DECISION Inter Partes 37 C.F.R. § 42.108 inter partes · Ex. 1001. The ’701 patent relates to...

[email protected] Paper No. 13 571.272.7822 Entered: August 18, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE ____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

____________

MUSCULOSKELETAL TRANSPLANT FOUNDATION, Petitioner,

v.

MIMEDX GROUP, INC., Patent Owner. ____________

Case IPR2015-00669 Patent 8,323,701 B2

____________ Before LORA M. GREEN, SUSAN L. C. MITCHELL, and CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION Denying Institution of Inter Partes Review

37 C.F.R. § 42.108

INTRODUCTION I.

Musculoskeletal Transplant Foundation (“Petitioner”) filed a

Corrected Petition requesting an inter partes review of claims 1, 2, and 5–8

of U.S. Patent No. 8,323,701 B2 (Ex. 1001, “the ’701 patent”). Paper 11

(“Pet.”). MiMedx Group, Inc. (“Patent Owner”) filed a Corrected

Preliminary Response to the Petition. Paper10 (“Prelim. Resp.”).

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We have jurisdiction under 35 U.S.C. § 314, which provides that an

inter partes review may not be instituted “unless . . . there is a reasonable

likelihood that the petitioner would prevail with respect to at least 1 of the

claims challenged in the petition.” 35 U.S.C. § 314(a). Upon considering

the Petition and the Preliminary Response, we determine that Petitioner has

not shown a reasonable likelihood that it would prevail in showing the

unpatentability of claims 1, 2, and 5–8. Accordingly, we decline to institute

an inter partes review of those claims.

A. Related Proceedings

Petitioner and Patent Owner state that the ’701 patent is the subject of

the copending district court case, MiMedx Group, Inc. v. Liventa Bioscience,

Inc. et al., Case No. 1:14-CV-1178-MHC (N. D. Ga.). Paper 7, 1; Pet. 1.

Petitioner also filed a petition for inter partes review of 8,372,437 B2

against Patent Owner in IPR2015-00664. Additionally, inter partes review

has been requested by a different Petitioner for related patents in IPR2015-

003201 (U.S. Patent No. 8,709,494 B2) and IPR2015-004202 (U.S. Patent

No. 8,597,687 B2).

B. The ’701 Patent (Ex. 1001)

The ’701 patent issued on December 4, 2012, with John Daniel,

Robert Tofe, Randall Spencer, and John Russo, listed as co-inventors.

Ex. 1001. The ’701 patent relates to tissue grafts derived from placenta,

wherein the grafts “are composed of at least one layer of amnion tissue

1 Institution of inter partes review was denied in this proceeding on June 29, 2015 (Paper 13). 2 Inter partes review was instituted in this proceeding on July 10, 2014 (Paper 11).

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where the epithelium layer has been substantially removed in order to

expose the basement layer to host cells.” Id. at 1:64–67.

According to the ’701 patent, in order to prepare the implant,

placental tissue is collected from a hospital. Id. at 3:46–47. The placenta is

removed from the sterile shipment bag and transferred to a sterile processing

basin preferably containing hyperisotonic saline (18% NaCl) solution at

close to room temperature. Id. at 4:48–52. The placenta is gently massaged

to help separate blood clots, allowed to reach room temperature to ease the

separation of the amnion from the chorion, and then placed on a processing

tray with the amniotic membrane layer facing down. Id. at 4:52–60. The

amnion is then separated from the chorion. Id. at 5:6–9.

The amnion is then placed into a processing tray with the fibroblast

layer down, and any residual blood is removed using a blunt instrument, a

cell scraper, or sterile gauze. Id. at 5:13–15. Care has to be taken in

cleaning the amnion tissue, because if the tissue is cleaned too aggressively,

the jelly-like fibroblast layer can be removed. Id. at 5:19–21. Thus, amnion

that appears to be clear “will be unacceptable and will ultimately be

discarded.” Id. at 5:21–23.

The epithelial layer on the amnion is then substantially removed in

order to expose the basement membrane. Id. at 5:25–26. As taught by the

’701 patent, “substantially removed” is defined as the removal of more than

90 to 99% of the cells. Id. at 5:25–31. The ’701 patent teaches:

The epithelium layer can be removed by techniques known in the art. For example, the epithelium layer can be scraped off of the amnion using a cell scraper. Other techniques include, but are not limited to, freezing the membrane, physical removal using a cell scraper, or exposing

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the epithelial cells to nonionic detergents, anionic detergents, and nucleases.

Id. at 5:41–46.

After removal of the epithelial layer, the graft is prepared. Id. at 6:62–

63. A layer of amnion is placed on a drying fixture with the exposed

basement membrane being adjacent to the surface of the drying fixture. Id.

at 6:62–66. Additional layers can then be applied to the base amnion layer

to produce the tissue graft. Id. at 7:50–53. With the amnion placed on the

drying fixture with the basement membrane side towards the drying fixture,

the fibrous layer of the amnion acts as an adhesive for the next layer. Id. at

7:55–61. According to the ’701 patent, the multilayer grafts “are thicker and

stronger than a single layer of base amnion.” Id. at 8:41–42.

Once the desired tissue graft is on the drying fixture, the drying

fixture is placed in a dehydration bag, sealed, and placed in a drying oven at

35 to 50 degrees Celsius for 30 to 120 minutes. Id. at 8:53– 9:2. The ideal

drying conditions, however, appear to be at 45 degrees Celsius for 45

minutes. Id. at 9:2–4. Once the tissue is dehydrated, it can be cut into

specific product sizes, and each cut allograft is placed into its own pouch.

Id. at 9:48–51.

C. Illustrative Claim

Petitioner challenges claims 1, 2, and 5–8 of the ’701 patent. Claim 1

is the only independent claim, is illustrative, and is reproduced below:

1. A tissue graft consisting of:

a first membrane comprising modified amnion wherein the modified amnion has a first side which is an exposed basement membrane and a second side which is an exposed jelly-like fibroblast cellular layer; and

one or more additional membranes sequentially layered such

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that the first additional membrane is layered adjacent to the exposed fibroblast layer of the first membrane;

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.

