`
`_____________
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________
`
`
`
`Musculoskeletal Transplant Foundation
`
`Petitioner
`
`
`
`v.
`
`
`
`MiMedx Group, Inc.
`
`Patent Owner
`
`_____________
`
`U.S. Patent No. 8,323,701
`
`_________________________
`
`
`
`DECLARATION OF HELEN N. JONES, PH.D.
`
`
`
`MTF Ex. 1008, p. 1
`
`
`
`I, Helen N. Jones, Ph.D., declare as follows:
`
`1.
`
`I have been retained by counsel for the Petitioner, Musculoskeletal
`
`Transplant Foundation, (i.e., Greenberg Traurig, LLP) to offer technical opinions
`
`in connection with a Petition for inter partes review (“the Petition”) on U.S. Patent
`
`No. 8,323,701 B1 (“the ‘701 Patent”). See Ex. 1001.1
`
`2.
`
`Specifically, this Declaration and the opinions expressed herein
`
`address the lack of novelty and/or obviousness of Claims 1, 2 and 5-8 of the ‘701
`
`Patent (“Challenged Claims”) in light of the prior art.
`
`I.
`
`QUALIFICATIONS
`
`3.
`
`I was awarded a Bachelor of Science in Biochemistry from the
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`University of St. Andrews in St. Andrews, Scotland in 2000 and a Doctorate in the
`
`field of Biomedical Sciences (Physiology) from the Rowett Research Institute,
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`University of Aberdeen in Aberdeen, Scotland in 2005. My current curriculum
`
`vitae is attached hereto as Ex. JONES-0001 and made part of this Declaration.
`
`4.
`
`After earning my Doctorate, I was a Postdoctoral Research Fellow for
`
`the Department of Obstetrics and Gynecology at the University of Cincinnati from
`
`2006-2009. I was a Research Associate at the Center for Molecular Fetal Therapy
`
`1 Where applicable, exhibits contained in Petitioner’s Exhibits will be referenced
`
`herein by their corresponding Exhibit numbers.
`
`
`
`MTF Ex. 1008, p. 2
`
`
`
`for Cincinnati Children’s Hospital Medical Center from 2009-2010. I was a
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`Research Assistant Professor at the Center for Molecular Fetal Therapy for
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`Cincinnati Children’s Hospital Medical Center, Department of Surgery, College of
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`Medicine, University of Cincinnati from 2010-2013. In 2013, I became an
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`Assistant Professor in the Divisions of Pediatric Surgery and Reproductive
`
`Sciences of Cincinnati Children’s Hospital Medical Center, Department of
`
`Surgery, College of Medicine, University of Cincinnati.
`
`5.
`
`I have been awarded the International Federation of Placenta
`
`Associations (IFPA) Y. W. (Charlie) Loke Young Investigator Awards in 2003,
`
`2004 and 2005; a Physiological Society Affiliate member travel grant in 2004; a
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`Society for Reproduction and Fertility travel grant in 2004; the International
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`Federation of Placenta Associations NIH New Investigator Award in 2006 and
`
`2007; the National institute of Child Health and Development Aspen Perinatal
`
`Symposium Travel Award in 2007; the Perinatal Research Society New
`
`Investigator Award in 2008; and the Perinatal Research Society Early Career
`
`Speaker award in 2013. I was also a nominated participant in the European
`
`Nutrition Leadership Programme (ENLP) in Luxembourg in 2005, and nominated
`
`for the Gabor Than Award in 2014.
`
`6.
`
`I have been invited to speak and lecture at various events and
`
`workshops including the Rank Prize Nutrition Mini-Symposium in Grassmere,
`
`MTF Ex. 1008, p. 3
`
`
`
`United Kingdom in 2005; the Imprinting Workshop, European Placental Group in
`
`Glasgow, United Kingdom in 2005; the Society for Gynecological Investigation in
`
`Glasgow, United Kingdom in 2009; the IFPA Latest Technologies Symposium in
`
`Santiago, Chile in 2010; the Placental Research to Solve Clinical Problems
`
`Workshop IFPA in Geilo, Norway in 2011; the Department Of Physiology of
`
`Cambridge University in 2011; and the Placenta and Health in Pregnancy
`
`Workshop at the University of Auckland in 2013.
`
`7.
