Ex Parte Asada et al

Board of Patent Appeals and Interferences

Nov 17, 2010

10524996 (B.P.A.I. Nov. 17, 2010)

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.
10/524,996 02/18/2005 Hiroyuki Asada 05105/HG 3212
1933 7590 11/17/2010
HOLTZ, HOLTZ, GOODMAN & CHICK PC
220 Fifth Avenue
16TH Floor
NEW YORK, NY 10001-7708
EXAMINER
WEBB, WALTER E
ART UNIT PAPER NUMBER
1612
MAIL DATE DELIVERY MODE
11/17/2010 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HIROYUKI ASADA and AKIO KIMURA
__________

Appeal 2010-009400
Application 10/524,996
Technology Center 1600
__________

Before CAROL A. SPIEGEL, ERIC GRIMES, and STEPHEN WALSH,
Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134(a) involving claims to
ophthalmic solutions comprising latanoprost and ε-aminocaproic acid. The

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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Patent Examiner rejected the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The invention concerns an opthalmic solution comprising latanoprost,
“a prostaglandin-type therapeutic agent for glaucoma.” (Spec. 1.)
Claims 6, 8, 10, 12, 14, and 16 are on appeal. Claims 6 and 12 are
representative and read as follows:
6. An aqueous ophthalmic solution comprising 0.005% (W/V)
latanoprost as an active ingredient, wherein the latanoprost is stabilized to be
stored at room temperature by adding ε-aminocaproic acid to the solution.

12. An aqueous ophthalmic solution comprising 0.005% (W/V)
latanoprost as an active ingredient, wherein the latanoprost is stabilized to be
stored at room temperature by adjusting the pH of the solution to 5.0 to 6.25
and adding ε-aminocaproic acid to the solution.

The Examiner rejected all the claims under 35 U.S.C. § 103(a) as
unpatentable over Schneider2 and Kimura.3
OBVIOUSNESS
The Issue
The Examiner’s position is that Schneider taught an ophthalmic
solution comprising a prostaglandin, such as latanoprost, at 0.001 to 0.005%
w/v and having a pH of 6 +/- 0.2. (Ans. 3.) The Examiner found that
Schneider recognized that prostaglandins are generally unstable and taught
the use of polyethoxylated castor oils as a stabilizing agent. (Id.) The

2 US Patent No. 6,011,062 issued to L. Wayne Schneider et al., Jan. 4, 2000.
3 US Patent No. 5,556,848 issued to Motoko Kimura et al., Sep. 17, 1996.

