Ex Parte Garst

Board of Patent Appeals and Interferences

Jan 11, 2010

09903954 (B.P.A.I. Jan. 11, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MICHAEL E. GARST
__________

Appeal 2009-0062221
Application 09/903,954
Technology Center 1600
__________

Decided: January 11, 2010
__________

Before ERIC GRIMES, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to methods of
treating degeneration of the optic nerve. The Examiner rejected the claims
as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 Allergan, Inc. is the real party in interest.
Appeal 2009-006222
Application 09/903,954

STATEMENT OF THE CASE
Claims 21-25 and 27 are pending and on appeal (App. Br. 5).2 Claim
21 is representative3 and reads as follows:
21) A method of treating degeneration of the optic nerve and
the retinal ganglion cells of a mammal in need of such
treatment, comprising administering to the mammal a
therapeutically effective amount of a prostaglandin and a
therapeutically effective amount of an alpha adrenergic agent of
formula (I)

formula (I)

wherein each Y is independently selected from the group
consisting of N, N-CH3, O, S and C-R1; R1 is hydrogen, lower
alkyl or oxo; R2, R3 and R4 are independently selected from
the group consisting of hydrogen, halogen, lower alkyl and
lower alkenyl; n is an integer from 1 to 3; and a broken line
beside a solid line indicates either a single or a double bond,
provided that two double bonds are not on the same carbon in
the case when n=l, and their pharmaceutically acceptable salts
and esters as appropriate.

2 Appeal Brief filed January 25, 2007.
3 Appellant filed an after-final amendment which, among things, deleted the
recitation “and the retinal ganglion cells” from the preamble of claim 21
(App. Br. 6, see also Amendment After Notice of Appeal, p. 2 (entered July
10, 2006)). While the Examiner has not considered this amendment, our
consideration of the appealed rejection is not affected by the amendment.
Therefore, in the interest of compact prosecution, we will decide the appeal
rather than remand the case to Examiner to consider the amendment.
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The Examiner cites the following documents as evidence of
unpatentability:
Woodward US 5,877,211 Mar. 2, 1999

Rochelle Nataloni, LASIK study shows brimonidine provides
neuroprotective effect, 17 OCULAR SURG. NEWS 28 (1999) (hereinafter
“Yavitz”).4

The sole rejection before us for review is the Examiner’s rejection of
claims 21-25 and 27 under 35 U.S.C. 103(a) as being obvious over Yavitz
and Woodward (Ans. 3-4).
OBVIOUSNESS
ISSUE
The Examiner finds that “Yavitz teaches the use of the claimed
compound, brimonidine, being an alpha adrenergic agonist, having
neuroprotective effect during ophthalmic surgery” (Ans. 3). The Examiner
concedes that Yavitz “differs from the claimed invention in the presence of a
prostaglandin receptor agonist” (id. at 3-4).
The Examiner nonetheless concludes that an ordinary artisan would
have considered it obvious “to add a prostaglandin to the composition of
Yavitz, considering that Woodward teaches the neuroprotective effect of
prostaglandin receptor agonists in [the] ophthalmic field” (id. at 4). The
Examiner reasons that the artisan would have been prompted to combine the
teachings of Yavitz and Woodward “since one relates to the use of the

4 While the cited article reports on a study by Dr. Yavitz, it appears to be
authored by Rochelle Nataloni. Nonetheless, both Appellant and the
Examiner refer to the article as “Yavitz,” and we do the same for
convenience.
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claimed alpha-adrenergic agent having neuroprotective activity in the
ophthalmic field and the other relates to the use [of] prostaglandins having
neuroprotective effect in the ophthalmic field” (id.).
Appellant argues each of the rejected claims separately, contending
that the Examiner failed to make a prima facie case of obviousness, for a
variety of reasons (App. Br. 9-17).
In view of the positions advanced by Appellant and the Examiner, the
issue with respect to this rejection is whether Appellant has shown that the
Examiner failed to make a prima facie case that an ordinary artisan would
have considered claims 21-25 and 27 obvious in view of Yavitz and
Woodward.
FINDINGS OF FACT (“FF”)
1. Yavitz discloses that a “small double-masked study showed almost
universal nerve fiber layer thinning after laser in situ keratomileusis
(LASIK). Further, the study showed that the nerve fiber thinning was
mitigated or totally prevented by brimonidine” (Yavitz 28).
2. Yavitz discloses that the “further implication in [t]his finding . . . is
that for one of the first times, it has been demonstrated on a limited basis
that brimonidine is neuroprotective” (id.).
“Neuroprotectivity is a hot topic and it has never been
proven in a human before. It has been shown in rat eye studies,
but never in human eyes. So the major implication of this is not
in refractive surgery at all, but in the fact that if [brimonidine]
indeed shows neuroprotection, it becomes the premier
glaucoma drop, at least until another drop shows the same kind
of neuroprotectivity,” Dr. Yavitz told OCULAR SURGERY NEWS.