D. The Asserted Grounds of Unpatentability

Petitioner challenges the patentability of claims 1, 2, and 5–8 of the

’701 patent on the following grounds:

References Basis Claims Challenged

Shenaq3 § 102(b) 1, 2, and 5–8

Shenaq, Ishino,4 Kinoshita-06,5 or Kinishito-076

§ 103(a) 1, 2, and 5–8

Shenaq, Dua,7 or Shimazaki8 § 103(a) 1, 2, and 5–8

Tseng,9 Ishino, Kinoshita-06, or Kinoshito-07

§ 103(a) 1, 2, and 5–8

3 Saleh M. Shenaq and Kathy Jo Gray, (“Shenaq”), Pub. No. WO 93/10722, published Jun. 10, 1993 (Ex. 1009). The “Shenaq” reference was identified as “Gray” in IPR2015-00320. IPR2015-00320, Paper 13, 5. 4 Ishino et al. (“Ishino”), Amniotic Membrane as a Carrier for Cultivated Human Corneal Endothelial Cell Transplantation, 45 INVESTIGATIVE

OPHTHALMOLOGY & VISUAL SCIENCE 800–806 (2004) (Ex. 1025). 5 Kinoshita et al. (“Kinoshita-06”), Pub. No. US 2006/0153928 A1, published Jul. 13, 2006 (Ex. 1022). 6 Kinoshita et al. (“Kinoshita-07”), WO 2007/013331 A1, published Jul. 19, 2006 (Ex. 1024). Note that Ex. 1024 is the English language translation of Ex. 1023. 7 Dua et al. (“Dua”), WO 2007/010305 A2, published Jan. 25, 2007 (Ex. 1034). 8 Shimazaki et al. (“Shimazaki”), JP 2001-0161353, published June 19, 2001 (Ex. 1027). Note that Ex. 1027 is the English language translation of Ex. 1026. 9 Tseng, U.S. Patent No. 6,152,142, issued Nov. 28, 2000 (Ex. 1010).

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References Basis Claims Challenged

Ishino, Kinoshita-06 or Kinoshito-07, Sulner,10 or Shenaq

§ 103(a) 5

Wei,11 Tseng, Sulner, or Shenaq

§ 103(a) 1, 2, and 5–8

Sulner § 102(e) 1, 2, and 5–8

ANALYSIS II.

A. Claim Construction

In an inter partes review, claim terms in an unexpired patent are

interpreted according to their broadest reasonable constructions in light of

the specification of the patent in which they appear. See 37 C.F.R.

§42.100(b); In re Cuozzo Speed Techs., LLC, No. 2014–1301, 2015 WL

2097949, at *5–*8 (Fed. Cir. July 8, 2015). Under that standard, and absent

any special definitions, we give claim terms their ordinary and customary

meaning, as would be understood by one of ordinary skill in the art at the

time of the invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257

(Fed. Cir. 2007). Any special definitions for claim terms must be set forth

with reasonable clarity, deliberateness, and precision. See In re Paulsen, 30

F.3d 1475, 1480 (Fed. Cir. 1994).

i. “a second side which is an exposed jelly-like fibroblast cellular layer”

Petitioner contends the “exposed jelly-like fibroblast cellular layer”

should be construed as including “an identifiable region of fibroblast cells.”

10 Sulner et al. (“Sulner”), Pub. No. US 2007/0038298 A1, published Feb. 15, 2007 (Ex. 1013). 11 Wei, CN 1757717 A, published Jul. 12, 2005 (Ex. 1012). Note that Ex. 1021 is the English language translation of Ex. 1011.

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Pet. 4. Patent Owner responds that Petitioner is reading the term “layer” out

of the claim, and replacing it with “two or more cells.” Prelim. Resp. 9.

Patent Owner contends that the claim phrase should be construed as

requiring that there be fibroblast cellular layer that “constitute[s] a sufficient

amount of fibroblast cells to form a fibroblast cellular layer (or a

recognizable cellular region) underlying the compact tissue layer of the

amnion.” Id.

We note that the language of claim 1 itself requires “a first membrane

comprising modified amnion wherein the modified amnion has a . . . second

side which is an exposed jelly-like fibroblast cellular layer.” Thus, the

“second side” “is” an “exposed jelly-like cellular layer.” The plain language

of the claim, therefore, requires the second side and the fibroblast layer to be

coextensive with the first side of the modified amnion. That does not mean,

however, that there cannot be some loss of cells during the method of

producing the graft, as long as the second side of the modified amnion has a

sufficient amount of fibroblast cells to constitute a fibroblast layer that

covers the second side of the modified amnion as required by the claim.

Thus, for purposes of this decision, we construe the claim language “a

first membrane comprising modified amnion wherein the modified amnion

has a . . . second side which is an exposed jelly-like fibroblast cellular layer”

as requiring a sufficient amount of fibroblast cells to constitute a fibroblast

layer, wherein the layer is coextensive with the first side of the modified

amnion.

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ii. All Remaining Terms

We determine that, for purposes of this Decision, none of the other

terms in the challenged claims requires express construction at this time.

B. Principles of Law

In order for a prior art reference to serve as an anticipatory reference,

it must disclose every limitation of the claimed invention, either explicitly or

inherently. In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997). We must

analyze prior art references as a skilled artisan would. See Scripps Clinic &

Res. Found. v. Genentech, Inc., 927 F.2d 1565, 1576 (Fed. Cir. 1991)

(stating that to anticipate, “[t]here must be no difference between the

claimed invention and the reference disclosure, as viewed by a person of

ordinary skill in the field of the invention”), overruled on other grounds by

Abbott Labs. v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009). “Inherency,

however, may not be established by probabilities or possibilities. The mere

fact that a certain thing may result from a given set of circumstances is not

sufficient.” In re Oelrich, 666 F.2d 578, 581 (CCPA 1981) (emphasis

added) (citation omitted).

