Ex Parte Ilsley-Tyree et al

Board of Patent Appeals and Interferences

Jun 15, 2009

10454686 (B.P.A.I. Jun. 15, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DIANE ILSLEY-TYREE and DOUGLAS A. AMORESE
__________

Appeal 2009-0004231
Application 10/454,686
Technology Center 1600
__________

Decided:2 June 15, 2009
__________

Before LORA M. GREEN, RICHARD M. LEBOVITZ, and
FRANCISCO C. PRATS, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

1 Agilent Technologies, Inc. is the real party in interest (App. Br. 3).
2 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).

Appeal 2009-000423
Application 10/454,686

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of performing a template dependent primer extension reaction. 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 1-25 and 34-40 are pending and on appeal (App. Br. 3).
Claims 1 and 19, the independent claims, are representative and read as
follows:
1. A method of performing a template dependent
primer extension reaction, said method comprising:
contacting an initial RNA template with a primer
composition comprising both a universal primer and at least one
RNA-binding gene specific primer, wherein said universal
primer and said at least one RNA-binding gene specific primer
are complementary to positions of a single RNA species of said
initial RNA template; and
maintaining said contacted RNA template and primer
composition under primer extension reaction conditions to
perform said template dependent primer extension reaction.

19. A method of linearly amplifying an initial RNA
template to produce an antisense RNA population, said method
comprising:
(a) contacting said initial RNA template with reverse
transcriptase reagents that include a primer composition made
up of both:
(i) an RNA polymerase promoter oligo dT primer; and
(ii) at least one gene specific primer,
wherein said oligo dT primer and said at least one
gene specific primer are complementary to positions of a
single RNA species of said initial RNA template;
(b) maintaining said template and reagents under reverse
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transcriptase conditions to produce a population of product
double stranded cDNAs, wherein at least a portion of said
product double-stranded cDNAs comprises an RNA
polymerase promoter region; and
(c) contacting at least said portion of said product double-
stranded cDNAs that comprises an RNA polymerase promoter
region with an RNA polymerase under conditions sufficient to
produce said antisense RNA population.

The Examiner cites the following documents as evidence of
unpatentability:

Van Gelder US 5,545,522 Aug. 13, 1996
Mougin WO 99/61661 A1 Dec. 2, 1999
Loehrlein US 2002/0160361 A1 Oct. 31, 2002

