Ex Parte Lin et al

Board of Patent Appeals and Interferences

Jan 5, 2009

10163018 (B.P.A.I. Jan. 5, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MARIE LIN, TOM CHIA,
and CHIU CHIN CHANG
__________

Appeal 2008-4479
Application 10/163,018
Technology Center 1600
__________

Decided: January 5, 2009
__________

Before DEMETRA J. MILLS, RICHARD M. LEBOVITZ, and JEFFREY
N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
homogeneous analytical method to detect binding pair members. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse.

Appeal 2008-4479
Application 10/163,018

Statement of the Case
Background
“There are a number of occasions on which a sample, particularly a
sample of a biological fluid obtained from an individual, is to be screened
for the presence of one or more analytes, particularly one or more chemical
substances” (Spec. 1:15-17). The Specification notes that “[c]urrently such
screening is done by subjecting the sample to a series of individual tests for
each substance or family of substances whose presence is sought to be
determined. In such tests the predetermined (cutoff) minimum or maximum
level may well be different for each substance” (Spec. 2:10-13). According
to the Specification, “[i]t would be advantageous to have available a method
whereby a sample could be simultaneously screened for the presence of such
multiple analytes in a single assay” (Spec. 2:32-33).
The Claims
Claims 1-4, 6-16, and 31 are on appeal. We will focus on claim 1, the
only independent claim on appeal, which is representative and reads as
follows:

1. A method for detecting the presence of one or more
non-serologically cross-reactive analyte types in a sample
using a competitive homogeneous assay: where the assay
detects a plurality of different analyte types that are non-
serologically cross-reactive and, where the assay involves
analyte and receptor binding pairs such that the presence of
one or more different analyte types is determined by enzyme
activity reflecting the concentration of analyte when present
in excess of a predetermined concentration of the cutoff said
method comprising the steps of:
(I) combining in an aqueous medium:
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(a) glucose-6-phosphate dehydrogenase
(G6PDH) analyte binding pair member conjugates,
the conjugates comprised of G6PDH covalently
linked to a plurality of known analyte binding pair
members of which at least two are non-serologically
cross-reactive;
(b) receptors able to bind to each analyte type
to be detected and to the G6PDH-analyte binding pair
member conjugates; and,
(c) a sample to be tested for the presence of any
of the plurality of analyte types; and,
(II) detecting increased G6PDH activity in the
aqueous medium due to competitive binding of the receptors
with the analyte types in the sample where analyte types
bind receptors permitting the G6PDH-analyte binding pair
member conjugates to exhibit maximal enzyme activity;
wherein:
(iv) concentrations of G6PDH-analyte binding pair
member conjugates and of the receptors are adjusted in the
aqueous mixture so that the enzyme rate at the
predetermined cutoff concentrations is approximately the
same for the different analyte types whose presence is to be
detected;
(v) wherein the G6PDH is deactivated by from about
20% to about 85% resulting from the covalent linkage to the
analyte binding pair member; and
(vi)wherein the deactivated G6PDH is inhibited by
from about 20% to about 85% when bound to the receptors.

The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Rubenstein et al. U.S. 3,875,011 Apr. 1 1975
Jakobovits et al. U.S. 6,033,890 Mar. 7, 2000
Jakobovits et al. U.S. 6,090,567 Jul. 18, 2000

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Wei Huang et al, Homogeneous Bioluminescence Competitive Binding
Assay for Folate Based on a Coupled Glucose-6-phosphate Dehydrogenase-
Bacterial Luciferase Enzyme System, 68 ANALYTICAL CHEMISTRY 1646-
1650 (1996).

Hallowell et al, Enzyme-amplified receptor assay screening test for
chlorpromazine trifluoperazine and phencyclidine, 4 J. CLINICAL
LABORATORY ANALYSIS 64-73 (1990) – Abstract only.

