Ex Parte Chen et al

Patent Trial and Appeal Board

Jan 29, 2013

10153043 (P.T.A.B. Jan. 29, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JUNE CHEN, DAVID F. WOODWARD,
and ALEXANDER B. KHARLAMB
__________

Appeal 2011-000022
Application 10/153,043
Technology Center 1600
__________

Before TONI R. SCHEINER, ERICA A. FRANKLIN, and JOHN G. NEW,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims directed to a composition for treating ocular hypertension. The
claims have been rejected as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).
We affirm-in-part.
Appeal 2011-000022
Application 10/153,043

2
STATEMENT OF THE CASE
Claims 18, 20, 22, 24, 25, 34-37, 39, 43, 44, 53, and 54 are pending
and on appeal. Claims 1-17, 19, 21, 23, 26-33, 38, 40-42, and 45-52 have
been canceled (App. Br. 5).
Appellants provide separate arguments for three groups of claims: (a)
claims 18, 22, 24, 25, 36, 37, 43, and 44; (b) claims 20 and 39; and (c)
claims 53 and 54. We select claims 18, 20, and 53 as representative for
purposes of deciding this appeal as provided by 37 C.F.R. § 41.37(c)(1)(vii).
Claims 18, 20, and 53 are as follows:
18. A composition comprising a blend of from 0.01% to 0.5%
timolol or pharmaceutically acceptable salts thereof and mixtures thereof
present in an amount effective to reduce ocular hypertension when applied to
a hypertensive eye, and from 0.0001% to 0.5% (w/v) of a hypotensive lipid
component, different from timolol, comprising cyclopentane N-ethyl
heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-
dihydroxy, [1α,2β,3α,5α], present in an amount effective to reduce ocular
hypertension when applied to a hypertensive eye.
20. The composition of claim 18 which, when applied to an eye,
produces at least one reduced side effect relative to a similar composition
including a larger amount of said hypotensive lipid component without said
timolol.
53. The composition of claim 18 comprising 0.5% (w/v) timolol
and 0.03% (w/v) of cyclopentane N-ethyl heptenamide-5-cis-2-(3α-hydroxy-
5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α].
The Examiner relies on the following evidence:
Bito et al. EP 0 286 903 A1 Oct. 19, 1988
Woodward et al. US 5,688,819 Nov. 18, 1997
Ashton et al. US 6,051,476 Apr. 18, 2000
Appellants rely on the following additional evidence:
Woodward et al. US 5,352,708 Oct. 4, 1994
Appeal 2011-000022
Application 10/153,043

3
Declaration of Dr. June Chen, submitted under 37 C.F.R. § 1.132, dated
September 9, 2005 (“Decl. I”).
Declaration of Dr. June Chen, submitted under 37 C.F.R. § 1.132, dated June
5, 2008 (“Decl. II”).
Claims 18, 20, 22, 24, 25, 34-37, 39, 43, 44, 53, and 54 stand rejected
under 35 U.S.C. § 103(a) as unpatentable over Bito, Ashton, and Woodward
'819.
THE ISSUES
The Examiner finds that Bito discloses a composition comprising
“timolol maleate, and a prostaglandin derivative, preferably PGF2a or a
PGF2a derivative, in effective IOP [intraocular pressure] reducing amounts
in an aqueous carrier solution” (Ans. 3), but fails to disclose “the
prostaglandin derivative CNEH[1] as being suitable for combination with
timolol maleate . . . for topical treatment of ocular hypertension” (id. at 4).
However, the Examiner finds that Woodward '819 teaches that “the
potential clinical usefulness of PGF2a is ‘greatly limited’ by its associated
side effects of conjunctival hyperemia and foreign body sensation” (id.), and
discloses prostaglandin derivatives, “of which CNEH is explicitly identified
as representative, [which] are potent ocular hypotensive agents which may
be significantly more potent than their respective parent compounds and
cause no or significantly lower conjunctival hyperemia than the parent
compound” (id.).
The Examiner concludes that it would have been obvious for one of
ordinary skill in the art “to have substituted [CNEH for] PGF2a in the

1 Cyclopentane N-ethyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-
pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α], the compound required by all the
claims on appeal.
Appeal 2011-000022
Application 10/153,043