The following rejections are before us for review:
Claims 1-9, 14-18, and 34-40 stand rejected under 35 U.S.C. § 103(a)
as being unpatentable over Mougin in view of Loehrlein (Ans. 4-6).
Claims 10-13 and 19-25 stand rejected under 35 U.S.C. § 103(a) as
being unpatentable over Mougin, Loehrlein and Van Gelder (Ans. 15-16).
OBVIOUSNESS -- CLAIMS 1-9, 14-18, and 34-40
ISSUE
The Examiner cites Mougin as teaching a nucleic acid amplification
method that uses two types of complementary primers, “a primer that
hybridizes indiscriminately with all of the related nucleotide sequences (ie.
Non specific universal primers)(page 4) and a primer that hybridizes with
only one of the related nucleotide sequences (i.e. specific for the nucleotide
sequence that are related to the desired sequence- gene specific
primers)(page 5)” (Ans. 4). With respect to claim 1, however, the Examiner
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concedes that “Mougin does not specifically teach analysis of RNA” (id. at
5).
To meet Mougin’s deficiencies, the Examiner cites Loehrlein as
teaching a method of gene expression analysis “which is highly sensitive,
rapid and inexpensive, ha[s] a high throughput and allow[s] the simultaneous
differential analysis of a defined set of genes (abstract). Loehrlein teaches
the invention provides methods for preparing a plurality of amplification
products from a plurality of mRNA target sequences (para 25)” (id. at 5-6).
Based on the references’ teachings, the Examiner concludes that a
person of ordinary skill in the art would have considered it obvious “to have
modified the amplification detection of Mougin with the detection method of
Loehrlein” (id. at 6). More specifically, the Examiner reasons that an
ordinary artisan would have been motivated to use RNA templates “to gain
understanding of the transcripts rather than the genomic sequences” (id.).
The Examiner further reasons that the ordinary artisan would have
been particularly motivated to use Loehrlein’s methods because Loehrlein
“teaches the use of microarrays . . . to measure the expression levels of RNA
for several thousands of genes simultaneously, generating a gene expression
profile of the entire genome of relatively simple organism. . . . Thus, high
throughput analysis in a simple cost effective manner is permitted” (id.).
Appellants contend that “all the elements of the rejected claims are
neither taught nor suggested by Mougin or Loehrlein because: 1 ) the cited
references fail to teach or suggest a universal primer as claimed; and 2) the
proposed modification renders the prior art unsatisfactory for its intended
purpose” (App. Br. 10).
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Specifically, Appellants argue, the Specification defines the term
“universal primer . . . as ‘a primer that is capable of hybridizing to each of
the constituent nucleic acid members in the template composition’” (id. at 12
(citing Spec. 13:18-19)). In contrast, Appellants urge, “[t]he primer
suggested in Mougin does not bind to every constituent nucleic acid member
in the template composition. As such, Mougin fails to teach or suggest a
universal primer as claimed” (App. Br. 13; see also Reply Br. 2-5).
Moreover, Appellants argue, Mougin’s methods are directed to the
analysis of structurally related genes, and modifying Mougin’s primer to
hybridize to all of the nucleic acid molecules in a sample “would result in
amplification of all the genes - both related and unrelated nucleotide
sequences. As a result, such modification would render Mougin
unsatisfactory for its intended purpose of analyzing a certain subgroup of
genes within a group of related genes- e.g., HLA-DRB1 genes within the
HLA-DR gene group” (App. Br. 14).
In view of the positions advanced by Appellants and the Examiner,
the issues with respect to this rejection are whether Appellants have shown
that the Examiner erred in concluding that one of ordinary skill in the art
would have interpreted the claim term “universal primer” as encompassing
Mougin’s primers, and whether Appellants have shown that modifying
Mougin’s process in the manner posited by the Examiner would have
rendered Mougin’s process unsatisfactory for its intended purpose.
FINDINGS OF FACT (“FF”)
Claims and Specification
1. Claim 1 recites a method of performing a template dependent primer
extension reaction. In the method, an initial RNA template is contacted with
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a primer composition that contains both a “universal primer” and at least one
RNA-binding gene specific primer.
2. The Specification states that “the template is employed in a protocol
or method in which a primer composition is characterized by including . . . a
universal primer, e.g., a primer that is capable of hybridizing to each of the
constituent nucleic acid members in the template composition” (Spec. 13).
3. The Specification states that “the universal primer component of the
primer compositions employed in the subject methods is a primer that is
capable of hybridizing under stringent conditions to all of the different
constituent template nucleic acids of the nucleic acid template” (Spec. 14).
Thus, “[i]n many embodiments, the universal primer is an oligo dT
primer, which includes a plurality of, e.g., at least about 6, sequential dT
residues to provide for hybridization to the polyA tail of template mRNAs in
the template nucleic acid preparation” (id.). According to the Specification,
“[s]uch oligo dT primers are well known in the art” (id.).
5. Claim 10 recites “[t]he method according to Claim 1, wherein said
universal primer is an oligo dT or oligo dTVN primer.”
6. Claim 10 is an originally filed claim, and has not been amended (see
Spec. 36 (filed June 3, 2003)).
7. The Specification discloses
Where the protocol being employed includes an
amplification step, e.g., in vitro transcription, the universal
primer may be a promoter primer that includes both a priming
domain or region and an amplification domain or region. In
embodiments that include amplification by in vitro
transcription, the amplification primer employed in the template
dependent primer extension reaction includes: (a) a poly-dT
region for hybridization to the poly-A tail of the mRNA; and
(b) an RNA polymerase promoter region 5' of the -poly-dT
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region that is in an orientation capable of directing transcription
of antisense RNA. In other embodiments that include
amplification the amplification primer contains a region that
facilitates amplification, e.g., the region may be a binding site
for a primer to be used in a linear PCR amplification method. In
certain embodiments, the primer may be a “lock-dock” primer,
in which immediately 3’ of the poly-dT region is either a “G[”],
“C”, or “A” such that the primer has the configuration of 5’-
TTTTTTTX ..... 3’, where X is “G”, “C”, or “A”. In these
embodiments, the poly-dT region is sufficiently long to provide
for efficient hybridization to the poly-A tail, where the region
typically ranges in length from 10-50 nucleotides in length,
usually 10-25 nucleotides in length, and more usually from 14
to 20 nucleotides in length.

(Spec. 14-15.)
8. In both of Appellants’ examples, the template composition contains
total RNA extracted from HeLa cells and the universal primer is an oligo dT
primer (Spec. 31-32).

