Ex Parte Yao

Patent Trial and Appeal Board

Aug 31, 2015

11117375 (P.T.A.B. Aug. 31, 2015)

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.
11/117,375 04/29/2005 Feng Yao 7570/84330 6291
66991 7590 08/31/2015
LAW OFFICE OF MICHAEL A. SANZO, LLC
15400 CALHOUN DR.
SUITE 125
ROCKVILLE, MD 20855
EXAMINER
MOSHER, MARY
ART UNIT PAPER NUMBER
1648
MAIL DATE DELIVERY MODE
08/31/2015 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 FENG YAO
_________

Appeal 2012-009015
Application 11/117,375
Technology Center 1600
__________

Before LORA M. GREEN, CHRISTOPHER G. PAULRAJ, and
ROBERT A. POLLOCK, Administrative Patent Judges.

PAULRAJ, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a
replication deficient HSV-1 viral vector. The Examiner rejected the claims
for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

1 Appellant identifies the Real Party in Interest as The Brigham and
Women’s Hospital, Inc. (see Br. 2).
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STATEMENT OF THE CASE
Background
The invention generally relates to herpes simplex virus type 1 (HSV-
1) “vectors in which gene expression is controlled using the tetracycline
operator and repressor.” Spec. 1 ll. 16–17.
According to the Specification:
Expression of sequences coding for the tetracycline repressor is
under the control of HSV-1 immediate-early promoters.
Because gene expression from HSV-1 immediate-early
promoters is significantly enhanced by the HSV-I virion-
associated transactivator VP-16 upon the entry of virus into a
host cell, a very high level of repressor expression occurs at the
time of infection. As a result, gene expression from promoters
under the control of tetracycline operator sequences is
essentially completely suppressed. Upon exposure of cells to
tetracycline, repressor is released from the operator sequence
and gene expression proceeds. Using this system, very high
levels of expression can be obtained in neurons in vivo and this
expression can be closely regulated.
Id. at 1 ll. 17–26.
The Claims
Claims 1–10 and 35–44 are under appeal. Independent
claim 1 is representative and reads as follows:
1. A replication deficient HSV -1 viral vector having a
genomic DNA construct comprising:
a) at least two tetR nucleotide sequences coding for the
tetracycline repressor, wherein the expression of each tetR
nucleotide sequence is under the control of a VP-16 responsive
immediate early promoter selected from the group consisting
of: the ICP-O immediate early promoter ofHSV-1; the ICP-4
immediate early promoter ofHSV-1; LAP2/ICPO; and
LAP2IICP4;
b) an additional promoter wherein said additional
promoter includes a TATA element;
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c) a tetracycline operator sequence positioned between 6
and 24 nucleotides 3' to said TATA element; and
d) a structural sequence whose expression is regulated by
said additional promoter and wherein
i) said viral vector does not include a functional
ICP-O gene and;
ii) said viral vector releases VP-16 that promotes
tetR gene expression from said VP-16 responsive immediate
early promoter at the time said viral vector infects a cell.

App Br. 14 (Claims Appendix).

The Rejections
The Examiner has rejected claims as follows:
I. Claims 1, 2, 4–6, 8, and 9 under 35 U.S.C. § 103(a) as being
unpatentable over the combination of Schmeisser,2 Yao,3 and
DeLuca.4
II. Claims 3, 7, and 35–44 under 35 U.S.C. § 103(a) as being
unpatentable over the combination of Schmeisser, Yao,
DeLuca, and Coffin.5
III. Claim 10 under 35 U.S.C. § 103(a) as being unpatentable over
the combination of Schmeisser, Yao, DeLuca, and Martinez.6

