DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/01/2026 has been entered.
Status of Claims
Claims 203-207 and 210-227 are under examination.
Affidavits/Declarations
The Declaration under 37 CFR 1.132 filed 05/01/2026 is insufficient to overcome the rejection of claims 203-207,210-221,223 and 227 as unpatentable over ‘840 in view of ‘523; claim 222 as unpatentable over ‘840 and ‘523 further in view of WO ‘999; claims 203,224 and 225 as unpatentable over ‘840 in view of Poopeiko et al.; and claims 203 and 226 as unpatentable over WO ‘840 in view of Gotfredsen et al., and claims 203 and 225 as unpatentable over ‘840 in view of Liu et al. based upon 35 U.S.C. 103 as set forth in the last Office action because:
While the results pointed out by Applicant do appear to show an unexpected effect, the issue is that these results are shown for specific species of the claimed genus and therefore it is not clear what exactly the unexpected results are attributed to. Applicant should explain what exactly is providing the effect. Is it the specific position only, is it a specific compound of formula II or V, is it a specific length of the oligonucleotide, do other chemical modifications affect the results?
"[A]pplicants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). MPEP 716.02(b).
For Example, the claims recite the oligomeric compound comprises a modified oligonucleotide consisting of 15-30 linked nucleosides. In contrast, the Examples and results above pointed out by Applicant are for modified oligonucleotides that are 16 nucleotides in length. Other differences between the scope of the claims with those pointed out above by Applicant in the Examples are the other chemical modifications at specific positions (phosphorothioate linkages, cEt modified sugar moieties, 5-methyl-Cytosine, substituted stereo-standard nucleosides (See page 48 describing modifications of oligonucleotides in Table 1). Another major consideration is the scope of the compounds of formula II and V encompassed by the claims versus the more specific structure of the compounds corresponding to formula II and V in the Examples. The compound of formula II in the claims encompass that one of J3 and J4 is H, and the other of J3 and J4 is selected from H, OH, F, OCH34, OCH2CH2OCH3, O-C1-C6 alkoxy, and the compound of formula V encompass that one of J9 and J10 is H and the other of J9 and J10 is selected from H, OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy and SCH3 (claim 203). However, the Examples cited by applicant for the unexpected results pertain to more specific compounds of Formula II and V (specifically J3 and J4 is H, and J9 and J10 is H) and therefore the Examiner is not able to determine if other compounds encompassed by Formulas II and V would also have the same unexpected effect. Example 5 page 52 says the modified oligonucleotides in Table 6 have either a 2’-beta-D-xylo-deoxyribosyl stereo-non-standard DNA nucleotide in the gap (a nucleoside of formula II, wherein J3 and J4 are each H) or a 2’-alpha-L-deoxyribosyl stereo-non-standard DNA nucleoside in the gap (nucleoside of formula V, wherein J9 and J10 are each H). Pages 52-53 show the specific structures of a beta-D-XNA and a 2’-alpha-L-DNA, and pages 59 and 61 showing a specific structure of Formula V wherein J9 and J10 are each H corresponding to the alpha-L DNA modification in the compounds of Tables 15-17,19. Therefore, the improved results claimed by Applicant would be for the scope of this specific compound of formula V, wherein J9 and J10 are each H, or the compound of formula II wherein J3 and J4 are H, and not for the entire scope of the compound of formula V or II encompassed by the claims wherein one of J9 or J10 could be other than H (OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy and SCH3). It is not clear if other compounds of formula V and II other than when J9 and J10 would also achieve these improved results. The Declaration does not indicate how the provided examples and comparison would extend to the full scope of the claims, specifically compounds with longer or shorter lengths, additional modifications, and compounds of formula II and V having substituents other than J3 and J4 being H, and J9 and J10 being H. If Applicant provided an explanation and results regarding the unexpected effect extending to the full scope of the claims, then the Examiner would consider that.
In addition, as ‘523 teaches analogues with improved antisense properties that combine increased affinity for complementary nucleic acids with the RNase H recruiting ability of natural DNA (page 5, lines 21-27), providing oligonucleotides that selectively hybridize to RNA, as well as avoiding or reducing toxic side effects of antisense or other gene-silencing oligonucleotides by reducing or eliminating their affinity towards DNA (Summary, page 6), one of ordinary skill in the art would expect that providing an oligonucleotide with an alpha-L-RNA monomer of formula I taught by ‘523 would reduce toxic side effects.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claim Objections
Claims 211 and 214 are objected to because of the following informalities: a conjunction is missing between the last two substituents in each claim. Specifically, each claim recites “2’-F, 2’-OCH3, 2’-MOE, 2’-NMA”, and therefore should have “and” between “2-MOE” and “2’-NMA”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 212 and 215 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 212 recites “wherein each bicyclic 5’-region nucleoside is selected from among…” and claim 215 recites “wherein each bicyclic 3’-region nucleoside is selected from among….”. The scope of the claims are not clear because of the inclusion of the word “among”. If the claims recited “selected from the group comprising”, or “selected from the group consisting of”, the scope of the claims would be clear, but using “among” makes the scope of the claim unclear and creates an issue of indefiniteness.
Maintained Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 203-207,210-221,223 and 227 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016044840 (’840), Published 24 March 2016 in view of WO 03/039523 (‘523), Published 15 May 2003, cited on an IDS.
Claim Interpretation: Page 15 of the instant specification defines “stereo-non-standard nucleoside” to mean a nucleoside comprising a non-bicyclic furanosyl sugar moiety having a configuration other than that of a stereo-standard sugar moiety and defines a “stereo-standard nucleoside” to mean a nucleoside comprising a non-bicyclic furanosyl sugar moiety having the configuration of naturally occurring DNA and RNA and that a stereo-standard DNA nucleoside is a nucleoside comprising a beta-D-2’-deoxyribosyl sugar moiety and a stereo-standard RNA nucleoside is a nucleoside comprising a beta-D-ribosyl sugar moiety as defined on page 14 of the specification.
Regarding claim 203, ‘840 teaches oligomeric compounds comprising one or
more modified nucleosides comprising a modified sugar moiety that provides desirable
properties such as enhanced nuclease stability or increased binding affinity with a target
nucleic acid (page 21, lines 2-5) and oligonucleotides comprising or consisting of a
region having a gapmer sugar motif, which comprises two external regions or “wings”
and a central or internal region or “gap” (page 29 lines 17-18). ‘840 teaches gapmer
sugar motifs in Table 5 (page 45), which shows the oligonucleotide gapmer may be
14-21 nucleosides in length. ‘840 teaches each nucleoside of the gap is a 2’-
deoxynucleoside, and the gap comprises one or more modified nucleosides (page 43,
lines 1-2). Page 44 of ‘840 teaches different nucleoside motifs of the gap of the gapmer
(lines 10-35), including that the 2nd deoxy region nucleoside from the 5’ end of the deoxy
region of the gap is “X” which is a modified nucleoside or a substituted sugar moiety,
including at least the following motifs: DXDDDDDDD, DXXDDDDDD, DXDDDDDXD,
DXDDDDXDD, DXDDDXDDD, DXDDXDDDD, DXDDDDDD, DXDDDDXD,
DXDDDXDD, DXDDXDDD, DXDXDDDD, DXXDDDDD, DXDDDDXD, DXDDDDD,
DXDDDXD, DXDDXDD, DXDXDDD, DXXDDDD, DXDDDD, DXXDDD, DXDXDD,
DXDDXD (page 44, lines 10-35).
Regarding claim 204, ‘840 teaches each nucleoside of the gap is a 2’-
deoxynucleoside (page 43, line 1) and the gap of the gapmer is 9-11 linked nucleosides
(Table 5, page 45). ‘840 teaches the 5’-most and 3’-most nucleosides of the deoxy
region are unmodified deoxynucleosides, and that only one nucleoside of the deoxy
region is a modified nucleoside or substituted sugar moiety (page 44, lines 10-13).
Regarding claim 205, ‘840 teaches the 3’-most nucleoside of the deoxy region is
an unmodified deoxynucleoside (page 44, lines 10-13).
Regarding claims 206 and 207, ‘840 teaches 1 or 2 nucleosides of the
deoxy region of the gap are modified nucleosides or a substituted sugar moiety, and the
remaining nucleosides of the gap are unmodified deoxynucleosides (page 44, lines
10-13).
