Ex Parte Ueno

Patent Trial and Appeal Board

Mar 5, 2013

11110698 (P.T.A.B. Mar. 5, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte RYUJI UENO
__________

Appeal 2011-010723
Application 11/110,698
Technology Center 1600
__________

Before TONI R. SCHEINER, FRANCISCO C. PRATS, and
STEPHEN WALSH, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to methods of
reducing intraocular pressure by administering an ophthalmic solution. The
Examiner entered a rejection for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm in part.
STATEMENT OF THE CASE
The Specification discloses that a number of prostaglandin derivatives
are “known to be useful as pharmaceutical agents in the ophthalmic area,
namely as an ocular hypotensive agent or an agent for treatment of
glaucoma” (Spec. 3). “Especially, isopropyl ester of 13, 14-dihydro-15-
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keto-20-ethyl-PGF2α has already been placed on the market under the name
of Rescula™ (common name: isopropyl unoprostone) ophthalmic solution
for treatment of glaucoma and ocular hypertension” (id. at 4).
Appellant’s invention is directed to “improving the duration of the
effect of [such] an ophthalmic solution comprising a prostaglandin
compound” by including in the solution “at least one viscosity-increasing
compound selected from the group consisting of acrylate polymers, polyols,
cellulose polymers, polysaccharides and polyl-lactams” (id. at 4-5).
Claims 14, 26, 30, 32, and 34-50 stand rejected and appealed (App.
Br. 4). Claims 14 and 30 illustrate the appealed subject matter and read as
follows (paragraph indentation added):
14. A method for improving the duration and/or potency of the
intraocular pressure lowering effect of an ophthalmic solution
comprising 13,14-dihydro-15-keto-20-ethyl prostaglandin F2α
isopropyl ester when administrated to the eyes of a subject,
comprising:
adding at least one viscosity-increasing compound which is a
polysaccharide and which is not a cellulose polymer to the ophthalmic
solution, wherein the at least one viscosity-increasing compound is
present in an amount of 0.001-30 w/v%.

30. A method for improving the duration and/or potency of the
effect of an ophthalmic solution comprising 13,14-dihydro-15-keto-
20-ethyl-prostaglandin F2α isopropyl ester when administered to the
eyes of a subject, comprising:
adding gellan gum in an amount of about 0.01- 10w/v% to the
ophthalmic solution.

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The sole rejection before us for review is the Examiner’s rejection of
claims 14, 26, 30, 32, and 34-50 under 35 U.S.C. § 103(a) as obvious over
Ueno
1
and Desai
2
(see Final Rejection 2 (entered March 19, 2010)).
3

DISCUSSION
The Examiner found that Ueno taught “the claimed prostaglandin in
combination with polysorbate 80, carboxymethylcellulose, methylcellulose
and carboxyvinyl polymers in an ophthalmic formulation for the treatment
of ocular hypertension” (Ans. 4). The Examiner found that Ueno differed
from Appellant’s claims in that Ueno did not “specifically us[e] a
polysaccharide other than cellulose” in its formulations (id.).
To address that deficiency, the Examiner cited Desai as evidence that,
in addition to cellulosic polymers, other polysaccharides such as xanthan and
locust bean gum were “well known” in the art to be useful in ophthalmic
formulations, including those containing prostaglandins (id.).
The Examiner reasoned, therefore, that an ordinary artisan would have
considered it obvious to include viscosity enhancing agents, such as xanthan
gum and locust bean gum, “into the composition of Ueno, motivated by the
teachings of Desai et al., which teaches the use of xanthan gum and other
types of gum as viscosity enhancing agents in ophthalmic formulations in

1
U.S. Patent No. 5,208,256 (issued May 4, 1993).
2
U.S. Patent No. 5,558,876 (issued September 24, 1996).
3
In restating the rejection in the Answer, the Examiner, presumably
inadvertently, listed the rejected claims incorrectly (see Ans. 4). The
Answer does, however, state that all of the pending claims, claims 14, 26,
30, 32, and 34-50 stand rejected (see id. at 2), and Appellant acknowledges
that those claims are subject to this rejection (see Reply Br. 3).
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combination with active agents, such as prostaglandins as old and well
known” (id.).
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.

