PETITION FOR INTER PARTES ET SEQ.fishpostgrant.com/wp-content/uploads/IPR2015-00320.pdf · PETITION...

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

TISSUE TRANSPLANT TECHNOLOGY LTD. &

HUMAN BIOLOGICS OF TEXAS, LTD. Petitioners

v. MIMEDX GROUP, INC.

Patent Owner

U.S. Patent No. 8,709,494 to Daniel Issue Date: April 29, 2014

Title: PLACENTAL TISSUE GRAFTS

Inter Partes Review No. __________________

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,709,494 UNDER 35 U.S.C. §§ 311–319 and 37 C.F.R. §§ 42.100 ET SEQ.

Mail Stop PATENT BOARD Patent Trial and Appeal Board U.S. Patent and Trademark Office P.O. Box 1450 Alexandria, Virginia 22313–1450

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TABLE OF CONTENTS

I. INTRODUCTION ......................................................................................... 1

II. NOTICES AND DISCLOSURES ................................................................ 1

A. Real Party-In-Interest ......................................................................... 1

B. Standing Certification ......................................................................... 1

C. Related Matters .................................................................................... 1

D. Petitioners’ Counsel ............................................................................. 2

E. Service Information ............................................................................. 2

F. Payment of Fees .................................................................................... 2

III. STATEMENT OF PRECISE RELIEF ....................................................... 2

A. Overview of the ‘’494 Patent ............................................................... 2

B. Person of Ordinary Skill in the Art .................................................... 3

C. Claimed Subject Matter of the ’494 Patent Utilizes is Old Technology ........................................................................................... 3

1. Structure of the Fetal Membranes ..................................................... 3

2. Techniques of the ’494 Patent Were Widely Known by Ordinary

Persons Skilled in the Art ................................................................................... 5

3. Priority Date of the ’494 Patent ........................................................ 7

4. File Wrapper Analysis of the ’494 Patent Family ............................. 8

D. Claims at Issue .................................................................................... 11

E. Petitioner Seeks Cancellation of all Claims of the ’494 Patent ..... 12

F. Construction of Relevant Claim Terms ........................................... 13

1. “laminate” or “laminated” ............................................................. 13

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2. “dehyrdrated” .................................................................................. 14

3. “amnion” ......................................................................................... 14

4. “chorion” ......................................................................................... 15

5. “epithelial cell layer” and “epithelial cellular layer” ................... 15

6. “fibroblast cell layer” and “fibroblast cellular layer”................... 15

7. “washed” and “substantially cleaned” ........................................... 15

IV. GROUNDS FOR UNPATENTABILITY .................................................. 16

A. Ground 1. Claims 9 and 10 are Anticipated Under 35 U.S.C. § 102(b) over Vishwakarma et al. ....................................................... 16

B. Ground 2. Claims 9 and 10 are Obvious Under 35 U.S.C. § 103(a) over Vishwakarma et al. ................................................................... 20

C. Ground 3. Claims 1 through 10 are Obvious Under 35 U.S.C. § 103(a) over Gray ................................................................................ 21

D. Ground 4. Claims 1-10 are Obvious Under 35 U.S.C. § 103(a) over Gray in view of Vishwakarma ................................................. 31

E. Ground 5. Claims 9 and 10 are Obvious Under 35 U.S.C. § 103(a) over Tseng in view of Miljudin. ....................................................... 36

F. Ground 6 Claims 1-10 are Obvious Under 35 U.S.C. § 103(a) over Hariri in view of Vishwakarma. ...................................................... 41

G. Ground 7. Claims 3, 9 and 10 are Obvious Under 35 U.S.C. § 103(a) over Gray in view of Miljudin or Tseng. ............................. 55

1. Claim 3 ............................................................................................. 55

2. Claims 9 and 10 ............................................................................... 57

V. CONCLUSION ............................................................................................ 60

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EXHIBITS

EXHIBIT NAME ABBREVIATION

BBA1001 U.S. Pat. No. 8,709,494, issued April 29, 2014

’494 Patent

BBA1002 Declaration of Daniel L. Mooradian, Ph.D. Mooradian Declaration

BBA1003

G. Bourne, The Foetal Membranes. A Review of the Anatomy of Normal Amnion and Chorion and Some Aspects of their Function, 38 POSTGRAD MED J. 193 (1962)

Bourne

BBA1004 Selected Excerpts of the Prosecution History of the ’494 Patent

’494 Patent Prosecution History

Excerpts

BBA1005 G. K. Vishwakarma et al., Amniotic Arthroplasty for Tuberculosis of the Hip, 68 J. BONE & JOINT SURGERY 68 (1986).

Vishwakarma

BBA1006 WO 93/10722, published June 10, 1992. Gray

BBA1007

E.S. Miljudin et al., Silica Gel Desiccation of Amniotic Membrane with Related Epithelium Cells for Ocular Surface Reconstruction, 5 CELL TISSUE BANK. 271 (2004).

Miljudin

BBA1008 U.S. Pat. No. 6,152,142, issued Nov. 28, 2000.

Tseng

BBA1009 U.S. Pat. Publ. No. 2004/0048796, published Mar. 11, 2004.

Hariri

BBA1010

Provisional Patent Application No. 60/838,467, entitled “Method and System for Preserving Amnion Tissue For Later Transplant,” filed Aug. 17, 2006

Provisional Application

BBA1011 U.S. Patent Application No. 11/840,728, entitled “Placental Tissue Grafts and

’728 Application

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Improved Methods of Preparing and Using the Same,” filed Aug. 17, 2007

BBA1012 Selected Excerpts of the Prosecution History of the ’728 Application

’728 Application Prosecution History

Excerpts

BBA1013 Placenta, http://www.uwyo.edu/wjm/repro/placenta.htm, (last visited November 6, 2014).

BBA1014 THE MERRIAM-WEBSTER DICTIONARY 277 (New Ed. 2005).

Definition of Laminate.

BBA1015 THE MERRIAM-WEBSTER DICTIONARY 129 (New Ed. 2005).

Definition of Dehydrate.

BBA1016 BARRON’S DICTIONARY OF MEDICAL TERMS 379 (6th Ed. 2013).

Definition of Mucus

BBA1017 Bone Bank Allografts Research Report 2014-02

Poser

BBA1018 Office Action, dated January 23, 2009, Hariri

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I. INTRODUCTION

Tissue Transplant Technology Ltd. (d/b/a Bone Bank Allografts) & Human

Biologics of Texas, Ltd. (collectively “Petitioners”) petition for Inter Partes

Review (“IPR”), seeking cancellation of claims 1-10 of U.S. Patent No 8,709,494

(“’494 Patent”) which is owned MiMedx Group, Inc. (“MiMedx”). The institution

of an IPR requires a threshold showing of “a reasonable likelihood that the

petitioner [will] prevail with respect to at least one of the claims challenged in the

petition.” 35 U.S.C. § 314(a). This Petition meets that threshold.

II. NOTICES AND DISCLOSURES

A. Real Party-In-Interest

Petitioners are the real parties-in-interest for this petition.

B. Standing Certification

Petitioners certify that the ’494 Patent is available for IPR. Petitioners are

not barred or estopped from requesting an IPR challenging the claims of the ’494

Patent on the grounds identified in this petition. This petition is filed within one

year of Petitioners being served the identified below patent infringement lawsuit.

C. Related Matters

MiMedx filed a lawsuit against the Petitioners asserting infringement of

claim 9 of the ’494 Patent and infringement of U.S. Pat. No. 8,597,687 (’687

Patent). The lawsuit, Case No. 1:14-CV-719-HLH, was filed May 16, 2014 and is

currently pending in the Western District of Texas, San Antonio Division.

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D. Petitioners’ Counsel

Lead Counsel Back-up Counsel Robert L. McRae (Reg. No. 53,309)

GUNN, LEE & CAVE, P.C. 300 Convent St., Suite 1080

San Antonio, TX 78205 (210) 886-9500 (Voice) (210) 886-9883 (Fax)

[email protected]

Jason E. McKinnie (Reg. No. 65,726) GUNN, LEE & CAVE, P.C. 300 Convent St., Suite 1080

San Antonio, TX 78205 (210) 886-9500 (Voice) (210) 886-9883 (Fax)

[email protected]

E. Service Information

Please address all correspondence and service to the address of both counsel

listed above. Petitioner consents to electronic service by email at

[email protected] and [email protected].

F. Payment of Fees

The required fee is paid via online credit card payment.

III. STATEMENT OF PRECISE RELIEF

A. Overview of the ‘’494 Patent

The ’494 Patent is directed to the processing of human placental fetal

membranes into a dual layer tissue graft that retains one or more cellular layers.

’494 Patent [BBA1001] at Abstract. The ’494 Patent teaches collection of placenta

after a Cesarean section birth. The placenta is washed in a saline solution and

blood clots are removed through physical manipulation of the tissue. BBA1001 at

6:12-24. If the placenta is found acceptable, the amnion and chorion layers of the

placenta are separated. Id. at 6:32-55. The separated amnion/chorion layers are

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further washed, cleaned of blood clots and other debris, and chemically treated

with antibiotics. Id. at 6:56-7:56. Multiple separated amnion and/or chorion

layers are then “placed on the same drying fixture to create a laminate-type

allograft material that is thicker and stronger than a single layer of allograft

material.” Id. at 8:52-57. The drying fixture, with the laminate, is put into a

dehydration bag and placed into a heated oven or incubator. Id. at 8:58-9:15. The

process results in a dried or dehydrated laminate. Id. at 9:4-22. The ’494 Patent

teaches a multi-layered laminate comprising of amnion only, chorion only, or a

combination of amnion and chorion. Id. at 10:36-51.

B. Person of Ordinary Skill in the Art

A person of ordinary skill in the art (“POSITA”), as of the priority date of

the ‘494 Patent, would likely have an advanced degree (Masters or Ph.D.) in

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

pathology or medicine. Declaration of Daniel L. Mooradian, Ph.D. [BBA1002], at

¶ 17. A POSITA would also have several years of experience in the processing of

tissues for clinical use. Id. When used in this report, the term POSITA refers to

the ordinary skill as of the priority date of the ’494 patent.

C. Claimed Subject Matter of the ’494 Patent Utilizes is Old Technology

1. Structure of the Fetal Membranes

The placental fetal membranes are comprised of an amnion layer and a

chorion layer. Bourne [BBA1003] at 193. The structure of the amnion and

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chorion layers has been well defined and known since at least as early as 1962.

Id.; BBA1002 at ¶¶ 18-19. The amnion is the innermost layer and is in contact

with the amniotic fluid, the fetus, and the umbilical cord. Id. at ¶ 20. The chorion

layer is in contact with maternal tissue. Id.

