Ex Parte Qiu et al

Patent Trial and Appeal Board

Aug 16, 2016

11578257 (P.T.A.B. Aug. 16, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111578,257 07/18/2007
65643 7590 08/18/2016
Arena Pharmaceuticals, Inc.
Bozicevic, Field & Francis LLP
1900 University A venue, Suite 200
East Palo Alto, CA 94303
FIRST NAMED INVENTOR
Jun Qiu
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
AREN-086 (86.US2.PCT) 1195
EXAMINER
LI, RUIXIANG
ART UNIT PAPER NUMBER
1646
NOTIFICATION DATE DELIVERY MODE
08/18/2016 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JUN QIU, ROBERT R. WEBB, DAVID J. UNETT, JOEL E.
GATLIN, and DANIEL T. CONNOLLY
Appeal2014-009038
Application 11/578,257 1
Technology Center 1600
Before ERIC B. GRIMES, LORA M. GREEN and DAVID COTTA,
Administrative Patent Judges.
COTT A, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of screening candidate compounds. The Examiner rejected the claims on
appeal as obvious under 35 U.S.C. § 103(a).
We affirm.
1 According to Appellants, the real party in interest is Arena
Pharmaceuticals, Inc. App. Br. 3.
Appeal2014-009038
Application 11/578,257
STATEMENT OF THE CASE
Claims 180, 181, 183, 196, 197, 204--206, and 208-217 are on
appeal. 2 Claim 180, the only independent claim, is illustrative and reads as
follows:
180. A method of screening, comprising:
(a) contacting a candidate compound with a G protein-
coupled receptor comprising an amino acid sequence having at
least 80% identity to SEQ ID N0:2, wherein said G protein-
coupled receptor is present on a recombinant host cell or an
isolated membrane thereof and wherein activation of said
GPCR enhances insulin stimulated glucose uptake in
adipocytes;
(b) identifying an agonist of said G protein-coupled receptor,
wherein said identifying comprises assaying said candidate
compound to determine whether the candidate compound
stimulates said G protein-coupled receptor; and
( c) obtaining a measurement of a blood glucose
concentration in a mammal that has been administered said
agonist, wherein said measurement is produced by measuring
blood glucose concentration before and after administration of
said agonist to said mammal.
2 Claim 207 is also pending but does not stand rejected.
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Appeal2014-009038
Application 11/578,257
The Examiner rejected claims 180, 181, 183, 196, 197, 204--
206 and 208-217 under 35 U.S.C. § 103 (a) 3 as unpatentable over the
combination of Kawamata 4 and Miljkovic. 5
The Examiner found that Kawamata taught a human G protein
coupled receptor ("GPCR"), which it identifies as TGR5, that is identical to
the amino acid sequence of SEQ ID N0:2 recited in the claims. Ans. 2. The
Examiner further found that Kawamata taught a method of screening for
agonists of the human GPCR by contacting CHO cells expressing TGR5
with bile acids, including cholic acid (CA), chenodeoxycholic acid (CDCA)
deoxycholic acid (CDA), lithocholic acid (LCA), and taurine-conjugated
lithocholine acid. Id. at 2-3.
The Examiner acknowledged that Kawamata did not disclose step ( c)
of claim 180, "obtaining a measurement of a blood glucose concentration in
a mammal that has been administered an agonist of GPR131 [i.e., SEQ ID
N0:2]." Id. at 3. The Examiner found that this step was taught in
Miljkovic, which disclosed "a method of identifying a compound that
reduces blood glucose concentration in a rat, comprising administering a bile
acid (a small molecule) to said rat and measur[ ing] blood glucose level in the
rat (see, e.g., claims 1---6; Fig. 2; Examples; Table 1 )." Id. The Examiner
3 In the Examiner's Answer, the Examiner withdrew the pending rejection of
claims 180, 181, 183, 196, 197, and 204--217 under 35 U.S.C. § 112 (b) as
being indefinite for failing to particularly point out and distinctly claim the
subject matter which the applicant regards as the invention. Ans. 2. This
issue is thus no longer a part of this appeal.
4 Kawamata, et al., A G Protein-coupled Receptor Responsive to Bile Acids,
Vol. 278, No. 11, THE JOURNAL OF BIOLOGICAL CHEMISTRY, 9435-9440,
published Jan. 10, 2003.
