

dehydrated, laminated tissue graft”, Klen discloses that the amniotic and chorionic

membranes are “cut along the shape of … [arranged] stripes” of a plastic net, and

stretched on arranged stripes of a plastic net to “facilitate drying” of the

membranes (emphasis added). Ex. 1013, 4-5. Klen further teaches that the grafts

are “covered by Tylexol [a thin tulle mesh material] and rolled up, … inserted into

vessels … and then stored under deep temperature up to the time when sufficient

quantity of preserves for freeze-drying is collected” (emphasis added). Id., 5. A

POSA would understand that freeze-drying, i.e., lyophilization, constitutes a tissue

dehydration process. Ex. 1010 ¶88. The freeze-dried graft may then be stored “at

room temperature in a dry and dark place” until the graft is to be used in a surgical

operation. Ex. 1013, 5. Thus, the Klen process includes Elm. F of Claim 1 (i.e., the

step of dehydrating the laminated graft). For the same reasons, Klen also discloses

Elm. Z of the PT Graft discussed above in Sec. VI. under the Thorpe analysis.

(g) The “consisting of” Language: Klen teaches a graft produced by a

process including only the steps recited in Claim 1. As discussed above, Klen

discloses that the umbilical cord attached to the placenta is tied to prevent bleeding,

and placed in a basin “with the side [with] the umbilical cord … attached on [the]


24 NJ 228940468v4

bottom … in order to have a good survey about the dimensions of membranes.” Id.,

4. The foregoing steps constitute part of the claimed steps of isolating an intact

amnion layer and isolating a chorion layer, as they facilitate isolation of the

amnion and chorion. Ex. 1010 ¶90.

Klen also discloses that the combined amnion-chorion graft is “covered by

Tylexol”, a thin tulle mesh material, before being rolled up, inserted into a vessel

and freeze-dried. Ex. 1013, 5. This covering step constitutes part of the claimed

step of dehydrating the laminated graft because the Tylexol mesh separates the

concentric rolled graft layers while the interstices of the mesh allow moisture to

escape from the graft to facilitate dehydration via freeze-drying. Ex. 1010 ¶91.

As the Klen process includes, and only includes, the isolating, washing and

substantially cleaning, laminating and dehydrating steps of Claim 1, Klen satisfies

the “consisting of” language of Claim 1. Id. ¶92. For the same reasons, Klen also

discloses Elm. U of the PT Graft discussed above in Sec. VI. under the Thorpe

analysis, in that the PT Graft “consists of” only Elms. V, W, X, Y and Z.

(h) Conclusion: For the reasons explained above in Secs. X.A.(1)(a-g),

Claim 1 is anticipated by Klen under §102(b).

(2) Claim 1 Is Obvious Over Klen In View Of Shimazaki (“Shim.”)

During prosecution of the ‘437 Pat., P. Owner argued that after the step of

washing and substantially cleaning, “the tissue graft was substantially clean from


25 NJ 228940468v4

blood clots and an intermediate layer” (emphasis added). Ex. 1002, 51-52 (see

also, Reasons for Allowance, Ex. 1002, 28-29 and ‘437 Pat., Ex. 1001, 6:42-44). If

the Board construes the washing and substantially cleaning step to require removal

of the intermediate (i.e., spongy) layer as “extraneous tissue,” Claim 1 would still

be unpatentable since it is obvious over Klen in view of Shim., which is not cited

in the ‘437 Patent.

Shim. teaches processing an amnion to manufacture a cell sheet for

transplantation. Ex. 1021-22, Abst. The Shim. process includes the step of

removing “the sponge layer” from the amnion, which is “not necessary.” Id.,

(0023). Further, because the spongy layer is attached to the separated amnion and

chorion loosely and unevenly, a POSA would know that it is debris-like, wherein

numerous random pieces of the spongy layer dangle or hang loosely from the

amnion and chorion. Ex. 1010 ¶98. A POSA would therefore construe the spongy

layer to be “extraneous tissue,” because it (i) is unnecessary for certain medical

applications, and (ii) is debris-like, Ex. 1010 ¶99. In such circumstances, “washing

and substantially cleaning” the amnion includes removal of the “sponge layer”.

(See Sec. X.A.(1)(d) above). Id. Thus, Claim 1 is obvious, under §103, over Klen

in view of Shim. For the same reasons, Klen as modified by Shim. also renders

obvious, under §103, the PT Graft discussed in Sec. VI under the Thorpe analysis.


26 NJ 228940468v4

(3) Claim 1 Is Obvious Over Klen In View Of Sulner or Shenaq

To the extent that Klen does not explicitly disclose a “laminating step” per

se, Claim 1 would still be unpatentable because it is obvious over Klen in view of

Sulner or Shenaq, as discussed below.

(a) Sulner: Sulner (which is cited in the ‘437 Patent, but was not relied

upon) discloses repairing a tympanic membrane using a collagen biofabric derived

from placental membranes (i.e., amnion and/or chorion). Ex. 1015, ¶¶[0007],

[0009]. The collagen biofabric may include two or more layers of placental

membrane that are “laminated to provide greater stiffness and durability during

the healing process” (emphasis added). Id. at ¶¶[0240]-[0242]. Sulner therefore

provides both a suggestion and motivation for laminating the separated amnion and

chorion of Klen together to form a stiffer, more durable two-layer graft. A POSA

would therefore have recognized the benefits of a two-layer graft over a single

layer graft (indeed, the ‘437 Patent itself discloses that laminated placental tissue

grafts are thicker and stronger than single layer grafts. Ex. 1001, 3:28-34). Given

the foregoing teaching of Sulner and the reasons discussed in Sec. X.B.7(a) below,

a POSA would be motivated to combine a separated amnion layer and a separated

chorion layer. Ex. 1010 ¶102.

Sulner was published on 2/15/07, and has an effective filing date of 6/30/05,

which is the filing date of the Sulner Provisional Application. All of the disclosures


27 NJ 228940468v4

of Sulner that are discussed above and relied upon herein were first disclosed in the

Sulner Provisional Application. Ex. 1025, ¶¶[0007], [0009], [0028], [0126], [0130],

[0131]. Accordingly, the effective date of Sulner as a prior art reference is 6/30/05.

For the reasons discussed above, Claim 1 is obvious over Klen in view of

Sulner under §103, and therefore unpatentable. For the same reasons, Klen as

modified by Sulner also renders obvious, under §103, the PT Graft discussed in

Sec. VI under the Thorpe analysis.

(b) Shenaq: Shenaq (not cited in the ‘437 Patent) discloses forming

tubular nerve and vessel grafts from amnion and/or chorion. Ex. 1016, 4:13-22.

Shenaq discloses that “amnion and chorion sheets are … wrapped in layers”

(emphasis added) when forming the tubular grafts. Id., 4:35-36. When considering

this disclosure in conjunction with Klen’s disclosure of rolling the grafts (Ex.

