Ex Parte Kim et al

Patent Trial and Appeal Board

May 26, 2017

13880792 (P.T.A.B. May. 26, 2017)

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.
13/880,792 06/26/2013 Jong-Yeon Kim 2280-092 5067
90395 7590
Revolution IP, PLLC
1940 Duke St.
Suite 200
Alexandria, VA 22314
05/31/2017 EXAMINER
ANDERSON, JAMES D
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
05/31/2017 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):
mail@revolutioniplaw.com
swkimlaw@gmail.com
mhlee @ revolutioniplaw. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JONG-YEON KIM, JONG-RYUL EUN, and YOUN-JU LEE
Appeal 2016-0034581
Application 13/880,792
Technology Center 1600
Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
DAVID COTTA, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims to a method of
treating or preventing alcoholic hepatitis. The Examiner rejected the claims
for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants state that the real party in interest “is the assignee, Industry-
Academic Cooperation Foundation, Yeungnam University of
Gyeongsangbuk-Do, Republic of Korea.” App. Br. 3.
Appeal 2016-003458
Application 13/880,792
STATEMENT OF THE CASE
The sole rejection before us for review is the Examiner’s rejection of
claims 1, 4, and 5 under 35 U.S.C. § 103(a), for obviousness over
Nakajima,2 Mendes,3 Lee,4 and Akriviadis5 (Ans. 2—11).
Claim 1, the sole independent claim on appeal, reads as follows (App.
Br. 15):
1. A method of treating or preventing alcoholic liver
disease in a subject, comprising administering a therapeutically
effective amount of cilostazol represented in Formula 1 or a
pharmaceutically acceptable salt thereof as a part of a
pharmaceutical composition to said subject:
[Formula 1]
wherein the alcoholic liver disease is alcoholic hepatitis.
2 WO 2009/008539 A1 (published Jan. 15, 2009).
3 Juliana Barros Mendes et al., Cilostazol and Pentoxifylline Decrease
Angiogenesis, Inflammation, and Fibrosis in Sponge-Induced
Intraperitoneal Adhesion in Mice, 84 Life Sciences 537—543 (2009).
4 Yin-Mei Lee et al., A Randomized Controlled Pilot Study of Pentoxifylline
in Patients with Non-Alcoholic Steatohepatitis (NASH), 2 Hepatol. Int. 196—
201 (2008).
5 Evangelos Akriviadis et al., Pentoxifylline Improves Short-term Survival in
Severe Acute Alcoholic Hepatitis: A Double-Blind, Placebo-Controlled
Trial, 119 Gastroenterology 1637—1648 (2000).
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OBVIOUSNESS
The Examiner’s Prima Facie Case
In rejecting claims 1, 4, and 5 for obviousness, the Examiner cited
Nakajima as disclosing that cilostazol, the drug recited in claim 1, was
“useful for preventing/treating NASH (non-alcoholic steatohepatitis) and/or
treating fatty liver and inhibiting the initial stages of NASH.” Ans. 4.
The Examiner cited Mendes as teaching that cilostazol, and another
drug, pentoxifylline, “have similar biological activities in decreasing
angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal
adhesion in mice.” Id. at 5. The Examiner noted in particular Mendes’s
teachings that “both cilostazol and pentoxifylline: 1) inhibit angiogenesis in
vivo (Figure 2); 2) decrease VEGF levels (Figure 2); 3) inhibit TNF-a
(Figure 3); and 4) decrease levels of the pro-fibrogenic cytokine TGF-pi and
decrease collagen deposition (Figure 4).” Id. at 6.
The Examiner cited Fee as evidence that, like cilostazol, “the PDE
inhibitor pentoxifylline was also known to be effective in treating patients
with NASH.” Id.
The Examiner cited Akriviadis as disclosing that “a cytokine-induced
acute inflammatory response and increased tumor necrosis factor (TNF)
levels have been implicated in acute alcoholic hepatitis.” Id. at 7. The
Examiner cited Akriviadis as also disclosing that “that treatment with
pentoxifylline improves short-term survival in patients with severe alcoholic
hepatitis.” Id. at 7.
