Ex Parte Susilo

Board of Patent Appeals and Interferences

Sep 23, 2010

10951724 (B.P.A.I. Sep. 23, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte RUDY SUSILO
__________

Appeal 2010-003174
Application 10/951,724
Technology Center 1600
__________

Before TONI R. SCHEINER, LORA M. GREEN, and
FRANCISCO C. PRATS, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1, 2, 5, 6, and 9, directed to a pharmaceutical compound. The claims
have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).

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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Application 10/951,724

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STATEMENT OF THE CASE
The present invention is directed to uridine esters, “use[ful] as
pharmaceutically active agents against a variety of diseases” (Spec. 1: 6-7).
Claims 1, 2, 5, 6, and 9 are pending and on appeal.2 Claim 1 is as
follows:
1. A compound having the general formula (I):

wherein
R represents R”-COO; and
R’ represents hydrogen or a hydroxy group;
wherein R” represents a monoenoic alkyl chain with 10 to 24 carbon
atoms, a monoenoic branched alkyl chain with 10 to 24 carbon atoms, a
polyenoic alkyl chain with 10 to 24 carbon atoms, a polyenoic branched
alkyl chain with 10 to 24 carbon atoms, a branched or unbranched alkyl
chain with 8 to 20 carbon atoms containing a carbocyclic or heterocyclic
ring, a monoynoic alkyl chain with 10 to 24 carbon atoms, a monoynoic
branched alkyl chain with 10 to 24 carbon atoms, a polyynoic alkyl chain
with 10 to 24 carbon atoms or a polyynoic branched alkyl chain with 10 to
24 carbon atoms; and
a pharmaceutically acceptable salt thereof.

2 Claims 3, 4, 7, and 8 have been canceled (App. Br. 5).
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Independent claim 2 is directed to a “pharmaceutical composition
comprising (a) at least one compound having the general formula (I)” (where
R” is as shown on page 33 of the Appeal Brief); (b) “a vitamin as an
additional therapeutically active compound;” and (c) “a pharmaceutically
acceptable carrier, excipient, adjuvant and/or diluent.”
Claims 1, 2, 5, 6, and 9 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over von Borstel.3
We affirm the rejection with respect to claims 1 and 9, and reverse
with respect to claims 2, 5, and 6.

ISSUES
The Examiner rejected the claims as unpatentable over von Borstel
based on von Borstel’s disclosure of a “subgenus” of acyl derivatives of
uridine, wherein the acyl substituent can be “derived from a carboxylic acid
that is a fatty acid having 2-18 carbon atoms” (Ans. 3); and von Borstel’s
express disclosure of selective 5'-acylation of uridine in Example V (id. at
6). The Examiner concluded that it would have been obvious for one of
ordinary skill in the art “to have prepared any compound suggested by the
subgenus of von Borstel” (id. at 4). With respect to claims 2, 5, and 6, the
Examiner additionally concluded that it would have been obvious to include
vitamins in a composition along with a uridine derivative because “the use
of vitamins in pharmaceutical compositions is well within the purview of a
skilled artisan” (id. at 5).

3 U.S. Patent 5,583,117, Acylated Uridine and Cytidine for Elevating Tissue
Uridine and Cytidine, issued December 10, 1996 to von Borstel et al.
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Appellant contends that the “the Examiner has not appropriately
resolved the Graham factors” (App. Br. 13), “as there is no reasonable
expectation of success” (id.), since von Borstel’s “prophetic Example V does
not enable or allow one of ordinary skill in the art to . . . achieve” selective
5'-acylation of uridine “with longer chain carboxylic acids having 10 or even
more carbon atoms” (id. at 15, 17). In any case, Appellant contends “[i]t
cannot be obvious to make ‘any compound’ of von Borstel” (id. at 13).
Finally, with respect to pharmaceutical composition claims 2, 5, and 6,
which require vitamins in addition to a uridine ester, Appellant contends that
the Examiner improperly “equate[s] that which is within the capabilities of
one skilled in the art . . . with obviousness” (id. at 30).
Given these conflicting positions, the issues raised by this rejection
are as follows:
Has the Examiner established that von Borstel suggests making
uridine derivatized at the 5' position with acyl substituents falling within the
scope of the claims?
Has Appellant established that von Borstel is not enabling for uridine
derivatized at the 5' position with acyl substituents falling within the scope
of the claims?
Finally, has the Examiner established that one of ordinary skill in the
art would have had a reason to combine vitamins with a uridine ester in a
pharmaceutical composition?
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FINDINGS OF FACT (FF)
1. von Borstel discloses preferred acyl derivatives of uridine
having the formula

