Michael Har-Noy

Patent Trials and Appeals Board

Nov 15, 2021

2021000072 (P.T.A.B. Nov. 15, 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.
13/800,066 03/13/2013 Michael Har-Noy M292.12-0037 2404
27367 7590 11/15/2021
WESTMAN CHAMPLIN & KOEHLER, P.A.
121 South Eighth Street
Suite 1100
Minneapolis, MN 55402
EXAMINER
CORDAS, EMILY ANN
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
11/15/2021 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):
docketing@wck.com
tsorbel@wck.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte MICHAEL HAR-NOY
__________

Appeal 2021-000072
Application 13/800,066
Technology Center 1600
__________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134(a) involving claims to a
composition comprising Type 1 T helper (Th1)/killer cells and cross-linking
agents for cross-linking CD3 and CD28 cell surface moieties. The Examiner
rejected the claims as obvious. 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 Mirror
Biologics, Inc. (see Appeal Br. 3). We refer to the Specification of Mar. 13,
2013 (“Spec.”); Final Action of Aug. 8, 2019 (“Final Act.”); Appeal Brief of
June 25, 2020 (“Appeal Br.”); Examiner’s Answer of Aug. 13, 2020
(“Ans.”); and Reply Brief of Oct. 1, 2020 (“Reply Br.”).
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Statement of the Case
Background
“Adoptive immunotherapy involves removing lymphocytes from the
patient, boosting their anti-cancer activity ex-vivo, growing the cells to large
clinically relevant numbers, and then returning the cells to the patient”
(Spec. ¶ 7). “While immunotherapies with adoptive transfer of CTL
[cytotoxic T cells] have demonstrated promise in many animal models, the
translation of these results to humans has proven to be difficult and elusive”
(id. ¶ 13). “CD4+ cells, especially of the Th1 subtype, would be an
attractive addition to the available immunotherapy armamentarium to
provide natural ‘help’ to adoptively transferred CD8+ killer cells” (id.).
However, “CD4+ T-cells expand in vitro less well than CD8+ cells and the
culture conditions significantly affect their characteristics. Finally, there is a
paucity of realistic animal models based on tumor-specific CD4+ cells.
These factors have limited translational research using CD4+ T cells and
limited their clinical use” (id.).
“The method of the current invention involves the ex-vivo culture of
purified, resting (CD25-), CD4+ T-cells with mixed memory and naive
phenotype (CD45RA and CD45RO, respectively). The cells are activated
multiple times with immobilized anti-CD3/anti-CD28 mAbs in the absence
of exogenous cytokines. The cells expand 25-100-fold after 9-days” (id.
¶ 19). The resulting “CD4+ T-cells with the combination of Th1
characteristics and NK characteristics can provide substantial therapeutic
capabilities for patients having a variety of diseases” (id. ¶ 30).

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The Claims
Claims 1, 2, 4, 5, 8, and 10–14 are currently pending. Independent
claim 1 is representative and reads as follows:
1. A composition comprising Type 1 T helper
(Th1)/killer cells and cross-linking agents for cross-linking
CD3 and CD28 cell surface moieties in non-nutritive buffer,
wherein the Th1/killer cells express granzyme B and
perforin, have Th1 characteristics and direct cytolytic
activity against a tumor cell line, wherein the Th1/killer cells
are ex vivo activated naive CD4+ cells, and wherein the
composition comprises at least about 106 cells/ml of the
Th1/killer cells in a state of activation with cross-linked
CD3 and CD28 surface moieties.

The Issues
A. The Examiner rejected claims 1, 2, 4, 5, 8, and 10–14 under 35 U.S.C.
§ 103(a) as obvious over Gruenberg ’395,2 Sharma,3 Yasukawa,4 Traidl,5
and Gruenberg ’2426 (Final Act. 3–8).
B. The Examiner rejected claims 1, 2, 4, 5, and 10–14 on the ground of
nonstatutory obviousness-type double patenting as being unpatentable over