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Based on the references’ combined teachings, the Examiner reasoned
as follows:
Given the known use of cilostazol in the treatment of
NASH, the disclosure in the prior art that both pentoxifylline
and cilostazol inhibit PDE and exert similar biological
responses in vivo, and the fact that pentoxifylline was known to
have therapeutic effectiveness in the treatment of both NASH
and alcoholic hepatitis, it would have been prima facie obvious
to one of ordinary skill in the art at the time the invention was
made to combine the teachings of the references so as to
administer cilostazol for the treatment of alcoholic liver disease
such as alcoholic hepatitis. One would have been motivated to
do so because each of the therapeutics were known to exert
similar biological effects in vivo and are both disclosed in the
prior art for the treatment of NASH. In light of the fact that
pentoxifylline was also known to be effective in treating
alcoholic hepatitis, the skilled artisan would predict that
cilostazol would be effective in treating alcoholic hepatitis.
Ans. 11.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
Appellants do not persuade us that a preponderance of the evidence
fails to support the Examiner’s conclusion of obviousness. To the contrary,
we agree with the Examiner’s findings of fact, and conclusion of
obviousness derived therefrom, and adopt them as our own. We include the
discussion below for emphasis.
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As the Examiner found, Akriviadis describes a study in which the
drug pentoxifylline was administered to treat alcoholic hepatitis, the disorder
treated in Appellants’ claim 1. Akriviadis 1637. Akriviadis based its
decision to study the effects of pentoxifylline on an “earlier pilot study from
our liver unit [that] suggested benefit from treatment with pentoxifylline
(PTX), an inhibitor of tumor necrosis factor (TNF), in severe acute alcoholic
hepatitis.” Id.', see also id. at 1644 (“The present study was initiated to test
the hypothesis that PTX, by inhibiting TNF production, might decrease both
the occurrence of progressive renal failure and the mortality rate associated
with severe alcoholic hepatitis.”) (emphasis added).
In the larger subsequent study reported in the Akriviadis article, the
researchers found that “[treatment with PTX improves short-term survival
in patients with severe alcoholic hepatitis. The benefit appears to be related
to a significant decrease in the risk of developing hepatorenal syndrome.
Increasing TNF levels during the hospital course are associated with an
increase in mortality rate.” Akriviadis 1637 (emphasis added).
Akriviadis explains that alcoholic hepatitis is associated with elevated
TNF levels. Id. (“[IJncreased tumor necrosis factor (TNF) levels have been
found in sera of patients with acute alcoholic hepatitis, particularly
in more severe cases.”); see also id. at 1644 (“TNF can cause hepatocyte
injury either directly by binding to cytokine receptors or indirectly by
attracting and activating neutrophils. Administration of human recombinant
TNF has been linked with reversible hepatotoxicity. Therefore, agents with
anticytokine effects could be of benefit in the treatment of severe acute
alcoholic hepatitis.”) (emphasis added).
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Akriviadis, thus, teaches that alcoholic hepatitis can be treated with a
TNF inhibitor, pentoxifylline. Unlike Appellants’ claim 1, however
Akriviadis does not treat the disorder with cilostazol.
Nonetheless, as the Examiner found, Mendes teaches that, in a mouse
model of post-surgery adhesion, cilostazol inhibited TNF-a production to the
same degree as pentoxifylline, and the two drugs exhibit a number of other
similar properties. See Mendes 537 (both drugs inhibit angiogenesis,
inflammation, fibrosis in mouse model); see also id. at 541 (“Levels of a
potent pro-inflammatory cytokine TNF-alpha were measured in the implants
of both groups and were found to decrease with both [cilostazol and
pentoxifylline] treatments (approximately 40%) at the higher doses (Fig.
3C)).”.
