AJINOMOTO CO., INC.

Patent Trials and Appeals Board

Sep 22, 2020

2020001258 (P.T.A.B. Sep. 22, 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.
15/008,865 01/28/2016 Shigekazu KURIHARA 464816US68CONT 1568
22850 7590 09/22/2020
OBLON, MCCLELLAND, MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA, VA 22314
EXAMINER
ANDERSON, JAMES D
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
09/22/2020 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):
OBLONPAT@OBLON.COM
iahmadi@oblon.com
patentdocket@oblon.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
________________

Ex parte SHIGEKAZU KURIHARA and
TAKASHI TSUCHIYA1
________________

Appeal 2020-001258
Application 15/008,865
Technology Center 1600
________________

Before FRANCISCO C. PRATS, JOHN G. NEW, and DAVID COTTA,
Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the term “Appellant” to refer to the “applicant” as defined in
37 C.F.R. § 1.142. Appellant identifies Ajinomoto Co., Inc. of Tokyo,
Japan as the real party-in-interest. App. Br. 1.
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SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 5–8, 12–23 and 26–29 as unpatentable
under 35 U.S.C. § 103 as being obvious over the combination of Shibahara
(US 7,767,714 B2, August 3, 2010) (“Shibihara”), S. Kurihara et al.,
Enhancement of Antigen-Specific Immunoglobulin G Production in Mice by
Co-Administration of L-Cystine and L-Theanine, 69(12) J. VET. MED. SCI.
1263–70 (2007) (“Kurihara”), S. Yoshida et al., Effects of Glutamine
Supplements and Radiochemotherapy on Systemic Immune and Gut Barrier
Function in Patients with Advanced Esophageal Cancer, 227(4) ANNS.
SURG. 485–91 (1998) (“Yoshida”), S. Kojima et al., Protective Effects of
Glutathione on 5-Fluorouracil-induced Myelosuppression in Mice, 77
ARCH. TOXICOL. 285–90 (2003) (“Kojima”), and J.F. Smyth et al.,
Glutathione Reduces the Toxicity and Improves Quality of Life of Women
Diagnosed with Ovarian Cancer Treated with cisplatin: Results of a
Double-Blind, Randomised Trial, 8 ANNS. ONCOL. 569–73 (1997)
(“Smyth”).2
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

2 Claims 14–16 and 18–28 were also rejected as unpatentable under 35
U.S.C. § 112(b) as being indefinite. Final Act. 5. The Examiner has
withdrawn this rejection. Ans. 16.
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NATURE OF THE CLAIMED INVENTION
Appellant’s claimed invention is directed to agents containing (A)
cysteine, or a derivative thereof, and (B) theanine, in combination, that are
useful for reducing side effects of cancer chemotherapy. Abstr.

REPRESENTATIVE CLAIM
Claim 5 is representative of the claims on appeal and recites:
5. A therapeutic drug for cancer, comprising:

cystine or a derivative thereof;

theanine; and

at least one anticancer agent selected from the group
consisting of a platinum preparation, an alkylating agent, an
antimetabolite, a plant alkaloid, an agent for molecular targeted
therapy, and a hormonal agent,

wherein the cystine or a derivative thereof and the theanine
are included in amounts sufficient to reduce a side effect of the
at least one anticancer agent, and

the derivative of cystine comprises at least one selected
from the group consisting of glutathione, glutathione disulfide,
glutathione alkyl ester, oxidized glutathione dialkyl ester,
cysteine, cysteine alkyl ester, 3-[(carboxymethyl)thio]alanine,
N-acylcysteine, N-acylcysteine alkyl ester, N-acylcystine, N-
acylcystine alkyl ester, N, Nʹ-diacylcystine, N, Nʹ-diacylcystine
dialkyl ester, and S-alkylcysteine sulfoxide.

App. Br. 14.
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ISSUES AND ANALYSES
We adopt the Examiner’s findings, reasoning, and conclusion that the
claims on appeal are prima facie obvious over the combined cited prior art.
We address the arguments raised by Appellant below.

