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 .
This application is the national stage entry of PCT/US21/33945, filed 24 May 2021; and claims benefit of provisional application 63/029,387, filed 22 May 2020.
Claims 89-106 and 109-117 are pending in the current application. Claims 97-98, 101, and 114-117, drawn to non-elected species, are withdrawn. Claims 89-96, 99-100, 102-106, and 109-113 are examined on the merits herein.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 89-106 and new claims 109-117, in the reply filed on 10 Sep 2025 is acknowledged.
Claims 107-108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 Sep 2025.
Withdrawn claims 107-108 are canceled in Applicant’s preliminary amendment, filed 10 Sep 2025.
Applicant’s election of species of
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in the reply filed on 10 Sep 2025 is acknowledged.
Claims 97-98, 101, and 114-117 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election of species was made in the reply filed on 10 Sep 2025.
Search and examination has expanded to include the method comprising contacting a compound having the structure of formula M-II of
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Claim Rejections - 35 USC § 112
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.
Claims 89-96, 99-100, 102-106, and 109-113 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.
Claim 89 recites at the top of the second page “LPS is a L, e.g., a covalent bond;”. The phrase “e.g.” or "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In this case it is unclear of the exemplary language limits this aspect of LPS to a different scope than the entire definition of L which follows. Claims 90-96, 99-100, 102-106, and 109-113 depend from claim 89 and do not clarify this definition of LPS.
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Stetsenko et al. (US 2017/0362270, published 21 Dec 2017, cited in PTO-892) in view of Shimizu et al. (9,598,458, issued 21 Mar 2017, provided by Applicant in IDS filed 21 Aug 2023).
Stetsenko et al. teaches modified oligonucleotides that contain one or more of the phosphate groups substituted at phosphorus and methods for their synthesis (abstract) Stetsenko et al. teaches the modified oligonucleotides have improved cell uptake and broadly speaking the oligonucleotide analogues are in the class of phosphoryl imines and analogues thereof, for example, phosphoryl guanidines (page 2, paragraphs 21-28). In one embodiment the modification is performed using 2-azido-4,5- dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate as the reagent (example 27 at page 24, paragraphs 384-387), addressing the elected species of compound AZ-1. Stetsenko et al. teaches the synthesis of the compounds using general Procedure B, comprising immersing a solid support to which a protected oligonucleotide or protected modified oligonucleotide containing said phosphorous acid derivative is attached, in a mixture containing said organic azide, a solvent, and, optionally, a silylating reagent and a base; and repeating steps (ii) to (iv) of Procedure A, where step (iii) of Procedure A is continuing solid-phase oligonucleotide synthesis according to desired protocol until the next desired position of modification (page 12, paragraphs 183 to 192), addressing the method to comprise a coupling step and the step of contacting a first compound with a second compound comprising a hydroxyl group or amino group. The compound may be a modified nucleotide or oligonucleotide (page 4, paragraph 44-46).
Stetsenko et al. does not specifically teach the method comprising contacting a compound having the structure of formula M-II (claim 89).
Shimizu et al. teaches a chiral reagent that is used to synthesize stereocontrolled phosphorus atom-modified oligonucleotide derivatives (column 1, line 5). Shimizu et al. teaches the working example of the oxazaphospholidine monomer 22a
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(example 64 at column 59, lines 5-40), addressing the claimed formula M-II where the BA and SU correspond to the elected species, LPS is O, PL is P, XN and XM are N and O, Ring M is the five-membered ring including two RM1 groups, one of which is a substituted arylaliphatic group and one of which forms a ring with the XN or XM group.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Stetsenko et al. in view of Shimizu et al. in order to improve the method of Stetsenko et al. in the same manner as taught in Shimizu et al. One of ordinary skill in the art would have been motivated to combine Stetsenko et al. in view of Shimizu et al. with a reasonable expectation of success because Shimizu et al. teaches it is desired to synthesize stereocontrolled phosphorus atom-modified oligonucleotide derivatives, and Stetsenko et al. teaches their method encompasses the reaction with protected modified oligonucleotides. Therefore it would have been obvious to improve the method of making modified oligonucleotides taught by Stetsenko et al. to synthesize stereocontrolled phosphorus atom-modified oligonucleotide derivatives by improving the method in the same way taught by Shimizu et al.