(Id.)
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3. Woodward discloses “the use of EP2 receptor agonists to provide a
neuroprotective effect to the eye of a mammal” (Woodward, col. 1, ll. 6-8).
4. Woodward discloses that glaucoma “is a disease of the eye
characterized by increased intraocular pressure” (id. at col. 1, ll. 16-17).
5. Woodward discloses:
It has long been known that one of the sequelae of
glaucoma is damage to the optic nerve head. This damage,
referred to as “cupping”, results in depressions in areas of the
nerve fiber of the optic disk. Loss of sight from this cupping is
progressive and can lead to blindness if the condition is not
treated effectively.

(Id. at col. 1, ll. 54-59.)
6. According to Woodward, the prior art recognized that “some
prostaglandins are highly effective ocular hypotensive agents and are ideally
suited for the long-term medical management of glaucoma” (id. at col. 2, ll.
65-67).
7. Woodward discloses that, among useful prior art prostaglandins, “in
particular PGE2 and PGF2α and the C1 to C5 alkyl esters of the latter
compound, were reported to possess ocular hypotensive activity and were
recommended for use in glaucoma management” (id. at col. 3, ll. 10-14).
8. Woodward discloses that the “isopropyl ester of PGF2α has been
shown to have significantly greater hypotensive potency than the parent
compound, which was attributed to its more effective penetration through
the cornea. In 1987 this compound was described as ‘the most potent ocular
hypotensive agent ever reported’” (id. at col. 3, ll. 19-24 (citations omitted)).
9. Woodward discloses, however, that certain side effects greatly limit
the “clinical potential of prostaglandins in the management of conditions
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associated with increased ocular pressure, e.g. glaucoma” (id. at col. 3, ll.
31-33).
10. According to Woodward, the prior art discloses certain “prostaglandin
esters with increased ocular hypotensive activity accompanied by no or
substantially reduced side-effects,” including “11-acyl-prostaglandins, such
as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl
PGF2α,” as well as “15-acyl prostaglandins” and “11,15- 9,15- and 9,11-
diesters of prostaglandins, for example 11,15-dipivaloyl PGF2α” (id. at col.
3, ll. 40-50).
11. In light of these prior art teachings, Woodward discloses that “EP2-
receptor agonists are potent neuroprotective agents. We have further found
that (±) trans-2-[-4(1-hydroxyhexyl)phenyl]-5-
oxocyclopentaneheptanoicacid, and certain other EP2-receptor agonists,
described below, and ester and unsaturated derivatives thereof, are especially
useful in providing a neuroprotective effect to the eye of a mammal, e.g. a
human” (id. at col. 3, l. 66, through col. 4, l 5).
12. Woodward measured the neuroprotective effect of test compounds by
exposing cultured rat hippocampal neuron cells to the excitatory amino acid
NMDA along with the test compounds, and using the amount of lactate
dehydrogenase (LDH) activity released from the cells as a measure of
cytotoxicity or neuron injury (id. at col. 7, l. 65 through col. 8, l. 44).
13. Woodward presents the results of its experiments in Figures 1A
through 1D, which “show a comparison of the neuroprotective effects of EP2
agonists, e.g. see FIGS 1C and 1D, with prostaglandins having no EP2
agonist activity, e.g. see FIGS 1A and 1B, in preventing neuronal damage”
(id. at col. 4, ll. 58-61).
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Figures 1C and 1D are reproduced below:

Figures 1C and 1D show, respectively, the effect of treatment of
cultured neurons with different concentrations of test compound AH 13205
and PGE2, measured as the amount of LDH released from the treated cells.
As can be seen, both AH 13205 and PGE2, the agonist of the EP2 receptor,
reduce the amount of LDH released compared to cells without added AH
13205 or PGE2 (“0M”).
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14. Figures 1A and 1B of Woodward are reproduced below:

Figures 1A and 1B show, respectively, the effect of treatment of
cultured neurons with different concentrations of PGF2α and PGF2α1-OH,
measured as the amount of LDH released from the treated cells. As can be
seen, neither compound appears to significantly affect the release of LDH
from NMDA-treated cells.
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15. Woodward interprets these results by stating that “PGF2α and PGF2α
1-OH are inactive, thereby indicating that this is a specific EP2 receptor
mediated effect” (id. at col. 8, ll. 49-51).
PRINCIPLES OF LAW
In KSR Int' l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme
Court addressed the question of obviousness, and ultimately reaffirmed that
“when a patent ‘simply arranges old elements with each performing the
same function it had been known to perform’ and yields no more than one
would expect from such an arrangement, the combination is obvious.” Id. at
417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273, 282 (1976)).
The Court reasoned that “if a technique has been used to improve one
device, and a person of ordinary skill in the art would recognize that it would
improve similar devices in the same way, using the technique is obvious
unless its actual application is beyond his or her skill.” Id.
As our reviewing court has pointed out, when evaluating claims for
obviousness, “the prior art as a whole must be considered. The teachings are
to be viewed as they would have been viewed by one of ordinary skill.” In
re Hedges, 783 F.2d 1038, 1041 (Fed. Cir. 1986).
Accordingly, “‘[i]t is impermissible within the framework of section
103 to pick and choose from any one reference only so much of it as will
support a given position, to the exclusion of other parts necessary to the full
appreciation of what such reference fairly suggests to one of ordinary skill in
the art.’” Id. (quoting In re Wesslau, 353 F.2d 238, 241 (CCPA 1965)).
Thus, “in a section 103 inquiry, ‘the fact that a specific [embodiment]
is taught to be preferred is not controlling, since all disclosures of the prior
art, including unpreferred embodiments, must be considered.’” Merck &
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Co., Inc. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989)
(quoting In re Lamberti, 545 F.2d 747, 750 (CCPA 1976)).
Also, it is well settled that “[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).
ANALYSIS
Appellant’s arguments do not persuade us that the Examiner failed to
make a prima facie case that an ordinary artisan would have considered
claims 21-25 and 27 obvious in view of Yavitz and Woodward.
Claim 21 recites treating optic nerve degeneration by administering to
a mammalian subject “a therapeutically effective amount of a prostaglandin
and a therapeutically effective amount of an alpha adrenergic agent of
formula (I) . . . and their pharmaceutically acceptable salts and esters as
appropriate.” It is undisputed that formula (I) encompasses brimonidine.
As the Examiner points out, Yavitz teaches that brimonidine likely
has neuroprotective properties, which would make it a useful treatment for
glaucoma (FF 1, 2). Yavitz does not appear to disclose combining
brimonidine with other drugs, such as prostaglandins, to treat glaucoma.
Woodward, however, discloses that optic nerve damage is one of the
symptoms and consequences of glaucoma (FF 5), and that “some
prostaglandins are highly effective ocular hypotensive agents and are ideally
suited for the long-term medical management of glaucoma” (FF 6). We
agree with the Examiner that an ordinary artisan, informed by the references
that brimonidine and prostaglandins were useful in treating glaucoma, would
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have considered it obvious to use both of those agents to treat glaucoma, and
its concomitant optic nerve degeneration.
Appellant urges that this conclusion is erroneous, because, although
“Woodward discusses the use of EP2 agonists to treat ocular nerve damage,
not all such agonist compounds are themselves prostaglandins” (App. Br.
10). Moreover, Appellant argues
Woodward teaches away from the use of “prostaglandins”
generally as neuroprotectants, since prostaglandin PGF2α and
other prostaglandin FP2α receptor agonists are said to be
“inactive”. The term “neuroprotection” in Woodward, as
evidenced by e.g., claim 1 of the ‘211 patent, appears to be
construed to exclude any neuroprotective benefits attendant to
lowering IOP (and thus avoiding a mechanical crushing injury
to retinal neurons). That the person of ordinary skill in the art
would so adopt this interpretation is a reasonable assumption
from a reading the text of Woodward, since prostaglandin F2α,
a potent ocular hypotensive, is said not to be active. '211 patent,
column 8, lines 49-51.