5 Miljkovic et al., U.S. Patent No. 6,060,465, issued May 9, 2000.
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Appeal2014-009038
Application 11/578,257
found that the bile acids disclosed in Miljkovic include cholic acid,
chenodeoxycholic acid, and deoxycholic acid. Id.
The Examiner concluded:
[I]t would have been obvious to one of skilled in the art to
modify the method of Kawamata et al. to include an additional
step of administering an identified agonist of human GPRl 31 to
a rat and measuring blood glucose level in the rat to determine
whether the identified agonist of human GPR131, such as
cholic acid, chenodeoxycholic acid, deoxycholic acid, or
lithocholic acid, and taurine-conjugated lithocholine acid,
reduces blood glucose level with a reasonable expectation of
success. One would have been motivated to do so because
Miljkovic et al. suggest that bile acids lower blood glucose
concentration in an animal (column 7, lines 48-52).
Ans. 4.
Appellants argue that the person of ordinary skill in the art would not
have thought to test blood glucose level after administration of agonists of
GPRl 31 - as required by step ( c) of claim 180 - because the teachings of
Kawamata and Miljkovic do not suggest a link between GPR131 and blood
glucose regulation. Br. 7-8.
FINDINGS OF FACT
1. Kawamata discloses a GPCR identified as TGR5. Kawamata
Fig. 1. The Examiner finds, and Appellants do not dispute, that TGR5 has
the amino acid sequence of SEQ ID N0:2 recited in claim 180. Ans. 2, Br.
7-8.
2. Kawamata discloses:
We co-transfected a reporter gene ( cAMP-responsive element
fused to luciferase gene (pCRE-Luc, Clontech)) and expression
vectors of human TGR5 and rat G protein a subunit Gi (to
reduce the basal level of luciferase) into CHO cells. We then
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Appeal2014-009038
Application 11/578,257
screened more than 1,000 compounds by measuring luciferase
activities induced in response to intracellular cAMP production
and detected specific increases due to bile acids including
TLCA, lithocholic acid (LCA), DCA, and CDCA at 25 µM.
Id. at 9436.
3. Kawamata discloses:
In addition we found that TLCA, LCA, DCA, CDCA, and
cholic acid (CA) dose-dependently induced the production of
cAMP in CHO-TGR5 cells (Fig. 3A) at the median effective
concentrations (ECso) of 0.33, 0.53, 1.01, 4.43, and 7.72 µM,
respectively. These bile acids did not induce the production of
cAMP in mock CHO cells (data not shown).
Id. at 9437.
4. Kawamata discloses that, as of the time of its publication, "no
cell surface receptor for bile acids has yet been identified." Id. at 9435.
5. Kawamata discloses: "Altogether, our results unequivocally
demonstrate that TGR5 functions as a specific cell surface receptor for bile
acids." Id. at 9438.
6. Kawamata discloses:
Although our results suggest that TGR5 plays a role in the
regulation of macrophage functions by bile acids, we do not
rule out the possibility that TGR5 has other unknown important
functions, because TGR5 mRNA is widely distributed not only
in lymphoid tissues but also in other tissues. Our findings that
TGR5 is responsive to bile acids will give an important clue in
revealing the physiological functions of TGR5 in future studies.
Id. at 9440.
7. Miljkovic discloses a method of "regulating serum glucose
levels in mammals by non-parenteral administration of a cholerically active
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Appeal2014-009038
Application 11/578,257
compound as an active ingredient." Miljkovic col. 2, 11. 52-55. Miljkovic
defines "cholerically active compound" to mean "any amphiphilic
compound which (a) comprises a bile acid or salt, (b) structurally resembles
a bile acid or salt, ( c) specifically reacts with a bile receptor, or ( d) has a
similar action in the gastrointestinal tract as a bile acid or salt." Id. at col. 3,
11. 8-11.
8. Miljkovic discloses: "There are many known bile acids,
including deoxycholic acid, cholic acid, taurocholic acid, glycocholic acid,
glycodeoxycholic acid, taurodeoxycholic acid, ursodeoxycholic acid and
chenodeoxycholic acid." Id. at col. 3, 11. 31-34.
