CELLECTIS

Patent Trials and Appeals Board

Oct 26, 2020

2020002327 (P.T.A.B. Oct. 26, 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.
13/892,805 05/13/2013 Roman Galetto DI2011-07US1 1953
76392 7590 10/26/2020
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
10/26/2020 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):
SAL@ARRIGO.US
legaladmin@arrigo.us
scott@arrigo.us
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
_________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
_________________

Ex parte ROMAN GALETTO, AGNÈS GOUBLE, STÉPHANIE GROSSE,
CÉCILE MANNIOUI, LAURENT POIROT,
ANDREW SCHARENBERG, and JULIANNE SMITH

_________________

Appeal 2020-002327
Application 13/892,805
Technology Center 1600
_________________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and
DAVID COTTA, Administrative Patent Judges.

KATZ, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 seeks our review2, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 49, 59, 62, and 72–91. We have
jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.

1 We use the word “Appellant” as defined in 37 C.F.R. § 1.42. Appellant
identifies the real party-in-interest as Cellectis. (Appeal Br. 4.)
2 We consider the Final Office Action issued August 6, 2019 (“Final Act.”),
the Appeal Brief filed October 25, 2019 (“Appeal Br.”), the Examiner’s
Answer issued December 4, 2019 (“Ans.”), the Reply Brief filed January 30,
2020 (“Reply Br.”), and the oral argument held on October 1, 2020, in
reaching our decision.
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Appellant’s Specification is directed to developing engineered T-cells
for immunotherapy that are both non-alloreactive, meaning that they do not
react to non-self tissues, and resistant to immunosuppressive drugs. (Spec.
1:9–10, 3:13–21.) Specifically, the Specification states that the inventors
have achieved the production of doubly-inactivated primary T-cells using
specific TALE-nucleases (also called “TALENs”) directed against both the
proteins that make up the T-cell receptor (“TCRalpha”/“TCRα” and
“TCRbeta”) and immunosuppressive agents. (See Spec. 5:23–28.)
The Examiner entered rejections of Appellant’s claims as lacking a
sufficient written or enabling description under 35 U.S.C. § 112, first
paragraph (independent claims 49, 89, and claims that depend on them), as
being indefinite under 35 U.S.C. § 112, second paragraph (all claims), and as
being obvious under 35 U.S.C. § 103(a) (independent claims 76–78, 86, 89–
91). (See Final Act. 2–41.) We discuss each of these rejections below.
35 U.S.C. § 112, first paragraph – Written Description
The Examiner rejects independent claims 49 and 89, and the claims
that depend on them, under 35 U.S.C. § 112, first paragraph and second
paragraph, for lack of a sufficient written and enabling description and for
indefiniteness. Appellant does not argue separately for the patentability of
any of the claims that depend on claim 49 or 89. Accordingly, we focus on
the independent claims in our review, addressing claim 49 first. See 37
C.F.R. § 41.37(c)(1)(iv).
Appellant’s claim 49 recites:
A method for generating a population of doubly-
inactivated primary human T-cells comprising:
providing primary human T cells from a single donor;
co-electroporating into said primary human T-cells:
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(a) RNAs encoding a first TALE-nuclease that cleaves a
T-cell receptor alpha (TCRα) sequence comprising SEQ ID
NO:37, and
(b) RNAs encoding a second TALE-nuclease that cleaves
a CD52 sequence comprising SEQ ID NO:40,
to generate a population of transfected human T cells
comprising at least 15.5% doubly-inactivated human T-cells
having both TCRα and CD52 genes inactivated; and
expanding the population of doubly inactivated human T-
cells to obtain a population of doubly-inactivated human T-cells
for infusing into an individual for immunotherapy treatment.
(Appeal Br. 47.) Claim 49 does not recite any sequence or other structural
limitations on the TALENs themselves, but requires a specific level of
double-inactivation of T-cells of “at least 15.5%” by cleaving the specific
TCRα and CD52 sequences.
The Examiner finds that the support Appellant cites on pages 6 and 58
of the Specification is inadequate because it does not support double
inactivation rates of more than 15.5%. (See Final Act. 4, citing Amendment
of May 6, 2016; see also Appeal Br. 6–8 (citing pages 6 and 58 in the
Summary of Claimed Subject Matter).) Specifically, the Examiner finds that
“[t]hroughout the originally filed specification, there is absolute[ly] no
disclosure indicating or suggesting that an efficacy greater than 15.5% (e.g.,
20%, 40%, 60% or more) could be attained for the generation of doubly-
inactivated human T cells prior to cell expansion as claimed.” (Ans. 6.)
As the Examiner finds, Table 8 on page 58 of the Specification
demonstrates that the inventors obtained a population of 15.5% doubly-
inactivated human T cells after co-electroporating cells with mRNAs
encoding half CD52-TALE nucleases and half TRAC-TALE-nucleases.
(See Final Act. 4.) Neither Table 8 nor any other part of the Specification
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identified by Appellant demonstrates that the inventors generated a
population of more than 15.5% doubly-inactivated cells, as encompassed
within the scope of claim 49. (See Final Act. 3–4.)
The Examiner cites further to statements made by inventor Poirot that
the 15.5% double inactivation level was “high” and that “[i]n [his] opinion,
the generation of this level of double negative T cells was unexpected before
we made this invention.” (See Final Act. 4–5 (emphasis omitted), quoting
Declaration of Laurent Poirot, Declaration Under 37 C.F.R. § 1.132, filed
May 6, 2016 (“2016 Poirot Decl.”) ¶¶ 12, 14.) We agree with the Examiner
that given the results of only 15.5% double-inactivation in the Specification
and Dr. Poirot’s statements, the Specification does not demonstrate that the
inventors were in possession of doubly inactivated cells at levels