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Examiner found that Schneider differed from the instant claims by not
teaching the addition of ε-aminocaproic acid to its composition. (Id. at 4.)
The Examiner found that Kimura taught an ophthalmic suspension
comprising difluprednate as the active ingredient and taught adding acetates
or ε-aminocaproic acid to its ophthalmic suspension. (Id.) According to the
Examiner, Kimura taught that these additives suppress formation of
agglomerates, prevent lowering of pH, and provide a suspension superior in
redispersability and stability. (Id.) The Examiner found that Kimura taught
that polyoxyethylene castor oils are also useful for these same functions.
(Id.)
The Examiner reasoned that “[b]ecause Schneider recognized the
stability problems of prostaglandins, it would have been obvious to a person
having ordinary skill in art at the time of applicants’ invention to add a
known stabilizing agent such as ε-aminocaproic acid at 0.01-2.0 w/v% to the
composition of Schneider….” (Id.) According to the Examiner, the skilled
artisan would have been motivated by Kimura’s teaching that ε-
aminocaproic acid beneficially suppresses formation of agglomerates,
prevents lowering of pH, and provides a suspension superior in
redispersability and stability. (Id.)
Appellants challenge the Examiner’s rejection by asserting differences
between each prior art reference and the claimed invention. Specifically,
Appellants assert that Schneider disclosed castor oil to stabilize latanoprost,
while the instant claims use ε-aminocaproic acid to stabilize latanoprost and
that these stabilizing agents “completely differ in their chemical structure
and their chemical properties.” (App. Br. 7.) Additionally, Appellants
assert that Kimura was directed to “enhancing the dispersion stability” in an
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ophthalmic suspension comprising a water-insoluble active ingredient,
difluprednate, while the instant claims are directed to “enhancing the
chemical stability” of a completely different active ingredient, latanoprost, in
a water-soluble ophthalmic solution. (Id. at 8-9.) Moreover, Appellants
assert that Kimura did not teach or suggest enhancing the chemical stability
of latanoprost or any active ingredient, in a water-soluble ophthalmic
solution, nor did Kimura teach that ε-aminocaproic acid would increase the
chemical stability of an active ingredient. (Id. at 9; Reply Br. 3-5.)
Appellants then contend that a skilled artisan would have “no reason
for substituting the active ingredient in Schneider et al. (a prostaglandin) for
the active ingredient in Kimura et al. (difluprednate), since these two active
ingredients are totally different.” (App. Br. 10.) Appellants additionally
contend that a skilled artisan “would not consider to employ ε-aminocaproic
acid as a substitute for the polyethoxylated castor oils employed by
Schneider et al.” because Kimura disclosed “ε-aminocaproic acid only as an
additional component, namely, a buffer.” (Id.)
Further, Appellants assert that the Specification provides evidence of
unexpected results relating to: (a) increased stability of latanoprost in a
solution comprising ε-aminocaproic acid, with respect to all of the rejected
claims; and (b) improved stability of latanoprost in a solution having a pH of
5 to 6.25, with respect to claims 12, 14 and 16. (Id. at 10-14.)
The issues with respect to this rejection are: whether the record
supports the Examiner’s conclusion that the combined references would
have made the claimed ophthalmic solutions prima facie obvious, and if so,
whether Appellants have provided evidence of unexpected results such that
the totality of evidence weighs in favor of nonobviousness.
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Findings of Fact
1. We agree with the Examiner’s explicit findings regarding the scope
and content of the prior art references. (See Ans. 3-5.)
2. Schneider disclosed that its compositions may further comprise
various formulary ingredients, including buffers in an amount between about
0.001 and about 1 wt %. (Schneider col. 7, ll. 10-13, 30-31.)
3. Schneider disclosed an exemplary formulation of its composition
comprising sodium acetate in an amount of 0.07% and having a pH of 5.
(Id. at col. 8, ll. 1-15.)
4. Kimura disclosed acetates, particularly sodium acetate, and ε-
aminocaproic acid as the preferable buffers that may be included in its
compositions. (Kimura col. 3, ll. 19-32.)
5. The Specification describes studying the effects of various additives,
including ε-aminocaproic acid, on stability of latanoprost by adding 100 ml
of an aqueous solution (pH 7) to 5 mg of latanoprost and then storing
samples of the mixture in an incubator at either 50°C or 80°C. (Spec. 13.)
6. The Specification disclosed that in the case of storage at 50°C and at
80°C, the residual ratio, i.e., stabilization effect, was higher in formulations
containing ε-aminocaproic acid as compared to formulation containing other
additives, not including sodium acetate. (Id. at 15 and 16, Table 3.)
7. The Specification describes an experiment in which latanoprost was
dissolved in a phosphate buffer having a pH of 4.0, 5.0, 5.5, 6.0, 6.25, 6.5,
6.7, and 8.0 and then stored at either 60°C or 70°C. (Id. at 8.)
8. The Specification disclosed that “in the case of storage at 60°C,
residual ratios of 95% or higher, namely stable samples, were in the range of
pH 5.0 to 6.25. Similarly in the case of storage at 70°C, residual ratios of
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90% or higher, namely stable samples, were also in the range of pH of 5.0 to
6.25.” (Id. at 8 and 10, Table 1.)
9. The Specification states, “From the above-mentioned results, it was
found that when pH of the latanoprost ophthalmic solution is adjusted to 5.0
