Ex Parte Dunne et al

Patent Trial and Appeal Board

Feb 4, 2015

11899599 (P.T.A.B. Feb. 4, 2015)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JUDE A DUNNE, JAVIER A. FARINAS,
IRINA G. KAZAKOVA, RAPHAELE GERBER,
COLEEN HACKER, ROGER DETTLOFF,
ESTHER HUANG, and THI NGOC VY TRINH
__________

Appeal 2012-007455
Application 11/899,599
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
ROBERT A. POLLOCK, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a method
of screening a compound for enzyme inhibition activity. The Examiner
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 Appellants identify the Real Party in Interest as Caliper Life
Sciences, Inc. (see App. Br. 3).
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Statement of the Case
Background
“With phosphorylation involved in so many cell functions and
diseases, identifying compounds that affect protein kinase activity is
tremendously important, not only to provide drug candidates that are active
in treating disease, but also to ensure that these drug candidates act without
causing adverse effects on other cellular functions” (Spec. 2, ll. 21–24).
The Claims
Claims 12–20 are on appeal. Independent claim 12 is representative
and reads as follows:
12. A method of screening a compound for enzyme
inhibition activity, the method comprising:
preparing at least one sample mixture using a kit
including first and second multiwell plates, the first
multiwell plate having a plurality of enzymes disposed
within a first plurality of wells, the second multiwell plate
having a plurality of enzyme substrates disposed within a
second plurality of wells, wherein the order in which the
enzymes are disposed on the first plate is determined by the
order in which the corresponding enzyme substrates are
disposed on the second plate, wherein a phosphate source is
disposed within each well of the second plate at a
concentration specific for the enzyme disposed in the
corresponding well of the first plate, and wherein a cofactor
is disposed within each well of the second plate at a
concentration specific for the enzyme disposed in the
corresponding well of the first plate;
providing the at least one sample mixture to a
microfluidic device, the sample mixture comprising an
enzyme, an enzyme substrate, a test compound, and a
product;
applying vacuum pressure to the sample mixture;
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flowing the sample mixture along a microchannel of
the microfluidic device in response to the applied pressure;
separating the product and the enzyme substrate based
upon a difference in electrophoretic mobility between the
product and the enzyme substrate;
detecting the separated product and enzyme substrate,
and determining enzyme inhibition activity of the compound
based on the detection of the separated product and enzyme
substrate.

The issues
A. The Examiner rejected claims 12–14, 17, and 20 under 35 U.S.C.
§ 103(a) as obvious over Knapp,2 Soldin,3 and Daniel4 (Ans. 4–11).
B. The Examiner rejected claims 15 and 18 under 35 U.S.C. § 103(a) as
obvious over Knapp, Soldin, Daniel, and Cravatt5 (Ans. 11).
C. The Examiner rejected claims 16 and 19 under 35 U.S.C. § 103(a) as
obvious over Knapp, Soldin, Daniel, and Zhu6 (Ans. 12).
D. The Examiner rejected claim 20 under 35 U.S.C. § 103(a) as obvious
over Knapp, Soldin, Daniel, and Vogels7 (Ans. 13).
A. 35 U.S.C. § 103(a) over Knapp, Soldin, and Daniel
The Examiner finds that Knapp teaches “performing enzymatic
assays, by providing in a microfluidic device a mixture, comprising the