encompassing the full scope of claim 49 that the encompasses a level of
double-inactivation of 15.5% or greater with unspecified TALE-nucleases
that cleave a target TCRα sequence encoding SEQ ID NO:37 and a target
CD52 sequence comprising SEQ ID NO:40. (See Final Act. 16.)
Appellant argues that the Examiner fails to consider all the evidence
of record. (See Appeal Br. 9–12.) Specifically, Appellant argues that the
Examiner looks at the Specification in isolation and fails to mention the
references of record or Dr. Poirot’s declaration. (See id. at 11–12.)
According to Appellant, focusing on what the Specification does not
disclose is “not the end of the appropriate legal analysis, but only the
beginning. The mere lack of certain words in the specification is insufficient
to support the Examiner’s conclusion.” (Appeal Br. 12.) Appellant cites
Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005), to argue that “[t]he
question is how the words that are present in the specification would be
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viewed by the skilled artisan in view of the knowledge in the art at that
time.” (Id.)
We disagree that the Examiner’s legal analysis was inappropriate or in
error. Although written description is to be viewed in the context of the state
of the art of the particular invention, the inventors must show that they had
possession of what is claimed. In Capon, the court held that it was not
necessary to repeat nucleotide sequences known in the art when presenting
the components of chimeric genes because it would have been understood
that known DNA segments would retain their DNA sequences when linked
by known methods. See Capon, 418 F.3d at 1358. In contrast, nothing that
Appellant points to in the Specification or in Dr. Poirot’s declaration
indicates a similarly predictable way to achieve doubly-inactivated human
T-cells at levels of 90% or more, as encompassed in claim 49. Nothing
indicates that one of ordinary skill in the art would have understood that the
inventors had possession of more than 15.5% doubly-inactivated human T-
cells.
The facts of Appellant’s disclosure are more similar to those of
AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d
1285, 1300 (Fed. Cir. 2014), where patent claims limited to the functional
element “koff rate constant of 1x10-2s-1 or less” lacked written description
support because the specification described only one type of antibody.
Similarly, Appellant’s Specification discloses only one pair of mRNAs
encoding TALENs that produces 15.5% doubly-inactivated cells and no
mRNAs encoding TALENs that produce a higher level of doubly-inactivated
cells.
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Appellant argues, further, that “the issue is whether one of skill in the
art could derive the claimed range from the application.” (Appeal Br. 15.)
Appellant misconstrues the law. The issue for compliance with the written
description requirement of 35 U.S.C. § 112, first paragraph, is whether the
specification “show[s] that the inventor actually invented the invention
claimed.” See Ariad Pharm., Inc. v. Eli Lilly & Co, 598 F.3d 1336, 1351
(Fed. Cir. 2010). “[A] description which renders obvious a claimed
invention is not sufficient to satisfy the written description requirement of
that invention.” Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d
1559, 1567 (Fed. Cir. 1997). An adequate written description requires more
than a reference to a potential method of making the invention. See id. at
1566–67.
Appellant cites to the testimony of inventor Poirot as evidence that the
claimed methods are supported by a sufficient written description, but his
statements discuss only how one would have derived the full scope of the
claimed method from the disclosure in the Specification, not how the full
scope of the method is disclosed in the Specification. (See Appeal Br. 17–
18.) Specifically, Appellant argues that “Dr. Poirot explained what was
known at the time of the invention and how the skilled artisan would have
used this information together with the teachings of the specification.” (Id.)
Appellant cites to Dr. Poirot’s statement that “at the time the application was
filed in 2012, much was known about the optimization of TALENs” and his
further statements about optimization techniques allegedly taught in Cermak
(T. Cermak et al., Efficient design and assembly of custom TALEN and other
TAL effector-based constructs for DNA targeting, Nucleic Acids Research,
39(12): e82 (2011)). (Declaration of Laurent Poirot, Declaration Under 37
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C.F.R. § 1.132, filed July 24, 2017 (“2017 Poirot Decl.”) ¶¶ 13–18; see
Appeal Br. 19.)
Similarly, Appellant argues that by increasing RNA stability and
TALEN translation, it would have been possible to obtain inactivation levels
close to the transfection efficiency, which was shown to be 95% in the
Specification. (See Appeal Br. 20–21, citing 2017 Poirot Decl. ¶¶ 23–30.)
Dr. Poirot testifies: “The teaching that 95% transfection efficiency could be
achieved, in combination with the demonstration of a level of about 45%-
50% single inactivated/15% double inactivated T cells in Example 2,
conveys that RNA stability and translation are amenable to optimization.”
(2017 Poirot Decl. ¶ 28.)
Even though Dr. Poirot cites to several optimization techniques (see
id. ¶¶ 32–58), his testimony is not persuasive because neither Appellant not
Dr. Poirot directs us to disclosure of such optimization techniques and their
results in the Specification. Instead, as discussed above, the mere suggestion
that an invention may be obtained does not demonstrate possession of the
subject matter and is not sufficient to fulfill the written description
requirement.
Appellant relies, further, on Dr. Poirot’s statement3 that “[t]here is
nothing in the application that suggests that double inactivation in T cells
could not be optimized based on routine techniques that were known in the
art in 2012.” (2017 Poirot Decl. ¶ 31; see Appeal Br. 22.) Appellant again