2 Schmeisser et al., Tetracycline-Regulated Gene Expression in Replication-
Incompetent Herpes Simplex Virus Vectors, 13, HUM. GENE THER. 2113,
2113–2124 (2002).
3 Yao et al., Tetracycline Repressor, tetR, rather than the tetR-Mammalian
Cell Transcription Factor Fusion Derivatives, Regulates Inducible Gene
Expression in Mammalian Cells, 9, HUM. GENE THER. 1939, 1939–1950
(1998).
4 DeLuca, US 6,261,552 B1, issued Jul.17, 2001.
5 Coffin et al., US 2004/0063094 A1, published Apr. 1, 2004.
6 Martinez et al., The Conserved Helicase Motifs of the Herpes Simplex
Virus Type 1 Origin-Binding Protein UL9 Are Important for Function, 66, J.
VIROLOGY 6735, 6735–6746 (1992).
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FINDINGS OF FACT
FF1. The Examiner finds:
Schmeisser teaches a replication-deficient HSV vector, with
a heterologous gene under the control of CMV IE promoter
and a tetracycline response element TRE (similar to a tet
operator), and a Tet transactivator protein under the control
of an ICPO promoter and the TRE. See Schmeisser Figure
5. Schmeisser teaches a burst of expression of the Tet
transactivator from the ICP0 promoter because of transient
activation by VP16 which is brought into the cell at the time
of vector infection, see page 2119.
Ans. 5.
FF2. The Examiner finds that “Schmeisser differs from the claimed
invention in using a single copy of a Tet transactivator gene
instead of two copies of a Tet repressor gene, and in failing to
teach the precise positioning of a tet operator sequence in relation
to a TATA element in the regulated promoter.” Id.
FF3. The Examiner finds that “Yao explicitly teaches the Tet
repressor as an alternative to a Tet transactivator: ‘the tetracycline
repressor (tetR) alone, rather than tetR-mammalian transcription
factor fusion derivatives, can function as a potent trans-modulator
to regulate gene expression in mammalian cells’ (Yao abstract).”
Id. at 6.
FF4. The Examiner finds that “[t]he Tet transactivator of Schmeisser
is just such a tetR-mammalian transcription factor fusion derivative
(see Schmeisser page 2114, first column, third paragraph).” Id.
FF5. The Examiner finds that “[a]lthough transactivation and
repression have opposite modes of action, both Tet transactivation
and Tet repression had been widely used in the art as alternative
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means of expression control at the time the invention was made
(see as evidence the reviews by Berens[7] or Corbel,[8] . . .” Id.
FF6. The Examiner finds:
Yao also teaches the use of Tet repressor to control a
promoter with the same TATA/operator positioning as
recited in the claims. See Yao Figure 1. Yao teaches that the
repressor control is able to achieve about 60-fold regulation
in vivo (abstract), and up to 3000-fold regulation in vitro
(Fig. 4, page 1948). Yao also suggests that the effectiveness
of control can be enhanced by increasing the molar ratio of
the Tet repressor coding sequence, see the passage spanning
pages 1942-1943.
Id.
ANALYSIS
The claimed invention utilizes a DNA construct having a sequence
coding for the tetracycline repressor (tetR) whose expression is under the
control of an HSV-1 immediate early (IE) promoter that is induced by the
transactivator protein VP-16. As explained by Appellant, “[t]he significance
of this arrangement is that VP-16 is released immediately upon the infection
of host cells by herpes simplex virus-1 (HSV-1),” and thereafter “VP-16
activates the IE promoter causing a burst of repressor protein at the time of
infection.” Br. 8. The receptor protein acts on the tet operator (tetO)
sequence in the construct, thereby immediately shutting down expression of
the recombinant gene until tetracycline is introduced into the system at a

