University of South Carolina

Patent Trials and Appeals Board

Oct 13, 2020

2020002013 (P.T.A.B. Oct. 13, 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.
15/347,996 11/10/2016 Boris Kantor USC-499 (1175) 2686
22827 7590 10/13/2020
DORITY & MANNING, P.A.
POST OFFICE BOX 1449
GREENVILLE, SC 29602-1449
EXAMINER
HAMMELL, NEIL P
ART UNIT PAPER NUMBER
1636
NOTIFICATION DATE DELIVERY MODE
10/13/2020 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):
USDOCKETING@DORITY-MANNING.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte BORIS KANTOR
__________

Appeal 2020-002013
Application 15/347,996
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
JOHN G. NEW, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a viral
vector. 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 the
University of South Carolina (see Appeal Br. 3).
2 We have considered the Specification of Nov. 10, 2016 (“Spec.”); Final
Office Action of Dec. 4, 2018 (“Final Action”); Appeal Brief of July 1, 2019
(“Appeal Br.”); and Examiner’s Answer of Oct. 21, 2019 (“Ans.”).
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Statement of the Case
Background
“The ability to alter the function of a targeted gene through genome
editing is desirable for both research and therapeutic perspectives” (Spec.
¶ 3). However, “significantly reduced levels of transgene expression in non-
integrating systems as compared to integrating systems remains a key issue
in developing clinically effective non-integrating gene editing vectors” (id. ¶
7). The Specification teaches “a delivery platform for use in gene editing”
that may “include a relatively short, highly efficient promoter that drives
transcription of a nucleic acid sequence that encodes a gene-editing
molecule, e.g., either a gRNA or a nuclease” (id. ¶ 27).
The Claims
Claims 1–7, 9, 10, 12, 15–18, and 20–25 are on appeal. Claim 1 is the
sole independent claim, is representative and reads as follows:
1. A viral vector comprising:
a region defined between a 5’ LTR and either a 3’ LTR or
a post-transcriptional regulatory element, the region containing
no additional LTRs;
a first transcription factor binding element within the
region, wherein the first transcription factor binding element is
an Sp1 transcription factor binding element or an NF-κB
transcription factor binding element;
a promoter within the region, wherein the promoter is an
RNA polymerase Ill promoter or an RNA polymerase II
promoter; and
a nucleic acid sequence encoding a gene editing molecule
within the region and operably linked to the promoter such that
the promoter is configured to initiate transcription of the nucleic
acid sequence encoding the gene editing molecule.

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The Rejections
A. The Examiner rejected claims 1–7, 9, 10, 12, 17, 18, 20, and 22–24
under U.S.C. § 103(a) as obvious over Sanjana,3 Hioki,4 Isomura,5 and
LentiCRISPR6 (Final Act. 3–6).
B. The Examiner rejected claims 15 and 16 under U.S.C. § 103(a) as
obvious over Sanjana, Hioki, Isomura, and Wanisch7 (Final Act. 6–7).
C. The Examiner rejected claims 21 and 25 under U.S.C. § 103(a) as
obvious over Sanjana, Hioki, Isomura, and Miyoshi8 (Final Act. 7–8).

A. 35 U.S.C. § 103(a) over Sanjana, Hioki, Isomura, and LentiCRISPR
The Examiner finds Sanjana teaches a “viral vector system
comprising a viral vector comprising a region defined between a 5ʹ LTR and
a 3ʹ LTR, the region containing no additional LTRs” and that “comprises a
U6 promoter (i.e. an RNA polymerase III promoter) . . . operably linked to a
nucleic acid sequence encoding a guide RNA (i.e. a gene editing molecule)”
(Final Act. 3). The Examiner finds the “promoter is configured to initiate
transcription of the nucleic acid sequence encoding the gene editing

