Ex Parte Goueli et al

Patent Trial and Appeal Board

Feb 9, 2018

12710087 (P.T.A.B. Feb. 9, 2018)

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.
12/710,087 02/22/2010 Said A. Goueli 016026-9373-US02 8008
91007 7590 02/13/2018
Michael Best & Friedrich LLP (Promega)
100 East Wisconsin Avenue
Suite 3300
Milwaukee, WI 53202
EXAMINER
SWOPE, SHERIDAN
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
02/13/2018 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):
madipdocket@michaelbest.com
heather.gerard@promega.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SAID A. GOUELI, KUEI-HSUAN HSIAO, MEERA KUMAR,
and JOLANTA VIDUGIRIENE1
Appeal 2017-001449
Application 12/710,087
Technology Center 1600
Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and DAVID COTTA,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to a method
of assaying for cyclic AMP (cAMP), which have been rejected as obvious.
We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
G-protein coupled receptors are “important] in developing new
medically useful compounds.” (Spec. 1:22—24.) Activation of GPCRs can
1 Appellants identify the Real Party in Interest as Promega Corporation.
(Appeal Br. 3.)
Appeal 2017-001449
Application 12/710,087
lead to either stimulation or inhibition of the conversion of ATP to cAMP.
{Id. at 1:17—22.) Cyclic AMP “is known to activate cAMP dependent
protein kinase (PKA).” {Id. at 2:11—12.) “[OJnce cAMP binds to PKA,
PKA transfers a phosphate from adenoside triphosphate (ATP) to a suitable
PKA substrate (e.g. Kemptide).” {Id. at 3:19-21.)
The Specification discloses
methods for monitoring the activation of a G-protein coupled
receptor (GPCR) by an agonist, or its inhibition by an antagonist.
... For example, the level of cAMP found upon addition of
agonist or antagonist to a sample comprising a GPCR is detected
and measured through the activation of PKA. Such activity (or
lack thereof) is detected by a measurable output that is correlated
to cAMP levels or amounts.
{Id. at 4:5-10.)
Claims 1—6, 12, 14, 17, 21, and 22 are on appeal. Claim 1 is the only
independent claim and reads as follows (emphasis added):
1. A method for determining the presence or amount of endogenous
cyclic nucleotide in a sample comprising a cell lysate, the method
comprising:
a) contacting a sample comprising a cell lysate which may contain
endogenous cyclic nucleotide, with (I) a cyclic nucleotide-dependent
protein kinase capable of being activated by the endogenous cyclic
nucleotide, wherein said protein kinase is Protein Kinase A and (II) a
detection system, the detection system comprising:
i) a substrate capable of being phosphorylated by the cyclic
nucleotide-dependent protein kinase;
ii) a luciferase enzyme capable of utilizing ATP to generate a
bioluminescent signal; and
(iii) ATP; and
b) detecting or measuring the bioluminescent signal thereby
determining the presence or amount of the endogenous cyclic
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Application 12/710,087
nucleotide present in the sample, wherein the cell lysate comprises the
cellular debris and fluid that is released from a cell when the cell
membrane is broken apart or lysed,
wherein the endogenous cyclic nucleotide is cAMP
DISCUSSION
The Examiner has rejected claims 1—5, 12, 14, 17, and 21 under
35 U.S.C. § 103(a) as obvious based on Handa,2 Bouchard,3 and Shults.4
(Ans. 3.) The Examiner has rejected claims 6 and 22 under 35 U.S.C.
§ 103(a) as obvious based on Handa, Bouchard, Shults, and Wang.5 (Ans.
5.) The same issue is dispositive for both rejections.
The Examiner finds that Handa “teaches a method for detecting
cAMP using the cAMP-dependent kinase (PKA), ATP, a substrate, and
luciferase. The method of Handa et al utilizes the ability of luciferase to be
activated by ATP.” {Id. at 3.) The Examiner finds that Handa “does not
teach using their luciferase detection method for analysis of cAMP in
cellular lysates.” {Id. at 4.)
2 Handa et al., “Assay of Adenosine 3’, 5’ Cyclic Monophosphate by
Stimulation of Protein Kinase: A Method Not Involving Radioactivity, ”
102 AnalBiochem. 332-339 (1980).
3 Bouchard et al., “Application Note, cAMP AlphaScreen™ Assay: A Method
for the Pharmacological Characterization and Screening of Gai-Coupled
Receptors in Whole Cells,” Perkin Elmer Life Sciences, Inc., 1-8 (2002).
