CELLECTIS

Patent Trials and Appeals Board

Sep 14, 2021

2021001450 (P.T.A.B. Sep. 14, 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.
14/894,426 11/27/2015 Roman GALETTO DI2013-31US1 7199
76392 7590 09/14/2021
ARRIGO, LEE, GUTTMAN & MOUTA-BELLUM LLP
2200 Pennsylvania Ave NW
Suite 400E
Washington, DC 20037
EXAMINER
NGUYEN, QUANG
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
09/14/2021 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):
SAL@ARRIGO.US
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PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ROMAN GALETTO, AGNES GOUBLE,
STEPHANIE GROSSE, CÉCILE SCHIFFER-MANNIOUI,
LAURENT POIROT, ANDREW SCHARENBERG, and
JULIANNE SMITH

Appeal 2021-001450
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Technology Center 1600
____________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.1

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected claims 28, 29, 32, 34–37, 48, 49, 52, 54–56,
58, and 59 under 35 U.S.C. § 103 as obvious and under nonstatutory
obviousness-type double-patenting. Pursuant to 35 U.S.C. § 134(a),

1 Administrative Patent Judge Eric B. Grimes participated in the Oral
Hearing held July 20, 2021, but he is not available for this decision. Judge
Fredman has replaced Judge Grimes on the merits panel. In re Bose Corp.,
772 F.2d 866, 869 (Fed. Cir. 1985).
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Appellant2 appeals from the Examiner’s decision to reject the claims. We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
The Examiner rejected claims 28, 29, 32, 34–37, 48, 49, 52, 54–56,
58, and 59 in the Final Rejection as follows:
1. Claims 28, 29, 36, 37, 48, 49, 56, 58, and 59 under 35 U.S.C. § 103
as obvious in view of Cooper et al (US 2014/0349402 A1, published Nov.
27, 2014) (“Cooper ’402”) and Gregory et al (US 9,597,357 B2, issued Mar.
21, 2017, with the effective filing date of Oct. 10, 2013) (“Gregory ’357”).
Final Act. 3.
2. Claims 28, 29, 36, 37, 48, 49, 56, 58, and 59 under 35 U.S.C. § 103
as obvious in view of Cooper ’402, Gregory ’357, and Rolland et al (US
2013/0071403 A1, published Mar. 21, 2013) (“Rolland”). Final Act. 15.
3. Claims 34 and 54 under 35 U.S.C. § 103 as obvious in view of
Cooper ’402, Gregory ’357, Rolland, Barber et al. (J. Immunol., 1998,
161:11−16 (1998) (“Barber), and Carrasco et al. (J. Exp. Med., 2001,
93:1045−1057 (“Carrasco”). Final Act. 27.
4. Claims 32 and 52 under 35 U.S.C. § 103 as obvious in view of
Cooper ’402, Gregory ’357, Rolland, and Arthaud (US 2007/0286857 A1,
published Dec. 13, 2007) (“Arthaud”). Final Act. 30.
5. Claims 28, 29, 32, 34–37, 48, 49, 52, 54, and 56, provisionally
rejected on the ground of nonstatutory obviousness-type double-patenting as

2 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 Cellectis.
Appeal Br. 3.
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obvious over claims 29, 31, 35, 36, 38, and 52–55 of co-pending Application
No. 14/889,686 (“the ’686 application”). Final Act. 34.
6. Claims 58 and 59, provisionally rejected on the ground of
nonstatutory obviousness-type double-patenting as obvious over claims 29,
31, 35, 36, 38, and 52–55 of the ’686 application and June et al. (US
8,906,682 B2, issued Dec. 9, 2014) (“June”). Final Act. 36.
7. Claims 28, 29, 34−37, 48, 49, 54–56, 58, and 59 on the ground of
nonstatutory obviousness-type double-patenting as obvious over claims
1−17 of U.S. Patent No. 10,426,795 (“the ’795 patent”) and Gregory ’357.
Final Act. 37.
8. Claims 32 and 52 on the ground of nonstatutory obviousness-type
double-patenting as obvious over claims 1−17 of the ’795 patent, Gregory
’357, and Arthaud. Final Act. 40.
9. Claims 28, 29, 35−37, 48, 49, 55, 56, 58, and 59, provisionally
rejected on the ground of nonstatutory obviousness-type double-patenting as
obvious over claims 26¬30 of co-pending Application No. 16/027,629 (“the
’629 application”) and Gregory ’357. Final Act. 41.
10. Claims 32, 34, 52, and 54, provisionally rejected on the ground of
nonstatutory obviousness-type double-patenting as obvious over claims 26–
30 of the ’629 application, Gregory ’357, Arthaud, Barber, and Carrasco.
Final Act. 44.
Independent claim 28 is representative and is copied below:
28. A population of isolated primary human T cells comprising
at least 105 isolated primary human T cells that:
a) express a chimeric antigen receptor (CAR);
b) have the TCRα or TCRβ alleles in the cells inactivated; and
c) have the PD-1 gene inactivated,
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wherein inactivation of the PD1 gene enhances the anti-
tumor activity of the population of isolated primary human T
cells.