`
`I have also been selected to chair and organize various events
`
`including the ECR plenary session IFPA 2011 in Geilo, Norway in 2011; the New
`
`Frontiers in Placental Biology Symposium for the Society for Gynecological
`
`Investigation in 2012; the ECR plenary session IFPA 2012 in Hiroshima, Japan in
`
`2012; the Placental Association of the Americas Satellite Symposium, SGI2013 in
`
`Orlando, Florida in 2013; and the Concurrent session, Placenta II for the Society
`
`for Gynecological Investigation in 2013. I have also been a member of many
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`societies in the field of physiology and placental research.
`
`8.
`
`I was chair of the IFPA Early Career Researcher (ECR) Committee
`
`from 2010-2012, the Early Career Researcher Representative on the IFPA
`
`Executive committee from 2010-2012, and a member of the Elsevier Oral Award
`
`Committee, IFPA in 2012. I am currently a member of the Elsevier Poster Award
`
`Committee, IFPA, the Society for Reproductive Investigation Abstract Committee,
`
`MTF Ex. 1008, p. 4
`
`
`
`the University of Cincinnati, University Research Council, Graduate Fellowship
`
`Committee, and the Postgraduate Research Grant committee of the University of
`
`Cincinnati. I am also a new investigator poster judge for the Society for
`
`Reproductive Investigation (SRI) and the program director for the Placental
`
`Association of the Americas Satellite Symposium, at the annual SRI conference.
`
`9.
`
`I have co-authored twenty (20) peer reviewed publications and two (2)
`
`publications which are currently in review. I have over a decade of experience in
`
`the field of physiology and placental research. I serve as a reviewer for the
`
`following peer-review
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`journals: Biology of Reproduction; Cell Biology
`
`International; Placenta; Trophoblast Research;
`
`Journal of Molecular
`
`Endocrinology; Nutrients; and British Journal of Nutrition. I also serve on the
`
`Editorial Board of Trophoblast Research.
`
`10.
`
`I have over a decade of experience in the field of physiology and
`
`placental research and as such am fully qualified to offer technical opinions
`
`concerning the unpatentability of the alleged invention claimed in the ‘701 Patent
`
`to the U.S. Patent Trial and Appeal Board (“PTAB”).
`
`II. COMPENSATION
`I am being compensated at the rate of $300 hour, and my
`11.
`
`compensation is not dependent on the outcome of this litigation.
`
`III. PRIOR EXPERT TESTIMONY
`
`MTF Ex. 1008, p. 5
`
`
`
`12. Other than submitting an EXPERT DECLARATION OF DR.
`
`HELEN
`
`JONES
`
`IN REBUTTAL TO REBECCA N. BAERGEN’S
`
`DECLARATION IN SUPPORT OF PLAINTIFF’S PROPOSED CLAIM
`
`CONSTRUCTIONS in MiMedx Group Inc. v. Liventa Bioscience, Inc. et al., Case
`
`No. 1:14-cv-01178-MHC (N.D. Ga.) (“Related Litigation”), in which the ‘701
`
`Patent is involved, I had never testified as an expert (either by submission of an
`
`expert report, deposition, or appearance in court).
`
`IV. MATERIAL CONSIDERED
`In addition to my personal knowledge, education, and experience,
`13.
`
`including as evidenced by my publications listed in my curriculum vitae, I have
`
`reviewed certain documents as part of this submission. I have identified some of
`
`them in this report, and others are identified at Ex. JONES-0002 to this report.
`
`V. LEVEL AND PERSON OF ORDINARY SKILL IN THE ART
`In my opinion, persons of ordinary skill in the art (“POSA”) of the
`14.
`
`‘701 Patent during the 2007-2008 time frame covering September 7, 2007 and
`
`September 8, 2008 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. A person of ordinary skill in the art as of the 2007-2008
`
`timeframe would also have at least two years of experience in and/or knowledge of
`
`MTF Ex. 1008, p. 6
`
`
`
`the processing of tissues for clinical and/or research use. I consider myself to be a
`
`person of at least ordinary skill in the art of the ‘701 Patent.
`
`VI. APPLICATIONS RELATED TO THE ‘701 PATENT
`I understand that the ‘701 Patent issued on December 4, 2012 from
`15.
