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 .
Election/Restrictions
Applicant’s election of Group I (claims 1-4,7,9,11-15,17,18,20-22,25,26,29-33,35-44,46 and 47) in the reply filed on 04/02/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 50,56,62,70,74 and 75 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election of species DA06-4A-27A (Examples 3-6 and Table 7, target genes are SMN2+SMN2 and the sequences comprising SEQ ID NO: 13 and SEQ ID NO: 14 operably linked via an S18 linker) in the reply filed on 04/02/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 14,33,37 and 39-44 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The examiner is expanding the species to include the divalent siRNAs and sequences taught by Alterman et al. and the bispecific SSO sequences taught by Bestas et al.
Claims 1-4,7,9,11-13,15,17,18,20-22,25,26,29-32,35,36,38,46 and 47 are under examination.
Priority
This application is a 371 of PCT/CN2022/074779, filed 01/28/2022 and claims foreign priority to PCTCN2021075958, filed 02/08/2021 as reflected by the most recent filing receipt.
Drawings
The drawings are objected to because there are many figures with multiple views that are labeled incorrectly. For Example, see FIG.1 labeled as “FIG.1” and then each view is separately labeled A,B,C. According to the standards below, they should be labeled FIG. 1A, FIG. 1B, FIG. 1C.
See 1.84 Standards for Drawings, (u) Numbering of views.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 3 is objected to because of the following informalities: line 2 recites “with the rest functional oligonucleotides being ASO(s)” and is missing “of the” and should recite “with the rest of the functional oligonucleotides being ASO(s)”. Appropriate correction is required.
Claim 14 is objected to because of the following informalities: there are two instances of reciting “and/orby” and therefore there is a space missing between “or” and “by”. Appropriate correction is required.
Claims 20 and 22 are objected to because of the following informalities: line 12 of claim 20 recites “in any one of a)~ g)”, and line 13 of claim 22 recites “in any one of a)~ ad)”. It is believed that claim 20 should recite “in any one of a)-g)” and claim 22 should recite “in any one of a)-ad)”, with a dash between a) and g) and a) and ad) respectively and without the extra space. Appropriate correction is required.
Claim 21 is objected to because of the following informalities: lines 1 and 4 each recite “wherein if presented” and should recite “wherein if present”. Appropriate correction is required.
Claim 29 is objected to because of the following informalities: line 2 recites “of functional oligonucleotides” and should recite “of the functional oligonucleotides”. In addition, claim 29 recites “SMN2 gene or protein”. At least the first recitation of a gene or protein name should be fully written for clarity. 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 2,3,17,30 and 38 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.
Regarding claim 2, which recites “the number of the functional oligonucleotides comprised in the multi-valent oligonucleotide agent is ranged from 2 to X, wherein X is an integer ranged from 3 to 10”, and claim 3 which depends on claim 2 and recites “wherein the number of dsRNA comprised in the agent is from 0 to X”, it is not clear if “X” in claim 3 has the same definition as “X” in claim 2. The lower limit is different in claim 2 than claim 3, and therefore the scope and definition of “X” is not clear.
Claim 17 recites the limitation "to the adjacent targeting oligonucleotide" in line 2. There is insufficient antecedent basis for this limitation in the claim as claim 17 depends on claim 1 and there is no recitation of a targeting oligonucleotide. Therefore, it is unclear whether the targeting oligonucleotide is one of the functional oligonucleotides recited in claim 1, or an additional oligonucleotide and therefore the metes and bounds are not clear.
Claim 30 recites “the ASO(s) increases the production of functional SMN protein by modulating SMN2 mRNA splicing or stability (SMN2 mRNA modulators). In this case, it is not clear that the limitation recited in parenthesis (SMN2 mRNA modulators) is of the same scope as the ASO increases the production of functional SMN protein by modulating SMN2 mRNA splicing or stability. SMN2 mRNA modulators seems to be a broader scope than an ASO that increases production of functional SMN protein by modulating SMN2 mRNA splicing or stability, as the ability of an ASO to increase production of functional SMN protein by modulating SMN2 mRNA could occur in a different way other than splicing or stability. Therefore, the term in parenthesis raises the question as to which term is required by the claim.
Claim 38 recites “wherein the multi-valent oligonucleotide agent is selected from or has at least 90% sequence identity to those shown in any one of Tables 7-20…”. See MPEP 2173.05(s) Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4,7,11,12,15,20-22 and 46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alterman et al. (Nature Biotechnology, Vol. 37, August 2019, 884-894), cited on an IDS.
Regarding claims 1-4,20-22 and 46, Alterman et al. taught divalent siRNA (di-siRNA), composed of two fully chemically modified, phosphorothioate containing siRNAs connected by a linker (Abstract, Fig. 1c).
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Alterman et al. taught the fully chemically modified PS-containing di-siRNA provided wide distribution and sustained gene silencing in rodent and non-human primate brain after a single administration into cerebral spinal fluid (page 3, first paragraph).
Regarding claims 7 and 11, Alterman et al. taught the di-siRNA has a 20-base guide strands and 15-base passenger strands (Results, page 3). Therefore, as the length of the di-siRNA falls within the range of 12-200 nucleotides, Alterman et al. teach the limitations of claim 11.
Regarding claim 12, Alterman et al. teach the two sense strands are covalently connected at the 3’ end through a tetra-ethylene glycol (TEG) linker (Results, page 3).
Regarding claim 15, Alterman et al. teach both of the siRNAs that are linked are fully chemically modified. As shown in Fig. 1C above, both strands of the siRNAs contain 2’-OMe and 2’F modifications.
Claims 1-3,9,11-13,15,17,20 and 46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bestas et al. (Nucleic Acid Therapeutics, Vol. 24, No. 1, 2014, pages 13-24), cited on an IDS.
Regarding claims 1-3,20 and 46, Bestas et al. teach bispecific splice switching oligonucleotides (SSOs) attached with C18 spacers (page 14, right column; page 17, left column).