1013, 5), a POSA would understand that wrapping amnion and chorion in layers

constitutes, or at least includes, laminating the amnion and chorion layers together.

Ex. 1010 ¶106. Shenaq also discloses that the amnion and chorion layers “can be

glued together … to prevent delaminating” (emphasis added). Ex. 1016, 5:6-8,

which indicates that the layers had already been laminated together, and that such

lamination does not require an adhesive. Ex. 1010 ¶107. Based on the foregoing

disclosures of Shenaq, a POSA would have been motivated to laminate the


28 NJ 228940468v4

separated amnion and chorion layers of Klen together to form a laminated amnion-

chorion graft. Id. ¶108.

For the reasons discussed above, Claim 1 is obvious over Klen in view of

Shenaq under §103, and therefore unpatentable. For the same reasons, Klen as

modified by Shenaq also renders obvious, under §103, and unpatentable the PT

Graft discussed in Sec. VI under the Thorpe analysis.

B. Claim 1 is Obvious Over Vishwakarma In View of Sulner or Shenaq

Vishwakarma (hereinafter “Vish.”), which was not cited during the

prosecution of the ‘437 Pat., discloses a multi-layered amniotic membrane graft

used as a cap in hip arthroplasty, and a method of preparing same. Ex. 1012, 1.

Vish. discloses all of the elements of Claim 1, with the exception of two (i.e.,

washing and substantially cleaning … the chorion layer, and including a chorion

layer in the laminated graft), which are disclosed in Sulner or Shenaq. The claim

elements will be compared to Vish. below.

1. Elm. A (“a dehydrated, laminated tissue graft … produced by a

process consisting of”): Vish. discloses a multi-layered amnion graft (i.e., cap)

and a process for preparing same. Id., 1-2. Accordingly, Vish. discloses Elm. A.

The phrase “consisting of” is satisfied by Vish., as discussed below in Sec. X.B.8.

2. Elm. B (“isolating an intact amnion layer”): The process for

producing the graft of Vish. includes Elm. B. As described by Vish., “[f]resh


29 NJ 228940468v4

placentae were collected … and … [the a]mnion was separated from the chorion”

(emphasis added) Id., 2. This separated/isolated amnion then undergoes cutting,

piling and drying steps Id., 1, as described below, but none of these steps would

disrupt the intact nature of the amnion. Ex. 1010 ¶¶117-119.

Under P. Owner’s construction of the claim term, “intact amnion layer,”

the isolated amnion layer must only retain “a sufficient number of cells to support

the desired purpose of the tissue graft.” To the extent that the P. Owner’s

construction means that the amnion layer is intact even if some cells are removed

during processing (i.e., the amnion layer contains fewer cells than a native amnion),

Vish. discloses such an intact amnion. Indeed, Vish. teaches that the “prepared

amniotic cap” was implanted in the hips of 25 patients, with successful results (Ex.

1012, 3), which necessarily means that the amnion layers of the amniotic cap

would retain “a sufficient number of cells to support the desired purpose of the

tissue graft,” i.e., treatment of tuberculosis of the hip.

The discussion in the last paragraph of Sec. X.A.(1)(b) above is also

applicable here, as Vish. discloses no steps of decellularizing the amnion. For

instance, washing and collecting an amnion in saline, as disclosed in Vish., would

not cause a relatively large number of cells to be removed from the amnion (i.e.,

relative to the total number of cells therein). Ex. 1010 ¶118. Rather, the effective

removal of a relatively large number of cells from the amnion would require


30 NJ 228940468v4

mechanical (e.g., scraping) and/or chemical methods (e.g., detergent, enzymatic).

Id. Notwithstanding the fact that Vish. discloses no steps of decellularizing the

amnion, a relatively small number of the cells could be removed from the amnion

by one or more of the steps of the Vish. process (e.g., the washing step, which

could remove some loose cells from the surface of the epithelial layer).

Nevertheless, a large majority, if not substantially all, of the cells of the amnion

would be retained therein after completion of the Vish. process, certainly enough

to constitute “a sufficient number of cells to support the desired purpose of the

tissue graft.” Id. ¶119. This is evident when the process of Vish. is compared to the

aggressive cleaning steps disclosed in the ‘437 Patent, which are discussed above

in Sec. X.A.(1)(b). In other words, if the amnion undergoing the cleaning steps of

the ‘437 Patent retains a sufficient number of cells to support the desired purpose

of the tissue graft, then Vish.’s amnion layers, which are denuded of mucus and

collected in normal saline, must also retain a sufficient number of cells. Id.

In view of the above, Vish. discloses Elm. B of Claim 1 (i.e., the step of

isolating an intact amnion layer), as such element has been construed by P. Owner.

For the same reasons, Vish. also discloses Elm. V of the PT Graft discussed in Sec.

VI. under the Thorpe analysis.

3. Elm. C (“isolating the chorion layer”): Vish. also discloses this step

by action of the previous step of separating the amnion and chorion. Ex. 1012, 2. In


31 NJ 228940468v4

other words, isolating the amnion by separating it from native chorion would also

necessarily isolate the chorion, i.e., by separating same from native amnion. Ex.

1010 ¶121. Thus, the process of Vish. includes Elm. C of Claim 1 (i.e., the step of

isolating a chorion layer), as such element is construed by P. Owner. For the same

reasons, Vish. also discloses Elm. W of the PT Graft discussed in Sec. VI. under

the Thorpe analysis.

4. Elm. D (“washing and substantially cleaning the amnion layer and

the chorion layer”): Vish. teaches washing a fresh placenta Ex. 1012, 2. The

placenta includes the amnion and chorion layers, which can be washed and

substantially cleaned while still at least partially connected to one another as part

of the placenta, as they are in Vish. Ex. 1010 ¶123.

Vish. also teaches that the amnion, once separated from the chorion, is

denuded of mucus and “collected in a beaker containing normal saline.” Ex. 1012,

2. A POSA would understand that freshly recovered amnion has blood clots and

other extraneous tissue (e.g., mucus) that must be removed prior to using it as a

graft for immunological reasons (i.e., to prevent or minimize the risk of causing an

adverse immune response in a graft recipient). Ex. 1010 ¶124. Denuding the

amnion of mucus would therefore result in the removal of extraneous tissues from

the amnion, while placing the amnion into saline would result in the removal of at

least some of the blood clots. Id. Removal of blood clots and extraneous tissue is


32 NJ 228940468v4

also discussed above in Sec. X.A.(1)(d), and is applicable here. Thus, the Vish.

process includes at least the step of washing and substantially cleaning the amnion

layer, as such element is construed by P. Owner. Id. While not explicitly taught in

Vish., the step of washing and substantially cleaning the chorion layer is disclosed

in Shenaq, thereby rendering Claim 1 obvious under §103, as discussed below in

Sec. X.B.7.


substantially cleaning step removes substantially all of the blood clots and spongy

layer, Vish. satisfies this narrower construction. Ex. 1010 ¶125. As discussed

above in Sec. X.A.1(d), the patentee argued during the prosecution of the ‘437 Pat.

that the term “extraneous tissue” was meant to include the intermediate spongy

layer. Ex. 1002, 51-52 (see also, Reasons for Allowance, Ex. 1002, 28-29 and ‘437

Pat., Ex. 1001, 6:42-44). As discussed in the immediately preceding paragraph,

Vish. discloses that the amnion is washed, denuded of mucus and collected in

normal saline. Ex. 1012, 2. Given that the spongy layer “consists of a complex

network of fine fibrils surrounded by mucus” (emphasis added), see Ex. 1026, 18,

a POSA would understand Vish.’s disclosure of denuding the amnion of mucus to

involve the removal of most, if not substantially all, of the spongy layer from the

amnion. Ex. 1010 ¶126-27.