Mougin
9. Mougin discloses that prior art processes of amplifying DNA and
RNA have certain shortcomings (Mougin 3-4), but that “[t]he present
invention obviates the risks of obtaining truncated amplification products
and the difficulties associated with obtaining primers that are specific for the
nucleotide sequence to be amplified” (id. at 4).
10. Specifically, Mougin discloses a process for amplifying “at least one
specific nucleotide sequence . . . within a reaction mixture, with the said
reaction mixture consisting of at least one nucleic acid that has at least two
related nucleotide sequences and/or at least two nucleic acids, each of which
includes at least one related nucleotide sequence” (Mougin 5).
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11. Mougin’s process uses “at least one type of amplification primer that
is capable of hybridizing with nucleic acid in order to allow the
amplification of related nucleotide sequences” (Mougin 5).
12. Mougin’s process also uses, in the same reaction mixture at least one
nucleotide sequence, “which serves as a blocking primer, which is able to . .
. [h]ybridize with at least one nucleotide sequence that is not the specific
nucleotide sequence or sequences to be amplified; and . . . inhibit, in its
immediate region, the elongation of the amplification trigger” (Mougin 5).
13. Thus, in Mougin’s amplification process:
[T]wo types of complementary primers are used, i.e., on the one
hand, a primer that hybridizes indiscriminately with all of the
related nucleotide sequences and, on the other hand, a primer in
which each primer hybridizes with only one of the related
nucleotide sequences. The primers of the first type, which are
non-specific, are used as elongation primers, and the primers of
the second type, which are specific for the nucleotide sequences
that are related to the desired sequence, block the elongation of
some of the said related nucleotide sequences.

(Mougin 4-5.)
14. Figures 1 and 2 of Mougin, reproduced below, illustrate the
mechanics of Mougin’s process:

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“As shown in Figure 1, amplification is performed with non-blocking
primers P1 and P2. The extension of the P1 and P2 primers takes place in an
altogether conventional way, and multiple amplicons A are obtained”
(Mougin 11).
Figure 2 shows the procedure of Figure 1 repeated exactly with non-
blocking primers P1 and P2 (id.). However, “on the complementary strand
and downstream of the progress of the elongation of the P1 primer, a
sequence is added that serves as a blocking primer (Fib), which is capable of
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hybridizing to the complementary strand, and of preventing amplification in
its immediately surrounding region. In this case, no amplicon will be
produced” (id.).
15. Mougin explains that its blocking primers “either overlap[] or [are]
located downstream (in relation to the nucleotide primer that enables the
amplification), . . . [and] consist of oligonucleotides that cannot serve as
initiating sequences for elongation or, consequently, for the amplification of
the downstream sequences” (Mougin 11).
16. Mougin’s method therefore allows a practitioner to block the
amplification of undesired sequences, such as undesired genes or alleles,
while amplifying only the desired sequences within a group of related
nucleic acids (see Mougin 11).
17. Mougin discloses that “[t]he claimed strategy has multiple
applications that can be implemented whenever a mixture of related
sequences is to be analyzed - for example, in human or animal genetics or in
the analysis of infectious agents (viruses, bacteria, parasites, etc.)” (Mougin
12).
18. For example, with respect to the MHC (i.e., “HLA”) genes, Mougin
discloses using “a mixture of (a) primers that are specific for the HLA-DRB
genes but non-specific for the HLA-DRB1 gene, and (b) blocking primers
that are specific for the HLA-DRB3, HLA-DRB4, and HLA-DRB5 genes”
(Mougin 15).
Thus, using the mixture of primers provides “selective amplification
of the HLA-DRB1 genes, thereby enabling easier determination of the two
HLA-DRB1 alleles, as observed for a given individual” (id.; see also
Mougin 17-29).
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Loehrlein
19. Loehrlein discloses methods “for gene expression analysis and gene
expression profiling. The methods of the invention are highly sensitive;
have a wide dynamic range; are rapid and inexpensive; have a high
throughput; and allow the simultaneous differential analysis of a defined set
of genes” (Loehrlein, abstract).
20. Loehrlein discloses that, in one embodiment, its methods “provide[]
compositions for preparing a plurality of amplification products from a
plurality of mRNA target sequences. The compositions include one or more
pairs of universal primers; and one or more pairs of target-specific primers”
(Loehrlein [0025]).
21. Loehrlein states:
[T]he methods of the present invention can be used to
investigate the profile and expression levels of one or more
members of complex gene families. As an illustration,
cytochrome P-450 isozymes form a complex set of closely
related enzymes that are involved in detoxification of foreign
substances in the liver. The various isozymes in this family
have been shown to be specific for different substrates. Design
of target-specific primers that anneal to variant regions in the
genes provides an assay by which their relative levels of
induction in response to drug treatments can be monitored.
Other examples include monitoring expression levels of alleles
with allele-specific primers, or monitoring mRNA processing
with primers that specifically hybridize to a spliced or unspliced
region, or to splice variants. One skilled in the art could
envision other applications of the present invention that would
provide a method to monitor genetic variations or expression
mechanisms.

