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 and Election
Claims 82 and 84-103 are pending. Applicant’s election with traverse of group I (claims 82, 84-96) in the Remarks filed 10/22/25 remains acknowledged. Claims 97-102 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim 82 is amended.
Examination on the merits commences on claims 82, 84-96 and 103.
§§ 102, 103, and NSDP rejections are maintained for reasons that follow.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 102 - MAINTAINED
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.
Claim(s) 82, 84, 90-93, 95, and 103 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Natarajan (Natarajan, R., US 20160348105 A1) as evidenced by PubChem (PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/79066, printed as pages 1/1 to 32/32).
Regarding claim 82, Natarajan teaches an isolated nucleic acid sequence capable of hybridizing to an RNA sequence downstream of the transcription start site of a mammalian microRNA-379 in a method of treating diabetic nephropathy in a subject by inhibiting expression of a mammalian microRNA-379 megacluster with said nucleic acid compound [0005-0006]. Natarajan teaches nucleobases within the method include nucleobase analogs in the context of nucleic acid bases as chemical moieties that can substitute for normal (i.e., physiological) nucleobases (i.e., A, T, G, C and U) in nucleic acids including oligonucleotides with the nucleobase analog 3-Methyluracil [0042].
Regarding the amendment of claim 82 further limiting the oligonucleotide to at least ten nucleobases, Natarajan teaches phosphorothioate oligonucleotides (phosphorothioate nucleic acids) are from about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length [0041], i.e. at least ten nucleobases.
Natarajan is silent as to the chemical structure of 3-methyluracil, however PubChem teaches the structure
PNG
media_image1.png
207
265
media_image1.png
Greyscale
is the claimed structure of claim 82:
PNG
media_image2.png
73
80
media_image2.png
Greyscale
(PubChem pg 1). Examiner is interpreting, based upon broadest reasonable interpretation of the chemical structure, that the wavy line pattern
PNG
media_image3.png
37
29
media_image3.png
Greyscale
is a placeholder for any chemical group, ranging from a simple methyl group to a complex sugar-phosphate backbone. Therefore, the structure
PNG
media_image1.png
207
265
media_image1.png
Greyscale
as disclosed by Natarajan reads on the
PNG
media_image2.png
73
80
media_image2.png
Greyscale
structure from claim 82.
Regarding claim 84, Natarajan teaches (FIGS. 16A-16B) the nucleotide designs include the backbone is phosphorothioated [0025] and [0040].
Regarding claim 90, Natarajan teaches the compound includes a nucleic acid sequence having a nucleobase analog with modified sugars [0006].
Regarding claim 91, Natarajan teaches the compound includes a nucleic acid sequence having a nucleobase analog with 2'-F modified sugars [0006].
Regarding claim 92, Natarajan teaches the compound includes a nucleic acid sequence having natural DNA sugars [0042-0043].
Regarding claim 93, Natarajan teaches the compound includes a nucleic acid sequence having functional group ligand moieties [0079].
Regarding claim 95, Natarajan teaches the compound is included in a pharmaceutically acceptable salt [0081].
Regarding claim 103, Natarajan teaches phosphorothioate oligonucleotides (phosphorothioate nucleic acids) are from about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length [0041].
Claim Rejections - 35 USC § 103 - MAINTAINED
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) 82, 85, 86, and 94 is/are rejected under 35 U.S.C. 103 as being unpatentable over Natarajan (Natarajan, R., US20160348105A1) as evidenced by PubChem (PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/79066, retrieved 7/10/25, printed as pages 1/1 to 32/32) as applied to claim 82, in view of Zhang (Zhang, J., WO2017210647A1).
The teachings of Natarajan and PubChem as applied above for claim 82 are incorporated here.