In view of the above, regardless of whether the Board adopts P. Owner’s


33 NJ 228940468v4

proposed construction of Elm. D, or a narrower construction, the process of Vish.

includes Elm. D of Claim 1 (i.e., the step of washing and substantially cleaning the

amnion layer). Id. ¶128. For the same reasons, Vish. also discloses the “washed

and/or substantially cleaned amnion” component of Elm. X of the PT Graft

discussed in Sec. VI. under the Thorpe analysis.

5. Elm. E (“laminating the amnion layer and the chorion layer

together”): Vish. teaches that layers of amnion “were then cut to squares and piled

on a glass mould the size of a femoral head[, with] … 50 to 60 layers [of amnion]

in each cap” (emphasis added). Ex. 1012, 2. Vish. therefore discloses that the

amnion layers are placed one on top of another and are thereby combined in a

stacked configuration (i.e., laminating the amnion layers) to form the cap. While

Vish. does not explicitly teach the use of chorion, Sulner or Shenaq discloses

laminated amnion-chorion grafts, thereby rendering Claim 1 obvious under §103,

as discussed below in Sec. X.B.7.

While Vish. discloses piling (i.e., stacking) the amnion layers on the glass

mould, the use of a glass mould is not required as Vish. suggests the use of multi-

layer amnion grafts for other surgical applications that do not require the use of a

mould. Ex. 1010, ¶130. More particularly, Vish. discloses the historic use of

amnion in relatively planar, non-cap-shaped surgical applications, including as a

biological dressing for full thickness wounds and for treating burns and bedsores.


34 NJ 228940468v4

Ex. 1012, 1, 4. Vish. further discloses that “the human amnion may be capable of

inducing the formation of diverse tissues” and that the potential of its application to

surgery “is now being realized and is as wide as imagination and experiment can

make it.” Id., 6-7. A POSA would therefore recognize that Vish. discloses the step

of laminating amnion layers without the use of a mould. Ex. 1010, ¶131.

In view of the above, Vish. discloses stacking amnion layers together, one

on top of another (i.e., the step of laminating). For the same reasons, Vish. also

discloses the “laminating” component of Elm. X of the PT Graft discussed above

in Sec. VI. under the Thorpe analysis. While not explicitly taught in Vish., the

inclusion of a chorion layer as part of the multi-layered (i.e., laminated) tissue graft

of Vish. is obvious in view of Sulner or Shenaq, thereby rendering Claim 1

unpatentable under §103 as discussed below in Sec. X.B.7.

6. Elm. F (“dehydrating the laminated graft …”): Vish. teaches that

the multi-layer amniotic cap “was dried at ambient temperature for six to eight

hours” Ex. 1012, 2. The Vish. process therefore includes Elm. F of Claim 1 (i.e.,

the step of dehydrating the laminated graft). For the same reasons, Vish. also

discloses Elm. Z of the PT Graft discussed in Sec. VI. under the Thorpe analysis.

7. The “chorion layer” limitation of Elms. D and E: While Vish. does

not explicitly disclose using a chorion layer in the multi-layered (i.e., laminated)

tissue graft disclosed therein, methods for preparing tissue grafts containing both


35 NJ 228940468v4

amnion and chorion layers were well-known in the prior art at the time of the

alleged invention. For example, both Sulner and Shenaq disclose the production of

a laminated amnion-chorion graft, thereby rendering Claim 1 obvious under §103,

as discussed below.

While Vish. does not explicitly disclose “washing and substantially

cleaning … the chorion layer,” washing and cleaning chorion for use in grafts was

well known in the art at the time of the alleged invention. Ex. 1010, ¶135. For

example, Shenaq discloses that the “chorion is rinsed repeatedly [along with the

amnion] with phosphate buffer solution or distilled water until clean.” Ex. 1016 at

4:28-30. Based on this disclosure, a POSA would be motivated to modify the Vish.

process by washing and substantially cleaning the chorion along with the amnion.

Ex. 1010, ¶140.

Use of chorion in multi-layer grafts in the prior art is further discussed

below.

a) Sulner: As discussed in Sec. X.A.3(a) above, Sulner

discloses a laminated collagen biofabric having “both a chorionic membrane and

an amniotic membrane” (emphasis added) Ex. 1015, ¶¶ [0234] and [0240]-[0242].

These teachings of Sulner would have motivated a POSA to include a chorion in

the multi-layered (i.e., laminated) tissue graft of Vish. That is, it would have been

obvious to (1) replace one or more of the multiple amnion layers of the graft of


36 NJ 228940468v4

Vish. with one or more chorion layers, or (2) include one or more layers of chorion

within the multiple amnion layers of Vish. Ex. 1010, ¶136.

A POSA would have been motivated to make one or both of the foregoing

modifications in order to conserve placental tissue resources and to increase the

yield resulting from each donated placenta (i.e., the total number of multi-layered

graft products that could be made from a single placenta). Id. ¶137. Because a

single placental source contains both amnion and chorion, using the chorionic

membrane in combination with the amniotic membrane would significantly

increase the amount of graft material available from each placental recovery. Given

the potential scarcity of human donor tissue and the difficulty and cost of obtaining,

screening, testing and processing such tissue (see, e.g., Ex. 1034 ¶[0007]), a POSA

would have recognized the benefit of using one or more chorion layers in the graft

of Vish. Ex. 1010, ¶137. This motivation was recognized by the Examiner during

the prosecution of the ‘437 Pat., when she rejected the pending claims as obvious

in view of a published patent application co-owned by the Assignee of Sulner that

contained similar disclosures (i.e., Hariri-04). See Ex. 1002, 76-77 and 110-112.

Because the chorion has been used in repairing tissue defects (see, e.g., Exs. 1013,

1015, 1016 and 1034), a POSA would have had a reasonable expectation that the

multi-layered (i.e., laminated) tissue graft of Vish., as modified in the foregoing

fashion, would work for its intended purpose (e.g., use in hip arthroplasty), Ex.


37 NJ 228940468v4

1012, 1.