Thus, given Akriviadis’ teaching that agents such as pentoxifylline,
that inhibit TNF production, are useful for treating alcoholic hepatitis, and
further given Mendes’ teaching that cilostazol inhibits TNF-a production to
the same degree as pentoxifylline and has a number of other anti­
inflammatory properties in common with pentoxifylline, we agree with the
Examiner that an ordinary artisan had ample reason for, and a reasonable
expectation of success in, using cilostazol to treat alcoholic hepatitis. The
disclosures in Nakajima and Lee, that cilostazol (Nakajima 6) and
pentoxifylline (Lee 196) possess the common property of being useful in
treating non-alcoholic steatohepatitis, further bolster the equivalence of the
two drugs for treating alcoholic hepatitis. Thus, given the teachings in the
cited references, we conclude that a preponderance of the evidence supports
the Examiner’s prima facie case that the method recited in claim 1 would
have been obvious to an ordinary artisan.
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Appellants’ arguments do not persuade us to the contrary.
Appellants contend that “the skilled artisan would not predict that
cilostazol would be effective in treating alcoholic hepatitis because [the]
applied references are silent as to inhibiting fatty acid synthase (FAS) gene
expression, and activity of caspase-3.” App. Br. 8; see also Reply Br. 1—3,
5. Appellants do not, however, identify any persuasive evidence of record
suggesting that an ordinary artisan at the time of Appellants’ invention
would have treated alcoholic hepatitis only with drugs that had been shown
to inhibit fatty acid synthase gene expression and caspase-3.
To the contrary, as seen above, rather than using inhibition of either
fatty acid synthase gene expression or caspase-3 as a criterion for treatment
of alcoholic hepatitis, Akriviadis based its treatment on pentoxifylline’s
capacity to inhibit TNF production. As also seen above, Mendes teaches
that cilostazol shares that property with pentoxifylline. Given that cilostazol
was known in the art to inhibit TNF-a, Appellants do not persuade us (see
App. Br. 9; Reply Br 2) that an ordinary artisan lacked a reasonable
expectation that cilostazol would be useful in treating alcoholic hepatitis.
See In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (“Obviousness does
not require absolute predictability of success. ... For obviousness under
§ 103, all that is required is a reasonable expectation of success.”). Indeed,
Appellants advance no persuasive evidence supporting their assertions (App.
Br. 9; Reply Br 2) that an ordinary artisan viewing the discussed teachings in
the cited references would have lacked a reasonable expectation of treating
alcoholic hepatitis with cilostazol.
As to Appellants’ contention that the Examiner failed to consider the
claimed process as a whole (App. Br. 9-12; Reply Br. 2—3), the sole step
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required in the method of claim 1 is administering cilostazol to a subject to
treat or prevent alcoholic hepatitis. See App. Br. 15 (claim 1). For the
reasons discussed above, we agree with the Examiner that the cited
references provided an ordinary artisan with ample reason for, and a
reasonable expectation of success in, using cilostazol to treat alcoholic
hepatitis.
Appellants direct us to Example 3 of the Specification, which shows
that, as compared to controls, caspase-3 activity and fatty acid synthase
(FAS) gene expression were inhibited when cilostazol was administered to
mice prior to administration of binge alcohol amounts. App. Br. 10—12
(citing Spec. 15—17 (Example 3), Figs. 8—11). Appellants contend that the
“characteristics of activity of caspase-3 and FAS gene expression are
present in the invention as a whole that lack any corresponding feature in the
applied reference.” App. Br. 12; see also Reply Br. 2—3.
Again, however, the sole process step required in Appellants’ claim 1
is administering cilostazol to a subject so as to treat or prevent alcoholic
hepatitis, as noted above. As discussed above, moreover, the cited
references provided an ordinary artisan with ample reason for, and a
reasonable expectation of success in, using cilostazol to treat alcoholic
hepatitis.
