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
Receipt of Arguments/Remarks filed on 06/03/2026 is acknowledged. Claim 1 was amended. Claims 8,9,13,50 and 84 were canceled. Claims 1,14,19,23,32,34,46,68-70 and 73 are pending.
Claim 74 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/05/2024.
Applicant elected SEQ ID NO: 3 as the species for Group A(ii) relating to claims 10 and 12 (now cancelled), SEQ ID NO: 14 for group A(iii) relating to claim 11 (now canceled), and SEQ ID NO: 35 for group A(iv) relating to claim 13 (now canceled). The species in claim 11 (now in amended claim 1) was expanded to include SEQ ID NOs: 13 and 15 and the species in claim 13 (now in amended claim 1) was expanded to include SEQ ID NOs: 34 and 36.
Applicant elected the compound of formula V in claim 32, wherein G1 is the phosphorothioate linkage and G2 is OCH3, and to leave Bx as it is since it depends on the sequence. In view of Prakash et al. above, the species election is expanded to include all of the species taught in Prakash et al.
Claims 1,14,19,23,32,34,46,68-70 and 73 are under examination.
Withdrawn Objections and Rejections
Applicant’s amendments, filed 06/03/2026, with respect to the objection to claim 1 have been fully considered and are persuasive due to the amendment to claim 1 adding a comma following “STXBP1”. The objection has been withdrawn.
Applicant’s arguments and amendments, see page 8, filed 06/03/2026, with respect to the 35 U.S.C. 112(b) rejection of claims 9,13 and 84 have been fully considered and are persuasive due to the cancelation of claims 9,13 and 84 and therefore the rejection is moot and has been withdrawn.
Applicant’s arguments and amendments, see page 8, filed 06/03/2026, with respect to the 35 U.S.C. 102(a)(1) rejection of claims 1,8,9 and 34 as anticipated by Krieg et al. have been fully considered and are persuasive due to the amendment to claim 1 which no longer is anticipated by Krieg et al. Therefore, the rejection has been withdrawn.
Applicant’s arguments and amendments, see page 8, filed 06/03/2026, with respect to the 35 U.S.C. 103 rejection of claims 68-70 as obvious over Lang and Prakash further in view of Campbell et al. have been fully considered and are persuasive due to the amendment to claim 1 incorporating limitations from now canceled claim 13. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 1 and a case of obviousness. See the modified 103 rejection of claims 68-70 below.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites “STXBP1”. At least the first recitation of a gene name should be fully written out for clarity, rather than just the acronym. Appropriate correction is required.
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 1,14,19,23,32,34,46 and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Lang et al. (Journal of Molecular Endocrinology (2015) 54, 65-73) in view of Prakash et al. (US 20160159846, Published 9 June 2016) and Saitsu et al. (Nature Genetics, Vol. 40, No. 6 June 2008, pages 782-788) as evidenced by NCBI Reference Sequence: NM_003165, cited in previous office action.
Regarding claim 1, Lang et al. teach determining the expression of Stxbp1 and its predicted pairing miRNAs in isolated islets treated with high levels of glucose for a short period, and Stxbp1 was found to be significantly upregulated, while two of the miRNAs, miR-218 and miR-322 showed the opposite tendency, and subsequent luciferase assays confirmed that miR-218 and miR-322 directly interact with the 3’UTR of Stxbp1 (page 66, left column, 2nd paragraph). Lang et al. teach transfection of MIN6 cells with miRNA mimics, inhibitors, or siRNAs, and teach sequences of Stxbp1 siRNAs as 5’-UAUCCUCCACAAUUGUGAUGCCCUC-3’ (sense) and 5’-GAGGGCAUCACAAUUGUGGAGGAU-3’ (antisense) (page 67, left column). Lang et al. teach that the entire 3’-UTR of Stxbp1 was inserted into a p-MIR-report plasmid, and equal amounts of mimics, inhibitors, or scrambled negative control RNA were transfected into cells (page 67, left column). Results showed that Stxbp1 is an important positive regulator in the insulin secretion process and implied Stxbp1 expression may be regulated by miRNAs (page 68, left column), and also found that miR-218 and miR-322 were involved in rapid glucose-stimulated insulin secretion through regulation of the expression of Stxbp1 (page 68, left column and right column).
