Kowa Company, Ltd.

Patent Trials and Appeals Board

May 15, 2020

2019001405 (P.T.A.B. May. 15, 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.
14/162,181 01/23/2014 Haruki Shibata P23320US01 4155
38834 7590 05/15/2020
WESTERMAN, HATTORI, DANIELS & ADRIAN, LLP
8500 LEESBURG PIKE
SUITE 7500
TYSONS, VA 22182
EXAMINER
STRONG, TORI
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
05/15/2020 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):
patentmail@whda.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte HARUKI SHIBATA, YASUNOBU YOSHINAKA,
and KIMIYUKI SHIBUYA
__________

Appeal 2019-001405
Application1 14/162,181
Technology Center 1600
__________

Before DONALD E. ADAMS, ERIC B. GRIMES, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating non-alcoholic steatohepatitis, which have been rejected as
obvious and for obviousness-type double patenting. We have jurisdiction
under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
Appellant’s Specification explains that non-alcoholic fatty liver
disease (“NAFLD”) is a fatty hepatic disorder. (Spec. ¶ 3.) NAFLD is

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 KOWA
COMPANY, LTD. (Appeal Br. 2.)
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classified into steatosis and nonalcoholic steatohepatitis (NASH). (Id.)
“The therapy of NASH is, in principle, an improvement in lifestyle based on
the diet and exercise therapy for lifestyle-related diseases such as obesity,
diabetes, dyslipidemia, and hypertension.” (Id. ¶ 5.) Because it is “difficult
to improve the lifestyle,” drug therapy is provided that targets, among other
things, “lipid metabolism abnormality.” (Id.)
“[T]he number of the patients with NASH is expected to increase, and
it is desired to establish a method of treating NASH.” (Id.) Appellant’s
invention is directed at such a method.
Claims 1 and 2 are on appeal.2 Claim 1 is representative and reads as
follows:
1. A method of treating non-alcoholic steatohepatitis
comprising:
administering a drug comprising an effective amount of
2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-
bis(methylthio)-6-methyl-3-pyridyl]acetamide, an acid-addition
salt thereof, or a solvate of the same to a patient in need thereof.
(Appeal Br. 17.)

The prior art relied upon by the Examiner is:
Name Reference Date
Shibuya US 6,969,711 B2 Nov. 29, 2005
K. Tolman and A. Dalpiaz, Treatment of non-alcoholic fatty liver disease,
3(6) Therapeutics and Clinical Risk Management 1153–63 (2007)
R. Vuppalanchi and N. Chalasani, Non-alcoholic fatty liver disease and
non-alcoholic steatohepatitis: Selected practical issues in their evaluation
and management, 49(1) Hepatology 306–17 (2009)