The amnion, having a thickness of approximately 0.02 to 0.5 mm, consists

of five layers: epithelial, basement membrane, compact, fibroblast, and spongy.

BBA1002 at ¶ 20-21. The epithelial layer is the inner-most layer of the amnion

which faces the fetus. Id. The epithelial layer is comprised of a continuous

monolayer of epithelial cells that are strongly anchored to the basement membrane.

Id. The basement membrane is a thin layer of reticular fibers. Id. The compact

layer is composed of dense reticular fibers and is largely devoid of cells. Id. The

fibroblast layer is the thickest layer of the amnion and is composed of loose

connective tissue populated by fibroblast cells. BBA1002 at ¶ 20-21. The spongy

layer is composed of wavy bundles of reticulin, bathed in mucin with the

occasional fibroblast. Id. The chorion is contiguous with the amnion and is in

contact with the maternal tissues of the uterus. Id. The layers of amnion and

chorion are illustrated in Figure 1 of Bourne:

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2. Techniques of the ’494 Patent Were Widely Known by Ordinary Persons Skilled in the Art

The Applicant of the ’494 Patent acknowledges “human placental membrane

(e.g. amniotic membrane or tissue) has been used for various types of

reconstructive surgical procedures since the early 1900s.” BBA1001 at 1:26-28;

see also BBA1002 at ¶ 23. The concept of creating a multi-layer, non-decelled

tissue graft from placental fetal membranes, as well as the processing to create

such a laminate, was known by a POSITA as confirmed by the prior art. There is

nothing novel or non-obvious disclosed in the ’494 Patent.

Prior to commercialization of tissue grafts, a POSITA knew placental fetal

membranes were harvested and processed within the hospital where they would be

used. BBA1002 at ¶ 24. Historically placental membranes were minimally

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manipulated which resulted in retention of the tissues’ natural layers and cells. Id.

at ¶¶ 24-28. During the commercialization era, the tissue grafts were often

decellularized in an effort to improve quality and safety. Id. at ¶¶ 29-30.

Decellularization, accomplished through a variety of methods depending on the

cell and cell layer, was generally done to reduce immunologic responses in the

patient and to reduce potential rejection of the graft. Id. at ¶¶ 30-33. A POSITA

knows that placental membrane cells, unlike cells of non-placental tissue origin,

are immunoprivileged and do not create an immune reaction or tissue graft

rejection. Id. at ¶¶ 34-36. Thus, a POSITA would know that decellularization of

placental membranes may not be necessary or beneficial absent a specific reason to

decellularize placental tissue. Id. at ¶ 36. Thus, a POSITA would be motivated to

utilize natural or minimally processed placental tissue to reduce processing

complexity and time. Id.

Finally, the processing techniques of the ’494 Patent were widely known by

a POSITA as reflected by the prior art:

Washing placental membranes. BBA1002 at ¶ 25; Vishwakarma [BBA1005] at 69; Gray [BBA1006] at 4:28-34; Miljudin [BBA1007] at 272; Tseng [BBA1008] at 5:6-11; Hariri [BBA1009] at ¶ 115.

Removing blood clots and other debris. BBA1002 at ¶ 25; BBA1005 at 69; BBA1006 at 7:1-8; BBA1007 at 272; BBA1008 at 4:60-62; BBA1009 at ¶ 89.

Chemically decontaminating placental membranes. BBA1002 at ¶ 26; BBA1006 at 4:28-34; BBA1008 at 4:64-5:1; BBA1009 at ¶ 0125.

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Sterilizing placental membranes. BBA1002 at ¶ 27; BBA1006 at 4:28-34; BBA1008 at 4:64-5:1; BBA1009 at ¶ 0125.

Layering placental tissue to form a laminate. BBA1005 at 6; BBA1006 at 4:35-5:9; BBA1008 at 5:38-39; BBA1009 at ¶ 0115.

Dehydrating placental tissue on a drying fixture. BBA1005 at 69; BBA1006 at 8:1-16; BBA1007 at 272-73; BBA1009 at ¶¶ 0104, 0115.

Specific physical and/or chemical methods are necessary to remove cells and/or layers of placental membranes. BBA1002 at ¶¶ 31-33; BBA1006 at 4:26-28; BBA1009 at ¶ 0014.

Specific cells may be removed without disrupting or removing the underlying extracellular matrices. BBA1002 at ¶¶ 31-33; BBA1006 at 4:26-28, BBA1009 at ¶ 0014.

3. Priority Date of the ’494 Patent

The ’494 Patent was filed on July 30, 2013 as a continuation of U.S. Pat.

App. Ser. No. 13/569,095, filed on August 7, 20121 which is a continuation of U.S.

Pat. App. Ser. No. 11/840,728 (“’728 Application”), filed on August 17, 2007.2

The ’728 Application claimed benefit under 35 U.S.C. §119(e) of U.S. Provisional

Pat. App. No. 60/838,467 filed Aug. 17, 2006 (“Provisional Application”). The

above applications were expressly incorporated by reference in the ’494 Patent.

The ’494 Patent requested a Track One priority review and issued on April 29,

2014.

1 Issued as U.S. Pat. No. 8,597,687. 2 Issued as U.S. Pat. No. 8,372,437.

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MiMedx claims a priority date of August 17, 2006 for the ’494 Patent based

on the Provisional Application. However, the Provisional Application fails to

disclose a dual layered graft having an amnion and chorion layer. Provisional

Application [BBA1010] at 51-53. In contrast to the claims of the ’494 Patent, the

Provisional Application expressly teaches the destruction or disposal of the chorion

layer; not use in a dual layer graft. BBA1010 at 39, 43. Support for a laminate

using chorion does not appear until the filing of the ’728 Application on August

17, 2007. ’728 Application [BBA1011] at 4:28-5:2. The claims of the ’494 Patent

that require a chorion layer have a priority date of August 17, 2007.

4. File Wrapper Analysis of the ’494 Patent Family

a) The ’494 Patent Family

On July 16, 2012, the claims of the ’728 Application concerning a multi-

layer laminate of amnion and/or chorion were rejected as obvious in light of U.S

Pat. Pub. No. 2004/0048796 to Harari (“Hariri”). ’728 Application Prosecution

History Excerpts [BBA1011] at 69-71. Hariri states “the collagen biofabric

comprising a chorionic membrane will have comparable properties as the collagen

biofabric of the invention comprising an amniotic membrane.” BBA1009 at ¶ 55.

Relying on this statement, the Examiner rejected the claims directed to a

chorion/amnion laminate because Hariri teaches a chorion membrane is the

“functional equivalent” to the amnion membrane. BBA1011 at 70. Applicant

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argued Hariri taught a completely decelled placental tissue which included the

removal of epithelial and fibroblast cells. Id. at 52-54. Through an interview,

Applicant distinguished its graft from natural placental membrane by claiming the

specification of the ‘728 Application taught removal of an alleged intermediate

layer between amnion and chorion. Id. at 29. Applicant claimed the language of

“washing and substantially cleaning” taught removal of an intermediate layer but

no source was given for the existence of an “intermediate layer.” Id. at 5-6, 29.

The ’728 Application ultimately issued with a single independent claim stating:

1. A dehydrated, laminated tissue graft, wherein the tissue graft is

produced by a process consisting of: isolating an intact amnion

layer; isolating a chorion layer; washing and substantially cleaning

the amnion layer and the chorion layer; laminating the amnion

layer and the chorion layer together; and dehydrating the laminated

graft to produce the dehydrated, laminated tissue graft.

b) The ’494 Patent

The prosecution of the ’494 Patent occurred approximately a year after the

substantive prosecution of the ’728 Application and occurred in front of the same

Examiner. In the ’494 Patent, the Examiner made the same § 103 rejection in view

of Hariri. BBA1004 at 23-40. Applicant amended its claims and argued: 1)

placenta comprises three layers and that the ’494 Patent removes the “middle”

layer and 2) Hariri teaches the removal of the fibroblast cell layer. Id. at 15-22.

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After an interview with the Examiner, Applicant’s amendments and arguments

were apparently sufficient to overcome Hariri. Id. at 1-11.

Both of Applicant’s submitted arguments are factually incorrect.

Applicant’s claim that the amnion and chorion are connected by an intermediate or

third layer is not supported by any reputable publication and directly conflicts with

the accepted and well known structure of placental membranes. BBA1002 at ¶¶

83-84; see also BBA1003. Applicant cited a website for support of a “middle

layer” but the website fails to identify an author, fails to show it was peer-

reviewed, and appears to be directed to non-human placenta tissue. Id.; BBA1013.

Simply stated an intermediate layer between the amnion and chorion does not

exist. BBA1003. Should such an intermediate layer exist, Applicant’s claim

language of “washed and substantially cleaned” appears insufficient to

simultaneously disclose an intermediate layer and its subsequent removal.

Applicant’s second argument concerning Hariri is factually incorrect. While

Hariri teaches decellularizing the amnion tissue, i.e. removing epithelial and

fibroblast cells, Hariri teaches “preserv[ation] [of] the architecture of the

underlying extracellular matrix.” BBA1009 at ¶ 14. A POSITA knows that

removal of the epithelial cells removes the epithelial layer because there isn’t an

underlying extracullar matrix. BBA1002 at ¶ 21; BBA1003 at 193. In contrast,

removal of the fibroblast cells does not remove the fibroblast cell layer due to the

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underlying extracullar matrix. BBA1002 at ¶ 85; BBA1003 at 195. Thus Hariri

fails to teach removal of the fibroblast layer itself.

D. Claims at Issue

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.

2. The dehydrated, laminated tissue graft of claim 1,

wherein said assembled and laminated layers are dehydrated together

in a drying fixture.


wherein one or both of the one or more amnion layers and the one or

more chorion layers are treated with an antibiotic prior to lamination.


wherein the tissue graft has been exposed to sterilizing conditions.


consisting essentially of one amnion layer and one chorion layer.

6. A dehydrated, laminated tissue graft, wherein the tissue

graft consists essentially of one or more amnion layers and one or

more chorion layers wherein each of the amnion and chorion layers:

are separated from a placenta to provide separate layers of

amnion and chorion,

washed and substantially cleaned without removal of the

fibroblast cell layer from the amnion layer, and

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are layered directly over each other and are laminated and

heat dehydrated together to provide the dehydrated,

laminated tissue graft.

7. The tissue graft of claim 6, consisting essentially of one

amnion layer and one chorion layer.

8. The tissue graft of claim 6, wherein at least one of the

amnion or chorion layers has been chemically decontaminated.

