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 9, 2026. The amendment, filed March 9, 2026, is entered, wherein claims 1, 10, and 21 are amended, claim 24 is canceled, and claims 1 – 9 are withdrawn.
Claims 1 – 23 are pending and claims 10 – 23 are currently examined.
Priority
3. This application is a national stage application of PCT/JP2021/018075, filed May 12, 2021, which claims benefit of foreign priority document JP2020-084641, filed May 13, 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application is only pertinent when interference arises.
Withdrawn Rejections
4. The rejection of claims 10 – 11, 14, and 16 – 23 in the previous Office Action, mailed December 9, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6 – 8, and 14 – 17 of U.S. Patent No. 12378275B2 has been considered and is withdrawn in view of Applicant’s Remarks regarding the claimed inorganic porous support of claim 10 having silyl group (C) and further having silyl group (D).
The rejection of claims 10 – 11, 14, and 16 – 23 in the previous Office Action, mailed December 9, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2 and 8 – 12 of U.S. Patent No. 12377409B2 has been considered and is withdrawn in view of Applicant’s Remarks regarding the claimed inorganic porous support of claim 10 having silyl group (C) and further having silyl group (D).
The rejection of claims 10 – 11, 14, and 16 – 23 in the previous Office Action, mailed December 9, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6 – 8, and 14 – 17 of U.S. Patent No. 12371451B2 has been considered and is withdrawn in view of Applicant’s Remarks regarding the claimed inorganic porous support of claim 10 having silyl group (C) and further having silyl group (D).
The rejection of claims 10 – 11, 14, and 16 – 23 in the previous Office Action, mailed December 9, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8 – 9, and 11 - 14 of U.S. Patent No. 12162765B2 has been considered and is withdrawn in view of Applicant’s Remarks regarding the claimed inorganic porous support of claim 10 having silyl group (C) and further having silyl group (D).
The following are maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed March 9, 2026, wherein claims 1, 10, and 21 are amended, claim 24 is canceled, and claims 1 – 9 are withdrawn. 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 10 – 11, 14, and 16 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over Padmanabhan et al. (Tetrahedron Letters, 2004, Vol. 46, Issue 2, page 343 – 347, cited in the previous Office Action mailed December 9, 2025) in view of Crozals et al. (RSC Advances, 2012, Vol. 2, Issue 31, cited in the previous Office Action mailed December 9, 2025).
a. Regarding claims 10 – 11, 14, and 16 – 20, Padmanabhan et al., teach the synthesis of functionalization of solid support and such solid support can be readily loaded with nucleosides for use in oligonucleotide synthesis (Abstract). The reaction for functionalization and loading of nucleoside on controlled-pore-glass (CPG) for making compound 4 is shown below (page 344, Figure 1):
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. The figure shows the reaction sequences for functionalization and loading of CPG and involve (Path A): (a) reaction of CPG with 3-aminopropyltriethoxysilane to give the amino-functionalized CPG, (b) reaction of aminated support 1 with succinic anhydride to give carboxy-terminated CPG 2, and (c) reaction of 2 with nucleoside 3 to give the nucleoside loaded CPG 4 (page 343. Right Col., para. 2), wherein CPG 4 contains the claimed limitations of X01 as a bond with the inorganic porous body; Y01 as a bond with the inorganic porous body while a is 2 and b is 0; A01/A02 as a propylene group; B1/B2 as a hydrogen atom; and C1/C2 as a nucleoside with a succinyl linker in which the reactive group is protected. Padmanabhan et al. teach that amination may be done with amination reagent APDS to yield compound 6 (page 345, Figure 2; Table 2):
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.
Compound 6 contains the claimed limitation of P01 as a bond with the inorganic porous; K1/K2 as a methyl group; M1/M2 as a methylene group; and N1/N2 as a ethyl group with an amine substituent.
However, Padmanabhan et al. do not teach the pore diameter of an inorganic porous body.
Crozals et al. teach oligonucleotide solid-phase synthesis on controlled pore glass (Title). Crozals et al. teach that the pore diameter must be at least six times the diameter of the nanoparticle in order to maintain efficient synthesis of oligonucleotides in the synthesizer (Abstract). In one embodiment, Crozals et al. teach DNA solid-phase synthesis on 50 nm NPs supported on CPG with a pore diameter of 300 nm (page 11859, Left Col., para. 1).