`
`U.S. Application No. 12/428,908 (“the ‘908 Application”) filed April 23, 2009. I
`
`understand that the ‘701 Patent was filed allegedly as a continuation of U.S.
`
`Application No. 12/206,508 filed September 8, 2008 (“‘508 Application”) and
`
`claims priority to U.S. Provisional Application Nos. 60/970,780, 60/989,299 and
`
`60/986,665 (collectively “Related Provisional Applications”), which I understand
`
`were filed on September 7, 2007, November 7, 2007, and November 9, 2007,
`
`respectively.
`
`VII. SUBJECT MATTER OF THE ‘701 PATENT
`16. The ‘701 Patent is directed to tissue grafts derived from the placenta.
`
`Ex. 1001 at 1:64-65. The grafts include a first membrane of amnion tissue having
`
`its epithelium layer substantially removed in order to expose the basement layer.
`
`Id. at 1:65-67. “By removing the epithelium layer, cells from the host can more
`
`readily interact with the cell-adhesion bio-active factors located onto [sic] top and
`
`within of the basement membrane.” Id. at 2:1-3.
`
`17. The first membrane of amnion also includes an exposed jelly-like
`
`fibroblast cellular layer. Id. at 13:13-14. One or more additional membranes are
`
`MTF Ex. 1008, p. 7
`
`
`
`sequentially layered such that the first additional membrane is layered adjacent to
`
`the exposed fibroblast layer of the first amnion membrane. Id. at 13:15-18. The one
`
`or more additional membranes are selected from the group consisting of amnion,
`
`chorion, allograft pericardium, allograft acellular dermis, amniotic membrane,
`
`Wharton's jelly, and combinations thereof. Id. at 2:23-24; 8:19-25.
`
`18. The method disclosed in the ‘701 Patent for making the tissue graft
`
`recited in the Challenged Claims is summarized below. After obtaining placental
`
`tissue and processing same, the amnion and chorion layers are separated. Id. at 5:1-
`
`3. Thereafter, the epithelium layer is removed by scraping the amnion with a cell
`
`scraper in order to expose the basement layer of the amnion. Id. at 5:25-26; 5:41-
`
`43. The ‘701 Patent contemplates other techniques for removing the epithelium
`
`layer, such as “exposing the epithelial cells to nonionic detergents, anionic
`
`detergents, and nucleases”. Id. at 5:43-46. After subjecting the amnion layer to
`
`chemical decontamination (see id. at 5:59-6:35), the amnion layer is laid on a
`
`suitable drying fixture, with the exposed basement membrane is positioned
`
`adjacent the drying fixture. Id. at 6:62-66. One or more additional layers of amnion
`
`or chorion is/are layered to the amnion layer positioned on the drying fixture to
`
`form the tissue graft. Id. at 7:50-53.
`
`
`
`
`
`MTF Ex. 1008, p. 8
`
`
`
`VIII. REPRESENTATIVE CLAIM OF THE ‘701 PATENT
`19. Claim 1, which is the sole independent claim of the ‘701 Patent, is
`
`reproduced in the following chart. To facilitate consideration and discussion, the
`
`claim elements will be referenced below by their corresponding element letters (i.e.,
`
`“Elements (A)-(E)”), which are provided in the left column of the chart.
`
`Claim 1
`
`
`(A) A tissue graft consisting of:
`(B)
`a first membrane comprising modified amnion wherein the modified amnion
`
`has a first side which is an exposed basement membrane and
`(C)
`[the modified amnion has] a second side which is an exposed jelly-like
`fibroblast cellular layer; and
`(D) one or more additional membranes sequentially layered such that the first
`additional membrane is layered adjacent to the exposed fibroblast layer of
`the first membrane,
`(E) wherein the at least one or more additional membranes is selected from the
`group consisting of amnion, chorion, allograft pericardium, allograft
`acellular dermis, amniotic membrane, Wharton's jelly, and combinations
`thereof.
`
`
`
`IX. CONSTRUCTIONS OF CERTAIN CLAIM TERMS IN THE ‘701
`PATENT
`
`20.
`
`I have been asked to apply the following claim constructions for the
`
`purpose of conducting my unpatentability analyses of the Challenged Claims in
`
`conjunction with the Petition. I understand that the following claim constructions
`
`have been proposed by the Patent Owner in related the Related Litigation.