Chorion is also much thicker than amnion (see Oxlund, Ex. 1027, 5

(showing, e.g., fresh chorion specimens of 185 µm and fresh amnion specimens of

47 µm)). Thus, using a layer of chorion in the graft of Vish. would result in using

much less amnion, further conserving amnion resources. For example, a single

layer of chorion provides a thickness that would otherwise require two or more

amnion layers, thereby conserving the amnion by reducing the number of amnion

layers required to make a graft. Ex. 1010, ¶138. The benefit of using chorion

would have been even more apparent to a POSA for the graft in Vish., because the

Vish. graft is made with a large number of amnion layers (i.e., 50 to 60 layers in

each cap). Ex. 1012, 2. Given its thicker size, the chorion would be a more

efficient material in producing a thick, multi-layered graft for hip arthroplasty.

A POSA would know that chorion also possesses biologic properties that

may be useful in treating wounds. In particular, chorion is known to contain

angiogenic and mitogenic factors and has been demonstrated to be capable of

eliciting greater mitogenic activity in fibroblast cultures compared to amnion,

thereby making it potentially more suitable for wound-healing applications. (see

Burgos Ex. 1028, 6). Thus, the different biological properties of amnion and

chorion, and the respective benefits afforded by same, would have motivated a

POSA to modify the Vish. graft, in view of Sulner, to use chorion, especially in


38 NJ 228940468v4

applications where using chorion would provide additional healing benefits (e.g.,

wound healing). Ex. 1010 ¶139.

b) Shenaq: As discussed in Sec. X.A.(3)(b) above, Shenaq

discloses methods for wrapping amnion and chorion sheets … in layers to form

tubes. Ex. 1016, 4:35-36. A POSA would have recognized that wrapping the

amnion and chorion layers constitutes, or at least includes, laminating the amnion

and chorion layers together. Ex. 1010 ¶144. Further, Example 3 of Shenaq

discloses that “human chorion was substituted for human amnion,” (emphasis

added) in forming nerve conduits. Ex. 1016, 12:6-14. A POSA would have

recognized that chorion and amnion may be interchangeable for certain

applications (indeed, the ‘437 Pat. itself contains multiple disclosures that suggest

that chorion is interchangeable with amnion. Ex. 1001, Abst., 2:33-35, 2:52-54,

3:28-34, 3:49-56, and 7:40-42). Ex. 1010 ¶145. In other words, amnion or chorion

may be appropriate for some surgical uses. Shenaq therefore provides both a

suggestion and motivation for modifying the process of Vish. to form a laminated

amnion-chorion graft. See Sec. X.B.7(a) above for additional reasons for this

modification.

8. The “consisting of” Language: As the Vish./Sulner or Vish./Shenaq

modified process includes, and only includes, the isolating, washing and

substantially cleaning, laminating and dehydrating steps of Claim 1, it satisfies the


39 NJ 228940468v4

“consisting of” language of Claim 1. Ex. 1010 ¶147. For the same reasons, Vish.,

in view of Sulner or Shenaq, also discloses Elm. U of the PT Graft discussed in

Sec. VI. under the Thorpe analysis, in that the PT Graft “consists of” only Elms V,

W, X, Y and Z.

9. Conclusion: For the reasons explained above in Secs. X.B.1-8, Claim

1 is obvious over Vish. in view of Sulner or Shenaq under §103, and therefore

unpatentable.

C. Claim 1 is Obvious Over Tseng In View of Sulner or Shenaq

While Tseng was cited during the prosecution of the ‘437 Pat., it was only

considered as a secondary reference in the Examiner’s rejections. Ex. 1002, 112.

Tseng is being applied as a primary reference herein in combination with Sulner

and/or Shenaq. This prior art combination, which was not considered or asserted

during the prosecution of the ‘437 Pat., renders Claim 1 unpatentable. Briefly,

Tseng discloses an amniotic membrane (i.e., amnion) graft made from placenta,

from which chorion has been separated. Ex. 1011, Abst. Sheets of separated

amnion are cut to size and placed on a filter paper. Id. Tseng teaches freezing the

amnion graft in a storage solution, thereby killing (but not removing) the cells and

preserving the amnion graft. Id. Tseng also teaches using multiple layers of amnion.

Id., 6:37-39. The teachings of Tseng are discussed in detail below.

Tseng discloses all of the elements of Claim 1, with the exception of two


40 NJ 228940468v4

(i.e., including a chorion layer in the laminated graft; and dehydrating the

laminated graft), both of which are disclosed in Sulner or Shenaq. The claim

elements will be compared to Tseng below.


process consisting of”): Tseng discloses an amniotic membrane graft suitable for

use in repairing eyes and other organs. Ex. 1011, 1:14-19. As indicated above,

Tseng does not explicitly teach preserving the grafts by dehydrating them.

However, Sulner and Shenaq disclose dehydrating grafts to preserve them, as

discussed below. The phrase “consisting of” is satisfied by Tseng, as also

discussed below in Sec. X.C.8.

2. Elm. B (“isolating an intact amnion layer”): In Tseng, the term

“amniotic membrane” is used interchangeably with the term “amnion”. Id. 1:37-38.

The process for forming the tissue graft in Tseng includes separating the amnion

“from the remaining chorion by blunt dissection, while immersed in [an]

antibiotics-containing balanced saline solution.” Id., 5:8-11. Such separation

constitutes isolating the amnion, which then undergoes freezing and layering steps,

as described below, but neither of these steps would disrupt the intact nature of the

amnion. Ex. 1010 ¶153.

Tseng teaches that the separated/isolated amnion is placed on a substrate

(e.g., a sterile nitrocellulose filter) such that the epithelial surface of the amniotic


41 NJ 228940468v4

membrane faces up. Ex. 1011, 5:12-15. Once the sheets of amniotic membrane are

placed on the filter, they are cut to different sizes and stored in a culture or storage

medium at a temperature below freezing so as to kill the cells of the membranes.

Id,. 5:27-36. Tseng states that “[a]lthough the cells could be killed by other,

conventional, means, the use of freezing-thawing does not introduce agents or

conditions which might adversely affect the stored membrane or the completed

graft, to cause it not to ‘take’ or be rejected, impair the healing of the eye, etc.”

(emphasis added). Id., 5:39-44. Further, while the cells of the amnion are killed by

freezing, Tseng discloses that “the integrity of the extracellular matrix is not

altered despite the freezing and thawing.” Id., 5:38-39.

Tseng further teaches that the amnion is stored in a storage media at a

freezing temperature, such as -80ºC, and subsequently thawed prior to its use (i.e.,

its application to a wound or surgical site). Id., 5:27-31, 5:46-48. Examples of

suitable storage media include a mixture of Dulbecco’s Modified Eagle’s Medium

(“DMEM”) and glycol, as well as “Liebowitz’s medium, MEM and NCTC.” Id.

5:53-67. The amnion is applied to a surgical site after its thawing. Tseng does not

teach or suggest performing any further step of processing the amnion between the

completion of the thawing process and the application of the amnion to the surgical

site. Ex. 1010 ¶157.