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 compound 1 used in the reactions for functionalization and loading of CPG with compound 6 as taught by Padmanabhan et al. because Padmanabhan et al. teach that both compounds 1 and 6 have the exact same tail of CH2CH2CH2NH2, which is expected to react the same way under condition (ii) to yield CH2CH2CH2NHC(O)CH2CH2COOH. Such substitution would have been obvious because of the predictable results. One of ordinary skill in the art would have had a reasonable expectation of success to substitute compound 1 used in the reactions for functionalization and loading of CPG with compound 6 as taught by Padmanabhan et al. because such substitution in the disclosed reaction would have yielded predictable results. For the elected Z1, compound 6 has a structure of dimethyl group connecting to the silicon. Compounds that differ only by the presence or absence of an extra methyl group or two are homologues. Homologues are of such close structural similarity that the disclosure of a compound renders prima facie obvious its homologue. As was stated in In re Grose, 201 USPQ 57, 63, “The known structural relationship between adjacent homologues, for example, supplies a chemical theory upon which a prima facie case of obviousness of a compound may rest.” The homologue is expected to be preparable by the same method and to have generally the same properties. This expectation is then deemed the motivation for preparing homologues. Of course, these presumptions are rebuttable by the showing of unexpected effects, but initially, the homologues are obvious even in the absence of a specific teaching to add or remove methyl groups. See In re Wood, 199 USPQ 137; In re Hoke, 195 USPQ 148; In re Lohr, 137 USPQ 548; In re Magerlein, 202 USPQ 473; In re Wiechert, 152 USPQ 247; Ex parte Henkel, 130 USPQ 474; In re Jones, 74 USPQ 152, 154; In re Herr, 134 USPQ 176; Ex parte Dibella, 157 USPQ 59; In re Zickendraht, 138 USPQ 22; Ex Parte Fischer, 96 USPQ 345; In re Fauque, 121 USPQ 425; In re Druey, 138 USPQ 39; In re Bowers and Orr, 149 USPQ 570; Redox Technologies Inc. v. Pourreau, 73 USPQ2d 1435, 1451; In re Henze, 85 USPQ 261; In re Basell Poliolefine Italia S.P.A., 89 USPQ2d 1030 (“As homologs are presumptively obvious over known compounds…..”). In all of these cases, the close structural similarity between two compounds differing by one or two methyl groups was itself sufficient show obviousness. As was stated directly in THE GENERAL TIRE & RUBBER COMPANY v. JEFFERSON CHEMICAL COMPANY, INC., 182 USPQ 70 (1974): “If any structural change is obvious to one skilled in the art, a substitution of the next higher homolog would seem to be.” Note also In re Jones, 21 USPQ2d 1942, which states at 1943 “Particular types or categories of structural similarity without more, have, in past cases, given rise to prima facie obviousness”; one of those listed is “adjacent homologues and structural isomers”. Similar is In re Schechter and LaForge, 98 USPQ 144, 150, which states “a novel useful chemical compound which is homologous or isomeric with compounds of the prior art is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compounds.” Note also In re Deuel 34 USPQ2d 1210, 1214 which states, “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties.” See also MPEP 2144.09, second paragraph.
It would also 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 modified compound 4 with unreacted compound 6 on the same inorganic porous body because Padmanabhan et al. teach that these modification on CPG will yield a functionalized solid support for oligonucleotide synthesis. It would have been obvious for one of ordinary skill in the art to do this because both modifications are known in the prior art for the purpose of oligonucleotide synthesis, and it would have been obvious to combine them for the same use. One of ordinary skill in the art would have had a reasonable expectation of success to combine the modified compound 4 with unreacted compound 6 on the same inorganic porous body because it is well known to combine materials used for the same purpose.
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 CPG as taught by Padmanabhan et al. into a CPG with a pore size of 300 nm in view of Crozals et al. because Crozals et al. teach the pore size of CPG that is used for oligonucleotide solid-phase synthesis. One would have been motivated to modify the CPG as taught by Padmanabhan et al. into a CPG with a pore size of 300 nm in view of Crozals et al. because both references teach the solid support to be used for the same purpose. One of the ordinary skill in the art would have a reasonable expectation of success to modify the CPG as taught by Padmanabhan et al. into a CPG with a pore size of 300 nm in view of Crozals et al. because it is known in the art that CPG with a pore size of 300 nm is able to synthesize oligonucleotide.