Lang et al. teach evaluation of the association of the miRs and Stxbp1 using a luciferase assay, and as shown in Fig. 3A (below), the target region in the 3’UTR of Stxbp1 was conserved among humans, mice and rats, and that co-transfection of miR-218 mimics with the reporter plasmid containing WT Stxbp1 3’UTR sequence into 293T HEK cells resulted in 50% reduction in the luciferase signal, and results indicate that miR-218 directly targets the 3’UTR of Stxbp1 mRNA (page 68, right column).
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Alignment of the above human Stxbp1 3’UTR sequence (Qy) with the instant target region sequence of SEQ ID NO: 13 (Db) is shown below:
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Shown below is the alignment of instant SEQ ID NO: 34 (Qy) with the 3’UTR Stxbp1 sequence ‘UGUUUGAAAGUACUGAAGCACAA’ of Fig 3A of Lang (Db):
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As can be seen above, nucleotides 3-20 of instant SEQ ID NO: 34 are complementary to nucleotides 23-6 of the 3’UTR Stxbp1 sequence of Lang, and therefore is missing the first two nucleotides ‘GT’ of instant SEQ ID NO: 34.
Similarly, alignment of instant SEQ ID NO: 54 (Qy) with the 3’UTR Stxbp1 sequence ‘UGUUUGAAAGUACUGAAGCACAA’ of Fig 3A of Lang (Db) is shown below and is missing the ‘GU’ at the beginning of SEQ ID NO: 54:
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Therefore, Lang et al. teach a target region sequence in the 3’UTR of Stxbp1 that has 18 contiguous nucleotides with 100% identity to nucleotides 1-18 of the target region sequence of instant SEQ ID NO: 13, and teaches the target region overlaps with a binding site for miR-218 (Fig. 3A above).
Lang et al. teach the levels of miR-218 were significantly increased after transfection with mimics, while they declined when cells were transfected with inhibitors, and that the expression levels of the STXBP1 protein were significantly reduced by the introduction of miR-218 and miR-322, whereas cells transfected with mimic control maintained a considerable amount of STXBP1 protein, and in contrast, inhibitors increased the relative expression levels of STXBP1 protein in MIN6 cells which indicates that miR-218 and miR-322 negatively regulate expression of STXBP1 protein (page 69, left column). Lang et al. teach transfecting MIN6 cells with miRNA mimics, inhibitors or siRNA against Stxbp1 to determine effects on insulation secretion of miR-218 and miR-322 targeting Stxbp1, and that MIN6 cells with blocking of miR-218 and miR-322 displayed a higher rate of insulin secretion compared to controls and the knockdown of Stxbp1 by its siRNA also leads to complete inhibition of insulin secretion.
In conclusion, Lang et al. taught the luciferase assays confirmed that miR-218 and miR-322 directly target the 3’UTR of Stxbp1, the overexpression of the two miRNAs in MIN6 cells leads to the inhibition of Stxbp1 expression and insulin secretion; while the knockdown of the two miRNAs relatively promoted the Stxbp1–insulin pathway (page 72, bottom right- page 73, top left).
While Lang et al. teach the target region sequence in the 3’UTR of Stxbp1 and motivation for targeting that region, and also teaches Stxbp1 miR mimics, inhibitors and siRNA, Lang et al. does not explicitly teach a single-stranded nucleotide that consists of 20-30 linked nucleosides which has a nucleobase sequence comprising a complementary region having at least 20 contiguous nucleobases complementary to an equal length portion within a target region sequence selected from the group consisting of SEQ ID NOs:13,14 and 15; and do not teach the single-stranded oligonucleotide comprises the DNA sequence of SEQ ID NO: 34 or RNA sequence of SEQ ID NO: 54, and wherein the single-stranded oligonucleotide comprises at least two modified sugar moieties.
Before the effective filing date, Prakash et al. recited a compound comprising a single-stranded oligonucleotide consisting of 13-30 linked nucleosides and having a nucleobase sequence complementary to a repeat region of an expanded repeat-containing target RNA (claim 1). Prakash et al. taught antisense mechanisms also include, without limitation RNAi mechanisms, which utilize the RISC pathway. Such RNAi mechanisms include, without limitation siRNA, ssRNA and microRNA mechanisms (paragraph 0312), and taught single-stranded antisense compounds, and that such oligonucleotides of ssRNA compounds or microRNA mimics (paragraph 0315).
