Ex Parte Giles et al

Board of Patent Appeals and Interferences

Jan 20, 2010

10729387 (B.P.A.I. Jan. 20, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte FRANCIS J. GILES and SRDAN VERSTOVSEK
__________

Appeal 2009-007452
Application 10/729,387
Technology Center 1600
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Decided: January 20, 2010
__________

Before LORA M. GREEN, FRANCISCO C. PRATS, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s final rejection of claims 1, 7, 9, 10, 14, 15, 17-22, 25-32, 39-45,
and 52-64. We have jurisdiction under 35 U.S.C. § 6(b).
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STATEMENT OF THE CASE
The claims are directed to a composition comprising troxacitabine
((-)-L-OddC) and imatinib mesylate (STI-571). Claim 1 is representative of
the claims on appeal, and reads as follows:
1. A pharmaceutical composition comprising at least one active
compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
B is cytosine, and
R is H; and
the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate,
wherein said compound of formula (I) or a pharmaceutically
acceptable salt thereof and the Bcr-Abl tyrosine kinase inhibitor are present
in a ratio of 1:5 to 1:2.

The Examiner relies on the following evidence:
Chu WO 96/07413 Mar. 14, 1996

Francis J. Giles, Troxacitabine, A Novel Dioxolane Nucleoside Analog, Has
Activity in Patients with Advanced Leukemia, Journal of Clinical Oncology,
Vol. 19, No. 3, 762-71 (2001).

Brian J. Druker, M.D., Activity of a Specific Inhibitor of the BCR-ABL
Tryosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute
Lymphoblastic Leukemia with the Philadelphia Chromosome, N. Engl J
Med., Vol. 344, No. 14, 1038-42 (2001).

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Guofu Fang, CGP57148B (STI-571) induces differentiation and apoptosis
and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to
antileukemic drugs, Blood, Volume 96, 2246-53 (2000).

J. Topaly, Synergistic activity of the new ABL-specific tyrosine kinase
inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic
myelogenous leukemia cells, Leukemia, 342-347 (2001).

We affirm.

ISSUE
The Examiner concludes that claims 1, 7, 9, 10, 14, 15, 17-22, 25-32,
39-45, and 52-64 are rendered obvious by the combination of Chu, Giles,
Druker, Fang, and Topaly.
Appellants argue that the claimed combination of agents demonstrates
unexpected synergy, and thus the claimed compositions and methods are not
rendered obvious by the combination as set forth by the Examiner.
Thus, the issue on appeal is: Have Appellants demonstrated
unexpected results in the form of synergy commensurate in scope with the
claimed subject matter?

FINDINGS OF FACT
FF1 The Specification teaches that the “present invention relates to
pharmaceutical combinations and methods useful in the treatment of
leukemia,” and more particularly, “to dioxolane nucleoside analogues with a
Bcr-Abl tyrosine kinase inhibitor.” (Spec. 1.)
FF2 The Specification teaches that in treating leukemia, patients may
receive a single drug or a combination of two or more drugs, and that
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“[a]pproximately 40 different drugs are now being used in the treatment of
leukemia either alone or in combination.” (Id. at 2.)
FF3 The Specification teaches further:
[T]he compounds of formula (I) contain at least two chiral
centers. The compounds of formula (I) thus exist in the form of
two different optical isomers (i.e. ( + ) or ( - ) enantiomers or β-
L and β-D). All such enantiomers and mixtures thereof
including racemic mixtures are included within the scope of the
invention.

