Stanton Gerson

Patent Trials and Appeals Board

Mar 4, 2020

13900166 - (D) (P.T.A.B. Mar. 4, 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.
13/900,166 05/22/2013 Stanton Gerson CWR-018350US ORD 6108
68705 7590 03/04/2020
TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP
1300 EAST NINTH STREET
SUITE 1700
CLEVELAND, OH 44114
EXAMINER
STONE, CHRISTOPHER R
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
03/04/2020 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):
docketing@tarolli.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STANTON GERSON1
Appeal 2018-005600
Application 13/900,166
Technology Center 1600
Before ERIC B. GRIMES, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of treating cancer, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
STATEMENT OF THE CASE
“Chemotherapeutic agents can work in a number of ways.” Spec. 4.
For example, “uracil . . . can be incorporated into DNA of cancer cells by

1 Appellant identifies the real party in interest as Case Western Reserve
University. Appeal Br. 3. We use the word Appellant to refer to “applicant”
as defined in 37 C.F.R. § 1.42(a).
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Application 13/900,166

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administering antimetabolite agents to the cancer cells[,] . . . leading to the
inhibition of DNA replication.” Id. ¶ 56. “In comparison to other anti-
metabolites, pemetrexed is the most potent inducer of uracil incorporation
into DNA.” Id. ¶ 91.
“‘[U]uracil DNA glycosyl[a]se’ or ‘UDG’ . . . [is] a conserved DNA
repair protein expressed in all types of human cells. It specifically removes
uracil from DNA and protect[s] cells from cytotoxicity.” Id. ¶ 54.
The UDG enzyme hydrolyzes the N-glycosidic bond between
the UDG substrate (e.g., uracil residue) and the deoxyribose
sugar of the DNA backbone, liberating the UDG substrate and
generating an abasic site (e.g., an apurinic or apyrimidinic (AP)
site). . . . The AP site is further processed by a 5'-3'
endonuclease (AP endonuclease (APE)) that . . . cleav[es] the
phosphodiester bonds at the AP sites.
Id. ¶ 57. An “AP endonuclease inhibitor . . . inhibit[s] repair of DNA” in
cancer cells treated with an antimetabolite agent. Id. ¶ 94. Methoxyamine is
an AP endonuclease inhibitor. Id. ¶ 95.
Claims 1, 5, 8, 13–16, and 23–28 are on appeal. Claims 1 and 8,
reproduced below, are illustrative:
Claim 1: A method of determining the susceptibility of human non-
small cell lung cancer in a subject to treatment with pemetrexed that induces
or promotes incorporation of a UDG substrate into DNA of cancer cells,
comprising:
obtaining a sample of cancer cells from the subject;
measuring the level of UDG in the cancer cells;
comparing the measured levels of UDG in the cancer cells to a
control level; wherein an increase in the measured levels of UDG in the
cancer cells compared to a control level indicates that the cancer is less
susceptible to treatment with pemetrexed;
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treating the cancer in the subject with pemetrexed and
methoxyamine if the measured level of UDG activity is increased relative to
the control level.

Claim 8: A method of treating human non-small cell lung cancer in a
subject comprising:
obtaining a sample of cancer cells from the subject;
measuring the level of UDG expression in the cancer cells;
comparing the measured levels of UDG expression in the
cancer cells to a control level; and
administering pemetrexed that induces or promotes
incorporation of a UDG substrate into DNA of cancer cells to the subject if
the measured level of UDG expression is decreased compared to a control
level or administering pemetrexed in combination with an AP endonuclease
inhibitor if the measured level of UDG expression is increased compared to
a control level.

OPINION
Claims 1, 5, 8, 13–16, and 23–28 stand rejected under 35 U.S.C.
§ 103(a) as obvious based on Theuer2 and Weeks.3 Ans. 4. The Examiner
found that Theuer “teaches a therapy for cancers being treated with an
antifolate, e.g. pemetrexed, including, human non-small cell lung cancers,
comprising administering the antifolate in combination with a base excision
repair inhibitor, e.g. methoxyamine.” Id. The Examiner found that Theuer
also teaches “that the combination results in synergistic efficacy, and that the
combination can be administered to a patient having a cancer that is at least

2 Theuer et al., US 2008/0234298 A1, Sept. 25, 2008.
3 Lachelle D. Weeks et al., Mice Deficient in Uracil DNA Glycosylase
(UDG) Display Increased Sensitivity to the Antifolate Pemetrexed, Cancer
Research 71(8 Suppl.):Abstr. 5490 (2011).
Appeal 2018-005600
Application 13/900,166

