Ex Parte Koizumi et al

Patent Trial and Appeal Board

Apr 26, 2017

13001714 (P.T.A.B. Apr. 26, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/001,714 01/27/2011 Makoto Koizumi P218147.US.01 3673
108196 7590 04/28/2017
Daiichi Sankyo Company, Limited
c/o Dorsey & Whitney LLP
1400 Wewatta St., Suite 400
Denver, CO 80202
EXAMINER
POLIAKOVA-GEORGA, EKATERINA
ART UNIT PAPER NUMBER
1674
NOTIFICATION DATE DELIVERY MODE
04/28/2017 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.
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MAKOTO KOIZUMI and YASUHIDE HIROTA1
Appeal 2016-001230
Application 13/001,714
Technology Center 1600
Before ERIC B. GRIMES, JOHN G. NEW, and TIMOTHY G. MAJORS,
Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to double-
stranded-polynucleotides, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
STATEMENT OF THE CASE
According to the Specification, Appellants’ “invention relates to a
novel double-stranded polynucleotide that is resistant to RNase and has an
RNA interference effect.” (Spec. 11.) More specifically, Appellants
1 Appellants identify the Real Party in Interest as Daiichi Sankyo Company,
Limited. (App. Br. 3.)
Appeal 2016-001230
Application 13/001,714
disclose “a double-stranded polynucleotide comprising an oligonucleotide
unit of DNAs and 2'-0-methyl RNAs alternatively combined” that “is
resistant to RNase, can be synthesized at low cost, and has an RNA
interference effect.” (Id. at 124.)
Claims 22, 23, and 41—72 are on appeal.2 Claim 22, 23, and 41 are
independent claims. Claim 22 is illustrative:
22. A double-stranded polynucleotide or a salt thereof,
comprising polynucleotides represented by formulas (IV) and
(V):
5'-(a-P)9-ap-Vn-3'(IV)
5'-8b -(a-P)9-Vn-3' (V),
wherein:
a and P are independently selected from a DNA and a 2'-
OMeRNA, wherein if a is a DNA, then p is a 2'-OMeRNA, and
if a is a 2'-OMeRNA, then p is a DNA;
each occurrence of 8 is independently selected from a DNA and
a 2'-OMeRNA;
each occurrence of X is independently selected from a DNA and
a 2'-OMeRNA;
each occurrence of n is independently selected from a DNA and
a 2'-OMeRNA;
p is an integer of 0 or 1;
m is 0 when p is 0 and is selected from any integer of 0 to 5 when
p is 1;
s is an integer of 0 or 1;
n is selected from any integer of 0 to 5;
(a-P)9 -ap in the polynucleotide represented by formula (IV) has
a nucleotide sequence identical to a target gene;
the nucleotide sequences of (a-P)g in formula (IV) and (a-P)9 in
formula (V) are complementary to each other.
2 The Examiner objected to claims 38 and 39, as dependent from a rejected
base claim. (Ans. 6.)
2
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Application 13/001,714
(App. Br. (Claims App’x (i)).)
Claims 22, 23 and 41—72 stand rejected as obvious under 35 U.S.C.
§ 103(a) over Allerson3 and Manoharan.4 (Ans. 3.)
DISCUSSION
The Examiner finds the “[cjlaims are drawn to a double-stranded
polynucleotide, in which both strands contain alternating 2'-0-Met and 2'-
deoxy modifications motif, one of the strands comprises [a] sequence
identical to a target gene, and a portion of both strands is complementary to
each other.” (Ans. 3.)
According to the Examiner, “Allerson et al teach double-stranded
constructs with alternating 2'-0-Met and 2'-deoxy modifications motif. . .
[and] exemplifies a number of possible double stranded polynucleotides.”
(Id.) More specifically, the Examiner finds Allerson discloses an antisense
sequence “where [every second nucleotide] is 2'-0-Met modification, the
rest are 2'-deoxy modifications, [which] can be represented as 5'-(a-P)9—
DNA-(2’-0-Met)-3', where a is DNA, p is 2'-0-MeRNA.” (Id. at 4 (citing
Allerson 106:4).) The Examiner further finds that Allerson teaches a sense
sequence “where [every second nucleotide] is 2'-0-Met modification, the
rest are unmodified ribonucleotides . . . where a is RNA, p is 2'-0-MeRNA.”
(Id. (citing Allerson 106:15).) According to the Examiner, “[h]ybridization
of this [sense] sequence with [antisense] seq. 8/335217 with modifications []
3 Allerson et al., WO 2004/044136 A2, published May 27, 2004.
4 Manoharan, RNA interference and chemically modified small interfering
RNAs, 8 Current Opinion in Chemical Biology 570-79 (2004).
3
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Application 13/001,714
creates double-stranded polynucleotides.” (Id.) In other words, the
Examiner finds Allerson teaches or suggests a double-stranded
polynucleotide comprising an antisense strand having an alternating 2'-0-
MeRNA/2-'H [DNA or deoxy] motif, and a sense strand having an
alternating 2'-0-MeRNA/2'-0H [RNA] motif.5
Because “Allerson do[es] not teach that the unmodified nucleotides of
the sense strand can be modified with 2'-deoxy modification the same way
as the antisense strand is modified,” the Examiner turns to Manoharan. (Id.
at 5.) According to the Examiner, “Manoharan teaches that full replacement
of 2'-OH groups in siRNAs by alternating 2'-OMet/2'-F motif improves the
activity and nuclease resistance of siRNA.” (Id.)
The Examiner concludes “[i]t would have been obvious ... to modify
unmodified 2'-OH groups of Allerson et al polynucleotides with 2'-deoxy
groups arriving at fully 2'-modified oligonucleotide similar to one described
by Manoharan.” (Id.) The Examiner reasons the skilled artisan “would be
motivated to do so in order to increase siRNA nuclease resistance and its
stability.” (Id.)
Appellants make several arguments. First, Appellants contend, “the
combination of the cited references does not disclose the entirety of the
claimed subject matter” — in particular “double-stranded polynucleotides
wherein nucleotides in both the sense and antisense strands are modified
with alternating 2'-0-methyl/2'-deoxy modifications.” (App. Br. 13—14.)
5 The polynucleotide modifications discussed herein relate primarily to
changes at the 2' position of the ribose ring. (See, e.g., Manoharan Figs. 3^4
(showing structure for DNA, RNA, and various modifications).)
4
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Application 13/001,714
According to Appellants, Allerson discloses the claimed modification only
in an antisense strand and Manoharan “requires the presence of alternating
2'-Q-methyl/2'-Fmodifications.” (Id. at 13.)
Second, Appellants contend the combination of the prior art would not
have led one of skill to modify the sense and antisense strands with
alternating 2'-0-methy/2'-deoxy motifs as proposed by the Examiner. (Id. at
14.) According to Appellants, Allerson teaches “the introduction of 2'-
deoxy nucleotides into double-stranded oligonucleotides reduces the activity
of the constructs.” (Id. at 14—15.) Appellants argue Manoharan similarly
provides no reason to make the claimed modification and, in fact, teaches
away from it. (Id. at 15—19.) Appellants contend “Manoharan teaches that
siRNA duplexes ‘must retain conformationally RNA-like A-type helical
characteristics for effective gene silencing.’” (Id. at 17 (quoting Manoharan
574).) And, Appellants contend, the skilled person “would expect that the
shift from A-form to B-form[6] caused by introduction of DNA [2'-deoxy
substitution] into the RNA constructs would decrease, if not abolish, the
desired activity of the polynucleotides as gene silencers.” (Id.) Appellants
6 Appellants assert that DNA readily forms B-form helices, which is a
narrower and more elongated helix than the A-form of RNA. (App. Br. 17;
see also Reply Br. 6—7.) According to Allerson, “[i]n general, RNA:RNA
duplexes are more stable and have higher melting temperatures (Tm’s) than
DNA:DNA duplexes).... The increased stability of RNA has been
attributed to several structural features, most notably the improved base
stacking interactions that result from an A-form geometry .... The
presence of the 2' hydroxyl in RNA biases the sugar toward a C3' endo
pucker . . . , which causes the duplex to favor the A-form geometry. ... On
the other hand, deoxy nucleic acids prefer the C2' endo sugar pucker . . .,
which is thought to impart a less stable B-form geometry.” (Allerson 1151.)
5
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Application 13/001,714
also contend Manoharan teaches substitutions with 2'-deoxy caused an
“unfavorable decrease in melting temperature and that gene silencing
activity was ‘almost completely abolished when either of the strands was 2'-
deoxy.’” (Id. at 18 (quoting Manoharan 575).) Further to this point,
Appellants contend Manoharan teaches duplexes “must not have 2'-deoxy
modifications (except in overhangs and terminal ends) because 2'-deoxy
modifications decrease activity.” (Id. at 17.)
Third, Appellants argue the claimed subject matter is not “obvious to
try.” (App. Br. 20—23.) Appellants contend, inter alia, the cited art provides
only general guidance, which is insufficient to invoke an obvious-to-try
rationale, especially given the number of possible modifications and
combinations that could be made in double-stranded polynucleotides. (Id.)
Appellants contend the number of potential modifications is in the millions.
(Id. at 21.) The Examiner is thus, Appellants assert, improperly using
hindsight to modify the prior art and select the specific construct that is
claimed. (Id.; Reply Br. 8—9.)
Based on the record before us, we are not persuaded the Examiner met
the burden to show that the claims would have been obvious.
The Examiner’s reasoning here for modifying the prior art does not
withstand scrutiny. The Examiner reasons it would have been obvious “to
modify unmodified 2'-OH groups of Allerson . . . with 2'-deoxy groups . . .
[and the skilled person] would be motivated to do so in order to increase
siRNA nuclease resistance and stability.” (Ans. 6.) But the Examiner
provided no persuasive evidence or scientific reasoning to support this
assertion. Quite the opposite, Manoharan, which the Examiner cites in
6
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Application 13/001,714
support of the proposed modification, attributes the increased activity and
nuclease resistance to substitution with an alternating 2'-0-methyl/2'-F motif
— not a deoxy substitution. (Manoharan 576.) The Examiner fails to
explain why the skilled person would reasonably expect the benefits of the
cited construct of Manoharan to also be present with a 2'-0-methyl/2'-deoxy
substitutions in both strands.
In the Advisory Action dated February 25, 2015, the Examiner asserts
“there is no perfectly known siRNA in existence, therefore any siRNA can
be improved further as evidenced by both Allerson and Manoharan
references.” (Adv. Act. 2; see also Ans. 9 (“polynucleotide activity can be
improved in a variety of ways and there is always a room for further
improvement.”) But “rejections on obviousness grounds cannot be sustained
by mere conclusory statements; instead, there must be some articulated
reasoning with some rational underpinning to support the legal conclusion of
obviousness.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)
(quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). Vague statements
concerning what can or could have been pursued to potentially improve on
the prior art are not sufficient to support a conclusion of obviousness —
instead the question is why the skilled artisan specifically and predictably
would have modified the prior art. See Belden Inc. v. Berk-TekLLC, 805
F.3d 1064, 1073 (Fed. Cir. 2015) (“[Ojbviousness concerns whether a
skilled artisan not only could have made but would have been motivated to
make the combinations or modifications of prior art to arrive at the claimed
invention”) (emphasis in original).
7
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Application 13/001,714
In addition, the cited prior art on balance suggests that deoxy
substitutions would not improve siRNA constructs. As persuasively argued
by Appellants, when deoxy substitutions in both strands (i.e., alternating 2'-
F/2'-H substitutions) were made, the activity of the constructs was reduced
by at least 12-fold compared to alternating 2'-F/2'-0-methyl substitutions.
(App. Br. 14—15.) The Examiner responds that this comparison is invalid
because the first substituted construct removes all 2'-0-methyl groups.
(Ans. 7.) The Examiner has not, however, shown why the skilled person
would regard 2'-0-methyl groups as necessary, and simply interchange
hydrogen with a hydroxyl or fluorine at the 2' position. Here again, the prior
art suggests such a change would have been unlikely to provide a benefit —
and more likely, would have been disadvantageous. Manoharan teaches that
2'-F modifications “provide significant increases in target binding affinity
. . . [while] 2'-H cause a decrease in TM (ATm = -0.5°C per modification).”
(Manoharan 574.) Manoharan further teaches that in RNA-DNA duplexes,
“activity was almost completely abolished when either of the strands was 2'-
deoxy, but 2'-deoxy residues were tolerated in the overhangs and at the
terminal ends.” {Id. at 575.) And, as noted above, Manoharan teaches “full
replacement of 2'-OH by alternating 2'-OMe/2'-F improved the activity of an
siRNA duplex significantly with an increase in nuclease resistance.” {Id. at
576.)7 Against this evidence, the Examiner has not persuasively explained
7 {See also Allerson 1154 (“relative duplex stability can be enhanced by
replacement of 2'-OH groups with 2'-F groups thereby increasing the C3'-
endo population . . . [that] may stabilize the stacked conformation in an A-
form duplex.”); see also Reply Br. 6—7.)
8
Appeal 2016-001230
Application 13/001,714
why the skilled person would have predictably designed double-stranded
polynucleotides with alternating 2'-0-methyl/2'-deoxy motifs.
SUMMARY
We reverse the rejection of claims 22, 23, and 41—72 as obvious over
Allerson and Manoharan.
REVERSED
9