9. A dehydrated, laminated, placental tissue graft which is a

laminate comprising two or more separated and washed layers which

layers are selected from amnion and/or chorion wherein the layers are

directly laminated to each other and at least one of said layers is an

amnion layer which retains an epithelial cellular layer.

10. A dehydrated, laminated, placental tissue graft which is

a laminate comprising two or more separated and washed layers

which layers are selected from amnion and/or chorion wherein the

layers are directly laminated to each other and at least one of said

layers is an amnion layer which retains a fibroblast cellular layer.

E. Petitioner Seeks Cancellation of all Claims of the ’494 Patent

Petitioners requests an Inter Partes Review and cancellation of claims 1-10

of the ’494 Patent. The chart below identifies the basis for cancellation. The full

statement of reasons for cancellation is set forth in detail in § V.

Ground Statutory

Basis Reference(s)

’494 Patent Claims

1 102(b) Vishwakarma 9, 10 2 103(a) Vishwakarma 9, 10

3 103(a) Gray 1-10

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4 103(a) Gray in view of Vishwakarma 1-10 5 103(a) Tseng in view of Miljudin 9, 10 6 103(a) Hariri in view of Vishwakarma 1-10 7 103(a) Gray in view of Miljudin or Tseng 3, 9, 10

F. Construction of Relevant Claim Terms

There are several terms/phrases of the ’494 Patent that should be construed.

“A claim in an unexpired patent shall be given its broadest reasonable construction

in light of the specification of the patent in which it appears.” 37 C.F.R.§

42.100(b). A claim term must be given its “ordinary and customary meaning [as

it] . . . would have to a person of ordinary skill in the art in question at the time of

the invention.” Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir. 2005); In re

Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2006); accord M.P.E.P.

§ 2111.01(I). All claim terms not specifically addressed below have been accorded

their broadest reasonable interpretation in light of the patent specification and its

plain and ordinary meaning to a POSITA.

1. “laminate” or “laminated”

The term “laminated,” and its variant “laminate,” appear sixteen times in the

claims of the ’494 Patent but is not expressly defined in the specification. As a

result, laminate must be given its ordinary and customary meaning to a POSITA.

A POSITA would construe laminate, in verb form, to mean layering or uniting two

or more layers. BBA1002 at ¶ 37; BBA1014. Laminate, as a noun, is the resulting

14

product. BBA1002 at ¶ 37; BBA1014. The relevant specifications support this

construction. The only disclosure concerning laminate in the Provisional

Application is single bullet point stating “[l]ayering amnion to create a laminate.”

BBA1010 at 74. The ’728 Application discloses “mounting one or more additional

layers of chorion tissue or amniotic layer onto the surface of the drying fixture

prior to the step of dehydration to create a plurality of laminated placenta

membrane tissue grafts . . . .” BBA1011 at 4:28-5:2 (emphasis added). Finally,

the ’494 Patent teaches “multiple layers of tissue are placed on the same drying

fixture to create a laminate-type allograft material that is thicker and stronger than

a single layer of allograft material.” BBA1001 at 3:33-39. It is important to note

that dehydration is not a requirement of lamination as commonly understood by a

POSITA nor is it expressly taught. BBA1002 at ¶ 37.

2. “dehyrdrated”

A POSITA would understand dehydrate to mean drying or removing fluid.

BBA1002 at ¶ 38.

3. “amnion”

A POSITA would construe the term amnion as one of the fetal membranes

comprising an epithelial layer, basement membrane, compact layer, fibroblast layer

and the spongy layer. BBA1002 at ¶ 39.

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4. “chorion”

A POSITA would construe the term chorion as one of the fetal membranes

comprising a cellular layer, reticular layer, a pseudo-basement membrane and the

trophoblast layer. BBA1002 at ¶ 40.

5. “epithelial cell layer” and “epithelial cellular layer”

A POSITA would construe the term epithelial cell layer as a single layer of

epithelial cells that are densely adherent to the basement membrane of amnion.

BBA1002 at ¶ 41.

6. “fibroblast cell layer” and “fibroblast cellular layer”

A POSITA would construe the term fibroblast cell layer as a layer of amnion

composed of loose connective tissue populated by fibroblast cells “embedded in a

mass of reticulin” or extracellular matrix. BBA1002 at ¶ 42.

7. “washed” and “substantially cleaned”

Applicant utilizes the claim terms of washed and substantially cleaned in a

variety of forms within the claims. Washed is referenced in the claims but not

referenced in the specification. The term “clean” is referenced in the specification

but not in combination with “substantially.” A POSITA would construe “wash” to

mean cleaning with water or other suitable aqueous (i.e., water-based) solution. A

POSITA would construe “substantially cleaned” as meaning free of a significant or

substantial portion of the blood, blood clots and other debris or contaminates that

16

may be present on the amnion or chorion layers at the time of processing.

BBA1002 at ¶ 43.

IV. GROUNDS FOR UNPATENTABILITY

A. Ground 1. Claims 9 and 10 are Anticipated Under 35 U.S.C. § 102(b) over Vishwakarma et al.

Vishwakarma is a printed publication concerning the treatment of

tuberculosis of the hip utilizing amniotic arthroplasty. The article, published in

January 1986 in the Journal of Bone and Joint Surgery, is more than one year prior

to the August 17, 2006 effective filing date of the ’494 Patent. Accordingly,

Vishwakarma is prior art under § 102(b) and § 103(a). Vishwakarma was not

identified in any of the Information Disclosure Statements submitted by the

Applicant in the ’494 Patent or related applications. BBA1004 at 61-66.

Vishwakarma teaches the preparation of an amniotic cap through lamination

and dehydration of placental tissue. BBA1005. In Vishwakarma, the authors teach

the collection of placenta tissue, washing it under running tap water for 10 minutes,

separating amnion from the chorion, submerging the separated amnion in saline,

layering the amnion (50 to 60 layers) on a glass mould, and drying the layered

amnion. BBA1005 at 69. Claims 9 and 10 of the ’494 Patent are anticipated by the

disclosure of Vishwakarma. Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,

683 F.3d 1356, 1361 (Fed. Cir. 2012) (“For a prior art reference to anticipate a

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claim, it must disclose all of the limitations of the claim, arranged or combined in

the same way as in the claim.”).

Vishwakarma’s processing of placental tissue is minimal. Prior to

separation, the placental tissue is washed under running tap water to remove or

denude the tissue of mucous. BBA1005 at 69. After separation, the amnion is

collected or submerged in saline and then laminated. Id. A POSITA would

understand mucus is a secretion, not a cell layer, and thus removal of mucus by

water would not result in the removal of any cell layers. BBA1002 at ¶ 46;

BBA1016. Furthermore, a POSITA knows that amnion naturally retains all of its

layers unless the processing includes physical scraping or application of specific

chemicals such as detergents or enzymes. BBA1002 at ¶ 47. Due to

Vishwakarma’s washing steps consisting of a tap water rinse and submergence in

saline, a POSITA would conclude the amniotic cap retains the epithelial and

fibroblast cell layers. BBA1002 at ¶ 47. Vishwakarma itself indicates the cells

remain in the tissue graft when it expressly notes “that no immunologic reaction or

rejection phenomenon” was observed in any of the patients treated due to

“[e]mbryonic cells being immunologically inert.” BBA1005 at 73; BBA1002 at ¶

48. Finally, during an interview with the Examiner in the prosecution of the ’728

Application, it was noted “that the method does not include any decellularization

18

steps- thus both the epithelial layer and the fibroblast cellular layer of the amnion

membrane must remain intact.” BBA1012 at 10-11.

Petitioners requested a histological study of placenta tissue processed in the

manner taught by Vishwakarma. This study confirmed the presence of epithelial

and fibroblast cell layers in the amnion. BBA1017; BBA1002 at ¶ 49. Washing

placenta in water or saline is insufficient to remove cell layers in native placenta.

The preservation of the epithelial and fibroblast layers in Vishwakarma is

logical when compared to the processing and washing disclosed in the ’494 Patent.

The ’494 Patent utilizes aggressive cleaning techniques including: 1) massaging

the placenta in hyperisotonic saline to remove blood clots; 2) use of cell scraper,

blunt instrument, finger, or gauze to further remove blood clots and debris from the

separated amnion/chorion; and 3) agitating the separated aminion/chorion on a

rocker platform for 30-90 minutes in a hyperisotonic solution. BBA1001 at 5:58 –

7:9. Thus, if the ’494 Patent retains the epithelial and fibroblast cell layers

utilizing the above washing and cleaning techniques, then Vishwakarma’s washing

under tap water and submergence in saline clearly retains the epithelial and

fibroblast cell layers.

Claims 9 and 10 utilize the inclusive and exclusive modifier and/or in stating

the “layers are selected from amnion and/or chorion.” As a result, claims 9 and 10

are read as requiring the layers to comprise: 1) amnion only; 2) chorion only; or 3)

19

a combination of amnion and chorion. However, claims 9 and 10 eliminate the

chorion only option by requiring “at least one of said layers is an amnion layer.”

The use of alternative limitations in claims is permitted, but “[w]hen a claim

covers several structures or compositions, either generically or as alternatives, the

claim is deemed anticipated if any of the structures or compositions within the

scope of the claim is known in the prior art.” Brown v. 3M, 265 F.3d 1349, 1351

(Fed. Cir. 2001). Vishwakarma’s teaching and disclosure of a multi-layer laminate

of amnion is sufficient to anticipate the claim’s alternative disclosure of chorion.

The following chart identifies the specific disclosure of Vishwakarma

relating to the limitations of claims 9 and 10. BBA1002 ¶ 50.

CLAIMS 9 & 10 VISHWAKARMA (BBA1005)

[Claims 9 & 10] A dehydrated, laminated, placental tissue graft which is a laminate

comprising

“Fresh placentae were collected . . . [a]mnion was separated from the chorion. . . cut into squares and piled on a glass mould” with “50-60 layers in each cap” the “amniotic cap was dried at ambient temperature for six to eight hours” BBA1005 at 69 (emphasis added).

[Claims 9 & 10] two or more separated and washed layers which

layers are selected from amnion and/or

chorion

“Fresh placentae were . . . washed in running tap water for 10 minutes. Amnion was separated from the chorion, and amniotic membrane, denuded of mucus, was collected in a beaker containing normal saline” BBA1005 at 69 (emphasis added).

20

[Claims 9 & 10] wherein the layers are directly laminated to

each other and

“Layers were then cut into squares and piled on a glass mould the size of a femoral head. There were 50 to 60 layers in each cap . . . The amniotic cap was dried at ambient temperature for six to eight hours” BBA1005 at 69 (emphasis added).

[Claim 9] at least one of said layers is an

amnion layer which retains an epithelial

cellular layer.

