Ex Parte Rabbani et al

Patent Trial and Appeal Board

Jun 17, 2016

10693481 (P.T.A.B. Jun. 17, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/693,481 10/24/2003
28171 7590 06/20/2016
ENZO BIOCHEM, INC.
Donna M. Tirella
527 MADISON A VENUE (9TH FLOOR)
NEW YORK, NY 10022
FIRST NAMED INVENTOR
Elazar Rabbani
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.
ENZ-60(CIP) 2531
EXAMINER
BERTAGNA, ANGELA MARIE
ART UNIT PAPER NUMBER
1637
MAILDATE DELIVERY MODE
06/20/2016 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 PATENT TRIAL AND APPEAL BOARD
Ex parte ELAZAR RABBANI, JANNIS G. STA VRIANOPOULOS,
JAMES J. DONEGAN, and JACK COLEMAN1
Appeal2013-007752
Application 10/693,481
Technology Center 1600
Before LORA M. GREEN, JOHN G. NEW, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 251-287.2 Specifically, claims 251,
252, 254, 256, 259-264, 269-273, 275, 281 and 284--287 stand rejected as
unpatentable under 35 U.S.C. § 103(a) as being obvious over the
combination of Lin et al. (US 6,197,554 Bl, March 6, 2001) ("Lin"),
1 Appellants state the real party-in-interest is Enzo Life Sciences, Inc. App.
Br. 2.
2 Claims 1-250 and 288---626 are canceled. App. Br. 4.
Appeal2013-007752
Application 10/693,481
Douglas Kyung Nam et al., Oligo(dT) Primer Generates a High Frequency
of Truncated cDNAs through Internal poly( A) Priming during Reverse
Transcription, 99(9) PNAS 6152---6156 (2002) ("Nam"), and Laird et al. (EP
1 201 768 A2, May 2, 2002) ("Laird").
Claims 253, 255, 257, and 258 stand rejected as unpatentable under 35
U.S.C. § 103(a) as being obvious over the combination of Lin, Nam, Laird,
and Kustu et al. (US 6,242, 189 B 1, June 5, 2001) ("Kustu").
Claims 265-268 stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Lin, Nam, Laird, and
Willis et al. (US 6,858,412 B2, February 22, 2005) ("Willis").
Claims 274 and 276 stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Lin, Nam, Laird, and
Sousa et al. (US 5,849,546, December 5, 1998) ("Sousa").
Claims 277, 278, and 280 stand rejected as unpatentable under 35
U.S.C. § 103(a) as being obvious over the combination of Lin, Nam, Laird,
and David L. Steffens et al., An Infrared Fluorescent dATP for
Labeling DNA, 5 GENOME RES. 393-399 (1995) ("Steffens").
Claim 279 stands rejected as unpatentable under 35 U.S.C. § 103(a) as
being obvious over the combination of Lin, Nam, Laird, Sousa, and Steffens.
Claims 282 and 283 stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Lin, Nam, Laird, and
Timothy Stinear et al., Detection of a Single Viable Cryptosporidium
parvum Oocyst in Environmental Water Concentrates by Reverse
Transcription-PCR, 62(9) APPLIED AND ENVIRON. MICROBIO. 3385-90
(1996) ("Stinear").
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We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' claimed invention is directed to compositions and
methods for controlling the extendability of various components used in
copying or amplification steps to provide an enhancement of the specificity
of the nucleic acids produced by these processes as well as potentially
increasing the amount of such products. Abstract.
REPRESENTATIVE CLAIM
Claim 251 is representative of the claims on appeal and recites:
251. A method for synthesizing one or more copies of a library
of nucleic acid targets that comprises the steps of:
a) providing:
(i) a library of nucleic acid targets;
(ii) primers or nucleic acid constructs compnsmg
sequences complementary to homopolymeric sequences in said
library of nucleic acid targets wherein said primers or nucleic
acid constructs comprise one or more terminal nucleotides at
their 3 ' ends, wherein said terminal nucleotides comprise
nucleotide analogues with substitutions on the 2' position of the
ribose ring;
(iii) synthesizing reagents for the synthesis of a nucleic
acid copy; and
(iv) addition reagents for the addition of a non-inherent
Universal Detection Target (UDT);
b) annealing said primers or nucleic acid constructs to said
homopolymeric sequences in said library of nucleic acid targets;
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c) extending the annealed primers or nucleic acid constructs
using said synthesizing reagents for the synthesis of at least one
nucleic acid copy of said library of nucleic acid targets; and
d) adding a non-inherent UDT to said extended primers or
said extended nucleic acid constructs.
