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 .
DETAILED ACTION
This Office Action is responsive to Applicant’s Amendment and Remarks, filed July 25, 2025. The amendment, filed July 25, 2025, has been entered, wherein claim 138 is amended and claims 1 – 124 are canceled.
Claims 125 – 145 are pending in this application and are currently examined.
Priority
3. This application is a national stage application of PCT/US2020/033196, filed May 15, 2020, which claims benefit of domestic applications 62/849,799 and 62/953,087, filed May 17, 2019 and December 23, 2019, respectively.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 365(c) or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/849,799, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The domestic application 62/849,799 does not provide support for the limitations of “a salt” recited in claim 125, “9:1 volumetric ratio of pyridine and water” recited in claims 126 and 134, “a halide salt” recited in claim 127, “iodine, bromide, chloride, or fluoride” recited in claim 128, “NaI, KI, LiI or pyridinium iodide” recited in claim 129, “I2 concentration is 0.04 M” and “0.06M” recited in claim 130, “the concentration of the salt is 0.01 – 0.07 M”, “the concentration of the salt is 0.04 – 0.06 M”, and “the concentration of the salt is 0.05 M” recited in claims 131 – 133, “0.05 M NaI” recited in claim 134, and “solid support” recited in claim 135. Thus, the priority date of claims 125 – 145 is December 23, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/25/2025 was filed after the mailing date of the previous Office Action on April 2, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objection
The objection of claim 138 in the previous Office Action, mailed April 2, 2025, is withdrawn in view of the amended claim 138.
The following are maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed July 25, 2025, wherein claim 138 is amended. Previously cited references have been used to establish the maintained / modified grounds of rejection.
Maintained / Modified 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
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.
Claims 125 – 137 and 142 – 145 are rejected under 35 U.S.C. 103 as being unpatentable over Maier et al. (WO0047593A1) in view of Bergstrom (The Journal of Organic Chemistry, 1992, Vol. 57, Issue 3, page 873 – 876, Reference included with PTO-892).
a. Regarding claims 125 – 137 and 142 – 145, Maier et al. teach an invention directed to methods for oxidizing an H-phosphonate internucleoside linkage in a compound which has at least one 2’-substituent group. This invention further relates to methods for the preparation of mixed backbone oligomeric compounds having internucleoside linkages including phosphodiester, phosphorothioate, phosphoramidate and boranophosphate linkages. The invention also relates to synthetic intermediates useful in such methods. Also included are mixed backbone oligomeric compounds having phosphodiester and boranophosphate internucleoside linkages or phosphodiester and boranophosphate internucleoside linkages in combination with other internucleoside linkages such as phosphorothioate and phosphoramidate internucleoside linkages (page 1, lines 4 – 13). The oxidation is effected by an oxidizing solution comprising an oxidizing agent, an aprotic solvent, a base, and water (page 4, lines 28 – 30). In this technique, an H-phosphonate monomer is reacted with a free hydroxyl on the growing oligomer chain to produce an intermediate phosphite compound, which is subsequently oxidized to PV state (page 11, lines 25 – 28). Useful oxidizing agents used to form the phosphodiester or phosphorothioate linkages, include iodine/tetrahydrofuran/water/pyridine (page 19, liens 1 – 3). The oxidation solution may be triethylamine (0.1 M) or 4-(dimethylamino)pyridine (DMAP, 0.1 M) in pyridine/carbon tetrachloride/water (9:5:1) (page 24, lines 19 – 23). In one embodiment, the oligomer is oxidized using iodine in 0.1 M (page 29, lines 18 – 19). In some preferred embodiments, a first monomer is attached to a solid support (page 11, lines 8 – 9). Maier et al. explicitly teach an oligomeric compound contains phosphodiester internucleoside linkages between nucleosides 3 to 6 and 15 to 20, phosphorothioate internucleoside linkages between nucleosides 6 to 15 (page 32, Example 11). Maier et al. further teach that it is generally preferable to perform a capping step either prior to or after oxidation or sulfurization of the internucleoside linkage (page 12, lines 15 – 17).
However, Maier et al. do not teach the salt, wherein the salt is NaI (claims 125 and 127 – 129). Maier et al. also do not teach the concentration of the salt used in the oxidization solution is 0.01 – 0.07 M (claims 131 – 134).
Bergstrom teaches the synthesis of (Dicarbonyl)(n5-cyclopentadienyl)iron-derived nucleoside phosphonate esters (Title). An intermediate phosphite ester 6, which was not isolated, but treated immediately with Fp ethylene (1) and, subsequently, with sodium iodide in acetone for 1 h at room temperature to yield 7 (Page 875, Left Col., para. 1):
PNG
media_image1.png
200
400
media_image1.png
Greyscale
(page 874, Scheme II).
In one example, the reaction mixture is further dissolve in acetone (5 mL). NaI (300 mg, 2 mmol) is added and the solution is stirred for 1 h at ambient temperature. The reaction mixture is dissolved in CH2Cl2 (10 mL) (page 876, Right Col., para. 2).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the oxidation solution comprising I2, pyridine, and water for synthesizing oligomeric compounds as taught by Maier et al. with NaI in view of Bergstrom because Bergstrom teaches that NaI has been used in the study to convert phosphite to phosphate. One would have been motivated to combine the oxidation solution comprising I2, pyridine, and water as taught by Maier et al. with NaI in view of Bergstrom because Bergstrom teaches the conversion of phosphite to phosphate using NaI, thereby, yielding predictable results. For the concentration of I2, one would have performed a routine experimentation to discover the best concentration of I2 to be used in the oxidation for the optimal reaction characteristics. Based on 5 mL of acetone and 10 mL of CH2Cl2, the concentration of NaI used in the reaction is calculated to be about 0.133 M. One would have performed a routine experimentation to discover the best concentration of NaI to be used in the oxidation for the optimal reaction characteristics. Moreover, the references do not teach any impurity. It is expected that the product contains minimal impurity. Therefore, one of the skills in the art would have had a reasonable expectation of success to combine the oxidation solution comprising I2, pyridine, and water for synthesizing oligomeric compounds as taught by Maier et al. with NaI in view of Bergstrom because Maier et al. teach the basic synthesis with oxidization solution comprising I2, pyridine, and water and Bergstrom teach the conversion of phosphite to phosphate, thereby, the inclusion of NaI will yield predictable results.
