Bruce Blazar et al.

Patent Trials and Appeals Board

Oct 17, 2019

11919901 - (D) (P.T.A.B. Oct. 17, 2019)

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.
11/919,901 08/21/2008 Bruce Blazar 2017.011US1 7339
26294 7590 10/17/2019
TAROLLI, SUNDHEIM, COVELL & TUMMINO L.L.P.
1300 EAST NINTH STREET, SUITE 1700
CLEVELAND, OH 44114
EXAMINER
DIBRINO, MARIANNE
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
10/17/2019 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):
docketing@tarolli.com
rkline@tarolli.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte BRUCE BLAZAR, JAKUB TOLAR, and
CATHERINE M. VERFAILLIE
____________

Appeal 2019-001236
Application 11/919,901
Technology Center 1600
____________

Before DEMETRA J. MILLS, ERIC B. GRIMES, and
RICHARD J. SMITH, Administrative Patent Judges.

SMITH, Administrative Patent Judge.

DECISION ON APPEAL

Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 39–43, 46, 47, 49, 50, 52, and 54–57.
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 Regents of
the University of Minnesota. Appeal Br. 3.

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STATEMENT OF THE CASE
The Specification indicates that the field of cellular therapy includes
“the use of stem cells, bone marrow transplants, and therapeutic cloning” to
replace diseased or dysfunctional cells with healthy, functioning ones. Spec.
2, ll. 1–4. However, cellular therapy remains “limited by complications such
as immune rejection and graft versus host disease (GVHD).” Id. at ll. 4–5.
Thus, according to the Specification, “there is a need for methods to
overcome the limitations of cellular therapies caused by the
immunoreactivity of the host.” Id. at ll. 8–9.
Claims on Appeal
Claims 39–43, 46, 47, 49, 50, 52, and 54–57 are on appeal. Claims
Appendix.2 Claim 39 is illustrative and reads as follows:
39. A method to increase persistence[3] of MHC-I[4] negative
cells comprising administering the MHC-I negative cells and an
effective amount of a pharmaceutical composition comprising an
anti-natural killer (NK) cell[5] antibody, or an active fragment
thereof, to a subject so that persistence of the MHC-I negative
cells increases compared to the method without administration of
the anti-NK cell antibody, or an active fragment thereof, wherein
the cells are non-ES, non-EG, non-germ cells that can

2 Submitted with Appellant’s Response to Notice of Non-Compliant Appeal
Brief (37 C.F.R. § 41.37), dated April 3, 2018, 3–5 (“Claims Appendix”).
3 “Persistence” is defined as “the ability of cells to resist rejection and
remain and/or increase in number over time (e.g., days, weeks, months,
years) in vivo.” Spec. 11, ll. 16–17.
4 MHC-I refers to “major histocompatibility complex (MHC) class I
molecules.” Spec. 4, ll. 8–9.
5 The Specification states that “Natural Killer (NK) cells are characterized,
in part, by cytolytic activity against cells which do not express significant
[MHC-I] molecules.” Spec. 4, ll. 7–9.

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differentiate into ectodermal, endodermal and mesodermal cell
types and are CD45 negative and CD34 negative.
Id. at 3.
Examiner’s Rejections6
1. Claims 39–41, 43, 46, 52, and 55–57 stand rejected under pre-AIA 35
U.S.C. § 103(a) as unpatentable over Chargui7 or Cho8 in view of Furcht,9 as
evidenced by Kasai.10 Final Act. 7–8.11
2. Claims 39–41, 43, 47, 50, and 55–57 stand rejected under pre-AIA 35
U.S.C. § 103(a) as unpatentable over Chargui or Cho in view of Furcht and
Zander,12 as evidenced by Penack.13 Id. at 8–10.
3. Claims 42, 49, and 51 stand rejected under pre-AIA 35 U.S.C.