Claims 12 – 13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Padmanabhan et al. (Tetrahedron Letters, 2004, Vol. 46, Issue 2, page 343 – 347, cited in the previous Office Action mailed December 9, 2025) in view of Crozals et al. (RSC Advances, 2012, Vol. 2, Issue 31, cited in the previous Office Action mailed December 9, 2025) as applied to claims 10 – 11, 14, and 16 – 20 above, and further in view of National Institute of Standards & Technology (Certificate of Analysis, 2012, cited in the previous Office Action mailed December 9, 2025).
b. Regarding claims 12 – 13 and 15, Padmanabhan et al. and Crozals et al. teach the limitations discussed above. Crozals et al. further teach that the amount of DNA obtained by the NP-CPG is 3.8 μmol/g (page 11860, Left Col., Table 1).
However, these references do not teach the cumulative pore volume and the specific surface area of the inorganic porous body as well as the I01/S01.
National Institute of Standards & Technology teaches that CPG with the diameter of 300 nm has a specific surface area of 10.73±0.68 m2/g or 10.99±0.68 m2/g depending on the measurement technique.
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 teachings of Padmanabhan et al. and Crozals et al. with National Institute of Standards & Technology to arrive at a CPG material having a pore size of 300 nm and a specific surface area of 10.73±0.68 m2/g or 10.99±0.68 m2/g as recited in the claimed invention. A person of ordinary skill in the art would have found it obvious to consult National Institute of Standards & Technology to determine or verify the expected physical properties, such as specific surface area, of a known CPG material having 300 nm pores, as disclosed in Crozals et al. This is because it is well-understood in the art that pore size and surface area are interrelated physical characteristics of porous materials, and determining or verifying such relationships would have been a matter of routine optimization. For the cumulative pore volume, it can be calculated based on the disclosed pore size and specific surface area using the equation of S = 4Vp/D, wherein S is specific surface area, Vp is pore volume, and D is pore diameter. The calculated pore volumes based on 10.73 m2/g and 10.99 m2/g are 0.805 mL/g and 0.824 mL/g, respectively. For I01/S01, it would be 0.35 based on the DNA amount and the specific surface area disclosed by Crozals et al. and National Institute of Standards & Technology. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine the teachings of Padmanabhan et al. and Crozals et al. with National Institute of Standards & Technology to arrive at a CPG material having a pore size of 300 nm and a specific surface area of 10.73±0.68 m2/g or 10.99±0.68 m2/g as recited in the claimed invention because the specific surface area is a predictable physical property related to the pore size of the material and it would have reasonably expected the resulting material to fall within the known and expected performance parameters for such pore sizes.
Claims 21 – 23 are rejected under 35 U.S.C. 103 as being unpatentable over Padmanabhan et al. (Tetrahedron Letters, 2004, Vol. 46, Issue 2, page 343 – 347, cited in the previous Office Action mailed December 9, 2025) in view of Crozals et al. (RSC Advances, 2012, Vol. 2, Issue 31, cited in the previous Office Action mailed December 9, 2025) as applied to claims 10 – 11, 14, and 16 – 20 above, and further in view of White (Humana Press, 1988, Vol. 4, cited in the previous Office Action mailed December 9, 2025).
c. Regarding claims 21 – 23, Padmanabhan et al. and Crozals et al. teach the limitations discussed above.
However, these references do not teach a nucleic acid production method by a phosphoramidite method.
White teaches the oligonucleotide synthesis, which starts with an appropriately base-protected nucleoside that also has its 5’-OH group protected with the dimethoxytrityl group and is coupled through its 3’-OH to controlled-pore glass support via a long-chain alkylamine arm and succinyl group. The elongation cycle for oligonucleotide synthesis, which consists of the following steps: (1) removal of the 5’-dimethoxytrityl group with dichloroacetic acid in dichloroethane; (2) coupling of the next monomer by adding the appropriate nucleoside 3’-O-phosphoramidite with the activating agent tetrazole; and (3) oxidation of the phosphite to phosphate with iodine/water. The elongation cycle is repeated until the oligonucleotide is completed (page 194, para. 2). When the synthesis is completed, the chain must be cleaved from the support and the base, phosphorus, and terminal 5’-OH-protecting groups removed (page 193, para. 1).
