Ex Parte Lea et al

Patent Trial and Appeal Board

Aug 1, 2018

11632746 (P.T.A.B. Aug. 1, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
11/632,746 03/26/2008 Peter Lea
24247 7590 08/03/2018
TRASKBRITT, P.C.
P.O. BOX 2550
SALT LAKE CITY, UT 84110
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.
3627-8169US 9970
EXAMINER
HARWARD, SOREN T
ART UNIT PAPER NUMBER
1631
NOTIFICATION DATE DELIVERY MODE
08/03/2018 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):
USPTOMail@traskbritt.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PETER LEA, DOMENICA DE LEO, and JUN LIU
Appeal 2017-007116
Application 11/632,746
Technology Center 1600
Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and
JEFFREY N. FREDMAN, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to a method
of determining an amount of an analyte in a sample. The Examiner rejected
the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b ). We
affirm.
Statement of the Case
Background
"The invention is directed to a method for internal dynamic
calibration of an assay device for determining the concentration of an
analyte in a sample" (Spec. 3:5---6). "Quality standards for immunoassays
1 Appellants identify the Real Party in Interest as SQI Diagnostic Systems
Inc. (App. Br. 2).
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have traditionally been driven by external calibration reference standards"
(Spec. 1:6-7). "Many of the problems associated with current methods
typical for immunoassays derive from the assay calibration being determined
by introducing external standard reference samples for calibration" (Spec.
6: 11-13). "There is therefore a need for an immunoassay that can be
reliably calibrated" (Spec. 3:3). "The present method provides more
accurate results by not using these standard external calibration samples"
(Spec. 6:13-14). The invention "is directed to a method for internal
dynamic calibration of an assay device for determining the concentration of
an analyte in a sample where the assay device has an assay surface" with a
"plurality of calibration dots containing pre-determined quantities of the
analyte" and "a test dot containing a reagent for binding said analyte"
printed thereon (Spec. 3:5-9).
The Claims
Claims 23-36 and 38 are on appeal. Claim 23 is representative and
reads as follows:
23. A method of determining an amount of an analyte in a
sample, the method comprising:
introducing the sample into a solution comprising a first
reagent able to specifically bind the analyte, wherein the first
reagent is labeled with a detectable marker, thereby forming a
sample solution, wherein the first reagent binds the analyte in
the sample solution to form a first binding reagent-analyte
complex;
introducing the sample solution onto an assay device
having a surface, wherein the surface comprises printed thereon
a plurality of calibration dots, each of the calibration dots
including a different pre-determined quantity of the analyte,
wherein the surface further comprises printed thereon a test dot
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including a second reagent able to bind the analyte, wherein the
first reagent is present in the solution in excess compared to the
total amount of analyte present in the sample and the plurality
of calibration dots, wherein the test dot and the plurality of
calibration dots are present together in a single well structure of
the assay device, and wherein the test dot and the plurality of
calibration dots are in fluid contact with each other through the
sample solution;
binding the first reagent in the solution to the analyte in
each of the calibration dots, and
binding the first binding reagent-analyte complex in the
solution to the second reagent in the test dot in a single discrete
fluid flow of the sample solution;
measuring an intensity of the detectable marker in each
of the calibration dots;
preparing a calibration curve correlating the amount of
analyte in each of the calibration dots to the measured intensity
of the detectable marker in each of the calibration dots;
measuring an intensity of the detectable marker in the test
dot; and
calculating an amount of analyte present in the test dot by
comparing the measured intensity of the detectable marker in
the test dot to the amount of analyte corresponding to said
intensity in the calibration curve.
The Issue
The Examiner rejected claims 23-36 and 38 under 35 U.S.C. § 103(a)
as unpatentable over Bellet2 in view of Duveneck3, Pawlak4, and Lamont5
(Ans. 2).
