Ex Parte Tovi et al

Patent Trial and Appeal Board

Sep 23, 2013

11416856 (P.T.A.B. Sep. 23, 2013)

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.
11/416,856 05/02/2006 Avi Tovi 12647/46302 8504
26646 7590 09/23/2013
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK, NY 10004
EXAMINER
NIEBAUER, RONALD T
ART UNIT PAPER NUMBER
1658
MAIL DATE DELIVERY MODE
09/23/2013 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 PATENT TRIAL AND APPEAL BOARD
____________

Ex parte AVI TOVI, CHAIM EIDELMAN, SHIMON SHUSHAN,
SHAI ELSTER, HAGI ALON, ALEXANDER IVCHENKO,
GABRIEL-MARCUS BUTILCA, GIL ZAOVI,
ELEONORA ALTERMAN, LEAH BAR-OZ, and TEHILA GADI
____________

Appeal 2012-001289
Application 11/416,856
Technology Center 1600
____________

Before DONALD E. ADAMS, ULRIKE W. JENKS, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

JENKS, Administrative Patent Judge

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims directed to
a protected leuprolide precursor. The Patent Examiner has rejected the

1 Appellants state that the Real Party in Interest is Novetide LTD. (App.
Br. 1.)
Appeal 2012-001289
Application 11/416,856

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claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.
STATEMENT OF THE CASE
The Specification provides that “[l]euprolide acetate is a synthetic
nonapeptide analog of naturally occurring gonadotropin-releasing hormone
(GnRH or LH-RH). . . . Leuprolide possesses greater potency than the
natural hormone.” (Spec. p. 1, 22-26.) Leuprolid acts by inhibiting the
production of testosterone in males and reduces estrogen production when
administered to females. (Spec. p. 1, 27-29.)
Claims 11 and 43 are on appeal and reproduced below:
11. The compound pGlu-His(Trt)-Trp-Ser(tBu)-Tyr(tBu)-D-
Leu-Leu-Arg(Pbf)-Pro-OH.
43. The compound pGlu-His(Trt)-Trp-Ser(tBu)-Tyr(tBu)-D-
Leu-Leu-Arg(Pbf)-Pro-NHEt.
The following ground of rejection is before us for review:
The Examiner has rejected claims 11 and 43 under 35 U.S.C. § 103(a)
as unpatentable over Sasaki,2,3 Rahimipour,4 and Sherwood.5

The Issue
The Examiner takes the position that Sasaki teaches a process for the
production of LH-RH (Luteinizing hormone - releasing hormone)

2 Yasuhiro Sasaki et al., WO 01/02428 Al, published Nov. 1, 2001.
3 Yasuhiro Sasaki et al., 2005/0261195 Al, published Nov. 24, 2005, the
Examiner relies on this publication as the English language equivalence of
WO 01/02428 A1 (Ans. 6).
4 Shai Rahimipour et al., Design, Synthesis, and Evaluation of a Long-
Acting, Potent Analogue of Gonadotropin-Releasing Hormone, 44 J. MED.
CHEM. 3645-3652 (2001).
5 Nancy M. Sherwood et al., WO 84/01771, published May 10, 1984.
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Application 11/416,856

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derivatives, specifically, leuprolide acetate (Ans. 6). The Examiner finds
that “[t]he peptides of Rahim[i]pour et al and Sherwood et al share high
homology with the peptide of Sasaki. Importantly, Rahim[i]pour et al and
Sherwood et al provide direction about specific protecting groups.” (Id. at
17.) Because, “Rahim[i]pour et al and Sherwood et al provide a pattern of
preference for the protected groups (which amino acids to protect and what
protecting groups to use) on the peptide . . . [and] the pattern of preference
as suggested by the references results in peptides as claimed, the claims are
obvious.” (Id. at 17-18.)
Appellants contend that the combination of references does not
suggest all the claim limitation (App. Br. 3). Appellants contend that Sasaki
does “not teach, or even suggest, the specific combination of protecting
groups that remain on the claimed peptide precursor after cleavage from the
solid support resin on which synthesis was performed.” (Id. at 6.) The
secondary references do not provide motivation or guidance to modify the
structure (id.).
The issue is: Does the evidence of record support the Examiner’s
conclusion of obviousness?

