Tocagen Inc.

Patent Trials and Appeals Board

Mar 16, 2020

14438564 - (D) (P.T.A.B. Mar. 16, 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.
14/438,564 04/24/2015 Harry E. Gruber 00014-017US1 1026
26138 7590 03/16/2020
Joseph R. Baker, APC
Gavrilovich, Dodd & Lindsey LLP
4370 La Jolla Village Drive, Suite 303
San Diego, CA 92122
EXAMINER
QIAN, CELINE X
ART UNIT PAPER NUMBER
1636
MAIL DATE DELIVERY MODE
03/16/2020 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
_________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
_________________

Ex parte HARRY E. GRUBER, DOUGLAS J. JOLLY, AMY H. LIN,
CHRISTOPHER R. LOGG, and NORIYUKI KASAHARA

_________________

Appeal 2019-000177
Application 14/438,564
Technology Center 1600
_________________

Before JEFFERY N. FREDMAN, DEBORAH KATZ, and JOHN E.
SCHNEIDER 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 1–9, 12, 16–18, 20–23, 25–32, 34–38,

1 We use the word “Appellant” as defined in 37 C.F.R. § 1.42. Appellant
identifies the real party-in-interest as Tocagen Inc. (Appeal Br. 2.)
2 We consider the Final Office Action issued May 4, 2017 (“Final Act.”), the
Appeal Brief filed April 5, 2018 (“Appeal Br.”), the Examiner’s Answer
issued on August 8, 2018 (“Ans.”), and the Reply Brief filed
October 8, 2018 (“Reply Br.”).
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51, and 52.3 (App. Br. 1.) We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE and enter a NEW GROUND OF REJECTION.
Appellant’s specification is directed to retroviral vectors for delivering
heterologous nucleic acids to cells in gene therapy. (See Spec. ¶ 2.)
Appellant’s claim 1 recites:
A recombinant replication competent gammaretrovirus
comprising:
a retroviral GAG protein;
a retroviral POL protein;
a retroviral envelope;
a retroviral polynucleotide comprising Long-Terminal Repeat
(LTR) sequences at the 3' end of the retroviral polynucleotide
sequence, a promoter sequence at the 5' end of the retroviral
polynucleotide, said promoter being suitable for expression in a
mammalian cell, a gag nucleic acid domain, a pol nucleic acid domain
and an env nucleic acid domain;
a therapeutic cassette comprising at least one mini-promoter
cassette having a mini-promoter that is regulated by an RNA
polymerase II, wherein the mini-promoter is about 70-500 bp in
length and operably linked to a heterologous polynucleotide, wherein
the therapeutic cassette is positioned 5' to the 3' LTR and 3' to the env
nucleic acid domain encoding the retroviral envelope, and wherein
when only one mini-promoter cassette is present the heterologous
polynucleotide is 1.2kb to 2.0 kb in length; and
cis-acting sequences necessary for reverse transcription,
packaging and integration in a target cell.

(App. Br. 28 (emphasis added).) Claim 1 recites a gammaretrovirus with
several limitations on a “therapeutic cassette” that is positioned 5' to the 3'

3 The Examiner includes claim 19 in the rejections (see, e.g. Ans. 3), but
Appellant’s listing of claim indicates that claim 19 was canceled (see Appeal
Br. 30.) Accordingly, we do not include claim 19 in our recitation of the
specific rejections.
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LTR and 3' to the env nucleic acid domain encoding the retroviral envelope.
The “therapeutic cassette” of claim 1 must have a “mini-promoter” that is
(1) regulated by RNA polymerase II, (2) about 70-500 bp long, (3) operably
linked to a heterologous polynucleotide.
35 U.S.C. § 102(b) over Kasahara
The Examiner rejects claims 1, 3, 5–9, 12, 16–18, 20, 26–32, 34, 37
and 38 under 35 U.S.C. § 102(b) as being anticipated by Kasahara.4 (See
Ans. 3–4.)
Kasahara teaches a recombinant retrovirus for gene delivery. (See
Kasahara abstract.) Appellant does not dispute that the recombinant
retrovirus taught in Kasahara has many of the elements recited in
Appellant’s claim 1, including: retroviral GAG, POL, and ENV proteins;
LTR sequences at the 5ʹ and 3ʹ ends; a 5’ promoter suitable for expression in
a mammalian cell of the gag, pol, and env nucleic acids; a heterologous
nucleic acid sequence operably linked to a regulatory nucleic acid sequence;
and cis-acting sequences to express proteins necessary for reverse
transcription, packaging, and integration of a heterologous nucleic acid in a
target cell. (See Kasahara ¶ 9; see Ans. 3; see Appeal Br. 10.)
Appellant does dispute that the heterologous nucleic acid sequence
operably linked to a regulatory nucleic acid sequence taught in Kasahara is a
therapeutic cassette comprising a “minipromoter” as required in claim 1.
(See Appeal Br. 8–11.) We agree with Appellant. Although Kasahara
teaches using a portion of the probasin promoter meeting the size