`
`
`
`
`
`MTF Ex. 1008, p. 9
`
`
`
`Claim Terms
` “a first membrane
`comprising modified
`amnion” in Claim 1
`
`Patent Owner’s Proposed Constructions
`Amniotic membrane separated from the chorionic
`membrane of native placenta and having at least a
`first side which is an exposed basement membrane
`and a second side which is an exposed jelly like
`fibroblast cellular layer
`
`The sticky side of the modified amnion, defined
`above, which includes an identifiable region of
`fibroblast cells
`The one or more additional membranes is layered in
`close proximity to, which can include having contact
`with the exposed fibroblast layer of the first
`membrane
`
` “exposed jelly-like
`fibroblast cellular layer”
`in Claim 1
`“such that the first
`additional membrane is
`layered adjacent to the
`exposed fibroblast layer
`of the first membrane” in
`Claim 1
`
`
`21.
`
`I believe that the Patent Owner’s proposed claim constructions are
`
`inconsistent with the principles of claim construction dictated in Phillips v. AWH
`
`Corp., 415 F.3d 1303 (Fed. Cir. 2005), and thus the Patent Owner’s proposed
`
`constructions should not be adopted in the Related Litigation. I understand,
`
`however, that the claims of the ‘701 Patent are to be construed in an inter partes
`
`review under a different claim interpretation standard (i.e., the “broadest
`
`reasonable interpretation” standard). I understand from Petitioner’s counsel that the
`
`Patent Owner’s foregoing construction of the claims for purposes of litigation
`
`should be considered as within the scope of the Office’s “broadest reasonable
`
`interpretation” standard for the purpose of the inter partes review requested by
`
`Petitioner on the ‘701 Patent.
`
`MTF Ex. 1008, p. 10
`
`
`
`X. BACKGROUND OF THE ALLEGED INVENTION IN THE ‘701
`PATENT
`
`22.
`
`In order to provide background for my analysis of the ‘701 Patent,
`
`reference is made to Parry et al., Premature Rupture of the Fetal Membranes, The
`
`New England Journal of Medicine 338(10), 663-670 (March 5, 1998) (“Parry”).
`
`See Ex. 1007. Parry contains an anatomical review of the fetal (i.e., placental)
`
`membranes, and reflects the knowledge of such membranes that a POSA would
`
`possess at the date of the alleged invention.
`
`23. The human placenta includes two membranes; namely the amnion and
`
`the chorion. See Ex. 1007 at 1. The amnion is sometimes referred to as the
`
`amniotic membrane in the literature and hereinbelow, and these terms are
`
`understood to be equivalent to each other. Similarly, chorion is sometimes referred
`
`to as the chorionic membrane in the literature and hereinbelow, and these terms are
`
`also understood to be equivalent to each other.
`
`24. The amnion is the innermost membrane of the placenta and is in
`
`contact with the amniotic fluid and the fetus. An intermediate (spongy) layer
`
`separates the amnion from the chorion, which is the outer-most membrane of the
`
`placenta, and which therefore is in contact with the maternal tissues of the uterus
`
`(i.e., the maternal decidua). The amnion and chorion each include several tissue
`
`layers that are identifiable anatomically and/or histologically. These are illustrated
`
`in Figure 1 of Parry (shown below). See id., 1-2.
`
`MTF Ex. 1008, p. 11
`
`
`
`
`
`25. The amnion includes five layers. The inner-most layer (nearest the
`
`fetus) is the epithelium, or epithelial layer. The epithelial cells of this layer form a
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`continuous monolayer that overlies the basement membrane of the amnion. The
`
`compact layer lies beneath and adjacent the basement membrane and forms the
`
`main fibrous skeleton of the amnion. The fibroblast layer lies beneath the compact
`
`layer, and is the thickest layer of the amnion. The fibroblast layer contains various
`
`cells within an extracellular matrix, including fibroblasts. The intermediate spongy
`
`layer lies between the fibroblast layer of the amnion and the underlying chorion,
`
`and absorbs physical stresses by permitting the amnion to slide along the chorion
`
`MTF Ex. 1008, p. 12
`
`
`
`without disrupting the firm adherence of the chorion to the maternal decidua (i.e.,
`
`the uterine wall). See id., 1-2.