wherein R is H or an acyl group derived from a carboxylic acid
selected from one or more of the group consisting of acetic
acid, glycolic acid, pyruvic acid, lactic acid, enolpyruvic acid,
an amino acid, a fatty acid other than acetic acid, lipoic acid,
pantothenic acid, succinic acid, fumaric acid, adipic acid,
acetoacetic acid, p-aminobenzoic acid, betahydroxybuteric acid,
orotic acid, and creatin, with the provisos that at least one R is
not hydrogen and not all of said R substituents are acetyl, or the
pharmaceutically acceptable salt thereof.
(von Borstel, col. 9, ll. 40-62.)
2. “‘Fatty acids’ are carboxylic acids having 2-18 carbon atoms.
Such fatty acids may be saturated, partially saturated or polyunsaturated”
(von Borstel, col. 13, ll. 42-44).
3. Example V of von Borstel describes two methods for selective
5'-acylation of uridine:
To 1 gram of uridine dissolved in 20 ml anhydrous
pyridine is added, at room temperature, 1.0 molar equivalent of
the acid anhydride of the desired acyl compound. The reaction
is then heated to 80°-85° C. for two hours, cooled, poured into
ice water, and the esters recovered by extraction three times
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with equal volumes of chloroform . . . the chloroform is
evaporated and the residual oil or crystals are subjected to
chromatography. The major product, which is isolated by
chromatography, is the 5'-substituted ester (adapted from
Nishizawa et al., Biochem. Pharmacol. 14:1605 (1965)).
Alternatively, selective 5'-acylation of uridine may be
accomplished by suspending 1 gram of uridine in 30 ml of 1:1
pyridine:N,N-dimethylformamide cooled to 0° C. in an ice bath.
1.0 molar equivalent of the acid chloride of the desired acyl
compound is added dropwise to the mixture, which is stirred at
0° C. for 12-24 hours. 3 ml of water is added, and then the
solvents are evaporated in vacuo at 50° C. The residue is
dissolved in methanol and adsorbed onto approximately 3
grams of silica gel, and the excess solvent is evaporated off.
Toluene is evaporated three times from the solid mass, and the
whole is loaded onto a . . . column of silica gel in chloroform,
and eluted . . . The appropriate fractions, as determined by TLC,
are combined, and the solvents are evaporated to yield the
desired product that is either recrystallized or dried in vacuo to
a glass (adapted from Baker et al., J. Med. Chem. 21:1218
(1978)).
(von Borstel, col. 25, 20-52.)
4. Dr. Rudy Susilo, in a declaration submitted November 29, 2007
under the provisions of 37 C.F.R. § 1.132 (“Decl.”), asserts that “[t]he
compounds of the present invention cannot be synthesized according to the
procedure of Example V of von Borstel” (Decl. 2).
According to Dr. Susilo:
Both methods theoretically described under Example V
in von Borstel . . . disclose the use of unprotected uridine.
Therefore, the esterification reaction will result in a mixture of
seven compounds of three mono-protected compounds, three
di-protected compounds and one tri-protected compound. . . .
Since the 5'-hydroxy group is a primary hydroxyl group . . . [it]
is slightly more active that the 2' and 3' hydroxy groups.
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Further, a moderate yield of compounds having a acyl
group at the 5' position can only be obtained with short chain
carboxylic acid chlorides or . . . anhydrides. Short chain
carboxylic acids are acetic acid, propionic acid and butyric acid
having 2 to 4 carbon atoms. The reactions theoretically
described for Example V . . . do not work with longer chain
carboxylic acids having 10 or even more carbon atoms. This is
because the slightly different activity of the 5' and 2' / 3'
hydroxy groups are no longer recognized by these long chain
fatty acid chlorides or . . . anhydrides.
Using the reaction protocol according to Example V . . .
with, for instance, EPA chloride (5,8,11,14,17-eicosopentaenoic
acid chloride) . . . or DHA chloride (4,7,10,13,16,19-
docosahexaenoic acid chloride) . . . only a mixture of the
mentioned 7 compounds is obtained together with a majority of
decomposition products. It was impossible to separate and
purify the 5' derivatized compound.
(Id. at 3.)
DISCUSSION
Claims 1 and 9
We agree with the Examiner’s conclusion that von Borstel suggests
making uridine derivatized at the 5' position with acyl substituents having 10
or more carbon atoms, given von Borstel’s disclosure of a subgenus of acyl
derivatives of uridine, wherein the acyl substituent can be a fatty acid having
2-18 carbon atoms (FF2), and von Borstel’s express disclosure of selective
5'-acylation of uridine in Example V (FF3).
Appellant contends that “[i]t cannot be obvious to make ‘any
