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
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed March 3, 2026. The amendment, filed March 3, 2026, is entered, wherein claim 1 is amended, claims 3 – 4,7, 9, 19, 21, 24 – 25, and 27 – 30 are canceled, and claims 13 – 18, 20, 22 – 23, 26, and 31 are withdrawn.
Claims 1 – 2, 5 – 6, 8, 10 – 18, 20, 22 – 23, 26, and 31 are pending in this application and claims 1 – 2, 5 – 6, 8, 10 – 12 are currently examined.
Priority
3. This application is a national stage application of PCT/CN2020/125164, filed October 30, 2020, which claims benefit of foreign priority document CN202010828506.7, filed August 18, 2020; this foreign priority document is not in English. Applicant filed a certified translation of the foreign priority document on October 21, 2025.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Objections
4. The objection of the abstract in the previous Office Action, mailed December 9, 2025, is withdrawn in view of the amended abstract.
Withdrawn Rejections
5. The rejection of claims 1, 5 – 6, and 8 – 12 in the previous Office Action, mailed December 9, 2025, under 35 U.S.C. 103 as being unpatentable over Wang et al. in view of Hayashi et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claim 2 in the previous Office Action, mailed December 9, 2025, under 35 U.S.C. 103 as being unpatentable over Wang et al. in view of Hayashi et al. as applied to claims 1, 5 – 6, and 8 – 12 above, and further in view of Ogata et al. has been considered and is withdrawn in view of the amended claim 1.
The following are new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed March 3, 2026, wherein claim 1 is amended, claims 3 – 4,7, 9, 19, 21, 24 – 25, and 27 – 30 are canceled, and claims 13 – 18, 20, 22 – 23, 26, and 31 are withdrawn. Previously and newly cited references have been used to establish the new grounds of rejection.
New 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 1 – 2, 5, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Horie et al. (EP3106519A1) in view of Chow et al. (US5656741) and Gosselin et al. (WO2009/140125A2).
a. Regarding claims 1 – 2, 5, 8, and 10, Horie et al. teach a method of cutting out RNA oligonucleotide from a solid phase carrier (para. [0001]). The method comprises a step of bringing the support carrying the RNA oligonucleotide in contact with an aqueous solution containing a alkylamine and a monovalent inorganic salt. The aqueous solution further comprises an alcohol (para. [0013]). The alkylamine is a primary alkylamine, such as butylamine (para. [0029]) and the alcohol is butanol (para. [0032]). The content of alcohol in the aqueous solution is preferably 1 – 80% by volume (para. [0033]). The volume ratio of alkylamine:alcohol used in the examples is 1:1 (para. [0057]). The disclosed method is able to suppress the production of a byproduct and increase the yield of the object RNA oligonucleotide (para. [0012]). In addition, Horie et al. disclose that cleavage with aqueous sodium hydroxide solution containing NaCl has also been used previously (para. [0005]). However, Horie et al. do not teach the claimed aminolysis solution comprising amino alcohol, the concentration of alkaline aqueous solution that is 2 – 10 M, and the volume ratio of the components.
Gosselin et al. teach an efficient and safer (easy to handle and environmentally less hazardous) protocol for cleavage and deprotection of synthetic oligonucleotides utilizing ethanolamine. The method cleaves the synthetic oligonucleotides from the solid support allowing the isolation and subsequent purification of the oligonucleotides (page 1, lines 19 – 24). Gosselin et al. teach that 10 mL of ethanolamine is used (page 4, line 19).
Chow et al. teach reagents that are useful for rapid processing of synthetic oligonucleotides, include a basic reagent for the cleavage and deprotection of the synthesized oligonucleotides from a support. The basic reagent optionally includes a wetting agent useful for the cleavage from lipophilic supports (Abstract). In a preferred embodiment, the basic reagent is provided in the form of a 2 M sodium hydroxide solution (Col. 6, lines 2 – 4). Using higher concentration of sodium hydroxide, the deprotection time can be shorten (Col. 10, lines 9 – 11). The wetting agents have the function of a accelerator of sodium hydroxide reactivity. The wetting agent is preferably added in an amount that is miscible with the basic solution yet sufficient to improve the wettability of the support and attached oligonucleotide (Col. 7, lines 55 – 58). Examples of suitable wetting agents includes alcohols and alkylamines, wherein the alkyl group is butyl (Col. 7, lines 60 – 63; Col. 8, lines 1 – 3). Chow et al. further teach that 0.5 mL of sodium hydroxide is used and about 5 volumes of reagent B for precipitation and neutralization follow.