App. Br. 21.
ISSUES AND ANALYSES
We agree with, and adopt, the Examiner's findings and conclusion
that the appealed claims are prima facie obvious over the cited prior art
references. We address the arguments raised by Appellants on appeal
below.
Claims 251, 252, 254, 256, 259-264, 269-273, 275, 281, and 284--
287
Issue
Appellants argue that there would be no reason for a person of
ordinary skill to combine the teachings of the combined cited prior art
references. App. Br 12.
Analysis
Appellants note the Examiner's findings that Lin teaches all elements
of claim 251 except "that the primers contain 3' terminal nucleotides that are
substituted with nucleotide analogues having a modification at the 2'
position of the ribose ring," and further note the Examiner finds "Lin also
does not teach the use of chimeric primers." App. Br. 10 (citing Final Act.
at 7). Appellants assert Laird is cited by the Examiner as teaching "methods
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for conducting PCR amplification using modified primers" including 2 '-0-
methylnucleotides, 2 '-fluoro-nucleotides, and 2 '-amino-nucleotides. Id.
(citing Final Act. 7-8). Finally, Appellants point out the Examiner relies
upon Nam as providing motivation to combine Lin and Laird to apply the
modified primers of Laird to the primers of Lin by teaching that: "oligo ( dT)
primers which were used in the method of Lin, could produce spurious
truncated amplification products during reverse transcription reactions due
to their ability to hybridize to internal poly A sequences contained in the
mRNA template in addition to the poly A tail of the mRNA template." Id.
(citing Final Act. 8).
According to Appellants, their Specification discloses:
Nucleotide analogues at the 3 ' end of primers have been
disclosed recently [by Laird] to increase discrimination between
target sequences and non-target sequences. However, in the
present invention, for library amplification where common
sequences of a library of multiple species of nucleic acids are the
targets for primer binding, this discrimination is not as relevant
and the dual properties of a) discrimination between extended
and unextended primers and b) increased synthesis of a library,
are the beneficial effects that are sought after and achieved by the
use of the nucleotide analogues at the 3' end of primers.
App. Br. 11 (quoting Spec. 17-18) (emphasis omitted). Appellants therefore
contend the problem of specificity that is solved by Laird does not offer any
particular advantages for the Lin method, where there is universal
amplification of any and all sequences having a poly-A tail. Id. at 10-11.
Consequently, Appellants argue, a person of ordinary skill would have
no reason to utilize the Laird primer design with the method of Lin, even
when the teachings of Lin and Nam are combined, because the problems
identified in Laird, primer-dimer formation and spurious expression results
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derived from priming at inappropriate sequences, are not problems
addressed in the teachings of Lin. App. Br. 12. Appellants assert that it is
only in their Specification that particular benefits are shown to be endowed
to a universal RNA amplification system for expression analysis by the
presence of nucleotide analogues at the 3 ' end of primers. Id. Therefore,
Appellants argue, a person of ordinary skill in the art would not be
motivated to combine the cited references.
Appellants contend further that they have discovered that the use of
modified nucleotides at the 3 ' terminus of primers can reduce the aberrant
forms of nucleic acid synthesis quoted in their Specification supra. App. Br.
13. Appellants argue these effects are not related to inappropriate extension
reactions, which is the heart of the advantages described by Laird for
application of modified primers in PCR. Id. Appellants consequently
dispute the Examiner's conclusion that "it is prima facie obvious to apply
known methods to a similar method to improve the method in the same way"
and argue it is inappropriate, since the application of modified primers in the
present invention does not "improve the method in the same way" described
by Laird. Id.
Appellants elaborate upon their arguments, pointing to use of
modified primers in Examples 1, 4, 5, and 7 of Laird, in which the
annealing/ extension step at 65 °C lasts for 40 seconds before the denaturation
step at 95°C in Examples 1, 4 and 5, and for 60 seconds in Example 7. App.
Br. 14. Appellants argue that, with inappropriate bindings slowed down by
the use of modified primers, a skilled artisan would understand that a PCR
cycle would be ended before an inappropriate extension could take place.
