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 .
Election/Restrictions
Applicant's election with traverse of Group I; and
the elected species of formula (I) known as 2-phenylisothiazolo[5,4-b]pyridin-3(2H)-one (also known in the specification as compound (Ic-1), on pg. 79, first recited compound) which is depicted as,
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, in the reply filed on February 23, 2026 is acknowledged.
The traversal of the restriction is on the grounds that:
(A) the Office did not adequately demonstrate groups I and II as claimed are independent and distinct, as the restriction had simply stated a conclusion, see Election/Restriction, pg. 3, paragraph 1; and
(B) a search on all the claims would not impose a serious burden on the Office, see Election/Restriction, pg. 3, paragraph 4.
With respect to Applicant’s arguments (A)-(B), the Examiner noted in the restriction/election mailed December 22, 2025 that inventions I and II are unrelated by different designs and modes of operation, as invention I is drawn to a method of producing an oligonucleotide; while invention II is drawn to a compound represented by formula (In).
Additionally, the Examiner noted invention I does not require the compound represented by formula (In) of invention II.
The Examiner’s reasoning is supported by the recitations of claim 1 of invention I and claim 27 of invention II themselves, as claim 27 depicts formula (In) as
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, which the Examiner notes potentially correspond to formula (I) recited in claim 1 of invention I, when X1 of formula (I) is -N(-R3)-.
However, the Examiner additionally notes recited in claim 1, lines 8-9 and claim 12, pg. 200, last line of the page – pg. 201, first line of the page, is the phrase “X1 is a single bond, a sulfur atom, an oxygen atom, -S(=O)2- or -N(-R3)-“.
Therefore, the recitation of “or” as discussed above is reasonably interpreted by the Examiner to mean X1 is selected from the recited Markush group and therefore, formula (I) of claim 1 within invention I does not require formula (In) of claim 27 within invention II as discussed above.
Therefore, Applicant’s arguments (A)-(B) have been fully considered but are not found persuasive.
Additionally, the traversal of the election of species is on the grounds that the Office has not provided any reasons or examples to support a conclusion that the species are indeed patentably distinct, see Election/Restriction, pg. 5, paragraph 2.
This is not found persuasive because elected invention I, as discussed above, recites formula (I) as the oxidant to be used in the method recited within independent claims 1 and 12.
Moreover, as evidenced by both independent claims 1 and 12 themselves, each claim recites formula (I) which comprise the variables X1, R1 and R2; and when X1 is chosen as required by each claim from the Markush group as discussed above, then formula (I) further recites and requires specific structural limitations which are not necessarily shared by each member of the Markush group as recited within each of independent claims 1 and 12 as discussed above.
Therefore, Applicant’s argument has been fully considered but is not found persuasive.
Thus, in view of the foregoing reasons above, the requirement is still deemed proper and is therefore made FINAL.
Claims 7-8, 18-19 and 27-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species or invention where applicable, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on February 23, 2026.
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 11/07/2023 has been considered by the Examiner inasmuch as foreign documents have been submitted into the file wrapper in English.
Claim Status
The claim set filed August 11, 2023 has been entered. Claims 7-8, 18-19 and 27-28 are withdrawn from further consideration as being drawn to either a nonelected species or invention where applicable.
Thus, claims 1-6, 9-17 and 20-26 as amended are examined on the merits herein.
Claim Objections
Claims 10 and 12 are objected to because of the following informalities:
(I) Claim 10 recites the following phrases:
“a phosphite ester bond or a phosphonate ester bond”, see lines 2-3;
“an oligonucleotide precursor having a phosphite ester bond”, see line 4; and
“an oligonucleotide precursor having a phosphite ester bond”, see line 8.
The Examiner notes the recited limitations of “a phosphite ester bond”, “a phosphonate ester bond” and/or “an oligonucleotide precursor” are all first recited in claim 1, lines 2-3; which the Examiner further notes claim 10 depends from claim 1.
Accordingly, to promote clarity the Examiner suggests each instant of the article “a” or “an” above be replaced with the word “the” to properly reference each limitation which is first recited in claim 1.
The Examiner also encourages the Applicant review the entire claim set to see if there are additional instances where previously recited limitations contain the article “a” or “an” before the limitation “a phosphite ester bond”, “a phosphonate ester bond” and/or “an oligonucleotide precursor”.