3 Appellant submitted two declarations by Dr. Poirot – one on May 6, 2016
and one on July 24, 2017. Appellant does not specify which declaration is
cited in regard to the rejection for lack of written description, but it appears
that the second, filed in 2017, is the intended source.
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mischaracterizes the requirement for a written description under 35 U.S.C.
§ 112, first paragraph. The absence of evidence is not evidence. Ergo the
absence of disclosure that a method cannot be optimized is not evidence of
possession of such techniques and their results and is not evidence of a
sufficient written description of a method.
Appellant argues that the Examiner “has set forth no legitimate
reasons to doubt the conclusions of Dr. Poirot and has ignored evidence of
routine optimization techniques that were well-known at the time the
application was filed.” (Appeal Br. 27.) Because Dr. Poirot’s testimony
regarding optimization techniques does not to show that those in the art
would have understood the inventors were in possession of the full scope of
the claimed method, we are not persuaded that the Examiner erred.
We note that, in addition to the testimony cited by Appellant, in his
2016 Declaration Dr. Poirot states:
Based on the above, I conclude that it could not have
been predicted prior to May of 2012 whether TALENs would to
allow for the generation of a population of doubly-inactivated
human T-cells sufficient for infusing into an individual for
immunotherapy treatment.
Only our experimental generation of a sufficiently high
level (i.e., 15.5%) doubly-inactivated human T-cells allows for
an expectation of success in using TALENS for generating of a
population of doubly-inactivated human T-cells sufficient for
infusing into an individual for immunotherapy treatment.
(2016 Poirot Decl. ¶¶ 38–39.) Dr. Poirot’s position is that at the time of
filing, there was nothing in the prior art to suggest that doubly-inactivated
cells could be generated, let alone at a level higher than 15.5%. Dr. Poirot
acknowledges that the field of TALENs inactivation was unpredictable at
the time of filing. As the AbbVie court explained:
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Functionally defined genus claims can be inherently
vulnerable to invalidity challenge for lack of written description
support, especially in technology fields that are highly
unpredictable, where it is difficult to establish a correlation
between structure and function for the whole genus or to predict
what would be covered by the functionally claimed genus.
AbbVie, 759 F.3d at 1301. Dr. Poirot’s testimony about the unpredictability
of the field and characterization of 15.5% double-inactivation as a “high
level” support the Examiner’s findings that one of ordinary skill would not
understand the inventors to have been in possession of a method that
achieves more than 15.5% inactivation as encompassed by claim 49.
Appellant’s claim 89 is similar to claim 49, reciting:
A method for generating a population of doubly-
inactivated primary human T-cells comprising:
providing primary human T cells from a single donor;
co-electroporating into said primary human T-cells:
(a) RNAs encoding a first TALE-nuclease that cleaves a
first gene, and
(b) RNAs encoding a second TALE-nuclease that cleaves
a second gene,
to generate, prior to expansion, a population of
transfected human T cells comprising at least 104 doubly-
inactivated human T-cells having both first and second genes
inactivated, and
expanding the population of doubly inactivated human T-
cells to obtain a population of doubly-inactivated human T-cells
for infusing into an individual for immunotherapy treatment.
(Appeal Br. 51–52.) Claim 89 fails to recite any sequence or other structural
limitations on the TALENs. Claim 89 is even broader with respect to the
TALEN sequences than claim 49 because it encompasses TALENs directed
to any gene. That is, the TALENs of claim 89 can cleave any first gene, not
necessarily limited to a gene encoding a component of a T-cell receptor or
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MHC recognition, and can cleave any second gene, not necessarily limited
to a gene encoding a target for an immunosuppressive agent. (See Final Act.
5.)
The Examiner finds that Appellant’s Specification describes only
TALENs that target T cells, or genes otherwise involved in MHC
recognition, and immunosuppressive agents. For example, the Specification
states that the invention “relates to methods for developing engineered T-
cells for immunotherapy that are both non-alloreactive and resistant to
immunosuppressive drugs. The present invention relates to methods for
modifying T-cells by inactivating both genes encoding target for an
immunosuppressive agent and T-cell receptor.” (Spec. 1:9–12; see Final
Act. 6.) The Specification states further that
the inventors have achieved the production of genetically
modified T-cells, which overcome the limitations of present
immunotherapy strategies, allowing them to be both non-
alloreactive and resistant to immunosuppressive agents. This
was made possible by gene inactivation using specific TALE-
nucleases directed against TCRalpha or TCRbeta, coupled with
inactivation of genes encoding targets for different
immunosuppressive agents, in particular CD52 and GR.
(Spec. 5:23–28; see also Spec. 7:4–7 (“The methods of the present invention
more particularly allow the precise modification of the genome of cells
relevant for immunotherapy by inactivating or replacing genes involved in
MHC recognition and or targets of immunosuppressive drugs for the
treatment of cancer and/or viral infections.”).) The record does not include
evidence to support that these portions of the Specification describe
TALENs that target other categories of genes. Accordingly, we agree with
the Examiner that the Specification does not provide written description
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support for cleaving or inactivating genes other than those that encode a
component of a T-cell receptor or are involved in MHC recognition and does
not support cleaving or inactivating a second gene other than one that
encodes a target for an immunosuppressive agent. (See Final Act. 5–6.)
Appellant points to the portion of the Specification stating:
In addition to the above conception of genetically
modified T cells, which can be both non alloreactive and
immunosuppressive resistant, the inventors, by the use and
design of specific TALE-nucleases, have concomitantly
inactivated these different genes in T-cells, thereby obtaining
double mutants. As a matter of fact, double gene targeting by
DSB has been so far unachieved in T cells due to the difficulty
of yielding and maintaining T-cells in culture over time, to their
low transformation rates, and loss during selection procedures.
These difficulties result in a low probability of success for
obtaining such cells.
(Spec. 6:4–10.) Appellant also cites to the portion stating:
The above description is presented to enable a person
skilled in the art to make and use the invention, and is provided
in the context of a particular application and its requirements.
Various modifications to the preferred embodiments will be
readily apparent to those skilled in the art, and the generic
principles defined herein may be applied to other embodiments
and applications without departing from the spirit and scope of
the invention. Thus, this invention is not intended to be limited
to the embodiments shown, but is to be accorded the widest
scope consistent with the principles and features disclosed
herein.
(Spec. 48:17–23; see also id. at 20:14–15 (“It has been shown by the
inventors that the use of TALE-nucleases was particularly advantageous to
achieve double inactivation in T-cells.”).) Although these portions provide
for TALENs generically, neither discloses any specific genes that can be
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targeted, other than T-cell receptor or MHC complex genes and CD52 or
other immunosuppressive genes, to achieve double-inactivation of T-cells.
Appellant also points to Dr. Poirot’s testimony that the “positive
results reported in Example 2 allowed us to predict that it would be possible
to produce engineered T cells available from donors on a regular basis, using
standard procedures (see pages 6 and 20 of the application).” (2017 Poirot
Decl. ¶ 9.) But this testimony indicates nothing about other TALEN targets
that the inventors demonstrated in the Specification could be used to produce
doubly-inactivated T-cells.
Appellant’s arguments regarding the written description support for
claims 49 and 89 are unpersuasive. Appellant does not argue for the
separate patentability of the claims that depend on claims 49 and 89.
Accordingly, we are not persuaded that the Examiner erred in rejecting these
claims under 35 U.S.C. § 112, first paragraph, for lack of sufficient written
description support.
35 U.S.C. § 112, first paragraph - Enablement
The Examiner rejects claims 49 and 89 and the claims that depend on
them under 35 U.S.C. § 112, second paragraph, for lack of an enabling
description. A patent specification must enable one of ordinary skill in the
art “to practice the claimed invention without undue experimentation.” Nat’l
Recovery Techs., Inc. v. Magnetic Separation Sys., Inc., 166 F.3d 1190, 1196
(Fed. Cir. 1999) (emphasis omitted). Whether undue experimentation would
be required is determined by analyzing a number of factors, including
(1) the quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
working examples, (4) the nature of the invention, (5) the state of
the prior art, (6) the relative skill of those in the art, (7) the
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predictability or unpredictability of the art, and (8) the breadth of
the claims.

