DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 1-20-26.
Claims 1-6, 11, 13, 14, 19, 30, 31, 100-104 and 117 are pending in the instant application.
Election/Restrictions
Claims 100-104 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species or invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1-20-26.
Applicant’s election without traverse of Group I, claims 1-6, 11, 13, 14, 19, 30 and 31, 117, R is C6 alkyl, the covalent linker and R1 as set forth on page 11 of the specification, R2 as the disulfide, and S-trityl as the S-PG end group, in the reply filed on 1-20-26 is acknowledged.
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Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 11, 13, 14, 19, 30 31, and 117 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.
In claims 1 and 2, the phrases “deprotectable under a deprotection condition,” stable under the deprotection condition” and “a cleavage condition that is not the deprotection condition” are vague and unclear.
The metes and bounds of the claims cannot be determined
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 11, 13, 14, 19, 30, 31, and 117 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims:
The claims are drawn to compositions comprising multimeric oligonucleotides comprising a plurality of subunits ******** and a protected sulfur-containing end group, wherein each of the subunits ******** is a single or double stranded oligonucleotide and is joined to another subunit by a covalent linker . , at least one of the covalent linkers is a sulfur-containing covalent linker 0,optionally comprising a sulfur-containing cleavable group, and which sulfur-containing end group is deprotectable under a deprotection condition, and each sulfur-containing covalent linker 0 is stable under the deprotection condition, or optionally wherein at least one sulfur-containing covalent linker 0 comprises a cleavable group, optionally a sulfur-containing cleavable group cleavable under a cleavage condition that is not the deprotection condition, which protected sulfur-containing end group optionally comprises a protected thiol group, or which sulfur-containing covalent linker 0 optionally comprises a linkage represented by -Rl-R2-Rl-, wherein each Ri is individually absent or a spacer group, and R2 is a thiopropionate or disulfide group, wherein at least one of the spacer groups R1 optionally comprises alkyl, alkyl ether, ester, aryl, heteroaryl, heterocyclyl, alkyl-aryl, alkyl-heteroaryl, or alkyl-heterocyclyl, or optionally wherein at least one of the spacer groups R1 comprises a phosphate linking group, a phosphorothioate linking group, a phosphonate linking group, or a dithiophosphate linking group.
The claims are further drawn to multimeric oligonucleotides optionally comprising structure 1:
L-R-[******** .]n********-R-S-PG
wherein L is a bioactive moiety that may be present or absent, each R is a spacer group that may be present or absent, each ******** is independently a single or double stranded oligonucleotide subunit, each . is a covalent linker joining adjacent oligonucleotide subunits, n is an integer in the range of 1 to 9, S-PG is a protected sulfur-containing end group, and at least one . is a sulfur-containing covalent linker 0, wherein at least one of the spacer groups R optionally comprises alkyl, alkyl ether, ester, aryl, heteroaryl, heterocyclyl, alkyl-aryl, alkyl-heteroaryl, or alkyl-heterocyclyl, optionally comprising C1-10 alkyl, C1-10 alkyl ether, C1-10 alkyl ester, 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, (C1-10 alkyl)-(6-10 membered aryl), (C1-10 alkyl)-(5-10 membered heteroaryl), or (C1-10 alkyl)-(5-10membered heterocyclyl, or which protected sulfur-containing end group comprises a protecting group selected from a substituted alkyl, alkoxyalkyl, trialkylsilyl, arylalkylsilyl, aryl, benzyl, acyl or benzoyl, and optionally wherein the protected sulfur-containing end group comprises a protecting group PG selected from trityl, methoxytrityl, dimethoxytrityl, methylmethoxy, triisopropylsilyl, dinitrophenyl, nitrophenyl, acetyl and benzoyl.
Teachings in the specification:
The specification teaches the following:
Example 1. Synthesis of Disulfide-linked Multimeric Oligonucleotides using Orthogonally Protected Thiols.
[00175] A bis-(triantennary GalNAc) homo-hexamer of TTR siRNA (siTTR) is prepared as outlined in Scheme1 (FIG.1). Two monomers of siTTR sense strand are prepared on the synthesizer, one with a terminal amino group, the other with a terminal tritylated thiol. Both have a disulfide group at the other terminus. A triantennaryGalNAc group is added to the terminal amino function of the first monomer and then the disulfide groups of both monomers are cleaved by DTT to the corresponding thiols.
[00176] The tritylated monomer is converted to a mono-DIME derivative by previously reported methods (see PCTPublication No. WO 2016/205410) and part of this material is reacted with the GaiNAc-siT.TR-thiol to yield a GalNAc-siIR single-stranded homodimer with an internal DTME linkage (-S-CL-S-) and a terminal thiol protected by a trityl group.