(II) Claim 12 recites the phrase “an one-pot synthesis”, which the Examiner notes is grammatically incorrect when referring to said synthesis. Thus, to promote clarity the Examiner suggests replacing the article “an” with the article “a” as discussed above.
Appropriate correction is required.
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.
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.
(I) Claims 1-6, 9-17, 20-23 and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Hirai et al. (Published 04 October 2018, US-20180282365-A1, IDS filed 11/07/2023) in view of Greene et al. (Published July 1975, Nucleic Acids Research, Vol. 2, Issue 7, pp. 1123-1128, PTO-892) and Liebeskind et al. (Published 08 November 2018, US-20180318818-A1, IDS filed 11/07/2023).
Regarding claims 1-6, 9-17, 20-23 and 25-26, Hirai teaches a method for producing an oligonucleotide comprising the following steps (1), (3), (4) and (6) (e.g. the method, required in claim 12, line 1 and claim 1), see paragraph [0018];
(1) condensing, in a non-polar solvent (e.g. condensing in a solution containing a non-polar solvent, claim 12, pg. 200, line 6), see paragraph [0020];
a nucleoside, nucleotide or oligonucleotide (b) wherein a 3’-hydroxy group or a 3’-amino group is phosphoramidited and a 5’-hydroxy group is protected by a temporary protecting group removable under acidic conditions (e.g. the nucleoside, nucleotide or oligonucleotide (b), required in claim 12, pg. 200, lines 2-5), see paragraph [0021]; and
a substituted nucleotide or oligonucleotide (α) wherein a 5’-hydroxy group is not protected, one hydroxy group of a 3’-phosphoric acid group is replaced by -OLn1-OH, wherein Ln1 is an organic group, the hydroxy group of -OLn1-OH is protected by a protecting group unremovable under acidic conditions but removable under basic conditions, see paragraph [0023]; and wherein said protecting group unremovable under acidic conditions but removable under basic conditions of the substituted nucleotide or oligonucleotide (α) is preferably a protecting group having a linear aliphatic hydrocarbon group having carbon atoms of not less than 10 or an organic group having at least one aliphatic hydrocarbon group having one or more branched chains and having a total carbon number of not less than 15 and not more than 300 (hereinafter sometimes to be abbreviated as an “anchor”), see paragraph [0256]; wherein the anchor imparts hydrophobicity to the substituted nucleotide or oligonucleotide (α) (e.g. the nucleotide or oligonucleotide (a), required in claim 12, pg. 200, lines 1-2), see paragraph [0257];
by adding the nucleoside, nucleotide, oligonucleotide (b) to a reaction solution comprising the substituted nucleotide or oligonucleotide (α) to give a reaction solution comprising a phosphite triester product (c) wherein the 5’-hydroxy group is protected by the temporary protecting group removable under acidic conditions (e.g. the oligonucleotide precursor, required in claim 10, lines 4-7 and the oligonucleotide precursor (c), required in claim 12, pg. 200, lines 7-10), see paragraph [0023];
the method further comprises the following step (2) after step (1) and before step (3), see paragraph [0034]; where step (2) adds a quencher to the reaction solution after condensation (e.g. step (2), required in claim 12, pg. 200, lines 11-14), see paragraph [0035]; and wherein Table 1 exemplifies water as the quencher (e.g. required in claim 20), see pg. 47, Table 1;
(3) oxidizing or sulfurizing the phosphite triester product (c) by adding an oxidant or a sulfurizing agent to the reaction solution comprising the phosphite triester product (c) to give a reaction solution comprising an oligonucleotide (d) wherein the 5’-hydroxy group is protected by the temporary protecting group removable under acidic conditions (e.g. the oligonucleotide (d), required in claim 12, pg. 200, lines 17-20), see paragraph [0024]; and wherein Table I teaches oxidation is performed in the presence of water (e.g. required in claim 9) as exemplified when the oxidant is selected as iodine in the presence of water and pyridine, see pg. 47, Table I.
