Ex Parte Lazar

Board of Patent Appeals and Interferences

Mar 23, 2011

10098851 (B.P.A.I. Mar. 23, 2011)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
10/098,851 03/15/2002 James G. Lazar 38521.00500US 3074
38647 7590 09/21/2011
MILBANK, TWEED, HADLEY & MCCLOY LLP
INTERNATIONAL SQUARE BUILDING
1850 K STRET, N.W., SUITE 1100
WASHINGTON, DC 20006
EXAMINER
JUNG, UNSU
ART UNIT PAPER NUMBER
3768
MAIL DATE DELIVERY MODE
09/21/2011 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte JAMES G. LAZAR
__________

Appeal 2010-008406
Application 10/098,851
Technology Center 1600
__________

Before DEMETRA J. MILLS, FRANCISCO C. PRATS, and MELANIE L.
McCOLLUM, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a signal
amplification method. The Examiner has rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
Claims 1, 2, 6-8, 12-18, 21-23, and 47 are pending (App. Br. 2). The
claims subject to each rejection have not been argued separately and
therefore stand or fall together. 37 C.F.R. § 41.37(c)(1)(vii). We will focus
on claim 1, which reads as follows:
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1. A method of signal amplification for detection of a target analyte
comprising:
(a) reacting a target analyte with a conjugated antibody, wherein said
antibody is conjugated to a binding molecule, and said antibody is
reactive with the target analyte, thereby forming an antibody complex;
(b) reacting the binding molecule of the antibody complex with a
conjugated binding partner, forming a binding pair, wherein said
binding partner is conjugated to a reagent; and
(c) reacting a detectably-labeled reagent-specific binding entity with
the reagent of the binding pair to form a detectable complex,
wherein detection of the complex provides signal amplification.
Claims 1, 6, 12, 13, 17, 18, 21, 22, and 47 stand rejected under 35
U.S.C. § 103(a) as obvious over Martinelli1 in view of Lazar2 (Ans. 4).
Claims 2, 7, and 8 stand rejected under 35 U.S.C. § 103(a) as obvious
over Martinelli in view of Lazar and Wogoman3 (Ans. 7).
Claim 14 stands rejected under 35 U.S.C. § 103(a) as obvious over
Martinelli in view of Lazar and Mantero4 (Ans. 8).
Claims 15 and 16 stand rejected under 35 U.S.C. § 103(a) as obvious
over Martinelli in view of Lazar and Chiswell5 (Ans. 9-10).
Claim 23 stands rejected under 35 U.S.C. § 103(a) as obvious over
Martinelli in view of Lazar and Wagner6 (Ans. 11).