Regarding claim 85 and 86, Natarajan also teaches the phosphorothioate nucleic acids include one or more nucleic acid analog monomers such as peptide nucleic acid monomer or polymer, locked nucleic acid monomer or polymer, morpholino monomer or polymer, glycol nucleic acid monomer or polymer, or threose nucleic acid monomer or polymer and other analog nucleic acids include those with positive backbones; non-ionic backbones, and nonribose backbones [0040].
Natarajan does not teach wherein each phosphorothioate linkage is independently chirally controlled.
However, Zhang teaches various modified oligonucleotides are useful and valuable as immunomodulatory agents which have improved immunomodulatory activity, stability, utility and/or effectiveness. [0003]. Zhang teaches phosphorothioate linked modified oligonucleotides within the method, wherein those phosphorothioate linked compositions are completely chirally controlled oligonucleotide composition, and wherein each chiral internucleotidic linkage of the oligonucleotide is independently chirally controlled [001105].
Further regarding claim 86, Natarajan teaches the compounds includes a nucleic acid sequence having a nucleobase analog. In embodiments, the nucleic acid sequence includes Locked Nucleic Acid (LNA), 2′-O-alkyl, 2′ O-Methyl, 2′-deoxy-2′fluoro, 2′-deoxy, a universal base, 5-C-methyl, an inverted deoxy abasic residue incorporation, or any combination thereof. In embodiments, the nucleic acid sequence may include analogs with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos) [0006].
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Natarajan’s method of employing non-negatively charged phosphorothioate nucleobase analogs within the nucleic acid compositions to treat diabetic nephropathy to also include the nucleobase analog modifications of Zhang such as phosphorothioate linkages wherein each chiral internucleotidic linkage of the oligonucleotides independently chirally controlled. 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 Zhang’s independently chirally controlled phosphorothioate linkages would be effective within Natarajan’s nucleobase phosphorothioate analog compositions because Zhang teaches such modified linkages within oligonucleotides are valuable as immunomodulatory agents with improved immunomodulatory activity, stability, and utility. The skilled artisan would therefore be motivated to modify Natarajan’s nucleic acids with Zhang’s nucleobase linkages so as to improve the treatment of diabetic nephropathy with enhanced oligonucleotide agents.
Regarding claim 94, Zhang further teaches wherein the modified oligonucleotide contains a ligand moiety such as a GalNAc [001332].
Claim(s) 82, 87-89 is/are rejected under 35 U.S.C. 103 as being unpatentable over Natarajan (Natarajan, R., US 20160348105 A1) as evidenced by PubChem (PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/79066, retrieved 7/10/25, printed as pages 1/1 to 32/32) in view of Zhang (Zhang, J., WO2017210647A1) as applied to claim 82, and in further view of Butler (Butler, D., WO2017062862A2) and Stetsenko (Stetsenko, D., US 20170362270A1).
Regarding claims 87, 88, and 89, the teachings of Natarajan, PubChem, and Zhang as applied above for claim 82 are incorporated here.
Natarajan does not explicitly disclose that the oligonucleotides contain one or more independently chirally controlled guanidine moieties such as with the structure
PNG
media_image4.png
96
107
media_image4.png
Greyscale
.
However, this deficiency is cured by Butler and Stetsenko. Butler discloses that oligonucleotide activity, toxicity, distribution, and pharmacokinetics can be adjusted by optimizing its pattern of backbone chiral centers ([004477] and [00478])) in combination with adjustment/optimization of chemical modifications and patterns thereof (i.e. linkage patterns and nucleoside modification patterns) ([0003]. Butler further discloses that these optimized chiral and chemical modification patterns, when combined with optimized stereochemistry patterns, impart enhanced properties such as low toxicity and better protein binding to said modified oligonucleotide [0013]. Additionally, Butler teaches that the purity of such a chirally controlled oligonucleotides can be controlled by stereoselectivity of each coupling step in its preparation process, in which each coupling step has a stereoselectivity of at least 60% (generating new internucleotidic linkages with at least 60% purity) and up to greater than 99% (thereby generating new internucleotidic linkages with greater than 99% purity) ([00463] and [00475]). Butler also discloses that the chemical modifications taught therein may comprise modified bases such as 5-methylcytosine and modified sugars such as 2’-MOE, which further enhance activity, stability, and/or selectivity of the composition [001201].
