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 .
Application Status
Claims 1-5 and 89-102 are pending.
Examination on the merits commences on claims 1-5 and 89-102.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. Specifically, the incorporation by reference statement in the substitute specification filed September 14 2023 is identifies the sequence file TIP0401USCNT1_SEQ_Listing.xml as 51 KB, however the actual file size is 51893 bytes.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Warning
Applicant is advised that should claims 93 and 94 be found allowable, claims 96 and 97 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 90 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 90 recites, “The pharmaceutical composition of claim 0, wherein the composition is suitable for intrathecal or intracerebroventricular delivery. However, there is no claim 0, therefore the metes and bounds of claim 90 are unclear and the claim is indefinite. Examiner suggests amending claim 90 to depend from claim 1. Examiner interprets claim 90 as depending from independent claim 1.
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.
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.
Claim(s) 1-5 and 89-94 and 96-102 are rejected under 35 U.S.C. 103 as being unpatentable over Polydoro (Polydoro Ofengeim, M., US20170175116A1) in view of Uhlmann (Uhlmann, E., AU661365B2) and Gryaznov (Gryaznov, Sergei M. "Oligonucleotide N3′→ P5′ phosphoramidates as potential therapeutic agents." Biochimica et Biophysica Acta (BBA)-Gene Structure and Expression 1489.1 (1999): 131-140.)
Regarding claim 1, Examiner is interpreting Formula I of claim 1 as a modified nucleotide containing 2' and 3' modifications which includes 2'-MOE (also known as 2′-O-MOE or 2'-O-(CH₂CH₂OCH₃)), (when R' is H), and a 3' phosphoramidate phosphorothioate modification where a 3'-NH replaces the 3'-O in the phosphorothioate linkage.
Regarding claim 1, Polydoro teaches antisense oligonucleotides targeting human microtubule-associated protein tau (MAPT), compositions comprising the antisense oligonucleotides, and methods for decreasing tau mRNA and protein expression using these antisense oligonucleotides for treating tau-associated diseases ([0006] and claim 1). Polydoro teaches the antisense oligonucleotide contains the 2′-modification 2′-O-methoxyethyl (2′-O-MOE) [0007]. Polydoro teaches the antisense oligonucleotides targeting MAPT includes phosphorothioate linkages [0009] and [0012]. Polydoro also teaches the oligonucleotide phosphodiester linkages can be modified to other phosphorous-containing linkages such as phosphorothioate or phosphoramidate linkages [0075]. Polydoro teaches the oligonucleotides comprise a nucleobase sequence that has 100% identity with the MAPT sequences of Tables 2-17 [0007].
Polydoro does not teach a modified 3' phosphoramidate phosphorothioate where a 3'-NH replaces the 3'-O in the phosphorothioate linkage.
Uhlmann teaches oligonucleotide analogs with valuable physical, biological and pharmacological properties and to a process for their preparation, as it relates to gene expression inhibition through antisense oligonucleotides (pg 1 line 5). Uhlmann teaches oligonucleotide analogs with specific activity, increased serum stability and good solubility (Pg 3 line 34). Uhlmann teaches the composition matching Formula I of instant claim 1, wherein U is an SH, Y is an NH, and W is an O (claim 1):
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454
661
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Gryaznov teaches oligonucleotide N3′→P5′ phosphoramidates, containing 3′-NH instead of 3′-hydroxyl nucleosides form very stable duplexes with complementary native phosphodiester DNA and exceptionally stable duplexes with RNA strands (abstract).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Polydoro’s oligonucleotide complementary to at least a portion of the MAPT gene which contains a 2′-O-MOE and 2′ phosphorothioate or 2′ phosphoramidate linkage such that the 3' linkage would be a phosphoramidate phosphorothioate where a 3'-NH replaces the 3'-O in the phosphorothioate linkage. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that the chemical modifications to oligonucleotides which include 2′-O-MOE and 2′ phosphorothioate or 2′ phosphoramidate linkages would be effective at targeting MAPT expression because Polydoro teaches each of these as effective modifications for gene expression inhibition. Regarding the 3'-NH linkage in Formula I of claim 1, it would have been predictable that a modified 2′ phosphorothioate where a 3'-NH replaces the 3'-O would be predictably effective at gene expression inhibition because Uhlmann teaches that exact modified oligonucleotide composition and because Gryaznov teaches oligonucleotide N3′→P5′ phosphoramidates containing 3′-NH instead of 3′-hydroxyl nucleosides, such as in Uhlmann’s composition, enhances oligonucleotide stability. The skilled artisan would therefore be motivated to apply the N3′→P5′ phosphoramidate in place of the of 3′-hydroxyl nucleosides of a phosphorothioate in order to enhance nucleotide stability and increase effectiveness of MAPT gene expression inhibition in the treatment of MAPT Tau related disease.