This appeal is related to Appeal 2020-001477, an appeal of the
rejections in the ’686 application.
An oral hearing was held July 20, 2021. A written transcript of the
hearing has been entered into the record.

CHIMERIC ANTIGEN RECEPTOR
The claims are directed to human T-cells expressing a CAR and
having an inactivated T-cell receptor and inactivated PD-1 gene. The claim
requires that inactivation of the PD1 gene enhances the anti-tumor activity of
the T-cells.
A T-cell comprising a CAR, or chimeric antigen receptor, was known
on the effective date of the application. The Specification explains:
Novel specificities in T cells have been successfully generated
through the genetic transfer of transgenic T cell receptors or
chimeric antigen receptors (CARs) (Jena, Dotti et al. 2010).
CARs are synthetic receptors consisting of a targeting moiety
that is associated with one or more signaling domains [such as
intracellular signal domains CD28, CD3zeta] in a single fusion
molecule. In general, the binding moiety of a CAR consists of
an antigen-binding domain of a single-chain antibody (scFv),
comprising the light and variable fragments of a monoclonal
antibody joined by a flexible linker.
Spec. 1:24–30; see also 2:1–4.
The Specification further discloses prior art in which “CARs have
successfully allowed T cells to be redirected against antigens expressed at
the surface of tumor cells from various malignancies including lymphomas
and solid tumors.” Spec. 2:2–4. In other words, replacing the normal T-cell
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receptor antigen binding site with an antibody engineered to bind to antigens
on tumors and cancers, allows the T-cell to be targeted to the tumor and
cancer cells, and exert antitumor activity.
PD-1, or the programmed cell death protein-1, was known to limit T-
cell effector functions and antitumor activity. Spec. 2:21. PD-1 is a receptor
on the surface on T-cells and its ligand is PD-L1 and PD-L2. Francisco3 2.
“Engagement of PD-1 by either of its ligands during TCR signaling can
block T-cell proliferation, cytokine production and cytolytic function, and
impair T-cell survival.” Id. 4. Some tumors and cancers express PD-L1
ligand, “thereby augmenting the suppression of anti-tumor T-cell responses
and allowing tumor progression.” Id. 20. The Specification discloses prior
art in which a PD1 antibody was administered in a clinical trial to inhibit
PD1 function in patients and tumour regression was observed in some cases.
Spec. 2:23–24.
Example 3 of the Specification describes inactivating PD-1 in human
primary T-cells and shows “restored cytotoxic activity against PDL-1
expressing HCT116 cells and improved cytotoxic activity against Daudi
cells.” Spec. 81:1–4.
OBVIOUSNESS REJECTIONS
All four obviousness rejections cite Cooper ’402 and Gregory ’357.
Rejections 2–4 cite additional publications. Appellant provided arguments
for rejection 1, and also addressed Rolland cited in rejection 2, but did not
address the remaining obviousness with separate arguments. Consequently,