Regarding the instantly claimed
PNG
media_image4.png
96
107
media_image4.png
Greyscale
modification of claim 88, Stetsenko teaches nucleotides and oligonucleotides having a modified phosphate group and methods for their synthesis [0001]. Stetsenko teaches such oligonucleotides wherein a phosphate linking adjacent nucleosides/nucleoside analogues comprises a phosphoryl guanidine [0064]. Stetsenko teaches one such structure depicted
PNG
media_image5.png
205
204
media_image5.png
Greyscale
, in which Y is selected from the 3’ end of a nucleoside, nucleoside analogue, oligonucleotide, or oligonucleotide analogue —H, —OH, —SH, NHRN, —O-PG, or S-PG, and X is selected from the 5’ end of a nucleoside, nucleoside analogue, oligonucleotide, or oligonucleotide analogue —H, —OH, —SH, NHRN, —O-PG, or S-PG ([0038] and [0062]). The structure disclosed in Stetsenko reads on the instantly claimed modification of claim 88. Additionally, Stetsenko discloses that substituting neutrally or positively charged groups (i.e. non-negatively charged) for natural anionic phosphate can improve cellular uptake of oligonucleotides for therapeutic purposes ([0021] and [0022]) and that the phosphates and modified phosphates taught therein may be chiral, encompassing both Rp and Sp configurations and all enantiomers and diastereomers are encompassed [0120].
Given the oligonucleotide modification teachings of Natarajan and Zhang as applied to claim 82 above and given the teachings of Butler who discloses optimized chiral and chemical modification patterns for therapeutic oligonucleotides, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the nucleic acid sequence disclosed in Natarajan with the chemical and backbone modifications disclosed in Zhang, Butler, and Stetsenko to predictably produce a chirally controlled therapeutic oligonucleotide with enhanced uptake efficiency, activity, toxicity, distribution, and pharmacokinetics. One of ordinary skill in the art would arrive at the specific patterns of modifications recited in the instant claim set because it would have amounted to applying a known chemical modification design strategies to yield predictable results through routine experimentation (see MPEP § 2144.05(II)(A)). One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutic oligonucleotide with enhanced uptake efficiency, activity, toxicity, distribution, and pharmacokinetics.
Regarding claim 96 which recites each phosphorothioate internucleotidic linkage in the oligonucleotide independently has a diastereomeric purity of at least 90%, Butler discloses that the purity of a chirally controlled oligonucleotide composition can be controlled by the stereoselectivity of each coupling step in the preparation process to generate said oligonucleotide, thereby modulating the activity, toxicity, distribution, and pharmacokinetics of said oligonucleotide ([00463], [00475], [004477], and [004488]). Butler explicitly discloses that each coupling step may have a stereoselectivity of at least 60% up to greater than 99%, thereby generating new internucleotidic linkages with at least 60% and up to greater than 99% purity ([00463] and [00475]). Thus, Butler discloses that each phosphorothioate internucleotidic linkage in the instantly claimed oligonucleotide has a diastereomeric purity of at least 90%.
Double Patenting - MAINTAINED
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.
Claim 82, 84-96 and 103 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 84-104, of co-pending Application No. 18/856553 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instant claims.
Regarding instant claims 82, 84-96 and 103, the teachings of Natarajan, Pubchem, Zhang, Butler, and Stetsenko, as applied above to claims 82 and 87-89 are incorporated here.
The co-pending claims teach.
An oligonucleotide, wherein the oligonucleotide comprises 5'-N1NoN-1-3', wherein each of N-1, No, and NI is independently a nucleoside; and wherein:(a) the nucleobase of No is BA, wherein BA is
PNG
media_image6.png
62
84
media_image6.png
Greyscale
.