(Loehrlein [0182].)
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22. Regarding its methods of gene expression analysis, Loehrlein
discloses that, in one embodiment:
The methods . . . include the steps of (a) obtaining a
plurality of target nucleic acid sequences, generally cDNA
sequences; (b) multiplex amplifying the target sequences using
a plurality of target-specific primers and one or more universal
primers; (c) separating one or more members of the resulting
plurality of amplification products; (d) detecting the one or
more members of the plurality of amplification products,
thereby generating a set of gene expression data; (e) storing the
data in a database; and (f) performing a comparative analysis on
one or more components of the set of gene expression data,
thereby analyzing the gene expression.

(Loehrlein [0087].)
23. Loehrlein discloses that the use of arrays for detecting amplified
products in gene expression analyses was known in the art:
Nucleic acid microarrays have been developed recently,
which have the benefit of assaying for sample hybridization to a
large number of probes in a highly parallel fashion. They can
be used for quantitation of mRNA expression levels, and
dramatically surpass the above mentioned techniques in terms
of multiplexing capability. These arrays comprise short DNA
sequences, PCR products, or mRNA isolates fixed onto a solid
surface, which can then be used in a hybridization reaction with
a target sample, generally a whole cell extract . . . . Microarrays
can be used to measure the expression levels of several
thousands of genes simultaneously, generating a gene
expression profile of the entire genome of relatively simple
organisms.

(Loehrlein [0081] (citations omitted).)
24. Loehrlein discloses that its methods are performed using a system that
has an “analyzing module . . . [which] includes, e.g., a computer or
computer-readable medium having one or more one or more logical
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instructions for analyzing the plurality of data points generated by the
detection system” (Loehrlein [0187]).
Loehrlein states that “[t]he instructions can include software for
performing difference analysis upon the plurality of data points.
Additionally (or alternatively), the instructions can include or be embodied
in software for generating a graphical representation of the plurality of data
points” (id.).
25. Loehrlein discloses that “[t]he computer employed in the analyzing
module of the present invention can be . . . [a] commercially common
computer which is known to one of skill” (Loehrlein [0188]), and can
include “software . . . [with] output elements for displaying and/or further
analyzing raw data, massaged data, or proposed results from one or more
computational processes involved in the analysis of the gene expression data
set” (id. at [0191]).
PRINCIPLES OF LAW
As the Supreme Court pointed out in KSR Int' l Co. v. Teleflex
Inc., 550 U.S. 398, 418 (2007), “a patent composed of several elements is
not proved obvious merely by demonstrating that each of its elements was,
independently, known in the prior art.” Rather, the Court stated:
[I]t can be important to identify 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 . . . because inventions in most, if not all, instances rely
upon building blocks long since uncovered, and claimed
discoveries almost of necessity will be combinations of what, in
some sense, is already known.