In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Appellant does not raise any separate arguments for the patentability
of claim 49, 89, or any of the dependent claims, referring only to claim 49 in
the arguments. (See Appeal Br. 29.) We focus on claim 49 in our review.
The Examiner’s findings reflect those for the written description
rejection. That is, the Examiner finds that claim 49 is broad, encompassing
a level of double-inactivation of 15.5% or greater with unspecified TALE-
nucleases that cleave a TCRα sequence encoding SEQ ID NO:37 and a
CD52 sequence comprising SEQ ID NO:40. (See Final Act. 16.) The
Examiner finds further that little was known in the field of TALE-nuclease
inactivation of primary human T cells at the time of filing, including the
stability and efficiency of the nuclease activity in primary human T cells,
citing Dr. Poirot’s statement that “the generation of this level [15.5%] of
double negative T cells was unexpected before we made this invention.”
(2016 Poirot Decl. ¶ 14; see Final Act. 16–17.) The Examiner finds that the
art was unpredictable because TALE-nuclease inactivation was known to be
variable for different sequences even within the same gene. (See Final Act.
20.) In support, the Examiner cites to experiments in Appellant’s
Specification wherein different TALE-nucleases were used to target several
different locations in the same immunosuppressive agent gene (the gene for
the glucocorticoid receptor (“GR”)), resulting in different levels of
inactivation in human T cells ranging from 0.04 to 26.2%. (See Final Act.
20, citing Spec. Tables 1 and 4.)
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The Examiner continues by finding that Appellant’s disclosure is
narrow, providing only a single example of using TALE-nucleases that
cleave the TCRα and CD52 genes with a level of 15.5% double-inactivation.
(See Final Act. 18–19, citing Spec. 58, Tables 5 and 8.) The Examiner finds
that the Specification is completely silent about guidance on how to improve
or enhance the efficiency rate of 15.5% for double-inactivation of TCRα and
CD52 in human T cells. (See Ans. 13.)
According to Appellant, the Examiner improperly limits Appellant to
the working example on page 58 of the Specification. (See Appeal Br. 29.)
Appellant argues that “[a]s long as the specification discloses at least one
method for making and using the claimed invention that bears a reasonable
correlation to the entire scope of the claim, then the enablement requirement
of 35 U.S.C. 112 is satisfied.” (Appeal Br. 29.) We are not persuaded by
this argument in light of the Examiner’s findings regarding the Wands
factors.4 (See Ans. 11–12.) Given the broad scope of the claims, the narrow
scope of the Specification, the nature of the art, and the other factors, we
agree with the Examiner that the full scope of the method of claim 49 is not
enabled.