2 Gruenberg et al., US 2003/0194395 A1, published Oct. 16, 2003.
3 Sharma et al., Granzyme B, a New Player in Activation-Induced Cell
Death, Is Down-Regulated by Vasoactive Intestinal Peptide in Th2 but Not
Th1 Effectors, 176 J. Immunol. 97–110 (2006).
4 Yasukawa et al., Granule exocytosis, and not the Fas/Fas ligand system, is
the main pathway of cytotoxicity mediated by alloantigen-specific CD4+ as
well as CD8+ cytotoxic T lymphocytes in humans, 95 Blood 2352–55 (2000).
5 Traidl et al, Disparate Cytotoxic Activity of Nickel-Specific CD8+ and
CD4+ T Cell Subsets Against Keratinocytes, 165 J. Immunol. 3058–64
(2000).
6 Gruenberg, US 2003/0175242 A1, published Sept. 18, 2003.
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claims 1, 6, 7, 9, 13, 17, and 18 of U.S. Patent No. 7,435,592 (Final Act. 9–
10).
C. The Examiner rejected claims 1, 2, 4, 5, and 10–13 on the ground of
nonstatutory obviousness-type double patenting as being unpatentable over
claims 1–3 and 6–8 of U.S. Patent No. 8,354,276 (Final Act. 10–12).
D. The Examiner rejected claims 1, 2, 4, 5, and 10–13 on the ground of
nonstatutory obviousness-type double patenting as being unpatentable over
claims 1–3 of U.S. Patent No. 8,679,841 (Final Act. 12–13).
A. 35 U.S.C. § 103(a)
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s finding that the cited prior art
renders the rejected claims obvious?
Findings of Fact
1. Gruenberg ’395 teaches “methods for the ex vivo production of
autologous T-cells and the resulting T-cells for adoptive immunotherapy”
(Gruenberg ’395 ¶ 3).
2. Gruenberg ’395 teaches “purifying T-cells cells from the source
material” where “[i]n an exemplary embodiment of the method herein, the
source material is first purified to obtain a starting population of CD4+ T-
cells” (Gruenberg ’395 ¶¶ 16, 19).
3. Gruenberg ’395 teaches that “frequent restimulation of T-cells
or T-cell subsets with, for example, immobilized anti-CD3 and anti-CD28
mAb, causes them to proliferate and differentiate into a highly pure
population of activated memory Th1 cells useful for adoptive
immunotherapy” (Gruenberg ’395 ¶ 18).

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4. Gruenberg ’395 teaches an embodiment in which “activation is
accomplished by coincubating the starting population of T-cells with
immunomagnetic beads conjugated with anti-CD3 and anti-CD28
monoclonal antibodies” (Gruenberg ’395 ¶ 20).
5. Gruenberg ’395 teaches cells produced by “the methods
provided herein are administered to the donor of the cells or to an allogenic
recipient. A sufficient number of cells are administered to ameliorate the
symptoms of the disease. Typically at least about 108–1011 cells”
(Gruenberg ’395 ¶ 30).
6. Gruenberg ’395 teaches that in adoptive immunotherapy, after
cells are processed, there is an “infusion of the processed cells into the same
subject as a therapy” (Gruenberg ’395 ¶ 33).
7. The Examiner acknowledges that “Gruenberg ’395 does not
teach the composition where the Th1 cells are in a nonnutritive buffer”
(Final Act. 4).
8. Gruenberg ’242 teaches “[a]doptive immunotherapy is a
treatment process involving removal of cells from a subject, the processing
of the cells in some manner ex-vivo and the infusion of the processed cells
into the same or different subject as a therapy” (Gruenberg ’242 ¶ 32).
9. Gruenberg ’242 teaches