Id. at 418-419 (emphasis added); see also id. at 418 (requiring a
determination of “whether there was an apparent reason to combine the
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known elements in the fashion claimed by the patent at issue”) (emphasis
added).
While holding that some rationale must be supplied for a conclusion
of obviousness, the Supreme Court nonetheless rejected a “rigid approach”
to the obviousness question, and instead emphasized that “[t]hroughout this
Court’s engagement with the question of obviousness, our cases have set
forth an expansive and flexible approach . . . .” Id. at 415. The Court also
rejected the use of “rigid and mandatory formulas” as being “incompatible
with our precedents.” Id. at 419; see also id. at 421 (“Rigid preventative
rules that deny factfinders recourse to common sense, however, are neither
necessary under our case law nor consistent with it.”).
The Court thus reasoned that the analysis under 35 U.S.C. § 103 “need
not seek out precise teachings directed to the specific subject matter of the
challenged claim, for a court can take account of the inferences and creative
steps that a person of ordinary skill in the art would employ.” Id. at 418; see
also id. at 421 (“A person of ordinary skill is . . . a person of ordinary
creativity, not an automaton.”).
During examination the PTO must interpret terms in a claim using
“the broadest reasonable meaning of the words in their ordinary usage as
they would be understood by one of ordinary skill in the art, taking into
account whatever enlightenment by way of definitions or otherwise that may
be afforded by the written description contained in the applicant’s
specification.” In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997).
The Examiner must therefore “determine[] the scope of claims in
patent applications not solely on the basis of the claim language, but upon
giving claims their broadest reasonable construction ‘in light of the
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specification as it would be interpreted by one of ordinary skill in the art.’”
Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed.Cir.2005) (emphasis
added) (quoting In re American Academy Of Science Tech Center, 367 F.3d
1359, 1364 (Fed. Cir. 2004).
Accordingly, “[c]laims are not to be read in a vacuum[;] while it is
true they are to be given the broadest reasonable interpretation during
prosecution, their terms still have to be given the meaning called for by the
specification of which they form a part.” In re Royka, 490 F.2d 981, 984
(CCPA 1974).
However, “while ‘the specification [should be used] to interpret the
meaning of a claim,’ courts must not ‘import[ ] limitations from the
specification into the claim.’ . . . [I]t is improper to ‘confin[e] the claims to
th[e] embodiments’ found in the specification . . . .” In re Trans Texas
Holdings Corp., 498 F.3d 1290, 1299 (Fed. Cir. 2007) (quoting Phillips, 415
F.3d at 1323 (citations omitted, bracketed text in internal quotes in original).
Thus, “during patent prosecution when claims can be amended,
ambiguities should be recognized, scope and breadth of language explored,
and clarification imposed.” In re Zletz, 893 F.2d 319, 321 (Fed. Cir. 1989).
Ultimately therefore, “absent claim language carrying a narrow
meaning, the PTO should only limit the claim based on the specification . . .
when [it] expressly disclaims the broader definition.” In re Bigio, 381 F.3d
1320, 1325 (Fed Cir. 2004); see also, In re Paulsen, 30 F.3d 1475, 1480
(Fed. Cir. 1994) (“Although an inventor is indeed free to define the specific
terms used to describe his or her invention, this must be done with
reasonable clarity, deliberateness, and precision.”).
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ANALYSIS
Appellants’ arguments do not persuade us that the Examiner erred in
concluding that one of ordinary skill in the art would have interpreted the
claim term “universal primer” as encompassing Mougin’s indiscriminate
primers. Nor are we persuaded that modifying Mougin’s process in the
manner posited by the Examiner would have rendered Mougin’s process
unsatisfactory for its intended purpose.
We note the Specification’s statement that a universal primer is, “e.g.,
a primer that is capable of hybridizing to each of the constituent nucleic acid
members in the template composition” (Spec. 13 (FF 2); see also Spec. 14
(“the universal primer component of the primer compositions employed in
the subject methods is a primer that is capable of hybridizing under stringent
conditions to all of the different constituent template nucleic acids of the
nucleic acid template”) (FF 3)).
However, viewing the Specification as a whole, we do not agree with
Appellants that the language on pages 13 and 14 conveys, with adequate
precision, that the term “universal primer” excludes primers, such as
Mougin’s, which hybridize to only a subset of the nucleic acid molecules in
the extension reaction mixture.
For example, originally filed claim 10 recites “[t]he method according
to Claim 1, wherein said universal primer is an oligo dT or oligo dTVN
primer.” Thus, according to Appellants’ originally filed disclosure, a
universal primer molecule can be an oligo dT primer with a variable
nucleotide (“VN”) immediately 3’ of the poly-dT region, the variable
nucleotide being either G, C, or A (Spec. 14 (FF 7)).
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Therefore, even if the only nucleic acid in the extension reaction
mixture was a cellular mRNA sample, a “universal primer” molecule having
G, C, or A adjacent to the poly-dT region would still only hybridize to a
subset of the nucleic acid molecules in the reaction mixture.
Moreover, Appellants’ examples use total RNA extracted from HeLa
cells as the starting material, whereas the universal primer is an oligo dT
primer (FF 8). Since the poly dT primer would, essentially, hybridize only
to the poly A tails of the messenger RNA in the sample, the universal primer
used in Appellants’ examples hybridizes only to a subset of all of the nucleic
acid molecules in the extension reaction mixture.
Thus, it would be understood from the Specification that a primer can
be “universal” even if it hybridizes with only a subset of the RNA molecules
in the reaction mixture. Moreover, the Specification, and claim 1 for that
matter, does not expressly state that the universal primer must be capable of
hybridizing to substantially every nucleic acid molecule in the reaction