A claim is unpatentable under 35 U.S.C. § 103(a) if the differences

between the subject matter sought to be patented and the prior art are such

that the subject matter as a whole would have been obvious at the time the

invention was made to a person having ordinary skill in the art to which said

subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406

(2007). The question of obviousness is resolved on the basis of underlying

factual determinations including: (1) the scope and content of the prior art;

(2) any differences between the claimed subject matter and the prior art;

(3) the level of ordinary skill in the art; and (4) objective evidence of

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nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). An

invention “composed of several elements is not proved obvious merely by

demonstrating that each of its elements was, independently, known in the

prior art.” KSR, 550 U.S. at 418. Moreover, a determination of

unpatentability on the ground of obviousness must include “articulated

reasoning with some rational underpinning to support the legal conclusion of

obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The

obviousness analysis “should be made explicit” and it “can be important to

identify a reason that would have prompted a person of ordinary skill in the

relevant field to combine the elements in the way the claimed new invention

does.” KSR, 550 U.S. at 418.

C. Anticipation by Shenaq (Ex. 1009)

Petitioner asserts that claims 1, 2, and 5–8 are anticipated by Shenaq.

Pet. 9–25.

i. Overview of Shenaq (Ex. 1009)

Shenaq is drawn to “fetal membrane tubes for nerve and vessel

grafts.” Ex. 1009, 1:6–7. Shenaq teaches that “[i]mmunological testing of

the amniotic and chorionic nerve conduits of the . . . invention showed a

minimal, nonsignificant immune response, thus, avoiding some of the

inhibiting factors that could influence the regenerating nerve.” Id. at 3:5–9.

Thus, Shenaq teaches that the amniotic and chorionic tubes of the invention

are non-immunogenic. Id. at 4:5–6.

As taught by Shenaq, the grafts are prepared by obtaining amnion and

chorion from fresh placentas. Id. at 4:23–24. According to Shenaq:

the amnion and chorion layers are separated from the placenta and each other, cellular monolayer material overlying the basal lamina on the fetal side of the membrane is removed, such as by exposure to trypsin or pepsin, the amnion and chorion is rinsed

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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, strengthens and permits remodeling the material from sheet to conduit form. 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. The number of wraps will depend upon the length and diameter of the tube. The tubes are then dried and placed in bottles which are sealed, labeled and, if desired, exposed to 2.5 M rads of gamma radiation to again sterilize and further cross-link the conduit collagen. If desired, the layers can be glued together by a suitable glue, such as a fibrin glue, to prevent delaminating, particularly in larger conduits, such as used for vascular grafts.

Id. at 4:25–5:9.

Shenaq teaches that it is also an object of the invention to provide a

graft that comprises a cylindrical wall formed by sheets of sterilized

collagen, Types I, II, and III, derived from human placenta from which the

cellular material has been substantially removed. Id. at 5:23–29.

As taught by Shenaq:

The amnion layer is separated from the placenta, such as by finger dissection. The largest possible pieces of amnion which are of uniform thickness are selected from all the amnion harvested. 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.

The cellular monolayer overlying the basal lamina on the fetal side of the membrane is removed, such as by exposure to trypsin. Membranes are immersed for two hours at room temperature in 1:1 solution of distilled water and trypsin. The trypsin used preferably is from the procine pancreas at a 25% concentration without calcium or magnesium. Following treatment with trypsin, the amnion is rinsed repeatedly,

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preferably with phosphate buffered saline, or with distilled water until clean, white membranes with no trace of pink trypsin are obtained.

Rinsed amnion sheets are bottled in distilled water and exposed to 500,000 rads of gamma radiation. Irradiating the amnion cross-links the collagen, sterilizes the tissue, provides animal protection against viral disease transmission and subsequent remodeling of the material from sheet to conduit or tubular form. The bottles are then stored in a freezer at -80°C. If desired, the amnion sheets may be crosslinked chemically such as with glutaraldehyde.

Id. at 7:1–26.

ii. Analysis

Petitioner asserts that claims 1, 2, and 5–8 are unpatentable as being

anticipated by Shenaq. Pet. 9–25. Petitioner relies on the Declaration of

Dr. Helen N. Jones (Ex. 1008) to support its anticipation challenge, as well

as providing a claim chart. Patent Owner disagrees. Prelim. Resp. 14–24.

Specifically, as to the issue of whether the grafts of Shenaq retain an

exposed jelly-like fibroblast cellular layer, which Petitioner refers to as

element C (Pet. 3), Petitioner argues that Shenaq does not disclose or

suggest removing the fibroblast layer. Pet. 13. In particular, relying on the

Declaration of Dr. Jones, Petitioner argues that Shenaq does not teach or

suggest that any tissue layers are removed during the finger dissection that is

used to separate the chorion from the amnion, and also does not teach any

subsequent processing steps that would result in the fibroblast layer being

removed from the amnion, thus, “the fibroblast layer must remain in the

final amnion.” Id. (citing Ex. 1008 ¶ 66).

Petitioner notes that Shenaq teaches a trypsin/pepsin step, but

contends that treatment step is intended to remove epithelial cells, and that it

“would not remove all, or even a majority, of the fibroblast cells from the

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fibroblast layer.” Id. at 17–18 (citing Ex. 1008 ¶ 75). Thus, Petitioner

asserts, the “amnion disclosed in Shenaq would inherently retain most, or

substantially all, of its native fibroblast cells and be therefore ‘cellular.’” Id.

at 17. Petitioner relies on Toda12 and Ishino (Ex. 1025) to demonstrate that

without performing a mechanical scraping process, which would be required

to remove the fibroblast layer, the fibroblast cells would be retained in the

fibroblast layer. Id. at 18. Specifically, according to Petitioner, Toda (Ex.