Prakash et al. taught the compounds of the invention comprise one or more modified nucleosides comprising a modified sugar moiety, having desirable properties such as enhanced nuclease stability or increased binding affinity with a target nucleic acid (paragraph 0197). Prakash et al. taught embodiments where each nucleoside of the region comprises the same RNA-like sugar modification (paragraph 0235). Prakash et al. also recites a single-stranded compound having multiple sugar modifications (claim 40).
Regarding claim 34, Prakash et al. taught modified sugar moieties including 2′-F, 2′-OCH3 (“OMe” or “O-methyl”), and 2′-O(CH2)2OCH3 (“MOE”) (paragraph 0198), LNA, cEt (paragraph 0203), and fluoro HNA (F-HNA) (paragraph 0215).
Saitsu et al. taught the STXBP1 mRNA sequence was publicly available before the effective filing date as evidenced by NM_003165 (Figure 2, page 784).
A search of the NCBI database for NM_003165 shows the mRNA sequence for human STXBP1 transcript variant 1.
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An NCBI Blast search of the 3’UTR Stxbp1 sequence ‘UGUUUGAAAGUACUGAAGCACAA’ of Lang et al. is shown below and shows that all 23 nucleotides of the sequence above of Lang et al. align with nucleotides 3788-3810 of Homo sapiens STXBP1 transcript variant 1 mRNA.
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Alignment of instant SEQ ID NO: 34 (Qy) (the DNA sequence of the compound), with the mRNA sequence of STXBP1 transcript variant 1 (Db) is shown below and shows that all 20 nucleotides of SEQ ID NO: 34 are complementary to nucleotides 3812-3793 of the mRNA sequence of STXBP1 transcript variant 1:
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Alignment of instant SEQ ID NO: 54 (Qy) (the RNA sequence of the compound), with the mRNA sequence of STXBP1 transcript variant 1 (Db) is shown below and shows all 20 nucleotides of SEQ ID NO: 54 are complementary to nucleotides 3812-3793 of the mRNA sequence of STXBP1 transcript variant 1:
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It would have been obvious to one of ordinary skill in the art before the effective filing date, to target the 3’UTR of STXBP1 having the sequence ‘UGUUUGAAAGUACUGAAGCACAA’ which overlaps with a binding site for miR218 as shown in Fig. 3A of Lang et al. with a single-stranded oligonucleotide of 13-30 nucleosides having a nucleobase sequence complementary to a target RNA and having at least two modified sugar moieties as taught by Prakash et al., and design the modified single-stranded oligonucleotide of Prakash et al. to target the 3’UTR sequence of STXBP1 of Lang et al. based on human Stxbp1 transcript variant 1 mRNA sequence being publicly available as taught by Saitsu et al. to arrive at the DNA sequence of instant SEQ ID NO: 34 and the RNA sequence of instant SEQ ID NO: 54 with a reasonable expectation of success. There would be a reasonable expectation of success, because Lang et al. taught the target human Stxbp1 3’UTR sequence ‘UGUUUGAAAGUACUGAAGCACAA’ (Fig 3A) which aligns with nucleotides 3788-3810 of Homo sapiens STXBP1 transcript variant 1 mRNA of NM_003165 and taught using miR mimics, inhibitors and siRNAs targeting Stxbp1, and Prakash et al. recites a single-stranded oligonucleotide 13-30 linked nucleosides with a nucleobase sequence complementary to a target RNA, and would amount to substituting one known element (miR mimics, inhibitors, siRNA targeting Stxbp1 of Lang et al.) with another (known single-stranded sugar modified oligonucleotides directed to any target mRNA of Prakash et al.). One of ordinary skill in the art would have been able to design a single-stranded oligonucleotide having the length and modified sugar moieties taught by Prakash et al., and would have readily and reasonably obtained the single-stranded oligonucleotide comprising SEQ ID NOs: 34 and 54, as the human STXBP1 mRNA sequence information was publicly available as NM_003165 before the effectively filed date as taught by Saitsu et al., and nucleotides 1-20 of SEQ ID NO: 34 and SEQ ID NO:54 aligns with nucleotides 3812-3793 of homo sapiens STXBP1 transcript variant 1 mRNA. Therefore, using the guidance provided by the 3’UTR target region sequence of STXBP1 taught by Lang et al. and motivation thereof for targeting this region, and using the publicly available mRNA sequence of NM_003165, the exact sequences of SEQ ID NOs: 34 and 54 for the single-stranded oligonucleotide targeting these sequences would have been obtained by an ordinary artisan using techniques and the sequences known in the art. One of ordinary skill in the art would have been motivated do to so because Lang et al. taught the relationship between miR-218 and the 3’ UTR of Stxbp1 and insulin secretion, including that miR-218 directly targets the 3’UTR of Stxbp1, inhibitors increased the relative expression levels of STXBP1 protein in MIN6 cells which indicates that miR-218 and miR-322 negatively regulate expression of STXBP1 protein, blocking of miR-218 and miR-322 displayed a higher rate of insulin secretion, the knockdown of the two miRNAs relatively promoted the Stxbp1–insulin pathway. One of ordinary skill in the art would have been motivated to use a single-stranded oligonucleotide with at least two modified sugar moieties in order to target the 3’UTR of human Stxbp1 region which overlaps with an miR-218 binding site because Prakash et al. taught antisense mechanisms also include, without limitation RNAi mechanisms, which utilize the RISC pathway. Such RNAi mechanisms include, without limitation siRNA, ssRNA and microRNA mechanisms and the benefits of the sugar modifications are desirable properties such as enhanced nuclease stability or increased binding affinity with a target nucleic acid.