2 Bellet et al., US 4,804,626, published February 14, 1989
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The Examiner finds Bellet teaches a "reverse sandwich immunoassay,
and that it is an advantageous replacement for a forward sandwich
immunoassay, but does not teach performing such assays on an 'assay
device having a surface' with calibration and test dots" (Ans. 2).
The Examiner finds Duveneck teaches "an immunoassay device that
has arrays of calibration and test dots printed on a surface"; that Pawlak
teaches "that arrays of calibration and test dots can be printed on a surface in
the same well of an assay device"; and that "Lamont teaches a forward
sandwich immunoassay that uses an assay device having arrays of test and
calibration dots on an assay surface, and that all the dots can be in fluid
contact with a single solution" (Ans. 2).
The Examiner finds the ordinary artisan would have had reason to
"use the solid surface immunoassay device of Duveneck, including the pre-
printed concentration standards, in the quantitative reverse-sandwich assay
procedure taught by Bellet, because Duveneck teaches that this device has
several advantageous features for performing immunoassays, including
replication of the assays and simultaneous detection and quantification of
multiple analytes" (Final Act. 9).
The Examiner finds the ordinary artisan would have had reason "to
perform the assay as spots in a single well of the assay device ... because
3 Duveneck et al., WO 03/096018 A2, published November 20, 2003 (WO
03/096018 A2 is the publication of International Application
PCT /EP2003/004 717 and is in German. All citations are to US
2005/0163659 Al, which is the publication of the United States National
Stage Entry of International Application PCT /EP2003/004 717).
4 Pawlak et al., US 2003/0148542 Al, published August 7, 2003.
5 Lamont et al., WO 03/031976 A2, published April 17, 2003.
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Pawlak teaches that such a format is advantageous for high-density
immunoassays, and Lamont teaches that having the calibration and test spots
in the same reaction is efficient" (Final Act. 9).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner's conclusion
that Bellet, Duveneck, Pawlak, and Lamont render claims 23 and 3 8 prima
facie obvious?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Bellet teaches a "reverse sandwich assay" for determining the
amount of an analyte, human chorionic gonadotropin (hCG), in a sample
(Bellet 2:55-57). Bellet explains that in the "reverse sandwich assay," the
first step introduces the sample where the "sample is initially incubated with
labelled indicator antibody, after which the solid phase immunoabsorbent
containing the two immobilized capture antibodies is added thereto, and a
second incubation is carried out" (Bell et 6: 1-5).
2. Bellet teaches that the analyte (hCG) is incubated with the
"detectably labelled indicator antibody for a time and under conditions
sufficient to allow hCG in the sample to bind to the labelled indicator
antibody" to form a binding reagent-analyte complex (Bellet 6: 12-15).
3. Bellet teaches combining the binding reagent-analyte complex
with a solid support, specifically mixing the complex with "solid phase-
bound antibodies and incubating the new resulting mixture for a time and
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under conditions sufficient to allow [ the analyte] bound to the labelled
antibodies to bind to the solid phase antibodies" (Bellet 6: 17-20).
4. Bellet teaches detecting "the labelled antibody bound to the
solid phase immunosorbent" (Bellet 6:24--25).
5. Bellet teaches that the carrier may also contain "a plurality of
containers each of which comprises different, predetermined amounts of
antigen" and that these calibration containers "can then be used to prepare a
standard curve into which can be interpolated the results obtained from the
sample containing [an] unknown amount of [ analyte ]" (Bell et 9: 10-15, Fig.
3).
6. Duveneck teaches an immunoassay device with "a plurality of
immobilized binding partners for the detection of one or more analytes in
one or more samples in a bioaffinity assay, said binding partners being
arranged and immobilized on the carrier substrate inside the sample
compartments always in two-dimensional arrays of discrete measuring
areas" (Duveneck ,r 32).
7. Duveneck teaches benefits from the use of a "single, common
solution" including that, "impacts of variations between different carrier
substrates on the [analysis] results are avoided" and that "the simultaneous
determination of a plurality of analytes or test of a plurality of samples under
identical conditions is enabled" (Duveneck ,r,r 22-24).
