KYOWA KIRIN CO., LTD.

Patent Trials and Appeals Board

Sep 13, 2021

2021000746 (P.T.A.B. Sep. 13, 2021)

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.
15/744,322 01/12/2018 Akihiro TOKUNAGA 2017-1854A 6272
513 7590 09/13/2021
WENDEROTH, LIND & PONACK, L.L.P.
1025 Connecticut Avenue, NW
Suite 500
Washington, DC 20036
EXAMINER
HUFF, SHEELA JITENDRA
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
09/13/2021 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):
eoa@wenderoth.com
kmiller@wenderoth.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte AKIHIRO TOKUNAGA, TOSHIHIKO ISHII,
MOTOYA MIE, and MUNETOSHI ANDO
__________

Appeal 2021-000746
Application 15/744,322
Technology Center 1600
__________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a method
for treating a tumor using the antibody mogamulizumab and an indoleamine
2,3-dioxygenase inhibitor. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as KYOWA
KIRIN CO., LTD (see Appeal Br. 3). We have considered the Specification
of Jan. 12, 2018 (“Spec.”); Final Office Action of Dec, 12, 2019 (“Final
Action”); Appeal Brief of Aug. 14, 2020 (“Appeal Br.”); Examiner’s
Answer of Sept. 11, 2020 (“Ans.”); and Reply Brief of Nov. 10, 2020
(“Reply Br.”).
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Statement of the Case
Background
“The expression of IDO [indoleamine 2,3-dioxygenase] is increased
in tumor tissues and induced by IFN-γ[]stimulation in cancer cells and
dendritic cells” (Spec. ¶ 2).
IDO1 is known to be expressed in tumors or the
microenvironment, and plays an important regulatory role in the
immunosuppressive mechanisms, which is responsible for
tumor’s escape from host immune surveillance. It has been
reported that tryptophan (Trp) metabolites, such as kynurenine
(Kyn), induce NK cell death, and weaken NK cell cytotoxicity
by inhibiting the expression of NK cell receptors. Therefore,
there is a possibility that IDO1 activity affects antibody
dependent cellular cytotoxicity (ADCC).
(id. ¶ 10). The Specification teaches “a therapeutic agent for a tumor
comprising an IDO inhibitor administered in combination with an antibody”
(id. ¶ 226).
The Claims
Claims 211, 214, 215, 217, and 218 are on appeal.2 Claim 211 is an
independent claim, is representative and reads as follows:
211. A method for treating a tumor comprising administering an
effective amount of
(ii) (a) an antibody which specifically binds to human CC
chemokine receptor 4 wherein the antibody is mogamulizumab,
and
(ii) an indoleamine 2,3-dioxygenase inhibitor which is Compound (I)
represented by formula (I).

2 The Examiner notes the remaining pending claims are withdrawn (see
Final Act. 2).
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wherein
R6 and R7 may be the same or different, and each represents a
hydrogen atom, or optionally substituted lower alkyl,
R8, R9, R10, and R11 may be the same or different, and each
represents a hydrogen atom, halogen, cyano, or lower alkyl,
R1 represents lower alkyl which may be substituted with lower
alkoxy, and
R3 represents an optionally substituted aromatic heterocyclic
group,
or a pharmaceutically acceptable salt thereof;
to a human in need thereof,
wherein the tumor is a tumor which expresses human CC
chemokine receptor 4.

The Rejections
A. The Examiner rejected claims 211, 214, and 215 under 35 U.S.C.
§ 103(a) as obvious over Banerjee,3 Ueda,4 Appendix A,5 and Fukuda6
(Final Act. 4–5).
B. The Examiner rejected claims 211, 214, 215, 217, and 218 under 35