Regarding claim 2, Polydoro teaches the above applied to claim 1.
Regarding claims 3-5, Polydoro teaches antisense oligonucleotides targeting MAPT are 12 to 25 nucleobases in length and where the antisense oligonucleotide targeting MAPT can comprise 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases [0008].
Regarding claim 89, Polydoro teaches compositions comprising any of the antisense oligonucleotides described within a pharmaceutical composition and pharmaceutically acceptable carrier [0019-0020].
Regarding claim 90, the antisense oligonucleotide targeting MAPT can be administered to the subject through an intrathecal delivery [0020].
Regarding claim 91 and 92, Polydoro teaches FIG. 2D where MAPT mRNA knockdown in the cortex of hTau BAC transgenic mouse [0024]. Polydoro teaches “knockdown” or “expression knockdown” refers to reduced mRNA or protein expression of a gene after treatment of a reagent, e.g., an antisense oligonucleotide and where expression knockdown can occur during transcription, mRNA splicing, or translation. [0041].
Regarding claims 93, 94, 96, and 97, Polydoro teaches antisense oligonucleotides used in treating a tau-associated disease in a subject with Alzheimer’s disease [0021-0022].
Regarding claim 98, Polydoro teaches the above applied to claim 1, i.e. antisense oligonucleotides targeting human microtubule-associated protein tau (MAPT). Polydoro further teaches antisense oligonucleotide that hybridizes with a target nucleic acid including a target genomic sequence, pre-mRNA, or mRNA molecule [0047-0048].
Regarding claim 99, Polydoro teaches the above applied to claim 1, i.e. antisense oligonucleotides targeting human microtubule-associated protein tau (MAPT). Polydoro further teaches antisense oligonucleotide that hybridizes with a target nucleic acid including a target genomic sequence, pre-mRNA, or mRNA molecule [0047-0048].
Regarding claim 100, Polydoro teaches antisense oligonucleotides used in treating a tau-associated disease in a subject with Alzheimer’s disease [0021-0022].
Regarding claim 101, Polydoro teaches the above applied to claim 1, i.e. antisense oligonucleotides targeting human microtubule-associated protein tau (MAPT). Polydoro further teaches antisense oligonucleotide that hybridizes with a target nucleic acid including a target genomic sequence, pre-mRNA, or mRNA molecule [0047-0048].
Regarding claim 102, Polydoro teaches targeting some regions in MAPT gene or transcript by antisense oligonucleotides is more effective to reduce tau expression than targeting other regions [0095]. Polydoro teaches SEQ ID NO: 293 which targets MAPT exon 5 (Table 1).
Claim(s) 1 and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Polydoro (Polydoro Ofengeim, M., US20170175116A1) and Uhlmann (Uhlmann, E., AU661365B2) and Gryaznov (Gryaznov, Sergei M. "Oligonucleotide N3′→ P5′ phosphoramidates as potential therapeutic agents." Biochimica et Biophysica Acta (BBA)-Gene Structure and Expression 1489.1 (1999): 131-140.) as applied for claim 1, and in further view of Ittig (Ittig, Damian, et al. Artificial DNA: PNA & XNA 1.1 (2010): 9-16.)
The teachings of Polydoro, Uhlmann, and Gryaznov as applied above for claim 1 are incorporated here.
Polydoro does not specify the oligonucleotide melting temperature of greater than 37 degrees Celsius.