4 Appellant argues that “the Examiner appears to concede that Appellant’s
specification fulfills the enablement requirement” (Reply Br. 3, 4),
presumably referring to the Examiner’s statement: “the fact that the person
of ordinary skill in the art could have carried out the claimed invention
without undue experimentation based on appellant’s disclosure is inadequate
to meet this requirement” (Ans. 8 (emphasis omitted)). We do not interpret
this statement to mean that the claimed methods are enabled, but instead to
be a refutation of Appellant’s argument conflating enablement and written
description.
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Appellant argues further by citing the testimony of Dr. Poirot: “by
using other well-known procedures, such as capping, pseudouridine
incorporation, and other RNA modifications, I expect that we could readily
increase the dKO efficiency to at least 75-90% with minimal additional
routine screening” that through routine optimization such levels of double-
mutated cells could have been readily obtained. (2017 Poirot Decl. ¶¶ 57–
58; see also id. ¶¶ 32–38, 41–43, citing Mockery et al., Biochemical &
Biophysical Res. Commc’ns, 340:1062–68 (2006), Kariko et al., Mol. Ther.
16:1833–40 (2008), Rodgers, et al., RNA 8:1526–37 (2002); see Appeal Br.
30.) We are not persuaded that the ways to optimize mRNA expression
(including by capping, polyadenylation, incorporation of pseudouridine, 3’
untranslated region usage) discussed by Dr. Poirot would necessarily be
known as ways to optimize TALEN inactivation without undue
experimentation because Dr. Poirot does not discuss the use of these
techniques with TALENs before the filing date of Appellant’s application.
Although Dr. Poirot discusses using at least some of these techniques with
TALE-nuclease mediated gene editing in regard to his own research, this
report was published in 2015, after the filing date of Appellant’s application.
(See 2017 Decl. ¶¶ 39, 44–57, citing Poirot et al., Cancer Res.,5 75:3853–64
(2015).) Thus, it does not necessarily describe the state of the art at the time
of filing.