Regarding claims 9 and 11, Bestas et al. teach an AON sequence, 5’-CCAUUCUCAUCCAAAGCUUUGAUUU-3’, which is 25 nucleotides in length and targets positions 304-328 of exon 2 of Mstn was chosen as the basis for the bispecific SSO design (page 16, bottom right). Table 1 also lists splicing switching oligonucleotide sequences.
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Regarding claims 12-13, Bestas et al. teach the bispecific SSOs are attached with C18 spacers (page 14, right column; page 17, left column), the structure of which the C18 linker is shown in Fig. 3A and is the same structure as instant Spacer-18.
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Regarding claim 15, Bestas et al. teach the bispecific SSOs are based on 2’-OMePS RNA chemistry (page 14, right column), and therefore teach both of the functional oligonucleotides comprise at least one chemically modified nucleotide.
Regarding claim 17, Fig. 3A above shows one end of the first AON linked to one end of the second AON with the C18 spacer in between, and therefore the first ASO is covalently linked to either the 3’ or 5’ end of the second AON.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4,7,9,11-13,15,17,18,20,21,25,26,29,30,46 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Winkelsas et al. (US 20200237931, Published 30 July 2020) in view of Saetrom et al. (US 20180305689, Published 25 Oct 2018) and Bestas et al. (Nucleic Acid Therapeutics, Vol. 24, No. 1, 2014, pages 13-24), cited on an IDS.
Regarding claims 1-4,7,9,11-13,20,21,29,30 and 46, Winkelsas et al. teach co-administration to a patient simultaneously, an oligonucleotide that is 17-35 nucleotides in length which is complementary to a region of the SMN2 promoter, wherein the oligonucleotide binding to the SMN2 promoter increases production of SMN2 mRNA (claim 17 and 20, paragraph 0003), and a splice-switching promoter which promotes exon 7 inclusion in SMN2 mRNA, and in which the splice switching promoter is nusinersin (an antisense oligonucleotide) (Claims 20-22). Winkelsas et al. teach that the splice switching oligonucleotide which can be nusinersen, may comprise the nucleotide sequence TCACTTTCATAATGCTGG (SEQ ID NO: 14) and this sequence is found in nusinersen (paragraph 0269).
Winkelsas et al. do not teach that the oligonucleotide targeting the SMN2 promoter region is a double-stranded saRNA, or wherein the oligonucleotide targeting the SMN2 promoter region and the SMN2 mRNA splice-switching oligonucleotide are covalently linked. Winkelsas et al. do not teach additional targeting nucleotides.
Before the effective filing date, Saetrom et al. taught saRNAs for upregulating the expression of a target gene (Abstract, paragraph 0010), and the saRNA may be double-stranded RNA that upregulates the expression of a specific gene, and each strand may comprise 14-30 nucleotides (paragraphs 0019,0111). Saetrom et al. taught saRNAs targeting the SMN2 gene (page 14). Saetrom et al. taught the saRNA can be conjugated to other polynucleotides, and that conjugation can increase stability and half-life and target the saRNA to specific sites in the cell, tissue or organism (paragraph 0125).
Regarding claims 25 and 26, Saetrom et al. taught the saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126).
Bestas et al. taught splice-switching oligonucleotides to modulate splicing patterns through binding to pre-mRNA, and that it is estimated that 20-30% of all disease-causing mutations affect pre-mRNA splicing, giving rise to diseases such as B-thalassemia, cystic fibrosis, cancers, spinal muscular atrophy and Duchenne muscular dystrophy (DMD) (Intro, left column). Bestas et al. taught that while splice switching oligonucleotides have therapeutic potential, targeting single mutations in DMD with SSO’s can only benefit a fraction of patients suffering from the disease since different mutations require different SSOs, and therefore effort to develop tools to skip multiple exons in DMD patients suffering from deletion mutations have been made. In addition, an important consideration is to devise efficient means of assuring equal delivering of multiple SSOs into the same cells, and that bispecific AONs to simultaneously target different mRNAs with the same AON have been developed most of which have been constructed to contains two antisense sequence spaced by nucleotide hairpins, and also in 2010 the first bispecific siRNA was reported in which a single molecule siRNA was cleaved inside the reductive environment of cells and could mediate robust RNA interference responses for both target genes (page 14, left column). Bestas et al. taught synthesis of bispecific SSOs were one arm targets exon 23 of the mouse Dmd locus and the other targets exon 2 of the Mstn gene to disrupt the reading frame, and having either internal disulfides or non-cleavable C18 spacers, and that results demonstrate such SSOs could effectively promote exon skipping of both transcripts in H2k mds myotubes (page 14, right column). Figure 1 of Bestas et al. shows the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets.
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Bestas et al. taught the bispecific SSOs are attached with C18 spacers (page 14, right column; page 17, left column), the structure of which the C18 linker is shown in Fig. 3A and is the same structure as instant Spacer-18.
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It would have been obvious to one of ordinary skill in the art before the effective filing date to have modified the oligonucleotide binding to the SMN2 promoter that increases production of SMN2 mRNA of Winkelsas et al. to be a double-stranded saRNA based on the teachings of Saetrom et al. and to provide the oligonucleotide binding to the SMN2 promoter that increases production of SMN2 mRNA and the splice-switching promoter which promotes exon 7 inclusion in SMN2 mRNA (ASO) of Winkelsas et al. covalently linked to each other based on the teachings of Bestas et al. with a reasonable expectation of success. There would be a reasonable expectation of success because this would amount to substituting the oligonucleotide that increases production of SMN2 mRNA of Wikelsas et al. with the double-stranded saRNA of Saetrom et al. that also upregulates the expression of a target gene in which SMN2 as the target gene is taught. In addition, there would be a reasonable expectation of success in covalently linking the saRNA targeting SMN2 to the splice switching oligonucleotide of Winkelsas et al. as this amounts to applying a known technical of covalently linking oligonucleotides to a known product ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Saestrom et al. taught the saRNA can be conjugated to other polynucleotides, and that conjugation can increase stability and half-life and target the saRNA to specific sites in the cell, tissue or organism (paragraph 0125). One of ordinary skill in the art would have been motivated to include additional targeting oligonucleotides which may be dsRNA or ASO because Saestrom et al. taught the saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126). An artisan would have been motivated by the teachings of Bestas et al. to covalently link the oligonucleotides of Winkelsas et al. and Saestrom et al. to each other because Bestas et al taught an important consideration is to devise efficient means of assuring equal delivery of multiple SSOs into the same cells, and taught the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets.