4 U.S. Patent Application 2005/0002903 A1, published January 6, 2005.
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Application 14/438,564

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requirements of claim 1 in a retroviral vector (see Kasahara ¶¶ 131-32), this
minimal promoter sequence is not “positioned 5' to the 3' LTR and 3' to the
env nucleic acid domain encoding the retroviral envelope,” as required in
claim 1. “A claim is anticipated only if each and every element as set forth
in the claim is found, either expressly or inherently described, in a single
prior art reference.” Verdegaal Bros. v. Union Oil Co. of California, 814
F.2d 628, 631 (Fed. Cir. 1987). Thus, we agree that claim 1 is not
anticipated by Kasahara.
The Examiner cites to Figure 2B of Kasahara to show the positioning
of the probasin promoter. (See Ans. 12.) Figure 2B of Kasahara is
reproduced below.

Figure 2B depicts IRES (internal ribosome entry site) and transgene
sequences located 3ʹ to the env gene sequence and 5ʹ to the 3ʹ LTR sequence.
Figure 2B depicts other sequences labeled “TISSUE SPECIFIC
PROMOTER ELEMENTS” in the 3ʹ LTR.
Kasahara explains that a “target specific polynucleotide sequence of
the retroviral vector can be a tissue-specific promoter sequence, for example
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a sequence associated with a growth regulatory gene, such as, for example,
probasin.” (Kasahara ¶ 9.) Example 6 of Kasahara explains further that “[a]
fragment of the rat probasin androgen-sensitive promoter (from -426 to +28)
that has been shown to specify prostate-specific gene expression has been
engineered into the U3 region of the retroviral 3' LTR in both ecotropic and
amphotropic RCR vectors.” (Kasahara ¶ 132.) Thus the tissue-specific
promoter probasin, is located in the 3ʹ LTR of the recombinant retrovirus of
Kasahara. This element corresponds to the element labeled “TISSUE
SPECIFIC PROMOTER ELEMENTS” in Figure 2B, not to the elements
labeled “IRES” and “transgene” in Figure 2B.
In comparison, Figure 8B of Appellant’s Specification depicts a
therapeutic cassette as recited in Appellant’s claim 1. (See Appeal Br. 10–
11.) The portion of Figure 8B highlighted by Appellant is reproduced
below.

This portion of Figure 8B depicts an element labeled “RSV,” which
Appellant has also labeled “mini-promoter” and which is 3ʹ to the env gene
and 5ʹ to the 3ʹ LTR.
A comparison of Figure 2B of Kasahara and Figure 8B of Appellant’s
Specification shows that the tissue-specific probasin promoter taught in
Kasahara would not be in the location of the mini-promoter of Figure 8B.
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The Examiner acknowledges that Figure 8 of Appellant’s
Specification differs from Figure 2B of Kasahara, but finds that elsewhere
Kasahara teaches heterologous sequences operably linked to a promoter with
other examples of integration sites. (See Ans. 13, citing Kasahara ¶ 73.)
Kasahara teaches
The heterologous sequence can be linked to a promoter, resulting in a
chimeric gene. The heterologous nucleic acid sequence is preferably
under control of either the viral LTR promoter-enhancer signals or of
an internal promoter, and retained signals within the retroviral LTR
can still bring about efficient integration of the vector into the host
cell genome. Accordingly, the recombinant retroviral vectors of the
invention, the desired sequences, genes and/or gene fragments can be
inserted at several sites and under different regulatory sequences.

