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 .
Response to Amendment/Status of Claims
The amendment filed 03/30/2026 has been entered. Claims 1 and 42 were amended, claims 11 and 40 were canceled. Claims 1,19,36,37,41-43 and 52 are pending and under examination.
Withdrawn Rejections
Applicants arguments and amendments, see page 4, filed 03/30/2026 with respect to the 35 U.S.C. 112(d) rejection of claims 11,40,42 and 43 have been fully considered and are persuasive based on the cancelation of claims 11 and 40, and amendment to claim 42 to recite “further comprising at least one alternative sugar moiety”, and in which claim 43 now further limits. Therefore, the rejection has been withdrawn.
Rejections Necessitated by Amendment
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.
Claim 41 is 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 41 recites, “The antisense oligonucleotide of claim 40, further comprising a pseudouridine or 5-methoxyuridine”. Claim 41 is indefinite being both incomplete, by its dependence on a canceled claim (claim 40); and for lack of antecedent basis for its limitation (“The antisense oligonucleotide) which is no longer present due to the cancellation of claim 40. See MPEP 608.01(n)(V). Amending claim 41 to refer to a claim which recites the antisense oligonucleotide or deleting the claim would obviate the rejection. The examiner is interpreting claim 41 to depend on claim 1 in the interest of compact prosecution.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 36 and 37 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 was amended to recite “and wherein the backbone is fully phosphorothioate-modified”. Therefore, claim 36 which recites “wherein the antisense oligonucleotide comprises at least one alternative internucleoside linkage does not further limit claim 1 which already requires full phosphorothioate-modifications of the backbone.
Regarding claim 37, which depends on claim 36 and recites “wherein the at least one alternative internucleoside linkage is a phosphorothioate internucleoside linkage, 2’-alkoxy internucleoside linkage, or alkyl phosphate internucleoside linkage”, as claim 1 already requires a fully phosphorothioate-modified backbone, additional backbone modification is not possible and therefore claim 37 does not further limit.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1,19,36,37,42,43 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Grabczyk et al. (US 20170183655, Published 29 June 2017) as evidenced by NCBI Reference sequence NM_000249.3, in view of Hung et al. (US 20070299027, Published 27 Dec 2007).
The examiner notes the limitations in claim 1 regarding “all cytosines within the DNA core sequence are substituted with 5’-methyl-2’-O-methoxyethyl-dCytosine, and wherein a thymidines in the flanking sequences are substituted with 5’-methyl-2’-O-methoxyethyl-Uracil, and wherein the backbone is fully phosphorothioate-modified” are supported by page 95, lines 33-39 of the instant specification. See below.
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Regarding claims 1,36 and 37, Grabczyk et al. teach oligonucleotides for treating DNA repeat expansion diseases and that DNA mismatch repair (MMR) contributes to genome instability and has been implicated in repeat expansions of numerous disorders including Huntington’s disease, myotonic dystrophy, Friedreich ataxia. Grabczyk et al. teach that there is no treatment or cure for Friedreich ataxia or many of the other DNA repeat expansion diseases [0006]. Grabczyk et al. teach an oligonucleotide comprising 15-30 nucleotide bases in length [0008] and that oligonucleotide compounds of the invention include antisense oligonucleotides which are single-stranded [0057], and the oligonucleotide compounds described comprise about 80%, or about 85% or about 90% up to 99% sequence complementarity to a target region within the target nucleic acid sequence [0061], and which oligonucleotides are specific for a polynucleotide of a subunit of the MMR system (MLH1) [0062]. Grabczyk et al. teach the oligonucleotides of 15-30 nucleotide bases in length targeted to a complementary nucleic acid sequence of a gene or gene product encoding a MutL subunit, MLH1, comprises a modification which is a phosphorothioate backbone for increased stability against nucleases and enhanced cellular uptake [0010,0070].
Grabczyk et al. also teach the genomic sequence for human MLH1 isoform 1 was publicly available in public databases before the effective filing date as evidenced by GenBank Accession number NM_000249.3 (paragraph 0050).
