The Johns Hopkins University

Patent Trials and Appeals Board

Dec 2, 2021

2021000688 (P.T.A.B. Dec. 2, 2021)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/639,162 03/05/2015 Zhiyong Xia 3474-SPL 5467
26085 7590 12/02/2021
THE JOHNS HOPKINS UNIVERSITY APPLIED PHYSICS LAB.
OFFICE OF PATENT COUNSEL
11100 JOHNS HOPKINS ROAD
MAIL STOP 7-127
LAUREL, MD 20723-6099
EXAMINER
MARVICH, MARIA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
12/02/2021 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
USPTOComm@jhuapl.edu
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ZHIYONG XIA, CHAO-WEI HWANG,
XIOMARA CALDERON-COLON,
VIRGINIA E. BOGDAN, and PETER V. JOHNSTON
____________

Appeal 2021-000688
Application 14/639,162
Technology Center 1600
____________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 1, 2, 5–7, 21, 22, and 24–27 (Appeal Br. 5). We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as “The Johns
Hopkins University” (Appellant’s June 10, 2020, Appeal Brief (Appeal Br.)
3).
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Application 14/639,162

2
STATEMENT OF THE CASE
Appellant’s disclosure relates “generally to therapeutic nanofiber
patches, and more particularly to a stem cell-impregnated nanofiber patch
that may provide a platform for paracrine factor production and angiogenesis
in the body” (Spec. ¶ 2). Claims 1, 22, and 24 are reproduced below:
1. A therapeutic patch, comprising:
at least one layer of a nanofiber fabric having a plurality
of pores,
a plurality of embedded stem cells embedded in the
nanofiber fabric, and
a plurality of embedded non-stem cells embedded in the
nanofiber fabric, the embedded non-stem cells including human
vascular endothelial cells,
wherein the at least one layer of the nanofiber fabric is a
nanofiber web,
wherein each pore of the plurality of pores comprises a
maximal pore size, the maximal pore size being a diameter of
the each pore,
wherein each of the embedded stem cells comprises an
embedded stem cell diameter,
wherein each of the embedded non-stem cells comprises
an embedded non-stem cell diameter,
wherein the maximal pore size of the each pore of the
plurality of pores is less than the embedded stem cell diameter
of each of the embedded stem cells to form a cage inside which
any one of the plurality of embedded stem cells is embedded
and retained thereby configuring the cage to prevent interaction
between cells of a subject and the plurality of stem cells in
response to the therapeutic patch being inserted into the subject,
wherein the maximal pore size of the each pore of the
plurality of pores is less than the embedded non-stem cell
diameter of each of the embedded non-stem cells attached to the
nanofiber fiber,
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wherein the maximal pore size of the each pore of the
plurality of pores is greater than a diameter of any of by-
products of the plurality of stem cells, nutrients provided for
growth of the plurality of stem cells, or waste produced by the
plurality of embedded stem or non-stem cells, and
wherein the plurality of embedded stem cells are seeded
onto the nanofiber fabric at a density from about 105 cells/cm2
to about 106 cells/cm2.
(Appeal Br. 22.)
22. The therapeutic patch according to claim 1, wherein the
plurality of embedded stem cells are seeded at a density of
about 4 x 105 cells/cm2.
(Id. at 23.)
24. A therapeutic patch, comprising:
a nanofiber fabric assembly defining a plurality of pores,
a plurality of embedded stem cells embedded in the
nanofiber fabric assembly, and
a plurality of embedded non-stem cells embedded in the
nanofiber fabric,
wherein the at least one layer of the nanofiber fabric is a
nanofiber web,
wherein each pore of the plurality of pores comprises a
maximal pore size of less than 10 microns, the maximal pore
size being a diameter of the each pore,
wherein each of the embedded stem cells comprises an
embedded stem cell diameter,
wherein each of the embedded non-stem cells comprises
an embedded non-stem cell diameter,
wherein the maximal pore size of the each pore of the
plurality of pores is less than the embedded stem cell diameter
of each of the embedded stem cells to form a cage structure
inside which any one of the plurality of embedded stem cells is
embedded and retained thereby configuring the cage to prevent
interaction between cells of a subject and the plurality of stem
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cells in response to the therapeutic patch being inserted into the
subject,
wherein the maximal pore size of the each pore of the
plurality of pores is less than the embedded non-stem cell
diameter of each of the embedded non-stem cells attached to the
nanofiber fiber, and
wherein the maximal pore size of the each pore of the
plurality of pores is greater than a diameter of any of by-
products of the plurality of stem cells, nutrients provided for
growth of the plurality of stem cells, or waste produced by the
plurality of embedded stem or non-stem cells.
(Id. at 23–24.)