2 Knapp et al., WO 98/45481 A1, published Oct. 15, 1998
(hereinafter “Knapp”).
3 Soldin, S., US 6,410,340 B1, issued June 25, 2002.
4 Daniel, R., US 4,919,894, issued Apr. 24, 1990.
5 Cravatt et al., US 2002/0045194 A1, published Apr. 18, 2002
(hereinafter “Cravatt”).
6 Zhu, X., US 6,589,758 B1, issued July 8, 2003.
7 Vogels et al., US 6,340,595 B1, issued Jan. 22, 2002 (hereinafter
“Vogels”).
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necessary reagents to perform the assay, and also electrophoretic separation
or purification of materials” (Ans. 5). The Examiner finds that Knapp lacks
a “specific example of an assay requiring enzymes, enzyme substrates, a
phosphate source and a cofactor” (Ans. 6).
The Examiner finds that Soldin teaches that “the use of enzymes (e.g.,
kinases), substrates, phosphate source and cofactors as reagents is well
known in the art for screening compounds for a particular biological
activity” (Ans. 6). The Examiner finds that Daniel teaches that “each
individual microwell can be identified by cross-indexing of the symbols . . .
and that each rows and columns of one sample holder (such as a microtiter
plate) can be provided to match corresponding rows and columns of another
sample holder” (Ans. 9).
The Examiner finds it obvious to “use such cross-indexing and
matching of microtiter plates to provide for the corresponding enzymes on
the first plate and applicable enzyme substrates and phosphate
concentrations in the second substrate, as such cross-indexing helps prevent
cross-contamination during performance of different assays” (Ans. 10).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that Knapp, Soldin, and Daniel
render the claims obvious?
Findings of Fact
The following findings of fact (“FF”) are supported by a
preponderance of the evidence of record.
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1. Knapp teaches “fluidic mixing assays, such as . . . inhibition
assays . . . . The results detected are digitized and read by computer 1820”
(Knapp 82, ll. 8–9).
2. Knapp teaches that “virtually any set of reagents can be
sampled and assayed in an integrated system of the present invention. For
example, enzymes and substrates . . . can all be assayed using the integrated
systems of the invention. . . . Thousands of compounds are easily screened
using this method, in a short period of time (e.g., less than an hour)” (Knapp
43, l. 30 to 44, l. 8).
3. Knapp teaches
[P]erforming fluidic operations that require a large number
of successive fluid manipulations, i.e., in performing a
number of preparative and analytical reactions or operations
on a given sample. By “successive fluid manipulations” is
generally meant a fluidic operation that involves the
successive treatment of a given fluid sample volume, i.e.,
combination/reaction with reactants, incubation,
purification/separation, analysis of products, and the like.

(Knapp 17, ll. 19–24.)
4. Knapp teaches that the “devices optionally include integrated
microfluidic structures, such as micropumps and microvalves, or external
elements, e.g., pumps and switching valves, for the pumping and direction of
the various fluids through the device” (Knapp 71, ll. 23–26).
5. Knapp teaches a “window or zone at which a signal is
monitored. This detection window typically includes a transparent cover
allowing visual or optical observation and detection of the assay results, e.g.,
observation of a colorometric, fluorometric or radioactive response, or a
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change in the velocity of colorometric, fluorometric or radioactive
component” (Knapp 75, ll. 21–25).
6. Knapp teaches “that reagent storage substrate 1310 can
conveniently be either above or below microfluidic substrate 1335. In
addition, although depicted with dried reagents, reagent storage substrate
1310 can be substituted with a microtiter dish having reagents in liquid
form” (Knapp 79, ll. 22–26).
7. Knapp teaches that “products are washed from the template . . .
and electrophoresed through size separation microchannel 2043. The
products separate by size, permitting detection of the products with detector
2045, which is operatively linked to computer 2050” (Knapp 82, l. 31 to 83,
l. 1).
8. Knapp teaches “performing fluidic operations that require a
large number of parallel fluid manipulations, i.e., to . . . screen test
compounds for drug discovery . . . . To carry out these operations, a
substrate will typically employ an array of parallel channels and/or channel
networks, interconnected by one or more common channels” (Knapp 18, ll.
6–11).
9. Soldin teaches that:
To determine effects of the immunophilin on enzyme
activities, the following protocols can be employed. For
detection of effects of a immunophilin on a cyclic AMP
(“cAMP”)dependent protein kinase, mixtures containing
enzyme, protein substrate (e.g., a histone or a partially
dephosphorylated casein), phosphorylating reagent -32P-
ATP, activator cAMP, cofactor Mg2+, and an immunophilin .
. . . Radio-labeled substrate protein may be detected by
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radioautography of the gel after SDS-PAGE separation of
the reactants and products. . . . Immunosuppressant drugs
(e.g. 60-600 nM) may be added to incubation
mixtures to determine their effect, if any, on the
immunophilin effect.
(Soldin, col. 6, ll. 14–31.)
10. Daniel teaches that:
[I]t is often necessary for lab personnel to be able to
determine which of the microwells have had the necessary
substance transported to it, and which remain to be so
inoculated. This is especially true when the laboratory
personnel working with the plate must transport fluid
samples from different identified sources to identified well
holes in the microtiter plate, such as when a substance is
removed from a tube in the test tube rack and placed in a
microwell. Accuracy in transporting the sample from the
properly identified source to the appropriate well is critical.