Regarding claims 210, 211 and 214, ‘840 teaches the gap of the gapmer to be 9-
11 linked nucleosides (Table 5, page 45), the 5’-wing to be 1-6 linked nucleosides (page
31, line 6), the 3’-wing to be 1-6 linked nucleosides (page 36, line 20), and that each 5’-
region nucleoside is a bicyclic nucleoside (page 31, lines 25-26) or each nucleoside of
the 5’-wing is a 2’-MOE or 2’-OMe nucleoside (page 32, lines 1-2), each nucleoside
of the 3’-wing of a gapmer is a bicyclic nucleoside (page 37, lines 1-2) or each
nucleoside of the 3’-wing of the gapmer is a 2’-MOE or 2’-OMe nucleoside (page 37,
lines 14-15).
Regarding claims 212 and 213, ‘840 teaches each 5’-region nucleoside is a
bicyclic nucleoside, and each bicyclic nucleoside is a constrained ethyl nucleoside or
LNA nucleoside (page 31, lines 25-28).
Regarding claims 215 and 216, ‘840 teaches each nucleoside of the 3’-wing of a
gapmer is a bicyclic nucleoside, and each bicyclic nucleoside is a constrained ethyl
nucleoside or a LNA nucleoside (page 37, lines 1-4).
Regarding claims 217-219, ‘840 teaches at least one phosphorothioate
internucleoside linkage, or at least one phosphodiester internucleoside linkage (page
65, lines 15-16) and each internucleoside linkage is selected from phosphodiester and
phosphorothioate (page 65, lines 15-18), and that it is desirable to arrange the number
of phosphorothioate and phosphodiester internucleoside linkages to maintain nuclease
resistance (page 66, lines 1-2).
Regarding claim 220, ‘840 teaches the oligonucleotide is modified by attachment
of a conjugate group that may modify the properties of the attached oligomeric
compound including pharmacodynamics, pharmacokinetics, stability, binding,
absorption, cellular distribution, uptake, charge and clearance (page 77, lines 1-5).
Regarding claim 221, ‘840 teaches a single-stranded antisense oligonucleotide
(page 4, lines 18-19).
Regarding claim 223, ‘840 teaches the antisense compounds comprising
oligonucleotides are 80-100% complementary to the target nucleic acid (page 87, lines
1-9), and the target nucleic acid is mRNA or pre-mRNA (page 95, lines 19-20).
‘840 does not teach a stereo-non-standard nucleoside having the structure of
formula II or of formula V.
However before the effective filing date, ‘523 teaches oligonucleotides
modified with one or more alpha-L-configurated nucleoside analogs (Field of Invention,
page 1). ‘523 teaches that antisense nucleic acids for therapy provide advantages of
specificity and point of attack for the target gene (page 4, lines 26-28), but that
oligonucleotides must satisfy a large number of different requirements to be useful as
antisense drugs, including binding with high affinity and specificity to its target mRNA,
the ability to recruit RNase H, to reach their site of action within the cell, resistance to
extra and intracellular nucleases, little or no toxicity at the relevant dose, and ability to
specifically hybridize to mRNA, leaving DNA unhybridized at physiological conditions
(Page 5, lines 13-20). ‘523 teaches natural DNA only exhibits modest affinity for RNA
and falls short on a number of other critical characteristics including nuclease resistance
and therefore a significant effort has been invested to identify novel analogues with
improved antisense properties that combine increased affinity for complementary
nucleic acids with the RNase H recruiting ability of natural DNA (page 5, lines 21-27).
Therefore, ‘523 teaches providing oligonucleotides that selectively hybridize to RNA, as
well as avoiding or reducing toxic side effects of antisense or other gene-silencing
oligonucleotides by reducing or eliminating their affinity towards DNA (Summary, page
6).
‘523 recites an oligonucleotide comprising at least a first alpha-L-RNA monomer
of formula I, wherein X is -O-, B is optionally protected nucleobases, R2 is F or OH, and
R2* is H (claim 1) and that the oligonucleotide comprises 8-100 nucleotides (claim 24).
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The oligonucleotide comprising the alpha-L-RNA monomer of formula I of claim 1
of ‘523 meets the definition of stereo-non-standard nucleoside as the alpha-L-RNA
monomer has a non-bicyclic furanosyl sugar moiety, and does not have the
configuration of a stereo-standard nucleoside which is the configuration of naturally
occurring DNA or RNA having a beta-D configuration, as the RNA monomer of ‘523 has
an alpha-L-RNA configuration, and falls within the limitations of instant formula II.
‘523 teaches the combination of alpha-L-RNA and LNA (Locked Nucleic Acid) nucleotides in the formation of said oligonucleotides (page 1 lines 14-15), and that incorporation of LNA monomers containing a 2’-O,4’-C-methylene bridge (Beta-D-LNA) into an oligonucleotide sequence led to unprecedented improvement in the hybridization ability of the modified oligonucleotide (page 3, lines 12-15). ‘523 further teaches that the number, order, and presence of further nucleosides may be of importance in the design of an oligonucleotide intended to hybridize to a specific target (page 81 lines 23-25).
‘523 recites the oligonucleotide according to claim 1, wherein B designates a nucleobase selected from uracil-1-yl, thymin-1-yl, adenin-9-yl, guanin-9-yl, cytosin-1-yl, and 5-methyl-cytosin-1-yl (claim 2).
Therefore, with respect to claims 203-207 and 227, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the gapmer having the 2nd deoxy region nucleoside from the 5’ end of the deoxy region as a modified nucleoside or substituted sugar moiety of ‘840, and replace the 2nd deoxy region modified nucleoside or substituted sugar moiety with the alpha-L-RNA monomer of formula I of ‘523 as the stereo-non-standard nucleoside at the 2nd deoxy region nucleoside from the 5’ end of the deoxy region, in order to optimize the properties of the oligonucleotide, including hybridization with an RNA complement. One of ordinary skill in the art would have been motivated to do so because ‘523 teaches analogues with improved antisense properties that combine increased affinity for complementary nucleic acids with the RNase H recruiting ability of natural DNA (page 5, lines 21-27), providing oligonucleotides that selectively hybridize to RNA, as well as avoiding or reducing toxic side effects of antisense or other gene-silencing oligonucleotides by reducing or eliminating their affinity towards DNA (Summary, page 6), and ‘840 teaches the limitations of the gapmer structure recited in the instant claims and the motifs regarding sugar modifications at the 2nd deoxy region nucleoside in the (page 44) and would make obvious the limitations of claim 203-207 and 227.
With respect to claims 210-219, it would have been obvious to one of ordinary
skill in the art at the time of the effective filing date to modify the number of nucleosides
of the wings and gap of the gapmer, the types of nucleosides and substitutions in the
nucleosides in the wings of the gapmer, as well as the types of internucleoside linkages
of the gapmer of ‘840 modified with the alpha-L-RNA monomer of formula I of ‘523 at
the 2nd deoxy region nucleoside from the 5’ end of the deoxy region, in order to provide
a gapmer with improved hybridization with an RNA complement. One of ordinary skill in
the art would have been motivated to do so because ‘523 teaches that incorporation of
LNA monomers containing a 2’-O,4’-C-methylene bridge (Beta-D-LNA) into an
oligonucleotide sequence led to unprecedented improvement in the hybridization
ability of the modified oligonucleotide (page 3, lines 12-15), and ‘840 teaches the
claimed structural limitations of the gapmer and that it is desirable to arrange the
number of phosphorothioate and phosphodiester internucleoside linkages to maintain
nuclease resistance (page 66, lines 1-2) and would make obvious the claimed
limitations of claims 210-219.
It would have been obvious to one of ordinary skill in the art at the time of the
effective filing date to modify the gapmer of ‘840 modified by the stereo-non-standard
nucleoside of ‘523 at the 2nd deoxy region nucleoside of the gap, with a conjugate
group for the purpose of modifying the properties of the oligonucleotide. One of ordinary
skill in the art would have been motivated to do so because ‘840 teaches an
oligonucleotide modified by attachment of a conjugate group that may modify the
properties of the attached oligomeric compound including pharmacodynamics,
pharmacokinetics, stability, binding, absorption, cellular distribution, uptake, charge and
clearance (page 77, lines 1-5), and would make obvious the limitations of claim 220.
It would have been obvious to one of ordinary skill in the art at the time of the
effective filing date to provide the gapmer of ‘840 modified by the stereo-non-standard
nucleoside of ‘523 at the 2nd deoxy region nucleoside of the gap, and wherein the
modified oligonucleotide is single-stranded or wherein the nucleobase sequence of the
modified oligonucleotide is at least 80% complementary to a target mRNA or pre-mRNA
in order to provide a single-stranded gapmer with increased complementarity to target
mRNA or pre-mRNA. One of ordinary skill in the art would have been motivated to
provide the modified gapmer of ‘840 as a single-stranded oligonucleotide
because ‘523 teaches oligonucleotides modified with one or more alpha-L-configurated
nucleoside analogs as avoiding or reducing toxic side effects of antisense
oligonucleotides by reducing or eliminating their affinity towards DNA (Summary, page
6) and ‘840 teaches single-stranded antisense oligonucleotides (page 4, lines 18-19)
and that the antisense compounds comprising oligonucleotides are 80-100%
complementary to the target nucleic acid (page 87, lines 1-9), and the target nucleic
acid is mRNA or pre-mRNA (page 95, lines 19-20), and would make obvious the
limitations of claims 221 and 223.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill at the time of the effective filing date.