infusion medium is an isotonic solution suitable for
intravenous infusion. Any such medium known to
those of skill in the art can be used. Examples of
infusion medium include, but are not limited to,
normal saline (NS), 5% dextrose (DSW), Ringer’s
Lactate, PlasmaLyte and Normosol and any other
commercially available medium or medium [known]
to one of skill in the art.
(Gruenberg ’242 ¶ 42). The Examiner finds that these are non-nutritive
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buffers (Final Act. 4).
10. Gruenberg ’242 teaches, in Example 8: “Purified CD4+ cells
were activated with anti-CD3/anti-CD28 conjugated beads every 3 days for
9 days. On day 12, the cells were harvested, washed and resuspended at
1x108 cells/ml in various infusion media” (Gruenberg ’242 ¶ 214).
11. Gruenberg ’242 teaches, in Example 9:
Human anti-CD3 and anti-CD28 mouse Monoclonal
antibodies are immobilized on Miltenyi Goat-
AntiMouse (GAM) micro-beads for Th1 cell
expansion. The beads are used for activation of
primed CD4+ T cells (CD4+ T cells activated using
Human anti-CD3 and anti-CD28 immobilized on
Dynal beads). Advantages of using these beads
include, for example: 1) The Miltenyi beads are
microparticles that remain in colloidal suspension, as
a result these beads do not settle at the bottom of the
flask in bioreactor; 2) Miltenyi micro-particles
following binding to CD4 T cells will be internalized
or shed, as a result the activation signal through CD3
and CD28 will be transient and not continuous; and 3)
the need to debead the product prior to infusion in
patients is eliminated.
(Gruenberg ’242 ¶ 217).
12. Gruenberg ’242 teaches, regarding Example 9, that
“reactivation in infusion medium containing antibody-conjugated colloidal
size particles also maintains viability, since the particles do not have to be
removed prior to infusion” (Gruenberg ’242 ¶ 216).
13. The Examiner finds
The cells taught by taught by the combined teachings
of Gruenberg ’395 and Gruenberg ’242 are the same
or similar because they are ex vivo activated naive
CD4+ cells which express CD4+ and IFN-gamma and
do not express IL-4. In addition, the characteristics of
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expressing Granzyme B and perforin, and direct
cytolytic activity against a tumor cell line are inherent
characteristics to CD4+ Th1 cells as evidenced by
Sharma, Traidl and Yasukawa.
(Final Act. 6–7).
14. Sharma evidences that “CD3 restimulation results in apoptosis
mediated solely by GrB [granzyme B]” (Sharma 97, col. 2).
15. Sharma teaches to generate effector cells, “CD4+ T cells . . .
were seeded in 12-well tissue culture plates containing immobilized anti-
CD3 . . . and anti-CD28 . . . abs” (Sharma 98, col. 1).
16. Yasukawa teaches “RT-PCR revealed that the main cytolytic
mediators of CTLs, including perforin, granzyme B, and Fas ligand, were all
expressed in all of the CD4+ . . . bulk lines and clones examined”
(Yasukawa 2354, col. 1).
17. Yasukawa teaches “[s]ome of the CD4+ CTL clones secreted
IL-10 and IFN-γ, but not IL-4” (Yasukawa 2354, col. 1).
18. Traidl teaches the “pattern of cytokines released by T cell
clones (Tcc) was evaluated on supernatants after 48-h activation with
immobilized anti-CD3 and soluble anti-CD28” (Traidl 3059, col. 1).
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19. Table I of Traidl is reproduced, in part, below:

“CD4 + and CD8- Tcc were isolated from the blood and lesional skin of
patients with ACD to nickel and were characterized for Ag specificity and
cytokine release as well as expression of the CLA and molecules mediating
cytotoxicity (Table I)” (Traidl 3059, col. 2 and 3060).
Principles of Law
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “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 Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007).
Analysis
We adopt the Examiner’s findings of fact and conclusion of law (see
Ans. 3–8; FF 1–19) and agree that the combination of prior art renders the
claims obvious. We address Appellant’s arguments below.
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Appellant contends
the cells in Gruenberg ’395 have been activated but
are not in a state of activation since the cells in
Gruenberg ’395 have been harvested and the
activating agents are removed during harvesting.
Gruenberg ’395 does not disclose or teach a
composition wherein the Th1 cells are in nonnutritive
buffer and in a state of activation due to the presence
of cross-linking agents.
(Appeal Br. 10). Appellant contends “neither Gruenberg ’395 nor
Gruenberg ’242 teach the presence of cross-linking agents in infusion
medium with the activated Th1 cells” and that “Gruenberg ’242 teaches
removing beads and that activation signals should be transient and not
continuous. See Gruenberg ’242, paragraph [0217]” (id.).
We find this argument unpersuasive as it is directly contradicted by
the teaching in Gruenberg ’242 in the paragraph preceding paragraph 217
cited by Appellant. Contrary to Appellant’s argument, Gruenberg ’242 does
not require removing activation beads and instead teaches “reactivation in
infusion medium containing antibody-conjugated colloidal size particles also
maintains viabil[i]ty, since the particles do not have to be removed prior to
infusion” (FF 12; cf. Ans. 17). Thus, Gruenberg ’242 expressly suggests
reactivation of cells with the anti CD3 and CD28 antibody conjugated
particles while in the nonnutritive infusion medium in order to improve cell
viability without removing the beads (FF 12).
We note that Example 8 also teaches a composition comprising CD4+
cells, the same cells recited in claim 1, stimulated with anti-CD3/anti-CD28
conjugated beads as recited in claim 1, in a variety of infusion media that are
nonnutritive buffers as recited in claim 1, in amounts of 1x108 cells/ml that
are greater than those required by claim 1, and suggests reactivation of the
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cells by the addition of the anti-CD3/anti-CD28 conjugated beads in the
infusion media (FF 10–12).
Appellant contends “Example 8 of Gruenberg ’242 clearly
demonstrates that not all buffers are equivalent and the selection of buffer
can result in vastly different and unpredictable cellular characteristics”
(Appeal Br. 11).
We find this argument unpersuasive for several reasons. First, the
argument is not commensurate in scope with claim 1 which recites a “non-
nutritive buffer” and therefore is reasonably interpreted as encompassing any
buffer and therefore imposes no limitation on which non-nutritive buffer is
used. Appellant has not provided evidence that any one buffer listed in
Example 8 does not meet the claim limitations of a “non-nutritive buffer.”
The claim also does not impose any requirement of the buffer, other than it
is “non-nutritive.” “[A]ppellant’s arguments fail from the outset because . . .
they are not based on limitations appearing in the claims.” In re Self, 671
F.2d 1344, 1348 (CCPA 1982).
Second, all five of the non-nutritive buffers tested in Example 8 of
Gruenberg ’242 resulted in at least 25% viable cells (see Gruenberg ’242 ¶
214). Because Gruenberg ’242 teaches the cells were “resuspended at 1x108
cells/ml in various infusion media” (FF 10), even if only 25% of those were
viable, that would still result in 2.5 x 106 cells/ml, exceeding the value
required by claim 1.
Lastly, to the extent that Appellant is trying to shift the burden back to
the Examiner, Appellant provides no persuasive evidence that the obvious
activated CD4+ cells would not have the other properties recited in claim 1.
And
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it is important for the examiner to have a few
procedural tools to aid her efforts to issue as patents
only those claims that meet the requirements of the
Patent Act . . . One of these procedural tools is the
prima facie case, an evidentiary burden-shifting
device available to the examiner.
In re Brandt, 86 F.3d 1171, 1176 (Fed. Cir. 2018). Appellant lacks evidence
responsive to the Examiner’s prima facie case of obviousness.
Appellant contends
The present Specification demonstrates that CAC
cells that are activated in culture by anti-CD3 and
anti-CD28 antibodies but are not reactivated and are
not in a state of activation due to the lack of presence
of cross-linking agents in the non-nutritive buffer do
not express Granzyme B and perforin. Thus, the
present Specification demonstrates that not all CD4+
Th1 cells express Granzyme B and perforin and that
the presence of Granzyme B and perforin is not
inherent in all CD4+ Th1 cells.
(Appeal Br. 11)
We find this argument unpersuasive for several reasons. First,
because Gruenberg ’242 directly suggests reactivating the cells using the
crosslinked CD3/CD28 antibodies in non-nutritive infusion media for the
benefit of increased cell viability (FF 12), the entire line of reasoning fails
because the composition rendered obvious by Gruenberg ’242 would be
reactivated, would be in a state of activation in the non-nutritive buffer and
therefore would be expected to express Granzyme B and perforin as required
by claim 1 (FF 1–12) as an inherent property (FF 13, 14, 16). “An inherent
characteristic of a formulation can be part of the prior art in an obviousness
analysis even if the inherent characteristic was unrecognized or
unappreciated by a skilled artisan.” Endo Pharm. Sols., Inc. v. Custopharm
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Inc., 894 F.3d 1374, 1381 (Fed. Cir. 2018). It is long settled that in the
