Ex Parte Bhat et al

Patent Trial and Appeal Board

Jun 7, 2016

11565858 (P.T.A.B. Jun. 7, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111565,858 12/01/2006
88395 7590 06/09/2016
BAKER & HOSTETLER LLP
CIRA CENTRE 12th FLOOR
2929 ARCH STREET
PHILADELPHIA, PA 19104
FIRST NAMED INVENTOR
Balkrishen Bhat
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
ISIS-6129/CORE0055US.C4 4837
EXAMINER
MCDONALD, JENNIFER SUE PITRAK
ART UNIT PAPER NUMBER
1674
NOTIFICATION DATE DELIVERY MODE
06/09/2016 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
eofficemonitor@bakerlaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte BALKRISHEN BHAT, THAZHA P. PRAKASH,
PRASAD DANDE, CHARLES ALLERSON,
RICHARD H. GRIFFEY, and ERICE. SWAYZE 1
Appeal2013-006008
Application 11/565,858
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
composition containing 2 '-modified nucleosides. The Examiner rejects the
claims as obvious and on the ground of nonstatutory obviousness-type
double patenting. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 According to Appellants, the Real Party in Interest is Isis Pharmaceuticals,
Inc. (Br. 1.)
Appeal2013-006008
Application 11/565,858
STATEMENT OF THE CASE
Claims 1, 28, 34-37, and 41 are on appeal, and can be found in the
Claims Appendix of the Appeal Brief. Claim 1 is representative of the
claims on appeal, and reads as follows:
1. A composition comprising first and second chemically
synthesized oligomeric compounds wherein:
the first oligomeric compound is fully complementary to a
selected nucleic acid target and to the second oligomeric
compound;
each of the first and second oligomeric compounds
independently consists of 19 nucleosides;
the second oligomeric compound is a symmetric gapped
oligomeric compound comprising
a 5' region consisting of three 2' -0-( CH2)2-0CH3 modified
nucleosides;
a central region consisting of thirteen B-D-ribonucleosides; and
a 3' region consisting of three 2' -O-(CH2)2-0CH3 modified
nucleosides;
the first oligomeric compound comprises nucleosides linked by
intemucleoside linking groups wherein the sequence of linked
nucleosides defines an alternating motif having the formula:
5' -A(-L-B-L-A)n(-L-B)nn 3'
wherein:
each Lis, independently, an intemucleoside linking group;
each A is a sugar modified nucleoside wherein each A has the
same sugar modification, and each A is either a 2 ' -F modified
nucleoside or a 2 '-OMe modified nucleoside;
each B is a sugar modified nucleoside wherein each B has the
same sugar modification and each B is either a 2' -F modified
nucleoside or a 2 '-OMe modified nucleoside;
the sugar modification of each A is different than the sugar
modification of each B;
2
Appeal2013-006008
Application 11/565,858
n is 9;
nn is O; and
the composition optionally further comprises one or more
overhangs, phosphate moieties, conjugate groups and capping
groups, and the composition reduces the level of target mRNA
present in a cell contacted with the composition.
The Examiner rejects the claims as follows:
I. claims 1, 28, 34-37, and 41 under 35 U.S.C. § 103(a) as
unpatentable over Fosnaugh,2 Crooke,3 Monia,4 and Giese;5 and
II. claims 1, 28, 34-37, and 41 on the grounds of nonstatutory
obviousness-type double patenting over U.S. Patent No. 7,541,344 in
view of Fosnaugh, Crooke, Monia, and Giese.
I. Obviousness over Fosnaugh, Crooke, Mania, and Giese
The Examiner's position is that
Fosnaugh teaches siRNA duplex molecules targeting
ADORAl .... Fosnaugh describes chemically modified
nucleotides as those with a modified backbone, such as with
phosphorothioate intemucleotide linkages ... , and those with
2' -sugar modifications, such as 2' -0-methyl and 2 '-F ....
Fosnaugh teaches that sugar, base, and phosphate modifications
can be introduced into nucleic acid molecules to enhance
nuclease stability.
(Office Act. 46.)
2 Fosnaugh et al., US 2003/0143732 Al, published July 31, 2003.
3 Crooke, US 6,107,094, issued Aug. 22, 2000.
4 Monia et al., US 6,033,910, issued Mar. 7, 2000.
5 Giese et al., US 2004/0180351 Al, published Sept. 16, 2004.
6 Office Action mailed Jan. 14, 2011.
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Appeal2013-006008
Application 11/565,858
Based on the teachings of the other cited references, the Examiner
concludes that it "would be a matter of simple substitution of known
equivalents and such an siRNA would have reasonably been expected to
have improved qualities over an unmodified siRNA." (Id. at 7.)
Appellants contend that the Examiner is applying improper hindsight
in making the rejection because "the examiner does not start with a specific
prior art composition that is described in the Fos[ n ]augh application and
propose changes to that specific composition based upon teachings from the
prior art." (App. Br. 6.) According to Appellants Fosnaugh discloses "[a]
vast genus of possible chemical modifications for nucleosides is presented in
the Fosnaugh application which teaches that such modifications can be
incorporated into siRNA molecules is a virtually unlimited number of
patterns and combinations." (Id. at 8.) Appellants contend that the "data
provided in Example 17 of the [present] specification ... illustrate the
significant improvement in inhibitory activity that resulted from the
particular type and pattern of chemical modifications claimed." (Id. at 9.)
