Ex Parte Iversen et al

Board of Patent Appeals and Interferences

Apr 1, 2010

10913996 (B.P.A.I. Apr. 1, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte PATRICK L. IVERSEN and DAVID A. STEIN
__________

Appeal 2009-013446
Application 10/913,996
Technology Center 1600
__________

Decided: April 1, 2010
__________

Before TONI R. SCHEINER, ERIC GRIMES, 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 anti-
flaviviral antisense compounds. We have jurisdiction under 35 U.S.C.
§ 6(b). We reverse.

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Statement of the Case
Background
“This invention relates to an oligonucleotide analog for use in treating
a flavivirus infection in animals, to an antiviral method employing the
analog, and to a method for monitoring binding of the analog to a viral
genome target site” (Spec. 1, ll. 10-12).
The Claims
Claims 17, 27, and 30 are on appeal. Claim 17 is representative and
reads as follows:
17. An anti-flaviviral compound composed of morpholino
subunits and phosphorus-containing intersubunit linkages
joining a morpholino nitrogen of one subunit to a 5'
exocyclic carbon of the adjacent subunit, and characterized
by:
(i) a nuclease-resistant backbone,
(ii) capable of uptake by virus-infected animal cells,
(iii) containing between 8-40 nucleotide bases,
(iv) having a sequence of 8 contiguous bases
complementary to the sequence identified by SEQ ID NO: 3,
and
(v) capable of forming with a flavivirus ssRNA
genome containing SEQ ID NO: 3, a heteroduplex structure
characterized by a temperature of dissociation of at least
45°C.

The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Summerton et al., Morpholino antisense oligomers: design,
preparation and properties, 7(3) ANTISENSE NUCLEIC ACID DRUG DEV 187-
195 (1997).
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Raviprakash et al., Inhibition of Dengue Virus by Novel, Modified
Antisense Oligonucleotides, 69(1) J. VIROLOGY 69-74 (1995).

Khromykh et al., Essential Role of Cyclization Sequences in
Flavivirus RNA Replication, 75(14) J. VIROLOGY 6719-6728 (2001).