The issues
A. The Examiner rejected claims 1, 6-16, and 31 under 35 U.S.C. §
103(a) as being obvious over Jakobovits ‘567, Jakobovits ‘890, and
Hallowell (Ans. 4-6).
B. The Examiner rejected claims 2 and 3 under 35 U.S.C. § 103(a) as
being obvious over Jakobovits ‘567, Jakobovits ‘890, Hallowell, and
Rubenstein (Ans. 7-8).
C. The Examiner rejected claim 4 under 35 U.S.C. § 103(a) as being
obvious over Jakobovits ‘567, Jakobovits ‘890, Hallowell, and Huang (Ans.
8-9).
A. 35 U.S.C. § 103(a) as over Jakobovits ‘567, Jakobovits ‘890, and
Hallowell
The Examiner rejected claims 1, 6-16, and 31 under 35 U.S.C. §
103(a) as being obvious over Jakobovits ‘567, Jakobovits ‘890, and
Hallowell (Ans. 4-6).
The Examiner finds that the “Jakobovits et al. (U.S. Patent
#6,090,567) teach an assay procedure to detect analytes with a glucose-6-
phosphate dehydrogenase enzyme” (Ans. 4). The Examiner further finds
that Jakobovits differs “from the instant invention in not specifically
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teaching an adjustment to the enzyme rate according to a predetermined
cutoff concentration for the different analyte types of interest” (id. at 5). The
Examiner finds that Hallowell teaches “calibration curves (predetermined
concentrations) with detection limits at n[a]nomolar levels of drug” (id. at
6).
The Examiner also finds that “the reagents and assays were merely
combined by Appellant in order to simultaneously access the analyte(s) of
interest” (id. at 10). The Examiner finds that “the claims read on single
analyte measurement” (id.).
Appellants contend that
Hallowell, like Jakobovits, describes three separate assays
for detecting drugs that bind to the acetylcholine receptor
but does not suggest combining the three different
drug:enzyme conjugates into a single assay mixture . . .
None of the cited prior art suggests combining different
analyte detecting reagents because such a combination of
reagents defeats the essential purpose of the prior art assays,
i.e., to inform the user whether a specific analyte is present
or not in a sample.

(App. Br. 9.)
Appellants contend that their assay “permit[s] the detection of any one
of a group of analytes at a predetermined cutoff concentration providing a
uniform signal” (Reply Br. 4). Appellants further contend that a “plurality
of conjugates with non-serologically cross-reactive analytes clearly requires
more than one conjugate type” (Reply Br. 5).
In view of these conflicting positions, we frame the obviousness issue
before us as follows:
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Did the Examiner err in finding that Hallowell and the two Jakobovits
patents teach an assay with glucose-6-phosphate dehydrogenase conjugates
“linked to a plurality of known analyte binding pair members of which at
least two are non-serologically cross-reactive”?
Findings of Fact (FF)
1. Jakobovits ‘5671 teaches “methods for homogenous
immunoassay of an analyte in a sample suspected of containing the analyte”
(Jakobovits ‘567, col. 4, ll. 5-7).
2. Jakobovits ‘567 teaches “combining in a liquid medium: (a) the
sample to be assayed, (b) a conjugate of (i) an analyte analog and (ii) a
mutant NAD+ dependent G6PDH [glucose-6-phosphate dehydrogenase]. . .
(c) a receptor for the analyte, and (d) substrates for the G6PDH” (Jakobovits
‘567, col. 4, ll. 8-13).
3. Jakobovits ‘567 teaches “determining the enzymatic activity of
the G6PDH in the medium; and . . . comparing the enzymatic activity to the
enzymatic activity observed with a sample containing the analyte”
(Jakobovits ‘567, col. 4, ll. 14-17).
4. Jakobovits ‘567 teaches that “[t]ypically, the mutant G6PDH is
conjugated to an sbp [specific binding pair] member analogous to the
analyte” (Jakobovits ‘567, col. 9, ll. 66-67).

1 Jakobovits ‘567 and Jakobovits ‘890 share identical specifications and
disclosures since both patents are divisional applications of U.S. patent
application 08/044,857 (see Jakobovits ‘567, Related U.S. Application
Data).

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5. The Examiner found that Jakobovits ‘567 teaches that in
“example III, the enzymatic activity was monitored by determining
maximum inhibition with a rabbit antidigoxin antiserum . . . [t]he desired
end point was 50-70% maximum inhibition . . . [t]he final % of deactivation
ranged from 26-40” (Ans. 4).
6. Hallowell teaches a G6PDH immunoassay procedure which
“yields calibration curves with detection limits at n[a]nomolar levels of drug,
with binding responses dependent on the amounts of receptor and enzyme-
labeled drug used” (Hallowell, abstract).
Principles of Law
Claim terms are interpreted using the broadest reasonable
interpretation in light of the Specification. See, e.g., In re Hyatt, 211 F.3d
1367, 1372 (Fed. Cir. 2000) (“[D]uring examination proceedings, claims are
given their broadest reasonable interpretation consistent with the
specification.”). Also see In re Morris, 127 F.3d 1048, 1054-56 (Fed. Cir.
1997). (“Absent an express definition in their specification, the fact that
appellants can point to definitions or usages that conform to their
interpretation does not make the PTO's definition unreasonable when the
PTO can point to other sources that support its interpretation.”).
In KSR, the Supreme Court rejected the rigid application of the
teaching, suggestion, and motivation test by the Federal Circuit, stating that
The principles underlying [earlier] cases are
instructive when the question is whether a patent claiming
the combination of elements of prior art is obvious. When a
work is available in one field of endeavor, design incentives
and other market forces can prompt variations of it, either in
the same field or a different one. If a person of ordinary skill
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can implement a predictable variation, § 103 likely bars its
patentability.

KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1740 (2007).
Analysis
In analyzing claim 1, our mandate is to give the terms in a claim their
broadest reasonable interpretation. See, e.g., In re Hyatt, 211 F.3d at 1372.
Claim 1 expressly teaches a method whose first step requires
combining in a medium G6PDH analyte binding pair member conjugates
which are “covalently linked to a plurality of known analyte binding pair
members of which at least two are non-serologically cross-reactive” (Claim
1).
The broadest reasonable interpretation of the word “plurality” is more
than one. The claim further clarifies that the claim does not read on multiple
molecules of a single type of analyte binding pair members by requiring that
“at least two [members] are non-serologically cross-reactive.”
Thus, the broadest reasonable interpretation of claim 1 is that in the
medium for detecting the analyte, there are at least two different binding pair
members which bind to different analytes. These two different binding pair
members must both be conjugated to the same enzymatic label, G6PDH.
While the Examiner has found that the prior art of Jakobovits ‘567,
Jakobovits ‘890, and Hallowell teach the remaining limitations of claim 1
(see FF 1-6), the Examiner failed to find a teaching or suggestion for two
serologically different binding pair members both conjugated to G6PDH and
both present in the aqueous medium for analysis (see Ans. 4-5).
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The Examiner contends that “that “the claims read on single analyte
measurement” (Ans. 10). The Examiner states that because claim 1 “recites
‘the presence of one or more different analyte types is determined’ . . . the
claims read on single analyte determination” (Ans. 11).
While claim 1 may encompass the situation where only a single
analyte is detected, claim 1 expressly requires that in the aqueous medium of
the assay contains “at least two [members, which] are non-serologically
cross-reactive” (Claim 1, step I (a)). None of Jakobovits ‘567, Jakobovits
‘890, and Hallowell teach or suggest putting two different binding pair
members simultaneously into an aqueous medium for analyte detection.
The Examiner contends that “a long line of cases have held that the
mere use of different starting materials, whether novel or known, in a
conventional process to produce the product one would expect therefrom
does not render the process unobvious” (Ans. 10). First, the Examiner
should reread Ochiai, which reversed the rejection of “Ochiai's claims,
limited as they are to the use of a particular nonobvious starting material for
making a particular nonobvious end product” In re Ochiai, 71 F.3d 1565,
1572 (Fed. Cir. 1995). The Examiner may also wish to reread 35 U.S.C. §
103(b), which states that “a biotechnological process using or resulting in a
composition of matter that is novel under section 102 and nonobvious under
subsection (a) of this section shall be considered nonobvious” with two
conditions.
Second, even in the cases of known starting materials, the mere use of
a conventional process does not necessarily result in a conclusion of
obviousness. In the instant case, it is necessary to apply the appropriate test
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for obviousness established by Graham v. John Deere Co., 383 U.S. 1
(1966). When comparing the differences between the prior art and claim 1
at issue, the only reasonable conclusion that can be drawn is that Jakobovits
‘567, Jakobovits ‘890, and Hallowell do not teach or suggest multiplexing
the immunoassay as required by claim 1 to include two non-serologically
cross-reactive analyte binding pair members both conjugated to G6PDH.
The Examiner has not satisfied the burden of providing evidence that the
prior art described a multiplicity of analytes in a single reaction.
KSR teaches that an invention “composed of several elements is not
proved obvious merely by demonstrating that each of its elements was,
independently, known in the prior art.” KSR, 127 S. Ct. at 1741. There must
be “a reason that would have prompted a person of ordinary skill in the
relevant field to combine the elements in the way the claimed new invention
does.” Id. at 1741. The Examiner has provided no such reason to place two
non-serologically cross-reactive analyte binding pair members both
conjugated to G6PDH in a single aqueous medium in the rejection.
We do not address the obviousness of cutoff concentrations for
multiple different analytes in a single aqueous medium, as required by claim
1, because the Examiner has not provided a prima facie case of obviousness
regarding the multiplex analysis required by claim 1.
Regarding potential future prosecution, we caution that merely finding
an evidentiary reference teaching multiplex analysis of different analytes
may not be sufficient to render claim 1 prima facie obvious. The ordinary
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multiplex reference either uses different labels2 or separates the analyte
complexes of the different binding pair members.3 Claim 1 requires that a
single G6PDH label is linked to the multiple different binding pair members
and that the detection occurs in the aqueous medium without a separation
step. The Examiner has failed to provide any evidence which demonstrates
these elements of claim 1 in the currently cited prior art and these elements
would be required to evidence a proper case of prima facie obviousness.
Conclusions of Law
The Examiner erred in finding that Hallowell and the two Jakobovits
patents teach an assay with G6PDH conjugates “linked to a plurality of
known analyte binding pair members of which at least two are non-
serologically cross-reactive.”