Vishwakarma does not disclose methods for the removal of the amniotic epithelial cellular layer. A POSITA would understand the removal of the epithelial layer would require mechanical and/or chemical methods and that simply washing the fetal membrane in water would not be sufficient to remove the epithelial layer. In the absence of such methods a POSITA would understand that the epithelial layer is retained. BBA1002 at ¶¶ 45-49.

[Claim 10] at least one of said layers is an

amnion layer which retains an fibroblast

cellular layer.

Vishwakarma does not disclose methods for the removal of the amniotic fibroblast cellular layer. A POSITA would understand that the removal of the fibroblast layer would require mechanical and/or chemical methods and that simply washing the fetal membrane in water would not be sufficient to remove the fibroblast layer. In the absence of such methods a POSITA would understand that the fibroblast layer is retained. BBA1002 at ¶¶ 45-49.

B. Ground 2. Claims 9 and 10 are Obvious Under 35 U.S.C. § 103(a) over Vishwakarma et al.

Ground 1, including the claim chart, is incorporated by reference. In the

alternative, should Vishwakarma be insufficient for any reason as a § 102(b)

reference, or fail to fully anticipate the elements of claims 9 and 10, it would be

obvious to a POSITA that Vishwakarma retains the epithelial and fibroblast cell

21

layers because Vishwakarma does not teach any methods to remove those layers.

BBA1002 at ¶¶ 45-49.

C. Ground 3. Claims 1 through 10 are Obvious Under 35 U.S.C. § 103(a) over Gray

Gray is a PCT Patent Publication disclosing the use of fetal membrane tubes

for nerve and vessel grafts. Gray published on June 10, 1993; more than one year

prior to the August 17, 2006 effective filing date of the ’494 Patent. Accordingly,

Gray is prior art under § 103(a). Gray was not identified in any of the Information

Disclosure Statements submitted by the Applicant in the ’494 Patent or related

applications. BBA1004 at 61-66.

Gray teaches the use of placenta membranes, isolated from human or animal,

for use in “construction of membrane tubes for nerve and vessel grafts.” BBA1006

at 1:6-7; 2:7-9. Amnion and chorion are obtained from a placenta, separated into

layers, “rinsed repeatedly with phosphate buffer solution . . . until clean” and

washed in saline “to remove blood and other debris.” Id. at 4:23-35; 7:1-8. A

POSITA would understand washing the amnion to remove blood and other debris

is the same as the ’494 Patent’s disclosure of substantially cleaning the tissue.

BBA1002 at ¶ 59. The amnion and chorion layers are sterilized and cross-linked

through radiation or chemically through glutaraldehyde. Id. at 4:23-35. A

POSITA knows glutaraldehyde is a sterilant, and while not a traditional antibiotic,

glutaraldehyde is an anti-bacterial agent that kills microorganisms. BBA1002 at ¶

22

58. The amnion and/or chorion sheets are wrapped or layered around a stainless

steel stent, or drying fixture, to form a laminated tube and heat dried. Id. at 8:1-16.

Gray discloses use of an adhesive to prevent delamination, if desired, which

implies the wrapping and layering as taught is lamination. Id.; BBA1002 at ¶ 54.

Gray discloses various embodiments and statements concerning the cellular

treatment of the placental tissue as well as various combinations of

amnion/chorion. In one embodiment the epithelial layer is removed through

application of trypsin and repeated washes with a phosphate buffered solution.

BBA1006 at 7:9-10. A POSITA would know trypsin is effective at removing the

epithelial layer but would be ineffective for removing fibroblasts embedded in a

three-dimensional extracellular matrix such as the fibroblast layer or spongy layer.

BBA1002 at ¶ 60. A POSITA would appreciate that trypsin does not remove

three-dimensional extracellular matrix such as would be found in the fibroblast

layer or spongy layers of the amnion. Id. As a result, the fibroblast layer is

retained even with use of trypsin. Id. A POSITA would understand Gray’s

reference to use of a “membrane free of cellular or epithelial material” is referring

to the removal of the epithelial layer considering Gray’s utilization of trypsin and

cleaning to remove blood and debris is insufficient to remove the fibroblast cell

layer. Id. A POSITA would understand Gray specifically teaches the removal of

23

the epithelial layer to promote axon growth and not for anything related to the

lamination or dehydration processing steps. Id. at ¶ 61.

In another embodiment Gray teaches that cell layers are not removed.

Gray’s submitted claims 1 and 2 state:3

1. A graft for bridging a gap between proximal and distal ends of a severed nerve and proximal and distal ends of a vessel comprising,

a cylinder having a length at least equal to the distance between the proximal and distal ends of the severed nerve or vessel and a diameter at least equal to the diameters of the proximal and the distal ends of the severed nerve or vessel,

said cylinder having a wall formed of at least one layer

of sterilized cross-linked membrane, said membrane comprising collagen selected from the group consisting of Type I, Type II, Type III, and mixtures thereof,

said collagen being derived from the group consisting of

amnion of a placenta, chorion of a placenta, and combinations thereof.

2. The graft of Claim 1 wherein,

said wall comprising at least two layers of said membrane in sheet form glued together effective to prevent delamination of the layers in use.

BBA1006 (emphasis added).

The result of claims 1 and 2 is a tissue graft that retains all cell layers, including

the epithelial cell layer.

3 M.P.E.P § 2136.02 (“entire disclosure of a . . . international application publication

having a an earlier effective U.S. filing date (which will include certain international filing dates) can be relied on to reject the claims.”).

24

It would be obvious to a POSITA to combine certain elements disclosed in

Gray to reach the specific claims disclosed in the ’494 Patent. “Combining two

embodiments disclosed adjacent to each other in a prior art patent does not require

a leap of inventiveness.” Boston Scientific Scimed, Inc. v. Cordis Corp., 554 F.3d

982, 991 (Fed. Cir. 2009). In the specification, Gray specifically teaches the

removal of the “cellular monolayer material overlying the basal lamina on the fetal

side of the membrane.” BBA1006 at 4:26-28. A POSITA would understand this

to be removal of the epithelial layer and exposure of the basement membrane.

BBA1002 at ¶ 60. According to Gray, laminin “has been shown to promote axon

extension by interacting with axonal glycoproteins that are members of the integrin

family of receptors.” Id. at 1:31-2:2. For nerve grafts, Gray teaches the fetal, or

shiny side, with the epithelial layer removed, is directed inward to specifically

promote axon growth. Id. at 4:20-22. A POSITA would understand Gray’s

disclosure of removing the epithelial layer as important for nerve grafts but not

necessary or preferred for blood vessel grafts. BBA1002 at ¶ 60.

A POSITA would further understand removal of the epithelial layer is not

required by Gray’s claim 1. A POSITA would recognize that not all applications

of placental tissue grafts require or desire exposure of the basement membrane.

BBA1002 at ¶ 61. A POSITA would be motivated to simplify Gray’s processing

to produce grafts for applications in which the epithelial layer does not need to be

25

removed. BBA1002 at ¶ 62. Therefore, a POSITA would understand that not

performing the trypsin step, necessary for removing the epithelial layer, would

simplify processing and shorten the procedure by several hours and would retain

the epithelial layer in the graft. BBA1002 at ¶ 62. Thus, it would not have

“require[d] a leap of inventiveness” to combine the teachings of Gray’s claim 1,

that teaches no removal of cell layers, with the specific washing and laminating

steps taught in the specification.

Finally, Gray’s specification teaches the creation of laminates using human

amnion only, human chorion only, and bovine amnion with bovine chorion.

Gray’s claim 1 is broader and teaches all options, including use of only two layers

(amnion and/or chorion), without specification to human or bovine. It would be

obvious, if not fully anticipated, that a POSITA would understand the viability of

amnion only, chorion only, or amnion/chorion, regardless if human or bovine. It

would not have “require[d] a leap of inventiveness” to combine the amnion only,

chorion only, or amnion/chorion combinations with washing and laminating steps

taught in the specification.

The following chart identifies the specific disclosure of Gray relating to the

limitations of claims 1 - 10 as grouped by independent claims. BBA1002 ¶ 63.

CLAIMS 1 - 5 GRAY (BBA1006)

A dehydrated, laminated “The amniotic and chorionic tubes of the present invention are well suited for use as nerve grafts or as

26

tissue graft bypass conduits for coronary bypass or vascular bypass surgery” BBA1006 at 4:8-1 (emphasis added). .

“The amnion and chorion sheets are then wrapped in layers” BBA1006 at 4:35 – 5:9 (emphasis added).

“The tubes which are on the stents are then dried in 40-60°C oven for about 30 minutes.” BBA1006 at 8:11-13 (emphasis added).

consisting essentially of one or more washed and/or substantially cleaned amnion layers and one or more washed and/or substantially cleaned chorion layers,

“the amnion and chorion layers are separated from the placenta and each other . . . the amnion and chorion is rinsed repeatedly with phosphate buffer solution or distilled water until clean” BBA1006 at 4:25-30 (emphasis added).

“The selected pieces of membrane are thoroughly washed, preferably with phosphate buffered saline, or distilled water to remove all the blood and debris. Then the membranes are further washed until they are white and transparent.” BBA1006 at 7:4-8 (emphasis added).

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

“said cylinder having a wall formed of at least one layer of sterilized cross-linked membrane, said membrane comprising collagen selected from the group consisting of Type I, Type II, Type III, and mixtures thereof, said collagen being derived from the group consisting of amnion of a placenta, chorion of a placenta, and combinations thereof.” BBA1006 at claim 1.

A POSITA would know that the methods of Gray do not remove fibroblasts or the fibroblast cell layer. BBA1002 at ¶¶ 60-61.

further wherein the amnion layer and the chorion layer are directly laminated to each other.

“The amnion and chorion sheets are then wrapped in layers so that the fetal surface, which is shiny, is directed toward the inner surface of the finished tube.” BBA1006 at 4:35 – 5:9 (emphasis added).

27

“said cylinder having a wall formed of at least one layer of sterilized cross-linked membrane, said membrane comprising collagen selected from the group consisting of Type I, Type II, Type III, and mixtures thereof,

said collagen being derived from the group consisting of amnion of a placenta, chorion of a placenta, and combinations thereof.” BBA1006 at claim 1 (emphasis added).

[Claim 2] The dehydrated, laminated tissue graft of claim 1, wherein said assembled and laminated layers are dehydrated together in a drying fixture.

“Preferably, wrapping of the amnion sheets in layers is effected by using a highly polished stainless steel stent. . . The tubes which are on the stents are then dried in 40-60°C oven for about 30 minutes. Drying allows the tubes to be removed from the stents easily.” BBA1006 at 8:1-16.

