Ex Parte Hilfinger et al

Board of Patent Appeals and Interferences

Jun 13, 2012

11690528 (B.P.A.I. Jun. 13, 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.
11/690,528 03/23/2007 John Hilfinger TSR-12602/38 3912
25006 7590 06/14/2012
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
06/14/2012 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 and WEI SHEN
__________

Appeal 2011-008509
Application 11/690,528
Technology Center 1600
__________

Before DONALD E. ADAMS, LORA M. GREEN, and
ULRIKE W. JENKS, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner‟s rejection of claims 1-19. The Examiner has rejected the claims
for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
Appeal 2011-008509
Application 11/690,528

2
STATEMENT OF THE CASE
Claims 1-19 are on appeal, and may be found in Appendix A to the
Appeal Brief (App. Br. 13-16). Claim 1 is representative of the claims on
appeal and defines “[a] composition, comprising: a prodrug having the
structural formula:

where R1, R2 and R3 are each independently H, or a substrate for a
transporter selected from the group consisting of: an amino acid, a dipeptide
and a tripeptide, where at least one of R1, R2 and R3 is an amino acid, a
dipeptide or a tripeptide; or a salt or hydrate thereof.”
The Examiner rejected claims 1-19 under 35 U.S.C. § 103(a) as
unpatentable over Lipper
1
and Han.
2

1
Robert A. Lipper et al., Inhibition of Drug Metabolism by a Prodrug: 9-β-
D-Arabinofuranosyladenine 5'-Valerate as an Inhibitor of Adenosine
Deaminase, 14 MOLECULAR PHARMACOLOGY 366-369 (1978).
2
Hoy-kyung 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).
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ISSUE
Does the preponderance of the evidence of record support the
Examiner‟s conclusion that the combination of Lipper and Han renders
obvious the composition of claim 1?

FINDINGS OF FACT
FF1. The Examiner‟s statement of rejection may be found at pages 4-6 of
the Answer. As Appellants do not argue the claims separately, we focus our
analysis on claim 1, and claims 2-19 stand and fall with that claim. 37 C.F.R.
§ 41.37 (c)(1)(vii).
FF2. 9-β-D-arabinofuranosyladenine (Ara-A) is an anti-viral nucleoside
that has low aqueous solubility and low lipophilicity that limit its clinical
usefulness (Lipper 366, paragraph bridging the columns).
FF3. The Examiner finds that the valerate prodrug of 9-β-D-
arabinofuranosyladenine (Ara-A), is an anti-viral nucleoside compound
(Ans. 4, see also Reply Br. 1).
FF4. The valerate modified ara-A compound has clinical usefulness
because it is more water soluble and more lipophilic, is readily taken up by
cells, and acts as a deaminase inhibitor in vitro (Lipper paragraph spanning
366-367, see also Reply Br. 1).
FF5. Amino acid ester prodrugs significantly improve the cellular uptake of
the parent drugs via peptide transport mechanisms and the L-configuration
of an amino acid allows more favorable uptake and faster prodrug-drug
conversion (Ans. 5, see also Han 1386).
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FF6. The specific drugs tested by Han are amino acid ester prodrugs of
acyclovir (ACV) and AZT, both parent compounds are known anti-viral
nucleosides (Ans. 5, see also Han 1382).
FF7. Amino acid prodrugs are rapidly converted to the active parent drug
by the intracellular hydrolysis. This provides more flexibility in the
structural modification targeting a peptide transporter to improve oral
absorption of poorly permeable drugs (Ans. 5, see also Han 1386).
FF8. Valcyclovir, the amino acid ester prodrug of ACV has been shown to
have increased oral bioavailability, follows a carrier mediated absorption
process, and has now been shown to be absorbed by peptide transporters (see
Han 1382 Introduction).