Id.
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Therefore, argue Appellants, in using the modified primers in a
succession of cycles, each cycle with an internal poly A sequence would
likely end before non-target extensions can accumulate. Id. However,
contend Appellants, this kinetic rationale for the use of modified primers in
Laird does not apply to the essentially isothermal reaction described in Lin,
in which the annealing/extension of a primer to a homopolymeric sequence
takes place over a period of 3 hours and does not affect any inappropriate
binding that might take place, because the long incubation time would allow
annealing and extension of the modified primers on improper internal poly A
sequences anyway. Id. (citing Lin, Examples 2, 4).
The Examiner finds an artisan of ordinary skill would have recognized
that it would have been useful to modify the oligo( dT) primers of Lin to
include the additional one or two target-specific 3 '-terminal nucleotides
taught by Nam, because it would reduce the production of truncated
amplification products stemming from undesired priming from internal
polyA sequences. Ans. 22-23. The Examiner finds that, because Nam
teaches that the disclosed anchored oligo( dT) primers reduced, but did not
eliminate, the production of undesirable truncated amplification products
during reverse transcription reactions, a person of ordinary skill would have
been motivated to additionally incorporate the teachings of Laird to modify
the primers such that one to three of the 3 '-terminal nucleotides were 2 '-0-
methylnucleotides, 2 '-fluoro-nucleotides, or 2 '-amino-nucleotides in order
to further improve the specificity of the amplification reaction. Id. at 23.
Responding to Appellants' argument that there would be no
motivation for a person of ordinary skill to combine the references, the
Examiner finds there is no requirement for Lin to explicitly describe
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problems associated with the disclosed method for motivation to exist. Ans.
24. Rather, the Examiner finds, a person of ordinary skill would have
recognized from the teachings of Nam that the primers of Lin could be
modified to minimize the high frequency of truncated cDNAs generated via
internal poly(A) priming. Id. The Examiner further finds an artisan of
ordinary skill would have been motivated to modify the conventional
oligo( dT) primers of Lin to include one or two target-specific 3 '-terminal
nucleotides, as taught by Nam, to further reduce the ability of the primers of
Lin to hybridize to internal poly A sequences other than the desired 3 ' -
terminal poly A sequence. Id.
The Examiner also finds a person of ordinary skill would have been
motivated to further include the specificity-enhancing modifications of
Laird, since Nam teaches that its anchored primer sequences3 reduce, but do
not eliminate, undesirable priming from internal poly A sequences. Ans. 24--
25.
Consequently, the Examiner finds Lin teaches a "base method" of
constructing a complete cDNA library that is similar to the claimed
invention. Ans. 25. However, the Examiner finds, the primers used in the
method of Lin do not include the nucleotide analogues. Id. The Examiner
3 Appellants contend that the term "anchored primer" does not appear in the
language of any of the claims. App. Br. 11. However, we agree with the
Examiner that the claim term "said primers or nucleic acid constructs
comprise one or more terminal nucleotides at their 3 ' ends, wherein said
terminal nucleotides comprise nucleotide analogues with substitutions on the
2' position of the ribose ring," as recited in claim 251, corresponds to the
"anchored primers" taught by Nam, modified to include "substitutions on the
2' position of the ribose ring," as taught by Laird. See Nam 6152, col. 2,
i13; Laird i-f 13.
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also finds Nam teaches non-specific amplification is known to occur when
primers having the same general features as those of Lin when used in
reverse transcription reactions, but that these non-specific amplifications
could be reduced by using "anchored primers," i.e., primers with additional
nucleotides at the 3' terminus. Id. The Examiner further finds Laird teaches
the claimed 2 '-modified nucleotide analogues were known in the art to be
useful for reducing nonspecific amplification. Id.
Consequently, the Examiner concludes, an artisan of ordinary skill
would have been motivated to modify the primers of Lin to include the
features identified by both Nam and Laird as being capable of reducing
nonspecific amplification.
We agree with the Examiner. Appellants do not dispute that the
combined cited prior art references teach all of the limitations of the claims.
