Ex Parte Sampson et al

Board of Patent Appeals and Interferences

Dec 18, 2009

10324409 (B.P.A.I. Dec. 18, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte JEFFREY R. SAMPSON,
ROBERT A. ACH, and PAUL WOLBER
____________

Appeal 2009-015422
Application 10/324,409
Technology Center 1600
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Decided: December 18, 2009
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Before ERIC GRIMES, LORA M. GREEN, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by the patent applicants from the
rejection of claims 1-50. The Board’s jurisdiction for this appeal is under 35
U.S.C. §§ 6(b) and 134. We affirm.

Appeal 2009-015422
Application 10/324,409

STATEMENT OF THE CASE
“Naturally occurring ribonucleic acid (RNA) and deoxyribonucleic
(DNA) acid molecules contain nucleotides which are capable of forming
base pairs through hydrogen bond interactions with complementary
nucleotides” (Spec. 1). Intramolecular base pairing between complementary
nucleotides in a single molecule of DNA or RNA results in the formation of
secondary structures, such as loops, duplexes, hairpin structures, three-way
junctions, and four-way junctions (Spec. 2). Secondary structure in a
nucleic acid molecule can interfere with hybridization of complementary
nucleic acid molecules, limiting “the sensitivity, specificity and utility of
applications that rely upon hybridization of probes used to analyze nucleic
acid molecules” (id.). These applications include in situ hybridization, DNA
array technology, and gene expression assays (id.).
To address the aforementioned problems, the instant application is
said to provide nucleic acid molecules which contain modified nucleotide
bases which do not form stable hydrogen bonds with each other, but which
base pair with their natural complements (id. at 4-5; see Fig. 1). Examples
include 2-aminoadenosine for adenine and 2-thiothymidine for thymine (id.
at 8). The nucleic acids which contain the modified nucleotides have
reduced secondary structure because of the absence of intramolecular base
pairing and are referred to by the inventors as “unstructured nucleic acids”
or “UNAs.” The modified nucleotides are called “UNA nucleotides”
because they impart reduced secondary structure when incorporated into a
nucleic acid.
This is the second time this application has been before us. A
previous Appeal (2007-2963) was decided October 31, 2007 (“Decision” or
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“Dec.”) in which we affirmed the rejections of claims 1-3, 5-7, and 9-50,
reversed the rejection of claims 4 and 8, and set forth a new ground of
rejection over claims 4 and 8. Appellants amended the claims (Feb. 1, 2008)
following the Decision. Subsequently, Appellants filed a Request for
Continued Examination (“RCE”; filed Jul. 18, 2008) in response to a Final
Rejection in which the Examiner had rejected the amended claims as
obvious over the Kutyavin and Vivekananda references and over copending
application No. 10/423,199 (Mar. 20, 2008). This appeal is from the
Examiner’s rejections in the RCE.
Claims 1-50, which are all the pending claims, stand rejected.
Appellants seek review of the following rejections:
Claims 1-50 under 35 U.S.C. § 103(a) as obvious in view of Kutyavin
et al. (U.S. Pat. No. 5,912,340, issued Jun. 15, 1999) and Vivekananda et al.
(U.S. Pat No. 6,569,630 B1, issued May 27, 2003) (Ans. 4); and
Claims 1-18 on the ground of nonstatutory obviousness-type double
patenting as unpatentable over claims 1 and 3-9 of copending Application
Serial No. 10/423,199 (Ans. 4-5).
Claim 1, which is representative, is reproduced below:
1. A first single-stranded unstructured nucleic acid molecule with reduced
secondary structure relative to a nucleic acid molecule of substantially
identical nucleotide sequence having naturally occurring nucleotides,
wherein said molecule possesses at least two sequence elements each of at
least three contiguous nucleotides that are complementary to one another,
wherein said complementary sequence elements have reduced levels of base-
pairing stability relative to a nucleic acid molecule of substantially identical
nucleotide sequence having naturally occurring nucleotides and said
sequence elements in said substantially identical nucleotide sequence having
naturally occurring nucleotides hybridize to each other to produce
intramolecular base pairs resulting in a secondary structure, wherein said
complementary sequence elements of the first unstructured nucleic acid
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molecule can form stable base-pairs with complementary sequence elements
present in a second nucleic acid molecule.