8. Duveneck teaches a calibration region within the immunoassay
device, teaching "at least one measuring area of an array or a partial surface
inside an array or sample compartment, respectively, is provided on the
carrier substrate for referencing purposes" (Duveneck ,r 34).
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9. Duveneck teaches that one way of depositing the binding
partners on the immunoassay device is printing via "ink jet spotting"
(Duveneck ,r 66).
10. Duveneck teaches printing the analyte on the substrate in
different concentrations, specifically where an "individual array comprises
recognition element spots with nine different surface densities of the
immobilized binding partners" (Duveneck ,r 252).
11. Duveneck teaches creating calibration curves and using the
immunoassay device for sandwich assays as well as (Duveneck ,r 234, Fig.
2-3).
12. Duveneck teaches that this assay format enables
"[ s ]imultaneous determination of multiple analytes on a common carrier
substrate with detection limits as low as possible" and "[i]mmediate
comparability of measurements in different sample compartments on the
common carrier substrate" where "at least one measurement area within
each array of measurement areas within a sample compartment" is a
reference control (Duveneck ,r,r 23, 25).
13. Pawlak teaches an assay device where "the biological or
biochemical or synthetic recognition elements are immobilized in discrete
(laterally separated) measurement areas" and teaches that sample
compartments or wells each comprise "one or more measurement areas or
segments or arrays of measurement areas" (Pawlak ,r,r 53, 68, 77, Fig. 1).
14. Pawlak teaches "to immobilize the biological or biochemical or
synthetic recognition elements applied for the analyte detection at known,
but different local concentration in the measurement areas dedicated for
calibration purposes" in order to generate "a standard curve representing the
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binding activity and the multitude of binding events between an analyte and
its recognition elements by application of a single calibration solution on an
array with recognition elements provided at a different immobilization
density" (Pawlak i-fl03).
15. Lamont teaches "[ m ]ultiple ligands can be disposed on the
surface of the support, each one defining individual discrete test regions
(DTRs) of defined small volumes (pl or nl), permitting the simultaneous
multiplexed detection and quantitation of multiple analytes in one sample"
(Lamont 1 :23-26).
16. Lamont teaches:
[T]he realisation that an internal calibration system can be used
as part of a microarray to improve the accuracy of the detection
system. The internal calibration system enables the calibration
of an assay to be performed within one microarray while at the
same time determining the unknown concentration of a target
analyte in a sample.
(Lamont 2 :2---6).
17. Lamont teaches that the assay device comprises "a support
material compris[ing] an array of discrete first reaction sites, each reaction
site comprising an immobilised first analyte, or a molecule that has affinity
for the first analyte, and a series of second reaction sites with different
known concentrations of a second analyte" and that the "series of reaction
sites of different known concentrations allows a calibration curve to be
established, which can be used to quantify the reaction occurring on the first
reaction sites" (Lamont 2:7-13).
18. Lamont teaches that, "[p ]lacing the calibration control reaction
on the same support as used to detect the presence of a target analyte in a
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biological sample, reduces the need for separate supports and allows all
reactions to be initiated together" (Lamont 3: 8-11 ).
19. Lamont teaches "each of the reaction sites that make up the
calibration system are on the same support, and are not separated by walls or
barriers that prevent the sites being in contact with the same fluid sample"
(Lamont 5: 15-17) and further explains the "series of calibration reaction
sites will be located at a known position on the microarray device, usually in
one comer to allow easy identification" (Lamont 5 :25-26).
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 (Final Act. 2-9; Ans. 2-8; FF 1-19) and
agree that the claims are obvious over the cited prior art. We address
Appellants' arguments below.