3 Banerjee et al., WO 2014/186035 A1, published Nov. 20, 2014.
4 Ueda et al., US 2006/0034841 A1, published Feb. 16, 2006.
5 Appendix A, ChemIDplus - 1159266-37-1 – Mogamulizumab, pp. 1–3
(access Aug. 20, 2019).
6 Fukuda et al., US 2013/0065905 A1, published Mar. 14, 2013.
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U.S.C. § 103(a) as obvious over Banerjee, Ueda, Appendix A, Fukuda,
Cowley,7 and Gabrilovich8 (Final Act. 5–8).
Because both of these rejections share the same issues and prior art,
we will consider these rejections together.
The issues with respect to these rejections are:
(i) Does a preponderance of the evidence of record support the
Examiner’s conclusion that the prior art renders the claims prima facie
obvious?
(ii) If so, has Appellant provided evidence of unexpected results that,
when considered together with the evidence of obviousness, shows the
claims to be non-obvious?
Findings of Fact
1. Banerjee teaches “pharmaceutical compounds that regulate
enzymes indoleamine 2,3-dioxygenase-1” (Banerjee 1).
2. Banerjee teaches
the compounds described herein are useful for treating diseases
associated directly or indirectly with IDO . . . such a disease is
associated with abnormal cellular proliferation . . . a disease
which is characterized by abnormal cellular proliferation is
cancer . . . Accordingly, the use of compounds for treating
cancer is provided. One of skill in the art would understand
that there is an established link between decreased kynurenine
levels and anti-tumor activity in the clinical setting.
(Banerjee 116).

7 Cowley et al., WO 2015/082499 A1, published June 11, 2015.
8 Gabrilovich, D., Combination of chemotherapy and immunotherapy for
cancer: a paradigm revisited, 8 Lancet 2–3 (2007).
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3. Banerjee teaches the “present invention also contemplates that
compounds of invention may be used in combination with other anti-cancer
agents such as antibody therapeutics. In a further embodiment, the
additional medication is a targeted antibody” (Banerjee 130).
4. Banerjee teaches to include “antibodies to immune co-
stimulatory molecules including but not limited to . . . CCR4” (Banerjee
131).
5. Banerjee teaches in an experimental cancer model that the IDO
inhibitor, compound 2 “significantly decreased tumor growth in compound
2-treated animal over 14 days compared to control vehicle-treated animals
. . . Similarly, mice dosed with [IDO inhibitor] compounds 97, 166 and 184
reduced tumor growth by 26%-38% . . . compared to control animals”
(Banerjee 333).
6. Ueda teaches “administering to a patient a monoclonal antibody
which specifically binds to a human CC chemokine receptor 4 (CCR4) . . .
wherein the diseases . . . are cancer” (Ueda ¶¶ 20–21).
7. Ueda teaches
a method which comprises depleting in vivo regulatory T cell
or Th2 cell to decrease IL-10 produced by regulatory T cell or
Th2 cell is exemplified. The diseases in which pathologic
conditions are deteriorated by in vivo regulatory T cell or Th2
cell include, for example, cancer and infectious diseases.
Specific examples include cancer such as lung cancer,
pancreatic cancer, breast cancer, gastrointestinal cancer, blood
cancer such as adult T cell leukemia/lymphoma and Hodgkin
disease, uterus cancer, ovarian cancer, rhinopharyngeal cancer,
dermal cancer, hepatic cancer, Kaposi sarcoma.
(Ueda ¶¶ 41–42).
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8. Ueda teaches an example “[u]sing Anti-CCR4 Humanized
Antibody KM8761” where “KM8761 suppressed significantly IL-10
production in the PBMC prepared from any of the donors. The results show
that KM8761 can treat the pathological conditions relating to IL-10
production” (Ueda ¶¶ 237–238).
9. Appendix A teaches that KM8761 is a synonym for
mogamulizumab (see Appendix A, Names and Synonyms, at 2).
10. Fukuda teaches
A nitrogen-containing heterocyclic compound represented by
formula (I):

