Ex Parte Xu

Patent Trial and Appeal Board

Sep 10, 2014

12102237 (P.T.A.B. Sep. 10, 2014)

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.
12/102,237 04/14/2008 Bo Xu 21381-00091-US2 9788
10574 7590 09/11/2014
NOVAK DRUCE CONNOLLY BOVE + QUIGG LLP
(Southern Research Institute)
1875 EYE STREET, N.W.
Suite 1100
WASHINGTON, DC 20006
EXAMINER
PAGONAKIS, ANNA
ART UNIT PAPER NUMBER
1628
MAIL DATE DELIVERY MODE
09/11/2014 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 Bo Xu1
__________

Appeal 2012–005937
Application 12/102,237
Technology Center 1600
__________

Before DONALD E. ADAMS, LORA M. GREEN, and
ROBERT A. POLLOCK, Administrative Patent Judges.

POLLOCK, Administrative Patent Judge.

DECISION ON APPEAL
Appellant appeals under 35 U.S.C. § 134(a) from the Examiner’s
rejection of the pending claims as obvious. We have jurisdiction under 35
U.S.C. § 6(b).
We affirm. We also enter a new ground of rejection.
STATEMENT OF THE CASE
Appellant’s invention relates to methods of enhancing the
radiosensitivity of cancer cells using the nucleoside analog clofarabine.

1 According to Appellant, the Real Party in Interest is Southern Research
Institute. (App. Br. 2).
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Application 12/102,237

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Representative independent claim 4 reads as follows:
4. A method of potentiating radiotherapy treatment
comprising administering to a patient in need thereof a
therapeutically effective amount of clofarabine, and
subjecting the patient to radiotherapy.
The following grounds of rejection are before us for review:
Claims 4-8, 12-14, 18-20, and 24-252 are rejected as unpatentable
under 35 U.S.C. § 103 over the combination of Cunningham3, USC-CPBD4,
and Cheson5.