A search of the NCBI database for NM_000249.3 shows the mRNA sequence for homo sapiens mutL homolog 1 (MLH1), transcript variant 1, mRNA.
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Sequence-to-sequence alignment of instant SEQ ID NO:325 shows that nucleotides 1-20 of SEQ ID NO:325 aligns with nucleotides 696-677 of Homo sapiens mutL homolog 1, transcript variant 1, mRNA as shown in the alignment below.
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Sequence-to-sequence alignment of instant SEQ ID NO:326 shows that nucleotides 1-20 of SEQ ID NO:326 aligns with nucleotides 697-678 of Homo sapiens mutL homolog 1, transcript variant 1, mRNA as shown in the alignment below.
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Sequence-to-sequence alignment of instant SEQ ID NO:769 shows that nucleotides 1-20 of SEQ ID NO:769 aligns with nucleotides 1536-1517 of Homo sapiens mutL homolog 1, transcript variant 1, mRNA as shown in the alignment below.
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Sequence-to-sequence alignment of instant SEQ ID NO:861 shows that nucleotides 1-20 of SEQ ID NO:861 aligns with nucleotides 1674-1655 of Homo sapiens mutL homolog 1, transcript variant 1, mRNA as shown in the alignment below.
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Grabczyk et al. also teach the oligonucleotide compounds can include variants in which a different base is present at one or more of the nucleotide position in the oligonucleotide (paragraph 0063), and that the oligonucleotides can comprise at least one region where the oligonucleotide is modified in order to exhibit one or more desired properties, including increased resistance to nuclease degradation, increased cellular uptake and/or increased binding affinity for the target nucleic acids, and include synthetic nucleotides having modified base moieties and/or modified sugar moieties (paragraph 0066). Grabczyk et al. teach modifications and combinations thereof, “the modification comprises a phosphorothioate backbone, a 5-methylcytosine nucleotide, a 2′-O-methoxyethyl sugar moiety, a locked nucleic acid subunit, an ethylene-bridged nucleic acid subunit, or a combination thereof (paragraph 0010). Therefore, Grabczyk et al. teach nucleotides with the combination of 5-methylcytosine and 2-O-methoxyethyl.
Grabczyk et al. do not teach the antisense oligonucleotide comprises a DNA core sequence comprising linked deoxyribonucleosides, a 5’ flanking sequence comprising linked nucleosides; and a 3’ flanking sequence comprising linked nucleosides; wherein the DNA core is positioned between the 5’ flanking sequence and the 3’ flanking sequence; wherein the 5’ flanking sequence and the 3’ flanking sequence each comprise at least 2 linked nucleosides and wherein at least one nucleoside of each flanking sequence comprises an alternative nucleoside, and wherein all cytosines within the core sequence are 5’-methyl-2’-O-methoxyethy-dCytosine, and wherein all thymidines in the flanking sequences are 5’-methyl-2’-O-methoxyethyl-Uracil and wherein the backbone is fully phosphorothioate-modified.
However, before the effective filing date, Hung et al. taught Huntington’s disease is a neurodegenerative disorder caused by mutation of the huntingtin gene [0003], and the mutation is a CAG expansion [0004], and that reducing the expression of the mutant huntingtin gene would be therapeutic for Huntington’s disease [0011]. Hung et al. taught antisense oligonucleotides 12-35 nucleotides in length, comprising at least 12 consecutive nucleotides of a specific nucleotide sequence [0012], [0094], [0095] as a therapeutic for treating Huntington’s disease [0020]. Hung et al. taught the antisense oligonucleotides comprise a chimeric oligonucleotide having a gap segment positioned between 5’ and 3’ wing segments, in which the gap segment is comprised of 2’-deoxynucleotides, and the wing segments are comprised of nucleotides having modified sugar moieties, the gap segment may consist of ten 2’-deoxynucleotides and each wing segment consists of five 2’-O-methoxyethyl-modified nucleotides, and in some embodiments each cytosine of the antisense oligonucleotide is a 5’-methylcytosine [0012,0014,0018]. Hung et al. taught 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability and are suitable base substitutions, even more particularly when combined with 2’-O-methoxyethyl sugar modification. Hung taught natural nucleobases include adenine, guanine, and the pyrimidine bases thymine, cytosine and uracil, and that the bases may be modified, including thymine derivatives and other 5-substituted uracils [0107].