Claims 138 – 140 are rejected under 35 U.S.C. 103 as being unpatentable over Maier et al. (WO0047593A1) in view of Bergstrom (The Journal of Organic Chemistry, 1992, Vol. 57, Issue 3, page 873 – 876, Reference included with PTO-892) as applied to claims 125 – 137 and 142 – 145 above, and further in view of Prakash et al. (WO2014/179620A1).
b. Regarding claims 138 – 140, Maier et al. and Bergstrom teach the limitations discussed above. Maier et al. further disclose that phosphorothioate oligonucleotides are presently being used as antisense agents in human clinical trials for various disease states (page 2, lines 22 – 23).
However, these references do not teach the oligomeric compounds further comprise a conjugate group (claims 138), wherein the conjugate group comprises one or more N-acetyl galactosamine moieties with the following formula (V) (claims 139 – 140):
PNG
media_image2.png
336
468
media_image2.png
Greyscale
.
Prakash et al. teach oligomeric compounds with conjugate groups, wherein the oligomeric compounds are conjugated to N-acetylgalactosamine (Abstract). In certain embodiments, conjugated antisense compounds are provided having the structure (page 10, lines 1 – 4):
PNG
media_image3.png
432
576
media_image3.png
Greyscale
,
wherein the conjugate group is cell targeting moiety.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the oligomeric compounds formed as taught by Maier et al. and Bergstrom with the N-acetylgalactosamine moiety in view of Prakash et al. because Prakash et al. disclose that the oligomeric compound is an antisense compound, thereby, the combination of the claimed oligomeric compounds with the N-acetylgalactosamine moiety will yield predictable results for the same purpose. One would have been motivated to combine the oligomeric compounds formed as taught by Maier et al. and Bergstrom with the N-acetylgalactosamine moiety in view of Prakash et al. because Prakash et al. teach that the conjugate group is a cell targeting moiety, which is the benefit of incorporating the moiety to the oligomeric compounds. Therefore, one of the skills in the art would have had a reasonable expectation of success to combine the oligomeric compounds formed as taught by Maier et al. and Bergstrom with the N-acetylgalactosamine moiety in view of Prakash et al. because Maier et al. teach the basic synthesis with oxidization solution comprising I2, pyridine, and water, Bergstrom teach the conversion of phosphite to phosphate, and Prakash et al. teach that the known conjugate group that linked to an antisense compounds is specifically for cell targeting purpose.
Responses to Applicant’s Remarks
Applicant’s Remarks, filed July 25, 2025, have been fully considered and are found to be not persuasive.
Regarding the claims, Applicant argues that the examiner has resorted to impermissible hindsight in an attempt to cure the deficiencies of the cited documents. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Moreover, Maier et al. already recognize that oligonucleotide synthesis requires oxidation of P(III) intermediates to the P(V) state to yield stable phosphodiester, phosphorothioate, or boranophosphate linkages. Bergstorm teaches that NaI is known to convert P(III) to P(V). It is reasonable to combine the references, with the reasonable expectation of success, to achieve the desired P(V) state.
Applicant argues that the lack of awareness of the impurity in the prior art supports the nonobviousness of the claimed methods. Applicant brings up In re Omeprazole to support that evidence of a problem unrecognized in the prior art but discovered by Applicant must be considered in the obviousness analysis. However, Omeprazole is distinguishable from the instant application because Omeprazole involved a hidden degradation pathway not apparent to those skilled in the art. Reducing impurities and optimizing reaction conditions have always been the goals in chemical practice. Therefore, the alleged lack of an explicit impurity disclosure does not support nonobviousness of the claimed invention.
Applicant further argues that the claimed salt leads to fewer unwanted phosphate diester impurities. However, the results in the instant specification on pages 47 – 52 demonstrate that oxidizer 1 (0.05 M I2, 9:1 pyridine:H2O) is able to achieve the impurity as low as 1% upon aging. The data also shows that oxidizer 4 (0.05 M I2, 8:1:1 pyridine:NMI:H2O) with 1.25 hours gaining is able to achieve a low impurity of 1.6%, which is the same impurity obtained from using oxidizer 5 (0.05 M I2, 0.05 M NaI, 9:1 pyridine:H2O) aged 1.25 hours. This demonstrates that impurity reduction is not uniquely tied to the claimed salt. The alleged results therefore do not establish an unexpected property. Furthermore, the data obtained does not commensurate with the scope of claim as “aging time” is not recited in the claims.
Applicant argues that the combination of Maier et al. and Bergstorm would not have rendered the independent claim 125 obvious and Prakash et al. do not remedy the deficiencies of Maier et al. and Bergstorm because Prakash et al. do not teach and would not have suggested “a process for synthesizing….and water” as recited in claim 125. As the arguments regarding Maier et al. and Bergstorm are not persuasive, the argument regarding Prakash et al. is moot because it is relied on the nonobviousness of claim 125.
Conclusion
No claim is found to be 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 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 HOI YAN LEE whose telephone number is 571-270-0265. The examiner can normally be reached Monday - Thursday 7:30 - 17:30.
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, SCARLETT GOON can be reached at 571-270-5241. 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.
/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693