Findings of Fact
FF 1. The Examiner finds that Sasaki disclosed the “preparation of
leuprolide (i.e. pGlu-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NHEt see
example 1).” (Ans. 7; Sasaki, p. 11, ¶¶ 0181-0183.)
FF 2. Sasaki disclosed “the LH-RH derivative obtained by . . . peptide
synthesis may be carried out, for example, either by a solid phase synthesis
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method or a liquid phase synthesis.” (Sasaki, p. 8, ¶ 0139 (emphasis added;
Ans. 8.)
FF 3. Sasaki disclosed LH-RH derivative with protective groups
include a peptide represented by the “formula (III) 5-oxo-Pro-His-Trp-Ser-
Tyr-Y-Leu-Arg(X)-Pro-Z wherein X indicates a protective group, Y
indicates a residue selected from DLeu, DAla, DTrp, DSer(tBu), D2Nal and
DHis(ImBzI) and Z indicates NH-C2H5 or GlyNH2, respectively, or a salt
thereof.” (Sasaki, p. 9, ¶ 0154-156 (emphasis added); Ans. 16.)
FF 4. Sasaki disclosed that “the protective group for imidazole in
histidine, for example, Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl,
DNP, benzyloxymethyl, Bum, Boc, Trt, Fmoc or the like is used.” (Sasaki,
p. 9, ¶ 0152 (emphasis added); Ans. 8.)
FF 5. Sasaki disclosed that “[t]he hydroxyl group of serine can be
protected, for example, by esterification or etherification. . . . examples of a
group suitable for the etherification include benzyl group, tetrahydropyranyl
group, t-butyl group and the like.” (Sasaki, p. 9, ¶ 0150, (emphasis added);
Ans. 8.)
FF 6. Sasaki disclosed that “the protective group for phenolic
hydroxyl group in tyrosine, for example, Bzl, Cl2-Bzl, p-nitrobenzyl, Br-Z, t-
butyl or the like is used.” (Sasaki, p. 9, ¶ 0151 (emphasis added); Ans. 8.)
FF 7. Rahimipour disclosed solid phase synthesis of a GnRH analog,
specifically, “pGlu-His(Trt)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Lys(Mtt)-Leu-
Arg(Pbf)-Pro-Gly-[Rink amide resin] (25 μmol), synthesized using a
multiple-peptide synthesizer.” (Rahimipour 3651.)
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FF 8. The Examiner finds that “Sherwood et al specifically teach
converting the C-terminal hydroxyl group to an amide (page 4, last
paragraph).” (Ans. 8.)

Principle of Law
“In determining whether obviousness is established by combining the
teachings of the prior art, the test is what the combined teachings of the
references would have suggested to those of ordinary skill in the art.” In re
GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal quotations
omitted).