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 incorporate the functionalized CPG as taught by Padmanabhan et al. and Crozals et al. with the nucleic acid production by phosphoramidite method in view of White because Padmanabhan et al. teach the functionalized CPG for oligonucleotide synthesis and White teaches the method for oligonucleotide synthesis that involves CPG support. One would have been motivated to incorporate the functionalized CPG as taught by Padmanabhan et al. and Crozals et al. with the nucleic acid production by phosphoramidite method in view of White because the functionalized CPG taught by Padmanabhan et al. is used in oligonucleotide synthesis. This incorporation would yield predictable results. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to incorporate the functionalized CPG as taught by Padmanabhan et al. and Crozals et al. with the nucleic acid production by phosphoramidite method in view of White because it is known in the art that oligonucleotide synthesis involves CPG and Padmanabhan et al. teach the functionalized CPG for the same purpose.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed March 9, 2026, have been fully considered and are found to be not persuasive.
Regarding the rejection, Applicant argues that claim 10 is amended to no longer recite embodiments of Q01 and R01 that include an amino group, a monoalkylamino group having 1 to 12 carbon atoms, and a dialkylamino group having 2 to 12 carbon atoms. Thus, an inorganic porous body having compounds 4 and 6 as disclosed in Padmanabhan et al. no longer fails within the scope of the amended claim 10. However, the argument is not persuasive. As discussed above, Padmanabhan et al. teach that the nucleoside loaded CPG contains the claimed limitations of X01 as a bond with the inorganic porous body; Y01 as a bond with the inorganic porous body while a is 2 and b is 0; A01/A02 as a propylene group; B1/B2 as a hydrogen atom; and C1/C2 as a nucleoside with a succinyl linker in which the reactive group is protected and compound 6 contains the claimed limitation of P01 as a bond with the inorganic porous; K1/K2 as a methyl group; M1/M2 as a methylene group; and N1/N2 as a ethyl group with an amine substituent. Amending the embodiments of Q01 and R01 do not overcome the rejection.
Regarding Padmanabhan et al., Applicant argues that Padmanabhan et al. do not disclose having two different types of silyl groups on the same support. However, the argument is not persuasive. As discussed above, it would also 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 modified compound 4 with unreacted compound 6 on the same inorganic porous body because Padmanabhan et al. teach that these modification on CPG will yield a functionalized solid support for oligonucleotide synthesis. It would have been obvious for one of ordinary skill in the art to do this because both modifications are known in the prior art for the purpose of oligonucleotide synthesis, and it would have been obvious to combine them for the same use. One of ordinary skill in the art would have had a reasonable expectation of success to combine the modified compound 4 with unreacted compound 6 on the same inorganic porous body because it is well known to combine materials used for the same purpose.
Furthermore, Applicant states that the claimed invention was created based on the finding that, by substituting a silanol group on the surface of an inorganic porous support with a specific silyl group during the synthesis of nucleic acid, the formation of byproducts in the production of an oligonucleic acid product is suppressed. Applicant refers to the superior effect of the claimed inorganic porous support. Applicant explains that the inorganic porous support used in Example 11 to 15 showed a lower relative 10% width compared to the inorganic porous support used in Comparative Example 2 and reference Examples 9 to 12, and the obtained oligonucleic acid had higher purity. However, the argument is not persuasive. The data is limited to a narrow set of specific embodiments and does not reasonably establish that the improvement would extend across the full scope of claim 10. For example, the data of Table 1 is directed to a limited number of tested supports under a limited set of conditions, whereas claim 10 encompasses a much broader genus of inorganic porous supports and silyl groups. Thus, the results are not commensurate in scope with the full breadth of the claimed invention. Furthermore, the comparisons to reference Examples 9 to 12 involves multiple variables differing among the compared examples. The data do not clearly show that the improvement is attributable to the claimed features.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the maintained / modified 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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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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