Response to Arguments
Applicant’s arguments, filed 05/01/2026 have been fully considered but are not persuasive.
Applicant summarizes the examiner’s rejection and arguments in the office action on pages 3-4 of the response. Applicant argues on page 5 that the examiner has failed to establish a prima facie case of obviousness, and cites MPEP 2143 (A)(1) that the prior art references much teach or suggest all of the claim elements and also cites KSR Intl Co. v. Teleflex Inc. and MPEP 2144 (III). Applicant submits on page 5 that the examiner has not established a prima facie case of obviousness because the cited references fail to teach and would not have suggested all of the structural elements of the claimed modified oligonucleotides and oligomeric compounds, and restates what the present claims are directed to. Applicant argues on page 6 that WO ‘523 describes modified oligonucleotides that are not gapmers and have different lengths and nucleoside motifs that those disclosed by WO ‘840, much less those of the present claimed oligomeric compound, and that the exemplified oligonucleotides in WO ‘523 are shorter (max length of 14 nt) than Applicant’s claimed oligomeric compounds of 15-30 nucleosides, and are not gapmers as recited in claim 203, and points to Example 1, Table 1, and Example 7, Table 2 of WO '523. Applicant argues, like WO '840, WO '523 does not teach or suggest an oligomeric compound that is a gapmer comprising a deoxy region having the specific modifications recited in present claim 203, nor does WO '840 provide direction suggesting modifying a deoxy region with a modification from WO '523 to arrive at the claimed compounds, and that none of the deoxy region modifications presented in Tables 6, 7, 8, and 9 of WO '840 allow modification of the 5'-most nucleoside of the deoxy region, and only 29 of 190 suggested deoxy region ('central region') motifs allow modification of the second deoxy region nucleoside from the 5'-end of the deoxy region. Applicant argues the Examiner has provided no reason that one of ordinary skill reading WO '840 and WO '523 would have modified the oligonucleotides of WO '804 to arrive at an oligomeric compound having the specific modifications of Applicant's claims.
This is not found persuasive, because the Examiner has provided reasons and motivation in the instant rejection for why one of ordinary skill in the art would want to modify the gapmer of ‘840 having the 2nd deoxy region nucleoside from the 5’ end of the deoxy region as a modified nucleoside or substituted sugar moiety of ‘840, and replace the 2nd deoxy region modified nucleoside or substituted sugar moiety with the alpha-L-RNA monomer of formula I of ‘523 as the stereo-non-standard nucleoside at the 2nd deoxy region nucleoside from the 5’ end of the deoxy region, in order to optimize the properties of the oligonucleotide, including hybridization with an RNA complement as taught by ‘523. The references in combination teach the claimed limitations and motivations for combining. ‘840 provides the structural limitations of the gapmer and the recited position of the deoxy region of the gap that can have a modified nucleoside or substituted sugar moiety. ‘523 teaches the benefits of the structure of the novel analogues with improved antisense properties that combine increased affinity for complementary nucleic acids with the RNase H recruiting ability of natural DNA. Therefore the 2nd deoxy region nucleoside of ‘840 is ready for improvement with any modified nucleoside or substituted sugar moiety, which can be the alpha-L-RNA monomer of formula I of ‘523 that is taught to impart selective hybridization to RNA, and combine increased affinity for complementary nucleic acids with the RNase H recruiting ability of natural DNA.
Regarding applicants arguments that WO ‘523 describes modified oligonucleotides that are not gapmers and have different lengths and nucleoside motifs than those disclosed by WO ‘840, the examiner argues that the WO ‘523 reference was not provided for the gapmer and length limitation, but rather WO ‘523 was provided to show the stereo-non-standard nucleoside structure that is recited in instant claim 203 and the benefit of incorporating a nucleoside analog of that structure into an oligonucleotide. WO ‘840 provided the limitations regarding the gapmer structure, length, and motif of modified nucleosides or modified sugars in the 2nd deoxy region nucleoside of the deoxy region. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The examiner has cited multiple motivations from the references as to why one of ordinary skill in the art would be motivated to incorporate a stereo-non-standard nucleoside having the structure of formula II or V into the specific nucleoside position of the gapmer of ‘840, including that ‘523 teaches natural DNA only exhibits modest affinity for RNA and falls short on a number of other critical characteristics including nuclease resistance and therefore a significant effort has been invested to identify novel analogues with improved antisense properties that combine increased affinity for complementary nucleic acids with the RNase H recruiting ability of natural DNA (page 5, lines 21-27), and teaches providing oligonucleotides that selectively hybridize to RNA, as well as avoiding or reducing toxic side effects of antisense or other gene-silencing oligonucleotides by reducing or eliminating their affinity towards DNA (Summary, page 6).
Applicant argues on page 6 that the Examples show treatment of cells with modified oligonucleotides containing 2’-substituted stereo-non-standard nucleosides as claimed reduces caspase activation and cytotoxicity to significantly different degrees compared to the control compound (see pages 49-70) and these differences are not predictable based on the placements and identities of the sugar modifications within the exemplified compounds even in compounds having the same nucleobase sequence.
This is not found persuasive. For example, in Table 2 on pages 49-50, Compound No. 1385842 is the only compound from Table 1 on page 48 that falls within the claimed scope (the stereo-non-standard nucleoside having the alpha-L-ribose configuration is in position 1 of the deoxy gap region), and this compound had % Caspase activation of 120. The results for caspase activation in Table 2, page 50 show that the other compounds with the stereo-non-standard nucleoside having the alpha-L-ribose configuration in different positions of the deoxy region than what is claimed, as well as compounds not having a stereo-non-standard nucleosides have similar results, such as Compounds 1385840 (118), 1385838 (124), and 1385839 (109). Therefore, there does not appear to be any criticality to the position of the stereo-non-standard nucleoside, as merely having that modification in any nucleotide positions 1-5 of the gap provides an effect. Compound 1385840 does not include any stereo-non-standard nucleoside (see Table 1 page 48), and has caspase activation % of 118 which is better than Compound No. 1385842 which has caspase activation % of 120 that falls within the claimed scope.
Applicant cites In re NTP, Inc., 654 F.3d 1279, 1299 (Fed. Cir. 2011) on page 7 of response, regarding avoiding hindsight reconstruction using the patent in suit as a guide and also cites MPEP 2142. Applicant concludes with the argument that one of ordinary skill in the art would have no reason to modify oligonucleotides of '840 in the particular way to arrive at the present claims, i.e., by specifically replacing at least one of the 5'-most nucleoside of the deoxy region or the 2nd deoxy region nucleoside from the 5'-end of the deoxy region with the alpha-L-RNA monomer of formula I of '523 as the stereo-non-standard nucleoside and that nothing in any of the cited references would have suggested Applicant's claimed gapmer having these specific modifications and it is only with impermissible hindsight that the Examiner constructs the present rejection.
This is not found persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The examiner did not use hindsight reconstruction using applicant’s disclosure, and relied on the references to teach the combination of limitations and the motivations for combining the references. As stated above, ‘840 teaches a gapmer comprising a modified nucleoside or a substituted sugar moiety at the 2nd deoxy region nucleoside of the gap, and ‘523 provides the structure of the stereo-non-standard nucleoside and the motivation and benefits thereof. Specifically, ‘523 teaches benefits of antisense nucleic acids for therapy but also the need for improved antisense properties that combine increased affinity for complementary nucleic acids with RNase H recruiting ability of natural DNA and the need to identify novel analogs with these properties. Therefore, the motivation to combine comes from the references themselves, and not applicant’s disclosure.