[Claim 3] The dehydrated, laminated tissue graft of claim 1, wherein one or both of the one or more amnion layers and the one or more chorion layers are treated with an antibiotic prior to lamination.

“the amnion or chorion is then cross-linked either by exposure to gamma radiation or chemical cross-linking such as with glutaraldehyde, which sterilizes the tissue, provides protection against viral disease transmission . . . The amnion and chorion sheets are then wrapped in layers” BBA1006 at 4:30-36 (emphasis added).

A POSITA understands glutaraldehyde kills microorganisims as does an antibiotic. BBA1002 at ¶¶ 55-58.

[Claim 4] The dehydrated, laminated tissue graft of claim 1, wherein the tissue graft has been exposed to sterilizing conditions.

“the amnion and chorion is rinsed repeatedly with phosphate buffer solution or distilled water until clean, the amnion or chorion is then cross-linked either by exposure to gamma radiation or chemical cross-linking such as with glutaraldehyde, which sterilizes the tissue, provides protection against viral disease transmission” BBA1006 at 4:28-34 (emphasis added).

28

[Claim 5] The dehydrated, laminated tissue graft of claim 1, consisting essentially of one amnion layer and one chorion layer.

The amnion and chorion sheets are then wrapped in layers so that the fetal surface, which is shiny, is directed toward the inner surface of the finished tube. BBA1006 at 4:35 – 5:9 (emphasis added).

“said cylinder having a wall formed of at least one layer of sterilized cross-linked membrane, said membrane comprising collagen . . . said collagen being derived from the group consisting of amnion of a placenta, chorion of a placenta, and combinations thereof.” BBA1006 at claim 1 (emphasis added).

“The graft of Claim 1 wherein, said wall comprising at least two layers of said membrane….” BBA1006 at claim 2 (emphasis added).

CLAIMS 6 -8 GRAY (BBA1006)

A dehydrated, laminated tissue graft,

Claim 1 above incorporated by reference.

wherein the tissue graft consists essentially of one or more amnion layers and one or more chorion layers wherein each of the amnion and chorion layers:

“The amnion and chorion sheets are then wrapped in layers so that the fetal surface, which is shiny, is directed toward the inner surface of the finished tube. BBA1006 at 4:35 – 5:9 (emphasis added).


are separated from a placenta to provide separate layers of amnion and chorion, washed and substantially cleaned without removal of the fibroblast cell layer from the amnion layer, and


“The amnion layer is separated from the placenta . . . selected pieces of membrane are thoroughly washed, preferably with phosphate buffered saline, or distilled water to remove all the blood and debris. Then the

29

membranes are further washed until they are white and transparent.” BBA1006 at 7:1-8 (emphasis added).

“In this example, human chorion was substituted for human amnion. The chorion membrane was separated from the amnion membrane and was then harvested and treated the same as 10 in paragraph A, and conduits formed the same as in paragraph B has properties similar to those set forth in Examples 1 and 2, and is satisfactory for both nerve growth and vascular tubes.” BBA1006 at 12:6-13 (emphasis added).


are layered directly over each other and are laminated and heat dehydrated together to provide the dehydrated, laminated tissue graft.

“The amnion and chorion sheets are then wrapped in layers so that the fetal surface, which is shiny, is directed toward the inner surface of the finished tube. BBA1006 at 4:35 – 5:9 (emphasis added).

“Preferably, wrapping of the amnion sheets in layers is effected by using a highly polished stainless steel stent. . . The tubes which are on the stents are then dried in 40-60°C oven for about 30 minutes. Drying allows the tubes to be removed from the stents easily.” BBA1006 at 8:1-16 (emphasis added).


[Claim 7] The tissue graft of claim 6, consisting essentially of one amnion layer and

“said cylinder having a wall formed of at least one layer of sterilized cross-linked membrane, said membrane comprising collagen . . . said collagen being derived from the group consisting of amnion of

30

one chorion layer. a placenta, chorion of a placenta, and combinations thereof.” BBA1006 at claim 1 (emphasis added).

“The graft of Claim 1 wherein, said wall comprising at least two layers of said membrane….” BBA1006 at claim 2 (emphasis added).

[Claim 8] The tissue graft of claim 6, wherein at least one of the amnion or chorion layers has been chemically decontaminated.

“the amnion or chorion is then cross-linked either by exposure to gamma radiation or chemical cross-linking such as with glutaraldehyde, which sterilizes the tissue, provides protection against viral disease transmission” BBA1006 at 4:30-34 (emphasis added).

A POSITA would also know that glutaraldehyde is a powerful antimicrobial and sterilant that functions as a chemical decontaminant. BBA1002 at ¶ 55.

CLAIMS 9 & 10 GRAY (BBA1006)

[Claims 9 & 10] A dehydrated, laminated, placental tissue graft which is a laminate

comprising

“The amniotic and chorionic tubes of the present invention are well suited for use as nerve grafts or as

bypass conduits for coronary bypass or vascular bypass surgery” BBA1006 at 4:8-1 (emphasis

added).


“The tubes which are on the stents are then dried in 40-60°C oven for about 30 minutes.” BBA1006 at

8:11-13 (emphasis added).

[Claims 9 & 10] two or more separated and

washed layers which layers are selected from amnion and/or chorion

“the amnion and chorion layers are separated from the placenta and each other . . . the amnion and

chorion is rinsed repeatedly with phosphate buffer solution or distilled water until clean” BBA1006 at

4:25-30 (emphasis added).

[Claims 9 & 10] wherein the layers are directly

laminated to each other and


31

[Claim 9] at least one of said layers is an amnion layer which retains an

epithelial cellular layer.

A POSITA would know that the methods disclosed in Claim 1 of Gray do not remove epithelial cells or the epithelial cell layer. Furthermore, it would obvious to a POSITA to eliminate the trypsin step when preparing grafts for non-nerve use. BBA1002 at ¶¶ 60-62.

[Claim 10] at least one of said layers is an amnion

layer which retains a fibroblast cellular layer.

A POSITA would know that the methods of Gray do not remove fibroblast cells or the fibroblast cell layer. BBA1002 at ¶¶ 60-61.

D. Ground 4. Claims 1-10 are Obvious Under 35 U.S.C. § 103(a) over Gray in view of Vishwakarma

Grounds 1 and 3, including claim charts, are incorporated by reference.

Vishwakarma discloses a simplified method of placenta processing resulting in a

dehydrated, non-decelled laminate comprised of amnion. Gray teaches a more

complex method of processing that includes additional washing, treatment to

reduce infection potential, and partial decellularization that results in a dehydrated

laminate comprised of amnion and/or chorion.

A POSITA would understand removal of the epithelial layer, or

decellularization in general, is not required in preparing placental tissue grafts

unless there is a specific reason warranting removal, e.g. promoting axon growth.

BBA1002 at ¶ 65. A POSITA would understand Gray specifically teaches the

removal of the epithelial layer to promote axon growth and not for anything related

to the lamination or dehydration processing steps. Id. Vishwakarama teaches

lamination and dehydration are both viable with non-decelled amnion. Without a

32

specific reason to decellularize, it would be obvious for a POSITA to eliminate the

decellularization step to simplify processing as taught by Vishwakarma. Id.

Furthermore, it would be obvious to a POSITA to include the more substantial

washing steps and treatment with a sterilant of Gray into the processing of

Vishwakarma to reduce infection potential without impacting the capability of the

non-decelled tissue to be laminated or dehydrated. Id. The following chart

identifies the specific disclosure of Gray in combination with Vishwakarma

relating to the limitations of claims 1 - 10 as grouped by independent claims. Id. at

¶ 66.

CLAIMS 1-5 DISCLOSURE

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,

GRAY (BBA1006)

Corresponding elements of claim 1, as disclosed in the claim chart for Ground 2 (Gray), are incorporated by reference.

wherein at least one of the amnion

layers contains its fibroblast cell

layer, and

GRAY (BBA1006)

“said cylinder having a wall formed of at least one layer of sterilized cross-linked membrane, said membrane comprising collagen . . . said collagen being derived from the group consisting of amnion of a placenta, chorion of a placenta, and combinations thereof.” BBA1006 at claim 1 (emphasis

33

added).


VISHWAKARMA (BBA1005)

Vishwakarma does not disclose methods for the removal of the amniotic fibroblast cellular layer. A POSITA would understand that the removal of the fibroblast layer would require mechanical and/or chemical methods and that simply washing the fetal membrane in water would not be sufficient to remove the fibroblast layer. In the absence of such methods a POSITA would understand that the fibroblast layer is retained. BBA1002, at ¶¶ 45-49

further wherein the amnion layer and the chorion layer

are directly laminated to each

other.

GRAY (BBA1006)


[Claims 2 - 5]

GRAY (BBA1006)

Claims 2-5, as disclosed in the claim chart for Ground 2 (Gray), are incorporated by reference.


A dehydrated, laminated tissue

graft, wherein the tissue graft consists essentially of one or more amnion layers and one or

more chorion layers wherein each of the amnion and

GRAY (BBA1006)


34

chorion layers

are separated from a placenta to

provide separate layers of amnion

and chorion,

washed and substantially

cleaned without removal of the

fibroblast cell layer from the amnion

layer, and

GRAY (BBA1006)


“The amnion layer is separated from the placenta . . . selected pieces of membrane are thoroughly washed, preferably with phosphate buffered saline, or distilled water to remove all the blood and debris. Then the membranes are further washed until they are white and transparent.” BBA1006 at 7:1-8 (emphasis added).

“In this example, human chorion was substituted for human amnion. The chorion membrane was separated from the amnion membrane and was then harvested and treated the same as 10 in paragraph A, and conduits formed the same as in paragraph B has properties similar to those set forth in Examples 1 and 2, and is satisfactory for both nerve growth and vascular tubes.” BBA1006 at 12:6-13 (emphasis added).




are layered directly GRAY (BBA1006)

35

over each other and are laminated and heat dehydrated

together to provide the dehydrated, laminated tissue

graft.


[Claims 7 - 8]

GRAY (BBA1006)

Claims 7-8, as disclosed in the claim chart for Ground 2 (Gray), are incorporated by reference.

CLAIMS 9 & 10 DISCLOSURE

[Claims 9 & 10] A dehydrated, laminated,

placental tissue graft which is a

laminate comprising two or more separated and

washed layers which layers are

selected from amnion and/or

chorion wherein the layers are

directly laminated to each other and

GRAY (BBA1006)

Corresponding elements of claims 9 and 10, as disclosed in the claim chart for Ground 2 (Gray), are incorporated by reference.