Regarding claim 15, Winkelsas et al. teach the oligonucleotides of the disclosure may comprise one or more nucleosides that have a modified sugar moiety, which can improve certain properties such as affinity and/or nuclease resistance (paragraph 0097).
Regarding claims 17 and 18, while Winkelsas et al. does not teach covalent attachment of the oligonucleotides and the direction of the linkage, Fig. 3A of Bestas et al. (above) shows one end of the first AON linked to one end of the second AON with the C18 spacer in between, and therefore the first ASO is covalently linked to either the 3’ or 5’ end of the second AON. It would have been obvious to one of ordinary skill in the art that the ASO is covalently linked to the adjacent targeting oligonucleotide (saRNA of Saestrom et al.) in a 3’ to 5’ orientation or in a 5’ to 3’ orientation as those are the only two options regarding the orientation, and likewise would have been obvious for the dsRNA (saRNA of Saestrom et al.) to be covalently linked to an adjacent ASO (the splice-switching ASO of Winkelsas et al.) at its 3’ end of the sense or antisense strand or at its 5’ end of the sense or antisense strand, as again those are all of the options regarding attachment to either the sense or antisense strand at either end.
Regarding claim 47, Winkelsas et al. teach the oligonucleotide can be admixed with a pharmaceutically acceptable diluent or carrier (paragraph 0020,0113,0147,0208).
Accordingly, the limitations of claims 1-4,7,9,11-13,15,17,18,20,21,25,26,29, 30,46 and 47 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 1-4,7,9,11,12,15,17,18,20-22,25,26,29,30,46 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Bhat et al. (US 20180312839, Published 1 Nov 2018) in view of Saetrom et al. (US 20180305689, Published 25 Oct 2018).
Regarding claims 1-4,7,9,11,12,20,21,29,30 and 46, Bhat et al. recites a compound for increasing expression of SMN protein in a human cell, the compound comprising a first oligonucleotide comprising at least 8 contiguous nucleotides complementary with the sequence set forth as: ATCTGTTCCACTATG (SEQ ID NO: 1) and a second oligonucleotide that is complementary with a splice control sequence of SMN2 pre-messenger RNA that promotes inclusion of exon 7 of the SMN2 pre-messenger RNA, wherein the first and second oligonucleotides are covalently linked (claim 1). Bhat et al taught single stranded oligonucleotides are provided that target a PRC2-associated region of a long non-coding RNA that inhibits expression of SMN (e.g., human SMN1, human SMN2) and thereby cause upregulation of the gene. For example, according to some aspects of the disclosure methods are provided for increasing expression of full-length SMN protein in a cell for purposes of treating SMA or other motor neuron diseases. Accordingly, aspects of the disclosure provide methods and compositions that are useful for upregulating SMN in cells (paragraphs 0005,0045).
Bhat et al. taught the first and second oligonucleotides are delivered to the cell simultaneously (paragraph 0016).
Bhat et al. does not teach that the first oligonucleotide is a double-stranded saRNA.
Before the effective filing date, Saetrom et al. taught saRNAs for upregulating the expression of a target gene (Abstract, paragraph 0010), and the saRNA may be double-stranded RNA that upregulates the expression of a specific gene, and each strand may comprise 14-30 nucleotides (paragraphs 0019,0111). Saetrom et al. taught saRNAs targeting the SMN2 gene (page 14). Saetrom et al. taught the saRNA can be conjugated to other polynucleotides, and that conjugation can increase stability and half-life and target the saRNA to specific sites in the cell, tissue or organism (paragraph 0125). Regarding claims 25 and 26, Saetrom et al. taught the saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126).
It would have been obvious to one of ordinary skill in the art before the effective filing date to have substituted the first oligonucleotide of Bhat et al. with the double-stranded saRNA of Saetrom et al. with a reasonable expectation of success. There would be a reasonable expectation of success because this would amount to substituting the oligonucleotide for upregulating SMN of Bhat et al. with the double-stranded saRNA of Saetrom et al. that also upregulates the expression of a target gene in which SMN2 as the target gene is taught. One of ordinary skill in the art would have been motivated to do so because Saestrom et al. taught the saRNA can be conjugated to other polynucleotides, and that conjugation can increase stability and half-life and target the saRNA to specific sites in the cell, tissue or organism (paragraph 0125), and taught the saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126).
Regarding claim 15, Bhat et al. recited each nucleotide of the first oligonucleotide is a 2’-modified nucleotide (claim 18), and each nucleotide of the second oligonucleotide is a 2’-modified nucleotide (claim 19)
Regarding claims 17 and 18, Bhat et al. teach the oligonucleotides can be linked through any part of the individual oligonucleotide, e.g., via the phosphate, the sugar (e.g., ribose, deoxyribose), or the nucleobase. In certain embodiments, when linking two oligonucleotides together, the linker can be attached e.g., to the 5′-end of the first oligonucleotide and the 3′-end of the second nucleotide, to the 5′-end of the first oligonucleotide and the 5′end of the second nucleotide, to the 3′-end of the first oligonucleotide and the 3′-end of the second nucleotide. In other embodiments, when linking two oligonucleotides together, the linker can attach internal residues of each oligonucleotides, e.g., via a modified nucleobase. One of ordinary skill in the art will understand that many such permutations are available for multimers (paragraph 0083).
