Ex Parte Arnold et al

Patent Trial and Appeal Board

Feb 19, 2013

10837530 (P.T.A.B. Feb. 19, 2013)

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.
10/837,530 04/30/2004 Lyle J. Arnold JR. 042602-0201 1989
30542 7590 02/19/2013
FOLEY & LARDNER LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
EXAMINER
CALAMITA, HEATHER
ART UNIT PAPER NUMBER
1635
MAIL DATE DELIVERY MODE
02/19/2013 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 LYLE J. ARNOLD and BOB D. BROWN
__________

Appeal 2011-005239
Application 10/837,530
Technology Center 1600
__________

Before LORA M. GREEN, JEFFREY N. FREDMAN, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
oligonucleotide. The Examiner rejected the claims as anticipated and as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.

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Statement of the Case
Background
The Specification teaches that “oligonucleotides containing a
‘molecular switch’ region are provided for use as a hybridization probe or
primer. This molecular switch region can be in an ‘open’ (non-hybridized)
or ‘closed’ (hybridized) position” (Spec. 2 ¶ 0008). According to the
Specification, in “the open position, the molecular switch can be used to
detect the presence of a ‘mismatch’ (i.e., at least one non-hybridizing base
pair) between the oligonucleotide and the target sequence” (Spec. 3 ¶ 0008).
The Specification teaches that in “the closed position, the molecular switch
can be used to detect a ‘match’, or a complementary nucleic acid sequence
between the oligonucleotide and the target sequence” (Spec. 3 ¶ 0008).
The Claims
Claims 1-8, 12-21, and 24-41 are on appeal.1 Claim 1 is
representative and reads as follows:
1. An oligonucleotide comprising:
(a) a nucleic acid anchor region complementary to a first
sequence of nucleic acid residues of a target nucleic acid; and
(b) a switch domain comprising at least one bridging domain
and at least one binding domain, wherein said binding domain
comprises 2-20 nucleic acid bases or analogs thereof complementary
to said target nucleic acid and said binding domain has less affinity for
said target nucleic acid than said anchor region,
wherein said bridging domain is located between said anchor
region and said binding domain and comprises 2-11 universal, generic
or mismatched natural bases or analogs thereof or a mixture of
universal and non-hydrogen bonding natural bases that do not form a

1 Claims 9-11, 22, and 23 are also pending, but stand witdrawn
from consideration (App. Br. 2).
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Watson-Crick hybridization complex with said target nucleic acid,
wherein two or more universal or non-hydrogen bonding natural bases
or analogs thereof or a mixture of universal and non-hydrogen
bonding natural bases in said bridging domain are juxtaposed, and
wherein said universal or non-hydrogen bonding natural bases in said
bridging domain substitute for bases complementary to nucleotide
bases of said target nucleic acid and enhance sensitivity to the
presence of a mismatch between the binding region of the switch
domain and the target sequence,
wherein said switch domain is able to discriminate between (i)
a sequence of nucleic acid residues of said target nucleic acid that is
complementary to said binding domain and (ii) a second mismatch
sequence of nucleic acid residues of said target nucleic acid that
contains at least one nucleic acid residue that is not complementary to
said binding domain; under conditions wherein said anchor region (a)
forms a stable duplex with said first sequence of nucleic acid residues
of said target nucleic acid; and
wherein said target nucleic acid comprises one or more
sequences selected from the group consisting of a sequence that is
associated with a disease or condition, a sequence that is associated
with an infectious organism, and a sequence comprising a genetic
variation.

The issues

A. The Examiner rejected claims 1-8, 12-17, 19, 20, and 24-41 under 35
U.S.C. § 102(e) as anticipated by Nazarenko2 (Ans. 3-11).
B. The Examiner rejected claims 18 and 21 under 35 U.S.C. § 103(a) as
obvious over Nazarenko and Jayasena3 (Ans. 12-13).

2 Nazarenko et al., US 5,866,336, issued Feb. 2, 1999.
3 Jayasena et al., US 2001/0055773 A1, published Dec. 27, 2001.
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A. 35 U.S.C. § 102(e) over Nazarenko
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s finding that Nazarenko anticipates claim 1?