Allowable Subject Matter
Claims 91-96, 99-100, 102-106, and 109-113 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art to claims 91-96, 99-100, 102-106, and 109-113 is deemed to be Stetsenko et al. (US 2017/0362270, published 21 Dec 2017, cited in PTO-892) in view of Shimizu et al. (9,598,458, issued 21 Mar 2017, provided by Applicant in IDS filed 21 Aug 2023) further in view of Knouse et al. (Science, 2018, 361, p1234-1238, cited in PTO-892) and Stec et al. (Nucleic Acids Research, 1991, 19(21), p5883-5888, cited in PTO-892).
Stetsenko et al. in view of Shimizu et al. teaches as above.
Stetsenko et al. in view of Shimizu et al. does not specifically teach the method wherein
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is
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(claim 91)
Knouse et al. teaches the state of the art before the effective filing date of the invention regarding stereocontrolled installation of the chiral motif in phosphorothioate nucleotides (page 1 of 5, abstract). Knouse et al. teaches three coupling paradigms have traditionally been employed to facilitate P–O bond formation, each relying on cumbersome P(III)-based reagent strategies. Coupling paradigm iii uses a phosphoramidate containing a P(III)-centered chiral auxiliary to control the phosphorous stereochemistry having general structure
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. Coupling paradigm ii relies on a similar strategy that begins with a P(III)-oxathiaphospholane loading reaction having general structure
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(page 1 of 5, middle column; page 2 of 5, figure 1). Knouse et al. teaches a P(V)-based platform bypassing the P(III) entirely, and the example of forming the reagent
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(page 3 of 5, figure 2; page 4 of 5, figure 3).
Stec et al. teaches synthesis and separation of diastereoisomerically pure 5'-O-DMT-nucleoside 3'-O-(2-thio-1,3,2-oxathiaphospholane) allows their use as synthons in DBU-catalyzed reaction with the 5'-hydroxyl function of solid-support-bound nucleoside moiety (page 5883, abstract). Stec et al. teaches the reaction of appropriately protected nucleosides with 2-N-diisopropylamino-1,3,2-oxathiaphospholane in the presence of tetrazole as catalyst. Without isolation, the resultant nucleoside 3'-O-[1,3,2-oxathiaphospholanes]were oxidized by means of elemental sulfur, resulting in nucleoside 3'-O-[2-thio-1,3,2-oxathiaphospholanes]
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(page 5884, left column, paragraph 3 and figure 1).
It would not have been obvious to one of ordinary skill in the art before the effective filing date to combine Stetsenko et al. in view of Shimizu et al. further in view of Knouse et al. and Stec et al. in a manner that arrives at the claimed method. While Knouse et al. teaches coupling paradigms
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and
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are known equivalents in the art of synthesis of nucleotides, Knouse et al. citing Stec et al. suggests one of ordinary skill in the art combining Stetsenko et al. in view of Shimizu et al. further in view of Knouse et al. and Stec et al. would have been motivated to contact the oxidized compound
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with the azide in the method of Stetsenko et al. This teaching differs from the claimed invention because the claimed invention recites contacting the compound of formula M-II with a compound of formula AZ-1, where the variable PL in formula M-II is P. In contrast, the prior art is asserted to make obvious the method where the variable PL in formula M-II is P(=S). Therefore the closest prior art does not teach or fairly suggest each and every limitation of the claimed invention.
Conclusion
No claim is currently in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan S Lau whose telephone number is (571)270-3531. The examiner can normally be reached Monday-Friday 9a-5p Eastern.
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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.
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/JONATHAN S LAU/Primary Examiner, Art Unit 1693
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