2 Claims 3–14 remain pending but are withdrawn from consideration on
appeal.
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The following grounds of rejection by the Examiner are before us on
review:
Claims 1 and 2 under 35 U.S.C. § 103(a) as unpatentable over
Shibuya, Vuppalanchi, and Tolman.
Claims 1 and 2 on the ground of non-statutory obviousness-type
double patenting as being unpatentable over claims 1–7 of Shibuya and
Vuppalanchi.
DISCUSSION
The Examiner finds that the claims as “broadly and reasonably
interpreted” include any treatment of the claimed disease, which includes
“co-morbidities that are part of the pathogenesis of the disease.” (Final
Action 5.)
Shibuya teaches the claimed compound, and that it is in a class of
compounds that are “inhibitors of acyl coenzyme A cholesterol
acyltransferase (ACAT).” (Final Action 6.) The Examiner further notes that
Shibuya teaches that ACAT inhibitors cause the following cascade of
events: inhibiting cholesterol ester production in the liver and suppressing
secretion of VLDL (very low density lipoprotein) from the liver. (Id.at 6–7;
Ans. 7.) The Examiner explains that this suppression “implicitly teaches a
reduction in fats that [are] secreted from the liver.” (Final Action 8.) The
Examiner further explains that the inhibition aspect “leads to free cholesterol
readily being taken up by high-density lipoprotein (HDL) and metabolized
in the liver (col. 2, l. 45–49).” (Id.) In sum, the Examiner finds that Shibuya
teaches the claimed compound results in “cholesterol reduction in the blood
and VLDL suppression from the liver.” (Id.; see also Ans. 12 (Shibuya
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teaches the claimed compounds provides “overall reduction of cholesterol in
the blood through prevention of esterification and promoting metabolism.”).)
Thus, the Examiner concludes that “Shibuya provides guidance to the
compounds having an effect outside of the liver ultimately having an
antihyperlipemic effect, which appears to be ACAT-1 activity.” (Id.)
The Examiner recognizes that Shibuya does not teach treating NASH
with the claimed compound. (Final Action 7.) However, the Examiner
concludes that Vuppalanchi and Tolman provide motivation for treating
NASH with the claimed compound with a reasonable expectation of success.
(Id. at 8.)
In particular, the Examiner finds that both references “teach weight
loss has improved the progression of the disease.” (Final Action 6.) In
particular, explains the Examiner, Vuppalanchi teaches that NAFLD is
associated with obesity and hyperlipidemia and that treatment involves
reducing fat or reducing risk factors, such as weight loss for obese patients.
(Final Action 7.) The Examiner explains that NAFLD “is the disease that
encompasses and leads to NASH; where it can be simple steatosis (NAFLD)
or steatohepatitis (NASH).” (Ans. 10.)
The Examiner finds that Tolman teaches treatment of NAFLD and
explicitly teaches that “obesity promotes progression of the disease (p. 1154,
col. 1, para. 6)” and that “the only categories of therapeutic intervention
include[] targeting steatosis, fat in the liver, or the pathogenesis of
progression (p. 1156, col. 1 para. 4).” (Final Action 7; see also Ans. 11
(Tolman “teaches that dyslipidemia is in the pathogenesis of the disease.”).)
The Examiner concludes that Tolman establishes “that treating obesity and
dyslipidemia is a standard method for treating NAFLD.” (Final Action 7.)
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In light of the foregoing, the Examiner concludes that one of ordinary
skill in the art would have had a reasonable expectation of success in treating
NASH with the claimed compound disclosed in Shibuya; stating:
Vuppalanchi and Tolman provide a rationale for targeting
hyperlipemia for treating NAFLD which leads to NASH and
further an example of treating NASH. The prior art provides a
rationale for administering antihyperlipemic agent to an overall
patient population with hyperlipemia, as well as the subgenus
patient population of NASH.
(Ans. 11; see also Ans. 14 (“The conclusions drawn are based on the nexus
that Shibuya teaches the claimed compound to have antihyperlipemic
activity and Vuppalanchi and Tolman teaching the pathogenic association
hyperlipidemia with NASH and exemplifying treatment of NASH with an
antihyperlipemic agent.”).)
We agree with the Examiner’s findings regarding Shibuya teaching
antihyperlipemic effects of the claimed compound in the blood and
conclusion of obviousness.
Appellant asserts that NASH involves the abnormal retention of lipids
in the liver and the inventors unexpectedly found that the claimed compound
“reduces the levels of cholesterol and triglyceride in the liver while
significantly inhibiting TNF-α expression and reduces the level of
macrophages in the liver i.e., treats NASH” and that Shibuya’s teaching of
“a suppression of secretion in VLDL from the liver to the blood should not
be interpreted as a reduction of fat in the liver.” (Reply Br. 2; Appeal Br. 6–
7 (“since cholesterol in the blood decreases due to suppression of VLDL
secretion from the liver, increase of liver fat may be expected but
decrease thereof should generally never be readable from Shibuya.”).)
Appellant’s arguments that the Examiner’s rejection is in error stem in large
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part from a difference in interpretation of the claimed method. Appellant
argues that “[t]he Examiner is narrowly construing the present invention as
reducing cholesterol, or that a reduction of cholesterol is a treatment of
NASH” but NASH “is broader than cholesterol.” (Reply Br. 2.)
We agree with the Examiner’s claim construction, and do not find it to
be a narrow construction. Rather, the Examiner’s construction is properly a
broad construction consistent with Appellant’s Specification. In re Hyatt,
211 F.3d 1367, 1372 (Fed. Cir. 2000) (“[D]uring examination proceedings,
claims are given their broadest reasonable interpretation consistent with the
specification.”) Appellant’s Specification states:
The therapy of NASH is, in principle, an improvement in
lifestyle based on the diet and exercise therapy for lifestyle-
related diseases such as obesity, diabetes, dyslipidemia, and
hypertension. However, it is actually difficult to improve the
lifestyle and thus drug therapy targeting insulin resistance,
oxidative stress, lipid metabolism abnormality, or hypertension
which is considered to be an important factor for the
progression of NASH is provided.
(Spec. ¶ 5.) In other words, Appellant’s Specification teaches broadly that
treatment of NASH includes drug therapy that targets lipid metabolism
abnormality. As the Examiner noted, Appellant’s claim “does not require
that treatment be focused on reducing fat in the liver only.” (Final Action
5.) Thus, we conclude that Appellant’s claimed method of treatment
includes administering an effective amount of the claimed compound that
targets abnormal lipid metabolism of a patient, and is not limited to
achieving a reduction of fat in the liver. And for this reason, we disagree
with Appellant’s argument that a method for treating NASH by targeting a
comorbidity (which the Examiner indicates to be treating hyperlipemia, (see,
e.g., Ans. 9–10)) “is not an actual treatment option for NASH” (Appeal Br.
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8). Additionally, for this reason, we do not find Appellant’s arguments that
Shibuya does not describe or suggest a change in the accumulated
cholesterol in the hepatocytes due to inhibition of ACAT activity (Appeal
Br. 11) or the reduction of cholesterol and triglyceride in the liver (Reply Br.
2–3) to be persuasive of non-obviousness. That Shibuya does not teach
these results in the liver does not negate the teaching of antihyperlipemic
effects that Shibuya does teach, which will be discussed below.
Tolman teaches that NAFLD “refers to a broad spectrum of liver
disease which varies from bland steatosis (NAFLD) to steatohepatitis
(NASH) to progressive fibrosis and, ultimately, cirrhosis with portal
hypertension.” (Tolman 1153; see also Vuppalanchi 3 (“The NAFLD can
be categorized into simple steatosis and steatohepatitis (NASH).”).) We
agree with the Examiner (1) that Vuppalanchi “explicit[ly] teach[es] that
hyperlipidemia is associated with NAFLD” (Ans. 10–11 (citing Vuppalanchi
2)); and (2) that Tolman indicates that dyslipidemia is one of the most
common causes of NAFLD (Ans. 11 (citing Tolman 1154)). Furthermore,
Tolman teaches that “[t]he presence of insulin resistance and/or obesity
permits/promotes disease progression” (Tolman 1154) and that “[t]reatment
falls into two categories: targeting either the steatosis or the pathogenesis of
progression” (id. at 1156). Tolman further states that “[i]n general, factors
that decrease steatosis consist of weight loss or pharmacologic therapy
directed at insulin resistance or dyslipidemia.” (Id. (emphasis added); see
also id. at 1160 (“Patients with insulin resistance can be treated with
thiazolidinediones while patients with dyslipidemia can be treated with lipid
lowering agents.”).) Vuppalanchi is consistent with Tolman’s teaching that
treatment includes targeting comorbidity. Vuppalanchi states:
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[i]t is generally recommended that overweight and obese
patients with NAFLD lose 7-10% of their body weight by
dietary modification and exercise over the course of 6-12
months. This is based on short-term studies showing that
gradual weight loss of this magnitude improves insulin
resistance and hepatic histology.
Vuppalanchi 5.
Appellant does not dispute that “obesity and dyslipidemia is
characterized by cholesterol and fats in the blood, not just focused in the
liver.” (Final Action 5.) Furthermore, Appellant does not dispute that
Shibuya teaches or suggests the claimed compound suppresses VLDL
secretion from the liver to blood which results in a decrease in cholesterol in
the blood (Appeal Br. 7) or that inhibition of production of cholesterol ester
by the ACAT inhibitor leads to free cholesterol readily being taken up by
high-density lipoprotein and being metabolized in the liver (Final Action 8,
Ans.8). Instead, Appellant argues just that Shibuya does not teach a
reduction of fat in the liver. (Appeal Br. 6; Reply Br. 3 (“Column 2, lines 45
to 49 of Shibuya . . . is referring only to the suppression of cholesterol
accumulation at the focus site of atherosclerosis.”); id. at 4 (“The Examiner
argues the effect of ACAT inhibitors on reducing fat in the liver is
recognized in the ‘state of the art’ but has provided no such evidence to base
said rational upon.”).)3