to 6.25, latanoprost is stabilized, and the opthalmic solution can be stored at
room temperature.” (Id. at 9.)
Principles of Law
“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). “Express
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).
It is well settled that unexpected results must be established by factual
evidence. In re Lindner, 457 F.2d 506, 508 (CCPA 1972). Additionally,
“the results must be shown to be unexpected compared with the closest prior
art.” Kao Corp. v. Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir. 2006).
Analysis
A. Prima Facie Obviousness
We are not persuaded by Appellants’ contentions. While we agree
with Appellants that differences exist between each of the individual prior
art references and the claimed invention (see App. Br. 7-9), the Examiner
rejected the claims over a combination of the two references. Their
combined teachings, not the separate teachings, serves as the basis of
comparison to the claimed invention. The Examiner combined Schneider’s
shelf stable aqueous pH 6 ophthalmic solution comprising latanoprost 0.005
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w/v% with Kimura’s ε-aminocaproic acid, which yields the claimed
composition.
Appellants assert that differences between Schneider and Kimura
support their contention that the Examiner’s combination would not have
been obvious. In particular, Appellants contend that a skilled artisan would
not consider (a) substituting Schneider’s prostaglandin for Kimura’s
difluprednate, or (b) substituting Schneider’s castor oil for Kimura’s ε-
aminocaproic acid. (App. Br. 10; Reply Br. 2.) However, the Examiner’s
combination did not involve either of these substitutions. Rather, the
Examiner explained that it would have been obvious “to add” Kimura’s ε-
aminocaproic acid to Schneider’s ophthalmic solution comprising
latanoprost and castor oil. (Ans. 4.) The inclusion of castor oil in this
combination is not beyond the scope of the claims which broadly recite an
aqueous composition using the open claim language “comprising.”
To the extent Appellants contend (Reply Br. 3-5) that Kimura did not
“teach that ε-aminocaproic acid can increase the chemical stability of active
ingredients,” e.g., Kimura’s difluprednate or Schneider’s latanoprost, we
agree. We also agree that Kimura disclosed the stabilizing effectiveness of
ε-aminocaproic acid with respect to a suspension. However, these facts do
not establish nonobviousness. As the Examiner explained, the references
provide a further basis of prima facie obviousness. (Ans. 6.) Specifically,
Schneider disclosed that its ophthalmic formulation may additionally
comprise a buffer, including sodium acetate. (Ans. 5; FF-2, 3.) Kimura also
disclosed adding a buffer to its composition, preferably sodium acetate or ε-
aminocaproic acid. (Ans. 5, FF-4.)
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The Examiner reasoned that a skilled artisan would have found it
obvious to add ε-aminocaproic acid as the buffer in Schneider’s composition
instead of sodium acetate because Kimura disclosed sodium acetate and
ε-aminocaproic acid as equivalent buffers. (Ans. 5-6.) This reasoning is
sound. See Fout, 675 F.2d at 301; KSR, 550 U.S. at 416. Moreover,
Appellants have not challenged this reasoning in their Reply. (See Reply 1-
10.)
B. Asserted Unexpected Results
Appellants contend that Table 3 in the Specification “shows that after
storage at 50°C for 8 weeks, the residual ratio of the latanoprost in an
ophthalmic solution is 93.1% when ε-aminocaproic acid is added to the
solution.” (App. Br. 10.) Additionally, Appellants assert that Table 3 shows
that after storage at 80°C for 4 weeks, the residual ratio of the latanoprost is
51.8% when ε-aminocaproic acid is added,” compared to 6.3-28.9% when it
is not added. (Id. 10-11.) Therefore, according to Appellants, “Table 3
clearly shows the stability of latanoprost in an aqueous ophthalmic solution
is significantly improved when ε-aminocaproic acid, out of numerous
additives, is added.” (Id. at 11.) However, the “numerous additives” tested
in the Specification study did not include sodium acetate, the buffer additive
used in the latanoprost composition disclosed in Schneider, and described as
an equivalent buffer to ε-aminocaproic acid by Kimura. (FF 3-6.) Thus,
Appellants have not shown that their results were unexpected compared to
the closest prior art, as required to overcome prima facie obviousness. See
Kao Corp., 441 F.3d at 970.
Regarding claims 12, 14, and 16, Appellants further assert that Table
1 in the Specification provides “[u]nexpected results for employing a pH
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range of 5.0 to 6.25” by demonstrating that “the stability of latanoprost
(residual ratio %) after storage for 28 days at 60°C and 70°C is substantially
better at a pH of 5.0 to 6.25, compared to at a pH of each of 4.0, 6.7 and
8.0.” (App. Br. 13.) However, Schneider disclosed that its shelf stable
latanoprost compositions had a pH of 6 +/- 0.2, which pH falls within the
instantly claimed and tested range. (See Ans. 3; see also FF-7, 8, 9.) Thus,
again, Appellants have not established that these results were unexpected
over, or even different than, the closest prior art so as to overcome prima
facie obviousness.
CONCLUSIONS OF LAW
The record supports the Examiner’s conclusion that the combined
references would have made the claimed ophthalmic solutions prima facie
obvious. Appellants have not provided evidence of unexpected results such
that the totality of evidence weighs in favor of nonobviousness.
SUMMARY
We affirm the rejection of claims 6, 8, 10, 12, 14, and 16 under
35 U.S.C. § 103(a) as unpatentable over Schneider and Kimura.

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
lp

Appeal 2010-009400
Application 10/524,996

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