Ex Parte Hilfinger

Board of Patent Appeals and Interferences

Feb 15, 2012

10972729 (B.P.A.I. Feb. 15, 2012)

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.
10/972,729 10/25/2004 John Hilfinger TSR-10402/38 1035
25006 7590 02/15/2012
GIFFORD, KRASS, SPRINKLE,ANDERSON & CITKOWSKI, P.C
PO BOX 7021
TROY, MI 48007-7021
EXAMINER
PESELEV, ELLI
ART UNIT PAPER NUMBER
1623
MAIL DATE DELIVERY MODE
02/15/2012 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 JOHN HILFINGER
__________

Appeal 2011-007845
Application 10/972,729
Technology Center 1600
__________

Before TONI R. SCHEINER, ERIC GRIMES, and LORA M. GREEN,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims relating to a
prodrug compound. The Examiner has rejected the claims as obvious. We
have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The Specification discloses prodrugs that are “transported from the
gastrointestinal lumen by a specific transporter and … enzymatically cleaved
to yield the pharmaceutical species” (Spec. 2:18-20). The Specification
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discloses that the HPEPT1 transporter is an example of an intestinal peptide
transporter (id. at 5, Table 2; 18:4-7).
Claims 1, 4, 6-8, 14-18, 21, 23, 26-29, and 31 are on appeal. The
claims have not been argued separately and therefore stand or fall together.
37 C.F.R. § 41.37(c)(1)(vii). Claim 1 is representative and is directed to a
“prodrug compound having a formula X-Y, where X is a pharmaceutical
species” that can be floxuridine or cytarabine, among others, and “Y is an
amino acid selected from the group consisting of valine, leucine, isoleucine,
and phenylalanine forming a covalent ester bond to the pharmaceutical
species wherein X-Y functions in a subject as an enzymatic cleavage
substrate and as an HPEPT1 membrane transporter substrate.” The full text
of claim 1 is reproduced in Appellant‟s Claims Appendix (Appeal Br. 12).

Issue
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 103(a) as being obvious in view of Han
1
and Alexander.
2
The Examiner
finds that Han discloses the L-valyl ester of acyclovir (Answer 3), and also
discloses that “amino acid prodrugs significantly improve the cellular uptake
of the parent drugs via peptide transport mechanism and that L-configuration
of an amino acid allows more favorable uptake and faster prodrug-drug
conversion” (id.). The Examiner finds that Alexander discloses that
“[d]rugs, such as cytarabine and floxuridine are well known in the art” (id.).