[00177]The trityl group is removed from the homo-dimer by treatment with aqueous silver nitrate and after purification is treated with one molar equivalent of the tritylated mono- DTME derivate to yield a GaiNAc-siTTR single-stranded homotrimer with two internal DIME linkages (-S-CL-S-) and a terminal thiol protected by a trityl group.
[00178] The trityl group is removed from the homo-trimer by treatment with aqueous silver nitrate and after purification is treated with one half-molar equivalent of DIME. to yield the single stranded homo-hexamer. Annealing of six equivalents of 'TR antisense siRNA yields the desired bis-(triantennary GalNAc) homo-hexamer of siTTR containing5 disulfide linkages.
The specification fails to provide adequate description or reasonable representation of the broad genus of multimeric oligonucleotides claimed. The specification, prior art and claims do not adequately describe the expansive genus of multimers, including the protection and deprotection conditions, the corresponding protected, deprotected covalent linkers in combination with sulfur containing cleavable and non-cleavable groups, and/or in combination with the multitude of spacer groups instantly claimed. The specification fails to provide a representative number of species, and do not indicate what distinguishing attributes are concisely shared by the members of this genus.
For the reasons stated above, the instant rejection for lacking adequate written description is proper.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 1-6, 11, 13, 14, 19, 30, 31, and 117 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mok et al (Nature Materials, Vol. 9, pages 272-278 (2020)), Muratovska et al (FEBS Letters, Vol. 558, pages 63-68 (2004), Chung et al (Bioconj. Chem., Vol. 22, pages 299-306 (2011)), Kang et al (Bulletin of the Korean Chem. Soc, Vol. 37, pages 1440-1444 (2016)), Subramanian et al (Nucleic Acids Res., Vol. 43, No. 19, pages 9123-9132 (2015)), Mok et al (Biopolymers, Vol. 89, No. 10, pages 881-888 (2008)), the combination in view of Kumelis et al (US 2019/0002410).
The claims are drawn to compositions comprising multimeric oligonucleotides comprising a plurality of subunits ******** and a protected sulfur-containing end group, wherein each of the subunits ******** is a single or double stranded oligonucleotide and is joined to another subunit by a covalent linker . , at least one of the covalent linkers is a sulfur-containing covalent linker 0,optionally comprising a sulfur-containing cleavable group, and which sulfur-containing end group is deprotectable under a deprotection condition, and each sulfur-containing covalent linker 0 is stable under the deprotection condition, or optionally wherein at least one sulfur-containing covalent linker 0 comprises a cleavable group, optionally a sulfur-containing cleavable group cleavable under a cleavage condition that is not the deprotection condition, which protected sulfur-containing end group optionally comprises a protected thiol group, or which sulfur-containing covalent linker 0 optionally comprises a linkage represented by -Rl-R2-Rl-, wherein each Ri is individually absent or a spacer group, and R2 is a thiopropionate or disulfide group, wherein at least one of the spacer groups R1 optionally comprises alkyl, alkyl ether, ester, aryl, heteroaryl, heterocyclyl, alkyl-aryl, alkyl-heteroaryl, or alkyl-heterocyclyl, or optionally wherein at least one of the spacer groups R1 comprises a phosphate linking group, a phosphorothioate linking group, a phosphonate linking group, or a dithiophosphate linking group.
The claims are further drawn to multimeric oligonucleotides optionally comprising structure 1:
L-R-[******** .]n********-R-S-PG
wherein L is a bioactive moiety that may be present or absent, each R is a spacer group that may be present or absent, each ******** is independently a single or double stranded oligonucleotide subunit, each . is a covalent linker joining adjacent oligonucleotide subunits, n is an integer in the range of 1 to 9, S-PG is a protected sulfur-containing end group, and at least one . is a sulfur-containing covalent linker 0, wherein at least one of the spacer groups R optionally comprises alkyl, alkyl ether, ester, aryl, heteroaryl, heterocyclyl, alkyl-aryl, alkyl-heteroaryl, or alkyl-heterocyclyl, optionally comprising C1-10 alkyl, C1-10 alkyl ether, C1-10 alkyl ester, 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, (C1-10 alkyl)-(6-10 membered aryl), (C1-10 alkyl)-(5-10 membered heteroaryl), or (C1-10 alkyl)-(5-10 membered heterocyclyl, or which protected sulfur-containing end group comprises a protecting group selected from a substituted alkyl, alkoxyalkyl, trialkylsilyl, arylalkylsilyl, aryl, benzyl, acyl or benzoyl, and optionally wherein the protected sulfur-containing end group comprises a protecting group PG selected from trityl, methoxytrityl, dimethoxytrityl, methylmethoxy, triisopropylsilyl, dinitrophenyl, nitrophenyl, acetyl and benzoyl.