Findings of Fact
1. The Specification teaches that “[u]niversal non-hydrogen
bonding natural bases or analogues thereof or a mixture of universal and
non-hydrogen bonding natural bases or analogues thereof suitable for use
with the embodiments described herein include . . . natural bases A, T, C, G
and U and analogs thereof” (Spec. 28 ¶ 0077).
2. Figures 1A and 1B of Nazarenko are reproduced below:

“FIGS. 1A-B illustrate schematically the structure of the hairpin primers of
the invention in the (A) closed (quenched) and (B) open (emitting signal)
states” (Nazarenko, col. 9, ll. 3-5).
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3. Nazarenko teaches that
the hairpin primer comprises four parts (FIG. 1): Part (d) is a
3' terminal sequence and comprises a sequence
complementary to the target sequence; it is a primer for
DNA polymerase. Part (c) is a first stem sequence on the 5'
end of the primer sequence. Part (b) forms a single-stranded
loop of nucleotides. Part (a) is a second stem sequence,
which is complementary to the first stem sequence. Parts (a),
(b), and (c) or portions thereof may or may not be
complementary to the target DNA to be amplified. Part (d) is
preferably 8-30 nucleotides long; Part (c) is preferably 6-30
nucleotides long; Part (b) is preferably 3-20 nucleotides
long.

(Nazarenko, col. 20, ll. 33-44).
4. Nazarenko teaches “(a) a first nucleotide sequence of 6-30
nucleotides, wherein a nucleotide within said first nucleotide sequence is
labeled” (Nazarenko, col. 19, ll. 42-44).
5. Nazarenko teaches “(b) a second, single-stranded nucleotide
sequence of 3-20 nucleotides” (Nazarenko, col. 19, ll. 50-51).
6. Nazarenko teaches “(c) a third nucleotide sequence of 6-30
nucleotides, wherein a nucleotide within said third nucleotide sequence is
labeled” (Nazarenko, col. 19, ll. 51-53).
7. Nazarenko teaches “(d) at the 3' end of said oligonucleotide, a
fourth, single-stranded nucleotide sequence of 8-40 nucleotides that
comprises at its 3' end a sequence sufficiently complementary to a
preselected target” (Nazarenko, col. 19, ll. 65-67).
8. Nazarenko teaches that the “oligonucleotides . . . can be used in
methods of diagnosis, wherein a 3' primer sequence is complementary to a
sequence (e.g., genomic) of an infectious disease agent, e.g. of human
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disease including but not limited to viruses, bacteria, parasites, and fungi,
thereby diagnosing the presence of the infectious agent” (Nazarenko, col. 19,
ll. 15-20).
9. Nazarenko teaches that the oligonucleotide “can be used in the
diagnosis or prognosis of a disease or disorder, the target sequence is a wild
type human genomic or RNA or cDNA sequence, mutation of which is
implicated in the presence of a human disease or disorder, or alternatively,
can be the mutated sequence” (Nazarenko, col. 19, ll. 24-27).
10. Nazarenko teaches that in “a specific embodiment, the second
nucleotide sequence (the loop structure) . . . do not contain a sequence
complementary to the target sequence” (Nazarenko, col. 20, ll. 16-20).
11. Nazarenko teaches that the “second nucleotide sequence and/or
the first nucleotide sequence and/or the third nucleotide sequence or any
portion of the foregoing sequences may also contain a sequence
complementary to the target sequence” (Nazarenko, col. 20, ll. 20-23).
12. Figures 24A and 24G are reproduced below:

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“FIGS. 24A-G show the fluorescence intensity of PSA cDNA amplified with
different FAM/DABCYL-labeled hairpin primers” (Nazarenko, col. 12, ll. 1-
3).
Principles of Law
“To anticipate a claim, a prior art reference must disclose every
limitation of the claimed invention, either explicitly or inherently.
Anticipation is an issue of fact, and the question of whether a claim
limitation is inherent in a prior art reference is a factual issue.” In re
Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997) (citations omitted).
Analysis
Claim Interpretation
We begin, like the Examiner, with claim interpretation. We interpret
claim 1 to require an oligonucleotide which contains three distinct structural
domains. Claim 1 requires a first structural element which is an “anchor”
domain, which the Specification teaches is “preferably about 15-150
nucleotides” (Spec. 4 ¶ 0011). This “anchor” domain binds to a target
nucleic acid. Continuing along the oligonucleotide, claim 1 then requires a
second structural element which is a “bridging” domain, composed of 2-11
nucleotides, and which does not bind to the target nucleic acid. The third
structural element required by claim 1 is a “binding” domain, composed of
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2-20 nucleotides and which has a lower affinity for the target nucleic acid
than the “anchor” domain. The final structural requirement of claim 1 is that
the target nucleic acid is a sequence associated with a disease, broadly open
to any genetic disease or mutation as well as any infectious disease.
Claim 1 also includes a functional requirement that the combined
“bridging” and “binding” domains have the capacity to discriminate between
a matching target nucleic acid and a mismatching target nucleic acid and that
the target nucleic acid comprises a disease or condition sequence.
Nazarenko
Analyzing Nazarenko in light of this claim interpretation, Nazarenko
teaches an oligonucleotide composed of four parts as shown in Figure 1 (FF
2). Part “d” is a sequence which binds to a target sequence that is 8 to 40
nucleotides in length (FF 3, 7). Nazarenko incorporates a part “c” of 6 to 30
nucleotides (FF 3, 6). Continuing along Nazarenko’s oligonucleotide,
Nazarenko teaches a part “b” of 3 to 20 nucleotides which forms a single-
stranded loop (FF 3, 5). The final structural element in Nazarenko is a part
“a”, composed of 6 to 30 nucleotides (FF 3, 4). We note that claim 1 uses
the open “comprising” transitional statement and therefore is open to
additional components such as part “c”.
Comparing Nazarenko to claim 1, Nazarenko’s part “d” reasonably
corresponds with “anchor” region in claim 1, part “b” with the “bridging
domain in claim 1, and part “a” with the “binding” domain in claim 1.
Nazarenko expressly teaches that part “d” binds to the target nucleic acid
(FF 7). Nazarenko teaches that part “b” “the second nucleotide sequence (the
loop structure) . . . do[es] not contain a sequence complementary to the
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target sequence” (Nazarenko, col. 20, ll. 16-20; FF 10). Nazarenko teaches
that part “a” “may also contain a sequence complementary to the target
sequence” (Nazarenko, col. 20, ll. 20-23; FF 11).
Nazarenko teaches target nucleic acids which are associated with a
disease or condition, as well as sequences that are associated with an
infectious organism, and sequences comprising a genetic variation (FF 8-9).
Figure 24A of Nazarenko, relied upon by the Examiner, exemplifies
an oligonucleotide where the 3' single stranded part “d” or “anchor”
sequence is composed of 12 nucleotides (GACCAAGTTCAT), the part “b”
or “bridging” sequence is composed of 6 nucleotides (ACCCTC), and the
part “a” or “binding” sequence is composed of 7 nucleotides (ACCTTCT).
Since the affinity of hybridization is based substantially the length of the
hybridizing sequence, the “a” or “binding” domain will necessarily have less
affinity for the target nucleic acid than the “d” or “anchor” sequence in
Figure 24A of Nazarenko.
Thus, Nazarenko teaches oligonucleotides which reasonably comprise
both the structural and functional requirements of the oligonucleotide of
claim 1.
Appellants contend that
Nazarenko fails to disclose any oligonucleotide having (1)
an anchor region complimentary to a target nucleic acid and
(b) a switch domain that includes (i) a binding domain with
bases complimentary to the target nucleic acid and (ii) a
bridging domain having 2-11 universal, generic or
mismatched bases or analogues thereof or a mixture of
universal and non-hydrogen bonding natural bases that do
not form a hybridization complex with the target nucleic
acid; and wherein the target nucleic acid includes a sequence
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that is associated with a disease or condition, that is
associated with an infectious organism or that includes a
genetic variation.

(App. Br. 8).
We are not persuaded. As we have discussed above, the
oligonucleotides taught by Nazarenko are reasonably composed of the
anchor region (part “d”) (FF 3, 7), a bridging domain (part “b”) (FF 3, 5) and
a binding domain (part “a”) (FF 3, 4) where the target nucleic acid is
associated with a disease (FF 8-9).
Appellants contend that the “Examiner has identified no target for the
Nazarenko figure 24 oligonucleotide that includes a sequence that is
associated with a disease or condition, or infectious organism, or any
sequence that includes a genetic variation” (App. Br. 9).
We are not persuaded. The rejection is not limited to Figure 24 of
Nazarenko. Nazarenko expressly teaches that the “oligonucleotides . . . can
be used in methods of diagnosis, wherein a 3' primer sequence is
complementary to a sequence (e.g., genomic) of an infectious disease agent,
e.g. of human disease including but not limited to viruses, bacteria, parasites,
and fungi, thereby diagnosing the presence of the infectious agent”
(Nazarenko, col. 19, ll. 15-20; FF 8). Nazarenko also teaches that the
oligonucleotide “can be used in the diagnosis or prognosis of a disease or
disorder, the target sequence is a wild type human genomic or RNA or
cDNA sequence, mutation of which is implicated in the presence of a human
disease or disorder, or alternatively, can be the mutated sequence”
(Nazarenko, col. 19, ll. 23-28; FF 9). These are express teachings to target
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the oligonucleotide to diseases or conditions, including infectious disease
agents or genetic variations (FF 8-9).
Appellants contend that the “Examiner has certainly not established
that the Nazarenko oligonucleotides could meet the functional requirements
of the claims by inherent anticipation” (App. Br. 10).
We are not persuaded. As we discussed above, Nazarenko teaches
oligonucleotides where part “d” hybridizes to the target nucleic acid, part
“b” is a non-hybridizing “loop” and part “a” may also hybridize to the target
nucleic acid (FF 3-7, 11). At least some of these oligonucleotides would
inherently satisfy the functional requirement of part “d” binding with greater
affinity than part “b” as in figure 24A discussed above (FF 12). Appellants
have not provided any evidence to the contrary. See In re Best, 562 F.2d
1252, 1255 (CCPA 1977) (“Where, as here, the claimed and prior art
products are identical or substantially identical, or are produced by identical
or substantially identical processes, the PTO can require an applicant to
prove that the prior art products do not necessarily or inherently possess the
characteristics of his claimed product.… Whether the rejection is based on
‘inherency’ under 35 U.S.C. § 102, on ‘prima facie obviousness’ under
35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same, and
its fairness is evidenced by the PTO’s inability to manufacture products or to
obtain and compare prior art products.)
Claims 24-25, 35
Appellants contend that the “Examiner has not and cannot point to
any Naz[a]renko oligonucleotide meeting the requirements of claim 1 in
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which the target the target nucleic acid comprises a sequence that is
associated with a disease or condition” (App. Br. 11).
We are not persuaded. Nazarenko teaches that the “oligonucleotides .
. . can be used in methods of diagnosis, wherein a 3' primer sequence is
complementary to a sequence (e.g., genomic) of an infectious disease agent,
e.g. of human disease including but not limited to viruses, bacteria, parasites,
and fungi, thereby diagnosing the presence of the infectious agent”
(Nazarenko, col. 19, ll. 15-20; FF 8). This is an express teaching to target an
infectious organism.
Claims 26-34
Appellants contend that the “Examiner has not and cannot point to
any Nazer[a]nko oligonucleotide meeting the requirements of claim 1 in
which the target the target nucleic acid comprises a sequence comprising a
human genetic variation” (App. Br. 11). For each of the further dependent
claims, specific human variations, including SNPs, are encompassed.
We are not persuaded. Nazarenko teaches that the oligonucleotide
“can be used in the diagnosis or prognosis of a disease or disorder, the target
sequence is a wild type human genomic or RNA or cDNA sequence,
mutation of which is implicated in the presence of a human disease or
disorder, or alternatively, can be the mutated sequence” (Nazarenko, col. 19,
ll. 24-27; FF 9). This is an express teaching to target human diseases,
including where a mutation, singular, is present and causative.