Regarding claim 22, Bhat et al. taught mixmer ASOs in which the binding of a mixmer ASO prevents the interaction between target RNA and its RNA or protein binding partners, and that mixmer ASOs consisting of LNA interspersed with 2’-O-meth nucleotides for high affinity binding to SMN-AS1 were generated and screened, and results demonstrate that selective inhibition of PRC2:SMN-AS1 interaction by a mixmer ASO leads to increase SMN2 expression (paragraph 0204).
Regarding claim 47, Bhat et al. teach any of the disclosed oligonucleotide and a carrier, including pharmaceutical composition provide that comprise any of the oligonucleotides disclosed herein and a pharmaceutically acceptable carrier (paragraph 0010).
Accordingly, the limitations of claims 1-4,7,9,11,12,15,17,18,20-22,25,26, 29,30,46 and 47 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 13 is rejected under 35 U.S.C. 103 as being unpatentable over Bhat et al. in view of Saetrom et al. as applied to claims 1-4,7,9,11,12,15,17,18,20-22,25,26,29,30,46 and 47 above and further in view of Bestas et al. (Nucleic Acid Therapeutics, Vol. 24, No. 1, 2014, pages 13-24), cited on an IDS.
The teachings of Bhat et al. and Saetrom et al. as applicable to claims 1-4,7,9,11,12,15,17,18,20-22,29,30,46 and 47 have been described above.
Bhat et al. and Saetrom et al. do not teach the first and second oligonucleotides are covalently linked with a C-18 linker.
Bestas et al. taught splice-switching oligonucleotides to modulate splicing patterns through binding to pre-mRNA, and that it is estimated that 20-30% of all disease-causing mutations affect pre-mRNA splicing, giving rise to diseases such as B-thalassemia, cystic fibrosis, cancers, spinal muscular atrophy and Duchenne muscular dystrophy (DMD) (Intro, left column). Bestas et al. taught that while splice switching oligonucleotides have therapeutic potential, targeting single mutations in DMD with SSO’s can only benefit a fraction of patients suffering from the disease since different mutations require different SSOs, and therefore effort to develop tools to skip multiple exons in DMD patients suffering from deletion mutations have been made. In addition, an important consideration is to devise efficient means of assuring equal delivering of multiple SSOs into the same cells, and that bispecific AONs to simultaneously target different mRNAs with the same AON have been developed most of which have been constructed to contains two antisense sequence spaced by nucleotide hairpins, and also in 2010 the first bispecific siRNA was reported in which a single molecule siRNA was cleaved inside the reductive environment of cells and could mediate robust RNA interference responses for both target genes (page 14, left column). Bestas et al. taught synthesis of bispecific SSOs were one arm targets exon 23 of the mouse Dmd locus and the other targets exon 2 of the Mstn gene to disrupt the reading frame, and having either internal disulfides or non-cleavable C18 spacers, and that results demonstrate such SSOs could effectively promote exon skipping of both transcripts in H2k mds myotubes (page 14, right column). Figure 1 of Bestas et al. shows the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets.
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Bestas et al. taught the bispecific SSOs are attached with C18 spacers (page 14, right column; page 17, left column), the structure of which the C18 linker is shown in Fig. 3A and is the same structure as instant Spacer-18.
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It would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the linkers of Bhat et al. that covalently link the first and second oligonucleotides of Bhat et al. with the C18 linker of Bestas et al. with a reasonable expectation of success. An artisan would have been motivated by the teachings of Bestas et al. regarding an important consideration is to devise efficient means of assuring equal delivery of multiple SSOs into the same cells, and taught the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets.
Accordingly, the limitations of claim 13 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 31,32,36 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Bhat et al. in view of Saetrom et al. as applied to claims 1-4,7,9,11,12,15,17,18,20-22,25,26,29,30,46 and 47 above and further in view of Li et al. (US 20230287416, effectively filed 31 July 2020) and Bestas et al. (Nucleic Acid Therapeutics, Vol. 24, No. 1, 2014, pages 13-24), cited on an IDS.
The applied reference (Li et al.) has a common Applicant and Inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Claim Interpretation: The instant specification discloses that the elected saRNA, DA06-4A-27A is DS06-4A3 + AS010-27 (Table 7 page 139 of instant specification). Page 136 says DS06-4A3 is a duplex saRNA derived from DS06-0004 with structure optimization and chemical modifications. DS06-0004 is duplex saRNA targeting promoter region of SMN2 gene to increase the mRNA expression of full length SMN2 (page 136) and ASO10-27 is a single-stranded ASO known to increase levels of SMN2FL (page 136).
The teachings of Bhat et al. and Saetrom et al. as applicable to claims 1-4,7,9,11,12,15,17,18,20-22,29,30,46 and 47 have been described above.
Bhat et al. and Saetrom et al. do not teach a saRNA having a nucleotide sequence of a sense strand that is at least 90% identical to the nucleotide sequence of DS06-4A3 (SEQ ID NO: 146) and/or a saRNA having a nucleotide sequence of an antisense strand that is at least 90% identical to the nucleotide sequence of DS06-4A3 (SEQ ID NO: 147), or wherein the dsRNA comprises a saRNA having a pair of nucleotide sequences of a sense strand and an antisense strand that is at least 90% identical to the nucleotide sequence pairs of DS06-4A3: SEQ ID NO: 146 and SEQ ID NO: 147. Bhat et al. and Saetrom et al. do not teach the sequence and modifications of instant SEQ ID NO: 11 for the antisense oligonucleotide.
Before the effective filing date, Li et al. taught a combination of one or more agents that increase the expression of SMN2 gene or protein and one or more agents that increase the production of functional SMN protein by modulating SMN2 mRNA splicing or stability (claim 1), including saRNA having one strand that has at least 75% homology or complementarity with a fragment of the promoter region of the SMN2 gene that is 16-35 nt in length (paragraph 0025), and wherein the SMN2 mRNA modulator is Nusinersen (claim 5).