4
composition of Bito, since the potential clinical usefulness of PGF2a is
‘greatly limited’ . . . and CNEH would have been expected to cause no or
significantly lower conjunctival hyperemia than the parent compound
PGF2a” (id.).
Appellants contend that “CNEH is not a prostaglandin” (App. Br. 14),
and “it would not have been predictable nor necessarily expected as of the
filing date to one of ordinary skill in the art, that substituting CNEH for
PGF2α, in combination with timolol, would have been a useful combination
in lowering IOP since CNEH and PGF2α act upon different cellular
receptors” (id. at 15). Moreover, Appellants contend that “Woodward ['819]
teaches many thousands of potential prostamides” and “does not specifically
identify CNEH as a compound causing little to no hyperemia” (id.), thus,
“one of ordinary skill in the art would [not] have been motivated to choose
CNEH, out of the thousands of potential prostamides . . . from the other
prostamides exemplified in Woodward ['819], particularly those pointed out
as being efficacious and causing less hyperemia” (id.).
In addition, Appellants contend that “the 2nd Declaration of June Chen
. . . conclusively rebuts . . . [a prima facie case of obviousness] by showing
that the claimed compositions have unpredictable and unforeseeable
properties over the prior art” (id. at 16).
The issues raised by this appeal are as follows:
Does the preponderance of the evidence of record support the
Examiner’s conclusion that it would have been obvious to combine timolol
and the hypotensive lipid, CNEH, in a single composition?
If so, have Appellants provided evidence of unexpected results
sufficient to rebut the Examiner’s conclusion?
Appeal 2011-000022
Application 10/153,043

5
FINDINGS OF FACT
1. Bito discloses a composition comprising “a mixture of an
adrenergic blocking agent and a prostaglandin or a prostaglandin derivative
in an ophthalmically compatible carrier,” in an amount effective “to reduce
the intraocular pressure of the eye and maintain such reduced intraocular
pressure” (Bito, col. 4, ll. 49-54). A preferred beta blocker is timolol
maleate, and a preferred prostaglandin is PGF2α or a PGF2α derivative,
specifically PGF2α -1-isopropyl ester (id. at col. 5, ll. 2-9).
2. Woodward '819 teaches that “prostaglandins appear to be
devoid of significant intraocular side effects, [but] ocular surface
(conjunctival) hyperemia and foreign-body sensation have been consistently
associated with topical ocular use of such compounds, in particular PGF2α
and its prodrugs, e.g. its 1-isopropyl ester, in humans” (Woodward '819, col.
2, ll. 41-46). According to Woodward '819, “[t]he clinical potential of
prostaglandins in the management of conditions associated with increased
ocular pressure, e.g. glaucoma, is greatly limited by these side effects” (id. at
col. 2, ll. 46-49).
3. Woodward '819 discloses certain prostaglandin derivatives,
specifically, “cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl
compounds and derivatives thereof wherein the carboxylic acid group is
replaced by a non-acidic substituent” (Woodward '819, col. 3, ll. 9-12).
According to Woodward '819, these compounds “have pronounced effects
on smooth muscle and are potent ocular hypotensive agents . . . [and] in
certain instances, may be significantly more potent than their respective
parent compounds and, in the case of glaucoma surprisingly, cause no or
Appeal 2011-000022
Application 10/153,043