1
Han et al., Cellular Uptake Mechanism of Amino Acid Ester Prodrugs in
Caco-2/hPEPT1 Cells Overexpressing a Human Peptide Transporter, 15
PHARMACEUTICAL RESEARCH 1382-1386 (1998).
2
Alexander et al., US 5,066,648, issued Nov. 19, 1991.
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The Examiner concludes that, in view of Han, “a person having ordinary
skill in the art … would have been motivated to prepare amino acid prodrugs
of the compounds disclosed by Alexander et al because such a person would
have expected to improve cellular uptake of said drugs” (id. at 3-4).
Appellant contends that neither of the cited references suggests any
pharmaceutical compounds other than acyclovir or azidothymidine coupled
to an amino acid (Appeal Br. 5). Appellant also contends that Han does not
suggest that “coupling an amino acid to any other drug will successfully
provide both uptake by HPEPT1 and provide a substrate for enzymatic
cleavage” (id.; see also id. at 7-8).
The issue presented is: Does the evidence of record support the
Examiner‟s conclusion that it would have been obvious to couple floxuridine
or cytarabine to valine with a reasonable expectation of success that the
resulting compound would function “as an enzymatic cleavage substrate and
as an HPEPT1 membrane transporter substrate” as specified in claim 1?
Findings of Fact
1. Han discloses that “[a]mino acid ester prodrugs of nucleoside
antiviral drugs have been reported to increase oral bioavailability … of the
parent drugs” (Han 1382, left col.).
2. Han discloses that “[d]ue to the broad substrate specificity, peptide
transporters can be a potential target in the prodrug design to improve oral
drug absorption” (id. at 1385, left col.).
3. Han discloses that “previous studies in the rat indicated that amino
acid ester prodrugs could be recognized as peptidyl derivatives and absorbed
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by peptide transporters, even though there was no peptide bond in their
structures” (id. at 1382, right col.).
4. Han discloses that confirmation of the “cellular uptake of amino
acid ester prodrugs … by a peptide transporter, even though there is no
peptide bond in the structures … will have a great impact on the prodrug
design” (id. at 1385, both cols.).
5. Han evaluated “the cellular uptake mechanism and hydrolysis of
the amino acid ester prodrugs of nucleoside antiviral drugs in the transiently
transfected Caco-2 cells overexpressing a human intestinal peptide
transporter, hPEPT1” (id., abstract).
6. Han discloses that “acyclovir and AZT were selected as the
different sugar modified purine and pyrimidine nucleoside antiviral drugs”
(id. at 1382, right col.).
7. Han discloses that the “L-Valyl ester of acyclovir (L-Val-ACV)
was approximately ten fold more permeable across the apical membrane
than acyclovir.… L-valyl ester of AZT (L-Val-AZT) exhibited three fold
higher cellular uptake than AZT. Therefore, amino acid ester prodrugs
significantly increased the cellular uptake of the parent drugs.” (Id.,
abstract).
8. Han discloses that the “prodrugs were rapidly hydrolyzed to the
parent drugs by the intracellular hydrolysis, following the apical membrane
transport” (id.).
9. Alexander discloses that known antiviral agents include acyclovir,
cytarabine, and floxuridine (Alexander, col. 4, ll. 56-57).
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10. The Specification states that floxuridine is a known fluorinated
pyrimidine compound that is “currently used as an anti-neoplastic anti-
metabolite” (Spec. 11:10-11).
Analysis
Claim 1 is directed to a prodrug compound having a formula X-Y,
where X can be floxuridine, Y is valine, leucine, isoleucine, or
phenylalanine, and the two are joined by an ester bond. Claim 1 also recites
that the prodrug compound functions as a substrate for enzymatic cleavage
and HPEPT1 membrane transport.
Han discloses that peptide transporters have broad substrate
specificity and therefore are targets for prodrug design to improve oral drug
absorption. Han discloses that, in cells overexpressing hPEPT1, the L-valyl
esters of acyclovir and AZT exhibited ten-fold and three-fold greater cellular
uptake, respectively, than the parent compounds. Han discloses that, after
transport, the prodrugs were rapidly hydrolyzed to the parent drugs by
intracellular hydrolysis. Han concludes that amino acid ester prodrugs
significantly improve the cellular uptake of the parent drugs.
Alexander discloses that acyclovir, cytarabine, and floxuridine are
known antiviral agents. In view of these disclosures, it would have been
obvious to one of ordinary skill in the art to substitute floxuridine or
cytarabine for the acyclovir in Han‟s L-valyl ester of acyclovir in order to
increase the cellular uptake and oral bioavailability of floxuridine or
cytarabine.
Appellant argues that it would not have been obvious to couple an
amino acid to any of the compounds recited in the claims because the cited
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references do not expressly suggest the specific modification of those
compounds required by the claims (Appeal Br. 4-5). Appellant argues that,
“for chemical matter, prima facie obviousness requires more than a mere
showing that independent elements of the claimed compound were known in
the prior art.... The particular modifications and locations of those
modifications must have been suggested.” (Id. at 5.)
This argument is not persuasive. Han expressly discloses that
conjugating the antiviral nucleosides acyclovir and AZT to valine by an ester
bond enhanced uptake in the gut via a peptide transporter. Thus, it would
have been obvious to conjugate other antiviral purines or pyrimidines,
including Alexander‟s antiviral pyrimidine floxuridine, to valine by an ester
bond, with a reasonable expectation of achieving enhanced uptake in the gut.
Appellant argues that those of skill in the art would not have had a
reasonable expectation that attaching valine to compounds other than
acyclovir and AZT would result in enhanced uptake via the HPEPT1
transporter or subsequent enzymatic cleavage of the prodrugs (Appeal Br. 6-
7). Appellant argues that Han found that the cellular uptake profiles for
modified ACV and modified AZT were quite different (id. at 7). Appellant
argues that Han discloses that “„for the general application of amino acid
esters to the peptide transporter-targeted prodrug strategy, structure-transport
relationship should be thoroughly investigated with the large structural
variation of prodrugs in future work.‟” (Id., citing Han at 1386, left col.)
This argument is not persuasive. Han suggests that peptide
transporters are potential targets for prodrug design because they have broad
substrate specificity. Han examined the cellular uptake of valine conjugated
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to either a purine (acyclovir) or a pyrimidine (AZT), and determined that the
prodrugs significantly improved the cellular uptake of the parent drugs.
Since Han discloses that peptide transporters generally have broad substrate
specificity and floxuridine, like AZT, is a known pyrimidine analog (see
Spec. 11:10), one of ordinary skill in the art would have had a reasonable
expectation that valine-conjugated floxuridine would also function as a
substrate for the hPEPT1 transporter. See In re O’Farrell, 853 F.2d 894,
903-04 (Fed. Cir. 1988) (“Obviousness does not require absolute
predictability of success.… For obviousness under § 103, all that is required
is a reasonable expectation of success.”.
Finally, Appellant argues that it would not have been obvious to
modify Alexander‟s floxuridine and cytarabine by valine attachment because
the resulting compound would be unsuitable for Alexander‟s purpose
(Appeal Br. 8-9). This argument is also unpersuasive, because the Examiner
only relies on Alexander as disclosing that floxuridine and cytarabine, along
with acyclovir, are known anti-viral drugs. The Examiner‟s rejection does
not require using the resulting compound as intended by Alexander.
Conclusion of Law
The evidence of record supports the Examiner‟s conclusion that it
would have been obvious to couple floxuridine or cytarabine to valine with a
reasonable expectation of success in obtaining a compound that would
function “as an enzymatic cleavage substrate and as an HPEPT1 membrane
transporter substrate.”
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SUMMARY
We affirm the rejection of claims 1, 4, 6-8, 14-18, 21, 23, 26-29, and
31 under 35 U.S.C. § 103(a).
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

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