Grounds of rejection before this Panel for review:
Claims 1, 2, 5–7, 21, 22, and 24–27 stand rejected under 35 U.S.C.
§ 112, second paragraph.
Claims 1, 2, 5–7, 21, 22, and 24–27 stand rejected under the written
description provision of 35 U.S.C. § 112, first paragraph.
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Claims 1, 2, 5–7, 21, 22, and 24–27 stand rejected under 35 U.S.C.
§ 1032 as unpatentable over the combination of Zussman,3 Simpson,4
Duttenhoefer,5 and ThermoFisher.6

DEFINITENESS and WRITTEN DESCRIPTION:
ISSUE
Does the preponderance of evidence support Examiner’s conclusion
that Appellant’s claims are indefinite and/or that Appellant’s Specification
fails to provide written descriptive support for the claimed invention?
ANALYSIS
Given the overlap in Examiner and Appellant’s reasoning relating to
both the indefiniteness and written description rejections, we consider both
rejections together.

2 Although Examiner makes reference to anticipation under 35 U.S.C.
§ 102(a)(2) in the statement of the rejection (see Ans. 3), Examiner’s
analysis makes clear that the rejection is based on obviousness (see id. at 6
(Examiner sets for a conclusion of obviousness and motivation to combine
references)). Appellant’s statement of this ground of rejection and
arguments are based on obviousness under 35 U.S.C. § 103. Therefore, we
find Examiner’s reference to anticipation under 35 U.S.C. § 102(a)(2) in the
statement of the rejection to represent a harmless typographical error on this
record.
3 Zussman et al., US 2011/0230411 A1, published Sept. 22, 2011.
4 Simpson et al., US 2008/0083617 A1, published Apr. 10, 2008.
5 F. Duttenhoefer et al., 3D scaffolds co-seeded with human endothelial
progenitor and mesenchymal stem cells: Evidence of prevascularisation
within 7 days, 20 European Cells and Materials 49–65 (2013).
6 ThermoFisher Scientific, Useful Numbers for Cell Culture, 1–2, last
accessed Aug. 5, 2019 (see Examiner’s August 9, 2019 Notice of References
Cited).
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Examiner finds Appellant’s claims indefinite in the recitation of the
phrase “configuring the cage to prevent interaction between cells of a subject
and the plurality of stem cells in response to the therapeutic patch being
inserted into the subject” (Ans. 7). Examiner further finds that Appellant’s
Specification fails to provide written descriptive support for a nanofiber
having a plurality of pores,
“wherein the maximal pore size of the each pore of the plurality
of pores is less than the embedded stem cell diameter of each of
the embedded stem cells to form a cage inside which a portion
of any one of the plurality of embedded stem cells is embedded
and retained thereby configuring the cage to prevent interaction
between cells of a subject and the plurality of stem cells in
response to the therapeutic patch being inserted into the
subject.[”]
(Id.)
According to Examiner, Appellant’s
claims suggest that the cells of the fiber do not interact with the
cells of the subject and hence it seems as if “all” of the cells
must be embedded in the pores. There is no such step requiring
this. Finally, the claims say that there is an “interaction”
prevented “in response to” the insertion of the patch. It is not
clear how an interaction between the cells of the patch and
those of the subject can be prevented by the cage formation.
(Id.; see also id. at 8.) Stated differently, Examiner asserts “that it is not
clear how to prevent interaction between the cells of the subject and the cells
of the patch because simply by inserting the patch into the subject there is
‘interaction’” (id. at 10–11; see also id. at 12 (Examiner defines the term
“interaction” to mean “influence” and reasons that in order to function
according to the claimed invention the cells of the patch influence subject’s
cells.)). We are not persuaded.
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As Appellant explains, its claims require that the cells of the
therapeutic patch are embedded in a nanofiber fabric that is configured to
retain, i.e. cage, the cells within the nanofiber fabric (Appeal Br. 19–20
(citing Spec. ¶¶ 24–25, 31, and 36); see also id. at 20; Reply Br. 12–13).
Thus, although products produced by the embedded cells may travel out of
the nanofiber fabric and interact with a subject’s cells, cells embedded
within the nanofiber fabric remain within the nanofiber fabric and, as
required by Appellant’s claimed invention, do not interact with a subject’s
cells (cf. Ans. 8–9).
CONCLUSION
The preponderance of evidence fails to support Examiner’s conclusion
that Appellant’s claims are indefinite. The rejection of claims 1, 2, 5–7, 21,
22, and 24–27 under 35 U.S.C. § 112(b) is reversed.
The preponderance of evidence on this record fails to support
Examiner’s finding that Appellant’s Specification fails to provide written
descriptive support for the claimed invention. The rejection of claims 1, 2,
5–7, 21, 22, and 24–27 under the written description provision of 35 U.S.C.
§ 112(a) is reversed.