A. Rejection of Claim 63

Issue

Appellant argues that the Examiner erred because a person of ordinary
skill in the art would not have been led to combine the teachings of the
references with a reasonable expectation of success. App. Br. 4.

Analysis
The Examiner finds that Shibahara teaches a tablet containing 175 mg
of L-cystine and 70 mg of L-theanine (i.e., a cystine:theanine ratio of 2.5: 1).
Final Act. 7 (citing Shibihara Ex. 4, col. 7, ll. 17–37).
The Examiner finds that Kurihara teaches that administration of both
cystine and glutamic acid increases the synthesis of glutathione (GSH),
which has a marked effect on immune cell function, as compared with
supplementation with either amino acid alone in human macrophages in
vitro. Final Act. 8. The Examiner finds that Kurihara teaches that, as
ingested glutamic acid is metabolized during intestinal transport, oral

3 Appellant makes no arguments with respect to claims 7, 8, 12–16, 18–23,
and 27–29. We therefore consider these claims as argued together with,
and standing or falling with, claims 5, 6, 17, and 26.
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administration of L-theanine (γ-glutamylethylamide), which is metabolized
to glutamic acid mainly in the liver, may act as a glutamic acid donor in
vivo. Id. The Examiner further finds that Kurihara teaches that co-
administration of L-cystine (200 mg/kg) and L-theanine (80 mg/kg) for
11 days prior to immunization significantly increased the levels of total
glutathione (“GSH”) in the liver six hours after immunization compared to
levels in control mice, and that Kurihara thus demonstrates that it was
known in the art at the time of Appellant’s invention that administration of
L-cystine and L-theanine increases levels of liver GSH. Id. (citing Kurihara
Abstr.).
The Examiner finds that Yoshida teaches that glutamine supplements
improved protein metabolism in tumor-bearing rats undergoing
chemotherapy, and reduced the toxicity of chemotherapy through an
enhancement of glutathione production. App. Br. 9 (citing Yoshida Abstr.).
The Examiner particularly points to Yoshida’s citation of K. Rouse et
al., Glutamine Enhances Selectivity of Chemotherapy through Changes in
Glutathione Metabolism, 221 Anns. Surg. 420–426 (1995) (“Rouse”), which
teaches that glutamine supplements reduced the toxicity of chemotherapy
because of enhanced glutathione synthesis in tumor bearing rats. Id. (citing
Yoshida 485–86).
The Examiner finds that Kojima teaches that GSH is important in the
detoxification of a variety of toxic xenobiotics, such as in acetaminophen-
induced liver injury, aflatoxin B1-induced liver tumors, alcoholic liver
toxicity, bromobenzene-induced liver necrosis, p-dichlorobenzene-induced
hepatotoxicity, eugenol-induced hepatotoxicity, pulmonary toxicity induced
by a metabolite of 4-ipomeanol, 5-fluorouracil-induced teratogenicity, and
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thiabendazole-induced nephrotoxicity, in various animal models. Final Act.
10 (citing Kojima 285). The Examiner finds that Kojima teaches that GSH
exerts a protective effect on 5-fluorouracil-induced myelosuppression in
mice. Id. (citing Kojima Abstr., 286).
The Examiner finds that Smyth teaches that GSH provides protection
from the toxic effects of cisplatin. Final Act. 11. The Examiner finds that
Smyth teaches that co-administering GSH and the chemotherapeutic agent
cisplatin (“CDDP”) allows more cycles of CDDP treatment to be
administered because less toxicity is observed and the patient’s quality of
life improved. Id. (citing Smyth Abstr.).
The Examiner concludes that a person of ordinary skill in the art
would have found it obvious to increase GSH levels to reduce the side
effects of cancer chemotherapeutic agents, such as 5-fluorouracil or
cisplatin, as taught by the combination of Yoshida, Kojima, and Smyth.
Furthermore, the Examiner reasons, because cystine and theanine were
known in the art to increase GSH levels when administered, as taught by
Kurihara, a skilled artisan would expect that administration of cystine and
theanine in combination with an anticancer agent, would reduce the toxicity
of chemotherapeutic agents such as cisplatin or 5-fluorouracil by increasing
GSH levels. Final Act. 15.
Appellant argues that Shibahara and Kurihara are directed to
administering L-cystine and L-theanine to healthy subjects, whereas
Yoshida, Kojima, and Smyth are directed to administering chemicals other
than L-cystine and L-theanine to cancer patients. App. Br. 5. Appellant
therefore contends that there is no overlap between the subject groups and
the chemicals described in these references. Id.
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Moreover, argues Appellant, even if Shibahara and Kurihara are
combined with Yoshida, Kojima, and Smyth, a person of ordinary skill in
the art would not have had a reasonable expectation that administration of L-
