Ex Parte Kufe et al

Board of Patent Appeals and Interferences

Jun 11, 2010

10447839 (B.P.A.I. Jun. 11, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DONALD W. KUFE,
SURENDER KHARBANDA, and STEVEN D. WEITMAN
__________

Appeal 2009-011955
Application 10/447,839
Technology Center 1600
__________

Decided: June 11, 2010
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Before DONALD E. ADAMS, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a double
stranded RNA interfering composition. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.

Appeal 2009-011955
Application 10/447,839

Statement of the Case
The Claims
Claims 1-6, 34, and 47 are on appeal. Claim 1 is representative and
reads as follows:
1. A double stranded RNA complex comprising a first
RNA sequence of 19 to 23 nucleotides that will hybridize to
SEQ ID NO: 19 under stringent conditions and a second
RNA sequence of 19 to 23 nucleotides that will hybridize to
said first RNA under stringent conditions.

The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Dobie US 6,716,627 B2 Apr. 6, 2004

Parrish et al., Functional Anatomy of a dsRNA Trigger:Differential
Requirement for the Two Trigger Strands in RNA Interference, 6
MOLECULAR CELL 1077-1087 (2000).

Jason R. Kennerdell and Richard W. Carthew, Heritable gene silencing in
Drosophila using double-stranded RNA, 17 NATURE BIOTECHNOLOGY 896-
898 (2000).

Hammond et al., Post-transcriptional gene silencing by double-stranded
RNA, 2 NATURE GENETICS 110-119 (2001).

Elbashir et al., RNA interference is mediated by 21- and 22-nucleotide
RNAs, 15 GENES & DEVELOPMENT 188-200 (2001).

The issues
A. The Examiner rejected claims 1-3 under 35 U.S.C. § 103(a) as being
obvious over Dobie, Hammond, and Elbashir (Ans. 3-6).
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B. The Examiner rejected claims 1-6, 34, and 47 under 35 U.S.C. §
103(a) as being obvious over Dobie, Hammond, Elbashir, Parrish, and
Kennerdell (Ans. 6-8).
A. 35 U.S.C. § 103(a) over Dobie, Hammond, and Elbashir
The Examiner finds that:
Given Dobie’s teaching of the relationship of MUC1 and
tumor progression and metastasis, one of ordinary skill
would be motivated to develop inhibitors of MUCl to study
cellular processes associated with cancer. Hammond et al.
provide a motivation to use double-stranded RNA to down-
regulate gene expression instead of an antisense
oligonucleotide, teaching that RNA interference using
double-stranded RNA reduces gene expression more
specifically than the well-known antisense method. Elbashir
et al. provide a motivation to make a double stranded RNA
as a siRNA, teaching that siRNAs are efficient mediators of
RNA interference [a means of isolating RNA from a crude
cellular extract].

(Ans. 5.)
Appellants argue that, based on Hammond, the ordinary artisan
“would have understood that RNA interference was not an established tool
for down-regulating gene expression at the time the present invention was
made. Thus, the cited references would have not motivated the skilled
artisan to substitute the successful application of antisense agents in Dobie
with double-stranded RNA” (App. Br. 7). Appellants argue that “Elbashir
does not remedy the deficiencies of Hammond because it does not provide
the missing motivation to apply RNA interference to downregulate MUC1”
(id. at 8). Appellants also argue that “the Examiner has not provided any
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reason that would have led a chemist to modify the antisense oligonucleotide
of Dobie into a double-stranded RNA complex” (App. Br. 10).
Appellants argue that “[o]ne of ordinary skill in the art would not
assume that a successful antisense approach could be duplicated with RNA
interference” (id. at 9). Appellants argue that “one of ordinary skill in the art
would not have any reasonable expectation of success that RNA interference
could be successfully applied in down-regulating MUC1” (id. at 11).
In view of these conflicting positions, we frame the obviousness issue
before us as follows:
Does the evidence of record support the Examiner’s conclusion that it
would have been obvious to make an siRNA to downregulate MUC1
expression?
Findings of Fact (FF)
1. Dobie teaches that there “remains a long felt need for agents
capable of effectively inhibiting mucin 1, transmembrane function.
Antisense technology is emerging as an effective means for reducing the
expression of specific gene products and may therefore prove to be uniquely
useful . . .for the modulation of mucin 1, transmembrane expression”
(Dobie, col. 5, ll. 23-31).
2. Dobie teaches that “[a]ntisense compounds are commonly used
as research reagents and diagnostics. For example, antisense
oligonucleotides, which are able to inhibit gene expression with exquisite
specificity, are often used by those of ordinary skill to elucidate the function
of particular genes” (Dobie, col. 8, ll. 55-59).
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3. Dobie teaches that the “term ‘oligonucleotide’ refers to an
oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid
(DNA) or mimetics thereof. This term includes oligonucleotides composed
of naturally-occurring nucleobases . . . as well as oligonucleotides having
non-naturally-occurring portions which function similarly” (Dobie, col. 9, ll.
49-55).
4. The Examiner finds that “Dobie teaches numerous antisense
oligonucleotides 20 bases in length (including Dobie’s sequence 35, which
hybridizes to positions 585-604 of SEQ ID NO: 19) that inhibit expression
of the MUC1 gene by binding to the coding sequence” (Ans. 4).
5. Dobie teaches that SEQ ID NO: 35 results in 55% inhibition of
human mucin 1 membrane RNA levels (see Dobie, col. 49, Table 1).
6. Hammond teaches that
Alternative methods for silencing specific genes have also
provided potentially powerful approaches. Antisense
methods, using either DNA or RNA, are relatively
straightforward techniques for probing gene function;
however, these methodologies have consistently suffered
from the spectre of artefacts that arise from questionable
specificity and incomplete efficacy. Recently, a new method
for silencing specific genes has emerged. In diverse
organisms, double-stranded (ds)RNAs have been shown to
inhibit gene expression in a sequence-specific manner.