5 We note that the citation of Dr. Poirot’s research was provided as “Poirot et
al., Res; 75(18); 3853-64. (2015)” but the correct journal name seems to be
Cancer Research.
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Furthermore, in contrast to Dr. Poirot’s conclusion that one of
ordinary skill in the art would have known that double-inactivation levels
could be readily increased to at least 75–90% with well-known techniques
and minimal screening, he also characterizes 15.5% double-inactivation as
“representative for this type of experiment in primary T cells” and as a “high
level of double negatives.” (2016 Poirot Decl. ¶¶ 8, 12.)
Appellant argues that even though Dr. Poirot testified that the
inventor’s results were unexpected prior to the invention, “[t]his does not
mean that, the results would be unexpected after Applicant’s invention.”
(Appeal Br. 30.) In light of Dr. Poirot’s testimony that 15.5% double-
inactivation is a “routine” and “high level” and the fact that he published the
use of optimization techniques for TALE-nuclease editing several years after
Appellant’s application was filed, we are not persuaded that levels higher
than 15.5% as recited in claim 49 would have been routine at the time of
filing, which is the time period at issue. See MagSil Corp. v. Hitachi Glob.
Storage Techs., Inc., 687 F.3d 1377, 1381 (Fed. Cir. 2012) (explaining that
“[t]he specification must contain sufficient disclosure to enable an ordinarily
skilled artisan to make and use the entire scope of the claimed invention at
the time of filing” and warning that “a patentee chooses broad claim
language at the peril of losing any claim that cannot be enabled across its
full scope of coverage”).)
Appellant does not dispute the Examiner’s finding that the
Specification fails to provide guidance for any optimization techniques. (See
Ans. 13.) Appellant argues only that the Examiner’s finding “merely
discounts the entire Declaration . . . .” (Reply Br. 5.) Appellant argues
further that “[s]ince the Examiner has not contested any of the specific
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conclusions in Dr. Poirot’s Declaration, nor presented any evidence to rebut
or doubt his conclusions, Dr. Poirot’s conclusions regarding the sufficiency
of Appellant’s disclosure should be taken as uncontested facts.” (Reply Br.
6.) The Examiner’s undisputed findings outweigh Dr. Poirot’s conclusions
because many of the Wands factors indicate that it would have required
undue experimentation to make and use the full scope of claim 49. (See
Ans. 11–17.) Despite Dr. Poirot’s testimony about possible optimization
techniques, the totality of the evidence of the Wands factors indicates that, as
of the filing date, the broad scope of claim 49 was not enabled. See In re
Vaeck, 947 F.2d 488, 493 (Fed. Cir. 1991) (finding lack of enablement
where “[t]here is no reasonable correlation between the narrow disclosure in
appellants’ specification and the broad scope of protection sought in the
claims . . .”).
Accordingly, we disagree that the Examiner erred in rejecting the
claims as lacking an enabling disclosure under 35 U.S.C. § 112, first
paragraph.
35 U.S.C. § 112, second paragraph - Indefiniteness
The Examiner rejects claims 49, 76 and 89 as being indefinite, finding
the claim terms “(a) RNAs encoding a first TALE-nuclease that cleaves . . . ,
and (b) RNAs encoding a second TALE-nuclease that cleaves . . .” to be
unclear. (See Final Act. 30.) The Examiner finds that usually a TALE-
nuclease is encoded by a single RNA, and thus it is unclear whether the
recited RNAs refer to a plurality of the same RNAs that encode the TALE-
nucleases or to RNAs of different structures that are not necessarily limited
to those encoding the two half TALE-nucleases. (Final Act. 30.) The
Examiner questions whether “multiple RNAs of different structures might
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encode a first TALE-nuclease that is comprised of three one-third-TALE
nucleases, or four one-fourth-TALE nucleases and so on.” (Final Act. 31.)
Appellant argues that the “RNAs” encode the nuclease and are co-
electroporated into said primary human T cells. (See Appeal Br. 33.)
Appellant cites to the Specification to argue that an RNA can encode an
entire nuclease or half of it. (See Appeal Br. 33, citing Spec. 30:18–19.)
Specifically, Appellant cites to the Specification statement that “[i]n
particular embodiments, as non-limiting examples, said RNA encodes a rare-
cutting endonuclase, one monomer of the rare-cutting endonuclease such as
Half-TALE-nuclease . . . .” (Spec. 30:18–19.)
We are not persuaded by Appellant’s argument because even if the
recited “RNAs” encode an entire nuclease or half of it, it is not clear why a
plurality of RNA are recited as encoding the first and second TALE-
nucleases. Appellant’s citation to the Specification does not clarify the term
“RNAs” because the Specification refers to a singular “RNA.” Accordingly,
we disagree that the Examiner erred in rejecting the claims as being
indefinite under 35 U.S.C. § 112, second paragraph.
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35 U.S.C. § 103(a)
The Examiner rejects claims 76–78, 86, 89, and 90 under 35 U.S.C. §
103(a) as being obvious over Cooper,6 Arthaud,7 Gregory,8 Fahrenkrug,9
GenBank Accession No. X02883.110, and Kaplan.11 (See Final Act. 32–39.)
Claim 89 is reproduced above. Claim 76 recites:
A method for generating a population of doubly-
inactivated primary human T-cells comprising:
providing primary human T cells from a single donor;
co-electroporating into said primary human T-cells:
(a) RNAs encoding a first TALE-nuclease that cleaves a
T-cell receptor alpha (TCRα) sequence comprising SEQ ID
NO:37, and
(b) RNAs encoding a second TALE-nuclease that cleaves
a CD52 sequence comprising SEQ ID NO:40,
to generate a population of transfected human T cells
comprising doubly-inactivated human T-cells having both
TCRα and CD52 genes inactivated; and
expanding the population of doubly inactivated human T-
cells to obtain a population of doubly-inactivated human T-cells
for infusing into an individual for immunotherapy treatment.
(Appeal Br. 49.) Neither claim 76 nor claim 89 is limited to a particular
level of double-inactivation or a specific TALE-nuclease sequence. Claim
89 does not limit the target genes of the TALE-nucleases to any specific
genes, although Appellant elected CD52 as the species of the first gene and