REJECTION OVER KUTYAVIN AND VIVEKANANDA
Statement of the issue
The claims are directed to a “single stranded unstructured nucleic acid
molecule” (“UNA”) as were the claims in the first appeal before us. The
claimed UNA:
possesses at least two sequence elements . . . that are
complementary to one another, wherein said complementary
sequence elements have reduced levels of base-pairing stability
relative to a nucleic acid molecule of substantially identical
nucleotide sequence having naturally occurring nucleotides.
In the previous Decision, we interpreted the aforementioned claim limitation
to mean that the sequence elements comprise modified complementary
nucleotides which are unable to base pair with one another, but retain the
ability to base pair with their naturally occurring complements (Decision 4-
5). For example, where one sequence element comprises an adenine (A)
nucleotide and the other sequence element comprises a thymine (T)
nucleotide, the modified nucleotides 2-aminoadenosine and 2-thiothymidine,
respectively, would be substituted. 2-aminoadenosine and 2-thiothymidine
are unable to base pair with each other, but form base pairs with their
naturally occurring complements, thymine and adenine, respectively (Spec.
8).
In the earlier Decision, we had affirmed the rejection of claim 1 over
Kutyavin alone because Kutyavin described a nucleic acid molecule
incorporating modified base pairs with a reduced ability to bind to each
other and therefore would have inherently been “unstructured” with
“reduced secondary structure relative to a nucleic acid molecule of
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substantially identical nucleotide sequence having naturally occurring
nucleotides” as required by claim 1 as it read then (Decision 7-8).
During subsequent prosecution, claim 1 was amended, inter alia, to
require that the recited two sequence elements each have “at least three
contiguous nucleotides” that are complementary to each other. Because the
claim requires that the “complementary sequence elements have reduced
levels of base-pairing stability,” the Examiner interpreted this to mean that
modified UNA nucleotides were incorporated at each of these positions.
The Examiner found that it would have been obvious to persons of ordinary
skill in the art to have designed a nucleic acid with two sequence elements,
each having at least three contiguous modified nucleotides that are
complementary to one another because “such minimal regions of
complementarity have been taught by both Vivekananda and Kutyavin (see
e.g. col. 6-7 of Vivekananda).” (Ans. 11.) The Examiner also reasoned that
the skilled worker “would have been motivated to design and synthesize
such nucleic acid molecules” with modified nucleotides for their advantages
as taught by Kutyavin and Vivekananda to control self-annealing so they
would be available to hybridize to target RNA or DNA (id. at 11-12).
Appellants state that “the appealed claims are different from those
present in the last appeal because they require a nucleic acid that has a pair
of complementary triplets [three contiguous nucleotides] that would cause
secondary structure if they weren’t substituted with UNA nucleotides.”
(App. Br. 8-9.) Appellants acknowledge that Kutyavin describes nucleic
acid molecules with UNA nucleotides and methods of making UNA
nucleotide-containing nucleic acids by synthetic and enzymatic methods (id.
at 9). However, Appellants contend that Kutyavin does not disclose or
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suggest “a nucleic acid that has a pair of complementary triplets that would
otherwise cause secondary structure if they weren’t substituted by UNA
nucleotides” (id.). Appellants argue that Kutyavin did not recognize UNA
nucleotides could be used to disrupt secondary structure, did not use them
for this purpose, and that its oligonucleotides did not have reduced
secondary structure (id. at 9 & 11). Because of these deficiencies,
Appellants contend
while one of skill in the art might find modified nucleotides in
Kutyavin’s disclosure, Kutyavin provides nothing that would
point one of skill in the art towards making an oligonucleotide
containing those modified nucleotides to reduce the secondary
structure of the oligonucleotide.
(Id. at 14.)
The issues in this appeal are: 1) whether the Examiner erred in
concluding that it would have been obvious to have made the claimed UNA
molecule in view of Kutyavin’s failure to recognize that UNA nucleotides
could be used to disrupt the secondary structure of a nucleic acid; and 2)
whether the Examiner erred in finding that Kutyavin’s nucleic acid
molecules had reduced secondary structure as compared to a molecule with
unmodified nucleotides.
Principles of Law
The question is not whether the combination was obvious to the
patentee but whether the combination was obvious to a person
with ordinary skill in the art. Under the correct analysis, 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. 398, 420 (2007).

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Findings of Fact (FF)
1. Kutyavin describes a matched pair of oligonucleotides (ODNs) which are
termed “Selective Binding Complementary (SBC) ODNs” (Kutyavin, at col.
1, ll. 64-65).
2. Each ODN includes modified nucleotide bases that form stable hydrogen
bonds with their natural complementary base partner, but which do not form
stable hydrogen bonds with their modified complementary base partner
(Kutyavin, at col. 1, ll. 40-47).
3. “[T]he matched pair of oligonucleotides . . . do not form substantially
stable hydrogen bonded hybrids with one another” (Kutyavin, at col. 1, ll.
51-53), but are able to form stable duplex hybrids with a complementary
target nucleotide sequence comprising only natural, unmodified bases (id. at
col. 2, ll. 14-23).
4. Kutyavin states that a “sufficient number of the modified . . . nucleotides
are incorporated such that complementary positions in both SBC ODNS are
modified into a matched pair of SBC ODNs of the present invention so that
the pair of the matched set does not form a stable hybrid” (Kutyavin, at col.
4, ll. 39-43).
5. However, both members of the matched pair are complementary to a
target sequence and able to form a stable hybrid with it (Kutyavin, at col. 4,
ll. 47-55; at col. 1, ll. 39-43).
6. Kutyavin states:
Due to the increased (approximately double) number of
hydrogen bonds in such hybrids (when compared to hybrids
that would be formed between a single ODN and duplex
nucleic acid) the hybrids formed with the ODN pairs of the
present invention are more stable, and lend themselves for gene
mapping, diagnostic and therapeutic use.
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(Kutyavin, at col. 1, ll. 58-64.)
7. Secondary structure occurs in a single molecule of DNA or RNA when
there are regions of sequence complementarity that permit the sequences to
hybridize together to form intramolecular loop, hairpin, duplex, and junction
structures (Spec. 1-2 & 6).
Analysis
It is undisputed that Kutyavin describes nucleic acid molecules which
contain modified UNA nucleotides (App. Br. 9). Based on this fact, the
Examiner found that Kutyavin’s nucleic acid would be unstructured and
have reduced secondary structure as compared to a nucleic acid with
naturally occurring bases as required by claim 1, because the former
incorporates modified nucleotides which do not base pair with one another
and therefore would not form the intramolecular bonds present in secondary
structure (FF2, 3, & 7; Ans. 14). This finding is supported by the facts and
consistent with our Decisions in related cases having similar claims also
rejected over the Kutyavin patent (Appeal No. 2008-5551 in Application
Serial No. 10/423,199, decided Feb. 4, 2009; Appeal No. 2007-2963 in
Application Serial No. 10/324,409, decided Oct. 31, 2007).
Appellants contend that the Examiner erred because Kutyavin did not
recognize that its modified nucleotides would serve to reduce secondary
structure and did not use them for this purpose (App. Br. 9 & 11).
This argument does not persuade us that the Examiner erred. It is true
that Kutyavin utilized its modified nucleotides to prevent two
complementary oligonucleotides from hybridizing together, a different
purpose than stated in the present application. It is also correct that
Kutyavin makes no explicit mention in its disclosure that its modified
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oligonucleotides would have reduced secondary structure as compared to the
same oligonucleotide prepared with naturally occurring nucleotides.
However, Kutyavin’s failure to recognize an inherent property of its nucleic
acid molecules does not defeat the rejection. The Examiner did not rely on
inherency as a basis for concluding that it would have been obvious to have
made the claimed unstructured nucleic acid molecules, but rather found
reason to make the modification in the reasons put forth by Kutyavin (Ans.
10-12).
Appellants’ argument fails to take sufficient account of the Supreme
Court’s ruling in KSR that “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.” 550 U.S. at 420.
Therefore, it is not fatal to the rejection that the Examiner had a different
reason for modifying the Kutyavin patent than the reason given by
Appellants in making the claimed unstructured molecule. The proper
question is whether the Examiner gave a sufficient basis for combining
Kutyavin with Vivekananda to have made the claimed UNA molecule.
As the reason for combining the prior art teachings, the Examiner
cited Kutyavin’s teaching of the desirability of making oligonucleotides with
modified nucleotide bases which do not form stable base pairs with one
another, but which are able to form stable duplex hybrids with a
complementary target nucleotide sequence comprising only natural,
unmodified bases (FF2-4 & 6; Ans. 6-7 & 11-12). These modified nucleic
acids are explicitly described by Kutyavin as useful in number of
applications, providing the reason to have made any desired nucleic acid
with any number of modified nucleotides according to Kutyavin’s directions
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(FF4; Ans. 11). Appellants do not identify a defect in the Examiner’s
reasoning other than to argue that Kutyavin’s purpose is different from their
own (App. Br. 13-14). However, as discussed above, this argument is
misplaced. The Examiner had a sufficient reason to combine the prior art
teachings and therefore established that the claimed invention was prima
facie obvious.
Appellants also argue that Kutyavin’s “oligonucleotides . . . do not
inherently contain reduced secondary structure as compared to otherwise
identical oligonucleotides made up of natural nucleotides.” (App. Br. 11.)
This argument is not convincing. As long as some complementary bases
were present in the oligonucleotides and substituted by modified UNA
nucleotides, they would have reduced structure in comparison to the same
oligonucleotide without them. These facts were established in the previous
Decision (Dec. 10, FF2) and have not been specifically disputed by
Appellants.

DOUBLE-PATENTING REJECTION
Claims 1-18 stand provisionally rejected on the ground of
nonstatutory obviousness-type double patenting as unpatentable over claims
1 and 3-9 of copending Application Serial No. 10/423,199.
Application Serial No. 10/423,199 is abandoned and is thus no longer
pending (see Notice of Abandonment, Apr. 27, 2009). Accordingly, we
dismiss the rejection as moot.

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CONCLUSION OF LAW AND SUMMARY
The Examiner did not err in concluding that it would have been
obvious to persons of ordinary skill in the art to have made the claimed
unstructured nucleic acid in view of the teachings of Kutyavin and
Vivekananda. The rejection of claim 1 is affirmed. Claims 2-50 fall with
claim 1 because separate reasons for their patentability were not provided.
37 C.F.R. 41.37(c)(1)(vii).
The obviousness-type double patenting rejection of claims 1-18 over
Application Serial No. 10/423,199 is dismissed as moot because the
application was abandoned.

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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