OBVIOUSNESS:
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?

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FACTUAL FINDINGS (FF)
FF 1. Zussman “relates to albumin fibers and fabrics and, more
particularly, but not exclusively, to methods of generating and using same in
various therapeutic applications” (Zussman ¶ 1; see Zussman ¶ 70 (Zussman
discloses “albumin nanofibers”); Ans. 3).
FF 2. Zussman discloses that “the term ‘fabric’ refers to a woven or non-
woven artifact made of the protein fiber of [Zussman’s] . . . invention,”
wherein the fabric may be “made with a controlled shape, dimension,
porosity and/or pore size” (Zussman ¶ 173; see also id. ¶ 174; Ans. 3).
FF 3. Zussman discloses that “the average pore size of the fabric can be
from about 1 to about 50 μm in diameter” (Zussman ¶ 179; see also id. ¶ 284
(Zussman discloses a fabric having an “average pore size [of] 14±2 μm in
length and 5±1 μm in width”)); id. ¶ 212 (Zussman discloses that its
“albumin fabric may be used to filter cells out of suspension (by controlling
the pore size in the fabric”); Ans. 3 and 5).
FF 4. Zussman discloses that its fiber is “capable of supporting growth of a
cell-of-interest,” including stem cells and non-stem cells (Zussman ¶¶ 51,
90, and 217); see also id. ¶ 215 (Zussman discloses stem cells capable of
forming blood tissue); id. ¶ 209 (Zussman discloses that its “albumin
fabric . . . can be used as an artificial blood vessel”); id. ¶¶ 216 and 221
(Zussman’s fabric provides for the “proliferation, differentiation, and/or
migration of the cells”); id. ¶ 224 (Zussman discloses that its fabric can be
“used for in vivo formation of a tissue (to induce tissue regeneration and/or
repair in a subject”); Ans. 4 (Examiner finds that Zussman discloses that its
“fabric comprises stem cells and non-stem cells” and a “patch to grow tissue
such as blood”)).
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FF 5. Zussman discloses that “[t]he concentration of stem cells which are
seeded on or within the albumin fabric . . . may depend on the type of cells
used and the structure of the albumin fabrics . . . (e.g., porosity and pore
size)” (Zussman ¶ 220 (emphasis added); see also id. ¶ 302 (Zussman
discloses that “a device based on vacuum was developed with the purpose of
forcing cells to penetrate within the scaffold” (emphasis added)); Ans. 4–5).
FF 6. Simpson discloses that “[t]he diameter of an average human cell is
about 20 μm to about 160 μm” (Simpson ¶ 389; see Ans. 5).
FF 7. ThermoFisher discloses that the density of cells seeded onto a
structure varies with surface area (ThermoFisher 1–2; see generally Ans. 4).
FF 8. Examiner relies on Duttenhoefer to disclose “seeding . . . [human
umbilical vein endothelial cells (HUVEC)] with stem cells to create a critical
combination of factors leading to improved vessel formation” (Ans. 4 (citing
Duttenhoefer, Abstr.)).
ANALYSIS
Examiner reasons that Zussman’s woven fabric, made from albumin
nanofibers, is inherently a nanofiber web (Ans. 3; see FF 1–2). Zussman
discloses that its fabric may be “made with a controlled shape, dimension,
porosity and/or pore size” (FF 2). Thus, Zussman discloses a nanofiber
fabric having a plurality of pores (see FF 2–3). Zussman discloses a
nanofiber fabric, in the form of a scaffold, having cells, such as stem cells
and non-stem cells, contained within the fabric (FF 4–5). Zussman discloses
that its nanofiber fabric may be used to produce an artificial blood vessel (FF
4). Duttenhoefer discloses the combination of stem cells and non-stem cells
to improve vessel formation (FF 8). Thus, the evidence of record makes
obvious a nanofiber fabric, wherein at least one layer of the fabric is a
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nanofiber web, having a plurality of stem and non-stem cells embedded in
the nanofiber fabric.
Simpson discloses that “[t]he diameter of an average human cell is
about 20 μm to about 160 μm” (FF 6). Zussman discloses that its nanofiber
fabric has and “average pore size of . . . from about 1 to about 50 μm in
diameter” and that the pore size is controlled, i.e. to prevent cells from
passing through the nanofiber fabric (see FF 2–3). Zussman further
discloses the use of a vacuum to force cells through pores to penetrate within
a scaffold prepared from its nanofiber fabric (FF 5). Thus, the evidence of
record makes obvious a nanofiber fabric having a plurality of pores
comprising a maximal pore, i.e. diameter, size that is less than the embedded
stem cells and non-stem cells contained within a scaffold prepared from a
nanofiber fabric.
ThermoFisher discloses that the density of cells seeded onto a
structure varies with surface area (FF 7). Thus, the evidence of record
supports a conclusion that a person of ordinary skill in this art would have
determined the appropriate density of stem cells seeded onto the nanofiber
fabric structure made obvious by the combination of Zussman, Simpson,
Duttenhoefer, and ThermoFisher through routine experimentation. See In re
Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (“‘[I]t is not inventive to
discover the optimum or workable ranges by routine experimentation.’”)
(Quoting In re Aller, 220 F.2d 454, 456 (CCPA 1955)).
Thus, we find no error in Examiner’s conclusion that the combination
of Zussman, Simpson, Duttenhoefer, and ThermoFisher makes obvious
Appellant’s claimed invention (see Ans. 3–6).