2 Appellant contends that claims 4-8, 9-11, 15-17, and 21-23 are on appeal.
(App. Br. 2, 5.) The Examiner agrees that “the statement of the status of the
claims contained in the brief is correct” (Ans. 3), and directs the sole
rejection to claims 4-11, 15-17 and 21-23 (id. at 4). Many of these claims
were previously cancelled. Claims 1-25 were pending as of the Final Office
Action dated July 29, 2010. By Amendment under 37 C.F.R. § 1.31 dated
September 17, 2012, Appellant requested cancelation of claims 1-3, 9-11,
15-17, and 21-23 and amendment of claims 4-8, 12-14, 18-20, 24, and 25.
The Advisory Action dated October 1, 2010 indicates that these amendments
would be entered such that only claims 4-8, 12-14, 18-20, 24, and 25 would
be pending. As these are the same claims set forth in Appellant’s Claims
Appendix, we consider claims 4-8, 12-14, 18-20, 24, and 25 the subject of
both the outstanding rejection and the instant appeal. We recognize that the
Examiner’s rejection did not include claims 12-14, 18-20, 24, and 25, but
find that this omission represents an inadvertent typographical error.
3 Cunningham et al., “Clofarabine administered weekly to adult patients with
advanced solid tumors in a phase I dose-finding study,” 2004 ASCO
Proceedings, J. Clin. Oncol. 22:14S (July 15 Suppl.), 3115.
4 University of Southern California, Center for Pancreatic and Biliary
Diseases, Treatment of Pancreatic Cancer, 2002.
5 Gregoir and Hittelman, Nucleoside Analogs as Radiosensitizing Agents, in
NUCLEOSIDE ANALOGS IN CANCER THERAPY, pp. 318-319 (Cheson et al.,
eds. 1997).
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FINDINGS OF FACT
FF. 1 Cunningham reports the administration of clofarabine to 30
adult patients with solid tumors in a phase I dose-finding study. This one-
page abstract describes clofarabine as “a next-generation nucleoside
analogue that inhibits DNA synthesis.” Cunningham further discloses that
clofarabine has shown “potent cytotoxic activity in a wide range of solid
tumor cell lines,” “therapeutic activity in murine tumor models,” and “has
demonstrated activity in acute leukemia in Phase I and II trials.”
(Cunningham, see also Ans. 4–5.)
FF. 2 USC—CPBD teaches the treatment of pancreatic cancer with
a combination of chemotherapy and radiation. (USC—CPBD 2–3; see also
Ans. 5.) The reference states:
The common chemotherapy drugs that are utilized for
treatment of pancreatic cancer included 5 flouro—uracil,
leukovirin and gemcitidine. Radiation therapy is delivered
in daily fractions over a six week period to a total dose of
approximately 5,000 rads. The chemotherapy may be
administered together or sequentially with the radiation
therapy.
(USC—CPBD 3.)
FF. 3 The instant Specification states that “[r]adiation is [a]
commonly used treatment for cancer” and is “[o]ften combined with
chemotherapy.” (Spec. 2:9–10.)
FF. 4 Cheson teaches that “[n]ucleoside analogs are particularly
attractive candidates for enhancing radiation response in tumors for several
reasons.” (Cheson 318.)
First, because of their cytotoxic activity in proliferating
cells, they have antitumor activity on their own.
. . .
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Second, as inhibitors of DNA replication, they also have the
potential for inhibiting DNA repair following ionizing
radiation treatment.
. . .
Third, some nucleoside analogs can be incorporated during
DNA synthesis and poison subsequent DNA synthesis by
either causing chain termination or serving as a poor
template in subsequent rounds of DNA synthesis.
. . .
Finally, nucleoside analogs are potentially attractive as
radioenhancers because as inhibitors of DNA synthesis they
can serve to slow tumor clonogen regrowth between
radiation dose fractions.
(Id. 318-19.)
FF. 5 Cheson further states that “emphasis will be placed on newly
developed nucleoside analogs (e.g. . . . gemcitabine) that have already
shown clinical activity on their own and in combination with other
chemotherapeutic agents and appear to be promising candidates for
combining with radiation.” (Id. 319.)
FF. 6 Clofarabine, 5-flourouricil (5-FU), and gemcitabine are
nucleoside analogs. (Ans. 9; App. Br. 14–15; Cunningham; Cheson 319.)
FF. 7 Example 5 of the Specification “compare[s] clofarabine’s
radiosensitizing potential with other proven radiosensitizing anti-
metabolites, radiosensitivity is tested in HeLa cells treated with a
combination of clofarabine, gemcitabine, or 5-FU with radiation therapy. . . .
the results are presented in Figure 4.” (Spec. 18:6-11; Fig. 4.)
FF. 8 Example 8 of the Specification describes the in vivo testing of
clofarabine and radiation on six different tumor types. (Spec. 20:25-22:18)
The Specification states that:
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Three out of the six tumor models tested showed marked
radiosensitization with clofarabine while another tumor
model showed an additive effect. Two out of the six
models tested showed no evidence of an interaction
between clofarabine and radiation. The data indicates a
trend showing clofarabine’s ability to radiosensitize tumor
cells.
(Id. 22:14–19.)
FF. 9 The Specification further states that
SR475HN head and neck tumors were radiosensitized by
clofarabine with T—C values (based on 2 tumor doublings)
of 18.2, 73.2, and> 162 days for clofarabine, radiation, and
the combination, respectively. PANC-l pancreatic tumors
were radiosensitized by clofarabine with T—C values
(based on 2 tumor doublings) of 17.2, 1.7, 5 and 63.8 days
for clofarabine, radiation, and the combination,
respectively. HCT-116 colon tumors were radiosensitized
by clofarabine with T—C values (based on 3 tumor
doublings) of 24.2, 29.3, and >78.9 days for clofarabine,
radiation, and the combination, respectively. The
radiosensitizing capacity of gemcitabine tracked with the
clofarabine results.
(Id. 22:1-9.)
FF. 10 The Examiner cites the ILEX Briefing document6 as evidence
that one of ordinary skill in the art “would not expect that 5-FU, gemcitabine
and clofarabine would have identical results when each is combined with
radiotherapy.” (Ans. 8.) ILEX states that:
Based upon its mechanism of action as an inhibitor of both
ribonucleotide reductase and DNA polymerase α and ε,
clofarabine is a member of a class of nucleoside analogues
that includes gemcitabine, fludarabine, and cladribine.