1 Martinelli et al., US 6,083,689, Jul. 4, 2000.
2 Lazar et al., Hybrid Capture®: A Sensitive Signal Amplification-based
Chemiluminescent Test for the Detection and Quantitation of Human Viral
and Bacterial Pathogens, 22 J. CLIN. LIGAND ASSAY 139-151 (1999).
3 Wogoman, US 4,990,075, Feb. 5, 1991.
4 Mantero et al., DNA Enzyme Immunoassay: General Method for Detecting
Products of Polymerase Chain Reaction, 37 CLIN. CHEM. 422-429 (1991).
5 Chiswell, US 4,716,106, Dec. 29, 1987.
6 Wagner et al., US 5,079,150, Jan. 7, 1992.
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Appellant argues:
The rejection of all of the pending claims is erroneous for the
following reasons . . . : (i) the proposed modification of the
Martinelli reference (adding the “universal nucleic acid
detection” technology of Lazar) impermissibly changes the
principle of operation of both the Martinelli and Lazar methods;
(ii) the Examiner has not provided a valid reason to explain
why one of ordinary skill in the art would have made the
Examiner’s proposed combination; (iii) the Examiner’s
conclusion of obviousness is based on impermissible hindsight
reconstruction; and (iv) the references, read as a whole, teach
away from making the combination.
(App. Br. 15.)
ISSUE
Does a preponderance of the evidence support the Examiner’s
combination of Martinelli and Lazar?
FINDINGS OF FACT
1. Martinelli discloses “immunoassay methods that use an
antibody-variant DNA conjugate as a tracer antibody, wherein the variant
DNA is a substrate for an RNA-dependent RNA polymerase (Martinelli,
col. 2, ll. 31-35).
2. Martinelli also discloses that the “antibody of the conjugate can
be directed to either analyte under assay or to an anti-analyte antibody used
in an immunoassay” (id. at col. 2, ll. 38-40).
3. In addition, Martinelli discloses that, “[a]fter incubation and
separation of unbound antibody-variant DNA conjugate from that bound to
the analyte under assay, the variant DNA template, bound to the analyte, is
transcribed, and the RNA transcript is replicated by contact with an
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appropriate amount of an RNA-dependent RNA polymerase, whose
substrate is the variant DNA” (id. at col. 2, ll. 40-46).
4. Martinelli also discloses that the “detection of RNA replication
products produced in the assay, indicates the presence of the analyte under
assay” (id. at col. 2, ll. 47-48).
5. In addition, Martinelli discloses:
Another embodiment wherein the antibody-variant DNA
conjugate can be considered to be a universal type of
immunoassay reagent is that wherein the variant DNA is linked
to avidin, and biotinylated anti-analyte antibodies are used. In
that embodiment, the universal immunoassay reagent is actually
the variant DNA linked to avidin, preferably the variant DNA
linked to streptavidin. The variant DNA-antibody conjugate in
that embodiment is prepared during the immunoassay
procedure.
(Id. at col. 8, ll. 43-52.)
6. Lazar discloses that “Hybrid Capture® is a universal nucleic
acid detection technology that utilizes long genomic probes and antibodies
specific for RNA:DNA hybrids to achieve a high level of signal
amplification by virtue of the fact that each copy of target can bind hundreds
or thousands of enzyme labels” (Lazar 139).
7. In particular, Lazar discloses:
Specimen DNA is denatured and then hybridized in solution to
genomic RNA probes forming RNA:DNA hybrids. Hybrids are
captured onto an antibody-coated solid phase and reacted with
an alkaline phosphatase-labeled conjugate. The alkaline
phosphatase acts upon a dioxetane substrate to generate light
that is measured in a luminometer.
(Id. at 140 (italics omitted).)
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8. In addition, Lazar discloses:
Target amplification protocols increase the total number of
nucleic acid molecules, thus permitting the use of less sensitive
signal detection methods. Though amplification techniques
such as the polymerase chain reaction (PCR) and ligase chain
reaction (LCR) are remarkably sensitive, extreme care must be
taken to avoid cross-contamination during sample processing.
In addition, quantitation of the original target is a challenge for
the user and is usually accomplished by the inclusion of
multiple internal and external controls. Some steps involved in
target amplification have unascertained or variable efficiencies,
especially in·the presence of crude clinical material, making it
difficult to accurately correlate the final copy numbers to the
original amounts of target.
(Id. at 139.)
9. In contrast, Lazar discloses:
Signal amplification methods increase the signal of the system
without changing the total number of target molecules. In
methods involving signal amplification, the nucleic acid of
interest is measured directly, and the resulting signal is directly
proportional to the concentration of the specific nucleic acid in
the sample. This type of direct detection method does not
require complex enzymatic reactions, and therefore, accurate
quantitation is preserved in the presence of relatively crude
specimens.
(Id.)
PRINCIPLES OF LAW
Obviousness “analysis need not seek out precise teachings directed to
the specific subject matter of the challenged claim.” KSR Int’l v. Teleflex
Inc., 550 U.S. 398, 418 (2007). Instead, it proper to “take account of the
inferences and creative steps that a person of ordinary skill in the art would
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employ.” Id. “A person of ordinary skill is also a person of ordinary
creativity, not an automaton.” Id. at 421.
A reference may be said to teach away when a person of
ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference, or
would be led in a direction divergent from the path that was
taken by the applicant. The degree of teaching away will of
course depend on the particular facts; in general, a reference
will teach away if it suggests that the line of development
flowing from the reference’s disclosure is unlikely to be
productive of the result sought by the applicant.
In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
ANALYSIS
Martinelli discloses a method for detection of a target analyte
comprising: reacting a target analyte with a conjugated antibody, wherein