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Claims 36-39
Appellants contend that “[n]one of the prior art cited by the Examiner
discloses, teaches or suggests any oligonucleotide having a universal base as
required by claims 36-39” (App. Br. 14).
We begin with claim interpretation. We first look to the Specification
to determine the meaning of the term “universal bases.” The Specification
teaches that “[u]niversal non-hydrogen bonding natural bases or analogues
thereof or a mixture of universal and non-hydrogen bonding natural bases or
analogues thereof suitable for use with the embodiments described herein
include . . . natural bases A, T, C, G and U and analogs thereof” (Spec. 28
¶ 0077; FF 1). Thus, read in light of Appellants’ Specification, the term
“universal bases” reasonably encompasses the natural bases A, T, C, and G.
Thus, the “bridging” domain may reasonably comprise universal bases
which are the natural bases A, T, C, and G. Nazarenko teaches the use of
ordinary bases in the equivalent “bridging” domain (FF 1, 3-7, 12).
Claims 40-41
Appellants contend that the “Examiner has not pointed to any
Naz[a]renko oligonucleotide meeting all the requirements of claim 1 and
that also has an anchor region at the 5' -end of the bridging domain, and a
binding domain is at the 3' -end of the bridging domain as required by the
claim” (App. Br. 15).
We are not persuaded. The oligonucleotide disclosed in Figure 24G
reasonably addresses the requirements of these claims. That oligonucleotide
shows a situation where the “a” region is 7 nucleotides, the “b” loop is 6
nucleotides, and the “d” region is 6 nucleotides, so that the “a” region will
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have greater affinity for a target sequence than the “d” region. Thus, the 5'
most “a” region may be interpreted as the “anchor”, followed by the “b”
region as the “bridging domain”, and the 3' most “d” region would function
as the “binding domain.” Since no specific target sequence is required, this
oligonucleotide reasonably satisfies the requirements of claims 40 and 41.
Conclusion of Law
The evidence of record supports the Examiner’s finding that
Nazarenko anticipates claim 1.
B. 35 U.S.C. § 103(a) over Nazarenko and Jayasena
The Examiner finds that “Nazarenko et al. do not teach all of the
limitations of claims 18 and 21” (Ans. 12). The Examiner finds that
“Jayasena et al. teach a 5' modification of an oligonucleotide, wherein the
modified oligonucleotide is resistant to digestion by enzymes possessing 5'
nuclease activity (see paragraph 0053, where 5' modification necessarily
prevents 5' nuclease digestion)” (Ans. 12). The Examiner also finds that
“Jayasena et al. teach the oligonucleotide is attached to an electron
conducting solid surface, and wherein the amount of hybridization to said
target nucleic acid controls the amount of current flow (see paragraph 0062,
where gold or silver are electron conducting solid surfaces)” (Ans. 13).
Claim 18
Appellants contend that
Instead of pointing to any reference or other evidence to
support the allegation that one would be motivated to add a
5'-modification group to an oligonucleotide to prevent
enzymatic degradation, the Examiner improperly relies on a
completely unsupported personal opinion that “it is well
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known in the art that modifying the 5' end of an
oligonucleotide will prevent digestion by 5' nucleases.”

(App. Br. 18).
We find the Examiner has the better position. Claim 18 requires a
structural “5' modification” to the oligonucleotide, and then includes a
functional recitation that “said modified oligonucleotide is resistant to
digestion by enzymes possessing 5' nuclease activity” (Claim 18). The
Examiner has provided a teaching by Jayasena that oligonucleotide
“[m]odifications can also include 3' and 5' modifications such as capping”
(Jayasena 6 ¶ 0053). Thus, the Examiner has provided evidence that 5'
modifications including capping represent known alterations of
oligonucleotides. The dictionary definition of “RNA Caps” is “[n]ucleic
acid structures found on the 5' end of eukaryotic cellular and viral messenger
RNA and some heterogeneous nuclear RNAs. These structures, which are
positively charged, protect the above specified RNAs at their termini against
attack by phosphatases and other nucleases.”4 Thus, while we also would
have preferred a citation rather than “common knowledge,” the dictionary
definition of “capping” in molecular biology is a modification which
protects against nucleases. We also find that, in the absence of evidence
presented by Appellants, incorporating the 5' modification of Jayasena into
the oligonucleotide of Nazarenko would inherently result in an
oligonucleotide resistant to 5' nuclease activity. Best, 562 F.2d at 1255.

4 See http://de.dict.md/definition/mRNA (accessed Feb. 13, 2013).
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Claim 21
Appellants contend that the “Examiner makes no attempt whatsoever
to explain why one would combine any of the disclosures of Jayasena
paragraph 0062 with any Nazarenko oligonucleotides” (Ans. 18).
The Examiner provides no response for claim 21, nor does the
Examiner provide a reason to place the oligonucleotide of Nazarenko onto a
solid support in the original grounds of rejection (see Ans. 13).
We are therefore constrained to reverse the rejection of claim 21 since
the Examiner has failed to establish a prima facie case of obviousness.
SUMMARY
In summary, we affirm the rejection claims 1-8, 12-17, 19, 20, and 24-
41 under 35 U.S.C. § 102(e) as anticipated by Nazarenko.
We affirm the rejection of claim 18 under 35 U.S.C. § 103(a) as
obvious over Nazarenko and Jayasena.
We reverse the rejection of claim 21 under 35 U.S.C. § 103(a) as
obvious over Nazarenko and Jayasena.

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-IN-PART

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