7 Berens et al., Gene regulation by tetracyclines, Constraints of resistance
regulation in bacteria shape TetR for application in eukaryotes, 270, EUR. J.
BIOCHEM. 3109, 3109–3121 (2003).
8 Corbel et al., Latest developments and in vivo use of the Tet system: ex
vivoand in vivo delivery of tetracycline-regulated genes, 13, CURR. OPIN.
BIOTECHNOL. 448, 448–452 (2002).
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later point to cause the repressor protein to be released. Id. at 8–9 (see Figs.
1–2).
The Examiner has rejected independent claim 1 as obvious over the
combination of Schmeisser, Yao, and DeLuca. The Examiner relies upon
Schmeisser’s teaching of tetracycline-regulated gene expression in
replication incompetent HSV vectors, in which the production of a “Tet
transactivator protein” (rtTA) is under the control of an ICP0 promoter and a
tetracycline response element (TRE). FF1. The Examiner acknowledges,
however, that “Schmeisser differs from the claimed invention in using a
single copy of a Tet transactivator gene instead of two copies of a Tet
repressor gene, and in failing to teach the precise positioning of a tet
operator sequence in relation to a TATA element in the regulated promoter.”
FF2. The Examiner therefore relies upon Yao’s teaching of tetR as an
alternative to the transactivator protein of Schmeisser. FF3–6.
While this is a close case, we determine that the preponderance of the
evidence does not establish a prima face showing of obviousness. Similar to
how the VP-16 responsive IE promoter utilized in the claimed invention
functions, Schmeisser teaches that the TRE/ICP0 promoter causes a “burst
of expression” of the transactivator protein due to VP-16 brought into the
cell at the time of vector infection. FF1; Schmeisser, 2119. But, as noted by
Appellant, Schmeisser’s ICP0 promoter leads to the opposite of what is
required by the claims, insofar as the transactivator induces gene expression
in the presence of tetracycline whereas tetR suppresses gene expression until
tetracycline is introduced. See Declaration Under 37 C.F.R. § 1.132 of Dr.
Feng Yao, ¶ 6(B) (Schmeisser’s “transactivator does not function in the
same way that a repressor functions in that, upon binding to tet operator
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sequences (see TRE in figure 5), it stimulates transcription rather than
blocking it.”).
We recognize that Yao teaches that gene expression may be repressed
using tetR in a plasmid vector where the tetO sequence is positioned
downstream of the promoter containing the TATA element. FF6; Yao,
1947. Indeed, even without a VP-16 responsive promoter, Yao teaches that
13-fold repression was detected 1 day after gene transfer and 60-fold
repression was detected on day 2 after gene transfer in the absence of
tetracycline. Yao, 1946. However, the Examiner has not identified any
teaching or suggestion in Yao, nor do we find any other basis in the record,
to conclude that a further burst of expression of the repressor protein would
also have been considered desirable at the time the vector is introduced into
the cell.
Moreover, the Examiner has not identified any basis for the skilled
artisan to conclude that the TRE/ICP0 promoter taught by Schmeisser could
also have been used to induce expression of tetR in an HSV-1 vector system.
We find the Examiner’s assertion that “both Tet transactivation and Tet
repression had been widely used in the art as alternative means of expression
control” to be an insufficient basis to substitute the tetR system of Yao into
Schmeisser’s HSV-1 vector. FF5. The Examiner cites to the review articles
of Berens and Corbel in support, but those references at most teach that tetR-
based transregulators utilizing an activation mechanism (tTA, rtTA) as well
as a repression mechanism (tTS) were both known in the art. See Berens,
3112 (Fig. 3); Corbel, 449 (Fig. 1). The fact that there were known
alternative methods for tetracycline regulated gene expression, however,
does not indicate that one of ordinary skill in the art would have recognized
that a tetR repressor protein could necessarily be substituted for another type
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of tetR-based fusion protein, especially one exhibiting the exact opposite
activity, and still achieve the desired result of suppressing gene expression.
In sum, the Examiner has not demonstrated that independent claim 1
would have been obvious over Schmeisser, Yao, and DeLuca. Because
“[d]ependent claims are nonobvious under section 103 if the independent
claims from which they depend are nonobvious,” we also reach the same
conclusion as to claims 2–10 and 35–44. In re Fine, 837 F.2d 1071, 1076
(Fed. Cir. 1988). The Examiner has not cited to any teachings in DeLuca,
Coffin, or Martinez that would make up for the deficiencies in Schmeisser
and Yao discussed above.

SUMMARY
We reverse the rejection of claims 1, 2, 4–6, 8, and 9 under 35 U.S.C.
§ 103(a) as being unpatentable over the combination of Schmeisser, Yao,
and DeLuca.
We reverse the rejection of claims 3, 7, and 35–44 under 35 U.S.C.
§ 103(a) as being unpatentable over the combination of Schmeisser, Yao,
DeLuca, and Coffin.
We reverse the rejection of claim 10 under 35 U.S.C. § 103(a) as
being unpatentable over the combination of Schmeisser, Yao, DeLuca, and
Martinez.
REVERSED
KRH