[Claim 9] at least one of said layers is

an amnion layer which retains an epithelial cellular

layer.

GRAY (BBA1006)



36

Vishwakarma does not disclose methods for the removal of the amniotic epithelial cellular layer. A POSITA would understand that the removal of the epithelial layer would require mechanical and/or chemical methods and that simply washing the fetal membrane in water would not be sufficient to remove the epithelial layer. In the absence of such methods a POSITA would understand that the epithelial layer is retained. BBA1002, at ¶¶ 45-49


an amnion layer which retains a

fibroblast cellular layer.

GRAY (BBA1006)




E. Ground 5. Claims 9 and 10 are Obvious Under 35 U.S.C. § 103(a) over Tseng in view of Miljudin.

Miljudin and Tseng relate to the processing of human placenta for

therapeutic use in humans. Miljudin is a printed publication that published in 2004

and Tseng issued as a U.S. Patent on November 28, 2000; both are more than one

year prior to the August 17, 2006 effective filing date of the ’494 Patent.

Accordingly, Miljudin and Tseng are prior art under § 102(b) and § 103(a).

Miljudin was not identified in any of the Information Disclosure Statements

37

submitted by the Applicant in the ’494 Patent or related applications. BBA1004 at

61-66. Tseng was identified and relied on by the Examiner of the ’494 Patent

during prosecution ’494 Patent. Id.

Tseng discusses the lengthy therapeutic history of human placenta as a tissue

graft. Tseng notes that a majority of references from the 1970s and 1980s teach

the use of “live” placenta or amnion. Utilizing live tissue limits the availability of

tissue and prevents long-term storage. Tseng noted that killing the cells of the

amnion was important to prevent rejection and allowed for long-term storage

and/or shipment.

Tseng’s method for creation of the amnion tissue graft comprises: 1)

collecting human placenta in sterile conditions, 2) rinsing human placenta with a

saline solution containing antibiotics, 3) separating the amnion from the chorion

while “immersed in the antibiotics-containing balanced saline solution,” 4)

mounting the amnion on a substrate such as nitrocellulose filter with the epithelial

side facing away from the filter, 5) cutting the amnion-adhered nitrocellulose filter

into relevant sizes, and 6) freezing the amnion-adhered nitrocellulose filter in a

culture medium such as DMEM at -80 degrees Celsius. Tseng [BBA1008] at

4:56–5:31. Tseng’s method does not remove any cell layers but kills the cells by

performing the freezing step. BBA1008 at 5:31-52. Tseng discloses that generally

only a single layer of amnion tissue graft is necessary but “it is also feasible to use

38

two or more layers” to fill deep ulcerations. Id. at 6:18-39. The layering of

multiple amnion membranes creates a laminate. BBA1002 at ¶ 74. The tissue

graft is secured into place though use of sutures. BBA1008 at 6:18-39.

Miljudin teaches dehydration as a simpler method for preparing non-

decelled amnion membrane that is capable of long-term storage. Miljudin

compares the use of a single layer dehydrated amnion tissue graft with a native

“live” amnion tissue graft in the treatment of eye trauma. Miljudin [BBA1007] at

272. While both samples retained the epithelial layer, the cells in the dehydrated

amnion tissue graft are non-viable whereas the native amnion graft is viable.

BBA1007 at 273. Ultimately, Miljudin determines the use of dried amnion

membrane “is, practically, no less effective” than using vital epithelial cells and

notes its methods of preservation are simpler and do not require use of a

nitrocellulose paper. Id. at 274.

Miljudin’s method includes the steps of: 1) aseptically collecting human

placenta, 2) separation of the amnion from the chorion, 3) washing the amnion free

of blood clots; 4) treating the amnion with antiseptics and antibiotics, 5) placing

the amnion on frames over silica gel to dehydrate, and 6) sterilizing the graft using

gamma radiation. BBA1007 at 272-73. The end result is a washed, sterilized, and

dehydrated non-decelled amnion tissue graft.

39

It would have been obvious to POSITA to combine the teachings of Tseng

and Miljudin. Both utilize non-viable, non-decelled, amnion membranes as tissue

grafts. Miljudin specifically teaches the use of dehydration in preparing amnion

and Tseng specifically teaches the creation of a multi-layered laminate. It would

be obvious to a POSITA, in light of Miludin and Tseng, to utilize more than one

layer of amnion to create a thicker tissue graft prior to the dehydration taught by

Miljudin. BBA1002 at ¶ 76 Similarly, it would be obvious to a POSITA to

combine the multi-layer laminate of Tseng with the dehydration and processing

steps of Miljudin. Id. Combining the teachings of Miljudin with Tseng simplifies

the processing of Tseng by eliminating the nitrocellulose paper and freezer based

storage. Id. The inclusion of Miljudin’s processing to Tseng ultimately results in a

more user-friendly tissue graft that does not negatively impact graft performance.

Id. As a result, Claims 9 and 10 are obvious in view of Miljudin in view of Tseng.

Id. at ¶ 77.


[Claims 9 & 10] A Dehydrated,

laminated Placental Tissue Graft,

TSENG (BBA1008)

“Except for deep ulcers, one layer of membrane generally is sufficient. But it is also feasible to use two or more layers.” BBA1008 at 6:38-39 (emphasis added).

MILJUDIN (BBA1007)

“Human placentas were collected aseptically...”

“The scarps of the amniotic membrane are fixed on frames

40

over silica gel for 18-24h.” BBA1007 at 272 (emphasis added).

[Claims 9 & 10] which is a laminate comprising two or more separated and

washed layers

TSENG (BBA1008)

“the placenta is rinsed several times with balanced salt saline to remove excessive blood clots.” BBA1008 at 4:60-62 (emphasis added).

“the placenta’s amniotic membrane is separated easily from the remaining chorion by blunt dissection” BBA1008 at 5:7-9 (emphasis added).


It would be obvious to POSITA that “two or more layers” layered on each other produces a laminate. BBA1002 at ¶¶ 74-75.

MILJUDIN (BBA1007)

“The amnion is separated from remnants of chorion washed free of blood clots” BBA1007 at 272 (emphasis added).

[Claims 9 & 10] which layers are


chorion

TSENG (BBA1008)


MILJUDIN (BBA1007)


[Claims 9 & 10] wherein the layers


other, and

TSENG (BBA1008)


It would be obvious to POSITA that “two or more layers”

41

layered on each other produces a laminate. BBA1002 at ¶¶ 74-75.

[Claim 9] at least one layer an


cellular layer.

TSENG (BBA1008)

“The separated amniotic membrane, as a sheet, then is mounted/apposed onto a substrate, for example, a sterile nitrocellulose filter, so that the epithelial surface is kept facing up when flattened. Thus, the stromal/ fibroblasticlayer lies on the filter.” BBA1008 at 5:11-15 (emphasis added).

MILJUDIN (BBA1007)

“The study of the histological preparations of the AM dried over silica gel proved our predictions about the considerable changes in the epithelium layer….the epithelial cells look thickened with homogenous oxyfilled cytoplasm” BBA1007 at 273 (emphasis added).


amnion layer which retains a fibroblast

cellular layer.

TSENG (BBA1008)

“The separated amniotic membrane, as a sheet, then is mounted/apposed onto a substrate, for example, a sterile nitrocellulose filter, so that the epithelial surface is kept facing up when flattened. Thus, the stromal/fibroblastic layer lies on the filter.” BBA1008 at 5:11-15 (emphasis added).

MILJUDIN (BBA1007)

“The nuclei of the preserved fibroblasts are in stick-like form” BBA1007 at 273 (emphasis added).

F. Ground 6 Claims 1-10 are Obvious Under 35 U.S.C. § 103(a) over

Hariri in view of Vishwakarma.

Hariri is a U.S. Patent Publication directed to methods for preparation and

use of collagen biofrabrics made of placenta tissue. Hariri published on March 11,

2004 which is more than one year prior to the August 17, 2006 effective filing date

42

of the ’494 Patent. Accordingly, Hariri is prior art under § 102(b) and § 103(a).

Hariri was disclosed in the Information Disclosure Statement submitted by the

Applicant in the ’494 Patent and relied on by the Examiner. Vishwakarma is

discussed in Ground 1 and incorporated by reference.

Hariri teaches the preparation of laminated collagen biofabrics consisting of

placental fetal membranes. Hariri utilizes the term “collagen biofabric” throughout

the specification and defines it as “collagenous amniotic membrane.” Hariri

[BBA1009] at ¶ 48. Hariri broadens this definition in discussing alternative

embodiments by stating “the invention provides a collagen biofabric comprising a

dehydrated, decelluarized, and substrate-free chorionic membrane, preferably a

human chorionic membrane.” BBA1009 at ¶ 55. Hariri teaches washing, cleaning,

separating the amnion from the chorion, utilizing sterile conditions, chemical

decontamination, and decellularizing the collagen biofabrics. [See chart infra].

Hariri teaches cross-linking the amniotic membranes and expressly states that any

cross-linking chemical reagent is permissible. A POSITA would know that

glutaraldehyde is a chemical cross-linking agent which is used with placental

membranes. BBA1002 at ¶ 81. A POSITA, as indicated by Gray, would also

know that glutaraldehyde is a chemical decontamination agent that sterilizes

tissues. BBA1002 at ¶¶ 55-58.

43

Hariri’s specification expressly teaches “a laminate comprising at least two

layers of the biofabric.” BBA1009 at ¶ 20. Considering Hariri’s definition of

biofabric includes amnion or chorion, it is logical Hariri teaches the lamination of a

chorion to amnion layer. However, if Hariri’s disclosure of lamination is

construed narrowly to exclude a combination of amnion and chorion, it would have

been obvious to a POSITA to construct a laminate with one amnion layer and one

chorion layer if simply for no reason other to increase yield of graft production per

placenta processed due to the presence of amnion and chorion in each harvested

placenta. BBA1002 at ¶ 80.

Furthermore, Hariri teaches “that a collagen biofabric comprising a

chorionic membrane will have comparable properties as the collagen biofabric of

the invention comprising an amniotic membrane.” BBA1009 at ¶ 55. As the

Examiner pointed out during prosecution of the ’494 Patent, Hariri teaches “the

biofabric produced from chorionic membrane is a functional equivalent to the

biofabric produced from amniotic membrane.” BBA1004 at 28-30 (emphasis in

original). Hariri further states a biofabric made of chorion may be included in

“medically useful forms” such as “laminates.” BBA1009 at ¶ 55. Thus, it is

obvious that a laminated biofabric may consist of amnion only, chorion only, or a

combination of both.