Applicant argues on pages 7-8 that it would not have been predictable that an oligomeric compound comprising a modified oligonucleotide having the recited stereo-non-standard nucleoside modifications would exhibit reduced toxicity without substantial loss in potency. One of ordinary skill in the art would not have been able to predict that a modified oligonucleotide having the particular modified sugar motif of a stereo-non-standard nucleoside having the structure of Formula II or V in at least one of the 5’ most nucleoside of the deoxy region of the 2nd deoxy region nucleoside from the 5’ end of the deoxy region as recited in claim 203 would lead to desirable therapeutic properties such as improved tolerability and/or activity. Applicant points to Examples in the specification showing that treating cells and mice with oligomeric compounds comprising the modified oligonucleotides containing 2’-substituted stereo-non-standard nucleosides at different positions results in significantly different levels of measured activity and/or cytotoxicity (See pages 49-70 of specification and the Declaration of Michael Todd Migawa filed herewith at paragraphs 12-16), and shows that placements of the sugar modifications within the exemplified compounds and the differences vary greatly. Applicant points to Examples 5,6,8,10 and 12 showing the effects of activity and tolerability which are not predictable. Applicant states including a nucleoside of formula V, wherein J9 and J10 are each H at one of positions 1-5 resulted in substantially different tolerability outcomes in treated mice and references Table 16 of Example 10 at a 50 mg/kg dose that the ALT levels in mice treated with modified oligos comprising the substitution at position 3 (compound 1215461) or position 5 (compound 1368054) of the central region were at least 13-fold and at least 2-fold higher than ALT levels in mice treated with modified oligos containing the substitution at positions 1 and 2 of the central region (compounds 1368034 and 1360853), and the result is even more pronounced at a 150 mg/kg dose. Applicant also points to the AST levels on Table 17 pg 60, where Compounds 1368034 and 1368053 which have the substitution at positions 1 and 2 of the central region have improved tolerability relative to compounds with substitution at positions 3-5 at the 150 mg/kg dose and relative to control compound 558807 at the 50 mg/kg dose. Applicant states including a nucleoside of Formula II, wherein J9 and J10 are each H at one of the positions 1-4 within a modified nucleotide resulted in substantially different tolerability outcomes in mice, and points to Table 9 and Table 12 at the 150 mg/kg dose showing ALT levels in mice treated with the modified oligos with the substitution at position 3 (compound 1263776) of the central region were at least 3-fold higher than those treated with the substitution at position 1 (1382781) and more than 200-fold higher than mice treated with modified oligos with the substitution at position 2 (1382782). Table 10 and Table 13 at the 150 mg/kg dose show AST levels in mice with the oligo with the substitution at position 3 (compound 1263776) of the central region were almost 6-fold higher than mice treated with the oligo substituted at position 1 (1382781) and more than 200-fold higher than mice treated with oligo substituted at position 2 (1382782). The reduction in toxicity was achieved without reduction in activity, as can be seen by comparing CXCL12 mRNAs levels in Tables 11 and 14. At the 150 mg/kg dose, modified oligos with the substitution at position 3 (compound 1263776) reduced CXCL12 mRNAs levels in the liver to 11% compared to treatment with PBS only with those with the substitution at position 1 or 2 (1382781 or 1382782) reduced CXCL12 mRNAs levels in the liver to 4% and 6% respectively.
This is not found persuasive. While the results pointed out by Applicant do appear to show an unexpected effect, the issue is that these results are shown for specific species of the claimed genus and therefore it is not clear what exactly the improved results are attributed to. Applicant should explain what exactly is providing the effect and how the unexpected results apply over the full range encompassed by the claims. There needs to be an explanation as to what features allows for the unexpected effect in order for the Examiner to determine that these results would occur over the full scope that is claimed. Is it the specific position only, is it a specific compound of formula II or V, is it a specific length of the oligonucleotide, do other chemical modifications affect the results? For Example, the claims recite the oligomeric compound comprises a modified oligonucleotide consisting of 15-30 linked nucleosides. In contrast, the Examples and results above pointed out by Applicant are for modified oligonucleotides that are 16 nucleotides in length. Other differences between the scope of the claims with those pointed out above by Applicant in the Examples are the other chemical modifications at specific positions (phosphorothioate linkages, cEt modified sugar moieties, 5-methyl-Cytosine, substituted stereo-standard nucleosides (See page 48 describing modifications of oligonucleotides in Table 1). Another major consideration is the scope of the compounds of formula II and V encompassed by the claims versus the more specific structure of the compounds corresponding to formula II and V in the Examples. The compound of formula II in the claims encompass that one of J3 and J4 is H, and the other of J3 and J4 is selected from H, OH, F, OCH34, OCH2CH2OCH3, O-C1-C6 alkoxy, and the compound of formula V encompass that one of J9 and J10 is H and the other of J9 and J10 is selected from H, OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy and SCH3 (claim 203). However, the Examples above cited by applicant pertain to more specific compounds of formula II and V. Example 5 page 52 says the modified oligonucleotides in Table 6 have either a 2’-beta-D-xylo-deoxyribosyl stereo-non-standard DNA nucleotide in the gap (a nucleoside of formula II, wherein J3 and J4 are each H) or a 2’-alpha-L-deoxyribosyl stereo-non-standard DNA nucleoside in the gap (nucleoside of formula V, wherein J9 and J10 are each H). Pages 52-53 show the specific structures of a beta-D-XNA and a 2’-alpha-L-DNA, and pages 59 and 61 showing a specific structure of Formula V wherein J9 and J10 are each H corresponding to the alpha-L DNA modification in the compounds of Tables 15-17,19. Therefore, the improved results claimed by Applicant would be for the scope of this specific compound of formula V, wherein J9 and J10 are each H, or the compound of formula II wherein J3 and J4 are H, and not for the entire scope of the compound of formula V or II encompassed by the claims wherein one of J9 or J10 could be other than H (OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy and SCH3). It is not clear if other compounds of formula V and II other than when J9 and J10 would also achieve these improved results.
Applicant also points to the Declaration on page 10 regarding that the effect of the stereo-non-standard nucleoside in at least one of the 5’ most nucleoside or 2nd deoxy region nucleoside from the 5’ end of the deoxy region is not dependent on a particular sequence context or target mRNA. The post-filing data in paragraphs 14-16 of the Declaration shows that compounds according to the present claims targeting different mRNAs (i.e., HDAC2, PABN-1, or DNM2) exhibit unexpectedly improved properties (i.e., improved toxicity without substantial loss in potency) compared to compounds comprising only stereo-standard DNA nucleosides in the central region.
This is not found persuasive. The Table showing the post-filing data pertains to a particular oligonucleotide sequence and target that is not commensurate in scope with the claims. It also appears that the nucleotide that is modified with alpha-L-DNA or beta-D-XNA is always a “T” as shown in the Table in paragraph 15, even though the targets are different. See the explanation above which also applies to this. It is not clear what is responsible for providing the unexpected results claimed by Applicant. Is it the specific position only, is it a specific compound of formula II or V, is it a specific length of the oligonucleotide. The compounds provided in paragraph 0015 are all 16 nucleotides in length compared to the recited length of 15-30 linked nucleosides. In addition, the improved results claimed by Applicant would be for the scope of this specific compound of formula V, wherein J9 and J10 are each H, or the compound of formula II wherein J3 and J4 are H, and not for the entire scope of the compound of formula V or II encompassed by the claims wherein one of J9 or J10 could be other than H (OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy and SCH3). It is not clear if other compounds of formula V and II other than when J9 and J10 would also achieve these improved results.
Applicant also provides arguments for surprisingly superior results compared to compounds comprising only stereo-standard nucleosides in the deoxy region on pages 10-11 of the response, and cites MPEP § 2141(II) citing Graham v. John Deere Co., 148 USPQ at 467. See also TriMed, Inc. v. Stryker Corp., 608 F.3d 1333, 1343 (Fed. Cir. 2010) ("We have repeatedly held that evidence of secondary considerations must be considered if present."); In re Eli Lilly & Co., 902 F.2d 943, 945 (Fed. Cir. 1990), and MPEP § 2145 citing Dillon, 919 F.2d at 692-93, 16 USPQ2d at 1901. Comparative data provided in the present application and in the Declaration at paragraphs 12-16 show that compounds according to the present claims exhibit unexpectedly improved properties, including improved toxicity without substantial loss in potency, compared to compounds comprising only stereo-standard DNA nucleosides in the central region. For example, compounds 1368034 and 1368053 (substitution at positions 1 and 2, respectively) described in Example 10 in the present application correspond to the oligomeric compound of present claim 203. These two compounds are 100% complementary to mouse CXCL12, GENBANK NT_039353.7 truncated from 69430515 to 69445350 (instant SEQ ID NO: 1), at position 6877 to 6892. Compounds 1368034 and 1368053 both demonstrated reduced liver toxicity in vivo compared to compound 558807 (which comprises only 2'-substituted stereo- standard nucleosides) in the experiment provided in Example 10.