2 See, e.g., Nelson et al, U.S. Patent 5,756,709, May 26, 1998, cited
in Appellants’ IDS of Sep. 30, 2002 which teaches a multiplex
assay with “different chemiluminescent labeling reagents”
(Nelson, abstract).
3 See, e.g., Chen, U.S. Patent 5,863,401, Jan. 26, 1999, cited in
Appellants’ IDS of Sep. 30, 2002 which teaches a multiplex assay
with a single label but requires that “[f]ollowing the competitive
binding reaction the antibody –labeled analyte complexes are
separated from the labeled analytes by CE [capillary
electrophoresis] techniques and detected with laser induced
fluorescence” (Chen, col. 8, ll. 17-20).
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B. 35 U.S.C. § 103(a) as over Jakobovits ‘567, Jakobovits ‘890,
Hallowell, and Rubenstein
The Examiner rejected claims 2 and 3 under 35 U.S.C. § 103(a) as
being obvious over Jakobovits ‘567, Jakobovits ‘890, Hallowell, and
Rubenstein (Ans. 7-8).
The Examiner finds that
It would have been obvious to one of ordinary skill in
the art at the time the invention was made to use conjugates
comprising a plurality of analyte types linked to G6PDH as
taught by Rubenstein et al. in the enzyme procedures of
Jakobovits et al. (U.S.Patent #6,090,567) or Jakobovits et al.
(U.S.Patent #6,033,890) in view of Hallowell et al. because
Rubenstein et al. taught that the use of glucose-6-phosphate
dehydrogenase as an enzyme conjugate provides selective
and sensitive tests for a wide variety of different drugs
having widely varying structures.

(Ans. 8.)
Appellants contend that “[c]laims 2-4 depend from claim 1 and are
rejected as obvious over Jakobovitz and Hallowell in combination with
additional prior art. If claim 1 is deemed patentable, all the pending claims
should be considered patentable” (App. Br. 4).
We found that the rejection of claim 1 was in error as discussed
above.
Therefore, we frame the obviousness issue before us as follows:
Did the Examiner err in finding that the teaching of Rubenstein, in
addition to the teachings of Hallowell and the Jakobovits patents, taught
multiple different analyte binding pairs as required by claim 1?
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Findings of Fact
7. Rubenstein teaches “[h]aptenic conjugates to glucose-6-
phosphate dehydrogenase are provided for employment in homogenous
enzyme immunoassays to provide high sensitivity in detecting extremely
small amounts of organic materials” (Rubenstein, col. 2, ll. 5-9).
8. Rubenstein teaches in analyzing for the presence of a
compound that “the appropriate enzyme conjugate was added which had
sufficient enzyme to provide an activity in the absence of antibody”
(Rubenstein, col. 21, ll. 16-18).
Analysis
While Rubenstein teaches the analysis of multiple different analytes
(FF 7-8), the Examiner does not identify any teaching in Rubenstein for
combining in an medium G6PDH analyte binding pair member conjugates
which are “covalently linked to a plurality of known analyte binding pair
members of which at least two are non-serologically cross-reactive” (Claim
1).
KSR teaches that an invention “composed of several elements is not
proved obvious merely by demonstrating that each of its elements was,
independently, known in the prior art.” KSR, 127 S. Ct. at 1741. There must
be “a reason that would have prompted a person of ordinary skill in the
relevant field to combine the elements in the way the claimed new invention
does.” Id. at 1741. The Examiner has provided no such reason to place two
non-serologically cross-reactive analyte binding pair members both
conjugated to G6PDH in a single aqueous medium in the rejection further
comprising Rubenstein.
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Conclusions of Law
The Examiner erred in finding that the teaching of Rubenstein, in
addition to the teachings of Hallowell and the Jakobovits patents, taught
multiple different analyte binding pairs as required by claim 1.
C. 35 U.S.C. § 103(a) as over Jakobovits ‘567, Jakobovits ‘890,
Hallowell, and Huang
The Examiner rejected claim 4 under 35 U.S.C. § 103(a) as being
obvious over Jakobovits ‘567, Jakobovits ‘890, Hallowell, and Huang (Ans.
8-9).
We reversed the rejection of claim 1 over Jakobovits ‘567, Jakobovits
‘890, and Hallowell as discussed above. Since Huang does not supplement
the deficiencies in that rejection, we are also compelled to reverse the
rejection of claim 4 as well.
SUMMARY
In summary, we reverse the rejections of claims 1-4, 6-16, and 31
under 35 U.S.C. § 103(a).
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

REVERSED

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