The issue is: Has the Examiner set forth a prima facie case of
obviousness and, if so, have Appellants provided sufficient evidence of
unexpected results that outweighs the evidence of prima facie obviousness?
Findings of Fact
We adopt the Examiner's finding and analysis concerning the scope
and content of the prior art as set out in the Office Action, Final Action 7 and
Answer. The following facts are repeated for reference convenience.
7 Final Action mailed Sept. 26, 2011.
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Appeal2013-006008
Application 11/565,858
FFl. Fosnaugh teaches that
the introduction of chemically modified nucleotides into nucleic
acid molecules ... provide[ s] a powerful tool in overcoming
potential limitations of in vivo stability and bioavailability ....
certain chemical modifications can improve the bioavailability
of nucleic acid molecules by targeting particular cells or tissues
and/or improving cellular uptake of the nucleic acid molecule.
(Fosnaugh ii 35.)
FF2. Figure 4D of Fosnaugh, reproduced below, shows a gapped
oligomeric compound.
SENSE STRAN:-J (~lf:Q m NO 32'.i.l
i\.U .. Rl~fl<.>NUCU,OTlDl'S LX(fi'T I'QSU1UNS (N Nl
.D N
. N' Ni '' N1 ~: N. N·' :..·: N~· .,.._, -~.: N·· XY N' N. N,· ~; N f>.Y N~·-·s.-· .s ~ 's i.'-~: 's r""< ~ 4 ' i'< ~ ~~).; _!"'C .:_':,: .~ • ~ s - :;t"t~ ~\~-~so'.'}
"N· '~) "'. ll..' N. 11., ·N· N· 11.~· N li>' N: .N "'' N .. N "'' N' N' ll..' N' {.: .. 'S~~ .. r~ r' r .~~: .t · r·~ l .~, 1 • .t .t1< ! : i .3 .r~~ .t '~?.· .~\·r's .i,
/1.NHS.E!'·;~n:.: 'f.LRAND (SEQ m N(> 3~,(.>J
;\LL RH-:IU"ES FXCFPT POSITIONS (N },:)
Figure 4D shows S = phosphororthioate or phosphorodithiate. (See
Fosnaugh Fig. 4D and ii 145 ; see also Office Act. 4 ("modified
siRNA molecules 19-21 nucleotides in length wherein the sense
strand has a gapped motif of phosphorothioate-linked nucleotides
flanking an internal region of B-D-ribonucleotides with
phosphodiester linkages").)
FF3. Figure 5A of Fosnaugh, reproduced below, shows a gapped
oligomeric compound.
~' .l>'-
(
15'-
-<
l 3'-
l
5
Appeal2013-006008
Application 11/565,858
Fig. 5A shows lower case= 2'-0-methyl; italic lower case= 2'deoxy-
2'fluoro; S = phosphororthioate or phosphorodithiate. (See Fosnaugh
Fig. 5A and ii 146; Office Act. 5 ("teaches an siRNA comprising a
second symmetric gapped oligomeric compound comprising a 5'
region consisting of one 2' -OCH3-modified nucleotide, a central
region consisting of five B-D-ribonucleosides, and a 3' region
consisting of one 2' -OCH3-modified nucleoside").)
FF4. Giese teaches
2' -0-methyl modified nucleotide and a non-modified
nucleotide ... are incorporated on both strands in an alternating
fashion, resulting in a strand having a pattern MOMOMOMOM
etc where M is a 2' -0-methyl nucleotide and 0 is a non-
modified nucleotide .... This particular arrangement, i.e. base
pairing of 2' -0-methyl modified and non-modified
nucleotide(s) on both strands is particularly preferred in case of
short interfering ribonucleic acids, i.e. short base paired double-
stranded ribonucleic acids.
(Giese ii 124; Office Act. 5.)
FF5. Crooke teaches that
In certain preferred oligomeric compounds ... , the first
or first and third segments of oligomeric compounds are formed
of nucleoside subunits that include 2' -substituent groups
thereon .... [A] preferred polyethylene glycol substituent is -O-
ethyl-0-methyl, i.e., methoxyethoxy or -O-CH2-CH2-0-CH3.
(Crooke col. 4. 1. 64 to col. 5, 1. 8; Office Act. 6.)
FF6. Monia teaches that"[ m ]odified oligonucleotides may also contain one
or more substituted sugar moieties .... A preferred modification
includes 2' -methoxyethoxy (2 '-O-CH2CH20CH3, also known as 2' -0-
(2-methoxyethyl) or 2'-MOE)." (Monia col. 8, 11. 12-34; Office
Act. 6.)
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Appeal2013-006008
Application 11/565,858
Principle ofLaw
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Analysis
Appellants contend that the Examiner is applying improper hindsight
in making the rejection because "the examiner does not start with a specific
prior art composition that is described in the Fos[ n ]augh application and
propose changes to that specific composition based upon teachings from the
prior art." (App. Br. 6.)
While we are fully aware that hindsight bias often plagues
determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36
(1966), we are also mindful that the Supreme Court has clearly stated that
the "combination of familiar elements according to known methods is likely
to be obvious when it does no more than yield predictable results." KSR,
550 U.S. at 416.
The KSR reasoning is applicable here, where the combination of
Fosnaugh, Crooke, Monia, and Giese each teaches siRNA molecules and
methods of stabilizing such molecules to improve the cellular uptake of such
compounds (see FF l-FF6; see also Ans. 5 ("phosphate modifications can be
introduced into nucleic acid molecules to enhance nuclease stability"), 6
("the alternating pattern ... demonstrate that siRNAs with such
modifications are active and stabilized against nuclease degradation"), 7
("gapped antisense oligonucleotides useful, also, for stabilizing antisense
oligonucleotides used for downregulating gene expression"), 7 (sugar
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Appeal2013-006008
Application 11/565,858
modification "with 2'-methoxy, 2'-F, and 2'-MOE substituents for the
purpose of increasing nuclease resistance").)
According to Appellants Fosnaugh discloses "[a] vast genus of
possible chemical modifications for nucleosides is presented in the Fosnaugh
application which teaches that such modifications can be incorporated into
siRNA molecules is a virtually unlimited number of patterns and
combinations." (App. Br. 8.)
We are not persuaded. Even if Fosnaugh's generic disclosure may be
directed to an almost unlimited number of possible siRNA molecules as
explained by the Examiner, "the breadth of Fosnaugh's generic disclosure is
effectively narrowed by examples presented in Fosnaugh." (Ans. 14.)
Appellants even acknowledge this point finding that Fosnaugh "describes a
very limited number of chemically modified siRNA molecules that were
actually produced." (App. Br. 8.) The rejection, however, is based on the
combination of several references, and even if Fosnaugh's generic disclosure
may encompass many modifications the Examiner relies on the additional
references of Crooke, Mania, and Giese to establish that combination as a
whole is obvious and even to shows that certain modification are shown to
be preferred (FF4-FF6).
Appellants further contend that references "provides absolutely no
information regarding the effect that additional types or patterns of chemical
modifications, such as alternating 2' modifications, would have on the
stability or activity of siRNA molecules." (App. Br. 8.) This is also not
convincing as explained by the Examiner the combined art provides
guidance "in the form of known, effective, and practiced types and patterns
of modifications. Gapmers were known. Alternating motifs were known.
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Appeal2013-006008
Application 11/565,858
The 2'-sugar modifications, -MOE, -0-methyl, and -fluoro, were frequently
used in gapmers and alternating motifs. One of skill in the art would
therefore be motivated to start testing such types and patterns of
modifications in siRNAs. . . . [T]he art, as a whole, suggests at least trying
to make an siRNA according to the instant claims." (Advisory Action 2,
mailed Dec. 30, 2011.)
We conclude that the Examiner has met the burden of presenting a
prima facie case based on the combination of Fosnaugh, Crooke, Mania, and
Giese for the reasons disclosed in the Office Action, Final Action and
Answer. Because the Examiner presents a prima facie case of obviousness,
we consider whether Appellants submit sufficient evidence or argument in
rebuttal. In re Rijckaert, 9 F.3d 1531, 1532 (Fed. Cir. 1993).
Appellants contend that the "data provided in Example 17 of the
[present] specification ... illustrate the significant improvement in
inhibitory activity that resulted from the particular type and pattern of
chemical modifications claimed." (App. Br. 9.)
We balance the evidence regarding unobviousness against that
provided in the cited prior art and we concluded that "an obviousness
finding was appropriate where the prior art 'contained detailed enabling
methodology for practicing the claimed invention, a suggestion to modify
the prior art to practice the claimed invention, and evidence suggesting that
it would be successful."' In re Kubin, 561F.3d1351, 1360 (Fed. Cir. 2009)
(citing In re O'Farrell, 853 F.2d 894, 902 (Fed. Cir. 1988)). Here,
Fosnaugh teaches the production of siRNA molecules including chemical
modification in order to improve the stability and bioavailability of the
molecules (FF l-FF3), Giese teaches the alternating motifs to improve
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Application 11/565,858
stability (FF4), while Crooke and Monia teach the desirability to incorporate
the methoxyethoxy group into the nucleoside subunit (FF5 and FF6). This
evidence, balanced against the assertion of unexpected results, supports a
finding that there would have been a "reasonable expectation of success"
and that the claims would have been obvious over the cited prior art.
We agree with the Examiner that based on the present facts,
Appellants have "not adequately shown that the results disclosed in the
specification are unexpected." (Final Act. 3.) The Examiner explains that
The IC50 values exhibited by siRNAs modified as in the
instant claims are well within the range of IC50 values
exhibited by all of the modified siRNAs. The IC50 values
range from