6 ILEX Products, 2004 Oncologic Drug Advisory Committee Briefing
Document for Clofarabine NDA 21–673 (27 October 2004) (“ILEX”).
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(ILEX 9.)
Clofarabine represents a novel oncolytic that has
demonstrated activity in patients with advanced-multiply
recurrent or refractory—leukemia. Clofarabine is a
nucleoside analogue that differs from similar approved
agents (ie, fludarabine and cladribine) in the following
respects:
The efficiency (VmaX/Km) of phosphorylation of
clofarabine by deoxycytidine kinase (dCK) is equal to or
greater than that of its natural substrate deoxycytidine
(dCyd), and significantly greater than that of cladribine (~3-
4 times greater) and fludarabine (~25 times greater).
. . . .
The inhibitory potency of clofarabine triphosphate on
ribonucleotide reductase was similar to that of cladribine
triphosphate, 10 times greater than fludarabine triphosphate,
and 100 times greater than gemcitabine triphosphate.
(Id. xii, 9 (same).)
ANALYSIS
The relevant dispute in this case is not over whether the prior art
discloses all of the claim elements, or over the motivation to combine the
prior art references, but the weight that should be accorded Appellant’s
evidence of secondary considerations.
Obviousness under 35 U.S.C. § 103 is a legal conclusion based on
underlying facts. Graham v. John Deere Co., 383 U.S. 1, 17 (1966). Factual
considerations that underlie the obviousness inquiry include the scope and
content of the prior art, the differences between the prior art and the claimed
invention, the level of ordinary skill in the art, and any relevant secondary
considerations. See Graham, 383 U.S. at 17–18. Relevant secondary
considerations include commercial success, long-felt but unsolved needs,
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failure of others, and unexpected results. KSR Int’l Co. v. Teleflex Inc., 550
U.S. 398, 406, (2007). Although evidence pertaining to secondary
considerations must be taken into account whenever present, it does not
necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v.
Apotex, Inc. 480 F.3d 1348, 1372 (Fed. Cir. 2007). (“Here, the record
establishes such a strong case of obviousness that Pfizer’s alleged
unexpectedly superior results are ultimately insufficient.”)
The Examiner finds that one of ordinary skill in the art would have
found it obvious to administer clofarabine in combination with radiotherapy
as taught by Cunningham and USC—CPBD “because [] each of the
therapeutics have been individually taught in the prior art to be successful
for the treatment of pancreatic tumors.” (Ans. 6.) Citing In re Kerkoven,
626 F.2d 846 (CCPA 1980), the Examiner finds that “it is prima facie
obvious to combine two agents each of which is taught by the prior art to be
useful for the very same purpose” thus, in the present case, one of ordinary
skill in the art would have had a reasonable expectation of success that
administering clofarabine in combination with radiotherapy would treat
pancreatic cancer tumors. (Id.)
The Examiner further finds that clofarabine is a nucleoside analog,
and because Cheson teaches the use of nucleoside analogs “to enhance
radiosensitivity and potentiate radiotherapy of solid tumors, . . . one of skill
in the art would have a reasonable expectation of success that by combining
clofarabine with radiation therapy, one would achieve a method to enhance
radiosensitivity and potentiate radiotherapy of pancreatic cancer tumors.”
(Id. 7.)
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Appellant argues that the rejection is “improper in view of the
unexpected synergistic results achieved by the combination of clorfarabine
with radiation therapy.” (App. Br. 5.) In particular, Appellant argues that “a
much more profound radiosensitizing effect was observed in clofarabine-
treated cells than cells treated with gemcitabine and 5-FU.” (Reply Br. 3.)
The survival curves for the treated cells are shown in Figure 4 of the instant
application and also illustrated in Figure 2 of Cariveau et al.7” (Id.)
If the compound has a strong radiosensitizing effect (strong
synergy), it will require less radiation to slow or stop cell
growth. In other words, the higher the SER the better the
radiosensitizing effect (synergy). The SER was 1.12 for 5-
FU, 1.73 for gemcitabine, and 2.71 for clofarabine. In other
words, the enhancement ratio for clofarabine was 2.4 fold
better than 5-FU and 1.6 fold better than gemcitabine. Thus,
clofarabine exhibits an unexpectedly greater synergistic
effect with radiotherapy than other nucleoside analogs
known to potentiate radiotherapy.
(Reply Br. 4 (emphasis in original.))
Although we are mindful of the Examiner’s disagreement over the
methodology underlying Appellant’s evidence unexpected results (Ans. 9),
for the purpose of this appeal we accept Appellant’s assertion that Figure 4
of the Specification and Figure 2 of Caraiveau et al. show an “enhancement
ratio for clofarabine [] 2.4 fold better than 5-FU and 1.6 fold better than
gemcitabine” in HeLa cells treated with a combination of clofarabine,
gemcitabine, or 5-FU with radiation therapy. (Reply Br. 3-4; Spec. 18:4-