Analysis
Appellants contend there is no reason to modify the references, and
even if there were a reason, the combination of references does not suggest
all the claim limitation without resorting to hindsight (App. Br. 3).
We are not persuaded. We agree with the Examiner’s fact finding,
statement of the rejection and responses to Appellants’ arguments as set
forth in the Answer and adopt them as our own. To summarize, the
Examiner finds that Sasaki disclosed a peptide having the general formula
pGlu-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NHEt (Ans. 6; FF 1), and even
suggests the addition of protective groups onto the peptide during synthesis
(Ans. 6; FF 3-6) but acknowledges that “Sasaki et al do not expressly teach
in a single embodiment the protected peptides of claims 11, 43.” (Ans. 6.)
The Examiner finds that Sasaki suggests adding protective groups
during the peptide synthesis phase to at least His, Ser, Tyr, and Arg (Ans. 6-
7; FF 3-6). The Examiner finds, and Appellants do not dispute (see App. Br.
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6; Reply Br. 2), that Sasaki disclosed a peptide containing a protective
arginine group that is not bound to a solid resin of formula (III): 5-oxo-Pro-
His-Trp-Ser-Tyr-Y-Leu-Arg(X)-Pro-Z (Ans. 14, 16; FF 3). The teaching of
Sasaki provides a peptide having the following structure: pGlu-His-Trp-Ser-
Tyr-DLeu-Leu-Arg-Pro-NHEt (FF1); discloses liquid phase synthesis for the
production of the peptide (FF 2); suggests adding protective groups to His,
Ser, Tyr, and Arg during synthesis, and even suggest the specific protective
groups His(Trt) (FF 4), Ser(tBu) (FF 5), and Tyr(Tbu) (FF 6). As
recognized by the Examiner, what is missing from Sasaki is the use of the
Pbf protective group on Arg (Sasaki, 9: ¶ 0156).
The Examiner turns to Rahimipour for teaching a LH-RH derivative
similar to the peptide of Sasaki (Ans. 7; FF 7) using His(Trt), Ser(tBu),
Tyr(tBu), and Arg(Pbf) protective groups during the synthesis of the LH-RH
peptide (id.). The Examiner concludes that “[s]ince Sasaki et al do not
specifically recite which protecting groups to use at which amino acids, one
would be motivated to use the specific protecting groups as taught by
Rahim[i]pour et al.” (Ans. 7.)
Appellants contend that “[t]here is no motivation to modify the
teachings in Sasaki et al and combine the various components therein to
arrive at the currently claimed invention.” (App. Br. 5.) Appellants contend
that Sasaki does not list using the Pbf protecting group for Arg and thereby
only teaches or suggests compounds that are structurally different from the
two claimed compounds (App. Br. 11-12, see table).
We are not persuaded. The test for obviousness is what the combined
teachings of the references as a whole would have suggested to those of
ordinary skill in the art. In re Keller, 642 F.2d 413, 425 (CCPA 1981). The
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Examiner found that Sasaki taught the underlying peptide sequence as
claimed (FF 1) and taught the use of peptide protective groups during
synthesis (FFs 3-6). In addition, solid and liquid peptide synthesis are
disclosed (FF 2). The Examiner relies on Rahimipour to guide the selection
of protective groups used during the synthesis of the LH-RH peptide (FF 7;
see also Ans. 14). “In United States v. Adams,. . . [t]he Court recognized
that when a patent claims a structure already known in the prior art that is
altered by the mere substitution of one element for another known in the
field, the combination must do more than yield a predictable result.” KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Rahimipour provides
the synthesis of a functionally and structurally similar LH-RH peptide and
suggests the use of the specific His(Trt), Ser(tBu), Tyr(tBu), and Arg(Pbf)
protective groups. Rahimipour thereby provides guidance to the specific
His(Trt), Ser(tBu), and Tyr(tBu) already disclosed in Sasaki and suggests
using the Arg(Pbf) protective group (FF 7), that is an art recognized
alternative peptide protective groups compared to those already disclosed in
Sasaki (Sakai 9: ¶ 0156). Thus, substituting the Pbf protective group on Arg
for another known protective group that is already suggested at the same
position in a structurally similar GnRH compound is obvious.
Appellants contend that the peptides in both Sasaki and Rahimipour
result in the loss of the protective groups from the peptide during the
removal process of the peptide from the solid support (App. Br. 6, 8). “Like
Sasaki et al, Sherwood et al makes only a passing reference to the possibility
that solution phase chemistry could be used to prepare the subject fish
gonadotropins.” (Id. at 10.) Appellants contend that “Sasaki’s teaching,
regarding protecting groups for solid phase synthesis, e.g., at paragraph
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[0145], . . . produces the final LH-RH derivative without producing a
protected peptide precursor that is cleaved from the resin with the protecting
groups intact.” (Id. at 6.)
We are not persuaded. The Examiner finds that Sasaki discloses the
synthesis of peptides in liquid phase (FF 2), these peptides would possess
the requisite protective groups during synthesis. The Examiner also finds,
and Appellants do not dispute, that Sasaki provides a generic example of
protected peptide derivatives that are not bound to solid support having the
formula (III): 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg(X)-Pro-Z (FF 3; see
App. Br. 7; Reply Br. 2). As pointed out by Appellants, this peptide of
formula (III) is structurally different form the claimed peptide (App. Br. 7;
Reply Br. 2), it nevertheless, provides a teaching of a non-bound protected
peptide having the same underlying peptide (unprotected) structure. “All of
the disclosures in a reference must be evaluated for what they fairly teach
one of ordinary skill in the art.” Application of Boe, 355 F.2d 961, 965
(CCPA 1966). It is well settled that disclosed examples and preferred
embodiments do not constitute a teaching away from a broader disclosure or
even non-preferred embodiments. See In re Susi, 440 F.2d 442, 446 n.3
(CCPA 1971). Here, Sasaki teaches that the peptides may be produced
using liquid phase synthesis procedures (FF 2), which does not require
cleavage from a solid surface in order to obtain a non-bound peptide. As
explained by the Examiner, one of ordinary skill in the art would be
motivated to use protecting groups because it is “consistent with the goal of
reducing impurities since a ‘protecting’ group functions to reduce
undesirable side reactions.” (Ans. 13.)
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We conclude that the preponderance of the evidence of record support
the Examiner’s conclusion that the subject matter of claims 11 and 43 is
obvious over the combination of Sasaki, Rahimipour, and Sherwood.

SUMMARY
We affirm the rejection of claims 11 and 43 under 35 U.S.C. § 103(a)
over Sasaki, Rahimipour, and Sherwood.

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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