85. (New) The oligonucleotide of claim 84, wherein the nucleobase of No is
PNG
media_image7.png
50
64
media_image7.png
Greyscale
86. (New) The oligonucleotide of claim 85, wherein the sugar of No is a 2'-OMe modified sugar.
87. (New) The oligonucleotide of claim 84, wherein the oligonucleotide has a length of about 10-200 nucleobases.
88. (New) the oligonucleotide of claim 84, wherein the oligonucleotide comprises one or more phosphorothioate linkages.
89. (New) The oligonucleotide of claim 88, wherein each phosphorothioate linkage is independently chirally controlled.
90. (New) The oligonucleotide of claim 84, wherein the oligonucleotide comprises one or more non- negatively charged linkages.
91. (New) The oligonucleotide of claim 84, wherein the oligonucleotide comprises one or more PN linkages.
92. (New) The oligonucleotide of claim 84, wherein the oligonucleotide comprises
PNG
media_image8.png
79
138
media_image8.png
Greyscale
94. (New) The oligonucleotide of claim 84, wherein the oligonucleotide comprises one or more modified sugars in addition to the sugar of No.
95. (New) The oligonucleotide of claim 94, wherein the oligonucleotide comprises one or more 2'-F modified sugars.
96. (New) The oligonucleotide of claim 94, wherein the oligonucleotide comprises one or more natural DNA sugars.
97. (New) A pharmaceutical composition which comprises or delivers an oligonucleotide of claim 84, and a pharmaceutically acceptable carrier.
99. (New) An oligonucleotide composition comprising an oligonucleotide of claim 84, wherein the oligonucleotide comprises a chiral linkage phosphorus atom, wherein diastereomeric purity of the linkage phosphorus is 85%-100%.
It would have been obvious to combine the patented claims into a single embodiment of the instant claims, given the teachings of over Natarajan (Natarajan, R., US 20160348105 A1) as evidenced by PubChem (PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/79066, retrieved 7/10/25, printed as pages 1/1 to 32/32) in view of Zhang (Zhang, J., WO2017210647A1) as applied to claim 82, and in further view of Butler (Butler, D., WO2017062862A2) and Stetsenko (Stetsenko, D., US 20170362270A1), given the §§ 102 and 103 rejections above applied to claims.
This is a provisional rejection because the copending claims have not yet been patented.
Response to Arguments
Applicants argue (Remarks pg 7-8) that
PNG
media_image9.png
35
24
media_image9.png
Greyscale
precludes a connection to a methyl group therefore the cited references do not teach the invention as claimed.
Applicant’s arguments have been thoroughly reviewed and found unpersuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., that the
PNG
media_image9.png
35
24
media_image9.png
Greyscale
is NOT a methyl group attachment ) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As stated above, Examiner is interpreting, based upon broadest reasonable interpretation of the chemical structure, that the wavy line pattern
PNG
media_image9.png
35
24
media_image9.png
Greyscale
is a placeholder for any chemical group, ranging from a simple methyl group to a complex sugar-phosphate backbone. Applicants themselves state (Remarks pg 7), that “
PNG
media_image9.png
35
24
media_image9.png
Greyscale
indicates a point of connection.” A point of connection can include a methyl group. Therefore, the structure
PNG
media_image1.png
207
265
media_image1.png
Greyscale
as disclosed by Natarajan reads on the
PNG
media_image2.png
73
80
media_image2.png
Greyscale
structure from claim 82. Examiner suggests Applicants specify the exact connection of the claimed structure and the oligonucleotide at the wavy line
PNG
media_image9.png
35
24
media_image9.png
Greyscale
.
Conclusion
No claims are allowable.
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 extension fee 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 date of this final action.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Jennifer Dunston, can be reached on (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
Prosecution Insights