(Kasahara ¶ 73.) Although this passage suggests control by various
regulatory sequences, it does not teach arrangement of a mini-promoter as
required in claim 1. We disagree with the Examiner that it supports
anticipation of claim 1.
The Examiner also finds that the claim term “minipromoter”
encompasses an IRES as taught in Kasahara because an IRES sequence
includes minimal elements necessary for translation of an operably linked
coding sequence. (See Ans. 12.) We are not persuaded that an IRES
sequence, which acts provides for initiation of translation from an internal
ribosome binding site, falls within the definition of “mini-promoter” being
“a regulatory domain that promotes transcription of an operably linked gene
or coding nucleic acid sequence” provided in Appellant’s Specification.
(Spec. ¶ 41, see also id. at ¶ 4.)
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7
Because the Examiner fails to show that Kasahara teaches the
limitations of a “therapeutic cassette” as recited in claim 1, we reverse the
rejection of claim 1 and the claims that depend on it.
35 U.S.C. § 102(e) over Gruber
The Examiner rejects claims 1–9, 12, 16–18, 20, 23, 25–32, 34–38,
51, and 52 under 35 U.S.C. § 102(e) as being anticipated by Gruber.5 (See
Ans. 4–6.)
The Examiner asserts that Gruber teaches a therapeutic cassette
comprising a mini-promoter cassette operably linked to a heterologous
polynucleotide and positioned 5ʹ to the 3ʹ LTR and 3ʹ to the env nucleic acid.
(See Ans. 5, citing Gruber 1:32–45.) The Examiner finds that Gruber
teaches a CMV promoter of 582 nucleotides, as well as an RSV promoter
and a CMV-R-U5 promoter. (See Ans. 5, citing Gruber 1:61–66, 2:1–5, and
24:46.)
Appellant’s arguments against the rejection over Gruber are similar to
those against the rejection over Kasahara. Appellant argues that Gruber
does not teach a “therapeutic cassette” meeting the requirements recited in
claim 1. (See Appeal Br. 13–15.) Specifically, Appellant argues that
although Gruber teaches a recombinant retrovirus comprising GAG, POL,
and ENV proteins and LTRs, it teaches that the retrovirus includes a cassette
comprising an IRES operably linked to a heterologous polynucleotide,
instead of a minipromoter. (See Appeal Br. 14.) Appellant asserts, and we
agree, that an IRES nucleotide is not a promoter sequence.

5 U.S. patent 8,829,173 B2, issued September 9, 2014.
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Appellant argues further that the teachings in Gruber of RNA
polymerase II promoters, such as the CMV promoter, do not meet the
requirements of Appellant’s claims because these promoters are located in
the LTRs, not in a therapeutic cassette as claimed. Appellant cites Figures
1A and 3 of Gruber in support, arguing that the 582 nucleotides of the CMV
promoter are in the LTR, not downstream of the env gene and upstream of
the 3ʹ LTR as required in claim 1. (See Appeal Br. 15.) Figure 3A of
Gruber is reproduced below.

Figure 3A provides a schematic drawing of a retrovirus genome, including
the notation “CMV” in the R-U5 element. We agree with Appellant that the
CMV element is not 3ʹ to the env gene in Figure 3A. Although Gruber
teaches heterologous sequences that can include promoter elements (see
Gruber 24:24–30; see Ans. 7), Gruber does not teach that such “cassettes”
are positioned between the env gene and the 3ʹ LTR.
Accordingly, we agree with Appellant that Gruber does not anticipate
claim 1 or the claims that depend on it.
The Examiner’s rejection for anticipation by Gruber includes
Appellant’s independent claim 51. (See Ans. 4.) Claim 51 recites “a
therapeutic cassette comprising a mini-promoter cassette operably linked to
a heterologous polynucleotide and a miRNA cassette comprising a polIII
promoter linked to a primary precursor miRNA (pri-miRNA) for an miRNA
or siRNA sequence . . . .” (Appeal Br. 34.)
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9
Although the Examiner finds that Gruber teaches a polIII promoter
(see Ans. 6 and 15, citing Gruber 17:30–366), we agree with Appellant that
the Examiner fails to show that Gruber teaches a therapeutic cassette with
two promoters, specifically with a mini-promoter and a polIII promoter that
are arranged together in a therapeutic cassette. (See Appeal Br. 15.)
Because the Examiner fails to show that Gruber teaches each and
every claim of either claim 1 or claim 51, we reverse the rejection of these
claims and the claims that depend on them.
Obviousness-type double-patenting
The Examiner made the following rejections under the doctrine of
obviousness-type double-patenting:
claims 1–9, 12, 16–18, 20–23, 25–32, 34–38, 51, and 52 over claims
1–29 of patent 8,829,173 (see Ans. 7);
claims 1–9, 12, 16–18, 20–23, 25–32, 37, and 38 over claims 1–13 of
patent 8,652,460 (see id.at 7–8);
claims 1–9, 12, 16–18, 20–23, 25–32, 37, and 38 over claim 21, 23–
25, and 51–61 of application 13/882,487, which issued as patent 9,669,049
(see id. at 8–9);
claims 1–9, 12, 16–18, 20–23, 25–32, 37, and 38 over claims 1–3, and
7–23 of application 14/274,556, which issued as patent 10,035,983 (see id.
at 8–9);