cystine and L-theanine to a cancer patient would result in reducing a side
effect of cancer chemotherapy performed by administering certain
anticancer agent(s). App. Br. 6. Appellant contends that Kurihara teaches
that oral administration of L-cystine and L-theanine increases the glutathione
(GSH) levels in the liver. Id. (citing Kurihara 1264, 1265). Furthermore
argues Appellant, Yoshida (citing Rouse) describes reducing toxicity of
chemotherapy because of enhanced glutathione synthesis after
administration of glutamine. Id. Appellant asserts that Rouse teaches oral
administration of glutamine and methotrexate (“MTX,” a chemotherapeutic
agent) to tumor-bearing rats, and demonstrates that GSH level decreased in
the tumor cells and increased in the host tissues. Id. (citing Rouse 421, 422).
According to Appellant, these references show that administration of GSH
precursors increases GSH levels in healthy subjects or tissues due to
synthesis of GSH in vivo. Id. at 7.
However, Appellant argues, unlike Kurihara and Yoshida (and
Rouse), Kojima and Smyth teach the direct administration of GSH and an
anticancer agent to a cancer patient. App. Br. 7. Appellant contends that
Kojima and Smyth neither teach nor suggest that GSH synthesized in vivo
can also be used to alleviate possible side effects of the anticancer agent. Id.
Appellant therefore argues that a person of ordinary skill in the art
would not have had a reasonable expectation that GSH, synthesized in vivo
as described in Kurihara, Yoshida, and Rouse, would act like directly
administered GSH, as described in Kojima and Smyth. App. Br. 7. Rather,
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Appellant asserts, a skilled artisan would have understood that
administration of GSH itself, as described in Kojima and Smyth, does not
necessarily increase metabolic GSH levels. Id. In fact, Appellant argues, it
was known in the prior art at the time of invention that oral administration of
GSH was unlikely to cause increases in metabolic GSH levels, because GSH
can be hydrolyzed and decomposed by the activity of γ-glutamyl transferase.
Id.
In support of this argument, Appellant points to the prior art teachings
of A. Witschi et al., The Systemic Availability of Oral Glutathione, 43(6)
EUR. J. CLIN. PHARMACOL. 667–69 (1992) (“Witschi”) and J. Allen et al.,
Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress
Biomarkers in Human Volunteers, 17(9) J. ALT. COMP. MED. 827–33 (2011)
(“Allen”). App. Br. 7. Appellant argues that Witschi teaches that orally-
administered GSH is hydrolyzed by intestinal and hepatic γ-
glutamyltranserase and therefore does not increase the amount of circulating
GSH. Id. (citing Witschi Abstr.). Similarly, argues Appellant, Allen teaches
that orally administered GSH did not increase GSH levels in healthy
humans. Id. (citing Allen Abstr., 829–30). Appellant therefore contends
that, because oral administration of GSH does not necessarily increase
metabolic GSH levels, as taught by Witschi and Allen, a skilled artisan
would have understood that the reduction of toxicity of the anticancer agents
taught by Kojima and Smyth must be caused by mechanisms other than
increases in metabolic GSH levels, and that there is no correlation between
metabolic GSH levels in situ and toxicity of an anticancer agent. Id. at 8.
Appellant asserts that a person of ordinary skill in the art, aiming to reduce
toxicity of the claimed anticancer agents, would not have been led to
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administer precursors of GSH, such as L-cystine and L-theanine, as a means
of increasing GSH level in a subject. Id.
We are not persuaded by Appellant’s arguments. We acknowledge
Appellant’s argument that the teachings of Witschi and Allen, at first glance,
may seem to contradict the teachings of Kojima that oral administration of
GSH can increase levels of circulating GSH. Indeed, we agree with
Appellant that Witschi teaches that GSH may be hydrolysed “by intestinal
and hepatic [γ]-glutamyltransferase” and that “dietary glutathione is not a
major determinant of circulating glutathione.” Witschi (Abstr., emphasis
added). However, in reaching this conclusion, Witschi expressly teaches
only that “oral administration of a single dose of 3g of glutathione” is
insufficient to achieve a “clinically beneficial” increase in circulating GSH.
Id.
Similarly, Allen teaches that “oral GSH supplementation (500 mg
twice daily) was given to the volunteers” and that: “No significant changes
were observed in biomarkers of oxidative stress, including glutathione
status, in this clinical trial of oral glutathione supplementation in healthy
adults.” Allen Abstr.
In contrast, Kojima teaches oral administration of GSH in mice at “at
a dose of 800 mg/kg … for 21 consecutive days.” Kojima Abstr. This is the
equivalent of a daily dosage in humans of approximately 50g over an
interval of three weeks.4 Although, direct comparisons between the