context of obviousness, the “mere recitation of a newly discovered function
or property, inherently possessed by things in the prior art, does not
distinguish a claim drawn to those things from the prior art.” In re Oelrich,
666 F.2d 578, 581 (CCPA 1981).
Second, contrary to Appellant’s argument, Yasukawa teaches “RT-
PCR revealed that the main cytolytic mediators of CTLs, including perforin,
granzyme B, and Fas ligand, were all expressed in all of the CD4+ . . . bulk
lines and clones examined” (FF 16). Because claim 1 does not impose any
amount or degree of expression of granzyme B and perforin, Yasukawa’s
very sensitive RT-PCR assay provides evidentiary support to the Examiner’s
position that the cells inherently express granzyme B and perforin (FF 13,
14, 16; cf. Ans. 19).
Third, figure 6 of the Specification itself, cited by Appellant, does not
support Appellant’s position because even cells that were not reactivated
were shown to express some amount of granzyme B and perforin (see Spec.
¶ 74). Specifically, claim 1 recites that the “cells express granzyme B and
perforin” but imposes no specific amounts of expression. The Specification,
when referring to figure 6, states: “Fig. 6A shows that CAC express very
little Granzyme B” and “Fig. 6C shows that Perforin can be detected only by
the use of western blot” (Spec. ¶ 74). Thus, even the Specification
acknowledges that the cells express both Granzyme B and perforin in
detectable amounts. Claim 1 does not recite an expression level or amount
and “limitations are not to be read into the claims from the specification.” In
re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993). And, as noted,
Gruenberg ’242 suggests reactivating cells (FF 12) which would reasonably
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be expected to inherently produce larger amounts of granzyme B and
perforin as an inherent property (FF 13, 14, 16).
Appellant contends “a person of ordinary skill in the art would not
have a reasonable expectation of success that a composition of at least 1 x
106 CD4+ Th1 cells with direct cytolytic activity can be obtained” (Appeal
Br. 12). Appellant further contends that the ordinary artisan “would not
have a reasonable expectation of success that a composition of at least about
1 x 106 CD4+ Th1 cells would have activity against a tumor cell line given
Traidl showing activity against autologous keratinocytes” (id.).
We are not persuaded because both Gruenberg ’395 and Gruenberg
’242 are drawn to adoptive immunotherapy (FF 1, 8) and both references
discuss treating cancer using these cells (see, e.g., Gruenberg ’395 ¶¶ 94, 95,
138; Gruenberg ’242 61, 136, 174). “Obviousness does not require absolute
predictability of success . . . all that is required is a reasonable expectation of
success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). The instant
situation is neither one of general inquiry into the field of immunotherapy
but rather both Gruenberg references are drawn to treatment of CD4+ cells
with anti-CD3/CD28 antibodies for adoptive immunotherapy (FF 1–12).
This is even more unlike throwing darts but rather is drawn to a specific
solution. We also note that both Gruenberg references are published
applications and are therefore “presumptively enabling barring any showing
to the contrary by a patent applicant.” In re Antor Media Corp., 689 F.3d
1282, 1288 (Fed. Cir. 2012). No such persuasive showing has been made by
Appellant.
Appellant contends
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immunology is an unpredictable field and a person of
ordinary skill in the art would expect that the response
of immune cells can vary unpredictably depending on
the components present during activation and the
methods used for activation. Applicant points out, for
example, that cells if placed in different buffers can
have different and unpredictable characteristics as
shown in Example 8 of Gruenberg ’242.
(Appeal Br. 13).
We find this general argument unpersuasive because the Examiner’s
rejection does not rely on immunology generally but rather on the specific
cells disclosed in Gruenberg ’395 and Gruenberg ’242; CD4+ cells
stimulated with anti-CD3/anti-CD28 conjugated beads with the teaching that
“reactivation in infusion medium containing antibody-conjugated colloidal
size particles” maintains viability (FF 1–13). The Examiner both cites
Yasukawa to evidence that CD4+ cells express granzyme B and perforin and
relies upon the doctrine of inherency for these cells (cf. Ans. 7). The
Examiner has reasonably established a prima facie case of unpatentability at
least based on inherency, thereby shifting to Appellant the burden of proving
that the obvious composition of Gruenberg ’395 and Gruenberg ’242 will
yield different results. See In re Best, 562 F.2d 1252, 1255 (CCPA 1977).
Appellant has not provided persuasive evidence.
Conclusion of Law
A preponderance of the evidence of record supports the Examiner’s
finding that the cited prior art renders the rejected claims obvious.

B.–D. Obviousness-Type Double Patenting
Appellant does not dispute the obviousness-type double patenting
rejections on the merits (see After-Final Resp. 4/27/2020 at 3). We therefore
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summarily affirm the provisional obviousness-type double patenting
rejection over claims of US 15/801,725. See Manual of Patent Examining
Procedure § 1205.02 (“If a ground of rejection stated by the examiner is not
addressed in the appellant’s brief, that ground of rejection will be summarily
sustained by the Board.”)
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
1, 2, 4, 5, 8,
10–14
103 Gruenberg ’395,
Sharma,
Yasukawa, Traidl,
and Gruenberg
’242
1, 2, 4, 5,
8, 10–14

1, 2, 4, 5, 10–
14
Obviousness-
Type Double
Patenting
1, 2, 4, 5,
10–14

1, 2, 4, 5, 10–
13
Obviousness-
Type Double
Patenting
1, 2, 4, 5,
10–13

1, 2, 4, 5, 10–
13
Obviousness-
Type Double
Patenting
1, 2, 4, 5,
10–13

Overall
Outcome
1, 2, 4, 5,
8, 10–14

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