6 The Examiner’s rejections of claims 44, 45, and 48 under 35 U.S.C.
§ 112(a) or 35 U.S.C. § 112 (pre-AIA), first paragraph, as failing to comply
with the written description requirement, and claims 39–57 under 35 U.S.C.
§ 112(b) or 35 U.S.C. § 112 (pre-AIA), second paragraph, as being
indefinite, are withdrawn. Ans. 3.
7 J. Chargui et al., Anti-NK antibodies injected into recipient mice enhance
engraftment and chimerism after allogeneic transplantation of fetal liver
stem cells, Thymus 24(4), 233–46 (1997) (“Chargui”).
8 S.G. Cho et al., Anti-NK cell treatment induces stable mixed chimerism in
MHC-mismatched, T cell-depleted, nonmyeloablative bone marrow
transplantation, Experimental Hematology 32, 1246–54 (2004) (“Cho”).
9 Furcht et al., WO 01/11011 A2, published Feb. 15, 2001 (“Furcht”).
10 M. Kasai et al., In vivo effect of anti-asialo GM1 antibody on natural
killer activity, Nature 291, 334–35 (1981) (“Kasai”).
11 Office Action dated Feb. 10, 2017.
12 A.R. Zander et al., ATG as part of the conditioning regimen reduces
transplant-related mortality (TRM) and improves overall survival after
unrelated stem cell transplantation in patients with chronic myelogenous
leukemia (CML), Bone Marrow Transplantation 32, 355–61 (2003)
(“Zander”).
13 O. Penack et al., The type of ATG matters — Natural Killer cells are
influenced differentially by Thymoglobulin, Lymphoglobulin and ATG-
Fresenius, Transplant Immunology 18, 85–87 (2007) (“Penack”).
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§ 103(a) as unpatentable over Chargui or Cho in view of Furcht, as applied
to claims 39–41, 43, 46, 52, and 55–57, and further in view of Tanaka.14 Id.
at 10–11.
4. Claims 42 and 49 stand rejected under pre-AIA 35 U.S.C. § 103(a) as
unpatentable over Chargui or Cho in view of Furcht, as applied to claims
39–41, 43, 47, 50, and 55–57, and further in view of Liu.15 Id. at 11–12.
5. Claims 49 and 54 stand rejected under pre-AIA 35 U.S.C. § 103(a) as
unpatentable over Chargui or Cho in view of Furcht, as applied to claims
39–41, 43, 46, 52, and 55–57, and further in view of Pessino.16 Id. at 12–13.
FINDINGS OF FACT
The following findings are included for emphasis and reference
purposes.
FF 1. “Natural Killer (NK) cells are characterized, in part, by cytolytic
activity against cells which do not express significant major
histocompatibility complex (MHC) class I molecules, such as MAPCs[17]
and embryonic stem (ES) cells.” Spec. 4, ll. 7–9.