6 Although the Examiner cites to column 17 of Gruber for a teaching of the
polIII promoter, polIII is not mentioned there. Instead, column 18, lines 49–
52 of Gruber refer to polIII, reciting: “[a]lternatively polIII transcription
units can be inserted in the viral genome with the appropriate siRNA or
miRNA's, typically downstream of the 3' envelope gene.”
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claims 1–9, 12, 16–18, 20–23, 25–32, 37, and 38 over claims 1–8, 12–
22, 27–29, 37, 38, and 54–57, and 61–64 of application 14/477,741 which
issued as claims 1–13 of patent 9,732,326 (see id. at 9).7
For each of these rejections, the Examiner states that “[a]lthough the
claims at issue are not identical, they are not patentably distinct from each
other because the claimed retrovirus comprises elements that overlaps in
scope” with the recited patent or application. (See, e.g., Ans. 7.) The
Examiner relies on reasoning similar to that asserted for the rejections under
35 U.S.C. § 102(b) and (e). (See Ans. 15–22.) For example, the Examiner
cites to the descriptions of the probasin promoter and IRES sequences in the
specification of patent 8,652,460 in an argument that the patent claims recite
a therapeutic cassette with a mini-promoter as Appellant currently claims.
(Ans. 17.)
For the reasons provided above, we are not persuaded that Appellant’s
claims are obvious over the claims of any of the recited patents or
applications because the recited patents and applications have not been
shown to teach or suggest a therapeutic cassette with the limitations recited
in independent claims 1 or 51. Accordingly, we reverse the Examiner’s
rejections under the doctrine of obviousness-type double-patenting.
New Ground of Rejection
Appellant does not dispute that both Kasahara and Gruber teach
recombinant retroviruses comprising many of the elements recited in claim

7 The Examiner also rejected Appellant’s claims 1–9, 12, 16–23, 25–32, 37,
and 38 over the claims of applications 13/638,490 and 15/016,201, but these
applications have been abandoned. (See Ans. 8 and 9.)

Appeal 2019-000177
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11
1, including: GAG, POL, and ENV proteins; LTR sequences at the 5ʹ and 3ʹ
ends; a 5’ promoter suitable for expression in a mammalian cell of the gag;
pol, and env nucleic acids; a heterologous nucleic acid sequence operably
linked to a regulatory nucleic acid sequence; and cis-acting sequences to
express proteins necessary for reverse transcription, packaging, and
integration of a heterologous nucleic acid in a target cell. (See Kasahara ¶ 9;
see Gruber 1:32–48.)
Both Kasahara and Gruber teach a “transgene cassette” that is located
3’ to the env gene sequencer and 5’ to the 3’ LTR. (See Kasahara ¶ 115,
Fig. 2; see Gruber 1:40–44, Fig. 3A.) Although these cassettes, as a whole,
are positioned as required in claim 1, neither Kasahara nor Gruber teaches a
therapeutic cassette as recited in claim 1 because both teach regulation of the
transgene by an IRES sequence, not a “mini-promoter” about 70-500 bp in
length.
According to the specification of both Kasahara and Gruber, IRES
sequences are a type of regulatory nucleic acid sequences that provide for
the replication, transcription and translation of a coding sequence in a
recipient cell. (See Kasahara ¶ 71; see Gruber 20:66–21:16.) Thus, the
IRES sequences taught in Kasahara and Gruber promote the expression of
the heterologous gene in the therapeutic cassette of claim 1.
Other means of promoting expression of a heterologous gene
expression were known in the art as of Appellant’s filing date. For example,
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12
Zhao-Emonet8 demonstrates that mini-promoters were known in the field of
retroviral gene therapy. Specifically, Zhao-Emonet teaches that gene
therapy vectors “can be designed by placing a gene of therapeutic interest
under the control of tissue-specific transcriptional elements.” (Zhao-Emonet
abstract.) More specifically, Zhao-Emonet teaches using a 190 bp human
minimal CD4 promoter in a Mo-MLV retroviral construct to drive
expression of EGFP. (See Zhao-Emonet 417.) This promoter falls within
the limitations of a mini-promoter as recited in Appellant’s claim 1.
Those of ordinary skill in the art would have had a reason to use a
mini-promoter as taught in Zhao-Emonet in the retroviruses of Kasahara and
Gruber instead of the IRES sequences because Papadakis9 teaches that “gene
therapy applications would . . . benefit from the specific optimisation of
‘tailormade’ expression cassettes to optimise their therapeutic efficacy.”
(Papadakis abstract.) Papadakis teaches further that “vector expression
cassettes to add further tissue selectivity (transcriptional targeting), may
yield significant advantages in gene therapy and serve to minimise the input
titer required to evoke a phenotypic response in vivo.” (Papadakis 89.)
Because one of ordinary skill would have had a reasonable expectation of
success in making a retroviral vector with mini-promoter regulatory
sequences to a recombinant retroviral vector in the position of the IRES
sequences taught in Kasahara and Gruber using the cloning techniques