44

Every claimed element of the ’494 Patent is taught and disclosed by Hariri

with the exception of Hariri’s decellularization step. In essence, Hariri takes the

subject matter of the ’494 Patent claims and adds decellularization steps that

include scraping and chemical applications that lyse the cells. BBA1002 at ¶ _86.

Placental fetal membranes were virtually always used in their native cellular state

unless there was a specific reason to decell the tissue. BBA1002 at ¶ 24. Hariri

teaches decelling for at least two reasons: 1) to reduce any potential

immunogenicity and 2) to create a biofabric that retains its collagen matrix but that

can also transport biomolecules or living cells. Without a specific reason to

decellularize, it would be obvious for a POSITA to eliminate the decellularization

steps of Hariri to simplify processing and shorten the time required. BBA1002 at ¶

86.

Should Hariri alone be insufficient to render claims 1-10 obvious, it would

be obvious for a POSITA to utilize the lamination techniques and gross tissue

processing disclosed in Hariri with non-decelled placental tissue as taught by

Vishwakarma. Vishwakarma expressly teaches lamination of at least two layers of

non-decelled amnion tissue with subsequent drying. Vishwakarma’s disclosure

retains the epithelial and fibroblast cell layers and teaches lamination is possible

with non-decelled tissue. Thus, it would be obvious for a POSITA to combine the

teachings of Hariri with the non-decelled tissue disclosed in Vishwakarma to

45

simplify the tissue processing by eliminating the unnecessary decellularization step

without creating an immunologic reaction or increasing host rejection. BBA1002

at ¶ 118.

It is noteworthy the additional decelling step of Hariri was insufficient for

patentability. The Examiner in Hariri rejected Hariri, in part, over the non-decelled

tissues in Tseng noting “[i]t would have been obvious to decellularize the amniotic

membrane of Tseng before implanting for tissue repair to reduce immunogenicity

. . . .” BBA1018 at 5. Thus, it would be highly unusual if the claims of the ’494

Patent, utilizing old techniques, minimal tissue processing, and placental tissue that

retains its cells, are novel; yet the extra step of decellularization of native amnion

is obvious.

As noted supra, the ’494 Patent was initially rejected as obvious in view of

Hariri. Both of Applicant’s submitted arguments were factually incorrect as there

is no middle or intermediate layer of placental tissue and Hariri does not teach

removal of the fibroblast layer. BBA1002 at ¶¶ 83-85; BBA1009 at ¶ 14. As

noted supra, Hariri teaches the depopulation of fibroblast cells from the fibroblast

layer but does not remove the fibroblast layer itself. BBA1002 at ¶ 85.

Importantly, Applicant failed to argue any reason why it would be non-obvious to

retain the epithelial and/or fibroblast cell layers. Considering the natural state of

placenta as an amnion/chorion laminate retaining all of its cell layers and the

46

documented 100-year history of use, Applicant simply cannot make any argument

that retaining the cell layers, to overcome Hariri, would not be obvious. It would

have been obvious to a POSITA to eliminate the decellulairzation step and utilize

non-decelled placental fetal membranes in the laminations as taught by Hariri to

reduce processing complexity and time. BBA1002 at ¶ 86. The following chart

identifies the specific disclosures relating to the limitations of claims 1-10.

BBA1002 ¶ 87.



graft

HARIRI (BBA1009)

“The present invention also provides a placental-derived amniotic membrane or biofabric that can be stored as dehydrated sheets without freezing or cryopreservation” BBA1009, Hariri at ¶ 0013 (emphasis added).

“layering at least two of the decellularized amniotic membranes in contact with each other so that an amniotic membrane laminate is formed; and drying the decellularized amniotic membrane laminate” BBA1009 at ¶ 0021 (emphasis added).

consisting essentially of one or more washed

and/or substantially cleaned amnion

layers and

HARIRI (BBA1009)

“the amnion is partially decellularized by physically removing all visible cellular material from the maternal side of the amniotic membrane. Sterile water is used to assist in the removal of cells and cellular debris, if needed.” BBA1009 at ¶ 0089 (emphasis added).

“washing the decellularized amniotic membrane at least once using the methods disclosed herein” BBA1009 at ¶ 0115 (emphasis added).

47

one or more washed and/or substantially

cleaned chorion layers,

HARIRI (BBA1009)

“a laminate comprising at least two layers of the biofabric” BBA1009 at ¶ 0020 (emphasis added).

“a collagen biofabric comprising a chorionic membrane will have comparable properties as the collagen biofabric of the invention comprising an amniotic membrane.” BBA1009 at ¶ 0055 (emphasis added).

“In a specific embodiment, the method further entails washing and drying the decelluarized chorionic membrane.” BBA1009 at ¶ 0112 (emphasis added).

wherein at least one of the amnion

layers contains its fibroblast cell

layer, and

HARIRI (BBA1009)

“The present invention provides a method for preparing a collagen biofabric […] and decellularizing the amniotic membrane while preserving the architecture of the underlying extracellular matrix” BBA1009 at ¶ 0014 (emphasis added).

POSITA would appreciate that the fibroblast cell layer of the amnion is retained following the methods described by Hariri. While Hariri teaches decelling the tissue, or removing the fibroblast cells, Hariri expressly does not remove the extracellular matrix. BBA1002 at ¶ 85.



further wherein the amnion layer and the chorion layer

HARIRI (BBA1009)

“a laminate comprising at least two layers of the biofabric”

48


other.

BBA1009 at ¶ 0020 (emphasis added).

“The invention provides a collagenous amniotic membrane, herein referred to as a collagen biofabric” BBA1009 at ¶ 0048 (emphasis added).

“layering at least two of the decellularized amniotic membranes in contact with each other so that an amniotic membrane laminate is formed” BBA1009 at ¶ 0115 (emphasis added).

“In alternative embodiments, the invention provides a method of preparing a collagen biofabric comprising a chorionic membrane. It is expected that the methods described above would be applicable to the method of preparing a biofabric comprising a chorionic membrane” BBA1009 at ¶ 0112 (emphasis added).


Hariri expressly teaches that a chorion membrane has comparable properties to that of an amnion membrane and that a chorion membrane may be processed in the same manner as an amnion membrane. A POSITA would have been motivated to combine amnion and chorion to increase yield of tissue graft. Utilizing chorion and amnion provides an approximate two-fold increase in the amount of material with which to make tissue grafts. A POSITA would likewise appreciate that the fetal membrane in its natural state is a laminate comprising one amnion and one chorion layer. The reconstitution of this form by combining one amnion layer and one chorion layer would be obvious to POSITA. BBA1002 at ¶ 87.

[Claim 2] The dehydrated,

laminated tissue graft of claim 1,

wherein said assembled and

HARIRI (BBA1009)

“The decellularized amniotic membrane is then flipped over so that fetal side is facing upwards, and place on a drying frame, preferably a plastic mesh drying frame (e.g., Quick Count® Plast Canvas, Unick, Inc. Wannakee, Wis). In other

49

laminated layers are dehydrated

together in a drying fixture.

embodiments, the drying frame may be any autoclavable material, including but limited to a stainless steel mesh.” BBA1009 at ¶ 0104 (emphasis added).

“layering at least two of the decellularized amniotic membranes in contact with each other so that an amniotic membrane laminate is formed; and drying the amniotic membrane laminate, using methods disclosed herein.” BBA1009 at ¶ 0115 (emphasis added).


laminated tissue graft of claim 1, wherein one or

both of the one or more amnion layers

and the one or more chorion

layers are treated with an antibiotic prior to lamination

HARIRI (BBA1009)

“In a particular embodiment, the collagen biofabric is impreganted with a therapeutically effective amount of an agent useful in the treatment of a wound infection, including but not limited to, an antibiotic, antimicrobial agent, and an anti-bacterial agent” BBA1009 at ¶ 0142 (emphasis added).

It would be obvious to POSITA that treatment with antibiotics would be beneficial during processing including but not limited to the killing and reduction in the growth of microorganisms. BBA1002 at ¶ 87.



wherein the tissue graft has been

exposed to sterilizing conditions.

HARIRI (BBA1009)

“Sterilization of the biofabric of the invention is preferably done by electron beam irradiation using methods known to one skilled in the art” BBA1009 at ¶ 0125 (emphasis added).



consisting essentially of one amnion layer and

HARIRI (BBA1009)


Hariri expressly teaches that a chorion membrane has comparable properties to that of an amnion membrane and that a chorion membrane may be processed in the same

50

one chorion layer. manner as an amnion membrane. A POSITA would be motivated to combine amnion and chorion to increase yield of tissue graft. Utilizing chorion and amnion provides an approximate two-fold increase in the amount of material with which to make tissue grafts. A POSITA would likewise appreciate that the fetal membrane in its natural state is a laminate comprising one amnion and one chorion layer. The reconstitution of this form by combining one amnion layer and one chorion layer would be obvious to a POSITA. BBA1002 at ¶ 87.



graft

HARIRI (BBA1009)



wherein the tissue graft consists

essentially of one or more amnion layers and one or

more chorion layers wherein each of the amnion and

chorion layers

HARIRI (BBA1009)

“The invention provides a collagenous amniotic membrane, herein referred to as a collagen biofabric” BBA1009 at ¶ 0048 (emphasis added).


are separated from a placenta to

HARIRI (BBA1009)

“The present invention provides a method of preparing a

51

provide separate layers of amnion

and chorion,

washed and substantially

cleaned without removal of the

fibroblast cell layer from the amnion

layer, and

collagen biofabric comprising providing a placenta, preferably a human placenta, separating the amniotic and chorionic layers from each other, and decellularizing the amniotic membrane while preserving the architecture of the underlying extracellular matrix. The method further entails washing and drying the decellularized membrane.” BBA1009 at ¶ 0014 (emphasis added).

“the amnion is partially decellularized by physically removing all visible cellular material from the maternal side of the amniotic membrane. Sterile water is used to assist in the removal of cells and cellular debris, if needed.” BBA1009 at ¶ 0089 (emphasis added).

“the membranes are further washed in order to effectively achieve the complete removal of all visible cellular material and cellular debris from both sides of the amniotic membrane.” BBA1009 at ¶ 0094 (emphasis added).




are layered directly over each other and are laminated and heat dehydrated

together to provide the dehydrated,

HARIRI (BBA1009)


“The invention provides a collagenous amniotic membrane, herein referred to as a collagen biofabric” BBA1009 at ¶

52

laminated tissue graft.

0048 (emphasis added).




“the invention encompasses heat drying the amniotic membrane of the invention under vacuum.” BBA1009 at ¶ 0107 (emphasis added).