3 Sanjana et al., Improved vectors and genome-wide libraries for CRISPR
Screening, 11 Nat. Methods, 783–4 (2014).
4 Hioki et al., Efficient gene transduction of neurons by lentivirus with
enhanced neuron-specific promoters, 14 Gene Therapy, 872–82 (2007).
5 Isomura et al., Two Sp1/Sp3 Binding Sites in the Major Immediate-Early
Proximal Enhancer of Human Cytomegalovirus Have a Significant Role in
Viral Replication, 79 J. Virology 9597–607 (2005).
6 LentiCRISPR, https://www.addgene.org/52961/, accessed July 7, 2017.
7 Wanisch et al., Integration-deficient Lentiviral Vectors: A Slow
Coming of Age, 17 Molecular Therapy 1316–32 (2009).
8 Miyoshi et al., Development of a Self-Inactivating Lentivirus Vector, 72 J.
Virology 8150–7 (1998).
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molecule” (id.). The Examiner acknowledges that “Sanjana does not
explicitly teach whether there is a Sp1 transcription factor binding element
or a NF-κB transcription factor binding element within the region” (Final
Act. 3).
The Examiner finds Hioki teaches lentiviral vectors and that “the
addition of human CMV enhancer immediately upstream of the neuron -
specific promoter resulted in increased expression levels in all hybrid
promoters tested” (Final Act. 3). The Examiner finds “Isomura describes
that the proximal enhancer of HMCV contains two Sp1 binding sites as well
as a NF-κB binding site” (id. at 4).
The Examiner finds it obvious to place “the human CMV enhancer of
Isomura immediately upstream of the EFS promoter [of Sanjana] . . . for the
advantage of increasing the gene expression of Cas9 as discussed by Hioki
who provides clear instructions to use the CMV enhancer to improve the
transcriptional activities of cellular promoters” (Final Act. 4).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that Sanjana,
Hioki, Isomura, and LentiCRISPR render the claims obvious?
Findings of Fact
1. Sanjana teaches “[t]o create a new vector capable of producing
higher-titer virus (lentiCRISPRv2), we made several modifications,
including removal of one of the nuclear localization signals, human-codon
optimization of the remaining nuclear localization signal and P2A bicistronic
linker sequences, and repositioning of the U6-driven sgRNA cassette”
(Sanjana 783, col. 1–2).
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2. Sanjana teaches the viral vector “changes resulted in an
approximately tenfold increase in functional viral titer over that of
lentiCRISPRv1” (Sanjana 783, col. 2).
3. Sanjana teaches that gene editing molecules “Cas9 (lentiCas9-
Blast) and sgRNA (lentiGuide-Puro) are delivered” in the viral vector and
that “the single-vector lenti-CRISPRv2 may be better suited for in vivo or
primary-cell screening applications” (Sanjana 784, col. 1).
4. LentiCRISPR evidences that Sanjana’s viral vector includes a
CMV early promoter, the human U6 promoter (a RNA polymerase III
promoter), guide RNA scaffold for CRISPR/Cas 9 system, and a CMV
immediate early enhancer (LentiCRISPR 1, 5).
5. Hioki teaches “[m]any gene delivery vectors have used viral
promoters, particularly cytomegalovirus (CMV) or rous sarcoma virus
promoter, because they have high transcription activities in all the infected
cells” (Hioki 872, col. 1–2). Hioki teaches “it is indispensable to utilize
neuron-specific promoters for stable neuron-specific expression” (Hioki 872,
col. 2).
6. Hioki “developed novel hybrid promoters by fusing CMV
enhancer to neuron-specific promoters, and quantitatively examined their
characteristics in vivo with VSV-G-pseudotyped lentiviral vectors” (Hioki
876, col. 2).
7. Hioki teaches “[a]fter addition of CMV enhancer to neuron-
specific promoters . . . the expression levels were increased by about two- to
four-fold in all the hybrid promoters” (Hioki 876, col. 2).
8. Isomura teaches that “[i]n the proximal enhancer of HCMV,
there are two Sp1/Sp3 binding sites (GC boxes)” and that the enhancer also
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contains NF-κB transcription binding sites (see Isomura 9598, col. 1).
9. Isomura teaches the “two Sp1 and Sp3 binding sites located in
the MIE proximal enhancer of the HCMV enhanced transcription in
transient transfection assay” (Isomura 9601, col. 2)
Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992). “The combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416
(2007).
Analysis
We adopt the Examiner’s findings of fact and conclusion of law (see
Final Act. 3–6, FF 1–8) and agree that Sanjana, Hioki, Isomura, and
LentiCRISPR render claim 1 obvious. We address Appellant’s arguments
below.
Appellant contends “the vectors described by Sanjana have been
designed with multiple modifications as compared to their first-generation
vectors, and these modifications have vastly improved the functional viral
titer over the first-generation vectors. Therefore, the problem proffered by
the Examiner has already been solved by Sanjana” (Appeal Br. 12).
We find this argument unpersuasive because in an obviousness
analysis, “[w]e start from the self-evident proposition that mankind, in
particular, inventors, strive to improve that which already exists.” Pro–Mold
& Tool Co., Inc. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1573 (Fed. Cir.
1996). Here, the ordinary artisan would have had reason to further increase
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expression levels in the LentiCRISPR vector in order to increase
transcription and translation levels, as Hioki explains “[m]any gene delivery
vectors have used viral promoters, particularly cytomegalovirus (CMV) or
rous sarcoma virus promoter, because they have high transcription
activities” (FF 5). Thus, the ordinary artisan, interested in improving
expression, would have reasonably considered the superior CMV enhancer
(FF 4, 7, 9).9
Appellant contends:
the promoters of Sanjana are simply not equivalent to the
promoters of Hioki. The promoters of Sanjana are not neuron-
specific promoters (or the more generic type of tissue-specific
promoters), and they are not weak in transcription activity.
Rather, they are well known in the art of gene editing, and
known to function efficiently and precisely in a wide variety of
mammalian systems and host cell types by providing a well-
defined transcription initiation site for a gene-editing
component of a vector.
(Appeal Br. 15).
We find this argument unpersuasive because promoters are a
necessary component for gene transcription, and promoter selection is based
on a variety of parameters including the cell type (see, e.g., FF 5). As the
Examiner finds in the Final Action, Hioki “provides clear instructions to use
the CMV enhancer to improve the transcriptional activities of cellular
promoters” (Final Act. 4; FF 9). Thus, an artisan interested in using a
promoter that functions in a wide variety of cells would select the CMV
promoter (FF 5) and would have had reason to further employ CMV