This is not found persuasive. While Applicant does show an unexpected effect for the specific oligonucleotide compounds described in the previous paragraph, the issue is whether the unexpected results apply over the full range encompassed by the claims, as the Examiner has addressed above. Compounds 1368034 and 1368053 described in Example 10 are very specific compounds and are species of the genus recited in the claims. These compounds pertain to a particular oligonucleotide sequence (SEQ ID NO: 5) and length (16 nt), particular chemical modifications at specific positions which are not claimed, and pertain to the sugar modification at the specific positions to be an alpha-L DNA. In contrast, the stereo-non-standard nucleosides that are claimed encompass other groups (one of J9 or J10, or one of J3 or J4 could be other than H (OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy and SCH3), and the oligomeric compound that is claimed can be 15-30 nucleosides in length and do not require the modifications shown at specific positions in Table 15. “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003). Note: MPEP 716.02(d).
Applicant argues on page 11, selected modified oligonucleotides were administered to wildtype BALB/c mice to assess tolerability. Specification at pages 58-60. To evaluate the effects of the modified oligonucleotides on liver and kidney function, plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. Tables 16 and 17 show results of treatment with 50 mg/kg of presently-claimed compound 1368034 resulted in ALT and AST values of 50 (U/L) and 86 (U/L), respectively, treatment with 50 mg/kg of presently-claimed compound 1368053 resulted in ALT and AST values of 39 (U/L) and 122 (U/L), respectively. In comparison, treatment with 50 mg/kg of compound 558807 resulted in an ALT and AST values of 4035 (U/L) and 4870 (U/L), respectively, or about 40- to 100-fold higher. These data indicate that tolerability of presently- claimed compounds 368034 and 1368053 is superior to that of compound 558807.
This is not found persuasive. See the Examiner’s response above regarding the differences between the scope of the claims and the specific oligonucleotides exemplified that Applicant is arguing unexpected results for, which apply to Applicants arguments here. “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance”. See MPEP 716.02. In addition, Tables 16 and 17 show that Compounds 1215462 and 1368054 also result in significantly decreased ALT and AST values at 50 mg/kg, and these compounds have the 4th, or 5th positions of the nucleotide in the central region modified with the nucleoside of formula V, wherein J9 and J10 are each H (top of page 59). Therefore, there does not appear to be any criticality to the position of the modifications, as the modification at position 1,2,4 or 5 all showed reduced ALT and AST values at 50 mg/kg compared to Compound 558807. While Tables 16 and 17 show 16.7 mg/kg resulted in reduction of ALT and AST levels in all of compounds 1368034,1368053,1215461,1215462 and 1368054, other amounts of 5.5 mg/kg or 1.8 mg/kg do not appear to be consistent with the ALT and AST levels in the compounds, or a significant difference among the compounds or in comparison with Compound 558807.
Applicant argues on pages 11-12 in addition to reduced toxicity, compounds 1368034 and 1368053 demonstrated equivalent potency in vivo compared to compound 558807 in the experiments of Example 10 of the present application. As shown in Table 18, compounds 1368034 and 1368053 reduced CXCL12 expression to similar levels as compound 558807 at the same dosages. For example, at the 50 mg/kg dose, compounds 1368034 and 1368053 reduced CXCL12 mRNA levels in the liver to 10% and 8%, respectively, compared to treatment with PBS only, and compound 558807 at the same dose reduced CXCL12 mRNA levels to 4%. Together, these data show that compounds 1368034 and 1368053 demonstrate significantly reduced liver toxicity, without any substantial loss in potency, compared to compound 558807. These results are unexpected and could not have been predicted from WO '840 or any other cited references.
This is not found persuasive because again, the unexpected results are not commensurate in scope with the claims (See the Examiners response above regarding the scope of what is claimed vs the specific compounds in the Examples that are showing the unexpected results). Other concentrations (16.7, 5.5 and 1.8 mg/kg) of compounds 1368034, 1368053, 1215461, 1215462 and 1368054 show reduction of CXCL12 expression compared to Compound 558807, which would not be an unexpected result. There does not appear to be any criticality to the position of the stereo-non-standard nucleoside, as merely having that modification in any nucleotide positions 1-5 of the gap provides an effect.
Applicant provides on page 12, that compounds 1382781 and 1382782 which have the substitutions at position 1 and 2 of the central region, respectively in Examples 5 and 8 correspond to the compound in claim 203, and both compounds demonstrated reduced liver toxicity in vivo in Example 8 compared to previously published compound 558807 that has only stereo-standard nucleosides) in Example 10, and explains that in these examples the modified oligos were administered to mice to assess tolerability, including effects on liver and kidney function, plasma levels of ALT and AST. Tables 9 and 10 shows treatment with 50 mg/kg of compound 1382781 resulted in ALT and AST values of 92 (U/L) and 124 (U/L), 50 mg/kg of compound 1382782 resulted in ALT and AST values of 28 (U/L) and 40 (U/L), while compound 558807 resulted in ALT and AST values of 4035 (U/L) and 4870 (U/L) or about 30- to 100- fold higher values. This shows tolerability of presently claimed compounds 1382781 and 1382782 is superior to that of compound 558807. Applicant argues on pages 12-13 that Compounds 1382781 and 1382782 also show equivalent activity in vivo compared to compound 558807 in Examples 8 and 10 as they reduced CXCL12 expression to similar levels compared to compound 558807 at the same dosages, which shows compounds 1382781 and 1382782 demonstrate significantly reduced liver toxicity without any substantial loss in activity compared to compound 558807. The Declaration is further discussed that the compounds of the present claims exhibit unexpectedly improved properties, including reduced toxicity without substantial loss in potency, independently of the particular sequence ad the targeted mRNA in paragraphs 14-16 of the Declaration, compared to compounds comprising only stereo-standard nucleosides in the deoxy region and the effect of the stereo-non-standard nucleoside is not limited to a specific individual sequence context or mRNA target. The compounds in the Declaration are 3-10-3 gapmers comprising a stereo-non-standard nucleoside (either alpha-L-DNA (Formula V) or beta-D-XNA (Formula II)) at the 2nd deoxy region nucleoside from the 5’ end of the deoxy region, and paragraph 15 shows ALT levels were substantially lower in livers of the mice treated with 50 or 100 mg/kg of the compounds comprising either an alpha-L-DNA or beta-D-XNA at the 2nd deoxy region nucleoside compared to mice treated with compounds comprising only stereo-standard nucleosides. This data shows that compounds comprising at least one stereo-non-standard nucleoside having the structure of Formula II or V in at least one of the 5’ most nucleoside of the deoxy region or the 2nd deoxy region nucleoside demonstrate significantly reduced liver toxicity without any substantial loss in activity, independently of the sequence of the targeted mRNA and with respect to compounds comprising stereo-non-standard nucleoside in a different position of the central region. Applicant argues these results were unexpected and could not have been predicted from the cited publications.
This is not found persuasive. While the results pointed out by Applicant do appear to show an unexpected effect, the issue is that these results are shown for specific species of the claimed genus and therefore it is not clear what exactly the improved results are attributed to. Applicant has not explained or shown whether the unexpected results apply over the full range encompassed by the claims, as the Examiner has addressed above. Applicant should explain what exactly is providing the effect. See the Examiners response above regarding the scope of what is claimed vs the specific compounds in the Examples that are showing the unexpected results.
Claim 222 is rejected under 35 U.S.C. 103 as being unpatentable over ‘840 (supra.) and ‘523 (supra.) as applied to claims 203-207,210-221,223 and 227 above, and further in view of WO 2017053999, hereinafter “’999”, Published 30 March 2017.
The teachings of ‘840 and ‘523 as applicable to claims 203-207,210-221,223 and 227 are described above.
‘840 and ‘523 do not teach an oligomeric duplex comprising the oligomeric compound of claim 203 and a second oligomeric compound comprising a second modified oligonucleotide.
However, at the time of the effective filing date, ’999 teaches that chemical modifications have increased the potency and efficacy of antisense compounds, but there is a need to facilitate uptake and distribution of antisense compounds into other cell types (page 2, lines 9,17 and 18). ‘999 teaches oligomeric compounds comprising a modified oligonucleotide and a conjugate group which enhances delivery of the modified oligonucleotide to one or more extra-hepatic tissues (page 2, lines 29-31) and teaches a duplex comprising a first oligomeric compound and a second oligomeric compound wherein the first oligomeric compound comprises a first modified oligonucleotide consisting of 10-30 linked nucleosides, and the second oligomeric compound comprises a second modified oligonucleotide consisting of 10-30 linked nucleosides and a conjugate group (Page 3, Embodiment 1, lines 5-11).