1039, 4, 11) demonstrates removing the epithelial layer using trypsin alone,

and Ishino (Ex. 1025, 213) demonstrates removing the epithelial layer using

EDTA alone. Pet. 18–19 (citing Ex. 1008 ¶¶ 77–82).

As to Shenaq’s teaching that it is an object of the invention to provide

a graft that comprises a cylindrical wall formed by sheets of sterilized

collagen, Types I, II, and III, derived from human placenta from which the

cellular material has been substantially removed (Ex. 1009, 5:23–29),

Petitioner asserts that it is merely an alternative embodiment, and does “not

affect the cell-retaining features of the embodiments taught in Shenaq

(described above).” Pet. 21 (citing Ex. 1008 ¶¶ 86, 89).

Patent Owner responds that Petitioner has not demonstrated that

“Shenaq discloses a tissue graft that has an exposed jelly-like fibroblast

cellular layer as required by the challenged claims.” Prelim. Resp. 15.

Specifically, Patent Owner contends that Shenaq advocates for

12 Toda et al. (“Toda”), The Potential of Amniotic Membrane/Amnion-Derived Cells for Regeneration of Various Tissues, 105 J. PHARMACOL. SCI. 215–228 (2007) (Ex. 1039). The page numbers refer to the page numbers added by Petitioner at the bottom of the pages of the reference (e.g. “MTF Ex. 1039, pg. 4”). 13 The page numbers refer to the page numbers added by Petitioner at the bottom of the pages of the reference (e.g. “MTF Ex. 1025, pg. 4”).

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decellularization, which would result in removal of the fibroblast cell layer.

Id. at 15–16. Patent Owner argues that Shenaq teaches that “the collagen

tubes of the invention are processed so that ‘cellular material is substantially

removed,’ as well as the purported benefits of substantial removal.” Id. at 16

(citing Ex. 1009, 5:23–35). Thus, Patent Owner contends, “because the goal

of Shenaq is creation of an immunogenic cell-free collagenous tube, Shenaq

requires removal of the jelly-like fibroblast cellular layer.” Id. at 18.

We agree with Patent Owner that Petitioner has not established a

reasonable likelihood that claims 1, 2, and 5–8 are anticipated by Shenaq.

Notably, we agree with Patent Owner that Shenaq teaches a graft comprising

sheets of sterilized collagen, Types I, II, and III, derived from human

placenta, and from which the cellular material has been substantially

removed. Ex. 1009, 5:23–29.

In that regard, Petitioner does not point us to any teaching in Shenaq

that specifies that the fibroblast cell layer is nonetheless retained in the

placental graft. Thus, while Petitioner asserts that Shenaq’s teaching that the

cellular material is substantially removed merely refers to an alternative

embodiment, it points us to no other teaching in Shenaq that would support a

process in which the fibroblast cellular layer is not removed.

We have also considered the disclosures of Ishino and Toda, as well

as the Declaration of Dr. Jones, but they do not convince us otherwise.

Petitioner relies on the Declaration of Dr. Jones to support its assertion that

the use of trypsin or pepsin will not remove the fibroblast cell layer.

Pet. 17–18 (citing Ex. 1008 ¶¶ 75–76). Dr. Jones, however, provides the

conclusory statement that it is her opinion that “it is not feasible to use

trypsin or pepsin alone to decellularize the fibroblast layer,” as the ordinary

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artisan would understand that the extracellular matrix of that layer would

have to disrupted by mechanical means. Ex. 1008 ¶ 77. Because Dr. Jones

does not point to any supporting evidence for that statement, it is entitled to

little weight. 37 C.F.R. § 42.65(a). In that regard we note that Kinoshito-07,

relied upon by Petitioner and discussed more in depth below, uses a frame

and only exposes the epithelial side of the amnion to trypsin to prevent the

trypsin from affecting the stratum compactum and the basal membrane of

the amnion. Ex. 1024 ¶¶ 55, 133. Petitioner notes that the ordinary artisan

would understand the term “stratum compactum” to include the fibroblast

layer, as well as the compact layer. Pet. 31 (citing Ex. 1008 ¶ 126). Neither

Petitioner nor its expert explains the reason that Kinoshito-07 takes such

care in only exposing the epithelial side of the amnion to trypsin if the

ordinary artisan would understand that trypsin would not affect the fibroblast

layer.

Petitioner appears also to be relying on Ishino and Toda to

demonstrate that the use of trypsin in Shenaq would inherently leave the

fibroblast layer intact. Petitioner, however, does not compare the methods

used in Toda and Shenaq specifically to the method of Shenaq, such as the

concentration and amount of agent used to remove the epithelial layer, the

amount of time the amnion is treated, etc. Moreover, Petitioner does not

account for the additional steps used by Shenaq, such as the use of gamma

irradiation and the potential use of a chemical crosslinker such as

glutaraldehyde on the fibroblast cellular layer. Thus, even if the protocols of

Ishino or Toda, which use trypsin or EDTA, may not affect the fibroblast

cellular layer, such teaching fails to demonstrate that treatment with trypsin

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using the protocol taught by Shenaq would necessarily leave the fibroblast

cellular layer unaffected.

iii. Conclusion

For the reasons set forth above, we conclude that Petitioner has not

established a reasonable likelihood that claims 1, 2, and 5–8 are anticipated

by Shenaq.

D. Obviousness over the Combination of Shenaq (Ex. 1009) with Ishino (Ex. 1025), Kinoshita-06 (Ex. 1022), or Kinishito-07 (Ex. 1024)

Petitioner contends that claims 1, 2, and 5–8 are unpatentable as

obvious over the combination of Shenaq with Ishino, Kinoshita-06, or

Kinishito-07. Pet. 25–32.

i. Overview of Ishino (Ex. 1025)

Ishino is drawn to using amniotic membrane (“AM”) as a carrier for

corneal endothelial cells. Ex. 1025, Abstract. Ishino teaches a method of

removing epithelial cells from the amniotic membrane. Id. at 801.