4 The average mass of a human, measured globally, is approximately 62 kg.
See S.C. Walpole et al., The Weight of Nations: an estimation of Adult
Human Biomass, 12 BMC PUBLIC HEALTH 439 (2012) (“Walpole”)
available at: https://doi.org/10.1186/1471–2458–12–439.
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metabolic capabilities of mice and humans is difficult, it is nevertheless
evident that Kojima teaches administration of a significantly more massive
equivalent dosage: more than 10 times that of Witschi and 50 times that of
Allen. This may have some bearing upon the differences between the
teachings of Witschi and Allen, on the one hand, and Kojima on the other.
Nevertheless, we acknowledge that Witschi teaches that it was known in the
contemporaneous art that GSH is hydrolysed in the gut and liver by γ-
glutamyl transferase and that this may prevent low dosages of GSH from
elevating circulating levels of GSH. See also Allen Abstr.
However, we find the teachings of Witschi and Allen with respect to
oral administration of GSH to be entirely irrelevant to the teachings of
Smyth. Smyth expressly teaches intravenous co-administration of GSH and
CDDP. See Smyth 570 (“A total of 151 women with ovarian cancer stage I-
IV (mean age 57 years, range 21–76) received i.v. CDDP 100 mg/m2 + GSH
3 g/m2 (placebo controlled) every three weeks for six courses”) (emphasis
added). We find that a person of ordinary skill in the art would have
understood that intravenous administration largely bypasses the enteric and
hepatic systems (and hence, hydrolysis of GSH by γ-glutamyl transferase)
and would directly increase circulating levels of GSH.
Nevertheless, we find that Appellant makes an important point,
although not, perhaps, the intended one, viz., that it was known in the art at
the time of invention that orally administered GSH can be hydrolyzed in the
gut and liver by γ-glutamyl transferase, and that this may prevent an increase
in circulating levels of GSH. However, it was also known in the
contemporaneous art that oral administration of GSH precursors, including
L-cystine and L-theanine, (and its derivatives, glutamine and glutamate) can
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increase circulating levels of GSH. See Kurihara Abstr. (“Supplementation
with both cystine and glutamic acid increases the synthesis of glutathione
(GSH)”). Similarly, Yoshida teaches that oral administration of another
rate-limiting precursor of glutathione, glutamine, can also increase GSH
levels, and that the concomitant increase in GSH levels following glutamine
administration can decrease anticancer agent toxicity in vivo. 5 See Yoshida
489–90; Rouse Abstr., 422–23.
Given these teachings of the prior art, we agree with the Examiner
that a person of ordinary skill in the art would have found it obvious to
combine the teachings of the cited prior art references (and those of Witschi
and Allen) and to administer precursors to GSH known to elevate circulating
levels of GSH, and to co-administer these precursors with an anticancer
agent, because Yoshida, Kojima, and Smyth (and Rouse) teach that elevating
levels of circulating GSH can reduce the side effects (including toxicity) of
anticancer agents. We consequently affirm the Examiner’s rejection of
claim 6. Furthermore, Appellant makes the same arguments with respect to
claim 5. App. Br. 12. For the reasons we have explained, we similarly
affirm the Examiner’s rejection of claim 5.