4 Shults et al., “A multiplexed homogeneous fluorescence-based assay for
protein kinase activity in cell lysates,” 2 Nat. Methods 227—283 (2005).
5 Wang et al., “The Role of Arachidonic Acid in Steroidogenesis and
Steroidogenic Acute Regulatory (StAR) Gene and Protein Expression,”
275 J. Biol. Chem. 20204-20200 (2000).
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Application 12/710,087
The Examiner finds, however, that Bouchard “teaches a chemi­
luminescent method for analysis of cAMP, in detergent-solubilized cellular
lysates, using a competition binding assay.” (Id.) The Examiner concludes
that it would have been obvious “to modify the method of Handa et al to
measure cAMP levels in cellular lysates” in order to “reduc[e] the number of
steps necessary for measuring cAMP.” (Id.) The Examiner finds that
Bouchard would support a reasonable expectation of success, because it
teaches that cAMP levels can be analyzed in cellular lysates. An
expectation of success is also provided by Shults et al, which
teaches that forskolin-induced cAMP levels (resulting PKA
activity) can be quantified in cell lysates using a substrate
comprising residues 1-6 of SEQ ID NO: 1 herein (Tablel; Fig4).
Thus, both Bouchard et al and Shults et al reduce to practice
determining cAMP levels in cellular lysates.
(Id.)
Appellants argue that Handa teaches using cell extracts, rather than a
lysate, for its cAMP assay. (Appeal Br. 6.) Appellants argue that, although
Handa states that cAMP can be measured in a crude extract of bacteria or
animal tissue, “a cell extract is, at a minimum, at least partially purified”
(id.), and Handa’s Figure 1 shows the purification procedure for all sample
types (id. at 6—7).
Appellants also argue that Bouchard would not have provided a
reasonable expectation of successfully carrying out Handa’s assay using a
lysate because “[t]he assay disclosed in Bouchard is an antibody-based
competition assay, which is very different from the kinase-based assay
disclosed in Handa.” (Id. at 7.) Finally, Appellants argue that Shults
“teaches a fluorescent kinase activity assay which uses a fluorescence-based
chemosensor strategy for direct measurement of kinase activities” rather
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Application 12/710,087
than “a method for measuring endogenous cyclic nucleotide in a sample
comprising a cell lysate using a luciferase,” as in Handa. (Id.) Appellants
thus conclude that “one of skill in the art would have no reasonable
expectation of success using a bioluminescence-based assay to detect cAMP
in a cell lysate based on the limited teachings of Handa, Bouchard, and
Shults.” (Id.)
We agree with Appellants that the Examiner has not provided
evidence showing that a person of ordinary skill in the art would have had a
reasonable expectation of success in carrying out Handa’s assay using a cell
lysate. “[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
[A] proper analysis under § 103 requires, inter alia,
consideration of two factors: (1) whether the prior art would
have suggested to those of ordinary skill in the art that they
should make the claimed composition or device, or carry out the
claimed process; and (2) whether the prior art would also have
revealed that in so making or carrying out, those of ordinary skill
would have had a reasonable expectation of success. Both the
suggestion and the reasonable expectation of success must be
founded in the prior art, not in the applicant’s disclosure.
In re Vaeck, 947 F.2d 488, 493 (Fed. Cir. 1991) (citation omitted).
Handa discloses “a cAMP assay . . . based on cAMP-dependent
protein kinase.” (Handa 332, abstract.)
Instead of measuring the cAMP-stimulated increase in the rate of
transfer of [y-32P] phosphate from [y-32P] ATP to protein, the rate
of loss of ATP from the reaction mixture is determined. The
ATP remaining after the protein kinase reaction is assayed by
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Application 12/710,087
ATP-dependent chemiluminescence of the firefly luciferin-
luciferase system.
(Id.)
Handa states that “[t]he purification scheme routinely used for the
preparation of samples is shown in Fig. 1.” (Id. at 334, left col.) The legend
of Handa’s Figure 1 reads: “Diagram illustrating the processing of all
samples prior to assay for cAMP.” (Id. at 334, Fig. 1 legend.)