Specifically, Ishino teaches:

Briefly, human AM was stored at –80°C in DMEM and glycerol (Nacalai Tesque, Kyoto, Japan) after the AM was washed with PBS containing antibiotics (5 mL of 0.3% ofloxacin). Immediately before use, the thawed AM was deprived of amniotic epithelial cells by incubation with 0.02% EDTA (Wako Pure Chemical Industries, Osaka, Japan) at 37°C for 2 hours, followed by gentle cell scraping with a cell scraper (Nalge Nunc International, Naperville, IL). The tissues were then washed twice with sterile PBS.

Id.

ii. Overview of Kinoshita-06 (Ex. 1022)

Kinishota-06 is drawn to an amnion-origin medical material that is

prepared by removing the epithelial layer from the amnion while retaining at

least a part of the basement membrane thereof. Ex. 1022, Abstract. The

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material is then dried in a way that slows the remaining basement membrane

to sustain a structure allowing the adhesion and proliferation of cells

thereon. Id.

Specifically, Kinishito-06 teaches:

In the step (i), an epithelial layer is removed. At this time, however, basement membrane is not removed together and at least a part of the basement membrane is allowed to remain. Such a process is carried out by denuding an epithelial layer with the use of a cell scraper, forceps, etc. Preferably, the adhesion between cells constituting the epithelia layer is loosen[ed] by using EDTA, proteolytic enzyme, and the like, in advance, and then the epithelial layer is denuded with the use of a cell scraper, etc. However, it is preferable that such a pre-process (process using EDTA, etc.) is carried out under conditions where the structure of the basement membrane involved in the adhesion of epithelial layer with respect to a stromal layer is not destroyed. For example, if [the] process is carried out using dispase under the general conditions (for example, dispase is added so that the concentration becomes 1.2 IU and reaction is carried out at 37° C. for one hour), not only an epithelial layer but also basement membrane are considerably damaged. When such a pre-processing is carried out, basement membrane holding the original function cannot be allowed to remain. An important point of the step (i) in the present invention is in that an epithelial layer is completely removed while a basement membrane is allowed to remain in a state in which at least a part of the basement membrane is allowed to remain with the original function thereof maintained. For example, when the pre-process is carried out with the use of EDTA (for example, EDTA is added so that the concentration becomes 0.02% to 0.1 % and reaction is carried out at 4° C. to 37° C. for one hour to four hours), the effect on the basement membrane is extremely small.

Id. ¶ 67.

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iii. Overview of Kinoshita-07 (Ex. 1024)

Kinishito-07 is drawn to a method of producing a sheet-like

composition using an amnion, which can be used “as a culture substrate for

producing artificial tissue (such as corneal epithelium), as a graft material

for reconstructing ocular surfaces and skin, and as an adhesion-preventing

material.” Ex. 1024 ¶ 1. Kinishito-07 teaches that an amnion with intact

components from the stratum compactum (Collagen I, III, V, and

Fibronectin) is preferable. Id. ¶ 32.

Kinishito-07 teaches a method of preparing an amnion with its

epithelium removed. Id. ¶ 129. Amnion is harvested; and blood

components are removed, as is the chorionic membrane. Id. ¶¶ 129–130.

The amnion is mounted on a sterilized film of fluorocarbon resin with the

epithelial side upward, and clips are used “to secure the sheet of

fluorocarbon resin to the frame of fluorocarbon resin, clamping the amnion

between the fluorocarbon resin sheet and the fluorocarbon resin frame

(securing of the frame).” Id. ¶ 131. The use of the frame allows only the

epithelial side of the amnion to be immersed in a trypsin solution, which aids

in preventing the trypsin from affecting the stratum compactum and the

basal membrane of the amnion. Id. ¶¶ 55, 133. Using this method, the

epithelium is completely removed, and no damage was observed in the

stratum compactum. Id. ¶ 137.

iv. Analysis


rendered obvious by the combination of Shenaq, Ishino, Kinoshita-06, or

Kinishito-07. Pet. 24–32. Petitioner relies on the Declaration of Dr. Jones

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(Ex. 1008) to support its obviousness challenge. Patent Owner disagrees.

Prelim. Resp. 25–32.

Petitioner relies on Shenaq as set forth above. Pet. 25. Petitioner then

relies on Ishino for disclosing a method of removing the epithelium from the

separated amnion layer. Id. at 25–26. Petitioner contends that the ordinary

artisan would have understood that the amnion of Shenaq could be de-

epithelialized by using the protocol of Ishino that requires EDTA, which

would result in an amniotic membrane that has its basement membrane

completely exposed, but retains fibroblast cells in the fibroblast layer. Id. at

26–27 (citing Ex. 1008 ¶¶ 107–108).

As noted by Patent Owner, however, Shenaq teaches decellularization

of the amniotic graft, and neither Petitioner nor Petitioner’s declarant

provides any reason to support whether the ordinary artisan could produce

the graft of Shenaq with it fibroblast cellular layer substantially intact, nor

has Petitioner nr Petitioner’s declarant provide any reason as to why the

ordinary artisan would leave the fibroblast cellular layer substantially intact.


As for the combination with Kinishito-06, Petitioner contends it

would have been obvious to the ordinary artisan to use a mechanical means

as taught by Kishinito-06, to remove the epithelial layer from the amnion of

Shenaq. Pet. 28. Moreover, Petitioner argues that even if the

chemical/enzymatic process of Kishinito-06 is used to remove the epithelial

layer from the amnion of Shenaq, the fibroblast layer would still contain

fibroblast cells. Id. at 28–29. The challenge based on Shenaq and

Kinoshita-06, however, suffers from the same deficiency as the combination

based on Shenaq and Ishino, set forth above. That is, neither Petitioner nor

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19

Petitioner’s declarant provides any reason to support whether the ordinary

artisan could produce the graft of Shenaq with it fibroblast cellular layer

substantially intact, or why the ordinary artsisan would produce the graft of

Shenaq with it fibroblast cellular layer substantially intact.