The issue
The Examiner rejected claims 17, 27, and 30 under 35 U.S.C. § 103(a)
as obvious over Summerton, Raviprakash, and Khromykh (Ans. 3-6).
The Examiner finds that “Raviprakash et al. teaches inhibition of
flavivirus using antisense oligomers targeted to 3’ regions essential for
replication, Summerton et al. teaches improved antisense oligomers using
morpholino subunits, and Khromykh et al. teaches sequences essential for
RNA replication and conserved among flavivirus” (Ans. 5). The Examiner
then concludes that the ordinary artisan “would have been motivated to
combine the morpholino antisense oligomers of Summerton et al., the
flaviviral sequence targets ‘containing’ or comprising SEQ ID NO:3 and
‘having’ or comprising SEQ ID NO:22 in light of the teachings of
Raviprakash et al. and Khromykh et al.” (Ans. 5).
Appellants argue that “Raviprakash et al. suggests that the antisense
oligonucleotides found to inhibit flavivirus replication ‘probably function
via an RNase H cleavage of the oligonucleotide:RNA heteroduplex.’” (App.
Br. 7). Appellants argue that the “Summerton et al. reference, disclosing a
morpholino oligonucleotide that is stated to act through an RNase H
independent mechanism, would therefore not be a logical starting point in
the solution of this problem” (App. Br. 7).
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Appellants argue that “the prior art teaches away from the morpholino
oligonucleotide compound selected as the starting point for the presently
claimed invention, by suggesting that the oligonucleotide must be able to
promote RNase H-dependent RNA cleavage in order to be effective in viral
inhibition” (App. Br. 7). Appellants argue that “based on the Raviprakash et
al. reference, one skilled in the art would have been led not to a cyclization
sequence as a logical target, but to a target region spanning the translation
initiation region” (App. Br. 8).
In view of these conflicting positions, we frame the obviousness issue
before us as follows:
Have Appellants demonstrated that the Examiner erred in concluding
that it would have been obvious to synthesize an antisense oligonucleotide
composed of morpholino and phosphorus linkages which comprises a
sequence complementary to SEQ ID NO: 3?
Findings of Fact (FF)
1. Summerton teaches “the design, preparation, and properties
of Morpholino oligos, a novel antisense structural type that solves the
sequence specificity problem and provides high and predictable activity
in cells” (Summerton 187, abstract).
2. Summerton teaches that “consideration of cost and ease of
synthesis, chemical stability, aqueous solubility, and affinity and
homogeneity of binding to RNA led us to focus on the phosphorodiamidite
shown in Figure 2 as our principle [sic] linkage type for oligos targeted
against single-stranded RNA sequences” (Summerton 189, col. 1).
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3. Summerton teaches that “Morpholino phosphorodiamidate
oligos of the type shown in Figure 2 are immune to a wide range of
nucleases” (Summerton 190, col. 1 to 2).
4. Summerton teaches that “antisense oligos can be easily
delivered into cultured cells simply by passaging anchorage-dependent cells
by the common procedure of scraping with a rubber policemen. This has
been shown to achieve significant oligo entry into the cytosolic
compartment” (Summerton 193, col. 2).
5. Summerton teaches that “a Morpholino oligo 25 subunits in
length, in both the presence and absence of RNase H, inhibits its targeted
mRNA somewhat better than the corresponding S-DNA oligo in the
presence of added RNase H” (Summerton 190, col. 2).
6. Summerton teaches that the RNA/Morpholino melting
temperature is 81.3°C (see Summerton 190, Table 1).
7. Raviprakash teaches that “[d]engue virus, a member of the
flavivirus family, causes one of the major infectious diseases in the tropical
regions of the world” (Raviprakash 69, col. 1).
8. Raviprakash teaches “significant inhibition of dengue virus type
2 in cells microinjected with antisense PS oligonucleotides containing C-5
propyne-substituted uridines and cytidines” (Raviprakash 69, col. 2).
9. Raviprakash teaches that in “determining the regions for
selection as targets for antisense oligonucleotides, we considered (i) the
predicted local secondary structure for dengue virus RNA as analyzed by the
Fold program . . . and (ii) the pyrimidine content of the sequence”
(Raviprakash 73, col. 2).
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10. Raviprakash teaches that:
[w]e chose five different target regions: the 5’ antisense
oligonucleotide spanned the translation initiation region,
including the last residue of the initiating methionine codon;
the NS5a and NS5b antisense oligonucleotides targeted two
different regions of the NS-5 gene, which presumably codes
for the RNA-dependent RNA polymerase; and the 3’a and
3’b antisense oligonucleotides targeted sequences in the 3’
untranslated region.

(Raviprakash 73, col. 2).
11. Raviprakash teaches that the “data presented here show that
although both the 5’-AS and 3’b-AS oligonucleotides . . . resulted in
significantly less viral replication than the controls, at the lower 0.1 µM
concentration the 5’-AS oligonucleotide appeared to be more effective”
(Raviprakash 74, col. 1).
12. Raviprakash teaches that the “3’a oligonucleotide, whose target
is only 100 bases upstream of the 3’b target, shows limited efficacy. These
differences are probably a reflection of the complex secondary structures
presented by the large (>10-kb) dengue virus RNA” (Raviprakash 74, col.
1).
13. Khromykh teaches that “[o]ur results with the KUN replicon
establish the essential role of both the 5’ and 3’ CS in replication”
(Khromykh 6726, col. 1).
14. Khromykh teaches that “the results obtained by mutation
analysis with the KUN replicon unequivocally establish the essential
requirement of complementary CS in the 5’ region and 3’ UTR for
replication in vivo. Because of the conservation of these motifs, the results
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can be extrapolated to other mosquito-borne flaviviruses” (Khromykh 6727,
col. 1).
15. Figure 1, panel C of Khromykh is reproduced below:

“FIG. 1. Computer-generated secondary-structure analysis of the interaction
between the genomic plus-strand RNA at the 5’ and 3’ ends for four
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mosquito-borne flaviviruses. . . . The conserved putative CS are boxed.”
(Khromykh 6721).

Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992) (“[T]he examiner bears the initial burden, on review of the
prior art or on any other ground, of presenting a prima facie case of
unpatentability.”).
“[R]ejections 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.” KSR Int'l v. Teleflex Inc., 550 U.S. 398, 418 (2007).
“To differentiate between proper and improper applications of
‘obvious to try,’ this court outlined two classes of situations where ‘obvious
to try’ is erroneously equated with obviousness under § 103. In the first class
of cases, what would have been ‘obvious to try’ would have been to vary all
parameters or try each of numerous possible choices until one possibly
arrived at a successful result, where the prior art gave either no indication of
which parameters were critical or no direction as to which of many possible
choices is likely to be successful.” In re Kubin, 561 F.3d 1351, 1359 (Fed.
Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988)).
Analysis
Summerton teaches morpholino antisense oligonucleotides which
comprise phosphorus-containing intersubunit linkages, are nuclease
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resistant, capable of uptake by virus-infected animal cells, contain between 8
and 40 nucleotides and have Tm values greater than 45°C (FF 1-6).
Raviprakash teaches antisense oligonucleotides directed to flaviviruses (FF
7-11). Raviprakash found that the “3’a oligonucleotide, whose target is only
100 bases upstream of the 3’b target, shows limited efficacy. These
differences are probably a reflection of the complex secondary structures
presented by the large (>10-kb) dengue virus RNA” (Raviprakash 74, col. 1;
FF 12).
Khromykh, while not an antisense reference, teaches that the
cyclization sequence is essential for flavivirus replication (FF 13-14).
The Examiner finds that the ordinary artisan would have had a
reasonable expectation of success since “Raviprakash et al. teaches use of
antisense oligomers for inhibiting flavivirus, Summerton et al. teaches
improvement of antisense technology through use of morpholino subunits
for antisense oligomers, and Khromykh et al. teaches essential sequences
conserved among flavivirus nucleotide sequences” (Ans. 5-6).
Appellants argue that “since Khromykh did not demonstrate the
ability of antisense compounds directed against a cyclization sequence to
inhibit viral replication, it is not predictable that an antisense compound
would have the same effect as a mutation created in this region” (App. Br.
8).
We find that Appellants have the better position in this very close
case. While Khromykh’s results suggest the criticality of the cyclization
sequence (FF 13-14), on this particularized set of facts, we do not agree with
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the Examiner that there was a reasonable expectation of success in selecting
the cyclization sequence as an antisense target.
The cyclization sequence is shown by Khromykh as being present in a
region of secondary structure (FF 15). Raviprakash teaches that the
oligonucleotide 3’a had limited efficacy because it was located in a region
with secondary structure (FF 12).
We conclude that selection of cyclization sequences for anti-flaviviral
antisense compounds was not predictable or simply the result of routine
experimentation. In Kubin, the court made clear that “where a defendant
merely throws metaphorical darts at a board filled with combinatorial prior
art possibilities, courts should not succumb to hindsight claims of
obviousness.” Kubin, 561 F.3d at 1359. While the Examiner’s case is better
than the situation outlined in Kubin, with Khromykh’s direction towards the
cyclization sequence region, the rejection is significantly weakened by
Raviprakash’s direct teaching that secondary structural regions, such as
those in which Khromykh’s cyclization sequences are found, limit antisense
efficacy (FF 12, 15).
Unlike Kubin, where performing the detailed methodology of cloning
would necessarily result in obtaining a molecule within the genus of nucleic
acids being claimed, there was no predictable expectation that selecting an
antisense oligonucleotide in a region of secondary structure in the flaviviral
genome would predictably, or even likely, result in a compound capable of
inhibiting flavivirus. The instant situation fits O'Farrell’s second kind of
error, since the prior art of Summerton and Raviprakash provide general
guidance regarding morpholino antisense to flavivirus, but do not identify
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the specific sequence of SEQ ID NO: 3 as an antisense target, as required by
claim 17. Khromykh also does not identify SEQ ID NO: 3 as an antisense
target. While Khromykh’s teaching of the criticality of the cyclization
sequence might represent a promising field of experimentation for antisense,
Raviprakash’s teaching that regions of secondary structure, where
cyclization sequences are found, have limited efficacy in antisense
inhibition, renders selection of the cyclization sequences as unpredictable
(FF 12).
Conclusion of Law
Appellants have demonstrated that the Examiner erred in concluding
that it would have been obvious to synthesize an antisense oligonucleotide
composed of morpholino and phosphorus linkages which comprises a
sequence complementary to SEQ ID NO: 3.
SUMMARY
In summary, we reverse the rejection of claims 17, 27, and 30 under
35 U.S.C. § 103(a) over Summerton, Raviprakash, and Khromykh.

REVERSED

alw

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