14 T. Tanaka et al., Selective Long-Term Elimination of Natural Killer Cells
In Vivo by an Anti-interleukin 2 Receptor β Chain Monoclonal Antibody in
Mice, J. Exp. Med. 178, 1103–07 (1993) (“Tanaka”).
15 Z-X Liu et al., NK Cells Cause Liver Injury and Facilitate the Induction of
T Cell-Mediated Immunity to a Viral Liver, J. Immunology 164, 6480–86
(2000) (“Liu”).
16 A. Pessino et al., Molecular Cloning of NKp46: A Novel Member of the
Immunoglobulin Superfamily Involved in Triggering of Natural Cytotoxicity,
J. Exp. Med. 188 (5), 953–60 (1998) (“Pessino”).
17 “MAPCs” refers to multipotent adult progenitor cells and are a type of
MHC-I negative cells. Spec. 1, ll. 28–29; 10, l. 3. The term “progenitor” as
used in the acronym “MAPC” does not limit those cells to a particular
lineage. Id. at 11, ll. 7–8.
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FF 2. “There are several antibodies available in the art which inhibit NK
cell function, including . . . anti-asialo-GM1.” Id. at 23, l. 32–24, l. 2.
FF 3. Chargui teaches that “Natural killer (NK) cells have been shown to
play a role in . . . resistance to transplantation of allogeneic stem cells,” and
describes an experiment in which anti-asialo GM1 rabbit antibodies (anti-
NK) and fetal liver (ES) cells were injected into one group of mice (Group
A). Chargui Abstract. Group A mice “demonstrated engraftment and
chimerism,” and stability of chimerism over time as compared to Group B
mice which received injections of normal rabbit serum rather than anti-NK
antibodies. Id. Chargui concludes that “[o]n the whole, anti-NK antibodies
were able to improve engraftment, chimerism and stability of allogenic stem
cell transplants.” Id.; see also Final Act. 7.
FF 4. Furcht teaches multipotent adult stem cells (MASCs), and that to
select the MASCs, “bone marrow mononuclear cells are derived from bone
marrow aspirates, which can be obtained by standard means known to those
of skill in the art.” Furcht 22, ll. 9, 29–31.
FF 5. Furcht teaches that “[t]he cells of the present invention . . . may have
the capacity to be induced to differentiate to form at least one differentiated
cell type of mesodermal, ectodermal and endodermal origin.” Id. at 9, ll. 4–
6. Furcht also teaches that the multipotent stem cell of the invention is
CD45 negative and CD34 negative. Id. at 106 (claims 1–4).
FF 6. Furcht teaches that “[u]sing cells from the developed individual,
rather than an embryo, as a source of autologous or allogenic stem cells
would overcome the problem of tissue incompatibility associated with the
use of transplanted embryonic stem cells, as well as solve the ethical
dilemma associated with embryonic stem cell research.” Id. at 8, ll. 3–7.
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DISCUSSION
Except as may otherwise be indicated, we adopt the Examiner’s
findings, analysis, and conclusions as our own, including with regard to the
scope and content of, and motivation to combine, the prior art.
Issue
Whether a preponderance of evidence of record supports the
Examiner’s rejections under pre-AIA 35 U.S.C. § 103(a).
Analysis
1. Obviousness over Chargui or Cho in view of Furcht, as evidenced by
Kasai (claims 39–41, 43, 46, 52, and 55–57)
We limit our consideration to claim 39 because claims 39–41, 43, 46,
52, and 55–57 were not argued separately. In addressing claim 39, we rely
solely on the combined teachings of Chargui and Furcht. See In re Bush,
296 F.2d 491, 496 (CCPA 1961) (holding that the Board may rely on fewer
references than relied upon by the Examiner without designating it as a new
ground of rejection).
The Examiner finds that, due to the role of NK cells in resistance to
transplantation of stem cells, Chargui teaches that anti-NK antibodies were
given prior to fetal (liver) stem cell transplantation, thereby increasing the
persistence and engraftment of the stem cells. Final Act. 7; FF 3. The
Examiner also finds that Furcht teaches isolated multipotent adult
mammalian stem cells that are CD45 negative and CD34 negative, and that
“these stem cells have the capacity to differentiate to form cells of
mesodermal, ectodermal and endodermal origin.” Final Act. 7–8; FF 4, 5.
The Examiner concludes that “[i]t would have been prima facie obvious to
one of ordinary skill in the art at the time the invention was made to have
used the adult multipotent mammalian stem cell[s] taught by [Furcht] in the
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method taught by Chargui;” namely, increasing persistence and engraftment
of transplanted stem cells by also administering an anti-NK antibody. Final
Act. 8.
Appellant’s Arguments
Appellant argues that the Examiner erred in concluding that one of
ordinary skill in the art would have been motivated to combine the cited
references.18 Appeal Br. 16–17. In particular, Appellant argues that “[t]he
Examiner assumes that the cells of Furcht would have been easier to obtain
simply because they are not derived from a fetal source,” but that, in fact, the
cells of Furcht are a rare population of cells that would have been
overlooked by the skilled artisan “in favor of a more robust source of stem
cells given the extremely low occurrence of the Furcht cells.” Id. at 16.
The Examiner responds that Furcht teaches that “these MASCs cells
are easily isolated from bone marrow using standard techniques and cultured
in vitro using standard techniques to expand to appropriate numbers prior to
administration.” Ans. 12 (citing Furcht 22, l. 22–24, l. 2; 24, ll. 18–22). The
Examiner also points to Furcht’s teachings of the advantages of using
MASCs and the disadvantages of using embryonic stem cells. Id. at 12–13
(citing Furcht 22, ll. 9–16; 7, l. 22–8, l. 2); FF 6.
We find that the Examiner has the better position because Furcht
provides reasons why one of ordinary skill in the art would have used
MASCs rather than embryonic stem cells in the technique of Chargui to