9. Miljkovic discloses that "satisfactory embodiments would
result in at least a 10%, a 20%, a 30% or a 40% reduction in glucose level
after one hour compared with controls." Id. at col. 4, 11. 31-34.
10. Table 1 of Miljkovic discloses "data from a comparative study
of iowering of the biood giucose concentration after nasai administration of
insulin, Na-salt of 3K,7K-dihydroxy,12-keto-52-cholanic acid (0.8%), a
mixture of insulin and Na-salt of3K,7K dihydroxy,12-keto-52-cholanic
acid, as well as after a subcutaneous administration of insulin." Id. at col 6,
11. 41--46. Table 1 is reproduced below.
"Ji\JJLE l
I:'.h.:crt!'ls:e of gL1co~e afl<::r 1rne>ni
;td m:in islmb.o rt of lx~Uo-.v giv(-;n ;;;obsl~l!JC~~s Lr:
phy£·iologic;~J solution (CU-'.~'-~' activB i'11 ;idmirnstrati0n of inwlin Jnd Na-saJt of
the above acid
foH1lin - ~11bcu~m.:.;;;o~i;;;ly
6
~"%.~
(du.cu~(:
d,.:: ..... ~e~tgi'.1-
12.9
Appeal2014-009038
Application 11/578,257
11. Miljkovic discloses that
[T]he above-described results can reasonably be extrapolated to
generalize glycoregulatory effects of transmucosal
administration of bile acids, their natural or synthetic
derivatives, analogs and homologs, per se, across many species.
Such extrapolation is based in part on the recognition that bile
acids and salts appear to have specific membranous receptor
sites, and in part on the recognition that the structure of bile
acids is extremely conservative over a very large number of
species spanning millions of years of evolution.
Id. at col. 7, 11. 23-32.
ANALYSIS
We agree with the Examiner that the rejected claims would have been
obvious over the combination of Kawamata and Miljkovic.
The Examiner relied on disclosures in the prior art relating to a single
group of GPR13 lagonists- bile acids- finding that it would have been
obvious to "determine whether the identified agonist of human GPR131,
such as cholic acid, chenodeoxycholic acid, deoxycholic acid, or lithocholic
acid, and taurine-conjugated lithocholine acid, reduces blood glucose level."
Ans 5---6. As an initial matter, we note that there is no need to determine
here whether it would have been obvious to test the blood glucose
concentration resulting from administration of all agonists of GPRl 31. If it
would have been obvious to perform the claimed method for one agonist of
GPR131- e.g. a bile acid-the entire claim is unpatentable. See, Ex parte
Kubin, No. 2007-0819, 83 USPQ2d 1410, 1414 (BPAI 2007)("A single,
obvious species within a claimed genus renders the claimed genus
unpatentable under§ 103."); ajf'd 561 F.3d. 1351 (Fed. Cir. 2009).
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Appeal2014-009038
Application 11/578,257
Appellants argue that bile acids have many physiological effects and it
is "not clear how any of these effects are mediated"; thus, "[ e ]ven if the
reference taught or suggested binding, one of skill in the art would have had
no reasonable expectation that such binding would mediate blood glucose
level." Br. 8. The claims, however, do not require mediation of blood
glucose level. All they require with respect to blood glucose is that one
"obtain[] a measurement of blood glucose concentration in a mammal that
has been administered said agonist." The relevant inquiry is thus not, as
Appellants contend, whether a person of ordinary skill would expect binding
to mediate blood glucose. Rather, the relevant inquiry is whether the person
of ordinary skill in the art would have reason to carry out the claimed
measurement and whether they would have a reasonable expectation that
they would succeed in doing so.
Here, while there may well have been some uncertainty as to how bile
acids mediate their physioiogicai effects, Miijkovic suggests that membrane
receptor sites are involved in blood glucose regulation. See, Miljkovic col.