Ittig teaches RNAi oligonucleotides with melting temperatures above 37 degrees Celsius (pg 12 col 2 para 2).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention that Polydoro’s oligonucleotides targeting MAPT would have a melting temperature of at least 37 degrees given the teachings of Ittig. Note that the melting temperature of the oligomeric compound could vary based on the routine optimization of doses/concentrations (i.e., ratio of monomer to dimer) such that it would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Therefore, claim 95 is obvious and is properly rejected under 35 U.S.C. 103.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5 and 89-102 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-32 of issued patent #US11453881B2, in view of Polydoro (Polydoro Ofengeim, M., US20170175116A1) and Uhlmann (Uhlmann, E., AU661365B2) and Gryaznov (Gryaznov, Sergei M. "Oligonucleotide N3′→ P5′ phosphoramidates as potential therapeutic agents." Biochimica et Biophysica Acta (BBA)-Gene Structure and Expression 1489.1 (1999): 131-140.) as applied for claim 1.
Regarding instant claims 1-5 and 89-102, patented claim 1-3 teaches an oligonucleotide complimentary to at least a portion of the MAPT gene comprising 2'-MOE (also known as 2′-O-MOE or 2'-O-(CH₂CH₂OCH₃)) and a 3' phosphorothioate linkage.
It would have been obvious to combine the reference issued claims into the modified oligonucleotide of instant claim 1, given the obviousness rational provided above as applied to claim 1.
The reference patented claims specifically teach:
1. A chimeric oligonucleotide complementary to at least a portion of the MAPT gene represented by Formula (VI):
5′X-Y-Z3′ (VI),
wherein
X-Y-Z is a chimeric oligonucleotide comprising a sequence of 18 to 22 nucleosides, and is optionally conjugated at the 5′ and/or 3′ end to a ligand targeting group;
X is a domain comprising a sequence of modified nucleosides that is 3-10 nucleosides in length;
Z is a domain comprising a sequence of modified nucleosides that is 3-10 nucleosides in length; and
Y is a domain comprising a sequence of 2 to 10 2′-deoxy-nucleosides linked through thiophosphate intersubunit linkages, and
wherein the oligonucleotide shows affinity to at least one of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO:5 or SEQ ID NO:6,
wherein the X and/or Z domain comprises one or more oligonucleotide where the modification is 2′-O-methoxyethoxy-N3′→P5′.
2. The chimeric oligonucleotide of claim 1, wherein the Y domain is 6 to 10 nucleosides in length.
3. The chimeric oligonucleotide of claim 1, wherein the X and/or Z domains comprise a sequence of modified nucleosides linked through N3′→P5′ phosphoramidate or N3′→P5′ thiophosphoramidate intersubunit linkages.
4. The chimeric oligonucleotide of claim 1, wherein the Y domain comprises at least one phosphodiester intersubunit linkage.
5. The chimeric oligonucleotide of claim 1, wherein the Y domain consists of 2′-deoxy-nucleosides linked through thiophosphate intersubunit linkages, and optionally one or two phosphodiester intersubunit linkage.
6. The chimeric oligonucleotide of claim 1, wherein the X domain comprises modified nucleosides where the modification is independently selected from the group consisting of 2′-F, 2′-F—N3′→P5′, 2′-OMe, 2′-OMe-N3′→P5′, 2′-O-methoxyethoxy, 2′-O-methoxyethoxy-N3′→P5′, conformationally restricted nucleosides, 2′-OH—N3′→P5′ thiophosphoramidate and 2′-OH—N3′→P5′ phosphoramidate.
7. The chimeric oligonucleotide of claim 1, wherein the functional domain of Z comprises modified nucleosides where the modification is selected from the group consisting of 2′-F, 2′-F—N3′→P5′, 2′-OMe, 2′-OMe-N3′→P5′, 2′-O-methoxyethoxy, 2′-O-methoxyethoxy-N3′→P5′, conformationally restricted nucleosides, 2′-OH—N3′→P5′ thiophosphoramidate and 2′-OH—N3′→P5′ phosphoramidate.
8. The chimeric oligonucleotide of claim 1, wherein the X and/or Z domains comprise one or more 2′-deoxy-nucleosides linked through a N3′→P5′ phosphoramidate intersubunit linkage.
9. The chimeric oligonucleotide of claim 1, wherein the X and Z domains comprise one or more 2′-arabino-F and/or 2′-ribo-F modified nucleoside, wherein each said nucleoside is independently linked through at least one of an N3′→P5′ phosphoramidate or N3′→P5′ thiophosphoramidate intersubunit linkage.