(wherein R6 and R7 may be the same or different and
each represent a hydrogen atom, optionally substituted lower
alkyl, optionally substituted cycloalkyl, or optionally
substituted aryl,
R8, R9, R10, and R11 may be the same or different and
each represent a hydrogen atom, halogen, cyano, optionally
substituted lower alkyl, optionally substituted lower alkenyl, or
optionally substituted lower alkynyl,
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R1 represents lower alkyl which may be substituted with
cycloalkyl or lower alkyl which may be substituted with lower
alkoxy, and
R3 represents optionally substituted aryl or an optionally
substituted heterocyclic group.
(Fukuda ¶¶ 30–34; paragraph numbers omitted).
11. Fukuda teaches “Compound (I) and a pharmaceutically
acceptable salt thereof are especially suitable as an active ingredient of a
preventive or therapeutic agent for a disease involving the production of
kynurenine . . . Examples of the disease involving the production of IDO
and/or kynurenine include cancers (tumors)” (Fukuda ¶¶ 102, 104).
12. Fukuda teaches:
Examples of the cancers (tumors) include hematopoietic tumor,
multiple myeloma, breast cancer, ovarian cancer, endometrial
cancer, cervical cancer, prostate cancer, bladder cancer, renal
cancer, gastric cancer, esophagus cancer, hepatic cancer, biliary
tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung
cancer, head and neck cancer, osteosarcoma, melanoma, brain
tumor, and the like. In particular, Compound (I) and a
pharmaceutically acceptable salt thereof are suitable for
prevention or treatment of gastric cancer, breast cancer, and the
like.
(Fukuda ¶ 105).
13. Cowley teaches “compounds of the invention may be for use in
any disease, condition or disorder that may be prevented, ameliorated or
treated using a TDO and/or IDO inhibitor. Typically this comprises a
disease condition and/or a disorder selected from: a cancer” (Cowley 116).
14. Cowley also teaches a kit that comprises the IDO inhibitor and
immunotherapeutic agents (see Cowley 119).
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15. Gabrilovich teaches “immunotherapy and chemotherapy target
different methods of tumour-cell survival and their combined effect would
be highly desirable” (Gabrilovich 2).
16. Gabrilovich teaches “data suggest a synergistic effect of
immunotherapy and chemotherapy . . . chemotherapy needs to be started
quickly after the administration of immunotherapy, otherwise the synergistic
effects of the combination will be lost” (Gabrilovich 2–3).
Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992). “The combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416
(2007).
Analysis
We adopt the Examiner’s findings of fact and conclusion of law (see
Final Act. 4–8, FF 1–16) and agree that the combination of Banerjee, Ueda,
Appendix A, Fukuda, Cowley, and Gabrilovich renders the claims obvious.
We address Appellant’s arguments below.
Prima Facie Obviousness
Appellant separately addresses deficiencies in each of the cited
references, noting “Banerjee provides no guidance or motivation to select an
IDO inhibitor other than those disclosed in the reference” and “Banerjee
teaches a wide variety of antibodies for treating cancer but fails to name
mogamulizumab as a suitable antibody” (Appeal Br. 10–11). Appellant
contends “Ueda does not disclose Compound (I) or combining a CCR4
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antibody with an IDO inhibitor” and Fukuda does not “teach that the
disclosed IDO inhibitors could be combined with another active agent, let
alone other cancer agents or CCR4 antibodies” (id.). Appellant also
contends
There is no motivation established to replace the IDO inhibitors
of Banerjee, the main objective of Banerjee, with other IDO
inhibitors. Further, the secondary references fail to provide a
motivation to modify the additional active agent of Banerjee to
specifically select mogamulizumab from a secondary reference
as the specific additional active agent from the myriad of
possibilities additional active agents (antivirals, antibacterials,
cancer agents, etc.) disclosed by Banerjee.
(id. 11–12).
We do not find these arguments persuasive. As to the deficiencies of
each reference, Appellant is arguing against the references individually
rather than the combination of the prior art as a whole. “Non-obviousness
cannot be established by attacking references individually where the
rejection is based upon the teachings of a combination of references . . . .
[The reference] must be read, not in isolation, but for what it fairly teaches
in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d
1091, 1097 (Fed. Cir. 1986).
In this case, Banerjee teaches that IDO inhibitors may be used for
treating cancer (FF 2) and that IDO inhibitors may be combined with “other
anti-cancer agents such as antibody therapeutics” (FF 3) including antibodies
to CCR4 (FF 4). The Examiner relies upon Fukuda to teach that the claimed
IDO inhibitors were known (FF 10) and suitable for treatment of a variety of
cancers (FF 11–12). The Examiner relies upon Ueda and Appendix A to
teach that the specific CCR4 antibody, mogamulizumab (FF 8–9) was
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suitable for use as an anticancer agent (FF 6–7). The Examiner recognized
claim 211 “recites a combination of elements that were all known in the
prior art, and all that was required to obtain that combination was to
substitute one . . . agent for another.” Wm. Wrigley Jr. Co. v. Cadbury
Adams USA LLC, 683 F.3d 1356, 1364 (Fed. Cir. 2012).
As to a reason to combine the teachings, Fukuda teaches IDO
inhibitors for treatment of cancer (FF 10–12) and Ueda teaches antibodies
such as mogamulizumab for treatment of cancer (FF 6–8). “It is prima facie
obvious to combine two compositions each of which is taught by the prior
art to be useful for the same purpose, in order to form a third composition
which is to be used for the very same purpose.” In re Kerkhoven, 626 F.2d