`
`26. The chorion includes three layers. The layer closest to the amnion is
`
`the reticular layer. A basement membrane (sometimes referred to as a “pseudo-
`
`basement membrane”) layer lies beneath the reticular layer. The final – and outer
`
`most - layer of the chorion is the trophoblast layer, which includes layers of
`
`trophoblast cells, some of which are in intimate contact with the maternal decidua
`
`(i.e., the uterine wall). See id., 2.
`
`27. As acknowledged by the ‘701 Patent, tissue grafts made from human
`
`placental membranes, including amniotic and chorionic membranes, have been
`
`used in various surgical procedures since the early 1900s. Ex. 1001, 1:16-17. Such
`
`surgical procedures included the treatment of a variety of conditions including
`
`corneal injuries, burns, peripheral nerve injuries, chronic ulcers of the leg, tissue
`
`adhesion (i.e., as preventative means), skin wounds and other conditions. See, e.g.,
`
`Shenaq (Ex. 1009), Tseng (Ex. 1010), Wei (Exs. 1011, 1012), Sulner (Ex. 1013),
`
`Klen (Ex. 1014), Dua-99 (Ex. 1015), Ward (Ex. 1016), Douglas (Ex. 1017), Dino
`
`(Ex. 1018), Hanada (Ex. 1019) Robson (Ex. 1020) and Rinastiti (Ex. 1021).
`
`28. Over the long history of using placental membranes, many different
`
`techniques have been developed and became widely known. For instance, methods
`
`of separating amnion and chorion from one another via their intermediary spongy
`
`MTF Ex. 1008, p. 13
`
`
`
`layer have been known. See, e.g., Shenaq (Ex. 1009), Tseng (Ex. 1010), Wei (Exs.
`
`1011, 1012), Sulner (Ex. 1013), Klen (Ex. 1014) and Vishwakarma (Ex. 1035).
`
`Because the spongy layer is formed by loosely arranged bundles of collagen fibers,
`
`the spongy layer would separate unevenly between the amnion and chorion. As a
`
`result, at least some of the spongy layer would separate from the amnion together
`
`with the chorion, while the rest of the spongy layer would separate from the
`
`chorion together with the amnion.
`
`29. Methods of removing the epithelial layer from amnion were also well-
`
`known prior to the date of the alleged invention recited in the Challenged Claims.
`
`See, e.g., Shenaq (Ex. 1009), Wei (Exs. 1011, 1012), Sulner (Ex. 1013), Kinoshita-
`
`06 (Ex. 1022), Kinoshita-07 (Exs. 1023, 1024), Ishino (Ex. 1025), Shimazaki (Exs.
`
`1026, 1027), Taguchi (Exs. 1028, 1029), Wang (Ex. 1030), Matsui (Ex. 1031),
`
`Hariri-03 (Ex. 1032) and Hariri-04 (Ex. 1033). When the epithelial layer is
`
`removed, the underlying basement membrane would be exposed. By exposing the
`
`basement membrane, cells from the host can more readily interact with factors
`
`available from the basement membrane, thereby facilitating tissue healing. See,
`
`e.g., Kinoshita-06 at Ex. 1022 ¶0056; Wei at Ex. 1012, 4.
`
`30.
`
`It was also known prior to the date of the alleged invention that the
`
`spongy layer could be removed from its associated amnion which has been
`
`separated from the chorion. See, e.g., Tseng (Ex. 1010), Dua-07 (Ex. 1034), Wei
`
`MTF Ex. 1008, p. 14
`
`
`
`(Exs. 1011, 1012) and Shimazaki (Exs. 1026, 1027). When the spongy layer is
`
`removed from the amnion, the underlying fibroblast layer would be exposed. See,
`
`e.g., Ex. 1010 at 5:15-16.
`
`31. Methods for layering multiple layers of amnion and/or chorion to
`
`form multi-layered tissue grafts were also well-known. See, e.g., Tseng (Ex. 1010),
`
`Shenaq (Ex. 1009), Sulner (Ex. 1013), Hariri-03 (Ex. 1032), Hariri-04 (Ex. 1033)
`
`and Vishwakarma (Ex. 1035). These multi-layering methods have been developed
`
`for the purpose of providing additional thickness, rigidity, material, etc. to a single-
`
`layer of amnion so as to improve its handling, efficacy and other properties.