6
significantly lower ocular surface hyperemia than the parent compounds”
(id. at col. 3, ll. 12-18).
4. Woodward '819 lists cyclopentane N-ethyl heptenamide-5-cis-
2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α],
i.e., CNEH or bimatoprost, as one of thirteen preferred representatives of its
disclosed compounds (Woodward '819, col. 7, ll. 9-21, 44-46).
5. According to Woodward '819, “[t]he therapeutically efficient
amount typically is between about 0.0001 and about 5% (w/v) preferably
about 0.001 to about 1.0% (w/v) in liquid formulations” (Woodward '819,
col. 8, ll. 4-7).
6. Woodward '708 discloses essentially the same prostaglandin
derivatives as Woodward '819, including CNEH, and teaches that
“[r]eplacement of the -COOH by a diverse variety of substituents resulted in
potent ocular hypotensive agents, despite the inability of these agents to bind
to prostanoid receptors” (Woodward '708, col. 13, ll. 28-31). Woodward
'708 also teaches that “such compounds may be significantly more potent
than their respective parent compounds and, in the case of glaucoma
surprisingly, cause no or significantly lower ocular surface hyperemia than
the parent compounds” (id. at col. 3, ll. 10-14).
7. Appellants submitted two declarations (Decl. I and Decl. II)
describing two studies (2005 and 2008) conducted to evaluate the safety and
efficacy of administering CNEH in combination with timolol maleate to
reduce intraocular pressure.
The 2005 study involved three arms: “Combination Therapy,” in
which subjects received a single solution containing 0.03% CNEH and 0.5%
timolol maleate once daily; “Concurrent Administration,” in which subjects
Appeal 2011-000022
Application 10/153,043

7
received a solution containing 0.03% CNEH once daily, and a second
solution containing 0.5% timolol maleate twice daily; and “Monotherapy
Administration” of a solution containing 0.03% CNEH once daily. Thus,
subjects in the Concurrent Administration arm of the 2005 study received
the same daily amount of CNEH, but twice as much timolol maleate, as
subjects in the Combination Therapy arm.
The 2008 study also involved three, albeit somewhat different, arms:
“Combination Therapy,” in which subjects received a single solution
containing 0.03% CNEH and 0.5% timolol maleate once daily; “Timolol
Monotherapy,” in which subjects received a solution containing 0.5%
timolol maleate twice daily; and “Bimatoprost [CNEH] Monotherapy,” in
which subjects received a solution containing 0.03% CNEH once daily.
Subjects in the Bimatoprost [CNEH] Monotherapy arm of the 2008 study
received the same amount of CNEH as subjects in the Combination Therapy
arm, while subjects in the Timolol Monotherapy arm received twice as much
timolol maleate as subjects in the Combination Therapy arm.
The results of the 2005 and 2008 studies are summarized with respect
to the incidence of hyperemia as follows:
2005 Study 2008 Study
Combination Therapy hyperemia 19.3% hyperemia 25.7%
Concurrent Therapy hyperemia 25.6% not done
CNEH Monotherapy no data reported hyperemia 43.4%
Timolol Monotherapy not done hyperemia 8.7%

Appeal 2011-000022
Application 10/153,043

8
PRINCIPLES OF LAW
Evidence of nonobviousness must be commensurate in scope with the
claims, i.e., it must provide a reasonable basis for concluding that untested
embodiments encompassed by the claims would behave in the same manner
as tested embodiments. See In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011)
(“If an applicant demonstrates that an embodiment has an unexpected result
and provides an adequate basis to support the conclusion that other
embodiments falling within the claim will behave in the same manner, this
will generally establish that the evidence is commensurate with scope of the
claims.”).
OBVIOUSNESS
We agree with the Examiner’s conclusion that it would have been
prima facie obvious for one of ordinary skill in the art to substitute
Woodward '819’s CNEH for PGF2α in Bito’s composition, given Woodward
'819’s teaching that the clinical potential of prostaglandins, particularly
PGF2α, in treating ocular hypertension is greatly limited by the occurrence of
hyperemia (FF2), and Woodward '819’s disclosure of a class of
prostaglandin derivatives (of which CNEH is one of thirteen explicitly
disclosed) that “may be significantly more potent than their respective parent
compounds and . . . cause no or significantly lower ocular surface hyperemia
than the parent compounds” (FF3).
Appellants contend that “it would not have been predictable nor
necessarily expected . . . to one of ordinary skill in the art, that substituting
CNEH for PGF2α, in combination with timolol, would have been a useful
combination in lowering IOP since [Woodward '708 teaches that] CNEH
and PGF2α act upon different cellular receptors” (App. Br. 15).
Appeal 2011-000022
Application 10/153,043