3 Francisco et al., 2010, Immunol. Rev., 236:219–242 (author manuscript
available July 1, 2011).

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we have grouped all obviousness rejections together for the purpose of
deciding the obviousness of the claimed subject matter.
The Examiner rejected the claims over the combination of Cooper
’402 and Gregory ’357. The Examiner found that Cooper ’402 describes a
CAR T-cell with inactivated T-cell receptor alpha- and beta-chain alleles as
required by the claim. Final Act. 4. The Examiner also found that the CAR
described in Cooper ’402 can comprise domains for additional co-
stimulatory signaling, such as CD3-zeta, CD28, 4-1BB/CD137,
OX40/CD134, or combinations thereof. Id. at 5. The signaling domains are
added to reconstitute the CAR’s function as a T-cell receptor.
The Examiner acknowledged that Cooper ’402 does not disclose CAR
T-cells comprising an inactivated PD-1 gene, but found that Gregory ’357
contains such a teaching. Id. at 6–7. The Examiner specifically cited
Gregory ’357 for the following disclosure:
As useful as it is to develop a technology that will cause a T-
cell to re-direct its attention to specific cells such as cancer cells
[using CAR], there remains the issue that these target cells
often express PD-1 ligand. As such, the PD1-PD-Ll/PD-L2
interaction enables the tumor to escape action by the CAR-
targeted T-cell by deactivating the T-cells and increasing
apoptosis and cell exhaustion.
Gregory ’357, 3:35–41.
Gregory ’357 also discloses:
Tumors have been found to express the PD1 ligand PD-L1 or,
more rarely, the PD1 ligand PDL2 which, when combined with
the up-regulation of PD1 in CTLs [cytotoxic lymphocytes],
may be a contributory factor in the loss in T-cell functionality
and the inability of CTLs to mediate an effective anti-tumor
response.
Gregory ’357, 2:6–11.
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To put it succinctly, binding of the PD-1 ligand to the PD-1 receptor
on T-cells was known to produce a phenomenon known as “T-cell
exhaustion,” which is a loss of T-cell effector function and cytotoxicity.
Gregory ’357 describes inactivating PD-1 gene in CAR T-cells to avoid
exhaustion:
The use of a CAR in a cell that has also been, or will be, treated
with PD1 and/or CTLA-4-specific nucleases or transcription
factors, in which the PD1 or CTLA-4 gene(s) is(are) knocked
out or otherwise similarly modulated, results in a T-cell
expressing a CAR of interest that is resistant to the PD1 ligand
produced by the cancer cell, and thus is not subject to PD-1
mediated T-cell exhaustion and/or resistant to CTLA-4
mediated T-cell inhibition.
Gregory ’357, 16:38–45.
Because PD-1 mediated T-cell exhaustion is eliminated, it would have
been expected that such cells would regain effector function and show
enhanced anti-tumor activity as required by the claims in this appeal.
The Examiner determined it would have been obvious to one of
ordinary skill in the art to modify Cooper ’402 with Gregory ’357’s teaching
to prevent or reduce T-cell inhibition in Cooper ’402’s CAR T-cells. Final
Act. 8.
Summary of Dr. Poirot’s arguments
To rebut the Examiner’s rejection, Appellant provides a declaration
under 37 C.F.R. § 1.132 by Laurent Poirot, a co-inventor of the ’426
application (“Poirot Decl.”) (“Dr. Poirot”).
Dr. Poirot’s principal argument is that one of ordinary skill in the art
would not have reasonably expected on the effective date of the application
that PD-1 gene inactivation in a CAR T-cell as claimed would enhance its
tumor activity. Thus, despite the extensive statements in Gregory ’357 about
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inactivating PD-1 in CAR T-cells, Dr. Poirot opines that the skilled worker
would not have believed that such approach would result in the successful
enhancement of the anti-tumor activity of CAR T-cells until experiments
had actually been performed in which a CAR T-cell with a knocked out and
inactivated PD-1 was made and tested against tumor cells. Poirot Decl. ¶ 13.
Dr. Poirot argues that this lack of an expectation of success is because
“of the well-known differences between exhausted T cells that have been
repeatedly and continuously exposed to their specific antigen (such as in
chronic infection) and CAR T cells.” Poirot Decl. ¶ 8. Dr. Poirot identifies
various difference between the two cell types throughout the declaration,
including differences in the receptor affinity for the antigen, the alleged
ability of CAR T-cells to bypass certain escape mechanisms through which
tumors avoid T-cell recognition, MHC independence, and PD1 sensitivity.
We address each of these arguments below to determine whether they
establish a lack of an expectation of success that PD-1 inactivation in CAR
T-cells would enhance anti-tumor activity.
Appellant contends that the Examiner misunderstood the differences
between exhausted T-cells and CAR T-cells. Appeal Br. 20. Appellant states
it is “indisputable” that Gregory ’357 “doesn’t show any results with CAR T
cells” and “can’t teach that PD-1 immunosuppression even exists in CART
cells.” Id. at 21.

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Differences between native and CAR T-cells
To illustrate the differences between a native T-cell and a CAR T-cell,
Figure 1 of Chmielewski4 is copied below:

Figure 1, reproduced above, shows that CAR is a one-chain protein
that comprises the zeta (ζ) (red) and CD28 (pink) domains that are part of
the T-cell receptor. The figure shows that CAR attempts to mimic the TCR,
and reconstitute its function, by placing certain effector components of the
TCR synapse on the same protein chain in CAR.

4 Chmielewski et al., 2013, Frontiers in Immunology, 2013, 4(371):1–7. This
reference was published after the effective date of the ’426 application, but
is relied upon to establish the state of the art on the application’s effective
date.
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Post-filing evidence
The claims require a CAR T-cell with an inactivated PD-1 gene.
Dr. Poirot cites to the Beatty5 and Long6 references, published after the
effective date of the ’426 application, as evidence that it was not known as
of the effective filing date that PD-1 plays a role in limiting CAR T-cell
efficacy. Poirot Dec. ¶¶ 17–23. Specifically, Dr. Poirot testified that Long7
and Beatty establish that T-cell exhaustion had not been studied prior to the
effective date of the application. Based on this evidence, Dr. Poirot
concluded, that despite the disclosure in Gregory ’357, it would not have
been reasonably expected that inactivating the PD-1 gene would enhance the
anti-tumor activity of the CAR T-cells. Id.
While it is true that there is no evidence before us of actual
experiments studying CAR T-cell exhaustion and PD-1 inactivation,
Gregory ’357, before the application’s effective filing date, describes
inactivating the PD-1 gene in CAR T-cells to make them resistant to T-cell
exhaustion. Gregory ’357, 16: 31–46. A prophetic example of this activation
is disclosed, but was not actually carried out. Id. at 48: 25–50 (Example 3).

5 Beatty et al., 2014, Oncolmmunology, 3:11, e970027. This reference was
published after the effective date of the ’426 application, but is relied upon
to establish the state of the art on the application’s effective date.
6 Long et al., 2015, Nat Med., 21(6): 581−590. This reference was published
after the effective date of the ’426 application, but is relied upon to establish
the state of the art on the application’s effective date.