3 Appellant refers to two declarations by Shibuya, one submitted June 28,
2016 (the First Shibuya Declaration) and the other submitted January 31,
2017 (the Second Shibuya Declaration) that “explained that the Examiner’s
interpretation of the Shibuya reference is incorrect.” (Appeal Br. 8.)
However, these declarations do not contradict the Examiner’s interpretation.
The First Shibuya Declaration states that “Shibuya is silent about ‘reducing
fat in the liver.’” (See First Shibuya Declaration ¶ 5.) The Second Shibuya
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Appellant’s argument is not persuasive because the Examiner’s
rejection does not rest on a conclusion that Shibuya teaches a reduction of
fat in the liver. The Examiner explains that Shibuya teaches that the claimed
compound results in a decrease in cholesterol in the blood as a result of
stopping production of cholesterol ester in the liver due to ACAT inhibition,
which in turn suppresses secretion of VLDL from liver into blood. (See,
e.g., Ans. 7.) We understand the Examiner’s position to be that Shibuya
teaches suppressing secretion of VLDL into the blood, which thus results in
a reduction of lipids/cholesterol in the blood. (Ans. 8–10.)
The Examiner indicates that Shibuya teaches an additional
antihyperlipemic activity of ACAT inhibition “even outside the liver,”
namely that the free cholesterol in cells not in the liver, produced by
inhibiting esterification there, is removed from the cells by HDL and
transmitted to the liver to be metabolized, and thus accumulation of
cholesterol “at the focus site is expected.” (Id. at 8.) We agree with the
Examiner that the claimed compounds is, thus, an “antihyperlipemic agent”
causing an overall reduction of lipids and cholesterol (id. at 5, 9), regardless
of the fact that Shibuya does not clearly teach anything about the claimed