6 US 2014/0349402 A1, published November 27, 2014.
7 US 2007/0286857 A1, published December 13, 2007.
8 US 2013/0196373 A1, published August 1, 2013.
9 US 2012/022143 A1, published August 30, 2012.
10 GenBank Accession No. X02883, Human gene for T-cell receptor alpha
chain C region, 3 pages (2016).
11 WO 2010/132697 A2, published November 18, 2010.
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TCRα as the species of the second gene for examination. (See Final Act.
32–33.)
Findings of Fact
1. Cooper teaches generating CAR+ T cells modified to eliminate
T-cell receptor and/or HLA for immunotherapy. (See Cooper Abstract; see
Final Act. 33.)
2. Cooper exemplifies modifying primary human T cells to
express a recombinant chimeric antigen receptor, propagating them for a
period of time to expand them, and using zinc fingers (“ZFNs”) to disrupt
the alpha and/or beta chains of the TCR. (See Cooper ¶ 9, Examples 2–6;
see Final Act. 33.)
3. Cooper teaches that
[a]lthough in specific embodiments the modifications of the
cells exclude functional TCR by any suitable means, in certain
aspects the modifications include knock out (or in alternative
embodiments, knock down, such as by siRNA and TALENs,
for example) of the α and/or β chains or the gamma and/or delta
chains of the TCR.
(Cooper ¶ 13; see Final Act. 34.)
4. Cooper teaches preparing subsets of recombinant T cells with
the antibody Campath, which binds CD52 on the T cell surface. (See
Cooper ¶ 126; see Final Act. 35–36.)
5. Cooper does not teach co-electroporating with RNAs to express
TALENs to inactivate both CD52 and a TCR. (See Final Act. 35.)
6. Arthaud teaches using the anti-CD52 antibody Campath as an
immunosuppressant in transplant patients. (See Arthaud ¶ 6; see Final Act.
36.)
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7. Gregory teaches enhanced TALEN pairs that target specific
genes, including TCR genes. (See Gregory ¶¶ 15–22; see Final Act. 36.)
8. Fahrenkrug teaches using TALENs to modify genes in somatic
primary cells. (See Fahrenkrug ¶¶ 39–50, 111–118 (Examples 3–8); see
Final Act. 36–37.)
9. Fahrenkrug teaches that theoretically, “cells that express a gene
cassette from a first vector are also likely to be successfully modified by a
TALEN delivered independently by mRNA or another vector.” (Fahrenkrug
¶ 45; see Final Act. 37.)
10. Fahrenkrug teaches that “[c]o-selection processes were also
effective when feeder cells were used, as demonstrated in Example 5. An
unexpectedly high proportion of bi-allelic modifications (about 17% to about
35% depending on the TALEN-pair) were observed.” (Fahrenkrug ¶ 41; see
Final Act. 37.)
11. GenBank Accession No. X02883.1 provides the sequence of
the TCRα chain constant region comprising SEQ ID NO: 37, which was
published at least by 1986. (See GenBank Accession No. X02883.1; see
Final Act. 35.)
12. Kaplan teaches the genomic sequence of CD52. (See Kaplan
¶ 66, Figs. 13A–B; see Final Act. 38.)
Analysis
The Examiner finds that an ordinarily skilled artisan would have
considered it obvious to modify the teachings of Cooper to include
disruption of the CD52 and TCR genes in modified T cells by co-
electroporating T cells with TALEN mRNAs specific for T-cell receptor
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alpha and CD52 genes in light of the teachings of Arthaud, Gregory, and
Fahrenkrug. (See Final Act. 38.)
Appellant argues that one of ordinary skill in the art would not have
had an expectation of success carrying out the claimed method from the
references cited. (See Appeal Br. 34–38.) Specifically, Appellant argues that
claims 76 and 89 require “expanding the population of doubly inactivated
human T-cells to obtain a population of doubly-inactivated human T-cells
for infusing into an individual for immunotherapy treatment,” but that none
of references provides an expectation of success that the efficiency of
TALE-nucleases would be sufficient to generate a population of cells for
infusion treatment in an individual. (See id.)
First, Appellant argues that Cooper fails to teach the use of TALENs
or double-inactivation. (See Appeal Br. 3512.) Appellant also argues that
Arthaud does not teach using a nuclease and that neither Gregory nor
Fahrenkrug teaches double-inactivation in human T cells. (See Appeal Br.
36–37, citing 2016 Poirot Decl. ¶¶ 56, 63.) Because the rejection is based on
obviousness, not anticipation, these arguments focusing on the deficiency of
each reference separately are not persuasive.
Appellant argues further, relying on the testimony of Dr. Poirot, that
both Gregory and Fahrenkrug teach producing cells at a “very low” or
“extremely low” efficiency, respectively. (See Appeal Br. 36–37, citing
2016 Poirot Decl. ¶¶ 55, 62.) Neither claim 76 nor claim 89 requires a