compound’ of von Borstel” (App. Br. 13). Nevertheless, Appellant doesn’t
explain why the claimed compounds wouldn’t have been suggested by von
Borstel’s disclosure, except to assert that the rejection is improper because
the synthesis procedures disclosed in the reference “do[ ] not enable or allow
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one of ordinary skill in the art to make and use or achieve the claimed
invention” (id. at 15), and “therefore cannot reasonably make the
compounds themselves obvious for a person of ordinary skill in the art”
(id.). Appellant relies on the experiments described in Dr. Susilo’s
declaration as evidence that von Borstel is not enabling.
“Whether a prior art reference is enabling is a question of law based
upon underlying factual findings.” Minn. Mining & Mfg. Co. v. Chemque,
Inc., 303 F.3d 1294, 1301 (Fed. Cir. 2002). Moreover, “[i]n patent
prosecution, the examiner is entitled to reject application claims as
anticipated by a prior art patent without conducting an inquiry into whether
or not that patent is enabled or whether or not it is the claimed material (as
opposed to the unclaimed disclosures) in that patent that are at issue.”
Amgen, Inc. v. Hoescht Marion Roussel, Inc., 314 F.3d 1313, 1355 (Fed. Cir.
2003) (footnote and citation omitted). Thus, “a presumption arises that both
the claimed and unclaimed disclosures in a prior art patent are enabled,”
which appellants “can then overcome [ ] by proving that the relevant
disclosures of the prior art patent are not enabled.” Id.
We have reviewed the Declaration, but are not persuaded that it
establishes that von Borstel is not enabling for synthesizing compounds
falling within the scope of the claimed invention. Leaving aside the issue of
whether or not the claims actually exclude mixtures of compounds, the fact
that acylating uridine with EPA, which has 20 carbon atoms, and DHA,
which has 22, resulted in a mixture of derivatives which were “impossible to
separate and purify” is insufficient evidence that von Borstels’ procedures
would not work with carboxylic acids having, say, ten carbon atoms - which
are encompassed by the present claims. While it’s true that substituents with
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20 or 22 carbon atoms fall within the scope of the present claims, the
showing in the declaration is not reasonably commensurate with the
relevant, overlapping disclosure of von Borstel - particularly synthesis of
compounds with substituents having as few as 10 carbon atoms.
Appellant’s evidence and argument are insufficient to establish that
von Borstel is not enabling for uridine derivatized at the 5' position with acyl
substituents falling within the scope of the claims. Therefore, Appellant has
not established that the Examiner erred in concluding that the claimed
compounds would have been obvious over von Borstel.
Claims 2, 5, and 6
Claims 2, 5, and 6 are directed to pharmaceutical compositions
containing (a) at least one compound having the general formula (I); (b) “a
vitamin as an additional therapeutically active compound;” and (c) a
pharmaceutically acceptable carrier.
According to the Examiner, “the use of vitamins is well within the
purview of a skilled artisan” (Ans. 5). However, “rejections on obviousness
grounds cannot be sustained by mere conclusory statements; instead, there
must be some articulated reasoning with some rational underpinning to
support the legal conclusion of obviousness.” In re Kahn, 441 F.3d 977, 988
(Fed. Cir. 2006). We agree with Appellant that the mere fact that a
modification is within the skill of the artisan does not provide a reason to
make the modification, and are compelled to reverse the rejection with
respect to claims 2, 5, and 6.

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CONCLUSION
The Examiner has established that von Borstel suggests making
uridine derivatized at the 5' position with acyl substituents falling within the
scope of the claims.
Appellant’s evidence and argument are insufficient to establish that
von Borstel is not enabling for uridine derivatized at the 5' position with acyl
substituents falling within the scope of the claims.
Finally, the Examiner has not established that one of ordinary skill in
the art would have had a reason to combine vitamins with a uridine ester in a
pharmaceutical composition.
Accordingly, the rejection of claims 1, 2, 5, 6, and 9 under 35 U.S.C.
§ 103(a) as unpatentable over von Borstel is affirmed with respect to claims
1 and 9, and reversed with respect to claims 2, 5, and 6.
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)(1)(iv)(2006).

AFFIRMED-IN-PART

cdc

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