(Id. at 8.)
FF4 The Specification presents an in vivo example (id. at 25 “In vivo
studies”) in which mice were injected with the tumor cells KBM-5 (chronic
myeloid leukemia cells) or KBM-5R (chronic myeloid leukemia cells
resistant to STI-571) (id.).
FF5 The mice were treated with each of TroxatylTM (i.e., troxacitabine/((-)-
L-OddC), a compound encompassed by formula (I)) or STI-571 (imatinib
mesylate) alone or with both compounds together (id. at 26).
The results are presented in Table 1, reproduced below:
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(Id. at 27.) Note that “LTS” means “long term survivors.” (Id. at 26.)
FF6 According to the Specification, the “results of the study show that the
combination of TroxatylTM with STI-571 gives a synergistic result in the
KBM-5 cell line.” (Id.)
FF7 The Examiner rejects claims 1, 7, 9, 10, 14, 15, 17-22, 25-32, 39-45,
and 52-64 under 35 U.S.C. § 103(a) as being obvious over the combination
of Chu, Giles, Druker, Fang, and Topaly (Ans. 4). As Appellants do not
argue the claims separately, we focus our analysis on claim 1, and claims 7,
9, 10, 14, 15, 17-22, 25-32, 39-45, and 52-64 stand or fall with that claim.
37 C.F.R. § 41.37(c)(1)(vii).1

1 37 C.F.R. § 41.37(c)(1)(vii) states, in relevant part:
Notwithstanding any other provision of this paragraph, the
failure of appellant to separately argue claims which appellant
has grouped together shall constitute a waiver of any argument
that the Board must consider the patentability of any grouped
claim separately. Any claim argued separately should be placed
under a subheading identifying the claim by number. . . . A
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FF8 The Examiner relies on Chu for teaching the use of (-)-L-OddC in the
treatment of cancer (id.).
FF9 The Examiner finds that Chu suggests the use of (-)-L-OddC in the
treatment of leukemia, and that the (-)-L-OddC can be administered “in
combination with other anticancer agents, including interferons, interleukins
and cytarabine.” (Id. at 5.)
FF10 The Examiner cites Giles for teaching “that the instantly claimed
doses of (-)-L-OddC for the treatment of leukemia were known in the art.”
(Id. at 6.)
FF11 The Examiner relies on Druker for teaching that the instantly claimed
dosages of STI-571 “for the treatment of leukemia were known in the art.”
(Id.)
FF12 The Examiner notes that neither Chu, Giles, nor Druker “disclose the
specific combination of troxacitabine and imatinib mesylate,” but notes
further that Chu suggests that “(-)-L-OddC can be combined with other
chemotherapeutic agents.” (Id. 6.)
FF13 The Examiner cites Fang and Topaly to “provide further motivation to
combine STI-571with other chemotherapeutic drugs wherein they disclose
that combined therapies comprising STI-571 and other antileukemic drugs
are synergistic when used to treat Bcr-Abl-positive human leukemia.” (Id. at
7.)

statement which merely points out what a claim recites will not
be considered an argument for separate patentability of the
claim.
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FF14 The Examiner finds that Fang teaches that “STI-571 induces
hemoglobin levels and apoptosis of K562 and HL-60/Bcr-Abl leukemia
cells,” and that “[c]o-treatment with STI-571 significantly increased the
percentage of apoptotic cells following exposure to Ara-C or doxorubicin.”
(Id.)
FF15 The Examiner cites Topaly for its finding that “STI-571 is
demonstrated to have a synergistic effect when administered with other
chemotherapeutic drugs on Bcr-Abl-positive CML cells.” (Id.)
FF16 The Examiner notes that the “prior art differs from the instant claims
in that it does explicitly teach the specific combination of chemotherapeutic
agents instantly claimed.” (Id. at 8.)
FF17 The Examiner concludes, however, that “one of ordinary skill in the
art (in this case, an M.D. with several years of experience) would have been
highly motivated to combine two known antileukemic agents for the
treatment of leukemia . . . . [a]s . . . such combinations are well known, in
fact routine, in the art.” (Id. at 8-9.)
FF18 The Examiner concludes further that the “prior art discloses that both
of these agents can be used to treat leukemia in the doses instantly claimed
and further demonstrates that STI-571 has a synergistic effect when
combined with other chemotherapeutic agents in the treatment of CML.”
(Id. at 9.)
FF19 The Examiner notes as to the evidence of synergy presented in the
Specification:
[E]ven if the Examiner were to accept that such results are
indeed unexpected, . . . the experimental results in the
specification are not commensurate in scope with the claims.
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For example, the claims recite compositions and methods
comprising compounds of Formula (I) having any
stereochemistry, in any amounts, to treat any type of leukemia,
in combination with any amount of STI-571, provided that the
compounds are present in a ratio of 1:5 to 1:2. However,
Appellant’s results are limited to the effects of a specific
combination of Troxatyl and STI-571, in doses of 10 mg/kg or
50 mg/kg “Troxatyl” administered qd x 5 (every day for 5 days)
and 50 mg/kg STI-571 administered bid x 10 (twice a day for
10 days) for the treatment of chronic myeloid leukemia.