7 “Exhausted T cells have low proliferative and cytokine producing
capacities, high rates of apoptosis, and express high levels of inhibitory
receptors such as PD-1, TIM-3, and LAG-3. Whether exhaustion plays a
significant role in limiting CAR efficacy, and how CAR structural design
impacts the development of exhaustion, has not been previously studied.”
Long 2 (Introduction) (footnotes omitted).
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Gregory ’357 did not actually test whether PD-1 inactivation would enhance
CAR T-cell activity, but that was the purpose of describing a CAR T-cell
with the PD-1 gene knocked out. The question is whether one of ordinary
skill in the art required actual experiments and experimental proof, as
asserted by Dr. Poirot, before it would have been believed that exhaustion
and PD-1 inhibition were involved in CAR T-cell efficacy? Poirot Decl.
¶¶ 23, 24.
To establish obviousness under 35 U.S.C. § 103, one of ordinary skill
in the art must have a reasonable expectation that the prior art, when
combined, would succeed in making the claimed invention, which here is
enhanced anti-tumor activity due to inactivation of the PD-1 gene. In re
Cyclobenzaprine Hydrochloride Extended–Release Capsule Patent Litig.,
676 F.3d 1063, 1068–69 (Fed. Cir. 2012). However, “[c]onclusive proof of
efficacy is not necessary to show obviousness.” Accorda Therapeutics, Inc.
v. Roxane Laboratories, Inc., 903 F.3d 1310, 1333 (Fed. Cir. 2018) (quoting
from Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir.
2014); see also Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68
(Fed. Cir. 2007) (reasoning that “the expectation of success need only be
reasonable, not absolute”).
Thus, the absence of actual experimental data, and the fact that
exhaustion had not been studied in CAR T-cells, is not dispositive on the
issue of whether the skilled worker would have reasonably expected PD-1
inactivation to enhance anti-tumor efficacy as required by claim 28. Rather,
we must look closely at the evidence provided by Dr. Poirot to determine
whether it upends the strong evidence in Gregory ’357 of using PD-1
inactivation to enhance the anti-tumor activity of CAR T-cells.
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Receptor affinity
Dr. Poirot argues that CAR T-cells have a stronger affinity for the
tumor antigen than native TCR, and thus the skilled worker would not have
been able to predict what effect PD-1 knockout would have on cells. Poirot
Decl. ¶ 52. Specifically, Dr. Poirot states that “it was thought . . . that the
extent of PD-1 inhibition depended on strength of TCR signal, with more
inhibition at lower levels of TCR stimulation.” Id. (citing Francisco and
Freeman8).
Dr. Poirot cited the following disclosure from Francisco to support his
argument:
Engagement of PD-1 by either of its ligands during TCR
signaling can block T-cell proliferation, cytokine production
and cytolytic function, and impair T-cell survival (19). The
extent of PD-1 mediated inhibition depends on the strength of
the TCR signal, with more inhibition occurring at lower levels
of TCR stimulation. PD-1 often inhibits cytokine production to
a greater extent than cell proliferation. CD28 costimulation (31)
or IL-2 (43) can override PD-1-mediated inhibition.
Francisco 4 (emphasis added).
Freeman teaches:
We have demonstrated that PD-L1 signaling can inhibit the
TCR-mediated proliferation of T cells. The capacity of the PD-
1–PD-L1 interaction to downregulate a CD3/CD28-stimulated
response shows that PD-1 engagement results in the delivery of
a strong inhibitory signal. However, the functional
consequences of the PD-1–PD-L1 interaction are dependent on
the relative strength of signals delivered via the TCR and
CD28. Increasing levels of TCR or CD28 signaling can
circumvent the inhibitory effects of PD-1 ligation at the
activation stage.

8 Freeman et al., 2006, JEM, 203(10): 2223–2227.
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Freeman 1033 (emphasis added).
Dr. Poirot, citing Sadelain (2013),9 states that because “CARs were
initially designed to maximally activate T-cells without any intent of
regulation and using antibodies selected to display high affinity,” he would
not have expected “in May of 2014 that CAR T cells would have been
subject to natural inhibitory loops in general and by PD-1 in particular.”
Poirot Decl. ¶ 54. He cited evidence that “the affinities of TCR interactions
with MHC-peptide complexes is in the micromolar range,” but in contrast
“the affinity between a CAR and its antigen is in the nanomolar range or less
. . . indicating thousand fold stronger affinity of the CAR.” Id. at ¶ 55. For
this reason. Dr. Poirot concluded that “PD1 inactivation in CAR T cells was
generally regarded as unnecessary or superfluous.” Id. at ¶ 56.
This argument does not persuade us that the skilled worker would
have been dissuaded from following Gregory ’357’s disclosure of knocking
out PD1 in CAR T-cells.
Dr. Poirot states that the CAR T-cells would be designed with high
affinity to the antigen to avoid PD1 activation. However, Sadelain (2013) is
not entirely consistent with Dr. Poirot’s opinion. First, Sadelain discloses
that the “optimal affinity of CARs is . . . little defined” and that it is
“uncertain whether CARs are as exquisitely sensitive as TCRs.” Sadelain
(2013) 2 (“CAR Targeting”). Second, Sadelain (2013) also discloses that
“the design of T cells that are effective, highly tumor-specific, and regulated
in their maximal accumulation and activation (so as to prelude toxic
cytokine elevation), will represent a valuable advance for the use of CARs.”
Sadelain (2013) 7. In other words, despite Dr. Poirot’s testimony, Sadelain