said antibody is conjugated to a binding molecule (biotin), and said antibody
is reactive with the target analyte, thereby forming an antibody complex; and
reacting the binding molecule of the antibody complex with a conjugated
binding partner (avidin), forming a binding pair, wherein said binding
partner is conjugated to a reagent (variant DNA) (Findings of Fact (FF) 1-5).
Lazar discloses reacting a detectably-labeled reagent-specific binding entity
(alkaline phosphatase-labeled conjugate) with a reagent (RNA:DNA
hybrids) to form a detectable complex, wherein detection of the complex
provides signal amplification (FF 6-7). For the reasons discussed below, we
conclude that it would have been obvious to combine these teachings to
provide the method of claim 1.
As noted by the Examiner, Lazar teaches that signal amplification
methods are advantageous because they “increase the signal of the system
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without changing the total number of target molecules,” “the resulting signal
is directly proportional to the concentration of the specific nucleic acid in the
sample,” and they do “not require complex enzymatic reactions, and
therefore, accurate quantitation is preserved in the presence of relatively
crude specimens” (FF 8-9). In view of these teachings, we agree with the
Examiner that it would have been obvious “to employ the universal nucleic
acid detection technology of Lazar . . . in the method of Martinelli et al. in
order to . . . increas[e] the signal of the resulting complex in the binding
assay of Martinelli et al. without changing the total number of target
molecules” (Ans. 6). In addition, we agree that,
[w]hile the RNA transcription amplification method of
Martinelli et al. may provide exponential signal production, the
detection method of forming DNA:RNA hybrids followed by
the use of specific antibodies against the hybrids has a further
advantage of being simple compared to the more complicated
process of facilitating RNA transcripts, which involve complex
enzymatic reactions.
(Id. at 21.) Thus, we do not agree with Appellant that “the Examiner has not
provided a valid reason to explain why one of ordinary skill in the art would
have made the Examiner’s proposed combination” (App. Br. 15).
For substantially the same reasons, we also do not agree with
Appellant that “the Examiner’s conclusion of obviousness is based on
impermissible hindsight reconstruction” (id.). In this regard, Appellant
argues that “the only reason to employ a ‘binding pair’ comprising the
‘binding molecule’ and its reagent-conjugate ‘binding partner’ is found in
the instant specification” (id. at 26). We do not agree. Instead, Martinelli
provides the reason to employ a “binding pair” comprising the “binding
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molecule,” biotin, and its “binding partner,” avidin, that is, to form “a
universal type of immunoassay reagent” (FF 5). As indicated by the
Supreme Court, “any need or problem known in the field of endeavor at the
time of invention and addressed by the patent can provide a reason for
combining the elements in the manner claimed.” KSR Int’l Co. v. Teleflex
Inc., 550 U.S. at 420.
In addition, we do not agree with Appellant that “the references, read
as a whole, teach away from making the combination” (App. Br. 15).
Martinelli may well be “unequivocally focused on signal amplification by
enzyme-based systems, using replicable DNA templates, to enhance the
sensitivities of immunoassays” (id. at 28-29). However, Lazar teaches
advantages of its amplification technique (FF 9). Appellant has not
adequately explained why Martinelli’s teaching of a particular amplification
method would discourage one of ordinary skill in the art from using Lazar’s
amplification method. Even if using Lazar’s amplification method would
result in less amplification than Martinelli’s method, Lazar’s amplification
method “does not require complex enzymatic reactions” and “accurate
quantitation is preserved” (FF 9). “The fact that the motivating benefit
comes at the expense of another benefit . . . should not nullify its use as a
basis to modify the disclosure of one reference with the teachings of another.
Instead, the benefits, both lost and gained, should be weighed against one
another.” Medichem S.A. v. Rolabo S.L., 437 F.3d 1157, 1165 (Fed. Cir.
2006). In the present case, Appellant has not provided sufficient evidence to
demonstrate that any loss in the amount of signal amplification would cause
one of ordinary skill in the art to avoid the claimed combination.
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Furthermore, we do not agree with Appellant that “the proposed
modification of the Martinelli reference . . . impermissibly changes the
principle of operation of both the Martinelli and Lazar methods” (App.
Br. 15). In particular, we do not agree that the Examiner’s combination is
either using Martinelli’s variant DNA itself to form RNA:DNA hybrids
(Reply Br. 3-5) or bodily incorporating Lazar’s genomic DNA into
Martinelli’s conjugate (App. Br. 16-20). Both approaches seem to treat the
skilled artisan as an automaton. Instead, we conclude that, based on the
teachings in Lazar, one of ordinary skill in the art would have used an
appropriately sized DNA in forming Martinelli’s conjugate, such that an
RNA:DNA hybrid thereof would react with a sufficient number of Lazar’s
labels to provide sufficient signal amplification.
CONCLUSION
The evidence supports the Examiner’s combination of Martinelli and
Lazar. We therefore affirm the obviousness rejection of claim 1. Claims 6,
12, 13, 17, 18, 21, 22, and 47 fall with claim 1. 37 C.F.R. § 41.37(c)(1)(vii).
In rejecting claims 2, 7, 8, 14-16, and 23, the Examiner additionally
relies on Wogoman, Mantero, Chiswell, or Wagner (Ans. 7-12). Appellant
does not point out any deficiencies in the Examiner’s reliance on these
references. Thus, having found no deficiencies in the combination of
Martinelli and Lazar, we affirm the obviousness rejections of claims 2, 7, 8,
14-16, and 23 for the reasons stated in the Examiner’s Answer.
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TIME PERIOD FOR RESPONSE
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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