Declaration is similar in stating that Shibuya does not describe “the change
in the accumulated cholesterol in the hepatocytes” or “to the change of in
vivo liver cholesterol accumulation.” (Second Shibuya Declaration ¶ 7 (iv).)
As discussed, however, that is not what the Examiner contends Shibuya
teaches. Rather as even noted in the First Shibuya Declaration, the
Examiner states that “Shibuya teaches the suppression of secretion of VLDL,
which implicitly teaches a reduction in fats that is secreted from the liver.”
(First Shibuya Declaration ¶ 4 (bold emphasis added).)
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compound’s effects in hepatocytes or in changing fat accumulation in the
liver (Appeal Br. 8–11; Reply Br. 3–5). The Examiner states:
The key take away is that Shibuya recognizes the
antihyperlipemic activity of the compounds through the known
pathways, particularly when Shibuya states (col.5, 1.5-9,
emphasis added):
"Those compo[u]nds of the present invention are
particularly useful as antihyperlipemic agents having
excellent cholesterol-lowering action in blood and also
preventive and therapeutic agents for arteriosclerosis, and
so on having an suppressing action to foaming of
macrophage."
Shibuya clearly illuminates the general antihyperlipemic
activity of the compounds in conjunction with treating
arteriosclerosis.
(Ans. 9.) In light of the foregoing, we agree with the Examiner that one of
ordinary skill in the art would have found it obvious to administer the
compound taught by Shibuya in treating NASH with a reasonable
expectation of success.
Appellant argues that there can be no reasonable expectation of
success because Tolman states:
“There are no FDA approved pharmacological agents and, in
fact, no FDA guidelines for such drugs despite the fact that
NAFLD is the most common liver disease in the US. The
treatment used to date are outlined in Table 3. Virtually all are
compromised by small numbers and lack placebo control”
(Emphasis Added).
(Appeal Br. 12 (quoting Tolman 1156).) Appellant further points to the fact
that Tolman suggests statins are promising agents for treatment but a study
published after Tolman “explains that no significant effect in the treatment
of NASH by statin monotherapy was demonstrated as a result of the double-
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blinded randomized placebo-controlled trial.” (Id. at 12–13.) We do not
find this argument persuasive for the reasons stated by the Examiner. (Ans.
12–13.) FDA approval is not necessary to establish a reasonable expectation
of success. “Only a reasonable expectation of success, not absolute
predictability, is necessary for a conclusion of obviousness.” In re Longi,
759 F.2d 887, 897 (Fed. Cir. 1985). And the absence of FDA guidelines
does not contravene the fact that Tolman “explicitly teaches that there are
treatment[s] used that have demonstrated improvement.” (Ans. 13.)
Regarding the reference offered by Appellant regarding statin monotherapy,4
the Examiner noted, and Appellant does not dispute in reply, that the statin
in that reference was a different one than the one that Tolman indicates
demonstrated improvement in a patient study. (Id.) Consequently, the
information relied on by Appellant does not cast doubt on the reasonable
expectation of success of the compound taught in Shibuya, a compound that
is also not a statin, for use in treating NASH.
In light of the foregoing, we affirm the Examiner’s rejection of claim
1 as being obvious over Shibuya, Vuppalanchi, and Tolman.
Regarding claim 2, Appellant urges that unexpected results have been
shown because Example 1 of the Specification illustrates that the claimed
compound “exhibited a significant decrease in TC and TG in the liver (FIG.
2) and significant decreases in inflammatory cytokine TNF-a expression in
the liver and macrophage CD11c (FIG. 3).” (Appeal Br. 15.) According to
Appellant, “even if the dose of the compound was in a range that did not