42 NJ 228940468v4




processing (i.e., the amnion layer contains fewer cells than a native amnion), Tseng

discloses such an intact amnion. Indeed, Tseng teaches that the amnion was

applied to the eye of a patient, and was “more effective [than previous methods] in

conjunctival surface reconstruction” (Ex. 1011, 6:46-47), which necessarily means

that the amnion would retain “a sufficient number of cells to support the desired

purpose of the tissue graft” (i.e., reconstruction of the conjunctival surface).


applicable here, as Tseng discloses only devitalizing the amnion, but no steps to

decellularize the amnion. For instance, immersing the placenta in an antibiotics-

containing balanced saline solution4 or freezing the amniotic membrane to kill the

cells therein, as disclosed in Tseng, would not cause a relatively large number of

cells to be removed from the amnion (i.e., relative to the total number of cells

therein). Ex. 1010 ¶160. Rather, the effective removal of a relatively large number

of cells from the amnion would require mechanical (e.g., scraping) and/or chemical

4 The use of a solution containing antibiotics is within the scope of Claim 1 of the

‘437 Patent, as Claim 2 recites same (see Sec. XI. for a discussion of Claim 2).


43 NJ 228940468v4

methods (e.g., detergent, enzymatic). Id. Notwithstanding the fact that Tseng

discloses no steps of decellularizing the amnion, a relatively small number of the

cells could be removed from the amnion by one or more of the steps of the Tseng

process (e.g., the immersing step, which could remove some loose cells from the

surface of the epithelial layer). Nevertheless, a large majority, if not substantially

all, of the cells of the amnion would be retained therein after completion of the

Tseng process, certainly enough to constitute “a sufficient number of cells to

support the desired purpose of the tissue graft.” Id. ¶161. This is evident when the

process of Tseng is compared to the aggressive cleaning steps disclosed in the ‘437

Patent, which are discussed above in Sec. X.A.(1)(b). Therefore, if amnion

undergoing the cleaning steps of the ‘437 Patent retains a sufficient number of cells

to support the desired purpose of the tissue graft, then Tseng’s amnion layers,

which are immersed in an antibiotics-containing balanced saline solution and

frozen to kill but not remove cells, must also retain a sufficient number of cells. Id.

In view of the above, Tseng discloses Elm. B of Claim 1 (i.e., isolating an

intact amnion layer), as such element has been construed by P. Owner. For the

same reasons, Tseng also discloses Elm. V of the PT Graft discussed in Sec. VI.


3. Elm. C (“isolating a chorion layer”): Tseng also discloses the step

of isolating the chorion layer by action of the previous step of separating the


44 NJ 228940468v4

amnion layer from the chorion layer. Ex. 1011, 5:8-11. In other words, isolating

the amnion layer by separating it from the native chorion would also necessarily

isolate the chorion layer (i.e., by separating same from the native amnion). Ex.

1010 ¶163. Thus, the process of Tseng includes Elm. C of Claim 1 (i.e., the step of

isolating a chorion layer), as such element has been construed by P. Owner. For the

same reasons, Tseng also discloses Elm. W of the PT Graft discussed in Sec. VI.



the chorion layer”): Tseng teaches that “the placenta is rinsed several times with

balanced salt saline to remove excessive blood clots.” Ex. 1011, 4:60-65. The

amnion and chorion may be washed and substantially cleaned while still at least

partially connected to one another as part of the placenta, as they are in Tseng. Ex.

1010 ¶165. Tseng also discloses that after the foregoing cleaning step, the amnion

of the placenta is separated from the chorion by blunt dissection, “while immersed

in the … saline solution.” Ex. 1011, 5:8-11. A POSA would understand that

separating the amnion and chorion while both membranes are immersed in saline

solution would facilitate the washing and cleaning of the separated amnion and

chorion. Ex. 1010 ¶166.

For reasons similar to those discussed above in Sec. X.A.(d) (i.e.,

regarding Klen), Tseng also inherently discloses that at least some of the


45 NJ 228940468v4

extraneous tissues found in the amnion and chorion would be washed away by

immersing the membranes in the saline solution. Ex. 1010 ¶167. In other words,

removing such extraneous tissues from the membranes would be necessarily

accomplished by rinsing and immersing the membranes in the saline solution

before further processing and production of the completed graft, in the same way

that blood clots are removed by rinsing the membranes, as discussed above in Sec.

X.A.(d). Id. Thus, Tseng discloses washing and substantially cleaning the amnion

layer and the chorion layer, as construed by P. Owner.


substantially cleaning step removes extraneous tissue that includes the spongy

layer, Tseng satisfies this narrower construction. P. Owner stated during the

prosecution of the ‘437 Pat. that “the intact amnion layer and chorion layer were

isolated and substantially cleaned[, and a]s such the tissue graft was substantially

free from blood clots and an intermediate layer (emphasis added), but a small

amount of blood clots and intermediate layer might remain in the tissue graft, as a

[POSA] would understand.” Ex. 1002, 51-52 (see also, Reasons for Allowance, Ex.

1002, 28-29 and ‘437 Pat., Ex. 1001, 6:42-44). As discussed above, Tseng teaches

that amnion is separated from chorion by blunt dissection, Ex. 1011, 5:8-11. The

separated amnion is then placed on a substrate (e.g., a filter), such that the

epithelial surface faces up. Id., 5:12-15. Tseng also teaches that “the


46 NJ 228940468v4

stromal/fibroblistic [sic] layer lies on the filter” (emphasis added). Id., 5:15-16.

Since Tseng specifically recognizes that “[t]he avascular stromal . . . includes the

compact layer, fibroblastic layer and spongy layer” (emphasis added), id. 3:51-53,

but explicitly teaches that the fibroblast layer lies on (i.e., in contact with) the filter,

the spongy layer must have been removed during the amnion/chorion separation

step, and/or the washing/cleaning step, to thereby expose the fibroblast layer

(otherwise, the fibroblast layer could not lie on the filter paper). Ex. 1010 ¶169.

Thus, regardless of whether the Board adopts P. Owner’s proposed construction of

Elm. D of Claim 1, or a narrower construction, Tseng discloses Elm. D (i.e., the

step of washing and substantially cleaning the amnion and chorion layers). Id. ¶170.

For the same reasons, Tseng also discloses Elm. X of the PT Graft discussed in Sec.



together”): Tseng teaches that two or more layers of amnion may be used,

especially for deep ulcers. Ex. 1011, 6:38-39. A POSA would recognize that when

two or more layers of amnion are used together, these layers would necessarily be

stacked one on top of another such that they are layered to each other to form a

multi-layered laminate structure. Ex. 1010 ¶171. For ease of use, these layers

would be prepared prior to the application of same to a patient’s eye. Id. While

Tseng does not explicitly teach the use of chorion, Sulner or Shenaq discloses


47 NJ 228940468v4

laminated amnion-chorion grafts, thereby rendering Claim 1 obvious under §103 as

discussed below in Sec. X.C.7.