7, 11. 21-32 (explaining that its blood glucose lowering results can be
extrapolated across species because "bile acids and salts appear to have
specific membranous receptor sites"). And Kawamata discloses that, as of
the time of its publication, "no cell surface receptor for bile acids has yet
been identified." FF5. At the time of the publication of Kawamata,
GPRl 31, the receptor identified by Kawamata was thus the only identified
cell surface receptor for bile acids. In addition, several of the bile acids that
Kawamata teaches bind the GPRl 31 receptor - specifically, cholic,
deoxycholic, and chenodeoxycholic acid - are among the bile acids
disclosed by Miljkovic. FF2, FF3, and FF8. We find that these combined
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Appeal2014-009038
Application 11/578,257
teachings would have, at a minimum, motivated the person of ordinary skill
in the art to measure the blood glucose concentration resulting from
administration of bile acid agonists of GPR131, identified as taught in
Kawamata, to determine whether they had an effect on blood glucose
concentration. We further find that a person of ordinary skill, so motivated,
would have a reasonable expectation that they would succeed in carrying out
the claimed blood glucose measurement.
Appellants argue that nothing in Kawamata suggests that GPRl 31 has
any role in glucose regulation and that Kawamata "focuses on the role of
bile acids in inflammatory responses, particularly immunosuppression." Br.
8. Appellants contend that this focus on inflammation "and the very low
expression of GPR131 in the pancreas relative to other tissues would have
lead one of skill in the art away from the idea that GPR131 had a role in
glucose regulation." Id. at 9.
These arguments are not persuasive. As an initial matter, one cannot
show nonobviousness by attacking references individually when the
rejection is based on a combination of references. In re Keller, 642 F.2d
413, 425 (CCPA 1981). Moreover, as Kawamata itself acknowledges, its
finding that GPR131 plays a role in immunosuppression does not rule out
that it has other functions. Kawamata, 9440 (concluding that GPR131 may
have other functions because it is "widely distributed not only in lymphoid
tissues but also in other tissues"). In addition, the Examiner found
Kawamata to disclose that "the expression of GPR131 in adipose tissue is
quite high." Ans. 6 (citing Kawamata Fig. 4). Kawamata thus does not
teach away from the notion that GPR131 may function in glucose regulation.
This is particularly true given that Appellants do not identify any specific
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Appeal2014-009038
Application 11/578,257
statement in Kawamata that discourages the notion that GPR131 functions in
glucose regulation. See, DyStar Textilfarben GmbH & Co. Deutsch/and Kg
v. CH Patrick Co., 464 F.3d 1356, 1364 (Fed. Cir. 2006) ("[M]ere failure
to discuss immediate use of his leuco indigo solution for dyeing is not the
same thing as Brochet stating in his article that ... his leuco indigo solution
may only be concentrated in paste form. We will not read into a reference a
teaching away from a process where no such language exists.")
Appellants argue that the teachings of Miljkovic can be disregarded
because Miljkovic inconsistently identified its one exemplified bile acid and
that even if these results are not disregarded, "one of ordinary skill in the art
would not automatically expect that cholic acid and chenodeoxycholic acid
would behave the same way as [the inconsistently identified] compound."
Br. 9--10. This argument is not persuasive because Miljkovic expressly
teaches its results can be "extrapolated to generalize glycoregulatory effects
of transmucosai administration of biie acids, their naturai or synthetic
derivatives, analogs and homologs." FFl 1. "It is thus contemplated that bile
acids, their natural or synthetic derivatives, analogs and homo logs are
effective ... to decrease concentration of D-glucose in the blood of many
animals, including mammals." Miljkovic, col. 7, 11. 48-52.
Finally, Appellants contend that the Examiner was required to provide
evidence that "a single GPCR could have roles in two very different
physiological processes (e.g., inflammation and glucose regulation)," and
that absent such evidence, "this rejection can be reversed without further
discussion." Br. 10. As discussed above, however, Kawamata itself
suggests that a single GPCR could have roles in different physiological
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Application 11/578,257
processes. FF6. No additional evidence was required to support this
proposition.
In sum, for the reasons discussed, Appellants' arguments do not
persuade us that a preponderance of the evidence fails to support the
Examiner's prima facie case of obviousness as to claim 180. Because they
were not argued separately, claims 181, 183, 196, 197, and 204-206 and
208-217 fall with claim 180. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
For these reasons and those set forth in the Examiner's Answer, the
Examiner's final decision to reject claims 180, 181, 183, 196, 197, 204--206
and 208-217 is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § l.136(a)(l).
AFFIRMED
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