Kim O'Connor et al.

Patent Trials and Appeals Board

Aug 27, 2020

2019006318 (P.T.A.B. Aug. 27, 2020)

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.
13/992,953 06/10/2013 Kim O'Connor TU:270-US 6380
11132 7590 08/27/2020
Boulware & Valoir
2603 Augusta Drive
Suite 1350
Houston, TX 77057
EXAMINER
MCNEIL, STEPHANIE A N
ART UNIT PAPER NUMBER
1653
NOTIFICATION DATE DELIVERY MODE
08/27/2020 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):
nseigel@boulwarevaloir.com
patent@boulwarevaloir.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte KIM O’CONNOR and KATIE RUSSELL

Appeal 2019-006318
Application 13/992,953
Technology Center 1600
____________

Before RICHARD M. LEBOVITZ, ULRIKE W. JENKS, and
MICHAEL A. VALEK, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 files this appeal from
Examiner’s decision to reject claims directed to a method of identifying
human multipotent mesenchymal stem cells as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 Appellant identifies the real party in interest as “The Administrators of the
Tulane Educational Fund.” Appeal Br. 1. We use the word “Appellant” to
refer to “applicant” as defined in 37 C.F.R. § 1.42(a).
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STATEMENT OF THE CASE
According to the Specification, bone marrow is a promising source of
mesenchymal stem cells (MSC). Spec. ¶ 5. “Single-cell analysis has
revealed that MSCs [derived from bone marrow] are a heterogeneous
mixture of cells that differ in their stage of lineage commitment and extent
of differentiation.” Id.
Claims 6, 8, 9, 11, 13, 14, and 21–302 are on appeal, and can be found
in the Claims Appendix of the Appeal Brief. Claim 6 is representative of the
claims on appeal, and reads as follows (bracketing and numbering added for
reference convenience):
6. A method of identifying human multipotent mesenchymal
stem cells capable of high proliferation that have a cell doubling
time of 30-hours or less, comprising the steps of
[1] collecting mesenchymal stem cells;
[2] measuring the expression of NG2; and
[3] isolating the mesenchymal stem cells having a colony
forming efficiency of greater than 40% with high expression of
NG2 by selecting the mesenchymal stem cells having high
antibody binding capacity (ABC) of anti-NG2 antibodies of at
least 100,000 molecules of anti-NG2 antibodies per
mesenchymal stem cell.
Appeal Br. 22 (Claims Appendix) (emphasis added).
Claim 6 recites three active steps: (1) collecting mesenchymal stem
cells, (2) measuring expression of NG2, and (3) selecting cells “having high
antibody binding capacity (ABC) of anti-NG2 antibodies of at least 100,000
molecules of anti-NG2 antibodies per mesenchymal stem cell.” The other
independent claims, claims 11, 21, and 26, recite a similar three step cell

2 Claims 10, 15, 33–36, and 41–44 are withdrawn from consideration.
Appeal Br. 3.
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identification method that also requires selection of cells based on ABC
values, but using either different starting tissue or a different combination of
markers.
REJECTIONS
Appellant requests review of the following grounds of rejection made
by Examiner:
I. Claims 6, 9, 21, 22, 24, and 25 under pre-AIA 35 U.S.C. 103(a)
as unpatentable over Crisan3 in view of Kozanoglu4 and
Stallcup;5
II. Claims 9, 11, 14, 26, 27, 29, and 30 under pre-AIA 35 U.S.C.
103(a) as unpatentable over Crisan in view of Kozanoglu,
Stallcup, and Silva Meirelles;6
III. Claim 8 under pre-AIA 35 U.S.C. 103(a) as unpatentable over
Crisan in view of Kozanoglu, Stallcup, and Shiels;7
IV. Claim 13 under pre-AIA 35 U.S.C. 103(a) as unpatentable over
Crisan in view of Kozanoglu, Stallcup, Silva Meirelles, and
Shiels;