Handa states that “[ajlgal cell or rat tissue samples were transferred to
0.5N HCIO4 and homogenized,” after which the homogenate was kept
overnight at -40°C, thawed, and centrifuged. (Id. at 334, right col. to 335 left
col.) The resulting supernatant was then brought to pH 7 by adding KOH,
precipitated KCIO4 was removed by centrifugation, and the supernatant was
brought to 50 mM Tris-HCl. (Id. at 335, left col.) Handa states that “[a]ll
samples in 50 mM Tris-HCl were passed through columns (1.2 x 10 cm) of
neutral alumina. . . . When the pH of the eluate rose above 4.5,” samples
were collected, lyophilized, and redissolved in distilled water (id.), and used
for determination of ATP levels as an indication of cAMP levels. (Id. at 336,
left col.)
Thus, Handa describes a process of preparing extracts of algal or tissue
samples before carrying out its assay for cAMP. Bouchard discloses an assay
(“AlphaScreen”) for cAMP “designed to directly measure levels of cAMP
produced upon modulation of adenylate cyclase activity by GPCRs.”
(Bouchard 2.) “The assay is based on the competition between endogenous
cAMP and exogenously added biotin-cAMP (Figure 1).” (Id.) While Figure
1 in the record copy of Bouchard is difficult to read, the assay includes donor
beads coated with streptavidin, acceptor beads conjugated to anti-cAMP
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antibodies, and biotinylated cAMP, which competes with intracellular cAMP
for binding to the anti-cAMP antibodies on the acceptor beads. Thus, “an
elevation in intracellular cAMP is stimulated using forskolin, resulting in a
decrease in AlphaScreen signal due to an inhibition of association between
the beads.” (Id.)
Bouchard’s assay relies on association of intracellular or exogenously
added cAMP with anti-cAMP antibodies, not on the effect of cAMP on the
activity of Protein Kinase A. We agree with Appellants that Bouchard does
not provide evidence of a reasonable expectation of success in carrying out
Handa’s process using a cell lysate rather than a purified extract.
Shults describes “a fluorescence-based chemosensor strategy for the
direct measurement of kinase activities in crude mammalian cell lysates.”
(Shults 1, abstract.) Shults states that the method is “useful for studying
protein kinase signaling in crude cellular extracts.” (Id.) Shults’ assay is a
“[f]luorescence-based chemosensor strategy for monitoring recombinant
kinase activity in vitro. . . . The fluorescence signal is generated when the
non-natural Sox amino acid undergoes chelation-enhanced fluorescence in
the presence of divalent magnesium.” (Id. at 1, right col.)
Shults states that “the sensitivity and selectivity of Sox-based
chemosensors are sufficient to measure kinase activities directly from
unfractionated cell lysates,” and are useful in measuring PKA activity. (Id.)
Shults’ assay is based on fluorescence emitted by a substrate that includes a
Sox amino acid and kinase-recognition element positioned so that the Sox
amino acid emits fluorescence when the kinase-recognition element is
phosphorylated by a kinase enzyme. (Id. at 2, Figure 1.)
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However, Shults’ assay does not depend on the effect of PKA-
mediated phosphorylation on intracellular ATP levels, as does Handa’s assay.
Thus, while Shults provides evidence that an assay for kinase activity can be
successfully carried out using a cell lysate, it does not show that an assay
such as Handa’s, which depends on the indirect effect of PKA on ATP levels
as an indicator of the amount of cAMP, could be successfully carried out
using a cell lysate.
In other words, Shults’ assay directly measures a fluorescent signal
resulting from phosphorylation of an artificial substrate by PKA, whereas
Handa’s assay is based on the signal produced by luciferase after depletion of
ATP levels caused by phosphorylation of a substrate by PKA, after PKA is
stimulated by cAMP. We agree with Appellants that Shults’ disclosure is
inadequate to provide a reasonable expectation of success in carrying out
Handa’s assay—based on an effect on luciferase activity resulting from
depletion of ATP that itself results from the activity of PKA, which is
stimulated by cAMP—using a cell lysate rather than the cell extracts
disclosed by Handa.
We therefore reverse the rejection of claims 1—5, 12, 14, 17, and 21
under 35 U.S.C. § 103(a) based on Handa, Bouchard, and Shults. We also
reverse the rejection of claims 6 and 22 under 35 U.S.C. § 103(a) based on
Handa, Bouchard, Shults, and Wang, because the Examiner does not point to
any disclosure in Wang that makes up for the deficiency of Handa, Bouchard,
and Shults discussed above.
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SUMMARY
We reverse both of the rejections on appeal.
REVERSED
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