Rather, they argue that a person of ordinary skill would have no reason, or
would not be motivated, to combine the teachings of Lin, Nam, and Laird to
arrive at the claimed invention. We do not agree. Appellants argue the
problem of specificity that is solved by Laird does not offer any particular
advantages for the Lin method, where there is essentially universal
amplification of any and all sequences having a poly-A tail. However,
Appellants' Specification discloses:
In the course of carrying out the amplification of nucleic acids,
one function may be desirable and the other function may be
undesirable for a particular nucleic acid. For instance, the well
known primer-dimer problem in PCR is the result of an
unextended primer being inappropriately used as a template.
There are other systems where this potential duality of
functionality may also be problematic.
Spec. 6.
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The Specification further discloses:
Thus, even when it is desired to generate cDNA copies by
priming with exogenously added oligo T, endogenous RNA
primers present in the total RNA preparation may also participate
in priming events. This effect can potentially lead to at least two
negative consequences. Firstly, when eukaryotic mRNA is used
as a template by these inadvertent primers, priming events can
take place at sites other than the 3' poly A end, thereby creating
incomplete copies. Secondly, the presence of primers that can
act at random implicitly negates the specificity for selective
copying of mature mRNA that was conveyed by the use of poly
A; instead, the total RNA population is now a potential source of
templates for cDNA synthesis. This population can be carried
through later steps of labeling and/or amplification and create a
higher potential for noise and background when hybridized to a
target or array of targets.
Spec. 7.
These are the issues addressed explicitly by both Nam and Laird with
respect to the basic method taught by Lin. See Nam Abstr. ("We have
analyzed a systematic flaw in the current system of gene identification: the
oligo( dT) primer widely used for cDNA synthesis generates a high
frequency of truncated cDNAs through internal poly( A) priming"); see also
Laird i-f 12 ("The present invention provides methods and reagents for the in
vitro amplification of a nucleic acid sequence using a primer-based
amplification reaction which provide a simple and economical solution to
the problem of nonspecific amplification").
We therefore agree with the Examiner that both Nam and Laird
address the issue of non-specific amplification that is a normally-occurring
result when practicing the teachings of Lin. Moreover, we agree with the
Examiner's reasoning that a person of ordinary skill in the art would be
motivated to combine the teachings of the cited prior art. As we have just
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related, we agree with the Examiner that Nam and Laird address problems
that arise from the methods taught by Lin and suggest means of reducing
those problems. Nam teaches the use of anchored primers can reduce, but
not eliminate binding of primers to complementary non-primer sequences,
and Laird teaches the use of 2 '-modified nucleotides at the 3 '-primer
terminus can also reduce non-specific amplification. See Nam 6155-56;
Laird i-f 12. We agree with the Examiner that a person of ordinary skill
would be motivated to combine these teachings to reduce the non-specific
amplification that arise from the methods taught in Lin.
Appellants suggest, but do not explicitly allege, that the Examiner
improperly relied upon hindsight analysis in arriving at the conclusion that
the claims are obvious over the teachings of the combined cited prior art.
See App. Br. 13 ("Without the benefit of the instant specification, the skilled
artisan would not understand that Laird's primers would have any utility in
the Lin method"). We are not persuaded. Any judgment on obviousness is,
in a sense, necessarily a reconstruction based upon hindsight reasoning, but
so long as the analysis takes into account only knowledge which was within
the level of ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from Appellants' disclosure, such
a reconstruction is proper. In re McLaughlin, 443 F.2d 1392, 1395
(C.C.P.A. 1971). Appellants have not persuasively pointed to any evidence
that would not have been within the knowledge of a person of ordinary skill
at the time of invention or could have been derived only from Appellants'
Specification. Rather, the Examiner has articulated a sufficiently rational
underpinning, based upon the prior art, as to why a person of ordinary skill
would be motivated to combine the teachings of the prior art to arrive at
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Appellants' claimed invention. See KSR Int'!. Co. v. Teleflex Inc., 550 U.S.
398, 418 (2007) ("[T]here must be some articulated reasoning with some
rational underpinning to support the legal conclusion of obviousness"). We
consequently affirm the Examiner's rejection of claims 251, 252, 254, 256,
259-264, 269-273, 275, 281and284--287.
Moreover, although Appellants argue claims 253, 255, 257 258, 265-
268, 274, 276, 277, 278-280, 282, and 283 separately, they advance the
same arguments presented with respect to the claims argued supra. See
App. Br. 16-19. We consequently affirm the Examiner's rejection of these
claims on the same grounds.
DECISION
The Examiner's rejection of claims 251-287 as unpatentable under 35
U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l). See 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
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