(4) removing the temporary protecting group of the 5’-hydroxy group by adding an acid to the reaction solution after the oxidation or sulfurization to give a reaction solution comprising an oligonucleotide (e) wherein the 5’-hydroxy group is not protected (e.g. step (5), required in claim 12, pg. 200, lines 23-27), see paragraph [0025];
(5) neutralize the acid used in step (4) after step (4) (deprotection) with a base which may be added to the reaction solution (e.g. a base, required in claim 25), see paragraph [0712]; and
(6) add a polar solvent to the reaction solution comprising the oligonucleotide (e) and purifying the oligonucleotide (e) by solid-liquid separation or extraction, (e.g. step (7), required in claim 12, pg. 200, lines 28-30), see paragraph [0026].
Hirai defines the term “oligonucleotide” means a compound wherein one or more nucleotides are bonded to a nucleoside; and the term also encompasses phosphorothioate-type oligonucleotides where the oxygen atom of the phosphoric acid group is replaced by a sulfur atom (e.g. the oligonucleotide precursor, required in claim 11 and claim 26), see paragraph [0201].
Although, Hirai does not teach (a) quencher (ii) for the oxidant is added to the solution after step (3) to quench the oxidant, see claim 12, pg. 200, lines 21-22; and (b) the oxidant, required in claim 12, pg. 200, lines 31.
However, in the same field of endeavor of oligonucleotide synthesis, with respect to limitation (a), Hirai further teaches step (3) (oxidation or sulfurization) and step (4) (deprotection) are performed after step (1) (condensation) to suppress production of a byproduct in steps (3) and (4), see paragraph [0686].
Additionally, Greene teaches formation of internucleotide 3’-5’ phosphoramidite links, see pg. 1123, title.
Greene teaches the stepwise synthesis of oligomers by means of triphenylphosphine (e.g. the quencher (ii), required in claims 21-23) and dipyridyl disulfide, see pg. 1123, abstract.
Greene teaches the triphenylphosphine-dipyridyl disulfide couple was chosen as a condensing agent, see pg. 1124, results, paragraph 1.
It would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have added a quencher (ii) before step (5) and after step (3) as required in claim 12 into the method of Hirai discussed above, by using triphenylphosphine as taught by the oligonucleotide synthesis of Greene above as part of a condensing agent with the oxidant as taught by Hirai above in order to perform the oligonucleotide synthesis as taught by Hirai above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results.
One of ordinary skill in the art would have had a reasonable expectation of success to have made such an addition as discussed above in order to suppress production of unwanted byproducts after the oxidation step (3) and before the deprotection step (4) as taught by Hirai above. One of ordinary skill in the art would have had a reasonable expectation of success to have incorporated the teachings of Greene as discussed above into the method of Hirai above, as both Hirai and Greene are drawn to methods of oligonucleotide synthesis; Greene teaches the use of a condensing agent comprising triphenylphosphine; and Hirai teaches the use of a quencher during oligonucleotide synthesis to suppress production of byproducts as discussed above.
Additionally, in the same filed of endeavor of coupling methods using catalytic molecules, with respect to limitation (b), Liebeskind teaches redox dehydration coupling catalysts and methods related thereto, see title.
Liebeskind teaches catalyzing a coupling reaction comprising mixing a) a compound comprising a hydroxy group, b) a PR3, wherein PR3 is a trisubstituted phosphine, c) a nucleophile, and d) a catalytic molecule such as a catalytic heterocycle comprising two bonded heteroatoms wherein one heteroatom is a nitrogen and the second heteroatom is not nitrogen, under conditions such that a compound is formed comprising the nucleophile in place of the hydroxy group, see paragraph [0016].
Liebeskind exemplifies the catalyst has a sulfur nitrogen heterocycle known as a benzoisothiazolone or derivative thereof, see paragraph [0108].
Liebeskind further exemplifies in Figure 3 the catalytic benzoisothiazolones includes the following structure,
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, see Figure 3, third line, second recited structure. The Examiner notes the exemplified benzoisothiazolone above is the elected species of Formula (I) discussed above and is recited in claims 1-6 and 12-17.
Liebeskind teaches catalytic molecules disclosed herein are useful as catalysts in the transformation of hydroxy group containing compounds to esters, see paragraph [0014].
It would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have used the exemplified catalytic benzoisothiazolone of Liebeskind as the oxidant in the condensation reaction within the method of oligonucleotide synthesis of Hirai above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to have made the addition as discussed above in order to use the exemplified catalytic benzoisothiazolone of Liebeskind as discussed above as the oxidant of Hirai also discussed above in order to transform the phosphite triester product (c) of Hirai to produce the oligonucleotide (d) of Hirai within the method of Hirai above. One of ordinary skill in the art would have had a reasonable expectation of success to have made the addition as discussed above because Liebeskind teaches catalytic molecules disclosed herein are useful as catalysts in the transformation of hydroxy group containing compounds to esters as discussed above.