Copied below are the sequences and modifications of the instant elected sequences for easy comparison with the sequences and modification taught in the art.
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As shown in the alignment below, nucleotides 4-18 of SEQ ID NO: 488 of Li et al. (Db) has 100% identity to all nucleotides of instant SEQ ID NO: 146 (Qy):
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The sequence listing of Li et al. shows the positions of the specific modifications for SEQ ID NO: 488 shown below. As position 4 of SEQ ID NO: 488 is what starts with the alignment of position one of instant SEQ ID NO: 146, it can be seen below that ‘G’ at position 4 of SEQ ID NO: 488 would have a 2’-fluoro modification which is what is required of instant SEQ ID NO: 146 at position 1. Likewise, “A” at position 5 of SEQ ID NO: 488 would have a 2’-O-methyl modification which is the same modification “A” at position 2 of instant SEQ ID NO: 146 has, and so on.
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SEQ ID NO: 496 of Li et al. has 100% identity to the nucleotide sequence of instant SEQ ID NO: 147:
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The sequence listing of SEQ ID NO: 496 and the modifications at the specification positions is shown below:
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Regarding instant SEQ ID NO: 11 in claim 35, Li et al. teach the SMN2 mRNA modulator may be Nusinersen (also referred to as ASO-10-27 herein) (claim 5, paragraph 0012) and that ASO-10-27 is a single stranded and 2′-O-2-methoxyethyl (MOE)-modified ASO and induces exon 7 inclusion by targeting an intronic splicing silencer (ISS) at intron 7 of SMN2 gene (Hua, Y, et al. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice.” Am J Human Genet (2008). The sequence for ASO-10-27 is: meU*meC*meA*meC*meU*meU*meU*meC*meA*meU*meA*meA*meU*meG*meC*meU*meG*meG, in which, me, 2′MOE, *, phosphorothioate (PS) backbone modification, all cytosines (Cs) are 5′methyl cytosine (paragraph 0206).
Regarding claim 36, wherein the multivalent oligonucleotide agent has a nucleotide sequence that is at least 90% identical to the nucleotide sequence of DA06-4A-27A (SEQ ID NO: 14) and an antisense saRNA strand having a nucleotide sequence of SEQ ID NO: 13 that has partial complementarity with the sense saRNA strand of SEQ ID NO: 14, and claim 38 in which Applicant elected DA06-4A-27A which is DS06-4A3 and ASO10-27 linked by S18 with the ASO linked in the 5’-3’ orientation, the sequences of Li et al. regarding ASO10-27 which is the same as the instant ASO01-27 of SEQ ID NO: 11, and the saRNA sequences of SEQ ID NOs: 488 and 496 which meet the sequence requirements of instant SEQ ID NOs: 146 and 147 have been shown above.
Bhat et al., Saetrom et al. and Li et al. do not teach a S18 linker.
Bestas et al. taught splice-switching oligonucleotides to modulate splicing patterns through binding to pre-mRNA, and that it is estimated that 20-30% of all disease-causing mutations affect pre-mRNA splicing, giving rise to diseases such as B-thalassemia, cystic fibrosis, cancers, spinal muscular atrophy and Duchenne muscular dystrophy (DMD) (Intro, left column). Bestas et al. taught that while splice switching oligonucleotides have therapeutic potential, targeting single mutations in DMD with SSO’s can only benefit a fraction of patients suffering from the disease since different mutations require different SSOs, and therefore effort to develop tools to skip multiple exons in DMD patients suffering from deletion mutations have been made. In addition, an important consideration is to devise efficient means of assuring equal delivering of multiple SSOs into the same cells, and that bispecific AONs to simultaneously target different mRNAs with the same AON have been developed most of which have been constructed to contains two antisense sequence spaced by nucleotide hairpins, and also in 2010 the first bispecific siRNA was reported in which a single molecule siRNA was cleaved inside the reductive environment of cells and could mediate robust RNA interference responses for both target genes (page 14, left column). Bestas et al. taught synthesis of bispecific SSOs were one arm targets exon 23 of the mouse Dmd locus and the other targets exon 2 of the Mstn gene to disrupt the reading frame, and having either internal disulfides or non-cleavable C18 spacers, and that results demonstrate such SSOs could effectively promote exon skipping of both transcripts in H2k mds myotubes (page 14, right column). Figure 1 of Bestas et al. shows the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets.
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Bestas et al. taught the bispecific SSOs are attached with C18 spacers (page 14, right column; page 17, left column), the structure of which the C18 linker is shown in Fig. 3A and is the same structure as instant Spacer-18.
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It would have been obvious to one of ordinary skill in the art before the effective filing date to have substituted the first oligonucleotide of Bhat et al. with an saRNA as taught by Saetrom et al., with the saRNA sequences of Li et al. and substitute the second oligonucleotide of Bhat et al. with ASO10-27 of Li et al. with a reasonable expectation of success. There would be a reasonable expectation of success because this would amount to substituting the oligonucleotide for upregulating SMN of Bhat et al. with the double-stranded saRNA of Saetrom et al. and Li et al. that also upregulates the expression of a target gene in which SMN2 as the target gene is taught, and substituting one ASO that promotes inclusion of exon 7 of the SMN2 pre-messenger RNA with the sequence of another specific ASO that performs the same function to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Saestrom et al. taught the saRNA can be conjugated to other polynucleotides, and that conjugation can increase stability and half-life and target the saRNA to specific sites in the cell, tissue or organism (paragraph 0125), and taught the saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126) and Li et al. taught a combination of one or more agents that increase the expression of SMN2 gene or protein and one or more agents that increase the production of functional SMN protein by modulating SMN2 mRNA splicing or stability (claim 1), including saRNA having one strand that has at least 75% homology or complementarity with a fragment of the promoter region of the SMN2 gene that is 16-35 nt in length (paragraph 0025), and wherein the SMN2 mRNA modulator is Nusinersen (claim 5).