(Id. at 11-12.)

PRINCIPLES OF LAW
When appealing a rejection to this Board, Appellants bear the burden
of showing error in the Examiner’s holding of unpatentability. See Ex parte
Catan, 83 USPQ2d 1569, 1570 (BPAI 2007) (precedential) (“The issue is
whether Appellant has shown that the Examiner erred in holding the
combination of [references cited by the Examiner] would have rendered the
subject matter of claim 5 obvious to one of ordinary skill in the art at the
time of the invention.”); see also Ex parte Smith, 83 USPQ2d 1509, 1512-
1514, 1519 (BPAI 2007) (precedential); Ex parte Yamaguchi, 88 USPQ2d
1606, 1608 and 1614 (BPAI 2008) (precedential); Ex parte Fu, 89 USPQ2d
1115, 1118 and 1123 (BPAI 2008) (precedential).
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
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The Supreme Court has recently emphasized that “the [obviousness] analysis
need not seek out precise teachings directed to the specific subject matter of
the challenged claim, for a court can take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” KSR
Int’l v. Teleflex Inc., 550 U.S. 398. 418 (2007). “The combination of
familiar elements according to known methods is likely to be obvious when
it does no more than yield predictable results.” Id. at 416. Moreover, an
“[e]xpress suggestion to substitute one equivalent for another need not be
present to render such substitution obvious.” In re Fout, 675 F.2d 297, 301
(CCPA 1982).
In KSR, the Supreme Court also noted the fact that a solution may
“obvious to try” may render the claimed invention obvious.
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that it was obvious under § 103.

Id. at 421.
The Court of Appeals for the Federal Circuit set forth in In re
O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988), two situations in which an
“obvious to try” rationale was usually improperly applied. The first
situation of “what would have been ‘obvious to try’ would have been to vary
all parameters or try each of numerous possible choices until one possibly
arrived at a successful result, where the prior art gave either no indication of
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which parameters are critical or no direction as to which of many possible
choices is likely to be successful.” (Id.) The second situation of “what was
‘obvious to try’ was to explore a new technology or general approach that
seemed to be a promising field of experimentation, where the prior art gave
only general guidance as to the particular form of the claimed invention or
how to achieve it.” Id. See In re Kubin, 561 F.3d 1351, 1358-60 (noting
that the rationale in O’Farrell was “affirmed in the logical inverse” in KSR,
550 U.S. at 417, in the Statement that “§103 bars patentability unless ‘the
improvement is more than the predictable use of prior art elements according
to their established functions.’”).
The burden of demonstrating unexpected results rests on the party
asserting them, and “it is not enough to show that results are obtained which
differ from those obtained in the prior art; that difference must be shown to
be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA
1972). Moreover, a showing of unexpected results must be commensurate in
scope with the breadth of the claims. In re Grasselli, 713 F.2d 731, 743
(Fed. Cir. 1983); see also In re Greenfield, 571 F.2d 1185, 1189 (CCPA
1978) (“[O]bjective evidence of non-obviousnesss must be commensurate in
scope with the claims.”)