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of the effective filing date, to further modify the gapmer of ‘840 modified by the stereo-non-standard nucleoside of ‘523 at the 2nd deoxy region nucleoside of the gap, with the teachings of ‘999, for the purpose of providing an oligomeric duplex to enhance delivery of the gapmer to extra-hepatic tissues. One of ordinary skill in the art would have been motivated to provide the gapmer of ‘840 modified by ‘523 as part of a duplex with a second modified oligonucleotide, because ‘999 teaches the need to facilitate uptake and distribution of antisense compounds into other cell types (page 2, lines 9,17 and 18), and that a duplex comprising a first oligomeric compound comprising a first modified oligonucleotide and a second oligomeric compound comprising a second modified oligonucleotide with a conjugate group can enhance delivery of the modified oligonucleotide to one or more extra-hepatic tissues (page 2, lines 29-31), and would make obvious the limitations of claim 222.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill at the time of the effective filing date.
Response to Arguments
Applicant’s arguments, filed 05/01/2026 have been fully considered but are not persuasive.
Applicant argues WO ‘840 and WO ‘523 each alone or in combination fail to teach the limitations recited in claim 203, and that WO ‘999 does not remedy the deficiencies of WO ‘804, and like ‘840 and ‘523, WO’999 does not teach or suggest a gapmer "wherein at least one of the 5'-most nucleoside of the deoxy region or the 2nd deoxy region nucleoside from the 5'-end of the deoxy region is a stereo-non- standard nucleoside, and wherein the at least one stereo-non-standard nucleoside has the structure of Formula II or of Formula V." Applicant argues the experimental results provided in the specification and Declaration demonstrate the unpredictability regarding activity of modified oligos containing stereo-non-standard nucleosides and the compounds of the present claims exhibit unexpectedly improved properties, including improved toxicity without substantial loss in potency, independently of sequence and targeted mRNA with respect to compounds comprising a stereo-non-standard nucleoside in a different position of the central region. Claim 222 depends from claim 203. Accordingly, claim 222 would not have been obvious over WO '840, WO '523, and WO '999, alone or in combination.
This is not found persuasive because as stated above in the response to the arguments against the 103 rejection of claims 203-207,210-221,223 and 227, the Examiner has provided a prima facie case of obviousness for ‘840 and ‘523 as teaching the limitations of claim 203 and motivation to combine them. WO ‘999 was provided in order to teach the additional limitation of the oligomeric duplex and motivation for modifying (i.e. for the purpose of providing an oligomeric duplex to enhance delivery of the gapmer to extra-hepatic tissues). WO ‘999 is not required to teach a gapmer, as the ‘840 ref teaches those limitations, and is not required to teach the stereo-non-standard nucleoside has the structure of Formula II or of Formula V, as the ‘523 reference teaches those limitations. The examiner has provided motivation for why one of ordinary skill in the art would want to provide an oligomeric duplex as stated above, and therefore has provided a prima facie case of obviousness. The Examiner has also addressed Applicant’s arguments regarding unexpected results in the response to ‘840 and ‘523 above.
Claims 203 and 224 are rejected under 35 U.S.C. 103 as being unpatentable over ‘840 (supra.) in view of Poopeiko et al. (Bioorganic and Medicinal Chemistry Letters, Published 24 April 2003, pages 2285-2290).
Regarding claims 203 and 224, ‘840 teaches oligomeric compounds comprising
one or more modified nucleosides comprising a modified sugar moiety that provides
desirable properties such as enhanced nuclease stability or increased binding affinity
with a target nucleic acid (page 21, lines 2-5) and oligonucleotides comprising or
consisting of a region having a gapmer sugar motif, which comprises two external
regions or “wings” and a central or internal region or “gap” (page 29 lines 17-18). ‘840
teaches gapmer sugar motifs in Table 5 (page 45), which shows the oligonucleotide
gapmer may be 14-21 nucleosides in length. ‘840 teaches each nucleoside of the gap is
a 2’-deoxynucleoside, and the gap comprises one or more modified nucleosides (page
43, lines 1-2). Page 44 of ‘840 teaches different nucleoside motifs of the gap of the
gapmer (lines 10-35), including that the 2nd deoxy region nucleoside from the 5’ end of
the deoxy region of the gap is “X” which is a modified nucleoside or a substituted sugar
moiety, including at least the following motifs: DXDDDDDDD, DXXDDDDDD,
DXDDDDDXD, DXDDDDXDD, DXDDDXDDD, DXDDXDDDD, DXDDDDDD,
DXDDDDXD, DXDDDXDD, DXDDXDDD, DXDXDDDD, DXXDDDDD, DXDDDDXD,
DXDDDDD, DXDDDXD, DXDDXDD, DXDXDDD, DXXDDDD, DXDDDD, DXXDDD,
DXDXDD, DXDDXD (page 44, lines 10-35).
‘840 does not teach the oligomeric compound wherein the at least one stereo-
nonstandard nucleoside has the structure of Formula II, wherein J3 and J4 are each H.
However, before the effective date, Poopeiko et al. teach xylo-configured oligonucleotides (XNA, xylo nucleic acids), containing xylo-configured 2’-deoxynucleotides (‘xylo-DNA’, monomer A, Figure 1), and that mixed XNAs revealed preferential hybridization towards RNA complements (page 2289).
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Therefore, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the gapmer of ‘840 having the 2nd deoxy region nucleoside from the 5’ end of the deoxy region as a modified nucleoside or substituted sugar moiety of ‘840 and replace the 2nd deoxy region modified nucleoside or substituted sugar moiety of the deoxy region with the xylo-configured 2’-deoxynucleotide of Poopeiko et al. for the purpose of creating an oligonucleotide having preferential hybridization towards RNA complements. One of ordinary skill in the art would have been motivated to do so because Poopeiko et al. teach that monomer A above induces protection against 3’-exonucleolytic degradation and would make obvious the claimed limitations of claims 203 and 224.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill at the time of the effective filing date.
Response to Arguments
Applicant’s arguments, filed 05/01/2026 have been fully considered but are not persuasive.
On page 15 of response, Applicant argues the Examiner has failed to establish a prima facie case of obviousness. As acknowledged by the Examiner, '840 does not teach the oligomeric compound wherein the at least one stereo- nonstandard nucleoside has the structure of Formula II, wherein J3 and J4 are each H, or wherein at least one stereo-nonstandard nucleoside has the structure of Formula V, wherein J9 and J10 are each H." Action at pages 13-14. More broadly, the Examiner also acknowledged that "'840 does not teach wherein at least one of the 5' -most nucleoside of the deoxy region, the 2nd, 3rd, or 4th deoxy region nucleoside from the 5'-end of the deoxy region is a stereo-non-standard nucleoside and wherein the at least one stereo-non-standard nucleoside has the structure of formula II or of formula V." Id. at 7. Applicant argues that Poopeiko describes modified oligonucleotides that are not gapmers, and that have different lengths and different nucleoside motifs than those disclosed by WO '840, much less those of the presently claimed oligomeric compound. For example, the modified oligonucleotides exemplified in Poopeiko are shorter (i.e., with a maximum length of 13 nucleosides) than Applicant's claimed oligomeric compounds (which have a length of 15-30 nucleosides) and are not gapmers as recited in present claim 203. See Table 1 on page 2287 of Poopeiko. Thus, Like WO '840, Poopeiko does not teach or suggest an oligomeric compound that is a gapmer comprising a deoxy region having the specific modifications recited in present claim 203. The Examiner has provided no reason that one of ordinary skill reading WO '840 and Poopeiko would have modified the oligonucleotides of WO '840 to arrive at an oligomeric compound having the specific modifications of Applicant's claims. Further, nothing in any of the cited references would have suggested Applicant's claimed gapmer having these specific modifications and it is only with impermissible hindsight that the Examiner constructs the present rejection. Applicant argues the experimental results provided in the specification and Declaration demonstrate the unpredictability regarding activity of modified oligos containing stereo-non-standard nucleosides and the compounds of the present claims exhibit unexpectedly improved properties, including improved toxicity without substantial loss in potency, independently of sequence and targeted mRNA with respect to compounds comprising a stereo-non-standard nucleoside in a different position of the central region.
This is not found persuasive, because the Examiner has provided reasons and motivation in the instant rejection for why one of ordinary skill in the art would want to modify the gapmer of ‘840 having the 2nd deoxy region nucleoside from the 5’ end of the deoxy region as a modified nucleoside or substituted sugar moiety of ‘840 and replace the 2nd deoxy region modified nucleoside or substituted sugar moiety of the deoxy region with the xylo-configured 2’-deoxynucleotide of Poopeiko et al. for the purpose of creating an oligonucleotide having preferential hybridization towards RNA complements. The references in combination teach the claimed limitations and motivations for combining. ‘840 provides the structural limitations of the gapmer and the recited position of the deoxy region of the gap that can have a modified nucleoside or substituted sugar moiety. Poopeiko et al teaches the structure and the benefits of the xylo-configured 2’-deoxynucleotide. Therefore the 2nd deoxy region nucleoside of ‘840 is ready for improvement with any modified nucleoside or substituted sugar moiety, which can be the xylo-configured 2’-deoxynucleotide of Poopeiko et al. for making an oligonucleotide having preferential hybridization towards RNA complements.