(Daniel, col. 1, ll. 27–37; emphasis added.)
11. Daniel teaches that
[C]ross-indexing is accomplished when a microtiter plate is
placed in one such device and a test tube rack placed in a
second device. When the guide members of the devices
have matching symbols and the side members of the devices
likewise have matching symbols, any one of the test tubes
may be cross-indexed to the corresponding microwell.

(Daniel, col. 2, ll. 18–24.)
12. Daniel teaches “an indexing means and method in which
symbols are used to identify each of the rows, and each of the columns of a
sample holder so that any particular holder may be identified by cross-
indexing of the symbols” (Daniel, col. 2, ll. 43–47).
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13. Daniel teaches a cross-indexing method “involving a symbol
for each of the rows and symbols for each of the columns of a sample
support holder which match the corresponding rows and columns of the
symbols for another sample holder, in order that the first sample holder may
be matched to its corresponding second sample holder” (Daniel, col. 2, ll.
52–58).
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” Id at 417.
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 4–11; FF 1–13) and agree that claim
12 is obvious over Knapp, Soldin, and Daniel. We address Appellants’
arguments below.
Appellants note that the Examiner acknowledges that Knapp does not
teach “an assay requiring enzymes, enzyme substrates, a phosphate source
and a cofactor” and contend that “nowhere does Sodin [sic] teach screening
large numbers of libraries nor does he teach screening using a plurality of
enzymes and a plurality of enzyme substrates as recited by Appellants”
(App. Br. 11–12).
We find this argument unpersuasive because it fails to combine the
teachings of Knapp and Soldin. Knapp teaches high throughput screening
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using enzymes and substrates (FF 2) as well as inhibition assays (FF 1), and
suggests applying this to drug discovery (FF 8). Soldin teaches an assay for
determining the effect of an immunophilin compound on a kinase in a
reaction which contains the kinase enzyme, the kinase substrate, a phosphate
source, cofactors, and well as immunosuppressant drugs (FF 9).
The ordinary artisan would have found it obvious to test the various
immunosuppressant drugs or immunophilin compounds of Soldin using the
high throughput screening assay of Knapp because Knapp teaches a method
where “[t]housands of compounds are easily screened using this method, in
a short period of time (e.g., less than an hour)” (Knapp 44, ll. 7–8; FF 2).
Appellants contend that
Daniel teaches means and methods for transferring
materials from one array of containers to another array of
containers such that the same materials are in the same order
in both arrays of containers. Daniel is silent with regard to
having a second set of different materials already disposed
in the second array of containers prior to the transfer, the
order of the second set of materials being determined by the
order of the materials present in the first set of containers.
I.e., [sic] Daniel does not teach that materials in the first set
of sample holders are in a specific order that would dictate
the order of materials predisposed in the second set of
sample holders.