Hung et al. taught gapmers having a 2’-deoxyoligonucleotide region flanked by non-deoxyoligonucleotide segments in which the flanking segments are referred to as “wings” and that the gap of the gapmer presents a substrate recognizable by RNase H when bound to the RNA target, and the wings do not provide such a substrate but can confer other properties such as duplex stability or advantageous pharmacokinetic effects [0117]. Hung et al. taught in addition to a 5-10-5 gapmer, other configurations are readily recognized by those skilled in the art, as well as the wings comprising 2’-MOE modified nucleotides and gapmers having phosphorothioate backbones [0117]. Hung et al. taught embodiments wherein each internucleoside linkage of the antisense oligonucleotide is a phosphorothioate internucleoside linkages (paragraphs 0013,0018,0051) and also exemplifies a chimeric antisense oligonucleotide (gapmer) in which the internucleoside backbone linkages are phosphorothioate throughout the oligonucleotide (paragraph 0175), and therefore teaches the limitations of the backbone being fully phosphorothioate-modified.
Regarding claims 42 and 43, Grabczyk et al. teach modifications of the oligonucleotide is a 2’-O-methoxyethyl sugar moiety, a locked nucleic acid, or an ethylene-bridged nucleic acid subunit, and that LNA and ethylene-bridged nucleic acids render the oligonucleotide compounds RNase H and nuclease resistant and increase affinity for target RNA (paragraphs 0010, 0072).
Regarding claim 52, Grabczyk et al. teach a pharmaceutical composition comprising an oligonucleotide comprising a nucleic acid sequence that hybridizes to a complementary target nucleic acid sequence of a gene or gene produce encoding a component of a mismatch repeat (MMR) complex, and a pharmaceutically acceptable carrier, and wherein the oligonucleotide comprises a sequence that hybridizes with a nucleic acid sequence encoding a subunit of the MMR system (MLH1) [0009].
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the single-stranded antisense oligonucleotide that binds MLH1 as taught in Grabczyk et al. to comprise or consist of the nucleobase sequence of any one of SEQ ID NOs: 325,326,769 and 861, and the gapmer antisense oligonucleotide structure and modifications as taught by Hung et al. for the purpose of studying in a cell line as a potential therapeutic for Huntington’s Disease with a reasonable expectation of success. It would have been obvious for one of ordinary skill in the art to choose any of the 20 nucleotide regions of the target MLH1, transcript variant 1 mRNA sequence to target and to arrive at instant SEQ ID NOs:325,326,769 or 861. One of ordinary skill in the art would have readily and reasonably obtained the single-stranded oligonucleotide of SEQ ID NOs: 325,326,769 or 861 as the human MLH1, transcript variant 1 mRNA sequence information was publicly available as NM_000249.3 before the effectively filed date, as taught by Grabczyk et al. and that the SEQ ID NOs: 325,326,769 and 861 align with nucleotides of human MLH1, transcript variant 1 mRNA as shown by the alignments above.
