Ex Parte Cook et al

Board of Patent Appeals and Interferences

Sep 13, 2010

10352586 (B.P.A.I. Sep. 13, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
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.
10/352,586 01/28/2003 Phillip Dan Cook ISIS-5137 8969
32650 7590 09/13/2010
WOODCOCK WASHBURN LLP
CIRA CENTRE, 12TH FLOOR
2929 ARCH STREET
PHILADELPHIA, PA 19104-2891
EXAMINER
VIVLEMORE, TRACY ANN
ART UNIT PAPER NUMBER
1635
MAIL DATE DELIVERY MODE
09/13/2010 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte PHILLIP DAN COOK and
ANDREW MAMORU KAWASAKI
__________

Appeal 2009-015388
Application 10/352,586
Technology Center 1600
__________

Before ERIC GRIMES, TONI R. SCHEINER, and LORA M. GREEN,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a
compound comprising 2' fluoro-substituted nucleosides. The Examiner has

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
Appeal 2009-015388
Application 10/352,586

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rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
The Specification discloses “nuclease resistant oligonucleotides which
are useful as therapeutics, diagnostics, and research reagents” (Spec. 1: 24-
26).
Claims 6, 7, 10, 12 and 18 are on appeal. Claim 10 is representative
and reads as follows:
10. A compound comprising a plurality of covalently-bound
nucleosides that individually include a ribose or deoxyribose sugar portion
and a base portion, wherein:
said nucleosides are joined together by internucleoside linkages such
that the base portion of said nucleosides form a mixed base sequence;
and wherein at least five of said nucleosides includes a modified
ribofuranosyl moiety bearing a 2'-fluoro substituent.

Issue
The Examiner has rejected claims 6, 7, 10, 12 and 18 under 35 U.S.C.
§ 103(a) as being obvious in view of Inoue,2 Ohtsuka,3 and Ikehara.4
The Examiner finds that Inoue discloses “probes comprising 2'-OMe
substituents whose thermal stability is comparable to all-RNA probes” and
are resistant to digestion by nucleases (Appeal Br. 4). The Examiner finds

2 Hideo Inoue et al., Synthesis and hybridization studies on two
complementary nona(2’-O-methyl)ribonucleotides, 15 NUCLEIC ACIDS
RESEARCH 6131-6148 (1987)
3 Ko Ohtsuka et al., Recognition by restriction endonuclease EcoRI of
deoxyoctanucleotides containing modified sugar moieties, 139 EUROPEAN
JOURNAL OF BIOCHEMISTRY 447-450 (1984)
4 Morio Ikehara et al., Polynucleotides. L. Synthesis and properties of poly
(2'-chloro-2'- deoxyadenylic acid) and poly (2'-bromo-2'-deoxyadenylic
acid), 4 NUCLEIC ACIDS RESEARCH 4249-4260 (1977)
Appeal 2009-015388
Application 10/352,586

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that Ohtsuka discloses “the chemical synthesis of oligonucleotides
comprising 2'-fluoro substituted nucleotides” (id.) and Ikehara discloses
“that polynucleotides comprising 2'-chloro and 2'-bromo substituents are
resistant to exonuclease digestion” (id.).
The Examiner concludes that the claimed compounds would have
been obvious to one of ordinary skill in the art because “those in the art were
aware of the availability of 2'-fluoro nucleotides … and because Inoue et al.
teach that [the] use of 2'-OMe substituents … increase[s] nuclease resistance
of RNA probes and Ikehara et al. teach that halogen substituents provide the
same property of increasing nuclease resistance” (id.).
Appellants contend that the evidence of record does not support the
Examiner’s assertion that a 2'-fluoro substituent would have been expected
to increase resistance of an oligonucleotide to nuclease digestion (Appeal Br.
6-8). Appellants also contend that the teachings of the references are
incompatible and can be combined only through hindsight (id. at 9-10).
Appellants also contend that the cited references would not make obvious
the limitations of dependent claims 7 and 18 (id. at 12-13).
The main issue presented is: Does the evidence of record support the
Examiner’s conclusion that one of ordinary skill in the art would have
considered it obvious to make an oligonucleotide with ribofuranosyl
moieties bearing 2'-fluoro substituents?
Findings of Fact
1. Inoue discloses that “2'-O-methyl oligoribonucleotides can be
utilized as an alternative to an oligoribonucleotide probe in RNA
hybridizations as the hybrid formed has a high, or a higher Tm, the probe is
Appeal 2009-015388
Application 10/352,586

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much easier to synthesize and it is less likely to be enzymatically degraded”
compared to unsubstituted ribonucleotide probes (Inoue, abstract).
2. Inoue discloses that “homo- and co-polymers containing 2'-O-
methyl ribonucleosides are stable to alkaline treatment and RNase digestion,
and resistant to digestion by certain nucleolytic enzymes” (id. at 6132).
3. Inoue discloses that “oligo(2'-O-methylribonucleotides) … can be
utilized as RNA hybridization probes or other biochemical tools” (id. at
6139).
4. Ohtsuka discloses that the “deoxyribooctanucleotide d(G-G-A-A-T-
T-C-C), containing the recognition sequence for EcoRI, d(G-A-A-T-T-C),
and analogs containing modified sugar moieties were tested for their activity
in cleavage with EcoRI” (Ohtsuka, abstract).
5. Ohtsuka discloses synthesis of oligonucleotides that include a 2'-
fluoroadenosine or 2'-fluoroguanosine subunit (id. at 447).
6. Ikehara discloses the synthesis of “[p]oly (2'-chloro-2'-
deoxyadenylic acid) [poly (Acl)] and poly (2'-bromo-2'-deoxyadenylic acid)
[poly (Abr)]” (Ikehara, abstract).
7. Ikehara discloses that “[p]olynucleotides … were incubated with
ribonuclease M.… While poly (A) was hydrolyzed completely in these
conditions, poly (Acl) and poly (Abr) were resistant to hydrolysis.” (Id. at
4253.)
8. Ikehara discloses that “[p]olynucleotides … were incubated with
snake venom phosphodiesterase.… While poly (A) was completely
hydrolyzed after 30 min, poly (Acl) and poly (Abr) were only hydrolyzed to
extents of 8% and 9%.… This fact suggests that large electronegative
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Application 10/352,586