To the extent Appellants suggest that inhibiting caspase-3 activity and
fatty acid synthase (FAS) gene expression is an inherent or unexpected
property of the claimed treatment not present in the prior art, Appellants’
Example 3 provides no comparative data with any prior art process to
support that proposition. See In re Baxter-Travenol Labs., 952 F.2d 388,
392 (Fed. Cir. 1991) (“[Wjhen unexpected results are used as evidence of
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nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.”).
As to such comparisons, Appellants contend that Figure 4 of the
Specification shows that “that the preventive effect of apoptosis in cilostazol
is superior than pentoxifylline.” App. Br. 12; see also Reply Br. 3^4 (Figure
4 reproduced at top of page 4 of Reply Brief).
As our reviewing court has pointed out, however, “[ejvidence of
secondary considerations must be reasonably commensurate with the scope
of the claims.” In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). In the
present case, the results shown in Figure 4 are based on treatment of cultured
cells (see Spec. 13), whereas claim 1 requires administering cilostazol to a
subject to treat or prevent alcoholic hepatitis. The results shown in Figure 4,
therefore, are not commensurate in scope with claim 1.
Moreover, although Appellants’ briefs assert that the results seen in
Figure 4 show cilostazol to be superior to pentoxifylline, the Specification
makes no such assertion. See Spec. 13 (stating only that “[referring to FIG.
4, nuclear fragmentation caused by ethanol was reduced by pretreatment
with cilostazol”). In the absence of evidentiary support, the assertions that
Figure 4 shows superiority of cilostazol over pentoxifylline are mere
attorney argument, which is entitled to no weight on this issue. See In re
Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997). In that regard, we discern no
significantly different result in Figure 4 between the cilostazol and
pentoxifylline treatments, nor do Appellants identify any significant
differences.
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Appellants also advance a series of three figures to further support
their assertion that “the preventive effect of apoptosis in cilostazol is
superior than pentoxifylline.” App. Br. 13; Reply Br. 4.
Appellants, however, do not identify the source of those figures, nor
do Appellants explain where, outside their briefs, those figures may be found
in the current record in this case. As explained in 37 C.F.R. § 1.132, “any
evidence submitted to traverse the rejection or objection on a basis not
otherwise provided for must be by way of an oath or declaration under this
section.” See also 37 C.F.R. § 1.68. Because Appellants do not identify
where the three figures shown on page 13 of the Appeal Brief (also shown at
the bottom of page 4 of the Reply Brief) may be found in the current record
in this case, it is not clear that the figures are properly advanced in this
appeal.
Moreover, while Appellants assert that those figures show the
superiority of cilostazol over pentoxifylline, Appellants do not explain with
any specificity what is shown in those figures, in particular what specific
experiments underlie the data, and why the data demonstrate the superiority
of cilostazol over pentoxifylline, in a manner commensurate in scope with
the treatment method recited in claim 1.
Lastly, we note that “[mjere improvement in properties does not
always suffice to show unexpected results. . . . [Wjhen an applicant
demonstrates substantially improved results . . . and states that the results
were unexpected, this should suffice to establish unexpected results in the
absence of evidence to the contrary.” In re Soni, 54 F.3d 746, 751 (Fed. Cir.
1995). In the present case, Appellants do not assert specifically or explain
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persuasively why any alleged superiority of cilostazol over pentoxifylline
would have been substantial or unexpected.
In sum, for the reasons discussed, Appellants do not persuade us that
the Examiner failed to make out a prima facie case of obviousness as to
claim 1. Because we are not persuaded, for the reasons discussed, that
Appellants have advanced objective evidence of nonobviousness sufficient
to outweigh the evidence of prima facie obviousness, we affirm the
Examiner’s rejection of claim 1 over Nakajima, Mendes, Lee, and
Akriviadis. Because they were not argued separately, claims 4 and 5 fall
with claim 1. 37 C.F.R. § 41(c)(l)(iv).
SUMMARY
For the reasons discussed, we affirm the Examiner’s rejection of
claims 1, 4, and 5 under 35 U.S.C. § 103(a), for obviousness over Nakajima,
Mendes, Lee, and Akriviadis
TIME PERIOD
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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