(Id.)
We are not persuaded by these arguments. It might be true that not all
EP2 receptor agonists are prostaglandins. However, Woodward discloses
that PGE2, an EP2 receptor agonist and one of the prostaglandins recited in
Appellant’s claims, not only was recognized in the art as having ocular
hypotensive activity recommending its use in treating glaucoma (FF 7), but
also had an EP2 receptor-mediated neuroprotective effect comparable to
other therapeutically active compounds tested by Woodward (FF 13).
Thus, in view of Woodward’s teaching that EP2 receptor agonists were
useful in treating glaucoma due to their neuroprotective effects (FF 3, 11),
we agree with the Examiner that an ordinary artisan would have been
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prompted to combine prostaglandin agonists of that receptor, such as PGE2,
with other glaucoma-treating agents, like brimonidine, to treat glaucoma and
its attendant optic nerve damage.
We are not persuaded that Yavitz fails to suggest using brimonidine in
such methods. We note, as Appellant argues, that Yavitz’s conclusions are
based on a small study relating to the optic nerve crush injury caused by
raising intraocular pressure during LASIK surgery (FF 1). However, Yavitz
affirmatively states that its findings suggest a neuroprotective effect for
brimonidine that would make it suitable for treating glaucoma patients (FF
2).
As noted above, “[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
at 903-04.
In the instant case Yavitz directly discloses the therapeutic agent,
brimonidine, as well as the target disorder, glaucoma and the nerve damage
that accompanies it (FF 2). Thus, Yavitz does much more than merely
provide the ordinary artisan with numerous possible choices for treatment
plans or a broad promising field with only general guidance for a solution.
Cf. O’Farrell, 853 F.2d at 903.
In sum, Appellant’s arguments do not persuade us that the Examiner
failed to make a prima facie case of obviousness with respect to claim 21.
Accordingly, we affirm the Examiner’s rejection of that claim as being
obvious in view of Yavitz and Woodward.
Claim 22 recites “[t]he method of claim 21 wherein the prostaglandin
is selected from the group consisting of PGF2α, PGE2 . . . and their
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pharmaceutically acceptable esters and salts, as appropriate.” Thus, PGE2 is
among the numerous compounds listed in claim 22 which may be combined
with brimonidine.
As noted above, Woodward discloses that PGE2 meets two criteria for
being useful in treating glaucoma. First, it has ocular hypotensive activity
(FF 7), and second, it has a neuroprotective effect (FF 13). Appellant’s
arguments therefore do not persuade us that the Examiner erred in finding
that an ordinary artisan would have been prompted to treat glaucoma, and its
concomitant optic nerve degeneration, with both PGE2 and brimonidine. We
accordingly affirm the Examiner’s rejection of claim 22 as being obvious in
view of Yavitz and Woodward.
Claim 23 depends from claim 22, and limits the prostaglandin to,
among others, PGF2α-11-pivalyl ester and PGF2α1-isopropyl ester. We
note, as Appellant argues, that Woodward discloses that “PGF2α and PGF2α
1-OH are inactive” in its test for neuroprotective activity, which shows that
those compounds do not have the EP2 receptor-mediated activity described
by Woodward (FF 16).
Woodward also discloses, however, that the 11-pivaloyl5 and
isopropyl esters of PGF2α were known in the art to be useful for treating
glaucoma (FF 7, 8, 10). Thus, while it may be true that claim 23 recites
prostaglandin derivatives which are not preferred by Woodward for treating
glaucoma, Woodward does in fact disclose that those compounds were
recognized in the art for treating that disorder.

5 Appellant does not dispute that Woodward’s “11-pivaloyl” ester is the
same as the “11-pivalyl” ester recited in claim 23.
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We are therefore not persuaded that the Examiner erred in finding that
an ordinary artisan would have been prompted to treat glaucoma, and its
concomitant optic nerve degeneration, with a prostaglandin derivative
encompassed by claim 23 and brimonidine. We accordingly affirm the
Examiner’s rejection of claim 23 as being obvious in view of Yavitz and
Woodward.
Claim 24 depends from claim 216, and limits the alpha adrenergic
agent recited in claim 21 to those encompassed by the formula (II) recited in
claim 24.7 Appellant does not dispute that formula (II) encompasses
brimonidine. As we agree with the Examiner that Yavitz and Woodward
would have prompted an ordinary artisan to treat glaucoma, and its attendant
optic nerve degeneration, with both brimonidine and a prostaglandin, we
affirm this rejection as well.
Claim 25 depends from claim 23 limits the alpha adrenergic agent to
brimonidine. We therefore also affirm this rejection, for the reasons
discussed above.
Claim 27 depends from claim 21, and limits the prostaglandin to the
11-pivalyl ester of PGF2α, and the alpha adrenergic agent to brimonidine.
As discussed above, while the 11-pivaloyl ester of PGF2α does not appear to
be among Woodward’s preferred neuroprotective agents, Woodward

6 In addition to reciting dependency from claim 21, claim 24 also recites that
“all other variables [in formula II] are defined as in claim 14.” As Appellant
points out, claim 14 has been canceled. We therefore treat claim 24 as if it
depended from claim 21.
7 It appears that the image of formula (II) was lost when the claims were
copied into the Appeal Brief (see App. Br. 21). The formula can be seen in
the copy of the claims entered into the electronic filewrapper on January 9,
2006, however.
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nonetheless discloses that that prostaglandin derivative is in fact useful for
treating glaucoma (FF 10).
We are therefore not persuaded that Woodward teaches away from
using the 11-pivaloyl ester of PGF2α to treat glaucoma. Nor do we agree that
the Examiner erred in concluding that an ordinary artisan would have
considered it obvious to treat glaucoma, and its concomitant optic nerve
degeneration, with both the 11-pivaloyl ester of PGF2α, and brimonidine,
given the disclosures of Yavitz and Woodward as discussed above. We
therefore affirm the Examiner’s rejection of claim 27 as being obvious over
those references.
SUMMARY
We affirm the Examiner’s rejection of claims 21-25 and 27 under 35
U.S.C. 103(a) as being obvious over Yavitz and Woodward.

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

cdc

ALLERGAN, INC.
CARLOS A. FISHER-T2-7H
2525 DUPONT DRIVE
IRVINE CA 92612

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