Finally, Petitioner relies on Kinishito-07 for essentially the same

teachings for which it relied on Ishino or Kinishito-06. Pet. 30–32. Thus,

that challenge also suffers from the same deficiency as the combination

based on Shenaq and Ishino or the combination based on Shenaq and

Kinishito-07.

v. Conclusion


established a reasonable likelihood that claims 1, 2, and 5–8 are rendered

obvious by the combination of Shenaq with Ishino, Kinoshita-06, or

Kinishito-07.

E. Obviousness over the Combination of Shenaq (Ex. 1009) with Dua (Ex. 1034), or Shimazaki (Ex. 1027)


obvious over the combination of Shenaq with Dua, or Shimazaki. Pet. 32–

34.

i. Overview if Dua (Ex. 1034)

Dua is drawn to the use of amniotic membrane to produce a growth

factor free amniotic membrane. Ex. 1034, 1:2–3. The membrane is

produced by isolating amniochorionic membrane from placenta, and then

removing the chorion membrane and spongy layer to produce the

substantially growth factor free amniotic membrane. Id. at 3:19–24.

According to Dua, other methods do not remove the spongy layer, and

therefore, “suffer the problem that they contain undefined, high

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20

concentrations of various growth factors, such as TGFβ, and therefore cause

excessive scarring when use[d] to treat wounds in patients.” Id. at 4:3–6.

ii. Overview of Shimazaki (Ex. 1027)

Shimazaki is drawn to “a cell sheet for transplantation in which

corneal epithelial cells have been cultured and proliferated on amnion.” Ex.

1027 ¶ 1. According to Shimazaki, the

amnion typically has a sponge layer, a compact layer, a basement membrane layer, and an epithelial layer, in sequence from the bottom. However, with the “amnion” used in the cell sheet for transplantation, the sponge layer and epithelial layer are not necessary, and so material may be used that has been treated to remove these layers.

Id. ¶ 23.

iii. Analysis


rendered obvious by the combination of Shenaq, Dua, or Shimazaki. Pet.

32–34. Petitioner relies on the Declaration of Dr. Jones (Ex. 1008) to

support its obviousness challenge. Patent Owner disagrees. Prelim. Resp.

32–37.

Petitioner contends that to the extent that Shenaq does not disclose “a

fibroblast cellular layer that is ‘exposed,’” Dua and Shimazaki teach

methods of removing the spongy layer. Pet. 32–34. Neither Dua nor

Shimazaki, however, remedies the deficiency of Shenaq as set forth in the

anticipation rejection. That is, neither Dua nor Shimazaki provides any

reason to support whether the ordinary artisan could produce the graft of

Shenaq with its fibroblast cellular layer substantially intact., nor any reason

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21

why the ordinary artisan would produce the graft of Shenaq with its

fibroblast cellular layer substantially intact

iv. Conclusion



obvious by the combination of Shenaq with Dua-, or Shimazaki.

F. Obviousness over Tseng, Ishino (Ex. 1025), Konishito-06 (Ex. 1022), or Kinoshito-07 (Ex. 1024)


obvious over the combination of Tseng with Ishino, Konishito-06, or

Kinoshito-07. Pet. 34–45.

i. Overview of Tseng (Ex. 1010)

Tseng is drawn to “amniotic membrane grafts especially usable in the

repair of injured eyes.” Ex. 1010, 1:14–15. Tseng teaches that the amnion

is histologically composed of five layers. Id. at 3:49. According to Tseng,

the “avascular stromal contains fetal mesenchyme and includes the compact

layer, fibroblastic layer and spongy layer. Id. at 3:51–53.

In preparing the graft of Tseng, the placenta is rinsed with balanced

saline, which preferably contains antibiotics, to remove excessive blood

clots. Id. at 4:60–65. While immersed in the solution, the amnion is

separated from the chorion by blunt dissection. Id. at 5:8–10. The separated

amniotic sheet is then mounted on a substrate, such as a sterile nitrocellulose

paper, such that the epithelial surface is kept facing up, and the

stromal/fibroblastic surface is layered on the substrate. Id. at 5:12–14.

According to Tseng, when used as a surgical graft to treat ulceration of the

eye, the amniotic membrane is peeled off the substrate. Id. at 6:16–31.

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22

Tseng teaches further that one layer is generally sufficient, but that “it is also

feasible to use two or more layers.” Id. at 6:38–39.

ii. Analysis


rendered obvious by the combination of Tseng with Ishino, Konishito-06, or

Kinoshito-07. Pet. 34–45. Petitioner relies on the Declaration of Dr. Jones

(Ex. 1008) to support its obviousness challenge. Patent Owner disagrees.


Specifically, as to the limitation that the graft has a modified amnion

wherein the modified amnion has a side which is an exposed jelly-like

fibroblast cellular layer, Petitioner contends that Tseng teaches that the

stromal/fibroblastic layer lies on the filter. Pet. 35 (citing Ex. 1010, 5:15–

16). Petitioner reasons:

Since Tseng specifically recognizes that “[t]he avascular stromal . . . includes the compact layer, fibroblastic layer and spongy layer” (emphasis added), id., 3:51–53, but explicitly teaches that the fibroblast layer lies on (i.e., in contact with) the filter, the spongy layer must have been removed during the amnion/chorion separation process so as to expose the fibroblast layer (otherwise, the fibroblast layer cannot lie on the filter paper). Ex. 1008 ¶144. Accordingly, Tseng discloses modified amnion having an exposed fibroblast layer. Id.

Id. at 35–36.

Petitioner relies on each of Ishino, Konishito-06, or Kinoshito-07 for

teaching methods of exposing the basement membrane. Id. at 39–44.