9 Sadelain et al., 2013 April, Cancer Disc., 3(4): 388–398.
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(2013) indicates that maximal activation of the CAR T-cells may not be
desirable because it could cause deleterious effects. Therefore, CAR is not
necessarily designed, as asserted by Dr. Poirot, to “maximally activate T-
cells without any intent of regulation.” Poirot ¶ 55.
We have not been guided to a teaching that would direct the skilled
worker to engineer a CAR with an affinity that would maximally stimulate
the T-cell to avoid PD-1 inhibition, when other deleterious effects, as
discussed by Sadelain (2013) (“regulated . . . to prelude toxic cytokine
elevation”), might be encountered at such levels. Even assuming that the
antibody has a higher affinity for the antigen than the native TCR, Appellant
did not provide evidence that a CAR with high affinity would suppress PD-
1.
We are not ignoring the evidence that CAR has a higher affinity for
the antigen as compared to a TCR. However, while the evidence does show
that strength of the binding determines “the functional consequences of the
PD-1–PD-L1 interaction” (Freeman 1033), the evidence does not show that
the high affinity of a CAR would completely abolish PD-1 activity,
particularly in the context of tumor cells producing the PD-1 ligand10 which
engage PD-1 and therefore could stimulate PD-1 and cause exhaustion,11
and the lack of evidence provided by Appellant of how much CAR
activation would result when stimulated. Obviousness does not require
absolute predictability of success. In re Kubin, 561 F.3d 1351, 1360 (Fed.
Cir. 2009).

10 “PD-L1 is also expressed in some cancers, as three ESTs are from human
ovarian tumors. This raises the possibility that some tumors may use PD-L1
to inhibit an antitumor immune response.” Freeman 1033.
11 Gregory ‘357, 2:6–11 (see supra, at 6).
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In our view, the teachings in Freeman, Francisco, and Sadelain (2013)
do not rise to a “teaching way” which would have dissuaded the skill worker
from knocking out the PD-1 receptor. As explained in In re Gurley, 27 F.3d
551, 553 (Fed. Cir. 1994):
A reference may be said to teach away when a person of
ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference, or
would be led in a direction divergent from the path that was
taken by the applicant. The degree of teaching away will of
course depend on the particular facts; in general, a reference
will teach away if it suggests that the line of development
flowing from the reference’s disclosure is unlikely to be
productive of the result sought by the applicant.
We have not been pointed to any persuasive evidence in Francisco
Freeman, and Sadelain (2013), when taken as a whole in in the context of
Gregory ’357, that would have discouraged the skilled worker from
following the guidance of Gregory ’357 in inactivating the PD-1 gene. Dr.
Poirot asserted that the high affinity would have led the skill worker to
believe that PD-1 would not be an issue, but as discussed above, Sadelain
(2013) discusses the affinity for CAR T-cells and does not establish that
high affinity was necessarily believed to be a goal in the CAR design, a basis
for Dr. Poirot’s opinion. In our view, Dr. Poirot’s opinion is speculative and
not enough to undermine the express teaching of Gregory ’357.

Bypass escape mechanism
In making his argument that the skilled worker would not have had a
reasonable expectation that inactivating PD1 would enhance tumor activity,
Dr. Poirot asserted that “chimeric receptor approach was thought to be able
to bypass many of the mechanisms by which tumors avoid
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immunorecognition, such as MHC down-regulation, lack of expression of
costimulatory molecules, CTL resistance, and induction of T cell
suppression.” Poirot Decl. ¶ 43 (citing Finney12).
This argument does not persuade us that the skilled worker would not
have followed the teaching by Gregory ’357 to inactivate PD-1. Finney, as
cited by Dr. Poirot has the following disclosure:
This chimeric receptor approach is especially suited to
immunotherapy of cancer, being able to bypass many of the
mechanisms by which tumors avoid immunorecognition, such
as MHC down-regulation, lack of expression of costimulatory
molecules, CTL resistance, and induction of T cell suppression
(3).
Finney 104.
Finney’s actual experiments involved including “CD28 signaling in
series with TCR in the same receptor have been demonstrated to activate
prestimulated human primary T cells more efficiently than a receptor
providing TCC[zeta]signaling alone.” Finney 104 (Abstract). While Finney
mentioned “T cell suppression” in its introduction, there is no further
discussion of it in the publication.13