5 Both glutamine and L-theanine are metabolized to glutamic acid, which is
one of the three peptides constituting GSH. See Kurihara 1263; Yoshida
489–90. Orally-administered glutamate is metabolized in the intestine and
consequently does not reach GSH-producing organs. See Kurihara 1263.
L-theanine and glutamine are thus precursors to glutamate, an essential and
rate-limiting precursor in GSH synthesis. See Yoshida 489–90. We
conclude that it would therefore have been obvious to a skilled artisan,
seeking to increasing metabolic GSH levels, to administer either of these
metabolic precursors to glutamate and GSH.
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B. Rejection of Claim 17
Issue
Appellant argues that the Examiner erred in finding that the combined
cited prior art teaches or suggests the limitation of dependent claim 17
reciting: “wherein the side effect of cancer chemotherapy is at least one
selected from the group consisting of anorexia, nausea, vomiting, diarrhea,
stomatitis, malaise, and exanthema.” App. Br. 10.
Analysis
Appellant argues that Kojima teaches only some side effects of 5-FU,
such as myelosuppression, and in particular thrombocytopenia, leukopenia,
erythrocytopenia, granulocytopenia, and reticulocytopenia. App. Br. 10
(citing Kojima 28–89). Appellant asserts that Kojima is silent about
reducing the specific side effects recited in claim 17, and that there is no
evidence of record showing that patients suffering myelosuppression also
necessarily suffer from the side effects recited in the claims. Id.
Appellant also contends that Smyth appears to mention nausea and/or
vomiting as a possible toxic effect of cisplatin administration, but Smyth
neither teaches nor suggests that its subjects suffer from nausea and/or
vomiting and the administration of cisplatin and GSH alleviate cisplatine-
induced nausea and/or vomiting. App. Br. 10.
We are not persuaded. Smyth teaches:
Each question in the Rotterdam Symptoms Checklist was
analysed separately. Forty-five of the 47 questions had the better
observed mean response in the glutathione group, when the
responses were scored from 1 to 4.

Eight of these differences were statistically significant at the 5%
level. These comprised the questions on nausea, vomiting,
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tingling hands/feet, loss of hair, short of breath, difficulty
concentrating, housekeeping and shopping. The overall finding
is one of improved mood in the GSH group.

Smyth 571, see also Table 4. Smyth thus teaches that the subjects of its
study reported that co-administration of GSH with cisplatin/CDDP
alleviated symptoms of nausea and vomiting as compared to administration
of cisplatin/CDDP alone. Smyth also teaches that fewer patients
discontinued treatment with cisplatin/CDDP when co-administered with
GSH (n=2) than those administered cisplatin alone (n=7). See id. Table 3.
We therefore agree with the Examiner that Smyth teaches that co-
administration of GSH with cisplatin/CDDP reduces the side effects of
cancer chemotherapy including nausea and vomiting, and we consequently
affirm the Examiner’s rejection of claim 17. Furthermore, Appellant makes
the same arguments with respect to claim 26. App. Br. 11–12. For the
reasons we have explained, we similarly affirm the Examiner’s rejection of
that claim.

CONCLUSION
The Examiner’s rejection of claims 5–8, 12–23, and 26–29 under
35 U.S.C. § 103 is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1).

AFFIRMED

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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
5–8, 12–23,
26–29
103 Shibihara,
Kurihara,
Yoshida,
Kojima, Smyth

5–8, 12–23,
26–29