Regarding applicants arguments that Poopeiko et al. describes modified oligonucleotides that are not gapmers and have different lengths and nucleoside motifs than those disclosed by WO ‘840 and the instant claims, the examiner argues that the Poopeiko et al. reference was not provided for the gapmer and length limitation, but rather to show the stereo-non-standard nucleoside structure that is recited in instant claim 203 and the benefit of incorporating a nucleoside analog of that structure into an oligonucleotide. WO ‘840 provided the limitations regarding the gapmer structure, length, and motif of modified nucleosides or modified sugars in the 2nd deoxy region nucleoside of the deoxy region. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The examiner has provided motivations from Poopeiko et al. as to the benefits of the xylo-configured 2’-deoxynucleotides (i.e., protection against 3’-exonucleolytic degradation, preferential hybridization towards RNA complements) and it would be obvious to incorporate the xylo-configured 2’-deoxynucleotides of Poopeiko et al. into a gapmer ready for improvement (the 2nd deoxy region nucleoside of ‘840 is ready for improvement with any modified nucleoside or substituted sugar moiety).
The Examiner has also addressed Applicant’s arguments regarding unexpected results in the response to ‘840 and ‘523 above.
Claims 203 and 226 are rejected under 35 U.S.C. 103 as being unpatentable over ‘840 (supra.) in view of Gotfredsen et al. (Bioorganic and Medicinal Chemistry, Vol. 4, No. 8 pp. 1217-1225, 1996), cited on an IDS dated 11/02/2021.
Regarding claims 203 and 226, ‘840 teaches oligomeric compounds comprising
one or more modified nucleosides comprising a modified sugar moiety that provides
desirable properties such as enhanced nuclease stability or increased binding affinity
with a target nucleic acid (page 21, lines 2-5) and oligonucleotides comprising or
consisting of a region having a gapmer sugar motif, which comprises two external
regions or “wings” and a central or internal region or “gap” (page 29 lines 17-18). ‘840
teaches gapmer sugar motifs in Table 5 (page 45), which shows the oligonucleotide
gapmer may be 14-21 nucleosides in length. ‘840 teaches each nucleoside of the gap is
a 2’-deoxynucleoside, and the gap comprises one or more modified nucleosides (page
43, lines 1-2). Page 44 of ‘840 teaches different nucleoside motifs of the gap of the
gapmer (lines 10-35), including that the 2nd deoxy region nucleoside from the 5’ end of
the deoxy region of the gap is “X” which is a modified nucleoside or a substituted sugar
moiety, including at least the following motifs: DXDDDDDDD, DXXDDDDDD,
DXDDDDDXD, DXDDDDXDD, DXDDDXDDD, DXDDXDDDD, DXDDDDDD,
DXDDDDXD, DXDDDXDD, DXDDXDDD, DXDXDDDD, DXXDDDDD, DXDDDDXD,
DXDDDDD, DXDDDXD, DXDDXDD, DXDXDDD, DXXDDDD, DXDDDD, DXXDDD,
DXDXDD, DXDDXD (page 44, lines 10-35).
‘840 does not teach the oligomeric compound wherein the at least one stereo-
nonstandard nucleoside has the structure of Formula V, wherein J9 is H and J10 is 2’-OMe.
However, at the time of the effective filing date, Gotfredsen et al. teach alpha-ODNs with alpha-2-O-Methyl-D-arabino-furanosyl thymine, and that alpha-ODNs K-O in Table 2, containing two to four alpha-2’-O-Me-araT monomers showed marked enhancements of duplex stability when complexed with RNA instead of DNA (pages 1220-1221), and that alpha-ODNs containing alpha-2’-OME-araT monomers display excellent hybridization properties, especially towards complementary RNA (Page 1221, Conclusion).
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the gapmer of ‘840 and replace at least one of the modified nucleobases or substituted sugar moieties at the 5’-most nucleoside, the 2nd deoxy region nucleoside, the 3rd deoxy region nucleoside or the 4th deoxy region nucleoside from the 5’-end of the deoxy region of the gap, with the alpha-2-O-Methyl-D-arabino-furanosyl thymine of Gotfredsen et al., for the purpose of enhancing duplex stability when complexed with RNA. One of ordinary skill in the art would have been motivated to modify the gapmer of ‘840 and replace at least one of the modified nucleobases or substituted sugar moieties at the 5’-most nucleoside, the 2nd deoxy region nucleoside, the 3rd deoxy region nucleoside or the 4th deoxy region nucleoside from the 5’-end of the deoxy region of the gap, with the alpha-2-O-Methyl-D-arabino-furanosyl thymine of Gotfredsen et al., because Gotfedsen et al. teach alpha-2-O-Methyl-D-arabino-furanosyl thymine ODNs showed marked enhancements of duplex stability when complexed with RNA instead of DNA (pages 1220-1221), and that alpha-ODNs containing alpha-2’-OME-araT monomers display excellent hybridization properties, especially towards complementary RNA (Page 1221, Conclusion), and would make obvious the limitations of claims 203 and 226.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill at the time of the effective filing date.
Response to Arguments
Applicant’s arguments, filed 05/01/2026 have been fully considered but are not persuasive.
Applicant argues on pages 17-18 that Gotfredsen describes modified oligonucleotides that are not gapmers, and that have different nucleoside motifs than those disclosed by WO '840, much less those of the presently claimed oligomeric compound. Like WO '840, Gotfredsen does not teach or suggest an oligomeric compound that is a gapmer comprising a deoxy region having the specific modifications recited in present claim 203. The Examiner has provided no reason that one of ordinary skill reading WO '840 and Gotfredsen would have modified the oligonucleotides of WO '840 to arrive at an oligomeric compound having the specific modifications of Applicant's claims. Further, nothing in any of the cited references would have suggested Applicant's claimed gapmer having these specific modifications and it is only with impermissible hindsight that the Examiner constructs the present rejection. Applicant argues the experimental results provided in the specification and Declaration demonstrate the unpredictability regarding activity of modified oligos containing stereo-non-standard nucleosides and the compounds of the present claims exhibit unexpectedly improved properties, including improved toxicity without substantial loss in potency, independently of sequence and targeted mRNA with respect to compounds comprising a stereo-non-standard nucleoside in a different position of the central region.
This is not found persuasive, because the examiner has provided reasons and motivation in the instant rejection for why one of ordinary skill in the art would want to modify the gapmer of ‘840 having the 2nd deoxy region nucleoside from the 5’ end of the deoxy region as a modified nucleoside or substituted sugar moiety of ‘840 and replace the 2nd deoxy region modified nucleoside or substituted sugar moiety of the deoxy region with the alpha-ODNs (alpha-2-O-Methyl-D-arabino-furanosyl thymine) of Gotfredsen for as they provide excellent hybridization properties, especially towards complementary RNA. The references in combination teach the claimed limitations and motivations for combining. ‘840 provides the structural limitations of the gapmer and the recited position of the deoxy region of the gap that can have a modified nucleoside or substituted sugar moiety. Gotfredsen teaches the structure and the benefits of the alpha-ODNs (alpha-2-O-Methyl-D-arabino-furanosyl thymine). Therefore the 2nd deoxy region nucleoside of ‘840 is ready for improvement with any modified nucleoside or substituted sugar moiety, which can be the alpha-ODN (alpha-2-O-Methyl-D-arabino-furanosyl thymine) of Gotfredsen for making an oligonucleotide with improved hybridization properties.
Regarding applicants arguments that Gotfredsen et al. describes modified oligonucleotides that are not gapmers and have different lengths and nucleoside motifs than those disclosed by WO ‘840 and the instant claims, the examiner argues that the Gotfredsen reference was not provided for the gapmer and length limitation, but rather to show the stereo-non-standard nucleoside structure that is recited in instant claim 203 and the benefit of incorporating a nucleoside analog of that structure into an oligonucleotide. WO ‘840 provided the limitations regarding the gapmer structure, length, and motif of modified nucleosides or modified sugars in the 2nd deoxy region nucleoside of the deoxy region. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The examiner has provided motivation from Gotfredsen as to the benefits of the alpha-ODNs (alpha-2-O-Methyl-D-arabino-furanosyl thymine) including enhancements of duplex stability when complexed with RNA instead of DNA (pages 1220-1221), and that alpha-ODNs containing alpha-2’-OME-araT monomers display excellent hybridization properties, especially towards complementary RNA, and therefore the examiner maintains it would be obvious to incorporate the alpha-ODNs (alpha-2-O-Methyl-D-arabino-furanosyl thymine) of Gotfredsen into an gapmer ready for improvement (the 2nd deoxy region nucleoside of ‘840 is ready for improvement with any modified nucleoside or substituted sugar moiety).