12 Finney et al., 2004, J. Immunol., 172:104–113.
13 Finney references publication “(3)” for T cell suppression. Publication (3)
is Sadelain et al., Jan. 2003, Nature Reviews, 3:35–45. Sadelain (2003) is a
review article. Sadelain (2003) discusses T cell engineering “to enhance
their antitumoral activities. This might be accomplished on different levels,
such as by increasing T-cell expansion, offsetting anergizing or pro-
apoptotic signals, expanding the range of tumoricidal functions and
protecting T cells against the suppressive effects of the tumour
microenvironment.” Sadelain (2003) 43. Sadelain (2003) does not indicate
that CAR would avoid T-cell suppression, but rather proposed engineering
T-cells to avoid suppression, consistent with Gregory ’357’s disclosure of
engineering a CAR T-cell by inactivating PD1. Sadelain (2003) is newly
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Dr. Poirot also made the same assertion about Sadelain (2013), stating
that “T cells had been designed to circumvent some immune escape
pathways.” Poirot Decl. ¶ 42. Dr. Poirot did not identify the passage in
Sadelain (2013) for this statement. We believe that Dr. Poirot is referring to
the following statement in Sadelain (2013):
Furthermore, CARs can target tumor cells that have
downregulated HLA expression or proteasomal antigen
processing, two mechanisms that contribute to tumor escape
from TCR-mediated immunity.
Sadelain (2013) 2.
This statement refers to HLA expression and antigen processing, not
to PD-1. Dr. Poirot did not explain how these “escape” mechanisms
involving pathways different from PD-1 would have led one of ordinary skill
in the art to lack a reasonable expectation of success that inactivating PD-1
would enhance antitumor efficacy of a CAR T-cell.
In sum, there is no evidence that CAR T-cells were expected to by-
pass escape mechanisms, such as exhaustion caused by PD-1 (see especially
fn. 11).

MHC
One of the differences between native T-cells and CAR T-cells
identified by Dr. Poirot is in the MHC (major histocompatibility complex).
Poirot Dec. ¶¶ 33, 35. Native T-cells, using a TCR with an antigen-binding
site, recognize the antigen in the context of MHC loaded with the processed
antigen peptide. See Chmielewski. CAR T-cells, however, are engineered

cited in response to Dr. Poirot’s reference to Finney, which referenced
Sadelain (2003) for the fact relied upon by Dr. Poirot.
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with a chimeric receptor that binds directly to the antigen without requiring
an interaction with MHC. It is independent of MHC. Id. This is a well-
known difference between native T-cells and CAR T-cells. Dr. Poirot did
not explain how this difference in antigen recognition by the T-cell has any
relationship to the question of whether it would have been reasonably
expected that a CAR T-cell would experience T-cell exhaustion.
Based on Beatty, Dr. Poirot further testified that on the effective date
of the application “little was known regarding whether PD-1 inhibition was
involved in CAR efficacy since it was thought that ‘T cells genetically
modified to express a CAR that recognizes a tumor associated antigen are
unaffected by tumor escape mechanisms involving the loss or
downregulation of major histocompatibility molecules.’” Poirot Decl. ¶¶ 20–
21. Again, Dr. Poirot did not explain how MHC-independence would
suggest lack of enhanced CAR efficacy caused by PD-1 inhibition.
Dr. Poirot also argued that the affinity difference between antigen
recognition by a CAR T-cell using the chimeric receptor and the native T-
cell using MHC. Poirot ¶¶ 33–37. This difference has been addressed above
(see “Affinity” supra.).

PD-1
Dr. Poirot states, citing Francisco, that it was known that “PD-1
expression is consequence of activation through TCR or BCR (B-cell
receptor) signaling.” Poirot Decl. ¶ 38. For this reason, Dr. Poirot concludes
that because “CAR T cells signal through a CAR, and not TCR, the skilled
artisan would not have known whether any PD-1 expression would occur in
CAR T cells. Id. at ¶ 39.
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This argument does not persuade us that it would not be reasonably
expected that CAR T-cells would engage PD-1.
Dr. Poirot states that he considered Rolland. Poirot Decl. ¶¶ 64-68.
Rolland, as indicated by the Examiner (Final Act. 19) describes the
interaction of PD-1 with T-cells. Rolland explains:
CD28, also expressed by T cells, likewise binds to CD80 and
CD86, however this binding leads to the opposite effect, the
generation of a T cell activation signal. . . . Engagement of PD-
1 by PD-L1 or PD-L2 negatively regulates immune responses
in a manner similar to but distinct from that produced following
CTLA-4 binding to CD80 or CD86 (in part based on distinct
expression patterns between these molecules). Like CTLA-4,
PD-L1 is also capable of binding CD80, and therefore through
competition for CD80 binding PD-L1 may also reduce CD28-
mediated costimulatory signals.
Rolland ¶ 45.
Rolland therefore teaches the PD-1 inhibition may result from
interactions with CD80 and CD28. The CAR receptor described in Gregory
’357 can contain CD28 (Gregory ’357, 15:14–17; 15:36–16:2). Thus,
contrary to Dr. Poirot’s opinion, there is evidence that the CAR receptor
would be subject to inhibition by PD1 because it contains CD28, in addition
to other molecules, such as CD28 normally expressed in the T-cell.
Francisco, cited by Dr. Poirot, is not inconsistent with Rolland because
Francisco did not address the mechanism of PD-1 inhibition and Francisco
describes the interaction of PD-1 with the native T-cell receptor, not CAR
comprising the CD28 signaling domain on the receptor itself.