3 Crisan et al., A Perivascular Origin for Mesenchymal Stem Cells in
Multiple Human Organs, 3 CELL STEM CELL 310–13 (2008) (“Crisan”).
4 Kozanoglu et al., Human bone marrow mesenchymal cells express NG2:
possible increase in discriminative ability of flow cytometry during
mesenchymal stromal cell identification, 11 CYTOTHERAPY 527–33 (2009)
(“Kozanoglu”).
5 Stallcup, The NG2 proteoglycan: Past insights and future prospects, 31 J.
Neurocytology, 423–35 (2002).
6 da Silva Meirelles, In Search of the In Vivo Identity of Mesenchymal Stem
Cells, 26 STEM CELLS 2287–99 (2008) (“Silva Meirelles”).
7 Shiels et al., US 2009/0274663 A1, published Nov. 5, 2009 (”Shiels”).
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V. Claim 23 under pre-AIA 35 U.S.C. 103(a) as unpatentable over
Crisan in view of Kozanoglu, Stallcup, and Lin;8 and
VI. Claim 28 under pre-AIA 35 U.S.C. 103(a) as
unpatentable over Crisan in view of Kozanoglu, Stallcup,
Silva Meirelles, and Lin.
I.–VI. Obviousness over Crisan, Kozanoglu, and Stallcup
Because all six rejections rely upon the teaching of Crisan,
Kozanoglu, and Stallcup regarding identifying human pluripotent
mesenchymal stem cells with a high proliferation potential, the same issue is
dispositive for all of these rejections, so we will consider the rejections
together. We elect claim 6 as representative.
Examiner finds that “pericytes [taught in Crisan] have multilineage
mesodermal potential and therefore adheres to the strict definition of
mesenchymal stem cells (MSCs).” Ans. 3. Examiner finds that Crisan uses
fluorescence-activated cell sorting (FACS) for cell selection. Id. Examiner
finds that “Crisan teaches monitoring the CD146 and NG2 express[ion] over
several passages.” Id. Examiner acknowledges that “Crisan does not
specifically teach using the method to select mesenchymal stem cells, or the
properties of the selected cells.” Id. at 4.
Examiner relies on Kozanoglu for teaching that “human bone marrow
mesenchymal stem cells that express NG2 can be isolated using flow
cytometry and antibodies specific to NG2.” Ans. 4. Examiner relies on
Stallcup for teaching “that NG2 functions to promote proliferation in cells.”
Id.

