Ex Parte Dong

Patent Trial and Appeal Board

Jan 28, 2013

10546303 (P.T.A.B. Jan. 28, 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.
10/546,303 08/19/2005 Zheng Xin Dong 129P/PCT2/US 3133
7590 01/28/2013
Brian R Morrill
Biomeasure Incorporated
27 Maple Street
Milford, MA 01757-3650
EXAMINER
GUPTA, ANISH
ART UNIT PAPER NUMBER
1654
MAIL DATE DELIVERY MODE
01/28/2013 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 ZHENG XIN DONG
__________

Appeal 2011-010047
Application 10/546,303
Technology Center 1600
__________

Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
STEPHEN WALSH, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to analogues of
glucagon-like peptide-1 (GLP-1). The Examiner entered a rejection for
obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
“In 1994, the therapeutic potential of GLP-1 was suggested following
the observation that a single subcutaneous (s/c) dose of GLP-1 could
completely normalize postprandial glucose levels in patients with non-
insulin-dependent diabetes mellitus” (Spec. [004] (citation omitted)).
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“GLP-1 is, however, metabolically unstable, having a plasma half-life
(t1/2) of only 1-2 min in vivo. . . . This metabolic instability limits the
therapeutic potential of native GLP-1” (id. at [006] (citation omitted)).
Accordingly, Appellant’s invention is directed to producing “GLP-1
analogues that are more active or are more metabolically stable than native
GLP-1” (id.). The GLP-1 analogues are produced by substituting alternative
moieties for the naturally occurring amino acids at various positions in the
GLP-1 sequence (see id. at [007]-[0974]).
The Specification discloses that in “a most preferred embodiment” the
GLP-1 analogue is (Ser8, Aib35)hGLP-l(7-36)NH2 (SEQ ID NO: 767) (id. at
[0957]). As the Specification explains, this nomenclature indicates that the
compound consists of amino acids 7 through 36 of the native peptide
sequence of human GLP-1, with the C-terminus having been amidated,
serine substituted at position 8 of the peptide sequence, and
α-aminoisobutyric acid (Aib) substituted at position 35 of the sequence (see
id. at [0974], [0958]).
Claims 15-18 stand rejected and appealed (see App. Br. 3-4). As
Appellant did not argue the patentability of the claims separately, the claims
stand or fall together. See 37 C.F.R. § 41.37(c)(1)(vii).
Claim 15 illustrates the appealed subject matter and reads as follows:
15: A compound wherein said compound is:
(Ser8, Aib35)hGLP-l(7-36)NH2; (SEQ ID NO.767)
(Abu8, β-Ala35)hGLP-l(7-36)NH2; (SEQ ID NO.768)
(Val8, β-Ala35)hGLP-l(7-36)NH2; (SEQ ID NO.769)
(β-Ala8,35)hGLP-l(7-36)NH2; (SEQ ID NO.770)
(Abu8, Aib35)hGLP-l(7-36)NH2; (SEQ ID NO.77l)
(Val8, Aib35)hGLP-l(7-36)NH2; (SEQ ID NO.772)
or (β-Ala8, Aib35)hGLP-l(7-36)NH2; (SEQ ID NO.773)
or a pharmaceutically acceptable salt thereof.
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In response to a species election requirement, Appellant elected the
preferred and first claimed compound, (Ser8, Aib35)hGLP-l(7-36)NH2 (SEQ
ID NO: 767), for prosecution on the merits (see App. Br. 4). We therefore
limit our analysis of claim 15 to the patentability of the elected compound,
and the extent to which the claims read on it. See Ex parte Ohsaka, 2
USPQ2d 1460, 1461 (BPAI 1987).
The sole rejection before us for review is the Examiner’s rejection of
claims 15-18 under 35 U.S.C. § 103(a) as obvious over Dong1 and Deacon2
(Ans. 3-4).
OBVIOUSNESS
The Examiner found that Dong described a GLP-1 analogue identical
to claim 15’s GLP-1 analogue having SEQ ID NO: 767, except that Dong’s
GLP-1 analogue had a glycine at position 8, rather than serine (Ans. 3-4
(citing Dong 40:8 (“Example 378 (Gly8, Aib35)hGLP-1(7-36)NH2”)).
To address that difference, the Examiner cited Deacon as teaching that
“substitutions at the 8th position with Gly or Ser of the GLP-1 molecule still
are biologically active and have prolong[ed] metabolic stability in vivo” (id.
at 4). The Examiner also noted Deacon’s teaching that “the Ser8 analog was
more stable than the Gly8” (id.).
The Examiner reasoned, therefore, that an ordinary artisan would have
considered it obvious to substitute Serine for Glycine at position 8 of Dong’s
GLP-1 analogue “because Serine in position 8 provides for more stability