Accordingly the limitations of claims 1 and 34 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Regarding claims 14,19,23 and 32, Lang et al. does not teach a single-stranded oligonucleotide comprising a terminal group at the 5’ end and the 5’ terminal nucleoside and terminal group of the compound has Formula I.
Prakash et al. taught the compounds of the invention are useful for studying, diagnosing and/or treating a disease or disorder, and the compounds comprise an oligonucleotide and a conjugate and/or terminal group (paragraph 0113). Prakash et al. taught the oligonucleotide compounds comprise a stabilized phosphate moiety at the 5’-terminus (paragraph 0116). Prakash et al. also recites a single stranded oligonucleotide consisting of 13-30 linked nucleosides and having a nucleobase sequence complementary to a region of target RNA, and the 5’-terminal nucleoside has formula I and recites the same limitations for the substituents and groups for the compound of formula I as instant claim 14 (claim 2).
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Regarding claim 19, Prakash et al. recite the same limitations in claim 26.
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Regarding claim 23, Prakash et al. recite the same limitations in claim 11.
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Prakash et al. recite the same limitations of instant claim 32 regarding the compound of formula V in claim 28 for the compound of claim 2 wherein the 5’-terminal nucleoside has Formula V:
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Wherein: Bx is selected among uracil, thymine, cytosine, 5-methyl cytosine, adenine and guanine; T2 is a phosphorothioate internucleoside linking group linking the compound of formula V to the remainder of the oligonucleotide; and G is selected from among: a halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)-N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, OCH2-N(H)-C(=NH)NH2 (claim 28).
Prakash et al. taught a phosphate stabilizing modification is a modification that results in stabilization of a 5’-phosphate moiety at the 5’-terminal nucleoside of an oligonucleotide relative to the stability of an unmodified 5’-phosphate of an unmodified nucleoside (paragraph 0045). Prakash et al. teach modifications that may be incorporated into an oligonucleotide comprising a nucleoside of formula I, II, III, IV or V at the 5’ terminus are well known in the art (paragraph 0195) and teach compounds with desirable properties such as enhanced nuclease stability or increased binding affinity with a target nucleic acid (paragraph 0197).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to target the 3’UTR of STXBP1 having the sequence ‘UGUUUGAAAGUACUGAAGCACAA’ which overlaps with a binding site for miR218 as shown in Fig. 3A of Lang et al. with a single-stranded oligonucleotide of 13-30 nucleosides having a nucleobase sequence complementary to a target RNA and having at least two modified sugar moieties as taught by Prakash et al. and arrive at the DNA sequence of instant SEQ ID NO: 34 and the RNA sequence of instant SEQ ID NO: 54, based on human Stxbp1 transcript variant 1 mRNA sequence being publicly available as taught by Saitsu et al., and to provide the single-stranded oligonucleotide with a terminal group at the 5’ end, and that the 5’ terminal nucleoside and terminal group of the compound has Formula I as taught by Prakash et al. with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so because Prakash et al. teach that phosphate stabilizing modification results in stabilization of a 5’-phosphate moiety at the 5’-terminal nucleoside of an oligonucleotide, and that compounds with such modifications have desirable properties such as enhanced nuclease stability or increased binding affinity with a target nucleic acid. One of ordinary skill in the art would be able to apply such a known technique regarding modification of the 5’-terminal nucleoside to a known oligonucleotide ready for improvement to yield predictable results that provide improved stabilization and increased binding affinity and would make obvious the limitations of claims 14,19,23 and 32.