Regarding the gapmer structure and modifications, it would have amounted to modifying a known antisense oligonucleotide to a known gene (MLH1) with known gapmer structures and modifications to yield predictable results. One of ordinary skill in the art would have been motivated to modify the antisense oligonucleotide of Grabczyk et al. as evidenced by NM_ 000249.3, with the antisense oligonucleotide having the gapmer structure of Hung et al. because Hung et al. teach the gap of the gapmer presents a substrate recognizable by RNase H when bound to the RNA target, and the wings can confer other properties such as duplex stability or advantageous pharmacokinetic effects. One would be motivated to provide the recited modifications at the particular regions and nucleobases of the antisense oligonucleotide because Grabczyk et al. teach modifications and combinations thereof, “the modification comprises a phosphorothioate backbone, a 5-methylcytosine nucleotide, a 2′-O-methoxyethyl sugar moiety, a locked nucleic acid subunit, an ethylene-bridged nucleic acid subunit, or a combination thereof (paragraph 0010), and Hung et al. teach the gap segment may consist of ten 2’-deoxynucleotides and each wing segment consists of five 2’-O-methoxyethyl-modified nucleotides, and in some embodiments each cytosine of the antisense oligonucleotide is a 5’-methylcytosine [0012,0014,0018] and that 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability and are suitable base substitutions, even more particularly when combined with 2’-O-methoxyethyl sugar modification. Hung teach natural nucleobases include adenine, guanine, and the pyrimidine bases thymine, cytosine and uracil, and that the bases may be modified, including thymine derivatives and other 5-substituted uracils [0107]. It is noted that 5-methyluracil is the chemical name for thymine. In addition, Hung et al. taught embodiments wherein each internucleoside linkage of the antisense oligonucleotide is a phosphorothioate internucleoside linkage (paragraphs 0013,0018,0051) and also exemplifies a chimeric antisense oligonucleotide (gapmer) in which the internucleoside backbone linkages are phosphorothioate throughout the oligonucleotide (paragraph 0175). An ordinary artisan would only have to pick from a few of the taught modifications and combinations (5-methylcytosine, 2’-O-methoxyethyl sugar moiety and combination thereof, thymine derivatives and other 5-substituted uracils, and fully phosphorothioate-modified backbones) and apply to any of the nucleobases of the antisense oligonucleotide of Grabczyk et al. and Hung et al. to arrive at the instant limitations regarding “wherein all cytosines within the DNA core sequence are 5’-methyl-2’-O-methoxyethyl-dCytosine and wherein all thymidines in the flanking sequence are 5’-methyl-2’-L-methoxyethyl-Uracil and wherein the backbone is fully phosphorothioate-modified.
Therefore, one of ordinary skill in the art would be motivated to use such a gapmer structure as taught by Hung et al., to target other genes associated with trinucleotide repeat disorders, such as MLH1 to study in a cell line or animal model as a potential therapeutic for Huntington’s Disease, and would be motivated to manipulate the chemical modifications in the DNA core and flanking sequences and on different nucleobases, in order to achieve the best stability and optimal number and placement of modifications in the antisense oligonucleotide. Grabczyk et al. teach all of the limitations of claims 36,37,42,43 and 52.
Accordingly, the limitations of claims 1,19,36,37,42,43 and 52 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 03/30/2026 have been fully considered but they are not persuasive.
Applicant summarizes the 103 rejection made by the office on page 5 of response. Applicant cites Pfizer Inc. v. Sanofi Pasteur Inc., on pages 5-6 and cites what amended claim 1 now recites. Applicant argues that even if Grabczyk and Hung are properly combined, which Applicant does not concede, nothing in the references directs a person of ordinary skill in the art to arrive at the claimed oligonucleotides with the claimed alternative nucleosides and do not motivate a person of ordinary skill in the art regarding an oligonucleotide having all DNA core cytosine deoxyribonucleotides being 5-methyl-2’-O-methoxyethyl-dCytosine, all flanking sequence thymidine ribonucleotides being 5-methyl-2’-O-methoxyethyl-Uracil and a fully phosphorothioate modified backbone. Applicant argues a person of ordinary skill in the art would not have been motivated to arrive at the instantly claimed oligonucleotides because the art taught that modifications would allegedly “confer upon the oligonucleotide increased resistance to nuclease degradation” (e.g., RNase H) per Hung paragraph 115 which is the opposite of the intended “inhibition of gene expression via an RNase H-mediated pathway”, See e.g., WO 2020/117705, page 26, lines 35-36.