4 We note that the reference submitted as Appendix III was not the Nelson
reference to which Appellant referred.
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affect the plasma lipid, the compound still had a direct effect on the liver and
reduced the levels of cholesterol and triglyceride in the liver.” (Id.)
We do not find the evidence establishes non-obviousness, because the
claim is not limited to a dose that has the exemplified effects. In other
words, the evidence is not commensurate in scope with the claims. In re
Dill, 604 F.2d 1356, 1361 (CCPA 1979) (“The evidence presented to rebut a
prima facie case of obviousness must be commensurate in scope with the
claims to which it pertains.”)
Consequently, we also affirm the Examiner’s rejection of claim 2 as
being obvious over Shibuya, Vuppalanchi, and Tolman.

Obviousness-Type Double Patenting
The Examiner relying on the same references set forth above finds the
claimed invention obvious. In this rejection, however, the Examiner relies
only on the claims of Shibuya that teach the claimed compound and claim 7
that recite a method for therapy of hyperlipemia, among other things,
where an effective amount is administered as an ACAT
inhibitor, an agent for inhibiting the transportation of
intracellular cholesterol, an agent for lowering the cholesterol in
blood or an agent for suppressing the storage of cholesterol in
macrophage as fat droplets.
(Final Action 11 (citing claim 7).)
Appellant argues the rejection is in error for the same reasons as
discussed with respect to the obviousness rejection. (Appeal Br. 15.)
We agree with the Examiner’s rejection in light of claim 7 of Shibuya
teaching the use of the claimed compound to achieve therapy of
hyperlipemia and Vuppalanchi’s teaching pharmacologic therapy directed
toward comorbidity such as dyslipidemia in treating NAFLD. (See
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Vuppalanchi 5–8 and Table 6.) As discussed above, we conclude that the
claim does not require that the compound will have an effect on reducing fat
in liver in order to have a reasonable expectation of success in treating
NASH. Moreover, one need not know that such an effect would arise to
have a reasonable expectation of success in treating NASH. A reasonable
expectation of treating NASH arises from the teaching of claim 7 in Shibuya
that hyperlipemia can be treated with the claimed compound and
Vuppalanchi’s teaching suggesting treating atherosclerosis and dyslipidemia
to treat NAFLD.
Consequently, we affirm the Examiner’s rejection of claims 1–2 on
the ground of non-statutory obviousness-type double patenting as being
unpatentable over claims 1–7 of Shibuya and Vuppalanchi.

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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 2 103 Shibuya,
Vuppalanchi,
Tolman
1, 2
1, 2 Obviousness-type
Double Patenting:
Shibuya,
Vuppalanchi
1, 2
Overall
Outcome
1, 2

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). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED