Ex Parte Allerson et al

Patent Trial and Appeal Board

Feb 27, 2013

10860265 (P.T.A.B. Feb. 27, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte CHARLES ALLERSON, BALKRISHEN BHAT,
ANNE B. ELDRUP, MUTHIAH MANOHARAN,
RICHARD H. GRIFFEY, BRENDA F. BAKER, and ERIC E. SWAYZE
____________

Appeal 2011-002405
Application 10/860,265
Technology Center 1600
____________

Before DEMETRA J. MILLS, RICHARD M. LEBOVITZ, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This appeal involves claims to a composition for use in gene
modulation comprising a double-stranded oligonucleotide having alternating
2‟-modified nucleosides. The Examiner has rejected the claims as obvious
and on the ground of obviousness-type double patenting. We have
jurisdiction under 35 U.S.C. § 134. We affirm.

Appeal 2011-002405
Application 10/860,265

2

I. STATEMENT OF THE CASE
Claim 36, the only independent claim on appeal, is directed to a
double-stranded oligonucleotide in which at least one strand comprises two
different 2‟-substituted nucleosides which are alternated with one another.
Claims 36, 44, 46-49, 52-64, 74-80, 93, 98-100, and 106 are pending
and stand rejected by the Examiner as follows:
1. Under 35 U.S.C. § 103(a) as obvious over Elbashir,
1
Giese,
2

Fosnaugh,
3
and Morrissey
4
in view of the combined teachings of Arnold,
5

Damha,
6
and McKay.
7

2. On the ground of nonstatutory obviousness-type double patenting
as obvious over claims 4, 5, 34, 37, 38,46,49-51, 53-63, 72, 74-78, 94-96,
104, and 105 of copending Application No. 10/701,007 (“the „007
application”). This is a provisional rejection as the „007 application claims
have not been patented.
3. On the ground of nonstatutory obviousness-type double patenting
as obvious over claims of copending Application No. 11/054,848 (“the „848

1
Elbashir et al., Functional anatomy of siRNAs for mediating efficient RNAi
in Drosophila melanogaster embryo lysate, 20 (23) The EMBO Journal
6877-6888 (2001).
2
Giese et al., US 2004/0180351 A1, published Sep. 16, 2004.
3
Fosnaugh et al., US 2003/0143732 A1, published Jul. 31, 2003.
4
Morrissey et al., US 2003/0206887 A1, published Nov. 6, 2003.
5
Arnold, Jr. et al., US 6,262,036 B1, issued Jul. 17, 2001.
6
Damha et al., US 2005/0142535 A1, published Jun. 30, 2005.
7
McKay et al., US 6,133,246, issued Oct. 17, 2000.
Appeal 2011-002405
Application 10/860,265

3
application”). This is a provisional rejection as the „848 application claims
have not been patented.
Appellants did not provide arguments as to Grounds 2 and 3.
Consequently, we summarily affirm these rejections. The „007 application,
upon which Ground 2 is based, is subject to Appeal 2011-002268 which has
concurrently been decided with this appeal. The „848 application upon
which Ground 3 is based, is subject to Appeal 2011-002314 which has
concurrently been decided with this appeal.
An oral hearing was held December 12, 2012. A transcript will be
entered into the record in due course.
Claim 36 is the only independent claim on appeal which is pending
and reads as follows:
36. A composition comprising first and second chemically synthesized
oligomeric compounds, wherein:
the first oligomeric compound is fully complementary to and capable
of hybridizing to the second oligomeric compound and to a selected nucleic
acid target;
each of the first and second oligomeric compounds independently
comprises from 17 to 23 nucleosides;
the first oligomeric compound comprises a contiguous sequence of
linked nucleosides that define an alternating motif of the formula:
5'-Q(-L-Z-L-Q)n(-L-Z)nn-3'
wherein:
each L is an internucleoside linking group;
each Q is a 2'-substituted nucleoside wherein each of the 2'-substituent
groups are the same and are other than H or OH;
each Z is a 2'-substituted nucleoside wherein each of the 2'-substituent
groups are the same and are other than H or OH and are also other than the
2'-substituent groups of each Q; and
n is from 8 to 14 and nn is 0 or 1.
II. OBVIOUSNESS REJECTION 1
Appeal 2011-002405
Application 10/860,265

4
The Examiner rejected the claims over a combination of prior art
publications: Elbashir, Giese, Fosnaugh, and Morrissey in view of Arnold,
Damha, and McKay.
The first group of publications (Elbashir, Giese, Fosnaugh, and
Morrissey) describe siRNA duplexes. SiRNA (silencing RNA) is a double-
stranded RNA (a “duplex”) that had been found in the prior art “to
specifically and potently disrupt the activity of genes” which contain
sequences homologous to the sequences in the siRNA. Spec. 3: ¶ 0008 & 4:
¶ 0010. Claim 36 encompasses siRNA double-stranded molecules.
The second group of publications (Arnold, Damha, and McKay)
describe single-stranded antisense RNA. Single stranded antisense
oligonucleotides are also known to disrupt gene activity, but by a different
mechanism than double stranded siRNA. Answer 18.
The Examiner determined that the siRNA prior art described various
2‟ modifications of the ribose sugar of the constituent nucleotides, but not an
alternating motif as recited in claim 36 in which two different 2‟-substituted
nucleosides are alternated with one another. Answer 8: 15-17. However,
the Examiner found that the antisense oligonucleotide prior art described
oligonucleotides comprising alternating 2'-modified nucleosides and the
advantages of such modifications with respect to enhanced target binding
stability, target binding, and uptake. Id. at 8-9. The Examiner determined it
would have been it would have been obvious to one of ordinary skill in the
art to have modified the prior art siRNA with the teaching of the single-
stranded antisense oligonucleotide prior art in order to enhance their binding
and stability. Id. at 9: 14 to 10:7

Appeal 2011-002405
Application 10/860,265

5
III. APPELLANTS‟ ARGUMENTS
One skilled in the art could not determine from the description
provided in Elbashir whether, for example, incorporation of one
or more 2' - substituents anywhere in an siRNA duplex would
result in active molecules, because the only 2' -substituent-
containing duplex tested in the experiments described in
Elbashir was inactive in RNAi.
App. Br. 7.
The full 2 'O-methyl compounds described in Elbashir, for
example, likely have improved stability and affinity for a target
RNA, but they are reported to have no activity, thus making
them unsuitable for use as siRNAs.
App. Br. 12.
The Giese application, however, does not describe with
particularity siRNA molecules having alternating 2'
modifications, and, accordingly, provides no information
regarding the stability and inhibitory activity of such siRNA
molecules.
App Br. 8.
Fosnaugh and Morrissey describe vast genuses of chemical
modifications and broadly discuss oligonucleotides comprising
any number of such modifications [but] . . . do not describe
with any particularity the effect that different motifs of
modifications have on siRNA activity, nor do they teach ways
of designing and optimizing chemically modified siRNAs.
App. Br. 9.
Single stranded antisense RNA reduces gene activity through a
pathway that requires RNase H activity. App. Br. 12.
The RNAi [siRNA] and RNAse H-dependent pathways [used
for anti-sense RNA] for reducing target RNA are sufficiently
different that there would have been no reason for those skilled
in the art to have believed at the time of the invention that the
types and patterns of chemical modifications beneficial for the
Appeal 2011-002405
Application 10/860,265

6
substrates utilized in one pathway would be also be beneficial
for the substrates utilized in the other.
App. Br. 13.
The claimed invention was not “obvious to try” because the number
of possible modifications is not “finite,” but rather there was a vast number
of choices and the efficacy of siRNA was not reasonably predictable at the
time of invention. App. Br. 18.

IV. FINDINGS OF FACT
The findings of fact (“FF”) are numbered below. The first time a
finding appears, the corresponding numeral is in bold and bracketed.