This is not found persuasive. Grabczyk et al. teach and suggest modifications and combinations thereof, “the modification comprises a phosphorothioate backbone, a 5-methylcytosine nucleotide, a 2′-O-methoxyethyl sugar moiety, a locked nucleic acid subunit, an ethylene-bridged nucleic acid subunit, or a combination thereof (paragraph 0010) and Hung taught the gap segment may consist of ten 2’-deoxynucleotides and each wing segment consists of five 2’-O-methoxyethyl-modified nucleotides, and in some embodiments each cytosine of the antisense oligonucleotide is a 5’-methylcytosine [0012,0014,0018] and that 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability and are suitable base substitutions, even more particularly when combined with 2’-O-methoxyethyl sugar modification. In addition, Hung taught natural nucleobases include adenine, guanine, and the pyrimidine bases thymine, cytosine and uracil, and that the bases may be modified, including thymine derivatives and other 5-substituted uracils [0107].
Hung et al. taught that the gap of the gapmer presents a substrate recognizable by RNase H when bound to the RNA target, and the wings do not provide such a substrate but can confer other properties such as duplex stability or advantageous pharmacokinetic effects [0117]. Hung et al. taught embodiments wherein each internucleoside linkage of the antisense oligonucleotide is a phosphorothioate internucleoside linkages (paragraphs 0013,0018,0051) and also exemplifies a chimeric antisense oligonucleotide (gapmer) in which the internucleoside backbone linkages are phosphorothioate throughout the oligonucleotide (paragraph 0175). Therefore, it is not found persuasive that the combination of Grabczyk et al. and Hung do not teach or suggest the instant claim limitations.
Regarding applicants argument that the art taught that modifications would allegedly “confer upon the oligonucleotide increased resistance to nuclease degradation” (e.g., RNase H) per Hung paragraph 115 which is the opposite of the intended “inhibition of gene expression via an RNase H-mediated pathway”, the instant claims do not recite any limitations regarding inhibiting gene expression via an RNase H-mediated pathway. In addition, the motivation can be different than that of the motivation of the instant invention. It is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV). The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
As an additional point, the paragraph cited by Applicant in Hung, paragraph 0115, states that chimeric antisense oligonucleotides typically contain at least one region which is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, alteration of charge, increased stability and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for RNAses or other enzymes. By way of example, RNAse H is a cellular endonuclease which cleaves the RNA strand of an RNA: DNA duplex, and activation of RNAse H therefore results in cleavage of the RNA target when bound by a DNA-like oligomeric compound, thereby greatly enhancing the efficiency of oligonucleotide mediated inhibition of gene expression (paragraph 0115 of Hung). Therefore, the Examiner does not see that Hung teaches away from what the instant invention discloses. The chimeric oligonucleotide can be modified to confer increased resistance to nuclease degradation of the oligonucleotide itself, while still serving as a substrate for RNAse H for RNAse H mediated pathway for degradation of the target mRNA. For these reasons, Applicant’s argument is not found persuasive.
Applicant argues a person of ordinary skill in the art could not have reasonably expected that the instantly claimed oligonucleotides would function successfully as demonstrated in the specification by substantially reducing the levels of MLH1 mRNA because the art suggests that 2’-MOE-modified nucleosides would not be susceptible to degradation by endonucleases. Applicant argues on page 7 that each of the claimed oligonucleotides substantially reduces the level of MLH1 mRNA, as shown in Table 12, MLH1 mRNA levels are reduced to below 20%, as well as demonstrated sub-nanomolar IC50 values in a dual-dose screen.