Indeed, Tseng discloses “[s]heets of amniotic membranes that have been

adhered/mounted onto the nitrocellulose filter” (emphasis added), see Ex. 1011

5:27-28, and “sheets of amniotic membrane, on the filter paper” (emphasis added),

see Ex. 1011 6:1-2. The foregoing disclosures of Tseng teach that multiple

amniotic sheets are mounted on a single filter paper. When considered together

with Tseng’s disclosure of using two or more layers (see id. 6:38-39), a POSA

would have recognized that multiple amniotic membranes could be placed one on

top of another (i.e., combined in a stacked configuration) to form a multi-layered

laminate structure. Ex. 1010 ¶172.

In view of the above, Tseng discloses stacking amnion layers together, one

on top of another (i.e., the laminating portion of Elm. E of Claim 1). For the same

reasons, Tseng also discloses the “laminating” component of Elm. Y of the PT

Graft discussed above in Sec. VI. under the Thorpe analysis. While not explicitly

taught in Tseng, the inclusion of a chorion layer in the multi-layer tissue graft of

Tseng is obvious in view of Sulner or Shenaq, thereby rendering Claim 1

unpatentable under §103 as discussed below in Sec. X.C.7.

6. Elm. F (“dehydrating the laminated graft …”): While Tseng does

not teach dehydrating the laminated graft, the dehydration of placental tissue grafts


48 NJ 228940468v4

was well-known in the art at the time of the alleged invention. See, e.g., Sulner,

Shenaq, Ward, Klen. For instance, Sulner discloses dehydrating the laminated

placental tissue grafts to store same. Ex. 1015, ¶¶[0231], [0236] and [0242]. More

particularly, the dehydrated collagen biofabric of Sulner “can be stored for several

years with no alteration in biochemical or structural integrity (e.g., no

degradation), without any alteration of the biochemical or biophysical properties

of the collagen biofabric” (emphasis added) Id., ¶[0236]. A POSA would therefore

have recognized that while dehydrating placental tissue grafts, as taught by Sulner,

kills the cells of the amnion and chorion, it is an “other, conventional, means” for

killing cells, which Tseng recognized may alternatively be used. Ex. 1011, 5:39-44.

Moreover, like freezing, dehydrating the tissue “does not introduce agents or

conditions which might adversely affect the stored membrane or the completed

graft, to cause it not to ‘take’ or be rejected, impair … healing of wounds,” as

Tseng characterizes the freezing process. Ex. 1011, 5:39-44. Ex. 1010 ¶179. Thus,

a POSA would have recognized that the graft of Tseng could be preserved with the

dehydration process of Sulner. Id. ¶180. See also KSR International Co. v. Teleflex,

Inc., 550 U.S. 398, 416-417 (2007) (recognizing that merely substituting one

element for another known in the field to achieve predictable results is obvious and

that using a known technique to improve similar devices in the same way is

obvious).


49 NJ 228940468v4

A POSA would also have known that of the two most commonly utilized

ways of preserving placental tissue grafts, i.e., dehydrating and freezing,

dehydrating is preferred due to the relative ease with which a dehydrated graft may

be stored at a hospital or clinic and prepared for use by an end-user relative to a

frozen graft. Ex. 1010 ¶180. For instance, the safe, effective long-term storage of

frozen grafts necessitates having the appropriate freezers and sufficient freezer

space available, while dehydrated grafts may be stored at room temperature

without such equipment. Preparation of a dehydrated graft for use before surgery is

a much faster and easier process than the thawing process required to prepare a

frozen graft. Also, once the frozen graft is thawed, it is wet and hard to handle in

the operating room, while the dehydrated graft is dry and more easily handled ((see

e.g., Hariri-04 (Ex. 1034, 12), Table 1 comparing the surgical preparation and

handling of frozen and dehydrated tissue grafts). The dehydrated graft can even be

applied directly to the wound or defect site, and will be rehydrated simply by

contact with the surrounding tissue. Ex. 1010 ¶180. For these additional reasons, a

POSA would have recognized that the graft of Tseng could be preserved with the

dehydration process of Sulner. Id.

7. The “chorion layer” limitation of Elm. E: This limitation

specifically requires that a layer of amnion and a layer of chorion be laminated

together. While Tseng does not explicitly disclose using one or more chorion


50 NJ 228940468v4

layers in the laminated tissue graft, multi-layered tissue grafts containing one or

more chorion layer were well-known in the art at the time of the alleged invention.

See, e.g., Sulner and Shenaq.

a) Sulner: As discussed in Secs. X.A.(4)(a) and X.B.7(a)

above, Sulner discloses a collagen biofabric having amnion and chorion layers that

are laminated to provide greater stiffness and durability during the healing process.

Ex. 1015 ¶¶ [0234] and [0240]-[0242]. Based on the teachings of Sulner, a POSA

would have been motivated to include one or more chorion layers in the multi-

layered (i.e., laminated) tissue graft of Tseng. That is, it would have been obvious

to (1) replace one of the multiple amnions of the graft of Tseng with a chorion, or

(2) include one or more layers of chorion within the multiple layers of amnion of

Tseng. Ex. 1010 ¶176.

For the reasons discussed above in Sec. X.B.7(a), a POSA would have been

motivated to form a laminated amnion-chorion graft based on the foregoing

teachings of Sulner. A POSA would have had a reasonable expectation that the

tissue graft of Tseng modified in this fashion would work for its intended purpose

(e.g., use “as a graft or dressing to cover burned or surgical skin wounds;” etc. Ex.

1011 7:4-15). Thus, a POSA would have been motivated to modify the process of

Tseng, in view of Sulner, to form a laminated amnion-chorion graft. Ex. 1010

¶176-77.


51 NJ 228940468v4

b) Shenaq: As discussed above in Sec. X.B.7(b), Shenaq

discloses forming tubular nerve and vessel grafts from amnion and chorion sheets

that are wrapped in layers. Ex. 1016, 4:35-36. A POSA would have recognized

that wrapping of the amnion and chorion layers would constitute, or at least

include, laminating the amnion and chorion layers together. Ex. 1010 ¶183.

Shenaq also discloses that “human chorion was substituted for human amnion,”

(emphasis added) in forming nerve conduits. Ex. 1016, 12:6-14. A POSA would

have had a reasonable expectation that the tissue graft of Tseng, modified in this

fashion, would work for its intended purpose (e.g., use “as a graft or dressing to

cover burned or surgical skin wounds;” etc. Ex. 1011 7:4-15) Ex. 1010 ¶183. As

such, and for the reasons discussed above in Sec. X.B.7(a), a POSA would have

been motivated to modify the process of Tseng in view of Shenaq to form a

laminated amnion-chorion graft. Id.