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partially resistant to the antifolate (pemetrexed) treatment alone to overcome
the resistance.” Id.
The Examiner also found that Theuer “teaches the measurement of
UDG levels from tumor tissue samples,” but “does not expressly teach
comparing the UDG levels to a control level and administering the
combination when UDG levels are increased relative to the control.” Id.
However, the Examiner found that “Weeks teaches that UDG expression
levels in cancers are markers for sensitivity to pemetrexed and that
decreased expression indicate[s] sensitivity and increased expression
indicate[s] resistance.” Id.
The Examiner concluded that it would have been obvious to measure
the UDG expression level in a cancer cell sample and compare it to a
control, then to administer a combination of pemetrexed and methoxyamine,
as taught by Theuer, “if the levels are increased relative to the control, since
Weeks teaches that UDG expression levels in cancers are markers for
sensitivity to pemetrexed and that decreased expression indicates sensitivity
and increased expression indicates resistance.” Ans. 5. That is, the
combination of pemetrexed and methoxyamine “would have [been] seen as
appropriate in the treatment of cancers with high UDG expression levels,
since this was known to indicate resistance to pemetrexed, and the
administration of the drug with methoxyamine was known to overcome such
resistance.” Id.
Appellant argues that, while Theuer teaches that “protein levels of
UDG are increased with the combination of pemetrexed and methoxyamine,
. . . there is no teaching in Theuer et al. regarding the comparison of UDG
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levels to control levels and/or the significance of such a comparison in the
treatment of cancer.” Appeal Br. 13. Appellant argues that Weeks “fails to
make up for the deficiencies of Theuer,” because Weeks discloses only that
“gene-targeted UDG-/- mice were more sensitive to DNA damage from
pemetrexed than UDG+/+ and UDG+/- mice,” and “fail[s] to provide any
disclosure regarding situations where UDG is increased in cancer cells
compared to control levels.” Id.
We agree with Appellant that the evidence cited by the Examiner does
not support a prima facie case of obviousness. Each of independent claims 1,
8, and 23 include the active steps of measuring the level of UDG in cancer
cells, comparing the measured level to a control level, and administering
pemetrexed in combination with methoxyamine (or another AP
endonuclease inhibitor) if the measured level of UDG expression is
increased compared to the control.
Theuer discloses administering an antifolate compound such as
pemetrexed in combination with methoxyamine “to enhance or increase the
effect (i.e. potentiate activity) of the antifolate anticancer agent.” Theuer
¶ 14. Theuer also discloses administering pemetrexed in combination with
methoxyamine to overcome resistance of cancer cells to pemetrexed alone.
Id. ¶¶ 17–20.
Theuer discloses that “protein levels of UDG are affected by treatment
[with] a combination of pemetrexed and MX [methoxyamine].” Id. ¶ 61.
That is, after treatment with pemetrexed and methoxyamine, UDG levels are
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changed.4 But Theuer does not disclose measuring the expression level of
UDG in cancer cells before treatment with pemetrexed and methoxyamine,
or comparing that level to a control, or administering pemetrexed and
methoxyamine when the UDG levels are increased compared to the control.
Weeks reports on “the role of UDG expression on pemetrexed
sensitivity in vivo using gene-targeted UDG-/- mice”; i.e., genetically
modified mice that lack a functional UDG gene. Weeks, abstract. The
UDG-/- mice were “compared to UDG+/+ and UDG+/- littermates”; i.e.,
mice that had either one (+/-) or two (+/+) copies of the normal, functional
UDG gene. Id.
Weeks reports that the results “strongly suggest[ed] that UDG
deficiency potentiates pemetrexed cytotoxicity in in vitro as well as in in
vivo models.” Id. Weeks also reports that the data “promote UDG as a target
for improving pemetrexed efficacy.” Id.
Thus, Weeks discloses that “UDG deficiency”—i.e., a lower level of
UDG compared to a normal-level control—results in increased pemetrexed
cytotoxicity, and therefore increased efficacy of pemetrexed against UDG-
deficient cancer cells. However, Weeks does not disclose anything about the
effect of UDG expression that is increased compared to a normal-level
control, because all of the mice described by Weeks had either normal (+/+)
or lower-than-normal (+/-, -/-) levels of UDG expression.
The evidence therefore does not support the Examiner’s finding that
Weeks teaches that increased UDG expression, compared to a control level,

4 Theuer’s Figure 7 appears to show increased UDG levels after treatment
with pemetrexed and methoxyamine. Theuer, Fig. 7.
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indicates pemetrexed resistance in cancer cells. See Ans. 5. That finding is
the basis for the Examiner’s conclusion that it would have been obvious to
administer a combination of pemetrexed and methoxyamine to treat cancers
with increased UDG expression levels. Id. We conclude that the rejection of
claims 1, 5, 8, 13–16, and 23–28 under 35 U.S.C. § 103(a) based on Theuer
and Weeks is not supported by a preponderance of the evidence, and we
therefore reverse it.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 5, 8, 13–
16, 23–28
103(a) Theuer, Weeks 1, 5, 8, 13–
16, 23–28

REVERSED