18 Appellant advances this argument with respect to the combination of
Chargui and Furcht and the combination of Cho and Furcht. Appeal Br. 16–
17. Although we limit our consideration to the combination of Chargui and
Furcht, we note that similar arguments are advanced by Appellant in
connection with the combination of Cho and Furcht. See id.
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arrive at the method of claim 39. In other words, the Examiner has provided
a persuasive “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.” See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
(2007). Appellant does not persuasively address the Examiner’s indicated
motivation with factual evidence.
Appellant also argues that the Examiner fails to indicate that “there
would have been a reasonable expectation that the claimed invention would
have been achieved.” Appeal Br. 17–18. Appellant specifically argues that
the Examiner has failed to establish that, even if there was a
sufficient motivation, one skilled in the art would have had a
reasonable expectation that, more likely than not, administering
an anti-NK cell antibody, or an active fragment thereof, with
the recited cells as a pharmaceutical composition would
increase persistence or engraftment of the recited cells.
Id.
We are not persuaded by this argument. The reasonable expectation
of success requirement “refers to the likelihood of success in combining
references to meet the limitations of the claimed invention.” Intelligent Bio-
Systems, Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367 (Fed. Cir.
2016). Here, claim 39 is a method to increase persistence of MHC-I
negative cells (as further defined in the “wherein” clause), and recites
administering MHC-I negative cells and an effective amount of a
pharmaceutical composition comprising an anti-natural killer (NK) cell
antibody, or an active fragment thereof. Claims Appendix at 3. The claimed
method is deemed satisfied when the “persistence of the MHC-I negative
cells increases compared to the method without administration of the anti-
NK cell antibody, or an active fragment thereof.” Id.
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Appellant acknowledges that natural killer (NK) cells are
characterized by cytolytic activity against both MAPCs and embryonic stem
cells. FF 1. Appellant further acknowledges that there are “several
antibodies available in the art which inhibit NK cell function,” including
anti-asialo GM1, which is the same antibody used by Chargui. FF 2, 3.
Thus, administering an anti-NK cell antibody would necessarily inhibit the
cytolytic activity of NK cells against both MAPCs and embryonic stem
cells. See Ans. 14.19 A person of ordinary skill in the art would thus have
had a reasonable expectation of success of inhibiting the cytolytic activity of
NK cells (thereby increasing persistence) by administering MHC-I negative
cells (as claimed), rather than embryonic stem cells, in connection with “an
anti-natural killer (NK) cell antibody.”
Accordingly, for the reasons of record and as set forth above, we
affirm the rejection of claim 39 as obvious over Chargui and Furcht. Claims
40, 41, 43, 46, 52, and 55–57 were not argued separately and fall with claim
39.
2. Obviousness over Chargui or Cho in view of Furcht and Zander, as
evidenced by Penack (claims 39–41, 43, 47, 50, and 55–57)
Appellant relies on the same arguments advanced in connection with
Rejection No. 1 above. Appeal Br. 18. Accordingly, Rejection No. 2 is
affirmed for the reasons of record and as set forth above in connection with
Rejection No. 1.

19 Appellant argues in its Reply Brief that the Examiner’s response at page
14 of the Answer constitutes an undesignated new ground of rejection.
Reply Br. 2–3. That is a matter for petition to the Director and not a matter
properly before the Board. See 37 C.F.R. § 41.40(a).
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3. Remaining Obviousness Rejections
Appellant does not contest Rejection Nos. 3, 4, and 5. Accordingly,
those rejections are summarily affirmed.
CONCLUSION
Rejection No. 1: A preponderance of evidence of record supports the
Examiner’s rejection of claim 39 under pre-AIA 35 U.S.C. § 103(a). Claims
40, 41, 43, 46, 52, and 55–57 were not argued separately and fall with claim
39.
Rejection No. 2: A preponderance of evidence of record supports the
Examiner’s rejection of claim 39 under pre-AIA 35 U.S.C. § 103(a). Claims
40, 41, 43, 47, 50, and 55–57 were not argued separately and fall with claim
39.
Rejection Nos. 3–5: A preponderance of evidence of record supports
the Examiner’s rejection under pre-AIA 35 U.S.C. § 103(a) of claims 42, 49,
and 51 (Rejection No. 3), claims 42 and 49 (Rejection No. 4), and claims 49
and 54 (Rejection No. 5).
SUMMARY
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
39–41, 43, 46,
52, 55–57
§ 103(a) Chargui or
Cho, Furcht,
Kasai
39–41, 43,
46, 52, 55–
57

39–41, 43, 47,
50, 55–57
§ 103(a)

Chargui or
Cho, Furcht,
Zander, Penack
39–41, 43,
47, 50, 55–
57

42, 49, 51 § 103(a)

Chargui or
Cho, Furcht,
Tanaka
42, 49, 51
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Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
42, 49 § 103(a)

Chargui or
Cho, Furcht,
Liu
42, 49
49, 54 § 103(a)

Chargui or
Cho, Furcht,
Pessino
49, 54
Overall
Outcome
39–43, 46,
47, 49, 50,
52, 54–57

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).
AFFIRMED