9
We are not persuaded. While Woodward '708 does discuss the
inability of derivatives like CNEH to bind prostanoid receptors, this
reference, like Woodward '819, nevertheless characterizes the derivatives in
general as potent ocular hypotensive agents that cause no or significantly
lower ocular surface hyperemia than their parent compounds (FF6). In any
case, “[o]bviousness does not require absolute predictability of success. . . .
For obviousness under § 103, all that is required is a reasonable expectation
of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).
Woodward '819 provides a reasonable expectation that its prostaglandin
derivatives will perform as well or better than prostaglandins in Bito’s
combination formulations.
Nor are we persuaded by Appellants’ argument that Woodward '819
discloses thousands of prostamides, and doesn’t specifically identify CNEH
as a compound causing little to no hyperemia (App. Br. 15), as opposed to a
few prostamides in the Examples, which are “pointed out as being
efficacious and causing less hyperemia” (id.).
As discussed above, Woodward '819 teaches that the disclosed
compounds, in general, are potent hypotensive agents, and in some cases,
cause relatively little or no hyperemia (FF3). CNEH is one of a handful
explicitly recited (FF4). We agree with the Examiner that it would have
been obvious to use any of those compounds in Bito’s composition, for the
reasons articulated by the Examiner. Again, all that is required is a
reasonable expectation of success, i.e., a reasonable expectation that the
combination would be effective in reducing ocular hypertension.
Nevertheless, we agree with Appellants that the combination of
timolol maleate and CNEH unexpectedly “decreases the incidence of
Appeal 2011-000022
Application 10/153,043

10
hyperemia seen using the same daily dose of CNEH alone” (App. Br. 18), at
least at the concentrations used in the 2008 study. That is, the incidence of
hyperemia was 43.4% among subjects who received a solution containing
0.03% CNEH once daily (CNEH Monotherapy), but only 25.7% among
subjects who received the identical amount of CNEH in a single solution
containing 0.03% CNEH and 0.5% timolol maleate once daily (Combination
Therapy) (FF7). Moreover, the 2008 study demonstrated that timolol alone
causes a modest amount of hyperemia (8.7% in the Timolol Monotherapy
arm), thus, we agree with Appellants that its presence in the combination
formula makes the lower incidence of hyperemia “even more surprising”
(Decl. II, ¶ 8).
Claims 53 and 54
As claims 53 and 54 are limited to the same concentrations of timolol
maleate and CNEH used in the 2008 study, we will reverse the rejection
with respect to these claims.
Claims 18 and 20
Claims 18 and 20, on the other hand, stand on a different footing, as
they are not limited to the concentrations of timolol maleate and CNEH used
in the 2008 study. While the claims require each component to be present in
an amount effective to reduce ocular hypertension (by some unspecified
amount), the concentrations asserted to be effective span a wide range, e.g.,
the concentration of CNEH may be as low as 0.0001% (w/v) and as high as
0.5% (w/v) - a range plainly not commensurate in scope with the showing in
the either declaration. Moreover, claim 20 merely requires that the CNEH
concentration is such that it produces a reduced side effect relative to a
larger amount of CNEH without timolol. Since hyperemia is associated
Appeal 2011-000022
Application 10/153,043

11
with prostaglandins, and to some extent, their prostamide derivatives, a
lower concentration of CNEH would be expected to produce less hyperemia,
with or without timolol. The burden of demonstrating unexpected results
rests on the party asserting them. In re Klosak, 455 F.2d 1077, 1080 (CCPA
1972). That burden has not been carried here as Appellants have not
provided a factual basis to support the conclusion that other concentrations
and/or ratios of timolol and CNEH encompassed by the claims will behave
in the same manner as the concentration tested. See Kao, 639 F.3d at 1068.
SUMMARY
The rejection of claims 18 and 20 as unpatentable over Bito, Ashton,
and Woodward '819 is affirmed as the preponderance of the evidence of
record supports the Examiner’s conclusion that it would have been obvious
to combine timolol and CNEH in a single composition. Claims 22, 24, 25,
34-37, 39, 43, and 44 have not been separately argued, and the rejection of
these claims is affirmed as well as provided by 37 C.F.R. § 41.37(c)(1)(vii).
The rejection of claims 53 and 54 as unpatentable over Bito, Ashton,
and Woodward '819 is reversed as Appellants have provided evidence of
unexpected results sufficient to rebut the Examiner’s conclusion with respect
to these claims.
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).

AFFIRMED-IN-PART

lp