V. DISCUSSION
Claim 36 is directed to a composition comprising first and second
“oligomeric compounds.” The first oligomeric compound is fully
complementary and capable of hybridizing to the second oligomeric
compound. The first oligomeric compound “comprises a contiguous
sequence of linked nucleosides that define an alternating motif” of
specifically recited formula. The formula specifically defines a sequence of
alternating nucleosides Q and Z, where each nucleoside is substituted at the
2‟ position of the ribose sugar and the 2‟-substituents are different for Q and
Z.
Appellants‟ arguments focus on the alleged large number of choices in
the cited prior art necessary to have made the claimed siRNA molecule and
the lack of predictability and direction from the cited siRNA or single-
stranded antisense prior art.
Appeal 2011-002405
Application 10/860,265

7
The fact is that Giese teaches siRNA which comprise an alternating
motif, including two different alternating 2‟-modified nucleosides. We
reproduce the relevant passages from Giese below which establish this fact
(emphasis added).
[FF1] (¶ 0065) FIG. 2 illustrates some embodiments of the
ribonucleic acid molecules of the present invention with
patterns of modified and unmodified groups of nucleotides
which are also referred to herein as a pattern of modification.
The modified groups of nucleotides are also referred to herein
as a group of modified nucleotides. The unmodified
nucleotides or unmodified groups of nucleotides referred to
as flanking group(s) of nucleotides herein, as used herein may
also have one or several of the modification(s) as disclosed
herein which, however, is/are different from the modification
of the nucleotides forming the group(s) of modified nucleotides.

[FF2] (¶ 0116) . . . The term “unmodified nucleotide” as
used herein means either not having any of the aforementioned
modifications at the nucleotide forming the respective
nucleotide or group of nucleotides, or having a modification
which is different from the one of the modified nucleotide
and group of nucleotides, respectively.

[FF3] (¶ 0124) In a particular embodiment of this aspect of the
present invention the interfering ribonucleic acid subject
comprises two strands, whereby a 2'-O-methyl modified
nucleotide and a non-modified nucleotide, preferably a
nucleotide which is not 2'-O-methyl modified, are incorporated
on both strands in an alternating fashion, resulting in a strand
having a pattern MOMOMOMOM etc where M is a 2'-O-
methyl nucleotide and O is a non-modified nucleotide.
In paragraph 124 (FF3), Giese describes an alternating pattern of
modified and unmodified nucleotides. In paragraphs 65 (FF1) and 116
(FF2), Giese teaches that an “unmodified nucleotide” may have a
Appeal 2011-002405
Application 10/860,265

8
modification which is different from the modification of the “modified
nucleotide.” Thus, Giese clearly describes siRNA with a motif of alternating
modified nucleotides [FF4]. Modifications are described in paragraph 24 at
the 2‟-position of the nucleotide [FF5] so the alternating pattern described
by Giese clearly includes alternating different 2‟-modified nucleotides as
claimed [FF6]. For this reason, we do not agree with Appellants that the
“Giese application . . . does not describe with particularity siRNA molecules
having alternating 2' modifications.” App. Br. 8.
It is true that Elbashir teaches that complete substitution of one or
both strands of siRNA with 2‟-O-methyl substituted nucleotides (a 2‟
modification) abolished its gene silencing activity and that this is the only
teaching in Elbashir of the effect of 2‟-O-methyl substitution on siRNA
activity. Elbashir, Figure 3 at p. 6882; p. 6886, col. 2, ll. 6-10; App. Br. 7.
However, Elbashir is not the only prior art teaching of siRNA with 2‟-
modifications.
First, as already discussed, Giese teaches 2‟-modified nucleotides
incorporated into siRNA. Figures 10-12 and 15 of Giese show various
siRNAs with internal 2‟-O-methyl substituted nucleotides which had gene
silencing activity (Answer 7):
[FF7] (¶ 0076) FIG. 12 shows that alternating 2'-O-methyl
modification result in activity of the modified RNAi molecules
compared to unmodified forms. . . . As may be taken therefrom
RNAi molecules with alternating modifications are stabilized
against endonuclease degradation and active in mediating a
PTEN protein knock down.
[FF8] (¶ 0079) FIG. 15 shows that siRNA molecules with
distinct 2'-O-methyl ribonucleotides modifications show
increased stability in serum and mediate protein knock-down in
HeLa cells.
Appeal 2011-002405
Application 10/860,265