(App. Br. 13.)
We are not persuaded for several reasons. Even if Daniel were read to
require transfer of materials in the same order as argued by Appellants,
claim 12 lacks any limitation requiring that the orders of the enzymes and
the order of the corresponding enzyme substrates are not in the same order,
only that the order is co-determined. Thus, this limitation does not
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distinguish claim 12 from the teaching of Daniels. See In re Self, 671 F.2d
1344, 1348 (CCPA 1982) (“[A]ppellant’s arguments fail from the outset
because . . . they are not based on limitations appearing in the claims.”)
We also agree with the Examiner that Daniel reasonably suggests
using “cross-indexing and matching of microtiter plates to provide for the
corresponding enzymes on the first plate and applicable enzyme substrates
and appropriate phosphate concentrations and appropriate cofactor
concentrations in the second substrate, as such cross-indexing and matching
helps prevents cross-contamination during performance of different assays”
(Ans. 17). That is, the ordinary artisan interested in performing the high-
throughput drug discovery assays of Knapp (FF 1, 2, 8) to identify drugs
which effect Soldin’s kinase (FF 9) would have reasonably used Daniel’s
indexing means because Daniel teaches that “[a]ccuracy in transporting the
sample from the properly identified source to the appropriate well is critical”
(Daniel, col. 1, ll. 35–37; FF 10). Indeed, in any multiwell assay involving
multiple enzymes, drugs, or other components, Daniel evidences that the
ordinary artisan would have found it obvious to order the samples to
minimize error of transfer to the next reaction stage (FF 10–13).
Appellants “do not see how, without hindsight bias, their specifically
claimed first and second multiwell plates could be derived from a simple
method for ensuring correct materials are deposited in a reservoir” (App. Br.
14).
We are not persuaded. While we are fully aware that hindsight bias
often plagues determinations of obviousness, Graham v. John Deere Co.,
383 U.S. 1, 36 (1966), we are also mindful that the Supreme Court has
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clearly stated that the “combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield predictable
results.” KSR, 550 U.S. at 416.
Claim 12 requires two multiwell plates, one with enzymes, the other
with enzyme substrates, where each well of the first plate is properly
matched with the second plate. We do not think any hindsight is required
for the ordinary artisan in the highly skilled art of drug discovery,
particularly in light of Daniel’s cross-indexing teachings (FF 10–13), to
arrange two multiwell plates so that when the enzymes of one microwell
plate are transferred to a second microwell plate, the transfer accurately
transports each enzyme to the preplanned well on the second plate which
contains the appropriate enzyme substrate, phosphate source and cofactor, as
required by claim 12.
Appellants contend that “the multiwell plate of Daniel cannot
correspond to both of Appellants’ two specifically claimed multiwell plates”
(Reply Br. 6).
We note that this argument does not appear in the Appeal Brief,8 and
we find this argument unpersuasive because the rejection is for obviousness,
not anticipation. The combination of references, including Knapp and
Daniel, suggest transfer of one component to another for high-throughput
drug discovery (FF 2, 8), where at least one of the components is a

8 Ex parte Borden, 93 USPQ2d 1473 (BPAI 2010) (informative)
(new arguments not permitted in Reply Brief without showing of
good cause).

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microtiter plate (FF 6, 10–13). While Daniel may teach the use of test tubes
as the sample source (FF 11), the person of ordinary skill would have
reasonably recognized that just as the microwell plate in Daniel replaces a
test tube for assay performance, another microwell plate would have been an
obvious means to hold the starting sample material in place of the test tubes
of Daniel.
Appellants also contend that “Appellants do not mention cross-
contamination in their application, nor do they claim their method prevents
cross-contamination. Thus, this benefit offered by the method and apparatus
of Daniel does not connect the teachings of Daniel to Appellants’ claims”
(Reply Br. 7).
We are not persuaded. We recognize that the Examiner’s reason for
combining these references may not be identical to Appellants’ reasons.
However, that the prior art has a different reason or motivation to combine
the methods of Knapp, Soldin, and Daniel is of no moment as long as there
is a reason to make the combination. See In re Kemps, 97 F.3d 1427, 1430
(Fed. Cir. 1996) (“[T]he motivation in the prior art to combine the references
does not have to be identical to that of the applicant to establish
obviousness.”). Also see KSR, 550 U.S. at 419 (“In determining whether the
subject matter of a patent claim is obvious, neither the particular motivation
nor the avowed purpose of the patentee controls. What matters is the
objective reach of the claim. If the claim extends to what is obvious, it is
invalid under § 103.”).

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Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
Knapp, Soldin, and Daniel render the claims obvious.

B.–D. 35 U.S.C. § 103(a)
Appellants do not argue separately the claims in these obviousness
rejections. Having affirmed the obviousness rejection of claim 12 over
Knapp, Soldin, and Daniel for the reasons given above, we also find that
these further combinations render the remaining claims obvious for the
reasons given by the Examiner (see Ans. 11–23).
SUMMARY
In summary, we affirm the rejection of claim 12 under 35 U.S.C.
§ 103(a) as obvious over Knapp, Soldin, and Daniel. Pursuant to 37 C.F.R.
§ 41.37(c), claims 13, 14, 17, and 20 fall with claim 12, as these claims were
not argued separately.
We affirm the rejection of claims 15 and 18 under 35 U.S.C. § 103(a)
as obvious over Knapp, Soldin, Daniel, and Cravatt.
We affirm the rejection of claims 16 and 19 under 35 U.S.C. § 103(a)
as obvious over Knapp, Soldin, Daniel, and Zhu.
We affirm the rejection of claim 20 under 35 U.S.C. § 103(a) as
obvious over Knapp, Soldin, Daniel, and Vogels.

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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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