846, 850 (CCPA 1980).
Here, the Examiner further supports the reason to combine (see Final
Act. 5–7) by citing Banerjee’s express suggestion to combine IDO inhibitors
with antibody therapeutics (FF 3), by Cowley’s teaching to combine IDO
inhibitors (FF 13) with antibody therapeutics (FF 14), and by Gabrilovich’s
statements that “immunotherapy and chemotherapy target different methods
of tumour-cell survival and their combined effect would be highly desirable”
(FF 15) and that “data suggest a synergistic effect of immunotherapy and
chemotherapy” (FF 16).
Thus, the Examiner’s finding that it would have been obvious for the
ordinary artisan interested in treating cancers sensitive to IDO inhibitors and
CCR4 antibodies (FF 2, 7, 12) to treat using a combination of known IDO
inhibitors (FF 10) and known and functional CCR4 antibodies such as
mogamulizumab (FF 8–9) is supported by a preponderance of the evidence
because Banerjee, Cowley, and Gabrilovich suggest that combination
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therapy can be effective and even synergistic (FF 3, 14–16). The
Examiner’s reasoning “takes into account only knowledge which was within
the level of ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant’s disclosure.” In re
McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971).
Appellant contends
substituting a completely different IDO inhibitor from those
disclosed by Banerjee, which is the primary focus of Banerjee,
with those of Fukuda alone would not provide for a reasonable
expectation of success. Further, substituting mogamulizumab
for the other active agent of Banerjee would not provide for a
reasonable expectation of success. Substituting both the IDO
inhibitor and the other active agent certainly would not provide
for a reasonable expectation of success.
(Appeal Br. 12).
We find this argument unpersuasive because Banerjee demonstrates
that IDO inhibitors have anti-cancer activity (FF 5) and Ueda demonstrates
that the anti-CCR4 antibody mogamulizumab suppressed IL-10 (FF 8) that
is associated with cancer treatment (FF 7). Thus, the prior art provides
experimental evidence that IDO inhibitors and mogamulizumab function to
treat cancers (FF 5, 7, 8). Moreover, Gabrilovich states “immunotherapy
and chemotherapy target different methods of tumour-cell survival and their
combined effect would be highly desirable” (FF 15).
Banerjee, Fukuda, and Ueda and the other cited prior art are
“presumptively enabling barring any showing to the contrary by a patent
applicant.” In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012).
Appellant provides no evidence showing that these prior art references
would not have been enabled. Moreover, “[o]bviousness does not require
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absolute predictability of success . . . all that is required is a reasonable
expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009).
In this situation, where all of the cited prior art suggests that IDO inhibitors
and anti-CCR4 antibodies including mogamulizumab would be expected to
have anti-cancer activity, and Appellant has no adequate rebuttal evidence,
the preponderance of the evidence supports the Examiner’s position.
“Unsubstantiated attorney argument regarding the meaning of technical
evidence is no substitute for competent, substantiated expert testimony.”
Invitrogen Corp. v. Clontech Labs, Inc., 429 F.3d 1052, 1068 (Fed. Cir.
2005). That is, without evidence, we do not give weight to attorney opinions
(see, e.g., MPEP 716.01(c)).
Appellant contends “the Examiner cannot maintain an obviousness
rejection by mere conclusory statements. Instead, the Examiner must
provide some articulated reasoning with some rational underpinning to
support the legal conclusion of obviousness. The Examiner has failed to do
so” (Appeal Br. 14).
We find this argument unpersuasive for the reasons given above. The
Examiner identified specific teachings in the prior art showing that the anti-
cancer agents recited in claim 211 were known in the prior art (FF 6–12; cf.
Final Act. 45), and that Banerjee suggested the combination of IDO
inhibitors and antibodies including anti-CCR4 antibodies (FF 1–4; cf. Final
Act. 4). The Examiner also found that Banerjee, Cowley, and Gabrilovich
suggested the combination of chemotherapeutics such as the IDO inhibitors
and antibodies such as the anti-CCR4 antibody mogamulizumab would be
expected to improve, perhaps synergistically, cancer treatment (FF 1–5, 11–
16; cf. Final Act. 6–8). These findings are specific, detailed, and drawn to
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the obviousness of the claims at issue. The Examiner’s rejection has
substantial rational underpinning with clearly recited reasoning that supports
the Examiner’s legal conclusion of obviousness.
Secondary Considerations
Appellant contends they “found that a combination of a specific IDO
inhibitor (i.e. Compound (I)) with an antibody having ADCC activity (i.e.
mogamulizumab) exhibits useful combined effects for treatment of tumors
that are unexpected” (Appeal Br. 15). Appellant asserts that the data in
Figures 3, 7, and 9 of the Specification show that two compounds,
Compound A1 and Compound B1 “provide significant effects for treatment
of tumors by combining the specific IDO inhibitor (i.e. Compound (I)) with
the specific antibody having ADCC activity (i.e. mogamulizumab)” (Appeal
Br. 16–19).
We have evaluated these results and find them insufficient to
overcome the prima facie case of obviousness for two reasons.9 First, “any
superior property must be unexpected to be considered as evidence of non-
obviousness.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir.
2007). However, other than statements by attorney (see, e.g., Appeal Br.
15), Appellant provides no evidence that these results are unexpected.
As Geisler explains in distinguishing In re Soni, 54 F.3d 746 (Fed.
Cir. 1995), in Soni the applicants stated “in their application that the