7 Cariveau et al., “Clorfarabine Acts As Radiosensitizer In Vitro and In Vivo
by Interfering with DNA Damage Response,” 2007 Int. J. Radiation
Oncology Biol. Phys 70(1), 213-220.
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15.) Nevertheless, we are not persuaded that this evidence is sufficient to
outweigh the Examiner’s strong prima facie showing of obviousness.
As an initial matter, we agree with the Examiner that synergistic
results “do not appear to be unexpected,” because Cheson teaches that
nucleoside analogs (such as gemcitabine) are “particularly attractive
candidates for enhancing radiation response in tumors.” (Ans. 7; Cheson
318.) Thus, “the combination of radiation with a nucleoside analog, such as
clofarabine, per Cheson exhibits an enhanced radiation response . . . and thus
cannot be deemed unexpected.” (Ans. 7.)
We are also unpersuaded by Appellant’s argument that “clofarabine
exhibits an unexpectedly greater synergistic effect with radiotherapy than
other nucleoside analogs known to potentiate radiotherapy.” (Reply 4.)
“Unexpected results that are probative of nonobviousness are those that are
‘different in kind and not merely in degree from the results of the prior art.’”
Galderma Labs., LP v. Tolmar, Inc., 737 F.3d 731, 739 (Fed Cir. 2013)
(quoting Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322
(Fed. Cir. 2004). Results which differ by percentages are differences in
degree rather than kind, where the modification of the percentage is within
the capabilities of one skilled in the art at the time. See In re Harris, 409
F.3d 1339, 1344 (Fed.Cir.2005) (“32–43% increase in stress-rupture life . . .
does not represent a ‘difference in kind’ that is required to show unexpected
results”). Rather, we agree with the Examiner that one of ordinary skill in
the art “would not expect that 5-FU, gemcitabine, and clofarabine would
have identical results when each is combined with radiotherapy.” (Ans. 8.)
We support this conclusion with the following evidence.
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First, to illustrate the compound-to-compound variability among
therapeutic agents, the Examiner points to the ILEX Briefing document,
which compares the pharmacology of the nucleoside analog clofarabine with
“similar8 approved agents.” (Ans. 8; ILEX xii, 9.) As the Examiner points
out, ILEX states that “[t]he inhibitory potency of clofarabine triphosphate on
ribonuclease reductase was similar to that of cladribine triphosphate, 10
times greater than fludarabine triphosphate, and 100 times greater than
gemcitabine triphosphate.” (Ans. 10-11 (citing ILEX xii).) ILEX similarly
discloses that “The efficiency (Vmax/Km) of phosphorylation of clofarabine
by deoxycytidine kinase (dCK) is . . . significantly greater than that of
cladribine (~3-4 times greater) and fludarabine (~25 times greater).” (ILEX
xii, 9) Given that these biological activities can vary up to 100 fold between
clofarabine and “similar approved agents,” we are not convinced that a 1.6
or 2.4 fold difference in radiation enhancement is anything but an expected
compound—to—compound variation.
Second, despite Appellant’s assertion that “the enhancement ratio for
clofarabine was 2.4 fold better than 5-FU and 1.6 fold better than
gemcitabine” (Reply Br. 4 (underlining in original), these results, derived
from cultured tumor cells (see Spec. 16:4–15; Fig. 4; Cariveau Fig. 2), are
not consistent with other data in the Specification. In particular, Example 8
of the Specification describes the testing of six in vivo tumor models with
clofarabine and radiation. (Spec. 20:25–22:19.) Fifty percent of these
models produced no evidence of synergy:

8 Page 9 of ILEX teaches that “clorarabine is a member of a class of
analogues that includes gemcitabine, fludarabine, and cladribine.”
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Three out of the six tumor models tested showed marked
radiosensitization with clofarabine while another tumor
model showed an additive effect. Two out of the six
models tested showed no evidence of an interaction
between clofarabine and radiation.
(Id. 22:14–17.) In summarizing these results, the Specification merely
states that “[t]he data indicates a trend showing clofarabine’s ability to
radiosensitize tumor cells.” (Id. 22:17–18.)
Further, whereas Example 8 does not present numerical data for any
parallel experiments using other nucleoside analogs, the Specification
discloses that, for at least HCT-116 colon tumors, “[t]he radiosensitizing
capacity of gemcitabine tracked with the clofarabine results.”9 (Id. 22:6–10.)
Thus, to the extent Appellant’s demonstrates synergism and potentially
improved radiosensitivity as compared to other nucleoside analogs in vitro,
the in vivo results are not compelling.
In footnote 2, above, we note that the Examiner’s rejection did not
include claims 12-14, 18-20, 24, and 25, but find that this omission
represents an inadvertent typographical error. Claims 12-14 and 18-20 relate
to the radiosensitivity of cell populations, including tumor cells.
Representative claim 12 recites:
12. A method for enhancing radiosensitivity of a cell
population comprising exposing said cell population to a
sensitizing amount of clofarabine, and subjecting the cell
population to radiation.
Claim 12, thus, essentially parallels representative claim 4, with the caveat
that treated cell population is not necessarily within a human patient. As

9 The Specification does not make clear whether gemcitabine “tracking” also
applies to the SR475HN and PANC-1 tumor models. (See Spec. 22:1-9.)
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claim 12 is broader than claim 1, and Appellants have not provided separate
arguments for claims 12-14 and 18-20, we find that these claims fall with
claim 4.
Claim 24 and its dependent claim 25, similarly parallel claim 1 and its
dependent claim 8 but make explicit the “synergistic combination of
ionizing radiation and clofarabine.” As we do not find Appellants evidence
of synergy compelling, claims 24 and 25 fall with claim 4.

SUMMARY
We affirm the rejection of claim 4 as unpatentable under 35 U.S.C.
§ 103 over the combination of Cunningham, USC-CPBD, and Cheson.
Claims 5-8 are not separately argued and fall with claim 4. Separate
arguments were not provided for claims 12-14, 18-20, 24, and 25, which
also fall with claim 4. We recognize that the Examiner’s rejection did not
include claims 12-14, 18-20, 24, and 25, but find that this omission
represents an inadvertent typographical error.10 Nevertheless, in an excess
of caution we designate our affirmance of claims 12-14, 18-20, 24, and 25 a
new ground of rejection.

TIME PERIOD FOR RESPONSE
Regarding the affirmed rejection(s), 37 C.F.R. § 41.52(a)(1) provides
“Appellant may file a single request for rehearing within two months from
the date of the original decision of the Board.”

10 See footnote 2.
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In addition to affirming the Examiner’s rejection(s) of one or more
claims, this decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960
(August 12, 2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)).
37 C.F.R. § 41.50(b) provides “[a] new ground of rejection pursuant to this
paragraph shall not be considered final for judicial review.”
37 C.F.R. § 41.50(b) also provides that the Appellant, 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 proceeding 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….

Should the Appellant elect to prosecute further before the Examiner
pursuant to 37 C.F.R. § 41.50(b)(1), in order to preserve the right to seek
review under 35 U.S.C. §§ 141 or 145 with respect to the affirmed rejection,
the effective date of the affirmance is deferred until conclusion of the
prosecution before the Examiner unless, as a mere incident to the limited
prosecution, the affirmed rejection is overcome.
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If the Appellant elects prosecution before the Examiner and this does
not result in allowance of the application, abandonment or a second appeal,
this case should be returned to the Patent Trial and Appeal Board for final
action on the affirmed rejection, including any timely request for rehearing
thereof.

AFFIRMED; 37 C.F.R. § 41.50(b)

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