Appellant directs argument traversing the Examiner’s prima facie case
to all of the rejected claims, and also directs separate argument to claims 30,
32, and 34 (see App. Br. 9-11).
We are not persuaded that a preponderance of the evidence fails to
support the Examiner’s prima facie case of obviousness. As discussed
below, however, as to claim 30 and its dependents, we are persuaded that
Appellant has advanced sufficient evidence of unexpected results to
outweigh the evidence of prima facie obviousness.
We select claim 14 as representative of the first group of claims
argued. See 37 C.F.R. § 41.37(c)(1)(vii).
Appellant argues that the Examiner erred in finding that the cited
references suggest the combination of the prostaglandin recited in claim 14,
and a non-cellulose polysaccharide (App. Br. 9). Specifically, Appellant
argues, unlike the isopropyl prostaglandin ester recited in claim 14 and
described in Ueno, Desai is “specifically directed to acidic drug
formulations” (id.; see also Reply Br. 7)
In particular, Appellant notes that the prostaglandins used in Desai are
acids rather than esters (App. Br. 9-10). Thus, Appellant argues, “one would
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not have applied Desai's teachings to an ester such as Ueno’s Compound B”
(id. at 10).
We are not persuaded.
Ueno discloses that combining polysorbate 80 with the prostaglandin
compound recited in Appellant’s claim 14 potentiates the intraocular
pressure-reducing activity of the prostaglandin, and reduces measured side
effects (see Ueno, col. 15, l. 30, through col. 17, l. 12 (Test Example 2)). As
the Examiner found, Ueno discloses that ophthalmic solutions containing
those agents may also suitably contain “thickeners such as glycerol,
carboxymethylcellulose, carboxyvinyl polymer, etc.” (Id. at col. 10, ll. 1-3.)
Desai is directed to ameliorating the inherent eye-irritating effects and
formulation difficulties imparted to ophthalmic solutions by acidic carboxyl
group-containing compounds, including prostaglandins (see Desai, col. 1, ll.
14-17; id. at col. 2, ll. 1-3). Desai teaches that combining Vitamin E TPGS
and caffeine synergistically reduces eye discomfort and potentiates the
efficacy of a preservative included in the solutions (id. at col. 2, ll. 27-33).
Desai also discloses that its ophthalmic solutions can suitably contain
a number of additional excipients including “[v]iscosity building agents,
e.g., . . . cellulose derivatives including alkyl and hydroxyalkyl cellulose like
methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, etc.;
gums like locust beam, xanthan, agarose, karaya, guar, etc.; and other
polymers including . . . tragacanth and hyaluronic acid” (id. at col. 2, ll. 49-
57).
We agree with Appellant that the central thrust of Desai’s disclosure
is solving the problems encountered when using acidic drugs in ophthalmic
solutions. In our view, however, an ordinary artisan would have recognized
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from Desai that the Vitamin E TPGS/caffeine combination was singular to
solving the acidic drug problem, and would therefore be of limited
application to non-acidic drug formulations, whereas the disclosure of
suitable thickening agents, appearing in a relatively long list of other
generally applicable excipients, would not be limited to the acidic drugs in
Desai’s formulations.
Indeed, because the list of thickeners suitable in Ueno’s ophthalmic
solutions includes carboxymethylcellulose, which is also among the suitable
thickeners described in Desai, we agree with the Examiner that an ordinary
artisan preparing Ueno’s ophthalmic solutions would have reasoned that the
thickeners in Desai’s list would also be suitable in Ueno’s formulations,
particularly given that both references describe using prostaglandins in
ophthalmic solutions.
We also note Ueno’s disclosure that prostaglandin-containing
ophthalmic solutions containing methylcellulose have a less potent
intraocular pressure-reducing activity than solutions which only contain the
active prostaglandin (see Ueno, col. 15, ll. 22-25 (comparing Formulation 1
and Formulation 2)). However, given Ueno’s express teaching of the
suitability of thickening agents in its formulations (which according to its
invention also contain the potentiating compound polysorbate 80), and given
the fact that the methylcellulose-containing composition actually had
intraocular pressure-reducing activity, we are not persuaded that Ueno
would have directed an ordinary artisan away from using known thickeners,
such as those described in Desai, in its prostaglandin formulations.
Accordingly, Appellant’s arguments do not persuade us that a
preponderance of the evidence fails to support the Examiner’s prima facie
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case of obviousness as to claim 14. As Appellant does not direct argument
regarding unexpected results to claim 14, we affirm the Examiner’s rejection
of that claim as obvious over Ueno and Desai.
As they were not argued separately, and do not depend from a claim
that was argued separately, claims 26, 35, 39, 41, 43, and 45-50 fall with
claim 14. See 37 C.F.R. § 41.37(c)(1)(vii).
Claim 30 and its dependents stand on a different footing, however.
As Appellant notes, claim 30 requires its practitioner to include a
specific polysaccharide, gellan gum, in an ophthalmic solution that contains
the claimed prostaglandin. As Appellant also notes (Reply Br. 6), neither
Desai, nor Ueno for that matter, appears to specifically teach the use of
gellan gum as a thickening agent for ophthalmic solutions.
As Appellant further points out, the Tabuchi Declaration
4
presents a
comparison between a Rescula
TM
formulation (an ophthalmic solution
containing the claimed prostaglandin derivative) and similar formulations
that include gellan gum and methyl cellulose, among other thickeners (see
Tabuchi Declaration 2-4). The declarant explicitly states:
Methyl cellulose and gellan gum could improve the
duration and/or potency of the IOP [intraocular pressure]
lowering effect of the ophthalmic solution comprising l3,14-
dihydro-15-keto-20-ethyl-PGF2α isopropyl ester while glycerol,
polyvinyl alcohol (PVA) and polyvinyl pyrro[l]idone(povidone)
could not. The effects obtained by using methylcellulose or
gellan gum shown in the above tables are unexpected over the
references cited by the examiner.