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 modify the oligonucleotide cut-out composition of Horie et al., which teaches an aqueous solution containing an alkylamine and alcohol, wherein the alkylamine may be butylamine and the alcohol may be butanol, by further including an amino alcohol, such as ethanolamine, in view of Gosselin et al., and by employing an alkaline aqueous solution, such as aqueous sodium hydroxide at a concentration of 2 M further in view of Chow et al. because all of the cited references are directed to cleavage/deprotection of synthetic oligonucleotides from solid support and teach known reagents useful for that same purpose. One would have been motivated to combine these components in order to provide an oligonucleotide cleavage/deprotection composition having suitable cleavage rate, deprotection efficiency, and product purity because Horie et al. teach alkylamine/alcohol cut-out compositions that suppress byproducts and increase yield, Gosselin et al. teach that the utilization of ethanolamine in cleaving and deprotection processes results in an efficient method, and Chow et al. teach that the higher concentration of sodium hydroxide increase reaction rate. With respect to the claimed volume ratios, the relative amounts of alkylamine, alcohol, amino alcohol, and alkaline aqueous solution would have been result-effective variables that a person of ordinary skill in the art would have adjusted through routine experimentation to obtain suitable cleavage rate, deprotection rate, and oligonucleotide purity. Horie et al. teach that the alcohol content may vary broadly, for example 1 – 80% by volume, while Chow et al. teach that the wetting agent is added in an amount sufficient to improve wettability without interfering with the intended cleavage/deprotection function, and that increasing sodium hydroxide concentration increases cleavage/deprotection rate. Once the known alkylamine/alcohol oligonucleotide cut-out system of Horie et al. is further modified to include the known amino alcohol deprotection reagent of Gosselin et al. and the known alkaline aqueous cleavage reagent of Chow et al., one would have performed routine experimentation to discover the volume ratio of the components for the optimal cleavage and deprotection reaction based on the starting ratio and volume disclosed in Horie et al., Gosselin et al., and Chow et al.
One of ordinary skill in the art would have had a reasonable expectation of success to modify the oligonucleotide cut-out composition of Horie et al., which teaches an aqueous solution containing an alkylamine and alcohol, wherein the alkylamine may be butylamine and the alcohol may be butanol, by further including an amino alcohol, such as ethanolamine, in view of Gosselin et al., and by employing an alkaline aqueous solution, such as aqueous sodium hydroxide at a concentration of 2 M further in view of Chow et al. because it is well known to combine multiple reagents for the performing the same cleavage and protection reaction.
Claims 6 and 11 – 12 are rejected under 35 U.S.C. 103 as being unpatentable over Horie et al. (EP3106519A1) in view of Chow et al. (US5656741) and Gosselin et al. (WO2009/140125A2) as applied to claims 1 – 2, 5, 8, and 10 above, and further in view of Hayashi et al. (Polymer Journal, 1993, Vol. 25, Issue 5, page 481 – 488, cited in the previous Office Action mailed December 9, 2025).
b. Regarding claim 6 and 11 – 12, the references teach the limitations as discussed above.
However, these references do not teach that the amino alcohol is 5-amino-1-pentanol.
Hayashi et al. teach that 5-amino-1-pentanol is used in aminolysis reaction for preparing copolypeptides (Abstract).
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 substitute the ethanolamine as taught by Gosselin et al. with 5-amino-1-pentanol in view of Hayashi et al. because Gosselin et al. teach that an amino alcohol is useful for cleavage and deprotection of synthetic oligonucleotides from solid support and Hayashi et al. teach that 5-amino-1-pentanol, an amino alcohol, is a known aminolysis reagent. The prior art identify amino alcohols as a suitable class of reagents for aminolysis/deprotection. It would have been obvious to employ 5-amino-1-pentanol as a predictable alternative amino alcohol reagent in the same composition. One of ordinary skill in the art would have had a reasonable expectation of success to substitute the ethanolamine as taught by Gosselin et al. with 5-amino-1-pentanol in view of Hayashi et al. because the modification merely involves use of another known amino alcohol reagent and Hayashi et al. teach that 5-amino-1-pentanol is capable of performing aminolysis.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed March 3, 2026, have been fully considered and are found to be not persuasive.
Regarding Wang et al., Applicant argues that Wang et al. do not teach the inclusion of amino alcohol, an alkaline aqueous solution concentration of 2 – 10 M, and the claimed volume ratio of the components. Applicant explains that the amine is the active aminolysis component, the butanol is the reaction solvent, and the amino alcohol functions as both active component and solvent. Applicant further argues that the alkaline aqueous solution is present only as a catalyst to accelerate aminolysis and does not affect yield or quality. However, this argument is not moot because the new rejection does not rely on Wang et al. The new rejection is based on Horie et al., Gosselin et al., and Chow et al. Horie et al. teach an oligonucleotide cut-out composition containing an alkylamine and an alcohol, including butylamine and butanol for cleavage/deprotection of synthetic oligonucleotides from solid support. Gosselin et al. teach that an amino alcohol, such as ethanolamine, is useful for cleavage and deprotection of synthetic oligonucleotides from solid support. Chow et al. teach that an alkaline aqueous solution, such as sodium hydroxide, is useful for oligonucleotide cleavage/deprotection and that a concentration of 2 M is suitable. Thus, the claimed components are taught in the art for the same purpose, and the fact that Applicant characterizes each component as having a particular role does not distinguish over the combined teachings of references.