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Claims 1 and 24:
We are not persuaded by Appellant’s contentions regarding cell
migration, which is an embodiment of Zussman’s broader disclosure, which
provides for “the proliferation, differentiation, and/or migration of the cells”
(see FF 4 (emphasis added); cf. Appeal Br. 12 (Appellant contends that
“Zussman discloses allowing the migration of cells outwardly through the
scaffold to allow for the formation of tissue,” which “is in contrast to the
claimed subject matter”); Appeal Br. 14 (Appellant contends that the
combination of Zussman and Duttenhoefer would require a modification of
the structures pore size to permit migration); Appeal Br. 16, 18; Reply Br.
7–8). See In re Lamberti, 545 F.2d 747, 750 (CCPA 1976) (A reference
disclosure is not limited only to its preferred embodiments, but is available
for all that it discloses and suggests to one of ordinary skill in the art.); see
also In re Susi, 440 F.2d 442, 446 n.3 (CCPA 1971) (Disclosed examples
and preferred embodiments do not constitute a teaching away from a broader
disclosure or non-preferred embodiments.).
Zussman discloses that its fabric may be “made with a controlled
shape, dimension, porosity and/or pore size” (FF 2). Zussman discloses that
the pore size of its nanofiber fabric may be controlled in such a manner to
filter cells out of suspension, i.e., prevent cells from passing through the
nanofiber fabric (see FF 3). In addition, Zussman discloses that the pore size
of structures made from its fabric may be configured such that vacuum
pressure is required to force cells through pores to penetrate within a
scaffold prepared from its nanofiber fabric (FF 5). Therefore, we are not
persuaded by Appellant’s contention that “Zussman provides no disclosure
relating to a nanofiber fabric assembly that includes a plurality of pores that
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each provide a cage[, i.e. scaffold,] in which a stem cells is embedded”
(Appeal Br. 12–13; see also id. at 16; Reply Br. 8). For the foregoing
reasons, we are not persuaded by Appellant’s contention that the
combination of Zussman, Simpson, Duttenhoefer, and ThermoFisher fails to
make obvious the relationships between cell diameter and pore size required
by Appellant’s claimed invention (Appeal Br. 12–13 and 16–17; see also
Reply Br. 8–9; cf. FF 3–6).
As discussed above, the combination of Zussman, Simpson,
Duttenhoefer, and ThermoFisher makes obvious a nanofiber scaffold, i.e.
cage, containing cells within the scaffold. The cells within this structure will
not interact with a subject’s cells when the structure is implanted into a
subject, as required by Appellant’s claimed invention. We find no evidence
on this record to support a contrary conclusion. Therefore, we are not
persuaded by Appellant’s contentions to the contrary (see Appeal Br. 12–13;
see also id. at 16–17; Reply Br. 8).
For the foregoing reasons, we are not persuaded by Appellant’s
contention that Zussman teaches away from Appellant’s claimed invention
or that the “proposed modification of Zussman would appear to constitute a
substantial redesign of the articles of Zussman and render them unfit for
their intended purpose of allowing the migration of stem cells out of the
scaffold” (Appeal Br. 13; see also id. at 14; id. at 17–18; Reply Br. 9).
As discussed above, the combination of Zussman, Simpson,
Duttenhoefer, and ThermoFisher supports a conclusion that a person of
ordinary skill in this art would have determined the appropriate density of
stem cells seeded onto the nanofiber fabric structure made obvious by the
combination of Zussman, Simpson, Duttenhoefer, and ThermoFisher
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through routine experimentation. See In re Geisler, 116 F.3d at 1470.
Therefore, we are not persuaded by Appellant’s contentions regarding
seeding density (see Appeal Br. 14; Reply Br. 9).