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substituents inhibit hydrolysis catalyzed by snake venom phosphodiesterase
to some extent.” (Id.)
Analysis
Claim 10 is directed to a nucleoside-containing compound comprising
at least five nucleosides having a 2'-fluoro ribofuranosyl moiety.
Ikehara discloses that poly (2'-chloro-2'-deoxyadenylic acid) and poly
(2'-bromo-2'-deoxyadenylic acid) showed substantial resistance to hydrolysis
by snake venom phosphodiesterase and ribonuclease M in comparison to
unsubstituted poly (A). Ohtsuka discloses synthesis of oligonucleotides
having 2'-fluoroadenosine or 2'-fluoroguanosine as one of the nucleotides.
In view of these disclosures, it would have been obvious to one of ordinary
skill in the art to produce polynucleotides that have nucleosides with a 2'-
fluoro substituent on the ribofuranosyl moiety because Ohtsuka discloses
that such nucleosides are known and Ikehara discloses that modified
nucleosides having a halogen substituent at the 2' position provide resistance
to nuclease digestion. Ikehara, Ohtsuka, and Inoue all provide evidence that
such 2'-substituted oligonucleotides would be recognized by those skilled in
the art as useful research tools.
Appellants argue that the prior art does not support the Examiner’s
position that resistance to nuclease digestion is a general consequence of 2'-
substitution (Appeal Br. 7). Appellants cite Uhlmann5 as disclosing “that 2'-
O-Me oligoribonucleotides are not resistant to snake venom
phosphodiesterase” (id.). Appellants also argue that Inoue’s statement that

5 Eugen Uhlmann et al., Antisense Oligonucleotides: A New Therapeutic
Principle, 90 CHEMICAL REVIEWS NO. 4, 544-584 (1990)
Appeal 2009-015388
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2'-O-methyl probes have nuclease resistance was based on a citation to two
other references, which do not in fact support Inoue’s statement (id. at 7-8).
These arguments are not persuasive because, whatever the prior art
discloses about 2'-O-methyl modifications and nuclease resistance, Ikehara
shows that 2'-halogen substitutions (i.e., chloro and bromo substitutions)
increase the nuclease resistance of polynucleotides. Based on Ikehara, a
skilled worker would reasonably expect that a 2’-fluoro substitution, another
halogen, would also increase the nuclease resistance of an oligonucleotide.
Although Appellants argue that Ikehara states that its “findings are limited to
the effects observed with ‘large electronegative susbtituents [sic]’ (as
opposed to, for example, relatively small substituents such as 2'-F)” (Appeal
Br. 8), they provide no evidence or sound scientific reasoning to show that a
skilled worker would not expect Ikehara’s results to apply to another
halogen like fluorine.
Appellants also argue that the “teachings of the applied references are
inherently incompatible” because Ohtsuka discloses a modified DNA
sequence while Inoue teaches that ribonucleotides are preferable to
deoxyribonucleotides (Appeal Br. 9). Appellants also argue that the
references are incompatible because they teach different numbers of
substituted nucleotides in their products (id.) and different uses for 2'-
substituted oligonucleotides (id.), and because they teach that different 2'-
substitutions have different effects on hybridization (id. at 10).
These arguments are not persuasive. All of the references cited by the
Examiner disclose oligonucleotides with subunits substituted at the 2'
position of the ribofuranosyl moiety, and each of the references discloses
that the substituted oligonucleotides are useful research tools (e.g., as
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Application 10/352,586

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hybridization probes). We therefore do not agree with Appellants’ position
(Appeal Br. 9) that the references can be combined only with the benefit of
hindsight.
With regard to claim 7, Appellants argue that the “compounds
described in Ohtsuka are octamers while those described in Inoue are
nonamers” (Appeal Br. 12), and the Examiner has not adequately explained
why one of skill in the art would have made a compound comprising 12 to
25 nucleosides, as recited in claim 7 (id.). Similarly, with regard to claim
18, Appellants argue that the Examiner has not shown that an
oligonucleotide having at least two nucleosides with a 2'-fluoro substituent,
as required by claim 18, would have been obvious (id. at 13)
These arguments are not persuasive. We agree with the Examiner’s
position (Answer 11) that the evidence shows that oligonucleotide synthesis
was well known in the art and it would have been routine, and therefore
obvious, for a skilled worker to synthesize a 2'-substituted oligonucleotide of
any desired size or with any desired number of 2'-modified substituents.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that one
of ordinary skill in the art would have considered it obvious to make an
oligonucleotide with ribofuranosyl moieties bearing 2’-fluoro substituents.
SUMMARY
We affirm the rejection 6, 7, 10, 12 and 18 under 35 U.S.C. § 103(a).
Appeal 2009-015388
Application 10/352,586

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TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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WOODCOCK WASHBURN LLP
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