With respect to limitations (i) “one-pot synthesis”, required in claim 12, lines 1-2; and (ii) “oligonucleotide (d) having a phosphate ester bond”; the Examiner reasonably interprets these limitations are physical limitations when performing the method of claim 12. Since the combination of Hirai, Greene and Liebeskind teach the method of claim 12, including all method steps and structural limitations required of the method recited within claim 12, the physical limitations (i) and (ii) are met by the combined teachings of Hirai, Greene and Liebeskind as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included limitations (a)-(b) as taught by Greene and Liebeskind, respectively, into the method of Hirai as discussed above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to include limitations (a)-(b) into the method of Hirai in order to perform the method taught by Hirai as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success to include limitations (a)-(b) as discussed above into the method of Hirai above, because Hirai, Greene and Liebeskind are all drawn to condensation reactions as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(II) Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Hirai et al. (Published 04 October 2018, US-20180282365-A1, IDS filed 11/07/2023), Greene et al. (Published July 1975, Nucleic Acids Research, Vol. 2, Issue 7, pp. 1123-1128, PTO-892) and Liebeskind et al. (Published 08 November 2018, US-20180318818-A1, IDS filed 11/07/2023) as applied to claims 1-6, 9-17, 20-23 and 25-26 above, and further in view of Mazur et al. (Published 26 June 2014, US-20140179875-A1, IDS filed 11/07/2023).
Hirai, Greene and Liebeskind address claims 1-6, 9-17, 20-23 and 25-26 as written above. Hirai further teaches the use of aniline or more preferably 2,6-dimethylaniline in suppressing side reactions in between step (4) (deprotection) and step (3) (oxidation or sulfurization), see paragraphs [700] and [0706]. Hirai exemplifies when DDTT is used as the sulfurizing agent a side reaction occurs during step (4) (deprotection) where a decomposition product of DDTT is added to a 5’-hydroxy group, and wherein thereafter the condensation reaction is inhibited, see paragraph [0700].
Although, Hirai does not teach the use of either aniline or 2,6-dimethylaniline after the oxidation step as required in claim 24.
However, in the same filed of endeavor of oligonucleotide synthesis, Mazur teaches deprotection to yield a phosphorothioate oligonucleotide, see paragraph [0101]; wherein the deprotection may be accomplished by treating a protected nucleotide with a substituted or unsubstituted aromatic amine, for example a substituted aniline, wherein a suitable aromatic amine includes 2,6-dimethylamine, see paragraph [0106].
It would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have included an aromatic amine, such as aniline or 2,6-dimethylaniline as taught by Mazur above, into the oligonucleotide synthesis as taught by Hirai above as combining prior art elements according to known methods to yield predictable results.
One of ordinary skill in the art would have been motivated to use the teachings of Mazur in order to deprotect and yield a phosphorothioate oligonucleotide, as the Examiner particularly notes the oligonucleotide synthesis method of Hirai above includes either an oxidation or sulfurization step before deprotection as discussed above and wherein Hirai also teaches the term “oligonucleotide” also encompasses phosphorothioate-type oligonucleotides. One of ordinary skill in the art would have had a reasonably expectation of success to have incorporated the teachings of Mazur as discussed above into the oligonucleotide synthesis method as taught by Hirai above; because both Hirai and Mazur use aromatic amines, such as aniline or 2,6-dimethylaniline, in oligonucleotide synthesis; and wherein Mazur specifically teaches use of aromatic amines within the deprotection step as discussed above.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated the teachings of Mazur as discussed above into the oligonucleotide synthesis method of Hirai above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to incorporate the teachings of Mazur into the method of oligonucleotide synthesis taught by Hirai above, in order to deprotect and yield an oligonucleotide with both phosphate ester and phosphorothioate ester bonds produced by the method of Hirai above. One of ordinary skill in the art would have had a reasonable expectation of success to have incorporated the teachings of Mazur into the method of Hirai above, because Mazur teaches use of aromatic amines, exemplifying aniline or 2,6-dimethylaniline, for deprotection and yield of a phosphorothioate oligonucleotide as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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