Lang et al. do not teach internucleoside linkages of the modified oligonucleotide, or having mismatches with the target region, or a pharmaceutical composition.
Regarding claim 46, Prakash et al. taught nucleosides may be linked together using any internucleoside linkage, including phosphodiesters, phosphotriesters, and phosphorothioates, and that modified linkages can be used to increase nuclease resistance of the oligonucleotide (paragraph 0228).
Regarding claim 73, Prakash et al. taught a pharmaceutical composition comprising an antisense compound and a pharmaceutically acceptable diluent or carrier (paragraph 0337), and which pharmaceutical compositions can be administered to an animal (paragraph 0352).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to target the 3’UTR of STXBP1 having the sequence ‘UGUUUGAAAGUACUGAAGCACAA’ which overlaps with a binding site for miR218 as shown in Fig. 3A of Lang et al. and arrive at the DNA sequence of instant SEQ ID NO: 34 and the RNA sequence of instant SEQ ID NO: 54, based on human Stxbp1 transcript variant 1 mRNA sequence being publicly available as taught by Saitsu et al., and using a single-stranded oligonucleotide as taught by Prakash et al. and provide each internucleoside linkage of the single-stranded oligonucleotide with phosphorothioate and/or phosphate internucleoside linkages and to provide the oligonucleotide in a pharmaceutical composition based on the teachings of Prakash et al. with a reasonable expectation of success. There would be a reasonable expectation of success because Prakash et al. teach these limitations of the single-stranded oligonucleotides of the invention which an target any mRNA and the benefits thereof. One of ordinary skill in the art would have been motivated to provide a single-stranded oligonucleotide as taught by Prakash et al. to target the 3’UTR region of Stxbp1 as taught by Lang et al., and to provide each internucleoside linkage as phosphorothioate or phosphate internucleoside linkages because Prakash et al. taught nucleosides may be linked together using any internucleoside linkage, including phosphodiesters, phosphotriesters, and phosphorothioates, and that modified linkages can be used to increase nuclease resistance of the oligonucleotide. It would have been obvious to provide the single-stranded oligonucleotide of Prakash et al. designed to target Stxbp1 3’ UTR as taught by Lang et al. in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent because Prakash et al. taught such pharmaceutical compositions and can be administered to an animal for treatment.
Accordingly, the limitations of claims 46 and 73 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 and amendments, see page 8, filed 06/03/2026 with respect to the rejection(s) of claim(s) 1,8,9,14,19,23,32,34,46,50 and 73 under 35 U.S.C. 103 have been fully considered and are persuasive due to the amendment to claim 1 incorporating limitations of now canceled claim 13. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claim 1 using the combination of references used in the rejection for now canceled claims 13 and 84.
Applicant argues on page 9 that the miRNA inhibitors of Lang would have the sequence of the target region of the miRNA, not a sequence complementary to the target region of the miRNA.
This is not found persuasive. The Examiner is not sure what Applicant is arguing above that the miRNA inhibitors of Lang would have the sequence of the target region of the miRNA not a sequence complementary to the target region of the miRNA, because Lang was relied upon for teaching motivation to target the 3’ UTR of STXBP1 and as teaching sequences of Stxbp1 siRNAs as 5’-UAUCCUCCACAAUUGUGAUGCCCUC-3’ (sense) and 5’-GAGGGCAUCACAAU UGUGGAGGAU-3’ (antisense) and that the instant target sequence of SEQ ID NO: 13 shares 18 contiguous nucleotides with the 3’UTR sequence of ‘UGUUUGAAAGUACUGAAGCACAA’ and that nucleotides 3-20 of instant SEQ ID NO: 34 are complementary to nucleotides 23-6 of the 3’UTR Stxbp1 sequence of Lang.
Applicant argues Prakash does not teach that its oligonucleotides are designed or shown to upregulate the targeted gene, and Prakash’s experimental examples are directed exclusively toward inhibition of mutant ATXN-3 and ATN-1 protein expression, and is focused entirely on selective inhibition of mutant expanded-repeat containing RNA. The claimed compounds result in increased STXBP1 expression through steric occupancy of a miRNA binding site (See Fig. 6). Applicant argues the ability of a compound to increase expression of a protein encoded by the target mRNA is a property of the compound and cites In re Papesch.