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Co-stimulatory signaling regions
Both Finney and Imai14 are cited in Dr. Poirot’s declaration as
describing CAR having costimulatory domains that enabled the engineered
T-cells “to survive and proliferate in response to AG” and exert “powerful
and specific cytotoxicity against ALL cells,” respectively. Poirot Decl. ¶¶
45–47. Similarly, Dr. Poirot cited Milone15 for showing the efficacy of CAR
T-cells having a receptor with a costimulatory domain. Poirot Decl. ¶¶ 48–
49.
Dr. Poirot did not explain the relevance of these disclosures to the
expectation of success that knocking out PD-1 would increase CAR efficacy.
Presumably, Dr. Poirot’s unstated point is that efficacy, and even superiority
was observed with T-cells comprising signaling domains in CAR cells,
raising the question of whether it was necessary to inactivate PD-1.
This evidence is not persuasive.
First, as explained in Gregory ’357, T-cell exhaustion in response to
PD-1 up-regulation is “defined as a progressive loss of key effector
function.” Gregory ’357, 1:60-62. Thus, while efficacy might be observed,
this does not rule out that effector function could be lost progressively over
time.
Second, Sadelain (2013) disclose there was antitumor efficacy with T-
cells comprising CAR comprising stimulatory domains, yet Sadelain (2013)
still considered that T-cell function and survival could be improved, and
even mentioned exhaustion:

14 Imai et al., 2004, Leukemia, 18:674–684.
15 Milone et al., 2009, Molecular Therapy, 17(8):1453–1464.

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A first clinical study utilizing a CD20-specific CD28/4-
1BB/CD3[zeta]did not shown dramatic responses, (31) but this
early result should not in anyway detract from the potential
value of these “triple-decker” CARs. Overall, more
investigation is needed to attain a better understanding of
optimal CAR signaling to promote sustained T cell function and
survival, preventing premature death, rapid exhaustion or undue
proliferation.
Sadelain (2013) 3.
Thus, co-stimulation did not lead to sustained T cell function and
survival, even when costimulatory domains were present.

Experimental evidence
Experiments are described in the Specification (Spec. ¶¶ 80–81) in
which a TALEN nuclease was introduced into T-cells to knock out the PD-1
gene, and then a week later, CAR mRNA was introduced into the same cells
to produce a final cell population of T-cells comprising CAR and an
inactivated PD-1 gene. Poirot Decl. ¶¶ 81–82. The CAR comprised a signal
peptide, an anti-CD19 scFv, a CD8a hinge, a 4-1BB co-stimulatory domain
and a CD3ζ signaling domain. Id. at ¶ 82.
According to Dr. Poirot, the “antitumor activity” of the cells “was
measured in [a] cellular cytotoxicity assay using CD19+ Daudi cells (vs.
K562 as control) or HCT116 cells, which express PD1 ligand 1 (PDL 1)
transduced with CD19 expression vector (vs. parental HCT116 cells as
control).” Poirot Decl. ¶ 83. “PD1 TALEN transfection restored cytotoxic
activity against PDL1-expressing HCT116 cells and improved cytotoxic
activity against Daudi cells.” Spec. 81:1–4.
We address these results below in the next section.