(Id. at 4 (emphasis added).)

4
Declaration of Reiko Tabuchi under 37 C.F.R. § 1.132 (declaration
executed February 2, 2007).
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In rejecting the evidence of unexpected results, the Examiner urges
that the Tabuchi Declaration
shows that the addition of a different polysaccharide such as
gellan gum for cellulose obtained the same IOP lowering results
as methyl cellulose. Furthermore, Desai et al. teach that the
addition of gellan gum to the ophthalmic compositions as a
viscosity enhancing agent as old and well known. All
Appellant has done has replaced one polysaccharide for the
functionally similar polysaccharide taught by the prior art as
being used in ophthalmic formulation without any superior IOP
lowering activity.

(Ans. 6.)
We find that a preponderance of the evidence supports Appellant’s
position. We first note, as pointed out above, that Desai does not actually
appear to specifically mention gellan gum, contrary to the Examiner’s
assertion.
We agree, however, with the Examiner’s finding that gellan gum and
methyl cellulose appeared to potentiate the intraocular pressure lowering
effect of the claimed prostaglandin to a similar degree (see Tabuchi
Declaration 3). Nonetheless, the Examiner points to nothing in the prior art
suggesting that an ordinary artisan expected either gellan gum or methyl
cellulose to have that potentiating effect.
To the contrary, the only specific disclosure of record in the prior art
regarding the comparative effect of adding a thickener to a prostaglandin-
containing ophthalmic solution appears to be Ueno’s Formulation Example
2, in its Test Example 1. As discussed above, however, methyl cellulose is
seen to inhibit, rather than potentiate, the intraocular pressure lowering
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effect of the tested prostaglandin (see Ueno, col. 13, l. 60, through col. 15, l.
27).
We acknowledge that the prostaglandin in Test Example 1 is the
methyl ester, rather than the isopropyl ester recited in Appellant’s claim 30.
The Examiner does not, however, point to any teaching in the cited
prior art, or elsewhere in the record, suggesting that methyl cellulose, when
combined with the isopropyl prostaglandin ester recited in claim 30, would
have been expected to function in a manner opposite that observed when
combined with a prostaglandin compound that was identical, except for
being a methyl ester. Moreover, the Examiner does not point to any specific
evidentiary basis in the prior art for questioning the validity of the Tabuchi
Declaration’s assertion that gellan gum’s capacity to potentiate the
intraocular pressure reducing effect of claim 30’s prostaglandin was
unexpected.
Accordingly, as a preponderance of the evidence does not support the
Examiner’s finding that Appellant failed to advance evidence of unexpected
results adequate to rebut the evidence of prima facie obviousness, we reverse
the Examiner’s rejection of claim 30, and its dependents, over Ueno and
Desai.
SUMMARY
We affirm the Examiner’s obviousness rejection of claims 14, 26, 35,
39, 41, 43, and 45-50 over Ueno and Desai.
However, we reverse that rejection as to claims 30, 32, 34, 36-38, 40,
42, and 44.

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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-IN-PART

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