Patent Owner contends that the combination of Tseng with any one of

Ishino, Konishito-06, or Kinoshito-07 fails to teach or suggest a graft having

modified amnion wherein the modified amnion has a side which is an

exposed jelly-like fibroblast cellular layer. Prelim. Resp. 40. Specifically,

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23

Patent Owner argues that Tseng defines the spongy layer as being part of the

stromal layer. Id. at 41–42 (citing Ex. 1010, 3:51–53). Thus, when Tseng

teaches that the stromal/fibroblastic layer is in contact with the filter, that

layer includes the spongy layer. Id. at 42 (citing Ex. 1010, 5:14–15). Patent

argues further that Tseng does not provide any disclosure of specifically

removing the spongy layer. Id.

We agree with Patent Owner that Petitioner has not demonstrated a

reasonable likelihood that the combination of Tseng, Ishino, Konishito-06,

or Kinoshito-07 renders the challenged claims obvious. In particular, Tseng

does not teach that the amniotic membrane is placed on the filter with the

fibroblast layer down, but with the stromal/fibroblastic side down. Ex. 1010,

5:12–15. Given Tseng’s teaching that the stromal layer includes the spongy

layer (Ex. 1010, 3:51–53), as well as the lack of any teaching in Tseng that

the spongy later is removed, we agree with Patent Owner that the ordinary

artisan would not have understood Tseng as teaching that the

stromal/fibroblastic layer of the amniotic membrane has the spongy layer

removed to expose the fibroblast layer.

iii. Conclusion



obvious by the combination of Tseng with Ishino, Konishito-06, or

Kinoshito-07.

G. Obviousness over the Combination of Tseng (Ex. 1010), Ishino (Ex. 1025), Kinoshita-06 (Ex. 1022), Kinoshito-07 (Ex. 1024),

Sulner (Ex. 1013), or Shenaq (Ex. 1009)

Petitioner contends that claim 5 is unpatentable as obvious over the

combination of Tseng with Ishino, Kinoshita-06, Kinoshito-07, Sulner, or

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24

Shenaq. Pet. 45–48. Petitioner relies on the Declaration of Dr. Jones (Ex.

1008) to support its obviousness challenge. Patent Owner disagrees.


Petitioner relies on Sulner and Shenaq for teaching the claim 5

limitation of “a chorion layer layered to the first membrane adjacent to the

exposed jelly-like fibroblast cellular layer.” Pet. 45. Thus, as Petitioner

does not rely on Sulner and Shenaq to remedy the deficiency of the

combination of Tseng, Ishino, Konishito-06, or Kinoshito-07, as discussed

above, Petitioner has not established a reasonable likelihood that claim 5 is

rendered obvious by the combination of Tseng with Ishino, Kinoshita-06 or

Kinoshito-07, Sulner, or Shenaq.

H. Obviousness over the Combination of Wei (Ex. 1012), Tseng (Ex. 1010), Sulner (Ex. 1013), or Shenaq (Ex. 1009)


obvious over the combination of Wei with Tseng, Sulner, or Shenaq. Pet.

48–56.

i. Overview of Wei (Ex. 1012)

Wei is drawn to “a cell free dried active amnion that can be preserved

for a long term.” Ex. 1012, 4.14 In the method of Wei, placenta is obtained,

and is sterilized. Id. at 5–6. Wei teaches:

Isolate the amnion from chorion, scraping off the spongy layer as much as possible with the side surface of a razor blade or glass slide, spreading and then fixing the amnion on a nitrocellulose paper (provided by Bio-Tissue) with its epithelial side facing upward, cutting the nitrocellulose paper fixed with the amnion into a suitable size; next incubating at 37°C for 1/2

14 The page numbers refer to the numbered pages of the exhibit found at the bottom of the page (e.g. “MTF Ex. 1012, pg. 4”).

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25

to 4 hours in a mixed solution containing 0.05 to 0.5% trypsin and 0.01 to 0.1% EDTA, a solution containing 0.05 to 0.5% trypsin, or a solution containing 0.01 to 0.1% EDTA, removing epithelial cells with a cell scraper or a cotton swab, washing with a normal saline repeatedly, confirming under a microscope that the epithelial side has no cell; then placing into a freeze dryer, freeze drying it along with the nitrocellulose paper in vacuo, vacuum packaging at room temperature, and finally irradiating with gamma ray; and taking sample from each batch of product for bacterial culture.

The amnion obtained according to the method described above appears like a bamboo paper. It is translucent with a thickness of about 20 microns. After rehydration it has desirable performance in the resistances to tension and shear force. The rehydrated product has an increased transparency than that of the dried product.

Id. at 6.

According to Wei, the method removes the cells from the amnion,

greatly reducing its antigenicity, but retains the “effective substrate active

components.” Id.

ii. Analysis

Petitioner asserts that claims 1, 2, and 5–8 are unpatentable as obvious

over the combination of Wei with Tseng, Sulner, or Shenaq. Pet. 48–56.

Petitioner relies on the Declaration of Dr. Jones (Ex. 1008) to support its

obviouness challenge. Patent Owner disagrees. Prelim. Resp. 51–58.



fibroblast cellular layer, Petitioner contends that “Wei teaches that the

spongy layer is scraped off ‘as much as possible with the side surface of a

razor blade or glass slide.’” Pet. 49 (quoting Ex. 1012, 6:7–8). Petitioner

argues that such scraping would remove the spongy layer, necessarily

exposing the fibroblast layer, which is inherently jelly-like and sticky. Id.

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26

According to Petitioner:

Wei does not disclose or suggest any step of removing the fibroblast layer from its amnion layer, or any cells from the fibroblast layer. [Ex. 1008] ¶206. For the reasons discussed in Sec. IX.A.1.c. above, the trypsin/EDTA step disclosed in Wei would not remove the fibroblast layer. Id. Moreover, Wei does not teach or suggest that any of the underlying fibroblast layer is removed when scraping the spongy layer off the amnion. Id. ¶207. Since the fibroblast layer is known in the art as a component that is distinct and separate from the spongy layer, a POSA would have understood Wei as teaching removal of the spongy layer only. Id. As a result, the fibroblast layer would remain on the amnion. Id.

Id. at 50.

Petitioner relies on Tseng, Sulner, and Shenaq for teaching multilayer

grafts. Id. at 54.