This is not found persuasive. The argument pertaining to the art regarding 2’-MOE-modified nucleosides and degradation by endonucleases has been addressed above. Regarding Applicant’s argument about the results of the oligonucleotide reducing the level of MLH1 mRNA shown in Table 12, to below 20%, Applicant has not stated what the expected result would be in order to determine if the results are actually unexpected. Applicant has not compared the instant claimed oligonucleotides to an oligonucleotide outside of the claimed scope to show criticality with regards to the modifications, or another structural difference between the prior art and instant claims to show that the instantly claimed sequences are unexpected. Table 12 just shows that the sequences work and no evidence has been provided that one of ordinary skill int eh art would not expect them to work. 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.
Therefore, the 35 U.S.C. 103 rejection of claims 1,19,36,37,42,43 and 52 as unpatentable over Grabczyk et al. as evidenced by NCBI Reference sequence NM_000249.3, in view of Hung et al. is maintained.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Grabczyk et al. as evidenced by NCBI Reference sequence NM_000249.3, and Hung et al. as applied to claims 1,19,36,37,42,43 and 52 above, and further in view of Davis (Nucleic Acids Research, 1995, Vol. 23, No. 24, pages 5020-5026).
Claim Interpretation: As claim 41 recites “the antisense oligonucleotide of claim 40” and claim 40 has been cancelled, the examiner is interpreting claim 41 to depend on claim 1 in the interest of compact prosecution.
The teachings of Grabczyk et al. as evidenced by NCBI Reference sequence NM_000249.3, and Hung et al. as applicable to claims 1,19,36,37,42,43 and 52 are described above.
Grabczyk et al. as evidenced by NCBI Reference sequence NM_000249.3, and Hung et al. do not teach an antisense oligonucleotide comprising pseudouridine or 5-methoxyuridine.
However, before the effective filing date, Davis teach that pseudouridylation is by far the most common nucleoside modification found in nature and occurs predominantly in putative single-stranded regions (Discussion, page 5025). Davis teach that the UV, CD and NMR experimental data presented here establish that a relatively simple RNA oligonucleotide containing pseudouridine is conformationally stabilized compared to an analogous oligonucleotide containing uridine, and that neighboring nucleosides also experience stabilization of their conformation with concomitant increase in base stacking (pages 5025-5026).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have further modified the single-stranded antisense oligonucleotide of Grabczyk et al. as evidenced by NCBI Reference sequence NM_000249.3, and Hung et al. based on the teachings of Davis and to provide a pseudouridine as an additional nucleobase modification. One of ordinary skill in the art would have been motivated to do so because Davis teaches that an RNA oligonucleotide containing pseudouridine is conformationally stabilized compared to an analogous oligonucleotide containing uridine, and that neighboring nucleosides also experience stabilization of their conformation with concomitant increase in base stacking.
Accordingly, the limitations of claim 41 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 03/30/2026 have been fully considered but they are not persuasive.
Applicant states on page 7 of response that the limited disclosure of Grabczyk, GenBank, and Hung are discussed above and Davis does not cure the deficiencies thereof because Davis is also silent to an oligonucleotide having all DNA core cytosine deoxyribonucleotides being 5-methyl-2’-O-methoxyethyl-dCytosine and all flanking sequence thymidine ribonucleotides being 5-methyl-2’-O-methoxyethyl-Uracil and a fully phosphorothioate-modified backbone, and restates the that cited references do not disclose or suggest the oligonucleotide of amended claim 1 or claim 41 and therefore is not obvious in view of the cited references.
This is not found persuasive. The Examiner’s arguments pertaining to the rejection of claims 1,19,36,37,42,43 and 52 as unpatentable over Grabczyk as evidenced by GenBank and in view of Hung et al. has been explained above. The examiner is maintaining the 35 U.S.C. 103 rejection of claims 1,19,36,37,42,43 and 52 over Grabczyk as evidenced by GenBank and in view of Hung et al. based on these arguments, and therefore also maintains the 35 U.S.C. rejection of claim 41 as unpatentable over Grabczyk et al. as evidenced by NCBI Reference sequence NM_000249.3, and Hung et al. and further in view of Davis as no additional arguments were made that were not already previously addressed above.
Conclusion
Claims 1,19,36,37,41-43 and 52 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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