9 We also agree with the Examiner’s point that improvement to viral titers in
Sanjana is not the same as improvements to gene transcription as discussed
by Hioki (see Ans. 10; cf. FF2 and FF 5).
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enhancer components that were known to improve transcription of the
desired RNA (FF 7, 9).
Appellant contends the “Office has articulated no finding to support a
contention that all promoters are considered to be equivalent to one another
in the art” (Appeal Br. 15).
We find this argument unpersuasive because the Examiner does not
rely on promoter equivalence but rather on the reasoning that the
“combination of familiar elements according to known methods is likely to
be obvious when it does no more than yield predictable results.” KSR, 550
U.S. at 416 (see Final Act. 4). Rather, the Examiner finds that the CMV
promoter and enhancer are superior choices for improved expression (FF 5,
7, 9).
Appellant asserts:
the expected results of adding the CMV enhancer element to the
highly functioning vector of Sanjana would have been
unknown. The vectors of Sanjana have already been modified
so as to be highly functioning, and there is simply no support
for the suggestion that adding the CMV enhancer to the vectors
of Sanjana, which have high functioning promoters, would have
the same effect as adding the CMV enhancer to the vectors of
Hioki that include tissue-specific and transcriptionally weak
promoters.
(Appeal Br. 17).
We find this argument unpersuasive because Hioki teaches the CMV
promoter has “high transcription activities in all the infected cells” (FF 5)
and both Hioki and Isomura teach that the use of the CMV enhancer results
in increased transcription (FF 7, 9). Therefore, both Hioki and Isomura
support a general expectation of success in improving transcription using the
CMV promoter and enhancer. “Obviousness does not require absolute
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predictability of success . . . all that is required is a reasonable expectation
of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). Appellant
provides no evidence, as opposed to argument, that there would not have
been a reasonable expectation of success here using well known promoters
and enhancers.
Appellant asserts the use of the CMV enhancer “would also be
unpredictable as it could lead to the reintroduction of undesirable features in
the Sanjana context, such as epigenetic silencing as is known to occur with
CMV promoters as discussed in the captioned application” (Appeal Br. 19).
We find this argument unpersuasive for several reasons. First,
Appellant does not identify any specific part of the Specification that teaches
the use of the CMV enhancer would result in epigenetic silencing. The only
apparent disclosure regarding silencing in the Specification occurs in
paragraph 7, in the context of negative elements, not shown to be present in
the CMV enhancer. Second, this entire argument regarding unpredictability
is simply attorney argument without evidence regarding the rejection as
presented by the Examiner. See In re De Blauwe, 736 F.2d 699, 705 (Fed.
Cir. 1984)
Conclusion of Law
A preponderance of the evidence of record support the Examiner’s
conclusion that Sanjana, Hioki, Isomura, and LentiCRISPR render the
claims obvious.

B. U.S.C. § 103(a) further including Wanisch or Miyoshi
Appellant does not separately argue these obviousness rejections,
instead relying upon their arguments to overcome the combination of
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Sanjana, Hioki, Isomura, and LentiCRISPR. We do not find these
arguments persuasive for the reasons given above. The Examiner provides
sound fact-based reasoning for combining Wanisch and Miyoshi (see Final
Act. 6–8). Having affirmed the obviousness rejection of claim 1 over
Sanjana, Hioki, Isomura, and LentiCRISPR, we also find that the further
combinations with Wanisch and Miyoshi renders the rejected claims obvious
for the reasons given by the Examiner.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. §  Reference(s)/Basis Affirmed Reversed
1–7, 9, 10,
12, 17, 18,
20, 22–24
103  Sanjana, Hioki,
Isomura,
LentiCRISPR
1–7, 9, 10,
12, 17, 18,
20, 22–24

15, 16 103 Sanjana, Hioki,
Isomura, Wanisch
15, 16
21, 25 103 Sanjana, Hioki,
Isomura, Miyoshi
21, 25
Overall
Outcome
1–7, 9, 10,
12, 15–18,
20–25

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