`
`32. As indicated below, the tissue graft recited in the Challenged Claims
`
`was already known in the art at the time of the alleged invention. Accordingly, it is
`
`my opinion that the Challenged Claims are unpatentable over one or more prior art
`
`references. My opinions regarding the unpatentability of the Challenged Claims
`
`and the bases therefor will be discussed in detail below.
`
`XI. ANTICIPATION AND OBVIOUSNESS
`I understand that a claimed invention is anticipated, and is therefore
`33.
`
`unpatentable, under 35 U.S.C. §102 if all of the elements or features recited in the
`
`claim are found expressly or inherently in a single prior art document or device. I
`
`understand “inherent” anticipation to mean that although a particular element of
`
`the invention is not expressly disclosed in the prior art document or device, the
`
`MTF Ex. 1008, p. 15
`
`
`
`element is inherently disclosed because the prior art necessarily and inevitably
`
`contains it.
`
`34.
`
`I understand that a claimed invention can also be unpatentable under
`
`35 U.S.C. §103(a) if it is obvious over the prior art. I understand that the
`
`obviousness of an invention claimed in a patent is to be determined as of “the time
`
`the invention was made.” I understand that a patent claim composed of several
`
`elements is not proved obvious merely by demonstrating that each element was
`
`independently known in the prior art. I also understand that if all of the elements of
`
`the claim are not found in a single prior art reference, a patent claim may still be
`
`invalid for obviousness only if the differences between the claimed subject matter
`
`and the prior art are such that the claimed subject matter as a whole would have
`
`been obvious at the time the invention was made to a person of ordinary skill in the
`
`art. I further understand that the following factors are considered in determining
`
`whether a patent claim would have been obvious at the time of the invention:
`
`i. the scope and content of the prior art;
`
`ii. the level of ordinary skill in the relevant art at issue;
`
`iii. the differences between the prior art and the claims at issue;
`
`iv. objective factors demonstrating non-obviousness of the invention, such
`
`as, for example (a) a long felt but unresolved need for the invention; (b)
`
`failure of others to solve the problems solved by the invention; (c)
`
`MTF Ex. 1008, p. 16
`
`
`
`copying of the invention; and (d) commercial success with a connection
`
`or “nexus” to the claimed invention.
`
`35.
`
`I understand that, in patent law, the level of ordinary skill in the art is
`
`based upon factors such as the educational level of those who work in the industry
`
`and the sophistication of the technology involved, in addition to the type of
`
`problems encountered in the art, and the prior art solutions to those problems. I
`
`understand that prior art is reasonably pertinent if it is in the same field as the
`
`claimed invention, or is from another field that a person of ordinary skill in the art
`
`would look to in trying to solve the problem. I also understand that a hypothetical
`
`person of ordinary skill in the art is presumed to have knowledge of all the relevant
`
`prior art.
`
`36.
`
`I understand that a patent claim may be obvious if the prior art or
`
`other factors would have suggested to, or motivated, one of ordinary skill in the art
`
`to combine certain prior art references to arrive at the elements of the claimed
`
`invention. I understand that this suggestion or motivation may come from the
`
`references themselves, the fact that certain references are of particular interest in
`
`the relevant field, the fact that the very nature of the problem can cause an inventor
`
`to examine certain references to seek a solution to that problem, the fact that a
`
`reference discloses a solution to a similar problem, or from the knowledge of one
`
`MTF Ex. 1008, p. 17
`
`
`
`of ordinary skill in the art. I understand that the motivation or suggestion to
`
`combine cannot come from hindsight.
`
`37.
`
`I also understand that when the prior art teaches away from combining
`
`certain prior art references, discovery of a successful means of combining them is
`
`more likely to be nonobvious. I also understand that a prior art reference may be
`
`said to “teach away” from combining it with other references when a person of
`
`ordinary skill, upon reading the reference, would be discouraged from following
`
`the path set out in the reference, or would be led in a direction divergent from the
`
`path that was taken by the inventor of the patent claim.
`
`38. The Challenged Claims recite the transitional phrase “consisting of”. I
`
`understand that by using the phrase “consisting of”, the Challenged Claims exclude
`
`any element, step or ingredient not specified in the claims. As a result, in order to
`
`anticipate or make obvious the Challenged Claims, the prior art needs to disclose
`
`or suggest a device or product containing only the elements recited in the claims.