The Examiner has also addressed Applicant’s arguments regarding unexpected results in the response to ‘840 and ‘523 above.
Claims 203 and 225 are rejected under 35 U.S.C. 103 as being unpatentable over ‘840 (supra.) in view of Liu et al. (Bioconjugate Chem. 2018, 29, 2265-2277).
Regarding claims 203 and 225, ‘840 teaches oligomeric compounds comprising
one or more modified nucleosides comprising a modified sugar moiety that provides
desirable properties such as enhanced nuclease stability or increased binding affinity
with a target nucleic acid (page 21, lines 2-5) and oligonucleotides comprising or
consisting of a region having a gapmer sugar motif, which comprises two external
regions or “wings” and a central or internal region or “gap” (page 29 lines 17-18). ‘840
teaches gapmer sugar motifs in Table 5 (page 45), which shows the oligonucleotide
gapmer may be 14-21 nucleosides in length. ‘840 teaches each nucleoside of the gap is
a 2’-deoxynucleoside, and the gap comprises one or more modified nucleosides (page
43, lines 1-2). Page 44 of ‘840 teaches different nucleoside motifs of the gap of the
gapmer (lines 10-35), including that the 2nd deoxy region nucleoside from the 5’ end of
the deoxy region of the gap is “X” which is a modified nucleoside or a substituted sugar
moiety, including at least the following motifs: DXDDDDDDD, DXXDDDDDD,
DXDDDDDXD, DXDDDDXDD, DXDDDXDDD, DXDDXDDDD, DXDDDDDD,
DXDDDDXD, DXDDDXDD, DXDDXDDD, DXDXDDDD, DXXDDDDD, DXDDDDXD,
DXDDDDD, DXDDDXD, DXDDXDD, DXDXDDD, DXXDDDD, DXDDDD, DXXDDD,
DXDXDD, DXDDXD (page 44, lines 10-35).
‘840 does not teach the oligomeric compound wherein the at least one stereo-
nonstandard nucleoside has the structure of Formula V, wherein J9 and J10 each are H.
However, before the effective filing date, Liu et al. teach alpha-anomers of 8-aza-2’-deoxyguanosine (alphaGd*) and 2’-deoxyguanosine (alphaGd) and their incorporation into 12-mer duplexes (Abstract). Liu et al. teach naturally occurring nucleosides display beta-D configuration for linkages between nucleobases and sugar moieties, but gamma irradiation under anaerobic conditions can cause DNA lesions resulting in formation of DNA with alpha-nucleotides, and that these alpha-anomeric lesions can be bypassed by human polymerases (Introduction, page 2265).
Liu et al. teach the structure of the anomeric nucleoside (alphaGd*) to be
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146
157
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The structure of the alphaGd* anomeric nucleoside above meets the structural limitations of the compound of Formula V, wherein J9 and J10 are each H.
Liu et al. teach alpha-nucleosides can develop selective base pairing and stacking interactions with beta-D compounds in canonical DNA, and alpha-D and beta-D residues can communicate with each other in a very selective way, and the discriminatory efficiency was significantly better for alpha-nucleosides than their beta-anomeric counterparts (page 2271, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the gapmer having the 2nd deoxy region nucleoside from the 5’ end of the deoxy region as a modified nucleoside or substituted sugar moiety of ‘840, and replace the 2nd deoxy region modified nucleoside or substituted sugar moiety with the alphaGd* anomeric nucleoside of Liu et al. in order to improve stability and discriminatory efficiency. One of ordinary skill in the art would have been motivated to do so because Liu et al. teach alpha-nucleotides can be bypassed by human polymerases (Introduction, page 2265) and can develop selective base pairing and stacking interactions with beta-D compounds in canonical DNA, and alpha-D and beta-D residues can communicate with each other in a very selective way, and the discriminatory efficiency was significantly better for alpha-nucleosides than their beta-anomeric counterparts (page 2271, right column).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill at the time of the effective filing date.
Response to Arguments
Applicant has not provided any response to the rejection of claims 203 and 225 under 35 U.S.C. 103 as being unpatentable over ‘840 (supra.) in view of Liu et al. Therefore, the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 203,220,223,224 and 227 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 246-250,263-266 of copending Application No. 17635096 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because 17635096 claim 246 recites an oligomeric compound comprising a modified oligonucleotide consisting of 12-30 linked nucleosides wherein at least one nucleoside of the modified oligonucleotide is a stereo-non-standard nucleoside having formula II, and instant claim 203 comprises an oligomeric compound comprising a modified oligonucleotide consisting of 15-30 linked nucleosides, and is a gapmer comprising a deoxy region wherein at least one of the 5’-most-nucleoside of the deoxy region or the 2nd deoxy region nucleoside of the deoxy region is a stereo-non-standard nucleoside, and wherein the at least one stereo-non-standard nucleoside has the structure of Formula II and is a species of the oligomeric compound recited in 17635096. 17635096 claim 247 comprises that J4 is H, claim 248 that J4 is F, and claim 249 that J4 is OCH3, while instant claim 203 reads on J4 being these substituents. 17635096 claim 250 comprises wherein Bx is selected from uracil, thymine cytosine, 4-methyl cytosine, adenine and guanine, as does instant claim 227. 17635096 claim 263 comprises that the oligonucleotide has a nucleobase sequence of the targeting region is at least 85% complementary to an equal length portion of the nucleobase sequence of a target RNA, and instant claim 223 comprises that the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of the nucleobase sequence of a target nucleic acid selected from mRNA and pre-mRNA. 17635096 claims 264-266 comprise the oligomeric compound comprising a conjugate, and instant claim 220 comprises a conjugate group. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
On page 18 of the response, Applicant argues that the claims are otherwise allowable that the provisional rejection should be withdrawn in accordance with MPEP 804(I)(B)(1)(b)(i).
The examiner acknowledges applicant’s response, and as the claims are not yet in condition for allowance, the rejection is maintained.
New Claim Rejection
Claims 203-207,210-224 and 227 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,332,733 (Issued May 17, 2022).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 203-207,210-224 and 227 a recite an oligomeric compound comprising a modified oligonucleotide consisting of 15-30 linked nucleosides, and is a gapmer comprising a deoxy region wherein at least one of the 5’-most-nucleoside of the deoxy region or the 2nd deoxy region nucleoside of the deoxy region is a stereo-non-standard nucleoside, and wherein the at least one stereo-non-standard nucleoside has the structure of Formula II or V. Similarly claims 1-20 of Patent 11,332,733 recite an oligomeric compound comprising a modified oligonucleotide consisting of 14-16 linked nucleosides wherein the modified oligonucleotide has a 5’-region, a central region, and a 3’-region wherein the 5’-region consists of 1-3 linked nucleosides, each comprising a 4’ to 2’- linked bicyclic sugar moiety, the 3’ region consists of 1-3 linked nucleosides, each comprising a 4’-to-1’ linked bicyclic sugar moiety; and the central region consists of 9-10 linked nucleosides wherein the central region has the following formula
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As shown in the instant Example 5, a 2’-beta-D-xylo-deoxyribosyl stereo-non-standard nucleoside is a nucleoside of Formula II (see instant page 52 of specification). Therefore, the 5’-most nucleoside of the central region (deoxy region) of Patent 11,332,733 falls within the stereo-non-standard nucleoside of instant formula II and is a species thereof. In this case, the claim under examination, is generic to a species or sub-genus claimed in the 11,332,733 patent (the entire scope of the reference claim falls within the scope of the examined claim. In such a situation, a later patent to a genus would, necessarily, extend the right to exclude granted by an earlier patent directed to a species or sub-genus.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gupta et al. (Organic and Biomolecular Chemistry, 2009, 7, 2389-2401) teach alpha-configured arabino nucleic acids having structures that fall within Formula II and V of the instant claims.
Gotfredsen et al. (Bioorganic and Medicinal Chemistry, Vol. 4, No. 8 pp 1217-1225, 1996) teach synthesis of the alpha anomer of 2’-OMe-araT and incorporation into ODN analogues.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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