8 Zhao-Emonet et al., “T Cell-specific expression from MoMLV retroviral
vectors containing a CD4 min-promoter/enhancer,” Journal of Gene
Medicine 2(416–25 (2000).
9 Papadakis, et al., “Promoters and Control Elements: Designing Expression
Cassettes for Gene Therapy,” Current Gene Therapy 4:89–113 (2004).
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13
described in Zhao-Emonet, it would have been obvious to make the vector
recited in Appellant’s claim 1. (See Zhao-Emonet 417.)
Accordingly, we enter a new ground of rejection of claim 1 under 35
U.S.C. § 103(a) over the combined teachings of Kasahara or Gruber, Zhao-
Emonet, and Papadakis.
We limit our consideration to claim 1. We leave it up to the Examiner
to consider the remaining claims in light of these references and other prior
art. The PTAB serves as a board of review, not a de novo examination
tribunal. See 35 U.S.C. 6(b).

Conclusion
Upon consideration of the record and for the reasons given, we
REVERSE the Examiner’s rejections.
In summary:
Claims
Rejected
35 U.S.C.
§
Basis Affirmed Reversed New
Ground
1, 3, 5–9,
12, 16–18,
20, 26–32,
34, 37, 38
102(b) Kasahara 1, 3, 5–9,
12, 16–20,
26–32, 34,
37, 38

1–9, 12,
16–18, 20,
23, 25–32,
34–38, 51,
52
102(e) Gruber 1–9, 12,
16–18, 20,
23, 25–32,
34–38, 51,
52

1–9, 12,
16–18,
20–23,
25–32,
Obviousne
ss-type
Double
Patenting
over
1–9, 12,
16–18,
20–23,
25–32,

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14
34–38, 51,
52
claims 1–
29 of
patent
8,829,173
34–38, 51,
52
1–9, 12,
16–18,
20–23,,
25–32, 37,
38
Obviousne
ss-type
Double
Patenting
overs
claims 1–
13 of
patent
8,652,460
1–9, 12,
16–18,
20–23,
25–32, 37,
38

1–9, 12,
16–18,
20–23,
25–32, 37,
38

Obviousne
ss-type
Double
Patenting
over claim
21, 23–25,
and 51–61
of
application
13/882,48
7 (issued
as patent
9,669,049)
1–9, 12,
16–18,
20–23,
25–32, 37,
38

1–9, 12,
16–18,
20–23,
25–32, 37,
38

Obviousne
ss-type
Double
Patenting
over
claims 1–
3, and 7–
23 of
application
14/274,55
6, which
has issued
1–9, 12,
16–18,
20–23,
25–32, 37,
38

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as patent
10,035,98
310
1–9, 12,
16–18,
20–23,
25–32, 37,
38
Obviousne
ss-type
Double
Patenting
over
claims 1–
13 of
patent
9,732,326
1–9, 12,
16–18,
20–23,
25–32, 37,
38

1 103(a) Kasahara
or Gruber,
Zhoa-
Emonet,
and
Papadakis
1
Overall
Outcome
1–9, 12,
16–18,
20–23,
25–32,
34–38, 51,
52
1

This decision includes a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). 37 C.F.R. § 41.50(b) provides that “[a] new ground of
rejection ... shall not be considered final for judicial review.” 37 C.F.R.
§ 41.50(b) also provides that the Appellant:

10 As explained above, we do not reach this rejection per Ex parte Moncla,
Appeal No. 2009-006448 (PTAB June 22, 2010) (holding that it is
premature to address a provisional rejection) (designated precedential).

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WITHIN TWO MONTHS FROM THE DATE OF THE
DECISION, must exercise one of the following two options
with respect to the new ground of rejection to avoid termination
of the appeal as to the rejected claims:

(1) Reopen prosecution. Submit an appropriate amendment of
the claims so rejected or new Evidence relating to the claims so
rejected, or both, and have the matter reconsidered by the
examiner, in which event the prosecution will be remanded to
the examiner . . . .

(2) Request rehearing. Request that the proceeding be reheard
under § 41.52 by the Board upon the same record . . . .

(emphasis added).
REVERSED
37 C.F.R. § 41.50(b)