Mok et al (Nature Materials, Vol. 9, pages 272-278 (2020)) (See IDS filed 1-20-26) teach chemically crosslinked multimerized siRNA with cleavable disulphide or non-cleavable linkages (see esp. the abstract and introduction on page 272, Figure 1 on page 273, Figure 2 on page 274), Methods on page 277).
Muratovska et al (FEBS Letters, Vol. 558, pages 63-68 (2004)) (See IDS filed 1-20-26) teach siRNA molecules coupled to membrane permeant peptides, penetratin and transportan with thiol containing siRNAs. The disulfide binds were labile in the reducing environment of the cytoplasm of target cells (see esp. the abstract and introduction on page 63Section 2.3 on page 64, Figure 1 on page 65).
Chung et al (Bioconj. Chem., Vol. 22, pages 299-306 (2011)) (See IDS filed 1-20-26) teach siRNA dimeric conjugates linked by cleavable disulfide bonds for enhancing gene silencing efficiency. Monomer, dimer, trimer and tetramer oligomeric siRNA complexes were analyzed. Dimeric siRNA conjugates with 3’ thiolated sense strands of siRNA were reacted with dithio-bismaleimidoethane (DTME). Single strand pegylated siRNA with cleavable disulfide bonds were reacted with mPEG-NH2 activated with SPDP (see esp. the abstract and introduction on page 299, fourth and fifth full page on page 300, Figure 1 on page 301).
Kang et al (Bulletin of the Korean Chem. Soc, Vol. 37, pages 1440-1444 (2016)) (See IDS filed 1-20-26) teach aptamer and cell penetrating peptide mediated delivery of multimeric antisense strand of siRNAs. Di-thiolated antisense strands of siRNA were treated with dithiothreitol (DTT) and used for hybridization with aptamers linked with the RNA sense strands of the siRNA or peptide nucleic acids (see esp. the first full paragraph on page 144, and the second full paragraph on page 1443).
Subramanian et al (Nucleic Acids Res., Vol. 43, No. 19, pages 9123-9132 (2015)) (See IDS filed 1-20-26) teach novel antisense oligonucleotide (ASO) design using short ASO monomers as part of homo or heterodimers or multimers via phosphodiester linkers that are stable in plasma and cleaved inside cells, releasing active ASO monomers that target different target genes. Multiple target oligonucleotide constructs were synthesized in both RNase H activating and steric blocking oligonucleotides (see esp. the abstract and introduction on pages 9123-9124), first full paragraph on page 9126, Table 1 on page 9126Figure 1 and text on page 9127Z). Subramanian also teaches improved activity of ASO in the liver using triantennary N-acetyl galactosamine (GalNAc) conjugated ASO’s (see second full paragraph on page 9131)).
Mok et al (Biopolymers, Vol. 89, No. 10, pages 881-888 (2008)) (See IDS filed 1-20-26) teach the generation of novel self-crosslinked and reducible peptides for stably forming nanoscale complexes with siRNA-PEG conjugates. The fusogenic peptide, KALA, was altered to have two cysteine residues at both termini and was crosslinked via disulfide linkages under mild DMSO oxidation conditions. Reducible crosslinked KALA formed nanocomplexes with siRNA. KALA with terminally modified cysteine residues was dissolved and reacted with N,N,N’, N’-tetramethylazodicarboxamide and DMSO. Crosslinked KALA was then exposed to dithiothreitol (DTT) for cleavage of disulfide linkages. SiRNA-s-s-PEG conjugates were prepared by modifying the sense strand of the siRNA with a hexylamine group at its 3’ end (see esp. the abstract on page 881, text on pages 882-884, Figure 1 on page 884).
The primary references do not teach protected sulfur containing groups comprising trityl or methoxytrityl.
Kumelis et al (US 2019/0002410) teach protected sulfur-containing end groups comprising a protecting group PG selected from trityl or methoxytrityl (see esp. paragraphs 0060-0061, 0069, 0079, 0083, 0161).
It would have been obvious to design and optimize multimeric oligonucleotides comprising protected sulfur containing end groups because protected sulfur containing end groups have been routinely used to form polymers, as illustrated in the teachings of
Mok, Muratovska, Chung, Kang, Subramanian, and Mok. One of ordinary skill in the art would have been motivated to provide cleavable sulfur containing groups that are protected until deprotected conditions are provided, to allow intracellular cleavage of multimers after cytosol delivery to target cells, as taught previously by Muratovska and Kim. Sulfur containing covalent linkers have been well known in the prior art and routinely used to fabricate macromolecular delivery and therapeutic devices, as disclosed by Mok, Muratovska, Chung, Kang, Subramanian, and Mok. For these and the aforementioned reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Jane Zara
3-30-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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