mixture, as Appellants urge.
Rather, the Specification states that the universal primer must be
capable of hybridizing to each of the nucleic acids “in the template
composition” (Spec. 13 (FF 2), see also Spec. 14 (FF 3)). In the examples
on pages 31-32 of the Specification, it appears that the “template
composition” would mean the mRNA in the total extracted RNA (see FF8),
i.e the subset of RNA to be amplified.
We therefore do not agree with Appellants that a person of ordinary
skill in the art, giving the claims their broadest reasonable interpretation
consistent with the Specification, would have interpreted the term “universal
primer” to exclude primers, such as Mougin’s, which hybridize to only a
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subset of the nucleic acid molecules in the extension reaction mixture. That
is, we decline Appellants’ invitation to read into claim 1 a limitation neither
positively recited in the claim, nor unambiguously provided in the
Specification.
Because Mougin’s indiscriminate primer hybridizes with an entire set
of related molecules, such as the related set of HLA genes (see FF 11, 13,
18), we agree with the Examiner that Mougin’s primer can be considered
“universal” within the meaning of that term as it would be interpreted in the
light of the Specification. We also agree with the Examiner that modifying
Mougin’s process in light of Loehrlein’s disclosure would not have rendered
Mougin’s process unsatisfactory for its intended purpose.
Both Mougin (FF 17) and Loehrlein (FF 21) are concerned with
evaluating small differences in related sequences within gene families.
Thus, a person of ordinary skill in the art would have reasonably expected
that applying Mougin’s combination of universal/blocking primers to the
mRNA samples assessed by Loehrlein would allow discernment between
different members of a family of related expressed genes.
In sum, we are not persuaded that claim 1 fails to encompass
Mougin’s primers, nor are we persuaded that a person of ordinary skill in the
art would have inferred that modifying Mougin’s process in light of
Loehrlein’s disclosure would render Mougin’s process unsatisfactory for its
intended purpose. We therefore affirm the Examiner’s rejection of claim 1
as obvious over those references.
Because claims 2-7, 14, 16-18, 34, and 38-40 were not argued
separately, they fall with claim 1. See 37 C.F.R. § 41.37(c)(1)(vii).
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Claim 8 recites “[t]he method according to Claim 1, wherein said
universal primer and said RNA-binding gene specific primer are
complementary to positions of said single RNA species that are separated by
less than 15 nucleotides.” Claim 9 recites “[t]he method according to Claim
8, wherein said positions are immediately adjacent to each other.”
Appellants argue that Mougin does not expressly or inherently teach
or suggest the properties recited in claims 8 and 9 for the primers (App. Br.
16-17). Moreover, Appellants urge, Loehrlein does not remedy Mougin’s
deficiency in this respect (id.; see also Reply Br. 5-6).
Appellants’ arguments do not persuade us that the Examiner erred in
concluding that claims 8 and 9 would have been obvious to a person of
ordinary skill in the art. Mougin states that its blocking primers “either
overlap[] or [are] located downstream (in relation to the nucleotide primer
that enables the amplification), . . . [and] consist of oligonucleotides that
cannot serve as initiating sequences for elongation or, consequently, for the
amplification of the downstream sequences” (Mougin 11 (FF 15)).
Given the disclosure by Mougin that the blocking primers can overlap
the region complementary to the amplifying primer, and given that the
explicit purpose of Mougin’s blocking primers is to nullify amplification
from the upstream amplification primer, a person of ordinary skill in the art
would have reasonably inferred that it would be suitable for the blocking
primers to be complementary to sequences that are immediately adjacent to
the sequences that hybridize to Mougin’s indiscriminate amplification
primers. We therefore affirm the Examiner’s rejection of claims 8 and 9.
Claim 15 recites “[t]he method of claim [1 wherein said primer
composition comprises a plurality of gene specific primers, and] wherein
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said plurality of gene specific primers are complimentary to abundant RNAs
in said RNA template.” Appellants argue that Mougin’s blocking primers
hybridize to sequences which the practitioner does not wish to modify,
whereas, “abundant” RNAs are present in high copy numbers in template,
the most abundant being present at thousands of copies per cell (App. Br.
17-18; see also Reply Br. 6)
Appellants’ arguments do not persuade us that the Examiner erred in
concluding that claim 15 would have been obvious to a person of ordinary
skill in the art. Claim 15 merely recites that the gene-specific primers are
complementary to RNAs which are “abundant.”
Mougin discloses blocking the amplification of three genes, the HLA-
DRB3, HLA-DRB4, and HLA-DRB5 genes, while allowing HLA-DRB1
gene amplification to proceed (FF 18). Loehrlein discloses the desirability
of studying the expression of genes encoding various isozymes and/or allelic
forms (FF 21). In view of these disclosures that studying a particular allelic
form of a gene requires blocking the amplification of a significant number of
related sequences, a person of ordinary skill in the art would have been
prompted to provide Mougin’s blocking primers with sequences
complementary to RNAs present at high copy numbers in the reaction
mixture so as to block their amplification and enable the amplification of
only the desired sequences. We therefore affirm the Examiner’s rejection of
claim 15.
Claims 34-37 read as follows:
34. A method of detecting the presence of a nucleic acid
analyte in a sample of nucleic acids produced from in initial RNA
template according to the method of Claim 1, said method
comprising:
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(a) producing said sample of nucleic acids according to
the method of Claim 1;
(b) contacting said sample with a nucleic acid array;
(c) detecting any binding complexes on the surface of the
said array to obtain binding complex data; and
(d) determining the presence of said nucleic acid analyte
in said sample using said binding complex data.