Patent Owner responds that the combination of Wei, Tseng, Sulner, or

Shenaq does not teach or suggest “‘an exposed jelly-like fibroblast cellular

layer’ as required by the challenged claims.” Prelim. Resp. 54. Patent

Owner contends that the ordinary artisan would have understood that the

method of Wei would have not only have removed the spongy layer and the

epithelium layer, but also would have removed the fibroblast cellular layer.

Id. at 55. In particular, Patent Owner notes that Wei teaches that the

amniotic tissue obtained is translucent, but that the ’701 patent teaches that if

the amnion is cleaned too aggressively, it will appear clear, and will be

discarded. Id. at 55–56 (citing Ex. 1012, 6; Ex. 1001, 5:21–23). Patent

Owner argues further that Wei implies that the fibroblast cellular layer has

been removed by teaching “that its invention has ‘removed cells from the

amnion, which has greatly reduced the antigenicity of amnion, and

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27

meanwhile it has retained the effective substrate components.’” Id. at 56–57

(citing Ex. 1012, 6).

We agree with Patent Owner that Petitioner has not demonstrated a

reasonable likelihood that the combination of Wei, Tseng, Sulner, or Shenaq

renders the challenged claims obvious. In particular, as noted by Patent

Owner, Wei teaches that the resulting amnion “appears like a bamboo

paper,” and is “translucent.” Ex. 1012, 6. Wei also teaches that the method

prepares “a cell free dried active amnion.” Id. at 4. As noted by the ’701

patent, amnion that appears to be clear “will be unacceptable and will

ultimately be discarded.” Ex. 1001, 5:21–23. Thus, we agree with Patent

Owner that the ordinary artisan would read the disclosure of Wei as

retaining the fibroblast cellular layer.

iii. Conclusion



obvious by the combination of Wei with Tseng, Sulner, or Shenaq.

I. Anticipation by Sulner (Ex. 1013)


anticipated by Sulner. Pet. 56–60.

i. Overview of Sulner (Ex. 1013)

Sulner is drawn to a method of preparing tympanic membrane using a

collagen biofabric. Ex. 1013 ¶ 2. The collagen biofabric may be made from

a human placenta. Id. ¶ 214. Sulner teaches that after the amniotic

membrane is separated from the chorion,

[t]he amniotic membrane is substantially decellularized; that is, substantially all cellular material and cellular debris (e.g., all visible cellular material and cellular debris) is removed. Any

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28

decellularizing process known to one skilled in the art may be used, however, generally the process used for decellularizing the amniotic membrane of the invention does not disrupt the native conformation of the proteins making up the biofabric. “Substantial decellularization” of the amniotic membrane preferably removes at least 90% of the cells, more preferably removes at least 95% of the cells, and most preferably removes at least 99% of the cells (e.g., fibroblasts, amniocytes and chorionocytes). The amniotic membranes decellularized in accordance with the methods of the invention are uniformly thin, with variations in thickness of between about 2 and about 150 microns in the dry state, smooth (as determined by touch) and translucent.

Id. ¶ 218.

ii. Analysis


anticipated by Sulner. Pet. 56–60. Petitioner relies on the Declaration of Dr.

Jones (Ex. 1008) to support its obviousness challenge. Patent Owner

disagrees. Prelim. Resp. 58–60.



fibroblast cellular layer, Petitioner contends that Sulner contemplates that

“10% of the cells normally associated with the collagen matrix (such as

fibroblast cells) are not removed in one of Sulner’s ‘preferred’ removal

methods.” Pet. 57. Petitioner argues that if the claim language of a

modified amnion that has a side which is an exposed jelly-like fibroblast

cellular layer is construed as having an identifiable region of fibroblast cells,

that construction could cover as little as two fibroblast cells. Id. at 58. Thus,

“retention of 10% of the original fibroblast cells, as contemplated in Sulner,

would result in an ‘identifiable region of fibroblast cells.’” Id.

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Patent Owner responds that “Sulner teaches complete

decellularization of the amniotic tissue, which would include removal of the

fibroblast cellular layer.” Prelim. Resp. 58. Moreover, Sulner specifically

teaches that fibroblast cells are to be removed. Id. at 59 (citing Ex. 1013

¶ 218). Patent Owner contends that the challenge is based on a strained

claim construction, asserting that the “plain meaning of the term ‘layer’

requires there to be sufficient fibroblast cells to constitute a layer.” Id. at

59–60.

We have construed the claim phrase “a first membrane comprising

modified amnion wherein the modified amnion has a . . .second side which

is an exposed jelly-like fibroblast cellular layer” as requiring a sufficient

amount of fibroblast cells to constitute a fibroblast layer, wherein the layer is

coextensive with the first side of the modified amnion. Thus, we agree with

Patent Owner that Sulner, which retains at best, 10% of the cells normally

associated with the collagen matrix, does not meet that limitation.

iii. Conclusion


established a reasonable likelihood that claims 1, 2, and 5–8 are anticipated

by Sulner.

CONCLUSION III.

For the foregoing reasons, we are not persuaded that the Petition

establishes a reasonable likelihood that Petitioner would prevail in showing

that any of claims 1, 2, and 5–8 of the ’701 patent are unpatentable under 35

U.S.C. § 102(b) or (e) or 35 U.S.C. § 103(a).

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ORDER IV.

In consideration of the foregoing, it is hereby:

ORDERED that the Petition is denied as to all of the challenged

claims of the ’701 patent.

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PETITIONER:

Ralph W. Selitto, Jr. Greenberg Traurig, LLP [email protected] John K. Kim Greenberg Traurig, LLP [email protected]

PATENT OWNER:

Keith E. Broyles Alston & Bird LLP [email protected] Thomas J. Parker Alston & Bird LLP [email protected] Christopher TL Douglas Alston & Bird LLP [email protected]

DECISION Inter Partes 37 C.F.R. § 42.108 inter partes · Ex. 1001. The ’701 patent relates to...

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