9 We note that the results do require the use of interferon gamma (IFN-γ) and
unlike the mouse model of Banerjee (FF 5) or cell culture model of Ueda
(FF 8), Appellants do not establish whether these results would occur in an
actual tumor environment where interferon gamma may be absent, but we do
not rely on this deficiency.
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improved properties exhibited by the claimed compositions were ‘much
greater than would have been predicted,’ . . . while Geisler made no such
assertion in his application. Nor did Geisler submit any such statement
through other evidentiary submissions, such as an affidavit or declaration.”
Geisler, 116 F.3d at 1470–71 (citation omitted). Geisler concluded that
“naked attorney argument is ‘insufficient to establish unexpected results.’”
Id. at 1471 (citing Soni, 54 F.3d at 750).
We note that an electronic word search of the Specification does not
find any usage of either the terms “unexpected” or “surprising.” No
declaration or affidavit has been submitted to show that the results would
have been unexpected to one of ordinary skill the art. Therefore, the only
indication that any of these results constitutes an unexpected result is naked
attorney argument in the Appeal Brief, and these statements are not
evidence.
Second, unexpected results must be “commensurate in scope with the
degree of protection sought by the claimed subject matter.” In re Harris,
409 F.3d 1339, 1344 (Fed. Cir. 2005). Here, the evidence relates to, at most,
two specific IDO inhibitors, while the claim encompasses eight different R
groups, with the smallest two R groups encompassing the sixteen or so
compounds that may be hydrogen or lower alkyls, and the remaining six R
groups encompassing dozens more compounds, resulting in a total genus
that is immense. Appellant provides no evidence that the compounds all
would be expected to share features resulting in synergistic or unexpected
results with the mogamulizumab antibody.
And while we note that there is no requirement the each embodiment
need be demonstrated to establish unexpected results, in the instant case, it is
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also necessarily uncertain as to whether the two disclosed embodiments are
representative of the scope of claim 1. “Establishing that one (or a small
number of) species gives unexpected results is inadequate proof, for ‘it is the
view of this court that objective evidence of non-obviousness must be
commensurate in scope with the claims which the evidence is offered to
support.’” In re Greenfield, 571 F.2d 1185, 1189 (CCPA 1978). This is a
situation where only two species were tested and is therefore reasonably
found to be inadequate to demonstrate the full scope of the claim.
Conclusions of Law
(i) A preponderance of the evidence of record supports the Examiner’s
conclusion that the prior art renders the claims prima facie obvious.
(ii) Considering the entirety of the evidence before us, Appellant has
not established that the evidence of unexpected results shows the claims to
be non-obvious.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
211, 214,
215
103 Banerjee, Ueda,
Appendix A, Fukuda
211, 214, 215
211, 214,
215, 217,
218
103 Banerjee, Ueda,
Appendix A, Fukuda,
Cowley, Gabrilovich
211, 214,
215, 217, 218

Overall
Outcome
211, 214,
215, 217, 218

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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