35. The method according to Claim 34 wherein said method
further comprises a data transmission step in which a result from a
reading of the array is transmitted from a first location to a second
location.

36. A method according to Claim 35, wherein said second
location is a remote location.

37. A method comprising receiving data representing a result
of a reading obtained by the method of Claim 34.

With respect to claim 35, Appellants argue that Mougin and Loehrlein
“fail to teach a data transmission step in which a result from a reading of
the array is transmitted from a first location to a second location” (App. Br.
19). Specifically, Appellants urge that Loehrlein’s data processing step,
disclosed for example in Example 6, does not amount to data transmission
(id. at 19-20).
Regarding claim 36, Appellants argue that the Specification defines
“remote location” as “‘a location other than the location at which the array is
present and hybridization occur[s]’” (App. Br. 20). Appellants urge that the
cited references fail to meet this limitation because “[b]oth Mougin and
Loehrlein are completely silent as to whether the collected data is
transmitted to a location other than the location at which the array is present
and hybridization occur” (id.).
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Regarding claim 37, Appellants argue that “Loehrlein’s method
merely stores the detected data in a database. Thus, Loehrlein does not teach
or suggest receiving the detected data” (id. at 21).
Appellants’ arguments do not persuade us that the Examiner erred in
concluding that claims 35-37 would have been obvious to a person of
ordinary skill in the art. It may be true that neither Mougin nor Loehrlein
explicitly discloses transmitting the obtained data to a remote location where
it is received.
However, as the Supreme Court has explained, the analysis under 35
U.S.C. § 103 “need not seek out precise teachings directed to the specific
subject matter of the challenged claim, for a court can take account of the
inferences and creative steps that a person of ordinary skill in the art would
employ.” 550 U.S. at 418; see also id. at 421 (“A person of ordinary skill is
. . . a person of ordinary creativity, not an automaton.”).
Thus, in the instant case, Loehrlein discloses that the hybridization
data can be input to any commercially available computer for analysis (FF
23-24), and can employ “software . . . [with] output elements for displaying
and/or further analyzing raw data, massaged data, or proposed results from
one or more computational processes involved in the analysis of the gene
expression data set” (Loehrlein [0191] (FF 25)). In view of the disclosed
suitability of analyzing the derived data on a computer with an output
capacity, a person of ordinary skill in the art would have found it desirable to
transmit that data to interested parties at remote locations, as recited in
claims 35 and 36, and for interested parties to receive that data, as recited in
claim 37. We therefore agree with the Examiner that claims 35-37 would
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have been obvious to a person of ordinary skill in the art, and thus affirm the
Examiner’s rejection of those claims.
OBVIOUSNESS -- CLAIMS 1-9, 14-18, and 34-40
ISSUE
Claims 10-13 and 19-25 stand rejected under 35 U.S.C. § 103(a) as
being unpatentable over Mougin, Loehrlein and Van Gelder (Ans. 15-16).
Appellants argue these claims as a single group (App. Br. 22). Claim
10 is representative of the rejected claims and recites “[t]he method
according to Claim 1, wherein said universal primer is an oligo dT or oligo
dTVN primer.”
The Examiner concedes that “[n]either Mougin nor Loehrlein
specifically teaches using an RNA polymerase promoter oligo dT primer as
the indiscriminate primer” (Ans. 15). To meet that limitation, the Examiner
cites Van Gelder as teaching the use of “an RNA polymerase promoter oligo
dT primer as the indiscriminate primer complex for amplification. Van
Gelder teaches the promoter region is capable of inducing transcription from
an operably linked DNA sequence in the presence of ribonucleotides and a
RNA polymerase” (id.).
The Examiner concludes that a person of ordinary skill in the art
would have considered it obvious to modify “the indiscriminate or universal
primers of Mougin or Loehrlein with a RNA polymerase promoter oligo dT
primer” (id.). The Examiner reasons that the “ordinary artisan would have
been motivated to have substituted the primers taught by Mougin or
Loehrlein to be indiscriminate and able to hybridize with all of the related
nucleotide sequences, with known RNA polymerase promoter oligo dT
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primer which enable the synthesis of additional extension products with
ease” (id. at 15-16).
Appellants argue that using Van Gelder’s oligo dT primer as the
indiscriminate primer in Mougin’s methods “would indiscriminately amplify
all undesired genes that are not blocked by the blocking primers. Such use
would not allow selective amplification as Mougin intends for, rendering
Mougin inoperable for its intended purpose of focusing on a highly related
group of genes” (App. Br. 23).
Appellants further argue that, although mRNA molecules are related
in that they share a poly A tail, they “do not share ‘a high degree of
homology’ with each other as HLA-DRB1 genes share with other HLA-
DRB genes in Mougin” (id.). Moreover, Appellants urge “the proteins
translated from all RNA molecules do not share related functions” like the
proteins encoded by Mougin’s genes (id. at 24). Thus, Appellants urge,
“RNA molecules are not related within the meaning of Mougin” (id.; see
also Reply Br. 7-8).
In view of the positions advanced by Appellants and the Examiner,
the issue with respect to this rejection is whether Appellants have shown that
the Examiner erred in concluding that one of ordinary skill in the art would
have considered it obvious to use Van Gelder’s primers in Mougin’s
process.
FINDINGS OF FACT
26. Van Gelder discloses “methods for producing amplified
heterogeneous populations of RNA from limited quantities of cDNA or
other nucleic acids” (Van Gelder, col. 1, ll. 11-13).
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27. Van Gelder describes one embodiment as follows:
[T]he invention is directed to a processes for detecting
expression of a gene in a preselected cell population comprising
steps of:

(a) synthesizing double-stranded cDNA by treating
mRNAs from the cell populations with a primer complex
comprising an oligonucleotide complementary to one or more
of the RNA sequences, the primer linked to a promoter region
in an orientation capable of directing transcription of anti-sense
RNA;
(b) transcribing the cDNA into anti-sense RNA by
introducing an RNA polymerase capable of operably binding to
the promoter region; and
(c) determining the presence or absence of transcribed
anti-sense RNA complementary to mRNA corresponding to the
gene.

(Van Gelder, col. 2, ll. 52-67.)
28. Van Gelder discloses that “[i]n one general embodiment of the present
invention, cDNA strands are synthesized from a collection of mRNA’s using
an oligonucleotide primer complex, i.e., a primer linked to a promoter
region” (Van Gelder, col. 4, ll. 43-46).
29. Thus, “[i]f the target mRNA is the entire mRNA population, then the
primer can be a polythymidylate region (e.g., about 5 to 20, preferably about
10 to 15 T residues), which will bind with the poly (A) tail present on the 3’
terminus of each mRNA” (Van Gelder, col. 4, ll. 46-50).
30. “Alternatively, if only a preselected mRNA is to be amplified, then
the primer will be substantially complementary to a section of the chosen
mRNA, typically at the 3’ terminus” (Van Gelder, col. 4, ll. 50-53).
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ANALYSIS
Appellants’ arguments do not persuade us that the Examiner erred in
concluding that one of ordinary skill in the art would have considered it
obvious to use Van Gelder’s primers in Mougin’s processes. We note that
Van Gelder discloses the polyT primer for amplifying entire mRNA
populations (see FF 29), whereas Mougin’s methods are directed to
amplifying only related nucleic acids within a larger population of nucleic
acid molecules (see FF 16-18).
However, even if an ordinary artisan were to use a poly dT primer, for
examples as P1 in Mougin’s methods, the process would still also use the
second primer P2 which hybridizes to the complementary nucleic acid
strand, and is specific to the gene family of interest, as Mougin discloses
(see Mougin, Figures 1 and 2 (FF 14); Ans. 17). Thus, because Mougin’s
process also uses a second gene-specific primer, a person of ordinary skill in
the art would have reasonably inferred that using a poly dT primer would
result in amplification only the desired gene family, and not frustrate the
purpose of Mougin’s methods.
Moreover, Van Gelder explicitly discloses that primers configured to
hybridize to specific sequences at the 3’ end of the mRNA molecules are
useful when a practitioner desires to amplify only specific sequences within
the mRNA sample (FF 30). Given this disclosure, a person of ordinary skill
in the art would have reasonably inferred that using a primer with an oligo
dT moiety adjacent to a sequence complementary to a 3’ sequence specific
to a gene of interest would allow amplification of mRNAs of related genes
without amplifying undesired mRNAs.
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Thus, because a person of ordinary skill in the art would have
understood that oligo dT and oligo dTVN primers are not limited to non-
specific amplification of mRNAs, we are not persuaded that a person of
ordinary skill in the art would have been dissuaded from using those primers
in Mougin’s process. We therefore affirm the Examiner’s rejection of claim
10 as obvious in view of Mougin, Loehrlein, and Van Gelder.
Because they were not argued separately, claims 11-13 and 19-25 fall
with claim 10. See 37 C.F.R. § 41.37(c)(1)(vii).
SUMMARY
We affirm the Examiner’s rejection of claims 1-9, 14-18, and 34-40
under 35 U.S.C. § 103(a) as being unpatentable over Mougin in view of
Loehrlein.
We also affirm the Examiner’s rejection of claims 10-13 and 19-25
under 35 U.S.C. § 103(a) as being unpatentable over Mougin, Loehrlein and
Van Gelder.
TIME PERIOD
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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