12 Appellant refers to Dr. Poirot’s testimony to support this argument, but
does not provide a citation. In light of the other citations to Dr. Poirot’s
testimony, we assume that Appellant is referring to paragraphs 40–49 of
declaration submitted on May 6, 2016 by Dr. Poirot.
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specific level or range of efficiencies. Claim 89 recites that 104 doubly-
inactivated human T cells be produced, but this limitation is expressed as an
absolute number, not a level of efficiency. Furthermore, although claims 76
and 89 require producing cells “for infusing into an individual for
immunotherapy treatment,” Appellant does not direct us to a definition of
how many cells this would require or that such treatment indicates a certain
level of efficiency. In addition, it is not clear why one could not use enough
starting cells to generate the number claimed, regardless of a level of
efficiency. We are not persuaded that Gregory and Fahrenkrug fail to
contribute to the obviousness of the methods recited in claims 76 or 89
because they do not teach a high enough efficiency.
Appellant argues further that there would not have been a reasonable
expectation of success in performing the methods of Gregory or Fahrenkrug
in human T cells, because neither reference teaches using these cells. (See
Appeal Br. 36–37.) Appellant relies on Dr. Poirot’s testimony that
[b]ecause of the differences between T cells and in iPSC/
hESC cells and the lack of any indeterminate efficiencies,
Gregory et al. would not have provided any expectation that the
efficiency of TALE-nucleases in T cells would be sufficient to
generate a population of doubly-inactivated human T-cells for
infusing into an individual for immunotherapy treatment in
May of 2012.
(2016 Poirot Decl. ¶ 58.) Similarly, Dr. Poirot testifies that
[b]ecause of the differences between T cells and the
primary fibroblast cells used by Fahrenkrug, and the extremely
low efficiencies in primary fibroblasts, Fahrenkrug et al. would
not have provided any expectation that the efficiency of TALE-
nucleases in T cells would be sufficient to generate a population
of doubly-inactivated human T-cells for infusing into an
individual for immunotherapy treatment in May of 2012.
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(2016 Poirot Decl. ¶ 65.) Dr. Poirot does not support his testimony with
further explanation of the differences between the cells used in Gregory and
Fahrenkrug and the primary human T cells recited in claims 76 and 89.
Without further explanation, we are not persuaded that the primary
fibroblasts of Fahrenkrug are so different from primary T cells that one of
ordinary skill would not have expected success in the claimed method from
the results in Fahrenkrug.
Dr. Poirot states that “[a]lthough zinc finger nucleases (ZFNs) had
been used in primary T cells prior to May 2012, I would not have been able
to extrapolate success with ZFNs in T cells to success with TALE-nucleases
in T cells to that extent because of the differences between these nucleases.”
(2016 Poirot Declaration ¶ 18; see Appeal Br. 40–41.) He continues by
explaining that TALENs are larger than ZFNs and so may have different
inactivation effects. (2016 Poirot Decl. ¶ 19–33.) Despite Dr. Poirot’s
testimony, Cooper expressly suggests that TALENs can be used as well as
ZFNs to inactivate genes in primary cells and Fahrenkrug demonstrates gene
inactivation with TALENs in primary fibroblast cells. (See Ans. 24–25.)
We are not persuaded by Dr. Poirot’s testimony, particularly given that
claims 76 and 89 do not recite any limitation on the efficiency level of the
double-inactivation in primary human T cells.
We note, further, that Dr. Poirot refers only to claim 49 in his 2016
declaration, which requires an efficiency of at least 15.5%, but claim 49 was
not rejected under 35 U.S.C. § 103. (See 2016 Poirot Decl. ¶ 4.) Dr. Poirot
refers to the limitation on efficiency of 15.5% in several other of his
statements. (See id. ¶¶ 8, 11, 12, 39, 48, 57, and 64.) Although we consider
Dr. Poirot’s statements for their merits regarding the rejected claims, it is not
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clear to what extent his opinions relate to methods for generating doubly-
inactivated primary human T cells at a certain level of efficiency. (See Ans.
21–22.)
Appellant does not argue for the separate patentability of any of the
claims rejected as being obvious over Cooper, Arthaud, Gregory,
Fahrenkrug, GenBank Accession No. X02883.1, and Kaplan. Accordingly,
we are not persuaded that the Examiner erred in rejecting claims 76–78, 86,
89, and 90 under 35 U.S.C. § 103(a).
The Examiner also rejected claim 91 under 35 U.S.C. § 103(a) as
being obvious over Cooper, Arthaud, Gregory, Fahrenkrug, and June.13 (See
Final Act. 39–41). Claim 91 recites: “The method of claim 89, wherein the
method generates, prior to expansion, at least 106 doubly-inactivated human
T-cells having both first and second genes inactivated.” (Appeal Br. 52.)
Appellant argues that none of the cited references would provide an
expectation that the efficiency of TALE-nucleases would be sufficient to
generate, prior to expansion, the required 106 doubly-inactivated cells. (See
Appeal Br. 43–46.) Appellant refers to Dr. Poirot’s testimony that none of
the cited references demonstrates performance of double-inactivation or uses
TALENs in primary T cells. (See id. at 45–46.)
In addition to the lack of a recited level of efficiency in claim 91, we
are not persuaded by Appellant’s argument in light of the Examiner’s
findings and reasoning. Specifically, the Examiner cites June for its
teaching that 0.1 to 0.2 ml of stimulated T cells can be used at a
concentration of 1–3 x 108 cells/ml for generating CAR transfected T cells

13 US 2014/0227237 A1, published August 14, 2014.
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by electroporation. (See Final Act. 40, citing June Abstract, ¶¶ 253–256.)
The Examiner calculates that this starting population of 5 x 107 cells would
produce 106 doubly-inactivated cells with an efficacy rate of 2%. (See Final
Act. 40.) The Examiner further cites Fahrenkrug for its teaching that about
17% to about 35% bi-allelic modifications can be obtained with a TALEN-
pair. (See Final Act. 37, citing Fahrenkrug ¶ 41.) From these teachings, the
Examiner reasons that, given the high level of skill in the art, 2% is a low
enough efficiency level that one of ordinary skill in the art would have
considered it obvious to be able to obtain 106 cells. (See Final Act. 40; see
Ans. 25.)
Appellant’s argument that none of the cited references performed
double-inactivation or used TALENs in primary T cells address the
Examiner’s findings or indicate why they were made in error is
unpersuasive. Appellant refers only to Dr. Poirot’s testimony that he did not
expect success. (See Appeal Br. 45–46.) Without further explanation or
support, we are not persuaded that the cited prior art would not have
provided such an expectation.
Accordingly, we are not persuaded that the Examiner erred in
rejecting claim 91 under 35 U.S.C. § 103(a).
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Conclusion
Upon consideration of the record and for the reasons given, we affirm
the Examiner’s rejections.
In summary:
Claims
Rejected
35 U.S.C. § Basis/Reference(s) Affirmed Reversed
49, 59, 62,
72–75, 83–
85, 89–91
112, first
paragraph
Written
Description
49, 59, 62,
72–75, 83–
85, 89–91

49, 59, 62,
72–75, 83–
85
112, first
paragraph
Enablement 49, 59, 62,
72–75, 83–
85

49, 59, 62,
72–91
112, second
paragraph
Indefiniteness 49, 59, 62,
72–91

76–78, 86,
89, 90
103(a) Cooper, Arthaud,
Gregory,
Fahrenkrug,
GenBank
Accession No.
X02883.1, Kaplan
76–78, 86,
89, 90

91 103(a) Cooper, Arthaud,
Gregory,
Fahrenkrug, June
91
Overall
Outcome
49, 59, 62,
72–91

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.

AFFIRMED