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 .
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.
This office action is a response to applicant’s communication submitted January 30, 2026. This application is a CIP of 19/203,725 filed May 9, 2025 and claims benefit of provisional application 63/645,397 filed May 10, 2024.
Response to Amendment
The amendment filed January 30, 2026. has been entered. Claims 1-2, 6-7, 9-10, 12, 14, 16, 18-19 have been amended, and claims 8, 15, and 20 have been cancelled. Applicant’s amendments to the drawings, specification, and claims have overcome the respective objections, 112b, 112d, 102 and 103 rejection previously set forth in the Non-Final Office Action mailed October 23, 2025. Applicants cancellation of claims 8, 15, and 20 have rendered the corresponding rejections/objections moot. Applicants abandonment of copending application No. 19/203,725 (unpublished, cited in previous action) have rendered the corresponding double patenting rejections moot. As such, these rejections and objections are hereby withdrawn.
Modified/new rejections necessitated by Applicant’s amendment are addressed below. Applicant’s arguments filed January 30, 2025 as they currently apply were fully considered but they were not persuasive.
Claims 1-7, 9-14, and 16-19 are pending in this application.
New Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7 and 10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7, which depends from claim 1, recites wherein the converting step comprises oxidizing the dinucleotide intermediate. However, claim 1 already recites inter alia, “converting the P(III) linkage of the dinucleotide intermediate to a P(V) linkage….” which necessarily constitutes an oxidation. Thus, claim 7 fails to limit the method of claim 1.
Claim 10, which depends from claim 9, recites wherein the converting step comprises oxidizing the dinucleotide intermediate. However, claim 9 already recites inter alia, “converting the P(III) linkage of the dinucleotide intermediate to a P(V) linkage….” which necessarily constitutes an oxidation. Thus, claim 10 fails to limit the method of claim 9.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Modified/New 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.
Claims 1-3, 5-7, 9-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Paul (Molecules, 2023, cited in previous action) in view of Kupryushkin (Molecular Therapy: Nucleic Acids, 2022, cited on IDS filed October 15, 2025) and Stetsenko (WO 2016/028187, cited on PTO-892).
Regarding claims 1-3, 5-7, 9-14, and 16: Paul teaches the synthesis of a nucleotide with neutral internucleotide linkages (dimethyl-phosphoramidate) starting with commercially available 50-DMT-20-deoxyribothymidine linked to a polystyrene support (pg. 5, para. 2 pg. 6, scheme 4). The method comprises the following steps: removing a protecting group from the solid supported nucleotide, coupling with a morpholino nucleotide intermediate having a P(III) linkage through a condensation reaction, oxidizing to convert the P(III) linkage to a P(V) linkage, capping the solid support, deprotecting the dinucleotide, repeating the steps as needed to form a desired number of nucleotides, cleaving from the solid support and deprotecting the oligonucleotide intermediates, wherein the protecting groups are removed via detritylation (pg. 6, scheme 4, pg. 9, scheme 6). The bases can be modified thymine, cytosine, guanine, and adenine (pg. 6, scheme 4). Paul teaches an additional synthesis wherein the P(III) linkage is converted to a phosphorothioate (i.e. P(V)) via sulfurization (pg. 9, scheme 6). These syntheses can generate oligonucleotides having 15 to 20 or 20 to 25 units in length (pg. 7, para. 2, pg. 8, para. 2). Paul teaches the oligonucleotides can be used as antisense oligonucleotides (pg. 10, paras. 1 and 3).
Paul does not teach wherein the conversion step between the P(III) linkage to a P(V) linkage results in the formation of a P(V) phosphoryl guanidinium linkage that is subsequently present in the final oligonucleotide (i.e. an morpholino oligonucleotide with phosphoryl guanidinium linkages).
However, Kupryushkin teaches the preparation of antisense oligonucleotides containing phosphoryl guanidine (PG) groups that are prepared via Staudinger chemistry (abstract). Kupryushkin teaches that PG modifications increase nuclease resistance (abstract). Kupryushkin teaches the preparation of PG oligonucleotides utilizes a Staudinger reaction of the phosphite intermediate converting from P(III) to P(V) on a commercial automated synthesizer (pg. 214, col. 1, para. 3). Kupryushkin compares the stability of phosphodiester, phosphorothioate, and phosphoryl guanidine linkages and determined internucleotidic PG modifications have increased stability compared to phosphodiester, phosphorothioate linkages (pg. 212, figure 1, pg. 214, col. 2, para. 3). Additionally Stetsenko teaches the preparation of oligonucleotides comprising phosphoryl guanidine groups via the reaction between a cyanoethyl phosphite (i.e. P(III)) with a guanidine reagent (TMG) to form an oligonucleotide with a phosphoryl guanidine group (pg. 17, lines 6-25). Stetsenko teaches phosphoryl guanidine incorporation can also be utilized in nucleoside analogs, such as wherein the sugar is replaced with a morpholine group, such as in a PMO (pg. 22, lines 29-30, pg. 23, lines 1-12).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the method of Paul such that the P(III) to P(V) conversion step produces a phosphoryl guanidinium internucleotide linkage as taught by Kupryushkin and Stetsenko. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as this transformation is known in the art of synthesizing modified antisense oligonucleotides in order to form nuclease resistant internucleotide linkages.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Paul (Molecules, 2023, cited in previous action), Kupryushkin (Molecular Therapy: Nucleic Acids, 2022, cited on IDS filed October 15, 2025), and Stetsenko (WO 2016/028187, cited on PTO-892) as applied to claims 1-3, 5-7, 9-14, and 16 above in view of Caruthers (US 2023/0193266, cited in previous action).