An ordinary artisan could have used the sequences and modifications of Li et al. of the saRNA sequences and ASO10-27 sequence and modifications and covalently linked the two together based on the teachings of Bhat et al. with a reasonable expectation of success. In addition, one of ordinary skill in the art would have been motivated to use the C18 linker of Bestas et al. which was taught as linking bispecific ASOs and that results demonstrate such SSOs could effectively promote exon skipping of both transcripts in H2k mds myotubes (page 14, right column) and Figure 1 of Bestas et al. shows the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets in order to provide the same benefits of equal delivery of the saRNA and splice switching ASO, controlled release and simultaneous activity.
Accordingly, the limitations of claims 31,32,36 and 38 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Bhat et al. in view of Saetrom et al. as applied to claims 1-4,7,9,11,12,15,17,18,20-22,25,26,29,30,46 and 47 above and further in view of Rigo et al. (WO 2018014041, Published 18 January 2018).
The teachings of Bhat et al. and Saetrom et al. as applicable to claims 1-4,7,9,11,12,15,17,18,20-22,25,26,29,30,46 and 47 have been described above.
Additionally, regarding claim 35, Bhat et al. teach SEQ ID NO: 7 (Db) is 100% identical to instant SEQ ID NO: 11 (Qy):
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Bhat et al. teach both the transcriptional oligonucleotides and the splice correcting oligonucleotide showed upregulation of SMN2 mRNA and SMN protein, and the splice-correcting oligonucleotide has a sequence set forth as TCACTTTCATAATGCTGG (SEQ ID NO: 7) with each nucleotide being a 2′-O-methoxyethyl (2′MOE) nucleotide (paragraph 0192). Bhat et al. also teach splice correcting oligonucleotide sequences which are very similar to SEQ ID NO: 7 and which have certain chemical modifications, including wherein some of the cytosine nucleotides are 5-methylcytosine (paragraphs 0060).
Bhat et al. and Saetrom et al. do not teach the exact modification pattern of instant ASO10-27 of SEQ ID NO: 11.
Rigo et al. taught compounds and composition for modulation of SMN2 pre-mRNA (page 2, lines 7-8). Rigo et al. taught Isis 396443 means an oligonucleotide having the following structure (page 19):
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See also Example 1, page 59 teaching the same sequence and modification and which is identified by SEQ ID NO: 1 and Cmpd No: 396443 and testing in spinal muscular atrophy patient fibroblast cell line and measured the level of SMN2 with exon 7 and resulted in exon 7 inclusion.
Therefore, the sequence and chemical modifications of Cmpd No 396443 are the same as those of instant ASO10-27 of SEQ ID NO: 11. It is noted that the sequence of Rigo et al. contain T’s rather than U’s but it is known in the art that thymine is a uracil with a methyl group attached at the 5th carbon position.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to provide the splice switching oligonucleotide of SEQ ID NO: 7 of Bhat et al. with the chemical modifications of Isis 396443 of Rigo et al. also targeting SMN2 in order to provide a chemically modified oligonucleotide with exon 7 inclusion with a reasonable expectation of success, as this amounts to substituting one known splice switching oligonucleotide targeting the same gene with another known splice switching oligonucleotide of the same sequence but containing chemical modifications to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Rigo et al. taught that Cmpd No: 396443 when tested in spinal muscular atrophy patient fibroblast cell line and measured the level of SMN2 with exon 7 and resulted in exon 7 inclusion.
Accordingly, the limitations of claim 35 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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.
31,32,36 and 38
Claims 1-4,7,9,11-13,15,17,18,20-22,25,26,29,30,35,46 and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No.18/007,497 in view of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al., all cited above.
Claim 1 and 15 of ‘497 recites a pharmaceutical composition comprising a combination of one or more agents that increase the expression of SMN2 gene or protein and one or more agents that increase the production of functional SMN protein by modulating SMN2 mRNA splicing or stability (SMN2 mRNA modulators), with claims 2-3,6-12 of ‘497 reciting the agent increasing expression of SMN2 may be an saRNA, and claims 4-5 of ‘497 reciting the SMN2 mRNA modulators is an antisense oligonucleotide, including Nusinersen. Claims 13-14 of ‘497 recite a pharmaceutical composition
Claims 1-15 of ‘497 do not recite the saRNA is covalently linked to the agent for increasing production of functional SMN protein by modulating SMN2 mRNA splicing which may be an antisense oligonucleotide, including nusinersen, or wherein they are covalently attached using a C18 linker, or the presence of additional targeting oligonucleotides, or wherein the ASO that the saRNA is linked to increases production of functional SMN protein by modulating SMN2 mRNA splicing or wherein the ASO has a sequence at least 90% identical to the sequence of ASO10-27 (SEQ ID NO: 11).