10. The chimeric oligonucleotide of claim 1, wherein the X and Z domains comprise one or more 2′-OMe modified nucleosides, wherein each said nucleoside is independently linked through at least one of N3′→P5′ phosphoramidate, N3′→P5′ thiophosphoramidate, or thiophosphate intersubunit linkages.
11. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides in each of the X and Z domains are 2′-OMe modified nucleosides linked through thiophosphate intersubunit linkages, and wherein the modified nucleosides include 5-methylcytosine nucleobases.
12. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides include 2,6-diaminopurine nucleobases.
13. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides include 5-methyluracil nucleobases.
14. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides include 2,6-diaminopurine nucleobases, but not adenine and 5-methyluracil nucleobases.
15. The chimeric oligonucleotide of claim 1, wherein the Y domain comprises 6-8 2′-deoxy-nucleosides.
16. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides in each of the X and Z domains comprise 2′-OMe modified nucleosides and conformationally restricted nucleosides optionally linked through thiophosphate intersubunit linkages, and wherein the 2′-OMe modified nucleosides include 5-methylcytosine nucleobases.
17. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides in each of the X and Z domains comprise 2′-OMe and conformationally restricted nucleosides.
18. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides in each of the X and Z domains comprise conformationally restricted nucleosides and, wherein at least one modified nucleoside includes a N3′→P5′ phosphoramidate or a N3′→P5′ thiophosphoramidate intersubunit linkage.
19. The chimeric oligonucleotide of claim 1, wherein the Y domain comprises 7-8 2′-deoxy-nucleosides.
20. The chimeric oligonucleotide of claim 1, wherein the modified nucleosides include 2′-OMe modified nucleosides, and the 2′-OMe modified nucleosides include 5-methyluracil nucleobases.
21. The chimeric oligonucleotide of claim 1, wherein the Y domain comprises 9-10 2′-deoxy-nucleosides.
22. The chimeric oligonucleotide of claim 1, wherein the X and Z domains comprise nucleotides represented by the Formula (A1):
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808
826
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wherein
A is independently in each instance NH or O;
B is independently in each instance an unmodified or modified nucleobase;
W is independently in each instance OR SR, where R is H or a positively charged counter ion;
R′ and R″ are each independently in each instance selected from the group consisting of H, F, Cl, OH, OMe, Me, and O-methoxyethoxy;
R′″ is H, or R′ and R′″ together form —O—CH2— or —O—(CH2)2—, and
a is an integer of 3 to 9,
wherein when R′, R″ and R′″ are each H, then A is NH, and optionally when A is O, then W is SR.
23. The chimeric oligonucleotide of claim 1, wherein the X domain comprises one or more oligonucleotide where the modification is 2′-O-methoxyethoxy-N3′→P5′.
24. The chimeric oligonucleotide of claim 1, wherein the Z domain comprises one or more oligonucleotide where the modification is 2′-O-methoxyethoxy-N3′→P5′.
25. The chimeric oligonucleotide of claim 1, wherein the nucleobase sequence of the oligonucleotide corresponds to SEQ ID NO: 1, SEQ ID NO: 40, SEQ ID NO: 41 or SEQ ID NO: 42.
26. A pharmaceutical composition comprising an oligonucleotide of claim 1 and a pharmaceutically acceptable excipient.
27. The pharmaceutical composition of claim 26, wherein the composition is suitable for intrathecal or intracerebroventricular delivery.
28. A method of inhibiting MAPT gene expression in a CNS cell comprising contacting the cell with an oligonucleotide of claim 1.
29. A method of inhibiting transcription of MAPT mRNA in a CNS cell comprising contacting the cell with an oligonucleotide of claim 1.
30. The oligonucleotide of claim 1, wherein said oligonucleotide complexed with an MAPT gene has a melting temperature (Tm) of >37° C.
31. A method of inhibiting expression of a MAPT mRNA in a CNS cell comprising contacting the cell with an oligonucleotide or composition comprising an oligonucleotide of claim 1, wherein the oligonucleotide contains a nucleobase sequence that is complementary or hybridizes to at least a portion of the MAPT mRNA.
32. A method of modulating expression of a MAPT gene by contacting a target nucleic acid with an antisense compound comprising an oligonucleotide of claim 1, wherein the oligonucleotide contains a nucleobase sequence that is complementary or hybridizes to at least a portion of the MAPT gene.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637