Regarding claim 4: As discussed above, the prior art relied upon render obvious the method of claim 1 and the oligonucleotide of claim 12. Paul teaches the use of a universal CPG supports for oligonucleotides with morpholino phosphoramidate modifications (pg. 3, para. 1).
Paul does not teach wherein the solid support is CPG-500 as recited by instant claim 4. However, Caruthers teaches a method for synthesizing an oligonucleotide with neutral internucleotide linkages comprising: the 5'-DMT group of the 2'-deoxyribonucleoside attached to the solid support (CPG-500 support, Glen Research) was deprotected using deblock reagent (3% trichloroacetic acid in dichloromethane); the resulting 5'-hydroxyl-2'-deoxyribonucleoside was reacted with 6'-DMT-morpholinonucleoside phosphorodiamidite of mABz, mG'Bu, mCBz, mT or commercial 2'-OMe phosphoramidites in presence of 0.12 M ETT in anhydrous acetonitrile with a 600 s condensation time; the nascent P(III) linkage was converted to thiophosphoramidate (TMO) or phosphorothioate (DNA pS, 2'-OMe pS) by sulfurization using 3-[(Dimethylaminomethylene)amino]-3H-1,2,4-dithiazole- 5-thione (DDTT, 360 s); following sulfurization, conventional capping reagents (Cap A: Tetrahydrofuran/Acetic Anhydride and Cap B: 16% 1-Methylimidazole in Tetrahydrofuran; Glen Research) were used to acetylate any unreacted hydroxyl groups, completing one synthesis cycle; Subsequent deprotection of the DMT protecting group using deblock resulted in dinucleotides that were ready for repetitive cycles to generate ODNs with exclusively TMO linkages or TMO-DNApS/TMO-2'OMe pS chimeras; multiple synthesis cycles were repeated until an ODN of desired length and sequence was generated; The 5'-DMT group on the ODN was not deprotected as a last step following solid-phase synthesis to enable DMT-On/Off purification. Upon completion of synthesis, cleavage and deprotection (pg. 21, para. 0223). The PMOs can have 19 nucleotide units or 15-25 bases (drawings sheet 3, figure 1C-D, pg. 9, para. 0116).
Taken together, it would have been prima facie obvious to modify the method such that a CPG-500 solid support is utilized as taught by Caruthers. A person of ordinary skill in the art would have the motivation to do so as these supports are known in the art to be used for the synthesis of morpholino oligomers. Wherein CPG-500 supports and universal supports are utilized, it is prima facie obvious to substitute equivalents for the same purpose (See MPEP 2144.06 (II)).
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Paul (Molecules, 2023, cited in previous action), Kupryushkin (Molecular Therapy: Nucleic Acids, 2022, cited on IDS filed October 15, 2025), and Stetsenko (WO 2016/028187, cited on PTO-892) as applied to claims 1-3, 5-7, 9-14, and 16 above in view of Youngblood (Bioconjugate Chem. 2007, cited in previous action).
Regarding claims 17-19: As discussed above, the prior art render obvious the method of claim 1 and the oligonucleotide of claim 12.
They do not teach a bioconjugated construct comprising the uncharged oligonucleotide and a linker comprising a dithiol linker conjugated to a cell penetrating peptide as recited by instant claims 17-19.
However, Youngblood teaches cell-penetrating peptide-morpholino oligomer conjugates with disulfide and maleimide linkages:
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(pg. 53, figure 1). Cell penetrating peptides (CPPs) enhance cellular uptake of antisense oligonucleotides (i.e. enable intracellular delivery, abstract). The morpholino oligomers comprise A, C, T, G and are 18 nucleotides in length (pg. 51, table 1).
Taken together, it would have been prima facie obvious to conjugate the oligonucleotide to a cell-penetrating peptide by way of a dithiol linker as taught by Youngblood. A person of ordinary skill in the art would have had the motivation do so with a reasonable expectation of success as the preparation of bio-constructs with the claimed modification is a known application of antisense oligonucleotides, and a person of ordinary skill in the art would recognize the applicability of the phosphoryl guanidino morpholine antisense oligonucleotides for this purpose.
Response to Arguments
Applicant’s arguments filed January 30, 2026 with respect the claims have been fully considered but they are not persuasive.
On pages 8-9 of Applicant’s response, Applicant argues the newly amended claims are novel over Paul as Paul does not teach converting the P(III) to P(V) linkage to form a phosphoryl guanidine (PG) linkage as is in the amended claims.
As discussed above, this argument is moot in light of the amended claims as these rejections are withdrawn, see new/modified 103 rejections above over Kupryushkin and Stetsenko.
On page 9 of Applicant’s response, Applicant argues Paul uses a BIBS protecting group which cannot be used with standard CPG resin.
However, as discussed above, Paul also teaches an additional synthesis wherein the P(III) linkage is converted to a phosphorothioate, wherein the bases are protected with N-benzoyl groups (i.e. P(V)) via sulfurization (pg. 9, scheme 6).
On pages 9-10 of Applicant’s response, Applicant argues the rejections in view of Youngblood and Caruthers should be withdrawn as they do not teach the converting the P(III) to P(V) linkage to form a phosphoryl guanidine (PG) linkage in the amended claims.
As discussed above, this argument is moot in light of the amended claims as these rejections are withdrawn, see new/modified 103 rejections above over Kupryushkin and Stetsenko.
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
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.
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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693