This is not found persuasive, because the instant claims do not recite any limitations regarding upregulating expression of the target gene. In addition, the motivation provided by the art does not have to be the same as that contemplated by the inventor. 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)
Applicant argues a person reading Lang would not look at Prakash as the mechanism Prakash relies upon is RISC-mediated cleavage of the target RNA, and the compounds must load into RISC to result in decreased expression of the protein encoded by the target mRNA and argues that requirement is incompatible with an SBO compound whose function depends on steric occupancy of a miRNA binding site, not RISC loading. Applicant argues the Examiner’s combination relies on Applicant’s own disclosure to supply the missing conceptual link that an SBO (rather than an RNAi compound) should be used to achieve upregulation. Saitsu fails to rectify the deficiencies of the combination of Lang and Prakash.
This is not found persuasive for the reasons cited above regarding the motivation does not need to be the same as that addressed by the inventor. Regarding Applicant’s argument relying on the disclosure, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
Claims 68-70 are rejected under 35 U.S.C. 103 as being unpatentable over Lang et al. in view of Prakash et al., and Saitsu et al., as evidenced by NCBI Reference Sequence: NM_003165, as applied to claims 1,14,19,23,32,34,46 and 73 above, and further in view of Campbell et al. (Chem. Soc. Rev., 2011, 40, 5680-5689) cited in previous office action.
The teachings of Lang et al, Prakash et al., Saitsu et al. as evidenced by NCBI Reference Sequence: NM_003165 as applicable to claims 1,14,19,23,32,34,46 and 73 are described above.
Lang et al, Prakash et al., Saitsu et al. as evidenced by NCBI Reference Sequence: NM_003165 do not teach wherein the compound comprises an unlocked nucleic acid.
Before the effective filing date, Campbell et al. taught that incorporation of unlocked nucleic acids (UNA) into oligonucleotides reduces stability of the duplex, and destabilization of the duplex depends on where the UNA is positioned in the duplex and length of the duplex (3.2 page 5683). Campbell et al. teach modification of an oligonucleotide with UNA can also affect discrimination of mismatched sequences, and that a mismatch placed directly opposite to the site of UNA incorporation causes a large decrease in the ability of the oligonucleotide to distinguish between matched and mismatched duplexes, and increased discrimination is seen with mismatch sites neighboring UNA incorporation. When UNA incorporation(s) are added distal to the site of the mismatch, discrimination between matched and mismatched sequences is improved, and therefore UNA can be a very versatile modification that can either increase or decrease specificity of the oligonucleotide binding depending on the UNA design applied (3.2 page 5683). Campbell et al. taught that UNA inserted into an all 2’F-ANA ASO showed a 2-3 fold improvement in RNAase H cleavage of the target (5.3, page 5686).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the single-stranded oligonucleotide of Prakash et al. designed to target the 3’UTR of Stxbp1 as taught by Lang et al. and NCBI Reference Sequence: NM_003165 as evidenced by Saitsu et al., to comprise an unlocked nucleic acid for the purpose of enhancing binding to and/or cleavage of the target, and wherein the nucleobase attached to the sugar moiety of the UNA is mismatched relative to the corresponding nucleobase of the target region of the mRNA transcript, for the purpose of decreasing specificity of oligonucleotide binding. This would have a reasonable expectation of success as this amounts to applying a known technique to a known product ready for improvement to yield predictable results, and because Prakash et al. teach and suggest sugar modifications. One of ordinary skill in the art would have been motivated to modify the single-stranded oligonucleotide of Prakash et al. to comprise an unlocked nucleic acid because Campbell et al. teach that UNA inserted into an all 2’F-ANA ASO showed a 2-3 fold improvement in RNAase H cleavage of the target (5.3, page 5686) and would make obvious the limitations of claims 68 and 69.
One of ordinary skill in the art would have been motivated to modify the single-stranded oligonucleotide of Prakash et al. to comprise an unlocked nucleic acid wherein the nucleobase attached to the sugar moiety of the unlocked nucleic acid is mismatched relative to the corresponding nucleobase of the target region of the mRNA transcript, because Campbell et al. teach that a mismatch placed directly opposite to the site of UNA incorporation causes a large decrease in the ability of the oligonucleotide to distinguish between matched and mismatched duplexes. This would have a reasonable expectation of success as this amounts to applying a known technique to a known product ready for improvement to yield predictable results, and would make obvious the limitations of claim 70.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 1,14,19,23,32,34,46,50,68-70 and 73 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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