(Hammond 110, col. 1.)
7. Hammond teaches that “RNA interference, or RNAi, shows
several features that border on the mystical. In Caenorhabditis elegans, gene
silencing by RNAi can be initiated simply by soaking worms in dsRNA or
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by feeding worms Escherichia coli that express the dsRNA” (Hammond
110, col. 1).
8. Hammond teaches that “the mixture of sense and antisense
strands silenced expression of a target gene roughly tenfold more efficiently
than either strand alone” (Hammond 111, col. 1).
9. Hammond teaches that the
use of RNAi as a method to alter gene expression has been
attempted in a wide variety of organisms, using different
methods . . . and with varying degrees of success . . . A
second class of organism, including zebrafish, Xenopus and
mouse, has been shown to have some capacity for RNAi;
however, there seem to be significant limitations

(Hammond 116, col. 2).
10. Elbashir teaches that “RNAi was also observed subsequently in
insects (Kennerdell and Carthew 1998), frog (Oelgeschlager et al. 2000), and
other animals including mice (Svoboda et al. 2000; Wianny and Zernicka-
Goetz 2000) and is likely to also exist in human” (Elbashir 188, col. 1).
11. Elbashir teaches that “[i]t has been suggested that the 21–23-nt
RNA fragments generated by processing of dsRNAs are the mediators of
RNA interference and cosuppression” (Elbashir 189, col. 1).
12. Elbashir teaches that the “finding that synthetic 21- and 22-nt
siRNA duplexes can be used for efficient mRNA degradation demonstrates
that the targeting step can be uncoupled from the dsRNA-processing step”
(Elbashir 198, col. 1).
13. Elbashir teaches that “[t]his raises the prospects of using siRNA
duplexes as new tools for sequence-specific regulation of gene expression in
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functional genomics as well as biomedical studies. The siRNAs may be
effective in mammalian systems . . . As such, the siRNA duplexes may
represent a new alternative to antisense or ribozyme therapeutics” (Elbashir
198, col. 1).

Principles of Law
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
The Supreme Court has recently emphasized that “the [obviousness] analysis
need not seek out precise teachings directed to the specific subject matter of
the challenged claim, for a court can take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” KSR
Int'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
Id. at 416. “If a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability.” Id. at 417.
Analysis
Dobie teaches that inhibition of MUC1 expression is important in
research and therapeutics and that antisense oligonucleotides will function to
inhibit MUC1 expression (FF 1-5). In particular, Dobie teaches that a 20
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nucleotide antisense oligonucleotide which will hybridize to SEQ ID NO: 19
inhibits MUC1 expression (FF 4).
There is no dispute that Dobie does not teach RNAi (double stranded
RNA), but the Examiner relies upon Hammond and Elbashir to teach that
RNAi is an alternative method to antisense for inhibiting gene expression
(FF 6-13). In particular, Hammond teaches that RNAi is an alternative
method to antisense for inhibition of gene expression (FF 6-7). Hammond
teaches that RNAi “silenced expression of a target gene roughly tenfold
more efficiently than either strand alone” (Hammond 111, col. 1; FF 8).
Hammond teaches that RNAi functions in a variety of organisms (FF 9).
Elbashir teaches that RNAi operates in a variety of organisms (FF 10)
that RNAi molecules are optimally 21-23 nucleotides in length (FF 11-12),
and that “siRNA duplexes may represent a new alternative to antisense or
ribozyme therapeutics” (Elbashir 198, col. 1; FF 13).
Applying the KSR standard of obviousness to the findings of fact, we
conclude that the person of ordinary creativity would have predictably
followed the teachings of Hammond and Elbashir to use RNAi for inhibiting
MUC1 gene expression since both Hammond and Elbashir teach that RNAi
is a known alternative which Hammond teaches is tenfold more efficient (FF
8-13). Such a combination is merely a “predictable use of prior art elements
according to their established functions.” KSR, 550 U.S. at 417.
Appellants argue that, based on Hammond, the ordinary artisan
“would have understood that RNA interference was not an established tool
for down-regulating gene expression at the time the present invention was
made. Thus, the cited references would have not motivated the skilled
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artisan to substitute the successful application of antisense agents in Dobie
with double-stranded RNA” (App. Br. 7). Appellants argue that “Elbashir
does not remedy the deficiencies of Hammond because it does not provide
the missing motivation to apply RNA interference to downregulate MUC1”
(id. at 8).
We are not persuaded. The Federal Circuit has recognized that
an implicit motivation to combine exists not only when a
suggestion may be gleaned from the prior art as a whole, but
when the “improvement” is technology-independent and the
combination of references results in a product or process that
is more desirable, for example because it is stronger,
cheaper, cleaner, faster, lighter, smaller, more durable, or
more efficient.

DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464
F.3d 1356, 1368 (Fed. Cir. 2006). Not only do Hammond and Elbashir
teach that RNAi is a known alternative to antisense inhibition (FF 6-13), but
Hammond teaches that RNAi is tenfold more efficient than antisense at
silencing expression (FF 8). Thus, Elbashir demonstrates that RNAi is a
predictable alternative to antisense (FF 11-13) while Hammond provides a
specific advantage of RNAi, improved efficiency (FF 8).
Appellants also argue that “the Examiner has not provided any reason
that would have led a chemist to modify the antisense oligonucleotide of
Dobie into a double-stranded RNA complex” (App. Br. 10).
We are not persuaded since the Examiner has provided specific
reasons to substitute RNAi molecules for the antisense of Dobie, finding that
“RNA interference using double stranded RNA is a method that is more
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specific and more potent than antisense and Elbashir et al. teach that short
duplex RNAs mediate RNA interference” (Ans. 6).
Appellants argue that “[o]ne of ordinary skill in the art would not
assume that a successful antisense approach could be duplicated with RNA
interference” (App. Br. 9). Appellants argue that “one of ordinary skill in
the art would not have any reasonable expectation of success that RNA
interference could be successfully applied in down-regulating MUC1” (id. at
11).
In particular, Appellants rely upon the Declarations of Dr. Kufe,
arguing that “Dr. Kufe, who disagrees with the Examiner’s position, cites to
Miyagishi et al. (Antisense and Nucleic Acid Drug Development 13:1-7,
2003; Exhibit 1 of Third Declaration of Dr. Kufe” (id. at 10). Appellants
characterize Miyagishi as comparing “the effects of antisense antisense [sic]
oligonucleotides and siRNAs directed against the same targets in
mammalian cells . . . Results showed that there were significant differences
in the suppressive effects at each of the target sites” (id. at 10-11).
We are not persuaded. In fact, Miyagishi itself disagrees with
Appellants’ argument and states that there was “a low but significant
correlation between the effects of siRNA and antisense ODN” (Miyagishi 6,
col. 2). Further, Miyagishi would provide direct motivation to replace
antisense with siRNA, since Miyagishi teaches that “[i]t is important to note
that the IC50 value of the siRNA was about 100-fold lower than that of the
antisense ODN” (Miyagishi 5, col. 2). Thus, Miyagishi teaches that siRNA
is about 100 fold more efficient at inhibiting RNA expression than antisense
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RNA, which supports the motivation of the Examiner based on Hammond’s
10 fold improved efficacy of siRNA relative to antisense (FF 8).
We agree with the Examiner that the prior art provides a reasonable
expectation of success. Kubin stated that “[r]esponding to concerns about
uncertainty in the prior art influencing the purported success of the claimed
combination, this court [in O’Farrell] stated: ‘[o]bviousness does not require
absolute predictability of success … all that is required is a reasonable
expectation of success.”’ In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009)
(citing In re O’Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988)).

Conclusion of Law
The evidence of record supports the Examiner’s conclusion that it
would have been obvious to make an siRNA to downregulate MUC1
expression.

B. 35 U.S.C. § 103(a) over Dobie, Hammond, Elbashir, Parrish, and
Kennerdell
The Examiner finds it obvious to modify the Dobie, Hammond, and
Elbashir to use modified nucleotides as taught by Parrish and Kennerdell
since “Parrish et al. teaching that sugar and phosphate modifications well-
known in the art of antisense as providing better stability in cells are
tolerated by RNA interference” (Ans. 7). Further Kennerdell teaches “RNA
interference works with a hairpin RNA and that similar results were seen
with C. elegans, indicating that the phenomenon is general” (Ans. 8).
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The Examiner provides sound fact-based reasoning for combining
Parrish and Kennerdell with Dobie, Hammond and Elbashir. As Appellants
do not identify any material defect in the Examiner’s reasoning, and only
argue the underlying rejection of Dobie, Hammond and Elbashir which we
affirmed above, we affirm the this rejection for the reasons stated by the
Examiner.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as being obvious over Dobie, Hammond, Elbashir, Parrish, and
Kennerdell. Pursuant to 37 C.F.R. § 41.37(c) (1)(vii)(2006), we also affirm
the rejection of claims 2-6, 34, and 47, as these claims were not argued
separately.

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).
AFFIRMED

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