ANALYSIS
Appellants assert that the Specification “clearly discloses that the
combination of (-)-L-OddC and STI-571exhibits synergistic results.” (App.
Br. 6 (citing pages 26-28 of the Specification).) Appellants argue that the
combination as set forth by the Examiner does “not disclose or suggest
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treating leukemia with a combination of (-)-L-OddC and STI571,” and in
particular, that “the combination of (-)-L-OddC and STI571 would achieve
synergistic results.” (App. Br. 5-6.)
Appellants argue that while the Examiner relies on Fang and Topaly
to demonstrate that such synergistic results would not have been unexpected
to the ordinary artisan, the ordinary artisan would not expect based on those
references that STI-571 would “exhibit synergy with every anti-leukemia
agent.” (Id. at 7.) According to Appellants:
The structures of cytarabine (Ara-C), etoposide,
doxorubicin and mafosfamide are all clearly distinguishable
from that of (-)-L-OddC. Of these four agents, only cytarabine
has a nucleoside structure. While (-)-L-OddC does possess a
nucleoside-like structure, it has a dioxolane ring rather than a
typical sugar ring and does not have the pendant hydroxy
groups of the typical sugar ring, such as possessed by
cytarabine. Furthermore, as noted above, (-)-L-OddC
(troxacitabine) is recognized in the art as having a substantially
different pharmacokinetic behavior than that of ara-C. See the
discussion above regarding the article by Giles et al.

(Id.)
We agree with the Examiner that the prior art renders obvious the
pharmaceutical composition of claim 1, that is a composition comprising
troxacitabine ((-)-L-OddC) and imatinib mesylate (STI-571), as both
compounds were known to be useful in the treatment of leukemia, and as the
use of combination treatments is well known and routine in the treatment of
cancer. As to the question of whether Appellants have demonstrated
evidence of synergism, that is, unexpected results, sufficient to overcome the
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prima facie case, we agree with the Examiner that such showing has not
been made.
As demonstrated by Fang and Topaly, cited by the Examiner, STI-571
is known to show synergism with chemotherapautic agents of divergent
structures used in the treatment of leukemia. The data presented in those
references would have motivated the ordinary artisan to look for synergy for
other such therapautic agents, such as ((-)-L-OddC). That is, in this case, it
would be obvious to try and combine agents that are known to be useful in
the treatment of leukemia with STI-571 in order to obtain a synergistic
combination of agents. First, the art provides guidance as to the parameters
to obtain a synergistic combination, as the prior art references teach that
STI-571 demonstrates synergy with divergent agents useful in the treatment
of leukemia. Thus the combination of references cited by the Examiner does
not meet the requirements of the first situation of O’Farrell in which it is
improper to use an “obvious to try rational.” Second, the prior art as
combined does not only provide general guidance, but in fact provides
specific guidance by demonstrating that STI-571 demonstrates synergy with
divergent agents useful in the treatment of leukemia. Therefore the prior art
is not drawn a “new technology” and the combination does not meet the
requirements of the second situation of O’Farrell in which it is improper to
use an “obvious to try rational.”
Moreover, Appellants’ data is not commensurate in scope with the
subject matter of claim 1. For example, the claims encompass a compound
of claim 1 having any stereochemistry, while the purported evidence of
unexpected results is drawn only to the one enantiomer, (-)-L-OddC. While
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Appellants argue that “[i]t is not unreasonable to extrapolate results of
synergy shown for one compound of a relatively small genus to other
members of that genus” (Reply Br. 3), Appellants have not provided any
evidence that the ordinary artisan would expect the different enantiomers to
have the same activity, and arguments of counsel cannot take the place of
evidence in the record. In re Scarbrough, 500 F.2d 560, 566 (CCPA 1974).

CONCLUSION OF LAW
We conclude that Appellants have not demonstrated unexpected
results in the form of synergy commensurate in scope with the claimed
subject matter.
We thus affirm the rejection of claims 1, 7, 9, 10, 14, 15, 17-22, 25-
32, 39-45, and 52-64 under 35 U.S.C. § 103(a) as being obvious over the
combination of Chu, Giles, Druker, Fang, and Topaly.

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TIME PERIOD FOR RESPONSE
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

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