Applicant argues that Wang et al. fail to disclose amino alcohol and fails to provide any relevant technical inspiration to include an amino alcohol. Applicant also argues that the formula disclosed by Wang et al. differs from claim 1 because Wang et al. uses amine as the lowest volume component, whereas amine is the highest in claim 1. Applicant contends that the formulation disclosed by Wang et al. is different from the claimed formula. However, the arguments are moot because the new rejection no longer relies on Wang et al. As discussed above, Gosselin et al. disclose the missing amino alcohol teaching in the same oligonucleotide cleavage/deprotection field. It would have been obvious to use those known reagents together for the same purpose. The fact that the relative proportions differ from Wang does not render the claimed formulation unobvious because the relative amounts of these reagents are variables that would be adjusted to achieve suitable cleavage rate, deprotection efficiency, and product quality based on the disclosure of Horie et al., Gosselin et al., and Chow et al. as the starting point.
Applicant argues that the amine, butanol, amino alcohol, and alkaline aqueous solution cooperate with each other at a particular ratio to cleave the synthetic oligonucleotide, remove the protecting groups, and improve yield and purity, while a trace amount of alkaline aqueous solution catalyzes aminolysis and prevents the oligonucleotide from appearing white. Applicant concludes that the formula of claim 1 is not a conventional choice, and that the skilled artisan could not obtain the claimed component ratios from Wang et al. or would lack motivation and reasonable expectation of success in doing so. However, the argument is not persuasive. The examples do not establish that the recited ratio is critical. For example, the comparative evidence does not demonstrate that the claimed ratio is responsible for the improvement. Comparative example 1 does not differ from the working examples only by ratio. Instead, comparative example 1 changes multiple variables at the same time, including the amine component, the alcohol component, the absence of the claimed amino alcohol, and the alkaline aqueous solution concentration. Because multiple variables are changed, any reported difference in whitening, purity, or yield cannot reasonably be attributed to the claimed ratio alone.
Applicant argues that one skilled in the art would have had no motivation to arrive at the claimed 2 – 10 M concentration based on Wang et al. However, the argument is moot because the present rejection does not rely on Wang et al. Instead, Chow et al. teach aqueous sodium hydroxide for cleavage/deprotection of synthetic oligonucleotides and further teach a concentration including 2 M, as well as the principle that higher sodium hydroxide concentration shortens deprotection time. Therefore, Chow et al. provide direct support that base concentration is a variable affecting cleavage/deprotection rate. One of ordinary skill in the art would have been motivated to adjust the concentration of sodium hydroxide to obtain the desire reaction rate.
Regarding Hayashi et al., Applicant argues that Hayashi et al. uses a single aminolysis solution and therefore differs from the present application and Wang et al. Applicant concludes that one skilled in the art would have had no motivation to combine Hayashi with Wang et al. The argument is not persuasive because Hayashi et al. teach that 5-amino-1-pentanol is known in the art as an amino alcohol aminolysis reagent. As Gosselin et al. teach that an amino alcohol is useful in oligonucleotide cleavage/deprotection, it would have been obvious to use another known amino alcohol aminolysis reagent, such as 5-amino-1-pentanol because Hayashi et al. demonstrates that 5-amino-1-pentanol is operative in aminolysis chemistry.
Regarding Ogata et al., Applicant argues that Ogata et al. do not cure the deficiencies of Wang et al. and Hayashi et al. However, the argument is moot because the current rejection no longer relies on Wang et al. in view of Hayashi et al. and Ogata et al. The new rejection is based on Horie et al., Gosselin et al., and Chow et al. Horie et al. teach an oligonucleotide cut-out composition containing an alkylamine and an alcohol, including butylamine and butanol for cleavage/deprotection of synthetic oligonucleotides from solid support. Gosselin et al. teach that an amino alcohol, such as ethanolamine, is useful for cleavage and deprotection of synthetic oligonucleotides from solid support. Chow et al. teach that an alkaline aqueous solution, such as sodium hydroxide, is useful for oligonucleotide cleavage/deprotection and that a concentration of 2 M is suitable. Thus, the claimed components are taught in the art for the same purpose. The combination of Horie et al., Gosselin et al., and Chow et al. renders the claimed invention obvious.
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
Prosecution Insights