Appellants separately argue the teachings of Bellet, Duveneck,
Pawlak, and Lamont (see App. Br. 6-7) and contend
[ t ]he references do not teach or suggest binding the first reagent
in the solution to the analyte in each of the calibration dots, and
binding the first binding reagent analyte complex in the solution
to the second reagent in the test dot in a single discrete fluid
flow of the sample solution.
(App. Br. 5; cf Reply Br. 2-3). (Emphasis omitted).
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Application 11/632,746
We find Appellants' argument unpersuasive because it fails to
recognize that the rejection is based on the combination of references, not
any single reference alone. In re Keller, 642 F.2d 413,426 (CCPA 1981).
Bellet teaches reverse sandwich assays that bind reagent-analyte complexes
to assay surfaces with capture reagents and calibration using "different,
predetermined amounts of antigen" (FF 1-5). While Bellet, as
acknowledged by the Examiner, does not teach the calibration dots in a
single fluid sample (see Ans. 2), Duveneck, Pawlak, and Lamont each teach
placing calibration reagents into the same fluid mixture as the analyte
reagent (FF 12, 13, and 16). Lamont further provides reasons to do so,
teaching it will "improve the accuracy of the detection system" (FF 16) and
"reduces the need for separate supports and allows all reactions to be
initiated together" (FF 18). Thus, the combination of prior art provides
specific reasons to combine the calibration and analyte dots in a single fluid
flow of the sample as required by claim 23 (see FF 1-18).
Indeed, the advantage identified by Appellants in their argument, that
"simultaneous binding of reagents to both the test dots and the calibration
dots in a single fluid flow ... allows for more reliable measurements with
less possibility of internal error due to differing conditions" (App. Br. 6) is
the same reason provided by Lamont, who teaches
the realisation that an internal calibration system can be used as
part of a microarray to improve the accuracy of the detection
system. The internal calibration system enables the calibration
of an assay to be performed within one microarray while at the
same time determining the unknown concentration of a target
analyte in a sample.
(FF 16). Duveneck similarly teaches benefits from the use of a "single,
common solution" including that, "impacts of variations between different
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carrier substrates on the [analysis] results are avoided" and that "the
simultaneous determination of a plurality of analytes or test of a plurality of
samples under identical conditions is enabled" (FF 7). Thus, the cited prior
art recognized the benefits of simultaneous binding included improved
accuracy with reduced impact of different conditions (FF 7, 16).
Appellants contend that the "references do not teach or suggest that
the test dot and the plurality of calibration dots are in fluid contact with each
other through the sample solution" (App. Br. 7-8; emphasis omitted).
Appellants contend, "that while Lamont teaches fluid communication
between the calibration dots, Lamont makes no teaching or suggestion that
the test dots are also in fluid communication with the calibration dots."
(Reply Br. 3).
We find these arguments unpersuasive because Lamont teaches "each
of the reaction sites that make up the calibration system are on the same
support, and are not separated by walls or barriers that prevent the sites
being in contact with the same fluid sample" (FF 19). Lamont further
explains the "series of calibration reaction sites will be located at a known
position on the microarray device, usually in one comer to allow easy
identification" (FF 19). Thus, Lamont reasonably suggests fluid contact
between the reaction sites for test analyte dots and calibration curve dots, all
located on the same microarray device (FF 19) for "simultaneous
multiplexed detection" (FF 15) to "improve the accuracy of the detection
system" (FF 16).
Appellants contend, "the Examiner has not identified any teaching or
suggestion in the references that the detection reagent should be present in
an amount that takes into consideration the amount of analyte in the single
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solution and the amount of analyte present in the calibration dots" (App. Br.
8). Appellants further contend, "none of the cited references teaches or
suggests that the amount of first reagent in the solution should be in excess
to the total amount of analyte present in the sample and the plurality of
calibration dots" (Reply Br. 6).