Claim 22:
Because, as discussed above with respect to Appellant’s claim 1, a
person of ordinary skill in this art would have determined the appropriate
seeding density through routine experimentation, we are not persuaded by
Appellant’s contention that Zussman’s seeding density is “outside the
claimed range” (Appeal Br. 15).
We acknowledge Appellant’s disclosure “that human vascular
endothelial cells exposed to therapeutic nanofiber patches containing stem
cells spontaneously form tubules in a stem cell dose-dependent manner” (see
Spec. ¶ 42 (emphasis added); see also id. ¶ 10; Appellant’s Fig. 3). Thus,
Appellant’s disclosure relates to the effect a patch containing stem cells has
on free human vascular endothelial cells. Appellant’s claimed invention
does not require free human vascular endothelial cells.
To the contrary, Appellant’s claimed invention, reproduced above,
requires an undisclosed amount of human vascular endothelial cells
embedded in a scaffold with stem cells, wherein the embedded stem cells are
seeded at a density of about 4x105 cells/cm2. Appellant’s disclosure does
not disclose the effect stem cells have on human vascular endothelial cells
that are embedded into a patch together with stem cells. Stated differently,
Appellant’s disclosure fails to establish that human vascular endothelial cells
that are embedded in a structure with stem cells, as required by Appellant’s
claimed invention, will spontaneously form tubules.
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For the foregoing reasons, we are not persuaded by Appellant’s
contention that the combination of Zussman, Simpson, Duttenhoefer, and
ThermoFisher fails to make obvious “the unexpected rate of spontaneous
formation of tubules associated with the claimed seed density of about 4x105
cells/cm2” (Appeal Br. 15; see also id. at 16; Reply Br. 10–11).
CONCLUSION
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness. The rejection of claims 1, 22 and 24 under 35
U.S.C. § 103(a) as unpatentable over the combination of Zussman, Simpson,
Duttenhoefer, and ThermoFisher is affirmed. Claims 2, 5–7, 21, 26, and 27
are not separately argued and fall with claim 1. Claim 25 is not separately
argued and falls with claim 24.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 2, 5–7, 21,
22, 24–27
112(b) Indefiniteness 1, 2, 5–7,
21, 22,
24–27
1, 2, 5–7, 21,
22, 24–27
112(a) Written
Description
1, 2, 5–7,
21, 22,
24–27
1, 2, 5–7, 21,
22, 24–27
103 Zussman,
Simpson,
Duttenhoefer,
ThermoFisher
1, 2, 5–7,
21, 22, 24–
27

Overall
Outcome
1, 2, 5–7,
21, 22, 24–
27

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TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv) (2019).
AFFIRMED