`
`XII. PRIOR ART STATUS OF THE REFERENCES CITED HEREIN
`I understand that all of the references discussed below, with the
`39.
`
`exception of Kinoshita-07, Sulner, Dua-07 and Toda, were published more than
`
`one year prior to the filing dates of the Related Provisional Applications, and
`
`therefore constitute incontestable prior art under 35 U.S.C. §102(b).
`
`40. With respect to Kinoshita-07, Dua-07 and Sulner, I understand that
`
`MTF Ex. 1008, p. 18
`
`
`
`they were published prior to the filing dates of the Related Provisional
`
`Applications and thus constitute prior art, at least, under 35 U.S.C. §102(a) and/or
`
`(e). I understand that because at least some features claimed in the ‘701 Patent are
`
`not supported by the Related Provisional Applications, the ‘701 Patent is not
`
`entitled to the benefit of any of the Related Provisional Applications. Thus, I
`
`understand that the ‘701 Patent’s earliest possible effective filing date is the
`
`September 8, 2008 filing date of its parent application, which is more than one year
`
`after the publication dates of Kinoshital-07, Dua-07 and Sulner (thereby qualifying
`
`Kinoshital-07, Dua-07 and Sulner as prior art under §102(b)) and which is also
`
`after the publication date of Toda (thereby qualifying Toda as prior art, at least,
`
`under 35 U.S.C. §102(a)).
`
`41.
`
`I have reviewed certified English-language translations (see Exs.
`
`1012, 1024, 1027 and 1029) of Wei, Kinoshita-07, Shimazaki and Taguchi (Exs.
`
`1011, 1023, 1026 and 1028, respectively). Unless stated otherwise, citations to
`
`these foreign-language references are being made herein to these English-language
`
`translations. Also, unless stated otherwise, citations to the non-patent references
`
`are being made herein to the page numbers in the bottom-lower corners in the
`
`exhibits, while citations to the patent references are being made herein to the page,
`
`column, paragraph and/or line numbers in the published documents.
`
`MTF Ex. 1008, p. 19
`
`
`
`XIII. UNPATENTABILITY OF CLAIMS 1, 2 AND 5-8 OF THE ‘701
`PATENT
`A. CLAIMS 1, 2 AND 5-8 ARE UNPATENTABLE OVER SHENAQ
`
`(1) CLAIM 1 IS ANTICIPATED BY SHENAQ
`
`42. For the reasons discussed below, it is my opinion that Shenaq
`
`anticipates the tissue graft recited in Claim 1.
`
`43. Shenaq, which I understand was not cited during the prosecution of
`
`the ‘701 Patent, discloses a fetal membrane tube for use as a nerve and vessel graft.
`
`Ex. 1009, 1:6-7. The graft of Shenaq is made from sheets of amnion and/or
`
`chorion. Id., 6:2-3. For instance, sheets of amnion are prepared by obtaining a
`
`suitable placenta and by separating the amnion from the chorion. Id., 7:1-2. Shenaq
`
`discloses that “[t]he cellular monolayer overlying the basal lamina on the fetal side
`
`of the membrane is removed, such as by exposure to trypsin”. Id., 7:9-11. See also
`
`Id., 4:26-28. A POSA would understand that the “cellular monolayer” mentioned
`
`in the foregoing disclosure of Shenaq refers to the epithelial layer of the amnion,
`
`while the “basal lamina” refers to the basement membrane. Accordingly, Shenaq
`
`teaches that the epithelial layer of the amnion is removed, exposing the basement
`
`membrane, which had been located below the epithelial layer. Shenaq also teaches
`
`that when chorion layers are used, the trypsin exposure step may be omitted. Id.,
`
`12:13-14.
`
`MTF Ex. 1008, p. 20
`
`
`
`44. According to Shenaq, sheets of amnion and/or chorion are wrapped in
`
`layers over a stainless steel stent to form a tube. Id., 4:23-5:2, 8:1-4, 12:7-14.
`
`Shenaq therefore teaches forming a tube made from (1) sheets of amnion, id. 7:28-
`
`36, (2) sheets of amnion and chorion, id., 4:25-5:2, and (3) sheets of chorion, id.,
`
`12:7-14.