1 WO 00/34331 A2 (published June 15, 2000).
2 C. F. Deacon et al., Dipeptidyl peptidase IV resistant analogues of
glucagon-like peptide-l which have extended metabolic stability and
improved biological activity, 41 DIABETOLOGIA 271-278 (1998).

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relative to Glycine at position 8. There would have been a reasonable
expectation of success because Deacon et al. demonstrates that it takes
longer for a Ser8-GLP-1 analog to be degraded by porcine plasma than wild
type GLP-1 and Gly8-GLP-1” (id.).
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.

Appellant initially argues there is “nothing in the references of record
to lead a person of ordinary skill in the art to select the compound (Gly8,
Aib35)hGLP-1(7-36)NH2 out of a disclosure of 411 specific GLP-l analogues
in [Dong] for further modification” (App. Br. 7 (underlining omitted); see
also Reply Br. 3-11).
In particular, Appellant argues, “[t]he courts have made it clear that
there must be something in the prior art that leads a person of ordinary skill
in the art to make such selection as a ‘lead compound,’ or a compound that
would be most promising to modify, in formulating the claimed compound”
(App. Br. 7). However, Appellant urges, “[n]o data are presented in [Dong],
absent molecular weight and purity data, that would guide a person of
ordinary skill in the art to make the selection” of (Gly8, Aib35)hGLP-1(7-
36)NH2 as a lead compound that an ordinary artisan would have sought to
improve (id. at 8).
We do not find Appellant’s argument persuasive.
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“Obviousness based on structural similarity . . . can be proved by
identification of some motivation that would have led one of ordinary skill
in the art to select and then modify a known compound (i.e. a lead
compound) in a particular way to achieve the claimed compound.” Eisai
Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1357 (Fed. Cir. 2008).
Thus, in evaluating the prima facie obviousness of a new chemical
compound in view of similar prior art compounds, one must first determine
“whether a chemist of ordinary skill would have selected the asserted prior
art compounds as lead compounds, or starting points, for further
development efforts.” Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d
1280, 1291 (Fed. Cir. 2012).
As Appellant notes, our reviewing court has further advised:
While the lead compound analysis must, in keeping with KSR[
Int'l v. Teleflex Inc., 550 U.S. 398 (2007)], not rigidly focus on
the selection of a single, best lead compound . . ., the analysis
still requires the challenger to demonstrate . . . that one of
ordinary skill in the art would have had a reason to select a
proposed lead compound or compounds over other compounds
in the prior art.

Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir.
2010) (citation omitted).
Here, as the Examiner pointed out, Dong discloses a compound that
differs from the claimed compound only in that Dong’s compound has
glycine at position 8, rather than the serine of elected compound (see Dong
40 (Example 378 (Gly8, Aib35)hGLP-1(7-36)NH2)). We acknowledge, as
Appellant argues, that Example 378 is one of 411 exemplified compounds,
and is a single species of a broader generic disclosure (see Dong generally).
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Nonetheless, Dong discloses, as a general principle, that “the
administration of the compounds of this invention for purposes of eliciting an
agonist effect can have the same effects and uses as GLP-1 itself” (id. at 16
(emphasis added) (listing over 20 treatable disorders, including Type I and
Type II diabetes)). Thus, we are not persuaded that Dong failed to provide a
reason to select any of its exemplified compounds, including Example 378,
as a compound suitable for further improvement.
It may true, as Appellant argues, that Dong provides no specific
biological activity data for any of the exemplified GLP-1 analogues that
might allow an ordinary artisan to choose one of Dong’s compounds over
another as a lead compound. Appellant points to no evidence of record,
however, suggesting that an ordinary artisan would have expected any of the
exemplified compounds, including the compound of Example 378, to lack
the therapeutic properties described in Dong. Moreover, Appellant points to
no evidence of record suggesting that an ordinary artisan would have
ignored Dong’s general teaching of therapeutic efficacy, and instead only
would have selected as lead compounds those compounds for which specific
comparative data had been presented.
We note the statement in Daiichi Sankyo that, while the inquiry
should not rigidly focus on a single lead compound, “the analysis still
requires the [claim] challenger to demonstrate . . . that one of ordinary skill
in the art would have had a reason to select a proposed lead compound or
compounds over other compounds in the prior art.” Daiichi Sankyo v.
Matrix Labs.,619 F.3d at 1354 (emphasis added); see also Otsuka Pharm.
Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012) (“A lead
compound, as we have explained, is ‘a compound in the prior art that would
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be most promising to modify in order to improve upon its ... activity and
obtain a compound with better activity.’” (Emphasis added.) (citing Takeda
Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir.
2007)).
We are not persuaded, however, that Daiichi Sankyo, Otsuka, or other
lead compound cases mandate that the only compounds useful for evaluating
obviousness are those for which the prior art has provided specific
comparative data. In this case, for example, accepting such an interpretation
would effectively render Dong unavailable as prior art for determining
obviousness, simply because Dong did not provide data comparing the
biological properties of its compounds.
Such an outcome conflicts with the well settled broader principle that,
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); see also Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d
804, 807 (Fed. Cir. 1989) (“[I]n 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.’”) (quoting In re Lamberti, 545 F.2d 747, 750 (CCPA 1976)).
Moreover, as noted above, the Federal Circuit has tempered the
rigorousness of the lead compound analysis by stating that “the lead
compound analysis must, in keeping with KSR, not rigidly focus on the
selection of a single, best lead compound . . . .” Daiichi Sankyo v. Matrix
Labs., 619 F.3d at 1354 (citing Altana Pharma AG v. Teva Pharms. USA,
Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009)).
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In sum, given Dong’s teaching that its compounds possess GLP-1-like
therapeutic activity, we are not persuaded that the Examiner erred in finding
that an ordinary artisan had a reason to select the compound of Dong’s
Example 378 for further improvement. As discussed below, we are also not
persuaded that the Examiner erred in finding that Deacon would have
prompted an ordinary artisan to substitute serine for the glycine at position 8
of Dong’s compound.
Deacon, like Dong, discloses that GLP-1 “has great potential in
diabetes therapy due to its glucose-dependent stimulation of insulin
secretion, but this is limited by its rapid degradation, primarily by dipeptidyl
peptidase IV [DPP IV]” (Deacon 271 (abstract); see also Dong 2 (“This
metabolic instability limits the therapeutic potential of native GLP-1. Hence,
there is a need for GLP-1 analogues that are more active or are more
metabolically stable than native GLP-1.”)).
Deacon thus undertook a study to examine “whether small
modifications of the N-terminus of GLP-1 would also confer resistance to
degradation by DPP IV, while retaining the peptide’s biological activity” (id.
at 272). To perform the study, “[a]nalogues, substituted at position 8 of
GLP-1 with either threonine (Thr8-GLP-1 (7-37)), glycine (Gly8-GLP-1 (7-
37)), serine (Ser8-GLP-1 (7-36) amide) or α-aminoisobutyric acid (Aib8-
GLP-1 (7-36) amide and Aib8-GLP-1 (7-37)) were prepared” (id.).
Testing for stability, Deacon found that the native “GLP-1 (7-36)
amide was degraded by porcine plasma in vitro at 37°C; with a t1/2 of 28.1 ±
1.2 min (n = 12)” whereas “[i]ncubation of the GLP-1 analogues revealed a
significantly (p < 0.0001) prolonged t1/2 compared to GLP-1 (7-36) amide
itself (Gly8-GLP-1, 159 ± 12 min, n = 3; Ser8-GLP-1, 174 ± 12 min, n = 9;
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Thr8-GLP-1, 197 ± 14 min, n = 3)” with “[d]egradation of Aib8-GLP-1 (n =
9) being undetectable after 6 h” (id. at 273). Given the serine-substituted
analogue’s significant stability improvement over the native peptide, as well
as its superiority over the glycine analogue, we agree with the Examiner that
Deacon would have prompted an ordinary artisan to substitute serine for the
glycine at position 8 of the compound described in Dong’s Example 378.
We note, as Appellant argues (see App. Br. 10), that the serine
substitution at position 8 did not produce the most stable GLP-1 analogue
(see Deacon 273). As Appellant points out, the serine substituted analogue
also did not have the highest receptor binding affinity of the tested analogues
(id. at 274 (“The Aib8 and G1y8 analogues had similar affinities compared to
GLP-l (7-36) amide, while the other two analogues had lower receptor
affinities than GLP-l (7-36) amide.”)). As Appellant further points out,
while the serine substituted analogue exhibited biological activity when
contacted with isolated pancreas, it was not the most potent of the analogues
tested:
Of the analogues, Aib8-GLP-l (7-36) amide was at least as
potent as GLP-l (7-36) amide in stimulating insulin and
inhibiting glucagon secretion, and was significantly (p < 0.05)
more potent than the Ser8 and Thr8 analogues in raising insulin
output. It was also the most potent (p < 0.05) of all the
analogues in reducing glucagon output. The Gly8 analogue was
not significantly different to GLP-1 (7-36) amide in stimulating
insulin or inhibiting glucagon secretion, but was more potent (p
< 0.05) than the Ser8 and Thr8 analogues in inhibiting glucagon
release, while the Thr8 analogue was the least potent of the
analogues tested.