8. The “consisting of” Language: In the Tseng process for producing

the tissue graft, as modified in view of Sulner or Shenaq, the freezing step is

replaced with a dehydrating step, as discussed above in Sec. X.C.6. The modified

Tseng/Sulner or Tseng/Shenaq process therefore includes, and only includes, those

elements/steps recited in Claim 1 (i.e., the isolating, washing and substantially

cleaning, laminating and dehydrating steps), and thereby satisfies the “consisting

of” language of Claim 1. Ex. 1010 ¶184. For the same reasons, Tseng in view of


52 NJ 228940468v4

Sulner or Shenaq also discloses Elm. U of the PT Graft discussed in Sec. VI. under

the Thorpe analysis, in that the PT Graft “consists of” only Elms. V, W, X, Y and

Z.

9. Conclusion: For the reasons explained above in Secs. X.C.1-8, Claim

1 is obvious over Tseng in view of Sulner or Shenaq under §103, and therefore

unpatentable.

D. Claim 1 is Obvious Over Ward In View of Sulner or Shenaq

Ward (Ex. 1014, not cited in the ‘437 Pat.), renders Claim 1 unpatentable, as

discussed below. Briefly, Ward presents a trial comparing single-layer amnion

grafts undergoing four different processes, based on their respective “ease of

preparation, storage and use, and each one’s capacity to promote wound healing.”

Ex. 1014, 1. One of the processes involved lyophilizing/freeze-drying (i.e.,

dehydrating) the amnion. Id., 1-2.

Ward discloses all of the elements of Claim 1, with the exception of two (i.e.,

washing and substantially cleaning … the chorion layer, and laminating an amnion

layer and a chorion layer), both of which are disclosed in Sulner or Shenaq. The

claim elements will be compared to Ward below.


process consisting of”): Ward discloses a lyophilized/freeze-dried (i.e.,

dehydrated) amnion suitable for use as a skin graft in healing chronic venous leg


53 NJ 228940468v4

ulcers. Id., 1. Ward does not explicitly teach laminating layers of amnion and

chorion together. However, as explained above, laminating layers of placental

tissue (i.e., amnion and chorion) was known at the time of the alleged invention,

and it would therefore have been obvious to modify the process of Ward by

laminating the amnion together with chorion (e.g., in view of Sulner or Shenaq, as

discussed below in Sec. X.D.5). The phrase “consisting of” is satisfied by Ward, as

also discussed below in Sec. X.D.7.

2. Elm. B (“isolating an intact amnion layer”): Ward discloses that the

amnion and chorion are separated Id., 1, which constitutes isolating the amnion

layer. This separated amnion then undergoes cleaning and rinsing in phosphate

buffered saline (PBS) and lyophilization id., 1-2, as described below, but none of

these steps would disrupt the intact nature of the amnion. Ex. 1010 ¶192.





processing (i.e., the amnion layer contains fewer cells than a native amnion), Ward

discloses such an intact amnion. Indeed, Ward teaches that the lyophilized amnion

was applied to a leg ulcer Ex. 1014, 2, and “gave the best results both in the take of

the skin grafts …, and in the lowest number of complete failures of the grafts to


54 NJ 228940468v4

take,” Id., 3, which necessarily means that the amnion would retain “a sufficient

number of cells to support the desired purpose of the tissue graft,” i.e., healing leg

ulcers.


applicable here, as Ward discloses no steps of decellularizing the amnion. For

instance, cleaning and rinsing the amnion in PBS, as disclosed in Ward, would not

cause a relatively large number of cells to be removed from the amnion (i.e.,

relative to the total number of cells therein). Ex. 1010 ¶193. Rather, the effective

removal of a relatively large number of cells from the amnion would require

mechanical (e.g., scraping) and/or chemical methods (e.g., detergent, enzymatic).

Id. Notwithstanding the fact that Ward discloses no steps of decellularizing the

amnion, a relatively small number of the cells could be removed from the amnion

by one or more of the steps of the Ward process (e.g., the rinsing step, which could

remove some loose cells from the surface of the epithelial layer). Nevertheless, a

large majority, if not substantially all, of the cells of the amnion would be retained

therein after completion of the Ward process, certainly enough to constitute “a

sufficient number of cells to support the desired purpose of the tissue graft.” Ex.

1010 ¶194. This is evident when the process of Ward is compared to the aggressive

cleaning steps disclosed in the ‘437 Patent, which are discussed above in Sec.

X.A.(1)(b). Therefore, if amnion undergoing the cleaning steps of the ‘437 Patent


55 NJ 228940468v4

retains a sufficient number of cells to support the desired purpose of the tissue graft,

then Ward’s amnion layers, which are cleaned and rinsed in PBS, must also retain

a sufficient number of cells. Id.

In view of the above, Ward discloses Elm. B of Claim 1 (i.e., the step of

isolating an intact amnion layer), as such element has been construed by P. Owner.

For the same reasons, Ward also discloses Elm. V of the PT Graft discussed in Sec.


3. Elm. C (“isolating a chorion layer”): Ward also discloses the step of

isolating the chorion layer by action of the previous step of separating the amnion

layer from the chorion layer. Ex. 1014, 463:2:9-14. In other words, isolating the

amnion layer by separating it from the native chorion would also necessarily

isolate the chorion layer, i.e., by separating same from the native amnion. Ex. 1010

¶195. The process disclosed in Ward thus includes Elm. C of Claim 1 (i.e., the step

of isolating a chorion), as such element has been construed by P. Owner. For the

same reasons, Ward also discloses Elm. W of the PT Graft discussed in Sec. VI.



the chorion layer”): Ward teaches “cleaning and rinsing in PBS the amnion.” Ex.

1014, 463:2:15. Since Shenaq discloses the use of PBS to clean the membranes to

remove blood and debris, Ex. 1016, 7:4-6, a POSA would understand that cleaning


56 NJ 228940468v4

and rinsing the amnion in PBS would reduce the amount of blood clots and

extraneous tissue found in the native amnion.

While Ward does not explicitly disclose “washing and substantially

cleaning … the chorion layer,” doing so was well known in the art at the time of

the alleged invention, as evidenced by Sulner and Shenaq. Shenaq, for example,

discloses that along with the amnion, the “chorion is rinsed repeatedly with

phosphate buffer solution or distilled water until clean.” Ex. 1016, 4:28-30. Based

on this disclosure, and the understanding that any donor tissue must be properly

cleaned before use as a graft, a POSA would have been motivated to modify the

process of Ward by washing and substantially cleaning the chorion along with the

amnion. Ex. 1010 ¶199.


substantially cleaning step removes extraneous tissue including the spongy layer,

Ward satisfies this narrower construction, since a POSA would have known that

the spongy layer is unnecessary for certain medical applications, see, e.g., Ex. 1022,

(0023) and Ex. 1024, 6:7, and hence, extraneous tissue (for Sec. X.A.(1)(d) above).