Hariri expressly teaches that a chorion membrane has comparable properties to that of an amnion membrane and that a chorion membrane may be processed in the same manner as an amnion membrane. A POSITA would have been motivated to combine an amnion membrane with a chorion membrane to increase yield of tissue graft. Utilizing chorion and amnion provides an approximate two-fold increase in the amount of material with which to make tissue grafts. A POSITA would likewise appreciate that the fetal membrane in its natural state is a laminate comprising one amnion and one chorion layer. The reconstitution of this form by combining one amnion layer and one chorion layer would be obvious to POSITA. Furthermore it would be obvious to heat dry the laminate for the same storage purposes of a single layer. BBA1002 at ¶ 87.

[Claim 7] The tissue graft of claim

6, consisting essentially of one

HARIRI (BBA1009)

A POSITA would appreciate that the fetal membrane in its natural state is a laminate comprising one amnion and one

53

amnion layer and one chorion layer.

chorion layer. The reconstitution of this form by combining one amnion layer and one chorion layer would be obvious to POSITA. BBA1002 at ¶ 87.

[Claim 8] The tissue graft of claim 6, wherein at least one of the amnion or chorion layers

has been chemically

decontaminated.

HARIRI (BBA1009)

“Any cross-linking reagent and method known to one skilled in the art is within the scope of the present invention, including but not limited to, chemical cross-linking” BBA1009 at ¶ 0022 (emphasis added).

A POSITA would know that glutaraldehyde is a chemical cross-linking agent which is used with placental membranes. A POSITA, as indicated by Gray, would also know that glutaraldehyde is a chemical decontamination agent that sterilizes tissues.BBA1002 at ¶¶ 55-58.


[Claims 9 & 10] A dehydrated, laminated,

placental tissue graft which is a

laminate comprising

HARIRI (BBA1009)



[Claims 9 & 10] two or more

separated and washed layers

which layers are selected from amnion and/or

chorion

HARIRI (BBA1009)

“separating the amniotic membrane from the chorionic membrane . . . washing the decellularized amniotic membrane at least once using the methods disclosed herein” BBA1009 at ¶ 0115 (emphasis added).

[Claims 9 & 10] HARIRI (BBA1009)

54

wherein the layers are directly

laminated to each other and



an amnion layer which retains an epithelial cellular

layer.

HARIRI (BBA1009)

A POSITA would know that that given the immunoprilvilaged status of fetal cells, their removal may not be necessary or beneficial. A POSITA would know that retaining cells does not require a new or novel processing step. In dealing with native placental tissue, a POSITA knows that no action is required to retain cell and cell layers. In contrast, decellularization requires adding steps in processing the tissue which adds time and cost. BBA1002 at ¶¶ 30-36.


Vishwakarma does not disclose methods for the removal of the amniotic epithelial cellular layer. A POSITA would understand that the removal of the epithelial layer would require mechanical and/or chemical methods and that simply washing the fetal membrane in water would not be sufficient to remove the epithelial layer. In the absence of such methods a POSITA would understand that the epithelial layer is retained. BBA1002, at ¶¶ 45-49


an amnion layer which retains a

fibroblast cellular layer.

HARIRI (BBA1009)

“The present invention provides a method for preparing a collagen biofabric […] and decellularizing the amniotic membrane while preserving the architecture of the underlying extracellular matrix” BBA1009 at ¶ 0014 (emphasis added).


55



G. Ground 7. Claims 3, 9 and 10 are Obvious Under 35 U.S.C. § 103(a) over Gray in view of Miljudin or Tseng.

As explained in Ground 2, which is incorporated by reference, Gray is valid

prior art against the ’494 Patent and renders claims 1 – 10 obvious. Alternatively,

if Gray alone is found insufficient to render claims 3, 9 and/or 10 obvious, then

they are obvious over Gray in view of Miljudin or Tseng. As stated in Ground 3,

Miljudin and Tseng are prior art under § 102(b) and § 103(a).

1. Claim 3

Claim 3 requires the treatment of the amnion and chorion layers to be treated

with an antibiotic prior to lamination. Gray teaches the use of glutaraldehyde but it

is not a traditional antibiotic despite having the same effect. A POSITA knows

glutaraldehyde is a sterilizing agent that kills all living microorganisms in tissue

and knows that an antibiotic is also an agent that either kills or inhibits the growth

of a microorganism. BBA1002 at ¶¶ 55-58. Miljudin teaches treating separated

amnion with antibiotics prior to therapeutic use. BBA1007 at 272. Similarly,

56

Tseng teaches treating placental tissue with antibiotics prior separation of the

amnion from the chorion and prior to therapeutic use in patients. BBA1008 at

4:60-65; 5:8-11. In Tseng, the antibiotic treatment is performed prior to lamination

of amnion layers in a patient’s eye. Id. at 6:37-39. It would be obvious for a

POSITA, in view of Miljudin and Tseng, to treat the separated amnion and chorion

layers of Gray with antibiotics prior to lamination. BBA1002 at ¶¶ 92-93.

CLAIM 3 DISCLOSURE

[Claim 1]

GRAY (BBA1006)

Claim 1, as disclosed in the claim chart of Ground 2 is incorporated by reference.


laminated tissue graft of claim 1, wherein one or

both of the one or more amnion layers

and the one or more chorion

layers are treated with an antibiotic

prior to lamination..

GRAY (BBA1006)

“the amnion or chorion is then cross-linked either by exposure to gamma radiation or chemical cross-linking such as with glutaraldehyde, which sterilizes the tissue, provides protection against viral disease transmission . . . The amnion and chorion sheets are then wrapped in layers” BBA1006 at 4:30-36 (emphasis added).

A POSITA understands glutaraldehyde kills microorganisims as does an antibiotic. BBA1002 at ¶¶ 55-58.

TSENG (BBA1008) and/or MILJUDIN (BBA1007)

“the amnion is separated from the remnants of chorion washed free of blood clots. After processing in the solution of antiseptics and antibiotics the amniotic membrane is additionally treated in glycerol” BBA1007 at 272 (emphasis added).

“placenta’s amniotic membrane is separated easily from the remaining chorion by blunt dissections, while immersed in the above antibiotics-containing balanced saline

57

solution.” BBA1008 at 5:8-11 (emphasis added).

2. Claims 9 and 10

Should Gray’s disclosure as contained in Gray’s claim 1 be insufficient to

teach retention of the epithelial cell layers and/or fibroblast cell layers, then claims

9 and 10 are obvious over Gray in view of Miljudin or Tseng. Miljudin and Tseng

expressly retain the epithelial and fibroblast layers in their respective amnion tissue

grafts.

A POSITA would be motivated to combine the disclosures of Tseng and/or

Miljudin with Gray for purposes of 1) process simplification (i.e., remove

unnecessary steps associated with decellularization) without negatively impacting

graft performance (i.e., without risk of graft rejection) and 2) improve graft

performance by retaining “active proteins” that create conditions favorable to stem

cell proliferation. BBA1007 at 272; BBA1002 at ¶ 93.


[Claims 9 & 10] A Dehydrated,

laminated Placental Tissue Graft,

GRAY (BBA1006)

“The amniotic and chorionic tubes of the present invention are well suited for use as nerve grafts or as bypass conduits for coronary bypass or vascular bypass surgery” BBA1006 at 4:8-1 (emphasis added).



58


“Human placentas were collected aseptically...”

“The scarps of the amniotic membrane are fixed on frames over silica gel for 18-24h.” BBA1007 at 272 (emphasis added).

[Claims 9 & 10] which is a laminate comprising two or more separated and

washed layers

GRAY (BBA1006)




“the placenta is rinsed several times with balanced salt saline to remove excessive blood clots.” BBA1008 at 4:60-62 (emphasis added).




[Claims 9 & 10] which layers are


chorion

GRAY (BBA1006)


59




[Claims 9 & 10] wherein the layers


other, and

GRAY (BBA1006)







cellular layer.

GRAY (BBA1006)

“The amniotic and chorionic tubes of the present invention are well suited for use as nerve grafts or as bypass conduits for coronary bypass or vascular bypass surgery” BBA1006 at 4:8-1 (emphasis added).




60

“The study of the histological preparations of the AM dried over silica gel proved our predictions about the considerable changes in the epithelium layer….the epithelial cells look thickened with homogenous oxyfilled cytoplasm” BBA1007 at 273 (emphasis added).

“The separated amniotic membrane, as a sheet, then is mounted/apposed onto a substrate, for example, a sterile nitrocellulose filter, so that the epithelial surface is kept facing up when flattened. Thus, the stromal/ fibroblasticlayer lies on the filter.” BBA1008 at 5:11-15 (emphasis added).


amnion layer which retains a fibroblast

cellular layer.

GRAY (BBA1006)



“The nuclei of the preserved fibroblasts are in stick-like form” BBA1007 at 273 (emphasis added).

“The separated amniotic membrane, as a sheet, then is mounted/apposed onto a substrate, for example, a sterile nitrocellulose filter, so that the epithelial surface is kept facing up when flattened. Thus, the stromal/fibroblastic layer lies on the filter.” BBA1008 at 5:11-15 (emphasis added).

V. CONCLUSION

Petitioners respectfully requests that inter partes review of the ’494 Patent

be instituted and that claims 1 – 10 are found unpatentable for the reasons stated

above.

Dated: December 1, 2014 Respectfully submitted,

/Robert L. McRae, Reg. No. 53309/ Robert L. McRae, Reg. No. 53309

61

/Jason E. McKinnie, Reg. No. 65726/ Jason E. McKinnie, Reg. No. 65726

GUNN, LEE & CAVE, P.C. 300 Convent St., Suite 1080 San Antonio, TX 78205 Phone: (210) 886-9500 Fax: (210) 886-9883 Email: [email protected] Email: [email protected] ATTORNEYS FOR PETITIONERS

62

CERTIFICATE OF SERVICE

Pursuant to 37 C.F.R. §§ 42.8(b)(4) and 42.105(b), the undersigned certifies

that on December 1, 2014, a complete and entire copy of this Petition for Inter

Partes Review and all supporting exhibits were provided via FEDEX

STANDARD OVERNIGHT and email, costs prepaid, to the Patent Owner by

serving the correspondence address of record as follows:

MiMedx Group, Inc. c/o Foley & Lardner LLP 3000 K Street N.W. Suite 600 Washington DC 20007-5109

MiMedx Group, Inc. c/o ALSTON & BIRD LLP Dwayne C. Norton 2828 North Harwood St Suite 1800 Dallas, TX 75201 [email protected]

By: /Robert L. McRae, Reg. No. 53309/

Robert L. McRae, Reg. No. 53309 GUNN, LEE & CAVE, P.C. 300 Convent St., Suite 1080 San Antonio, TX 78205 Phone: (210) 886–9500 Fax: (210) 886–9883

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