(Id. at 274-275.)
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However, as the Examiner points out, “a finding that the prior art as a
whole suggests the desirability of a particular combination need not be
supported by a finding that the prior art suggests that the combination
claimed by the patent applicant is the preferred, or most desirable,
combination.” See In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004).
Moreover, the “prior art’s mere disclosure of more than one alternative does
not constitute a teaching away from any of these alternatives because such
disclosure does not criticize, discredit, or otherwise discourage the solution
claimed. . . .” Id. at 1201.
Here, both Dong and Deacon teach the desirability of modifying
GLP-1 so as to improve its stability, and as the Examiner found, Deacon
discloses that substituting a serine at position 8 of the native GLP-1
sequence results in a biologically active analogue which is significantly
more stable than native GLP-1, and which is also more stable compared to
an analogue having a glycine at position 8. While it might be true that an
ordinary artisan may have considered the serine substitution to be less
desirable than other substitutions tested by Deacon, that fact does not
demonstrate that an ordinary artisan would have considered the serine
substitution unobvious. See In re Fulton, 391 F.3d at 1200-1201.
Turning to the issue of unexpected results, “while not directly relating
to the rejections on Appeal, Appellant notes that multiple Rule l32
Declarations have been submitted during the prosecution of the application
to show the surprising and unexpected qualities of the elected species (Ser8,
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Aib35)hGLP-l(7-36)NH2” (App. Br. 12 (citing Zhang Declaration3 and
Taylor Declaration4)).
However, as the Examiner argues, neither of comparisons presented in
the Declarations and reproduced in the Appeal Brief compares the
compound under examination to the compound from Example 378 of Dong,
(Gly8, Aib35)hGLP-1(7-36)NH2, which forms the basis of the Examiner’s
obviousness rejection. Thus, as Appellant appears to concede (see App. Br.
12 (“while not directly relating to the rejections on Appeal”)), the
comparisons Appellant advances to show unexpected results are not
comparisons to the closest prior art. Compare In re Baxter Travenol Labs.,
952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art.”).
Moreover, while Appellant argues that the results presented in the
Zhang and Taylor Declarations are “surprising and unexpected” (App. Br.
12), Appellant points to no instance in either Declaration where the
Declarant actually states that the results obtained were unexpected. Thus,
the actual evidentiary showings Appellant relies on to show unexpectedness
lack clear or specific factual support for such a finding. Compare In re
Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997) (argument by counsel cannot
be substituted for actual evidence of unexpected results).

3 Declaration of Jundong Zhang, Ph.D. under 37 C.F.R. § 1.132 (declaration
executed February 27, 2009).
4 Declaration of John E. Taylor, Ph.D. under 37 C.F.R. § 1.132 (declaration
executed February 27, 2009).
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In sum, for the reasons discussed, Appellant’s arguments do not
persuade us that a preponderance of the evidence fails to support the
Examiner’s prima facie case of obviousness, nor are we persuaded that
Appellant has advanced evidence of unexpected results sufficient to
outweigh that prima facie case. Accordingly, we affirm the Examiner’s
rejection of claim 15 over Dong and Deacon.
Claims 16-18 fall with claim 15. See 37 C.F.R. § 41.37(c)(1)(vii).
SUMMARY
We affirm the Examiner’s obviousness rejection of claims 15-18 over
Dong and Deacon.

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

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