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Obvious to try
“When there is a design need or market pressure to solve a problem
and there are a finite number of identified, predictable solutions, a person of
ordinary skill has good reason to pursue the known options within his or her
technical grasp.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421, 127 S.Ct.
1727, 167 L.Ed.2d 705 (2007). If one of these “predictable solutions” leads
to the “anticipated success,” the combination was obvious to try. Id.
Our reviewing court has “identified two categories of impermissible
‘obvious to try’ analyses that run afoul of KSR and § 103:
when what was ‘obvious to try’ was (a) to vary all parameters
or try every available option until one succeeds, where the prior
art gave no indication of critical parameters and no direction as
to which of many possibilities is likely to be successful; or (b)
to explore a new technology or general approach in a seemingly
promising field of experimentation, where the prior art gave
only general guidance as to the particular form or method of
achieving the claimed invention. See In re Kubin, 561 F.3d
1351, 1359 (Fed. Cir. 2009) (quoting In re O’Farrell, 853 F.2d
894, 903 (Fed. Cir. 1988)). In re Copaxone Consolidated
Cases, 906 F.3d 1013, 1025 (Fed. Cir. 2018)
This appeal falls into neither of the two impermissible categories.
To begin, Gregory ’357 provides an expectation of “anticipated
success” that inactivating the PD-1 gene would prevent T-cell exhaustion
and result in enhanced anti-tumor activity because it teaches exactly that in
its disclosure, albeit with a prophetic example of such solution to the
problem of T-cell exhaustion.
We have reviewed all the evidence provided by Appellant to
challenge the anticipated success of Gregory ’357’s disclosure and prophetic
example, but as explained in detail above, we do not find the evidence
persuasively negated the anticipated success of applying Gregory ’357’s
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disclosure to Cooper ’403’s CAR T-cells. We acknowledge the differences
between a native T-cell and a CAR T-cell, but Appellant did not establish, in
view of Gregory ’357, that the skilled would have lacked a reasonable
expectation that PD-1 inactivation would lead to an enhancement of the
CAR T-cell’s effector functions. For example, Sadelain (2013) (at p. 4)
mentions exhaustion as something to be prevented in CAR T-cells and
Rolland provides a mechanism for PD-1 suppression involving CD28 which
is described by Gregory ’357 as present in its CAR. There is evidence that
CAR has a higher affinity for the antigen than the native TCR, and evidence
that the extent of PD-1 mediated inhibition depends on the strength of the
TCR signal, with more inhibition occurring at lower levels of TCR
stimulation. However, Appellant did not provide evidence that the stronger
binding to antigen observed with CAR would necessarily lead to high levels
of receptor stimulation and overcome PD-1 inhibition. In fact, the evidence
discussed by Sadelain (2013) about the lack of “dramatic responses” which
could be explained by T-cell inhibition, such as exhaustion, further indicates
the obviousness of using PD-1 inactivation to enhance antitumor activity as
disclosed by Gregory ’357. Overall, Dr. Poirot’s opinion is speculative.
Appellant also did not provide evidence that experimental approach
disclosed in the Specification, as described above, did anything different
than follow the guidance in the cited publications in accordance with the
level of ordinary skill in the art. Dr. Poirot, in describing the experiments,
did not identify a lack of direction in the prior art or a deficiency in the
guidance provided by Gregory ’357 and Cooper ’403. In our view, when the
reference tells a scientist how to engineer the cell to get a better antitumor
response (Gregory ’357, 2:6–11), and the scientist does just what it says,
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without having to invoke anything beyond routine technical skill to achieve
a successful result, that invention is obvious. See also Pharma Stem
Therpeutic, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1363–1364 (2007)
(“Scientific confirmation of what was already believed to be true may be a
valuable contribution, but it does not give rise to a patentable invention.”
The obviousness of claim 28 is affirmed. Claims 29, 32, 34, 36, 37,
48, 49, 52, 54, 56, 58, and 59 were not argued separately and therefore fall
with claim 28. 37 C.F.R. § 41.37(c)(1)(iv).

OBVIOUSNESS-TYPE DOUBLE PATENTING REJECTIONS
There are four provisional obviousness-type double-patenting
rejections over co-pending applications and two obviousness-type double-
patenting rejections over an issued patent.
Rejections 5 and 6 over Application 14/889,686 are summarily
affirmed because Appellant did not provide arguments disputing the
rejections. Rejections 7 and 8 over U.S. Patent No. 10,426,795 are reversed
because a terminal disclaimer over the patent was filed in the application.
The Terminal Disclaimer was entered July 26, 2020.
Appellant disputes the provisional obviousness-type double-patenting
rejections 9 and 10 over co-pending Application No. 16/027,629. Appeal Br.
26–31. Appellant makes the same arguments made for the rejection based on
Cooper ’403 and Gregory ’357. We therefore affirm the rejections for the
same reasons as discussed above for claim 28.

CONCLUSION
In summary:
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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
28, 29, 36,
37, 48, 49,
56, 58, 59
103 Cooper ’402,
Gregory ’357
28, 29, 36,
37, 48, 49,
56, 58, 59

28, 29, 36,
37, 48, 49,
56, 58, 59
103 Cooper ’402,
Gregory ’357.
Rolland
28, 29, 36,
37, 48, 49,
56, 58, 59

34, 54 103 Cooper ’402,
Gregory ’357.
Rolland, Barber,
Carrasco
34, 54
32, 52 103 Cooper ’402,
Gregory ’357.
Rolland, Arthaud
32, 52
28, 29, 32,
34–37, 48,
49, 52, 54,
56
Nonstatutory
Double Patenting
’686 application
28, 29, 32,
34–37, 48,
49, 52, 54,
56

58, 59 Nonstatutory
Double Patenting
’686 application,
June
58, 59
28, 29, 34-
37, 48, 49,
54–56, 58,
59
Nonstatutory
Double Patenting
’795 patent,
Gregory ’357
28, 29, 34-
37, 48, 49,
54–56, 58,
59
32, 52 Nonstatutory
Double Patenting
’795 patent,
Gregory ’357,
Arthaud
32, 52
28, 29, 35-
37, 48, 49,
55, 56, 58,
59
Nonstatutory
Double Patenting
’629 application,
Gregory ’357
28, 29, 35-
37, 48, 49,
55, 56, 58,
59

32, 34, 52,
54
Nonstatutory
Double Patenting
’629 application,
32, 34, 52,
54

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Gregory ’357,
Arthaud, Barber,
Carrasco
Overall
Outcome
28, 29, 32,
34–37, 48,
49, 52, 54–
56, 58, 59

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

AFFIRMED