9
Second, Fosnaugh also describes siRNA comprising nucleotides with
2‟-modified nucleotides:
[FF9] (¶ 0018]) The sense region of a siRNA molecule can
comprise one or more (e.g., about 1, 2, 3, 4, 5, or more) 2'-O-
methyl modified pyrimidine nucleotides.
[FF10] (¶ 0019) The antisense region of a siRNA molecule can
comprise one or more (e.g., about 1, 2, 3, 4, 5, or more) 2'-
deoxy-2'-fluoro modified pyrimidine nucleotides.
[FF11] As shown in Figure 4 reproduced below, Fosnaugh also
discloses examples of siRNA with “all pyrimidine nucleotides that may be
present [as] 2'-O-methyl modified nucleotides except for (N N) nucleotides”
and “all pyrimidine nucleotides that may be present [as] 2'-deoxy-2'-fluoro
modified nucleotides except for (N N) nucleotides.” Fosnaugh, p. 16, ¶ 145.

{Figure 4 shows examples of siRNAs with 2‟ modified nucleotides}.
Thus, while it may be true that the prior art did not explicitly teach
“with any particularity the effect that different motifs of modifications have
on siRNA activity” (App. Br. 9), the doubt that 2‟ modifications could be
Appeal 2011-002405
Application 10/860,265

10
incorporated into biologically active siRNA would have been dispelled by
the explicit teachings of Giese and Fosnaugh of siRNA comprising a variety
of different 2‟-modifications, including 2'-O-methyl modifications (FF7 &
FF8) and an alternating motif (FF1-FF7). And contrary to Appellants‟
contention that the prior art did not “teach ways of designing and optimizing
chemically modified siRNAs” (App. Br. 9), both Giese and Fosnaugh teach
how to design siRNAs and test them for activity. Fosnaugh, Examples 3, 5,
and 6; Giese, Examples 1, 7, 8 and 9 [FF12].
Appellants contend that well-established differences in the
mechanisms between siRNA and single-stranded antisense activity would
have deterred one of ordinary skill in the art from applying antisense
teachings to siRNA. However, the Examiner noted that the types of linkages
and modifications described in the siRNA art originated in the antisense
prior art (Answer 18: 4-6), providing clear evidence that one of ordinary
skill in the art looked to the antisense art for siRNA modifications that could
be routinely tested using siRNA assays, e.g., as taught by Fosnaugh and
Giese.
Obviousness is not determined by a rigid test, but rather is predicated
upon the totality of the evidence. In this case, where there are teachings of
biologically active siRNA comprising 2‟-modifications (FF7; FF8; Answer
7), including alternating motifs (FF1-FF6; FF7), a person of ordinary skill in
the art would have had reason to have made the claimed siRNA and a
reasonable expectation that such siRNA would be active. The only
information that could be seen to militate against such conclusion is
Elbashir‟s teaching that a strand wholly made of one type of 2‟-modified
nucleosides is inactive. But this teaching is countered by the express
Appeal 2011-002405
Application 10/860,265

11
disclosure in Giese of 2‟-modified siRNA with gene silencing activity (FF7
& FF8) and the routineness of testing for active siRNA constructs as
evidenced by both Giese and Fosnaugh.
As far as arguments as to the number of possible choices, the claims
are not limited to particular 2‟-modified nucleosides; the claims only require
the nucleosides are different from each other. Giese clearly teaches different
alternating nucleosides (F1F1-FF6).
For the foregoing reasons, we affirm the obviousness rejection 1 of
claims 36, 44, 46-49, 52-64, 74-80, 93, 98-100, and 106. Since the claims
were not argued separately, they fall together. We also summarily affirm
obviousness rejections 2 and 3 of claims 36, 44, 46-49, 52-64, 74-80, 93, 98-
100, and 106.

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

alw