8 Lin et al., US 2007/0128722 A1, published June 7, 2007 (“Lin”).
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Examiner concludes that based on the combination of references one
of skill in the art would have been motivated to use Crisan’s method of
sorting cells expressing high specific antibody and apply the sorting to MSC
cells expressing NG2. Ans. 6. Examiner finds that “[t]he recitation of
‘having a colony forming efficiency of greater than 40%’ and ‘ABC of anti-
NG2 antibodies of at least. . . .’ are inherent properties of the cells. . . . For
these reasons it appears that the MSCs expressing NG2 are identical to the
claimed cells, and therefore that they would have the same inherent
properties of the claimed cells.” Id. at 4.
Appellant argues that the Examiner did not address the claim
requirement that the selection of cells is based on “ABC values of at least
100,000 molecules of anti-NG2 antibodies per MSC [which] is the
numerical cut off as the selection criteria.” Appeal Br. 11; Reply Br. 3. In
addition, Appellant contends that “[t]he very first step [in the method] has
already limited the cell pool to MSCs. In other words, the claimed method
does not isolate cells from a pool of unsorted cells, but from heterogeneous
MSCs that have a broad and variable range of proliferation potentials.” Id. at
12.
The issue is whether the preponderance of evidence of record supports
Examiner’s conclusion that NG2 positive mesenchymal stem cells would
inherently meet the colony forming efficiency and ABC values as claimed?
A. Findings of Fact (FF)
FF1. Crisan teaches analyzing and sorting “perivascular cells by
using multicolor fluorescence-activated cell sorting (FACS).
. . . Perivascular cells were identified and sorted by high
CD146 expression and lack of CD34, the latter in order to
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ascertain the absence of endothelial cells within sorted
cells.” Crisan 302.
FF2. Crisan teaches that “CD146+ perivascular cells are also
positive for NG2 expression.” Id. Crisan teaches that “[a]fter
either 4, 8, or 14 passages, muscle derived perivascular cells
stably expressed NG2, CD146, and α-SMA, but not CD31,
CD34, CD45, or CD144, excluding the growth of
contaminating endothelial or hematopoietic cells.” Id. at
304–05.
FF3. Kozanoglu teaches flow cytometry on expanded adherent
human mesenchymal stromal cells (MSC) derived from
bone marrow (BM). Kozanoglu 528–29. Kozanoglu teaches
staining cells with NG2-PE. Id. at 528. Kozanoglu teaches
that “human BM MSC express NG2. . . . [suggesting] that
NG2 may be used as a marker to identify MSC.” Id. at 532.
FF4. Stallcup teaches that “NG2 with extracellular and
intracellular ligands regulates signaling events that are
important for both cell proliferation and cell migration.”
Stallcup, Abstract.
B. Analysis
Crisan teaches that cell surface markers can be used to collect cells
using fluorescent-activated cell sorting (FACS). FF1. Crisan teaches using
perivascular cells in their methods. Id. These cells are different from the
claimed mesenchymal stem cells. Crisan’s method uses CD146 as a marker
for sorting cells. Id. Crisan also teaches that the CD146 sorted perivascular
cells are positive for the NG2 marker. FF2. Kozanoglu teaches that NG2 can
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be used as a marker for identifying mesenchymal stem cells from bone
marrow using flow cytometry but does not teach cell sorting by FACS as
does Crisan. FF4.
Based on the teaching of Crisan and Kozanoglu, we agree with
Examiner it would have been obvious to one of ordinary skill in the art at the
time the invention was made to use NG2 as the marker for collecting human
bone marrow derived mesenchymal stem cells. Thus, the combination of
Crisan and Kozanoglu teaches steps [1] and [2] of claim 6. However, what is
missing from the Examiner’s analysis is a reason to perform step [3] of
claim 6. Specifically, Examiner has not provided evidence that an artisan
would have a reason for “selecting the mesenchymal stem cells having high
antibody binding capacity (ABC) of anti-NG2 antibodies of at least 100,000
molecules of anti-NG2 antibodies per mesenchymal stem cell.” See KSR
Int’l Co. v. Teleflex Inc., 550 U.S at 418 (obviousness rejections require
“some articulated reasoning with some rational underpinning”).
Antibody binding capacity (ABC) is a way of measuring the number
of antigens present on a cell surface. See Spec. ¶¶ 30, 31. We agree with
Appellant that none of the cited references disclose selecting cells among a
population of mesenchymal stem cells. See Appeal Br. 14; Reply Br. 3. The
combined references provide a reason to use NG2 as a marker for cell
sorting but do not provide a reason to select a particular population of among
the NG2 positive cells having the recited high antibody binding capacity.
Even knowing that NG2 is involved in cell proliferation (see FF4) the
Examiner has not provided an articulated reason why one of skill in the art at
the time the invention was made would have selected a population of NG2
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positive cells that has an ABC value of 100,000 antibody molecules or more
per stem cell.
We agree with Appellant that the limitation “having high antibody
binding capacity (ABC) of anti-NG2 antibodies of at least 100,000
molecules of anti-NG2 antibodies per mesenchymal stem cell” is not an
inherent property of all NG2 positive mesenchymal stem cells. Appeal Br. 6.
The art explains that it is only after culture expansion that mesynchymal
stem cells begin to express NG2. Kozanoglu 529. Kozanoglu further teaches
that “viability of the cells was preserved [over passage 1 to passage 9] by
MSC markers CD73, CD105 and CD166, NG2 expression decreased with
passages. This may be because of changing differentiation and growth
characteristics of MSC throughout passages.” Kozanoglu 532. From
Kozanoglu, we know that NG2 levels in cell population changes over time.
There is nothing in the cited art that informs us how many NG2 molecules
are found on the cell surface of any MSC expressing NG2 molecules. Even
knowing that NG2 may be involved in cell proliferation as suggested by
Stallcup (see FF4; Ans. 4), without more, there is no reason to select a
particular group of cells having an ABC cut off value for sorting cells that
bind 100,000 anti-NG2 antibodies on their cell surface.
C. Conclusion
We conclude that the preponderance of the evidence of record does
not support the Examiner’s conclusion that the combination of Crisan,
Kozanoglu, and Stallcup teaches a method having all limitations of
independent claim 6. Specifically, the step [3] limitation of “isolating . . . by
selecting the mesenchymal stem cells having high antibody binding capacity
(ABC) of anti-NG2 antibodies of at least 100,000 molecules of anti-NG2
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antibodies per mesenchymal stem cell” is missing from the references.
Appellant’s other independent claims recite the same limitation. We thus
reverse all of Examiner’s rejections because all of those rejections are
premised on the same combination of Crisan, Kozanoglu, and Stallcup.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
6, 9, 21,
22, 24, 25
103(a) Crisan, Kozanoglu,
Stallcup
6, 9, 21, 22,
24, 25
9, 11, 14,
26, 27, 29,
30
103(a) Crisan, Kozanoglu,
Stallcup, Silva
Meirelles
9, 11, 14,
26, 27, 29,
30
8 103(a) Crisan, Kozanoglu,
Stallcup, Shiels
8
13 103(a) Crisan, Kozanoglu,
Stallcup, Silva
Meirelles, Shiels
13
23 103(a) Crisan, Kozanoglu,
Stallcup, Lin
23
28 103(a) Crisan, Kozanoglu,
Stallcup, Silva
Meirelles, Lin
28
Overall
Outcome
6, 8, 9, 11,
13, 14,
21-30

REVERSED