The teachings of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al. have been described in the 103 rejections above.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified claims 1-15 of ‘497 with the teachings of Bhat et al. regarding a compound for increasing expression of SMN protein in a human cell, the compound comprising a first oligonucleotide and a second oligonucleotide that is complementary with a splice control sequence of SMN2 pre-messenger RNA that promotes inclusion of exon 7 of the SMN2 pre-messenger RNA, wherein the first and second oligonucleotides are covalently linked, Saetrom et al. regarding that a saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126), Bestas et al. regarding the use of a C18 linker between two ASOs, and Rigo et al. regarding the sequence and chemical modifications of Isis 396443 of Rigo et al. also targeting SMN2 in order to provide a chemically modified oligonucleotide with exon 7 inclusion, and arrive at the instant claims with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide the claimed saRNAs of ‘497 covalently linked with an antisense oligonucleotide that increases the production of function SMN protein by modulating SMN2 mRNA splicing, because Bhat et al. taught a compound for increasing expression of SMN protein in a human cell, the compound comprising a first oligonucleotide and a second oligonucleotide that is complementary with a splice control sequence of SMN2 pre-messenger RNA that promotes inclusion of exon 7 of the SMN2 pre-messenger RNA, wherein the first and second oligonucleotides are covalently linked, and methods for increasing expression of full-length SMN protein in a cell for purposes of treating SMA or other motor neuron diseases, methods and compositions that are useful for upregulating SMN in cells (paragraphs 0005,0045) and taught the first and second oligonucleotides are delivered to the cell simultaneously (paragraph 0016).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the linkers of Bhat et al. that covalently link the first and second oligonucleotides of Bhat et al. with the C18 linker of Bestas et al. with a reasonable expectation of success. An artisan would have been motivated by the teachings of Bestas et al. regarding an important consideration is to devise efficient means of assuring equal delivery of multiple SSOs into the same cells, and taught the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide the splice switching oligonucleotide which can be Nusinersen of ‘497 with the chemical modifications of Isis 396443 of Rigo et al. also targeting SMN2 in order to provide a chemically modified oligonucleotide with exon 7 inclusion with a reasonable expectation of success, as this amounts to substituting one known splice switching oligonucleotide targeting the same gene with another known splice switching oligonucleotide of the same sequence but containing chemical modifications to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Rigo et al. taught that Cmpd No: 396443 when tested in spinal muscular atrophy patient fibroblast cell line and measured the level of SMN2 with exon 7 and resulted in exon 7 inclusion.
This is a provisional nonstatutory double patenting rejection.
Claims 31,32,36 and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 18/007,497 in view of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al., all cited above and further in view of Li et al. (US 20230287416, effectively filed 31 July 2020).
The applied reference (Li et al.) has a common Applicant and Inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The teachings of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al. have been described in the 103 rejections above.
Claims 1-15 of ‘497, Bhat et al., Saetrom et al., Bestas et al., and Rigo et al. do not teach an saRNA having a nucleotide sequence of a sense strand that is at least 90% identical to the nucleotide sequence of DS06-4A3 (SEQ ID NO: 146) and/or a saRNA having a nucleotide sequence of an antisense strand that is at least 90% identical to the nucleotide sequence of DS06-4A3 (SEQ ID NO: 147), or wherein the dsRNA comprises a saRNA having a pair of nucleotide sequences of a sense strand and an antisense strand that is at least 90% identical to the nucleotide sequence pairs of DS06-4A3: SEQ ID NO: 146 and SEQ ID NO: 147, or the sequence and modifications of instant SEQ ID NO: 11 for the antisense oligonucleotide.
The teachings of Li et al. have been described in the 103 rejections above.
It would have been obvious to one of ordinary skill in the art before the effective filing date to have modified claims 1-15 of ‘497 with the saRNAs (SEQ ID NOs: 488 and 496) of Li et al. and as the agent increasing production of functional SMN protein by modulating SMN2 mRNA splicing or stability with ASO10-27 of Li et al. with a reasonable expectation of success. There would be a reasonable expectation of success because this would amount to substituting an oligonucleotide for increasing expression of SMN2 with another oligonucleotide that also upregulates the expression of SMN2 and substituting one ASO that promotes inclusion of exon 7 of the SMN2 pre-messenger RNA with the sequence of another specific ASO that performs the same function to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Saestrom et al. taught the saRNA can be conjugated to other polynucleotides, and that conjugation can increase stability and half-life and target the saRNA to specific sites in the cell, tissue or organism (paragraph 0125), and taught the saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126) and Li et al. taught a combination of one or more agents that increase the expression of SMN2 gene or protein and one or more agents that increase the production of functional SMN protein by modulating SMN2 mRNA splicing or stability (claim 1), including saRNA having one strand that has at least 75% homology or complementarity with a fragment of the promoter region of the SMN2 gene that is 16-35 nt in length (paragraph 0025), and wherein the SMN2 mRNA modulator is Nusinersen (claim 5).
An ordinary artisan could have used the sequences and modifications of Li et al. of the saRNA sequences and ASO10-27 sequence and modifications and covalently linked the two together based on the teachings of Bhat et al. with a reasonable expectation of success. In addition, one of ordinary skill in the art would have been motivated to use the C18 linker of Bestas et al. which was taught as linking bispecific ASOs and that results demonstrate such SSOs could effectively promote exon skipping of both transcripts in H2k mds myotubes (page 14, right column) and Figure 1 of Bestas et al. shows the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets in order to provide the same benefits of equal delivery of the saRNA and splice switching ASO, controlled release and simultaneous activity.
Accordingly, the limitations of claims 31,32,36 and 38 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 1-4,7,9,11-13,15,17,18,20-22,25,26,29-32,35,46 and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11,13,17,19 and 42-44 of copending Application No.17/419,569 (‘569) in view of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al., all cited above.
Claims 1-11,13,17,19 and 42-44 of ‘569 recite a saRNA comprising a sense nucleic acid fragment and antisense nucleic acid fragment, wherein the sense or antisense nucleic acid fragment have 100% homology or complementarity to a continuous sequence of 19 nucleotides in length of any one of SEQ ID NOs: 476-479 and claim 2 recites the complementary regions form a double-stranded nucleic acid structure between the two fragments that can activate expression of the SMN2 gene in a cell. Claim 17 if ‘569 recites a composition comprising the saRNA of claim 1 and a pharmaceutically acceptable carrier.
SEQ ID NO: 132 of ’569 which is recited in claim 42 has 100% identity to instant SEQ ID NO: 146:
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SEQ ID NO: 289 of ’569 which is recited in claim 42 has 100% identity to instant SEQ ID NO: 147:
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Claims 1-11,13,17,19 and 42-44 of ‘569 do not recite the saRNA is covalently linked to an antisense oligonucleotide, or wherein the linker is a C18 linker, or the presence of additional targeting oligonucleotides, or wherein the ASO that the saRNA is linked to increases production of functional SMN protein by modulating SMN2 mRNA splicing or wherein the ASO has a sequence at least 90% identical to the sequence of ASO10-27 (SEQ ID NO: 11).