We find these arguments unpersuasive because we agree with the
Exmainer that "Bellet teaches that both the forward (5:38--42) and reverse
(6:6-7) sandwich immunoassays include a step of washing away 'unbound[]
labelled indicator antibody', which implies that the labelled indicator
antibody is present in excess, even after all antibody-antigen complexes in
the solution have formed" (Ans. 5---6). Bellet also specifically teaches "to
provide incubation conditions sufficient to bind as much hCG as possible"
(Bellet 6:41--42), thereby also suggesting the use of an excess of labeled
indicator antibody. Moreover, Lamont teaches removing unbound second
and third ligands, which are labeled antibodies (Lamont 2:24) thereby also
suggesting the use of excess labeled antibodies. Thus, the ordinary artisan,
interested in optimizing conditions to bind as much hCG as possible, would
have recognized that the use of excess labeling antibody in the first assay
step of the reverse sandwich assay would have allowed maximum hCG
binding.
Appellants contend,
As set forth in the Declaration of Peter Lea ( of record) those of
skill in the art have concluded that the subject matter of the
currently pending claims embodies unexpected results.
Specifically, Exhibits Band C note that the claimed subject
matter provides increased sensitivity. Further, Exhibits B and
D note that the claimed methods provide increased drug
tolerance.
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(App. Br. 9). Appellants similarly contend "the Declaration of Peter Lea ( of
record) [shows] those of skill in the art have adopted the subject matter of
the currently pending claims" (App. Br. 9).
While we have considered the Lea Declaration 6, we are not persuaded
that the recited secondary considerations, when considered with the prima
facie case of obviousness, are sufficient to render the claimed invention
nonobvious. In particular, we agree with the Examiner that because the SQI
immunoassay platform discussed in Exhibits A-E includes many elements
not recited in the claims, there is no clear nexus between the asserted
industry praise/unexpected results and the claim recitations (see Ans. 7). "A
nexus is required between the merits of the claimed invention and the
evidence offered, if that evidence is to be given substantial weight enroute to
conclusion on the obviousness issue." Stratoflex, Inc. v. Aeroquip Corp.,
713 F.2d 1530, 1539 (Fed. Cir. 1983). Similarly, unexpected results must be
"commensurate in scope with the degree of protection sought by the claimed
subject matter." In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
Here, to the extent that any results are unexpected, they are not
commensurate in scope with the very different recitations of claim 23 that do
not require an automated system (see Exhibit A 7 which states the "company
sells a range of platforms from a semi-automatic bench top system through
to a high throughput fully automated system" (Ex. A, 1181, col. 2). Exhibit
A does not indicate that the reverse sandwich assay on a single array itself
6 Declaration of Dr. Peter Lea, dated April 22, 2016.
7 Mora et al., Next Generation Ligand Binding Assays-Review of Emerging
Technologies' Capabilities to Enhance Throughput and Multiplexing, 16
AAPS J. 1175-84 (2014).
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incorporates any unexpected results nor does the reverse sandwich assay
itself receive praise. Similarly, the Lea Declaration does not identify any
specific teachings in Exhibits B-E suggesting that the reverse sandwich
assay on a single array, rather than the integrated high throughput system,
receives industry praise or demonstrates unexpected results.
We also note that this evidence, including the Lea Declaration itself,
does not compare any data with the closest prior art of Bellet or Lamont,
much less demonstrate any improvement that is associated with the reverse
sandwich assay or calibration curves rather than the unclaimed machinery
used to perform the assay with a high throughput. See 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.").
Conclusion of Law
(i) The evidence of record supports the Examiner's conclusion that
Bellet, Duveneck, Pawlak, and Lamont render claims 23 and 3 8 prima facie
obvious.
(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
In summary, we affirm the rejection of claim 23 under 35 U.S.C.
§ 103(a) as obvious over Bellet, Duveneck, Pawlak, and Lamont. Pursuant
to 37 C.F.R. § 4I.37(c)(l), we also affirm the rejection of claims 24--36 and
3 8 as obvious over Bellet, Duveneck, Pawlak, and Lamont as these claims
were not argued separately.
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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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