A POSA would therefore have been motivated to remove the spongy layer from

the amnion and chorion, either based on Ward alone or combined with Shim. or

Wei. Ex. 1010 ¶198. Thus, regardless of whether the Board adopts P. Owner’s

proposed construction of Elm. D of Claim 1, or a narrower construction, Ward


57 NJ 228940468v4

discloses such element (i.e., the step of washing and substantially cleaning the

amnion and chorion layers). Id. For the same reasons, Ward also discloses Elm. X

of the PT Graft discussed above in Sec. VI. under the Thorpe analysis.


together”): Claim 1 specifically requires that a layer of amnion and a layer of

chorion be laminated together. While Ward does not explicitly disclose laminating

amnion and chorion together, multi-layered tissue grafts containing amnion and

chorion were well known in the art at the time of the alleged invention. See, e.g.,

Sulner and Shenaq.

a) Sulner: As discussed in Secs. X.A.(3)(a) and X.B.7(a)

above, Sulner discloses a collagen biofabric having two or more layers of

placental membrane [i.e., amnion and chorion] that are laminated to provide

greater stiffness and durability during the healing process (emphasis added). Ex.

1015 ¶¶[0234], [0240]-[0242]. Based on the teachings of Sulner, a POSA would

have been motivated to modify the single amnion layer graft of Ward to include

multiple layers of amnion and chorion. Ex. 1010 ¶204. For the reasons discussed

above in Sec. X.A.(3)(a) and X.B.7(a), a POSA would have been motivated to

form a laminated amnion-chorion graft based on the foregoing teachings of Sulner.

A POSA would have had a reasonable expectation that the tissue graft of Ward

modified in this fashion would work for its intended purpose (e.g., use as a graft to


58 NJ 228940468v4

heal leg ulcers Ex. 1014, 463). Thus, a POSA would have been motivated to

modify the process of Ward, in view of Sulner, to form a laminated amnion-

chorion graft. Id.

b) Shenaq: As discussed above in Secs XI.A.(3)(b) and

X.B.(1)(g)(ii), Shenaq discloses forming tubular nerve and vessel grafts from

amnion and chorion sheets that are wrapped in layers. Id., 4:35-36. A POSA

would have recognized that wrapping of the amnion and chorion layers constitutes,

or at least includes, laminating the amnion and chorion layers together. Ex. 1010

¶207. Shenaq also discloses that “human chorion was substituted for human

amnion,” (emphasis added) in forming nerve conduits. Ex. 1016, 12:6-14. For the

reasons discussed above in Secs. X.A.(3)(b) and X.B.7(a), a POSA would have

been motivated to form a laminated amnion-chorion graft based on the foregoing

teachings of Shenaq. A POSA would have had a reasonable expectation that the

tissue graft of Ward modified in this fashion would work for its intended purpose

(e.g., use as a graft to heal leg ulcers Ex. 1014, 463). Thus, a POSA would have

been motivated to modify the process of Ward, in view of Shenaq, to form a

laminated amnion-chorion graft. Ex. 1010 ¶207.

6. Elm. F (“dehydrating the laminated graft …”): As discussed above,

Ward teaches lyophilizing/freeze-drying amnion Ex. 1014, 464:1:14-17. Thus, the

process of Ward, as modified above in view of Sulner or Shenaq, includes the


59 NJ 228940468v4

dehydration step (i.e., Elm. F) of Claim 1. For the same reasons, Ward, as modified

in view of Sulner or Shenaq, also discloses Elm. Z of the PT Graft discussed above

in Sec. VI. under the Thorpe analysis.

7. The “consisting of” Language: The modified Ward/Sulner or

Ward/Shenaq process therefore includes, and only includes, those elements/steps

recited in Claim 1 (i.e., the isolating, washing and substantially cleaning,

laminating and dehydrating steps), and thereby satisfies the “consisting of”

language of Claim 1. Ex. 1010 ¶208. For the same reasons, Ward in view of

Sulner or Shenaq also discloses Elm. U of the PT Graft discussed above in Sec. VI.

under the Thorpe analysis, in that the PT Graft “consists of” only Elms. V, W, X,

Y and Z.

8. Conclusion: For the reasons explained above in Secs. X.D.1-7, Claim

1 is obvious over Ward in view of Sulner or Shenaq under §103, and therefore

unpatentable.

XI. Claim 2 is Unpatentable Over The Prior Art : Claim 2 of the ‘437 Pat.

recites that “the washing step [of Claim 1] is carried out in an antibiotic solution.”

A POSA would have known to use a solution containing antibiotics to treat

placental membranes, so as to more effectively clean same of contaminants (Ex.

1011, 4:64-65.). Ex. 1010 ¶210. In such circumstances, it would have been obvious

to further modify the prior art grounds discussed above in connection with Claim 1


60 NJ 228940468v4

in view of Tseng to perform the washing step in an antibiotic solution. Such

modifications include those of the following specific prior art combinations: Klen

in view of Tseng; Klen/Shim. in view of Tseng; Klen/Sulner, or Klen/Shenaq, in

view of Tseng; Vish./Sulner, or Vish./Shenaq, in view of Tseng; Tseng/Sulner;

Tseng/Shenaq; Ward/Sulner, or Ward/Shenaq, in view of Tseng.

XII. Conclusion: The foregoing evaluation of Claims 1 and 2 was undertaken

using two claim construction analyses (i.e., (i) treating the structural features and

process steps as claim elements, and comparing both types of elements to the

structural features and process steps of the prior art; and (ii) under the Thorpe

analysis discussed in Sec. V.(b)). Regardless of which analysis is used, Claims 1

and 2 are unpatentable in view of the prior art under §§102 and 103, and therefore

invalid.

* * *

For the foregoing reasons, the inter partes review is respectfully requested.

Respectfully submitted, Date: February 2, 2015 /Ralph W. Selitto, Jr./ Ralph W. Selitto, Jr., Reg. No. 26,996 John K. Kim, Reg. No. 37,002 Eric E. Bleich, Reg. No. 47,430 Attorneys for Petitioner Greenberg Traurig, LLP 200 Park Avenue, Florham Park, NJ 07932


61 NJ 228940468v4

CERTIFICATE OF SERVICE

The undersigned certifies service pursuant to 37 CFR §§ 42.6(e) and

42.105(b) on the Patent Owner by UPS overnight delivery of a copy of this Petition

for Inter Partes Review of U.S. Patent No. 8,372,437, including its accompanying

exhibits, at the correspondence address of record for U.S. Patent No. 8,372,437 B2,

namely, MiMedx Group, Inc., c/o Foley & Lardner LLP, 3000 K Street, N.W.,

Suite 600, Washington DC 20007-5109 on February 2, 2015.

Respectfully submitted, /John K. Kim/ John K. Kim, Reg. No. 37,002 Greenberg Traurig, LLP 200 Park Avenue Florham Park, NJ 07932 973-443-3560

in the united states patentandtrademark office€¦ · nj 228940468v4 atty. dock. no. 103248.037100...

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