The teachings of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al. have been described in the 103 rejections above.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified claims 1-11,13,17,19 and 42-44 of ‘569 with the teachings of Bhat et al. regarding a compound for increasing expression of SMN protein in a human cell, the compound comprising a first oligonucleotide and a second oligonucleotide that is complementary with a splice control sequence of SMN2 pre-messenger RNA that promotes inclusion of exon 7 of the SMN2 pre-messenger RNA, wherein the first and second oligonucleotides are covalently linked, Saetrom et al. regarding that teaching that a saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126), Bestas et al. regarding the use of a C18 linker between two ASOs, and Rigo et al. regarding the sequence and chemical modifications of Isis 396443 of Rigo et al. also targeting SMN2 in order to provide a chemically modified oligonucleotide with exon 7 inclusion, and arrive at the instant claims with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide the claimed saRNAs of ‘569 covalently linked with an antisense oligonucleotide that increases the production of function SMN protein by modulating SMN2 mRNA splicing, because Bhat et al. taught a compound for increasing expression of SMN protein in a human cell, the compound comprising a first oligonucleotide and a second oligonucleotide that is complementary with a splice control sequence of SMN2 pre-messenger RNA that promotes inclusion of exon 7 of the SMN2 pre-messenger RNA, wherein the first and second oligonucleotides are covalently linked, and methods for increasing expression of full-length SMN protein in a cell for purposes of treating SMA or other motor neuron diseases, methods and compositions that are useful for upregulating SMN in cells (paragraphs 0005,0045) and taught the first and second oligonucleotides are delivered to the cell simultaneously (paragraph 0016).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the linkers of Bhat et al. that covalently link the first and second oligonucleotides of Bhat et al. with the C18 linker of Bestas et al. with a reasonable expectation of success. An artisan would have been motivated by the teachings of Bestas et al. regarding an important consideration is to devise efficient means of assuring equal delivery of multiple SSOs into the same cells, and taught the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide the splice switching oligonucleotide of SEQ ID NO: 7 of Bhat et al. with the chemical modifications of Isis 396443 of Rigo et al. also targeting SMN2 in order to provide a chemically modified oligonucleotide with exon 7 inclusion with a reasonable expectation of success, as this amounts to substituting one known splice switching oligonucleotide targeting the same gene with another known splice switching oligonucleotide of the same sequence but containing chemical modifications to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Rigo et al. taught that Cmpd No: 396443 when tested in spinal muscular atrophy patient fibroblast cell line and measured the level of SMN2 with exon 7 and resulted in exon 7 inclusion.
This is a provisional nonstatutory double patenting rejection.
Claims 36 and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11,13,17,19 and 42-44 of copending Application No.17/419,569 (‘569) in view of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al., all cited above. and further in view of Li et al. (US 20230287416, effectively filed 31 July 2020).
The applied reference (Li et al.) has a common Applicant and Inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The teachings of Bhat et al., Saetrom et al., Bestas et al. and Rigo et al. have been described in the 103 rejections above.
Claims 1-11,13,17,19 and 42-44 of ‘569, Bhat et al., Saetrom et al., Bestas et al., and Rigo et al. do not teach the oligonucleotide that is at least 90% identical to the nucleotide sequences of SEQ ID NO: 14 and an antisense saRNA strand having a nucleotide sequence of SEQ ID NO: 13; or that the oligonucleotide agent is DA06-4A-27A.
The teachings of Li et al. have been described in the 103 rejections above.
It would have been obvious to one of ordinary skill in the art before the effective filing date to have modified 1-11,13,17,19 and 42-44 of ‘569 with the saRNAs (SEQ ID NOs: 488 and 496) of Li et al. and as the agent increasing production of functional SMN protein by modulating SMN2 mRNA splicing or stability with ASO10-27 of Li et al. with a reasonable expectation of success. There would be a reasonable expectation of success because this would amount to substituting an oligonucleotide for increasing expression of SMN2 with another oligonucleotide that also upregulates the expression of SMN2 to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Saestrom et al. taught the saRNA can be conjugated to other polynucleotides, and that conjugation can increase stability and half-life and target the saRNA to specific sites in the cell, tissue or organism (paragraph 0125), and taught the saRNA may be administered with, or further include one or more RNAi agents, siRNAs, shRNAs, antisense RNAs to achieve different functions (paragraph 0126) and Li et al. taught a combination of one or more agents that increase the expression of SMN2 gene or protein and one or more agents that increase the production of functional SMN protein by modulating SMN2 mRNA splicing or stability (claim 1), including saRNA having one strand that has at least 75% homology or complementarity with a fragment of the promoter region of the SMN2 gene that is 16-35 nt in length (paragraph 0025), and wherein the SMN2 mRNA modulator is Nusinersen (claim 5).
An ordinary artisan could have used the sequences and modifications of Li et al. of the saRNA sequences and ASO10-27 sequence and modifications and covalently linked the two together based on the teachings of Bhat et al. with a reasonable expectation of success. In addition, one of ordinary skill in the art would have been motivated to use the C18 linker of Bestas et al. which was taught as linking bispecific ASOs and that results demonstrate such SSOs could effectively promote exon skipping of both transcripts in H2k mds myotubes (page 14, right column) and Figure 1 of Bestas et al. shows the principle of equal delivery of both AO’s, controlled release in the cytoplasm, and simultaneous activity against two RNA targets in order to provide the same benefits of equal delivery of the saRNA and splice switching ASO, controlled release and simultaneous activity.
Accordingly, the limitations of claims 36 and 38 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 1-4,7,9,11-13,15,17,18,20-22,25,26,29-32,35,36,38,46 and 47 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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