PRINCIPLES OF LAW
“[S]tructural similarity between claimed and prior art subject matter,
proved by combining references or otherwise, where the prior art gives
reason or motivation to make the claimed compositions, creates a prima
facie case of obviousness.” In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990)
(en banc). Thus, in order to establish a prima facie case of obviousness,
there must be “a showing that the „prior art would have suggested making
the specific molecular modifications necessary to achieve the claimed
invention.”‟ Takeda Chemical Industries, Ltd. v. Alphapharm Pty., Ltd., 492
F.3d 1350, 1356 (Fed. Cir. 2007), quoting In re Deuel, 51 F.3d 1552, 1558
(Fed. Cir. 1995). That is, “in cases involving new chemical compounds, it
remains necessary to identify some reason that would have led a chemist to
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Application 11/690,528

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modify a known compound in a particular manner to establish prima facie
obviousness of a new claimed compound.” Takeda at 1357.

ANALYSIS
We agree with the Examiner‟s fact finding, statement of the rejection,
and response to Appellants‟ arguments set forth in the Examiner‟s Answer.
We provide additional comments. We conclude that the Examiner has set
forth a prima facie case of obviousness for the pending claims.

Appellants assert that due to the unpredictability in the chemical arts
“in order to find a prima facie case of unpatentability in such instances, a
showing that the „prior art would have suggested making the specific
molecular modifications necessary to achieve the claimed invention‟ [is]
also required.” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 83
USPQ2d 1169, 1174 (Fed. Cir. 2007) (quoting In re Deuel, 51 F.3d 1552,
1558 (Fed. Cir. 1995) (internal references omitted). (Reply Br. 2) The facts
in Takeda are distinguishable. The issue in Takeda concerned the
obviousness of the choice of lead compound for further modification. Here
the Examiner cited Lipper for the purpose of showing the lead compound,
3

the anti-viral nucleoside ara-A (FF2). Lipper cites only a single active
ingredient ara-A (FF2, FF3). The addition of valerate to the parent drug ara-
A created a prodrug
4
that was more soluble and more lipophilic than the

3
Ara-A represents the composition of claim 1 were R1, R2 and R3 are H.
4
Valerate ara-A represents the composition of claim 1 were R2 and R3 are H
and R1 is valerate.
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parent compound, in other words it improved the bioavailability of the
parent ara-A compound (FF4). Han provides motivation to create amino
acid prodrugs of anti-viral nucleosides so that the prodrugs are targeted to a
peptide transporter for improved oral absorption (FF5, FF8). Specifically
targeting the prodrugs to the active peptide transport system allows for a
controlled delivery of the drugs into the body (FF7). We agree with the
Examiner that substituting one anti-viral nucleoside for another would result
in an ara-A compound with improved bioavailability compared to the parent
compound.

Appellants further assert that “[t]he outstanding rejections go well
beyond that found non-obvious in Takeda and require change to an entirely
different chemical compound (ACV to ara-A), which has differing charge
properties, unmodified uptake properties, solubility, etc. than the compound
taught in Han et al” (Reply Br. 2). A rejection premised upon a proper
combination of references cannot be overcome by attacking the references
individually. See In re Keller, 642 F.2d 413, 426 (CCPA 1981). Here the
Examiner cited Lipper for the purpose of showing the lead compound, the
anti-viral nucleoside ara-A (FF2). The same reference discloses that valerate
ara-A, an alkyl ester prodrug of ara-A, has improved bioavailability as
shown by increased solubility, being more lipophilic and the ability to be
taken up by cells (FF3, FF4). The Examiner combined Lipper with Han to
show that amino acid modifications of poorly permeable drugs yields
prodrugs with improved oral absorption and improved cellular uptake (FF5).
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We agree with the Examiner that the combination of references renders the
claims obvious.

CONCLUSION OF LAW
We conclude that the preponderance of the evidence of record
supports the Examiner‟s conclusion that the combination of Lipper and Han
renders obvious the composition of claim 1.

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

alw