`
`45. Shenaq discloses that in forming the tube, the amnion and/or chorion
`
`sheets are oriented such that the fetal surface is directed towards the inner surface
`
`of the finished tube. Id., 4:35-5:2, 7:34-36. Since the basement membrane is
`
`exposed due to the removal of the epithelial layer, the fetal surface described in the
`
`foregoing disclosure of Shenaq refers to the exposed basement membrane of the
`
`amnion. Accordingly, when the amnion and/or chorion sheets are wrapped over the
`
`stainless steel stent, the exposed basement membrane faces the stent, as illustrated
`
`in the following drawing.
`
`
`
`MTF Ex. 1008, p. 21
`
`
`
`46. Because amnion is the layer that faces the fetus, a POSA would
`
`understand that the amnion’s epithelial layer is the fetal surface. That is, a POSA
`
`would not consider chorion as having a “fetal surface”. Because the epithelial layer
`
`of the amnion in Shenaq is removed, the “fetal surface” referenced in Shenaq
`
`corresponds to the exposed basement membrane, as illustrated in the foregoing
`
`drawing. Accordingly, Shenaq teaches that the amnion layer (see the layer labeled
`
`“A” in the foregoing drawing) is the inner layer contacting the stent. The other
`
`sheet (i.e., a sheet of chorion or amnion, as indicated by Letter “B” in the foregoing
`
`drawing) is layered to the amnion layer A so as to be wrapped together with the
`
`amnion layer A around the stent to form the tube.
`
`47. The following drawing illustrates a tube formed by the process
`
`described in Shenaq (prior to the tube’s removal from the stent). As illustrated in
`
`the following drawing, the basement membrane of the innermost layer (labeled as
`
`“Amnion Membrane A”) in the finished tube defines the tube’s inner wall and is
`
`exposed to the tube’s inner passageway for interaction with the host cells. The
`
`other layer (labeled as “Chorion/Amnion Membrane B”) is layered to the opposite
`
`side (i.e., the fibroblast layer) of the innermost amnion layer A.
`
`MTF Ex. 1008, p. 22
`
`
`
`
`
`48. Shenaq teaches that after sheets of amnion and/or chorion are wrapped
`
`in layers on a stent, the tube is dried in 40-60ºC oven and then removed from the
`
`stent. Id., 8:11-14. Optionally, an adhesive or glue may be applied to hold the
`
`layers or wraps together. Id., 8:14-16.
`
`49. After being placed in a sealed bottle, the tube is exposed to gamma
`
`radiation and is stored at -20ºC until use. Id., 8:16-20.
`
`50. As discussed above, in addition to a graft tube formed by layers of
`
`amnion, Shenaq discloses a tube formed with layers of chorion (see, e.g., id., 12:7-
`
`14). Shenaq also teaches a graft formed with layers of amnion and chorion. For
`
`MTF Ex. 1008, p. 23
`
`
`
`instance, Shenaq teaches that “amnion and chorion layers are separated from the
`
`placenta and from each other . . . The amnion and chorion is [sic] rinsed
`
`repeatedly with phosphate buffer solution . . . 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” (emphasis added). Id., 4:24 – 5:2. In this
`
`disclosure, Shenaq teaches that a single tube is made by wrapping a sheet of
`
`amnion and a sheet of chorion in layers.
`
`51. Shenaq also teaches “a graft in which the layers of amnion and/or
`
`chorion membranes are glued together” (emphasis added), id., 6:1-4; and “a nerve
`
`graft comprised of an amniotic and/or chorionic tube” (emphasis added), id. 6:14-
`
`19. The foregoing disclosures teach a graft made with (1) layers of amnion only,
`
`(2) layers of chorion only and (3) at least one layer of amnion and at least one layer
`
`of chorion.
`
`52. As mentioned above, Shenaq teaches that “the amnion and chorion
`
`sheets are . . . wrapped in layers so that the fetal surface, which is shiny, is directed
`
`toward the inner surface of the finished tube”. Id., 4:35 – 5:2. Shenaq also teaches
`
`that “the fetal side or shiny side of the membrane is the inward side, which in the
`
`case of nerve grafts promotes axon growth”. Id., 4:20-22. As discussed above, the
`
`amnion is the inner layer of the placenta which faces the fetus, while the chorion is
`
`the outer layer which faces the mother. Be
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