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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 19, 2026 has been entered.
Status of Claims/Rejections
Claims 1-13 and 15-31 are currently pending in the instant application. Claims 3, 16, and 23-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Accordingly, claims 1-2, 4-13, 15, 17-22, and 31 are under examination on the merits in the instant application.
Any rejections not repeated in this Office action are withdrawn, and the following rejections are the only rejections applied in this application.
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.
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, 4-13, 15, 17-22, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Shchepinov et al. (US 6,455,071 B1, of record) in view of Qu et al. (Applied Materials & Interfaces, 2017, 9:20324-20329, of record) and Radovic-Moreno et al. (PNAS, 2015, 112:3892-3897, of record).
Shchepinov teaches making an “oligofunctionalised” dendritic nucleic acid composition comprising “a multimeric structure having branched units” via “doubling, trebling or more, branching synthons” with different groups, “thereby increasing the available variety of functionalities which can be displayed on the surface.” See columns 1-2 and 5.
Shchepinov teaches that the dendritic nucleic acid composition includes “oligonucleotide dendrimers” comprising “components carrying oligonucleotides of different sequence” and that “the branched molecules which are the subject of the present invention offer novel ways of presenting multiple ligands with different geometries.” See column 6.
Shchepinov teaches that the second generation of the oligonucleotide dendrimer synthesized using trebling synthons produces “9” oligonucleotide branches. See column 13, lines 21-25. See also the following in Figure 6 as reproduced below.
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See also the following in Figure 6 as reproduced below.
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Shchepinov does not teach that the oligonucleotide dendrimers are immunostimulatory or TLR9 agonists, nor does Shchepinov teach that the dendrimer is “oligofunctionalised” with an antigen.
Qu discloses a DNA dendrimer comprising a stem oligonucleotide (“T”) linked to branched oligonucleotides (“Y2”) via a Y-shaped linker DNA (“Y1”), wherein the branched oligonucleotides comprise “single-stranded and double-stranded CpG ODNs” and further comprises a “TAT peptide”, which is “one of the outstanding cell penetrating peptides”, wherein the TAT peptide “was attached to DNA dendrimer in order to enhance the cell membrane permeability of the nanocarriers and accumulation to endosomes.” See pages 20325-20326; Figure 1.
Qu teaches, “Antigens and stimulatory peptides can also be loaded by this carrier and codelivered to realize improve[d] immunogenicity. DNA nanostructure/CpG ODNs system, such as CpG/doxorubicin-encapsulated DNA hydrogels or CpG/antigen-loaded DNA tetrahedral carriers, have been applied in vivo and elicited a strong, specific and long-lasting immune response.” (emphasis added). See page 20328.
Radovic-Moreno teaches making a spherical nucleic acid comprising a plurality of immunostimulatory TLR agonists (e.g., “TLR9” agonist) oligonucleotides (e.g., “PS CpG 1826”) and/or immunoregulatory TLR antagonist oligonucleotides, wherein the spherical nucleic acid structures “outperform linear nonlipidated phosphodiester deoxynucleic acids due to a rapid cellular up-take, predominant accumulation in endosomes, and increased resistance to nucleases”, wherein the spherical nucleic acids are “taken up into immune cells and reside in endosomes where they modulate toll-like receptor (TLR) activity.” See pages 3896-3897; Figures 1A-1B.
It would have been obvious to one of ordinary skill in the art before the effective filing date to incorporate “single-stranded and double-stranded CpG ODNs” as well as cell penetrating peptides, antigens, and/or stimulatory peptides into the unbranched stem as well as at least one branched oligonucleotide in Shchepinov’s “oligofunctionalised” “multimeric structure having branched units” of 6 or “9” oligonucleotides linked via a trebler moiety. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to make multi-functional “oligonucleotide dendrimers” comprising “available variety of functionalities” for providing “strong, specific and long-lasting immune response”, because Shchepinov’s “oligonucleotide dendrimers” comprising a stem oligonucleotide and branched oligonucleotides linked via “trebling” “branching synthons” were taught to be suitable for “multiple ligands” with “variety of functionalities”, wherein Shchepinov’s “oligofunctionalised” dendrimers were also taught to comprise “oligonucleotides of different sequence”, and because making a dendrimer structure comprising multiple branched immunostimulatory CpG oligonucleotides that further comprise cell penetrating peptides, antigens, and/or stimulatory peptides was an art-recognized goal for eliciting “a strong, specific and long-lasting immune response” as evidenced by Qu, who also taught that the dendrimer structure allows “accumulation to endosomes”, which is also corroborated by Radovic-Moreno, who reported that the non-linear, spherical structure comprising a plurality of immunostimulatory TLR agonists (“PS CpG 1826”) provides “predominant accumulation in endosomes”, “where they modulate toll-like receptor (TLR) activity.” As such, one of ordinary skill in the art would have reasonably determined that Shchepinov’s non-linear, spherical oligonucleotide dendrimer structure taught to be “oligofunctionalised” would be suitable and useful for incorporating TLR activity-modulating oligonucleotides, which would thus render obvious incorporating immunoregulatory TLR antagonist oligonucleotides into the unbranched stem as well as at least one branched oligonucleotide in Shchepinov’s dendrimer structure, because making a spherical nucleic acid comprising a plurality of immunoregulatory TLR antagonist oligonucleotides was an art-recognized goal as evidenced by Radovic-Moreno. In addition, since “antigens” or “stimulatory peptides” that are loaded in the DNA dendrimer as taught by Qu are for eliciting “a strong, specific and long-lasting immune response”, one of ordinary skill in the art would have reasonably expected that the “antigens” or “stimulatory peptides” that are loaded into the non-branched stem or the branched oligonucleotides would necessarily and inherently remain functional following delivery of the Shchepinov’s dendrimer structure to a cell.
In view of the foregoing, claims 1-2, 4-13, 15, 17-22, and 31 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on February 19, 2026 have been fully considered but they are not persuasive. Applicant argues that the claims are not obvious because Shchepinov does not teach immunostimulatory being present in the dendrimer structure. In response, applicant’s attention is directed to the fact that the instant rejection is not an anticipation rejection thus there is no legal requirement that Shchepinov alone should teach all structural limitations recited in the claims.
Applicant argues that the examiner erred by stating at page 10 of the last Office action a “factually incorrect” assertion that Qu’s Figure 1 shows that “all of the exposed oligonucleotides are immunomodulatory CpG oligonucleotides linked to the TAT peptide.” Applicant argues that Qu’s core “T” junction sequences are formed from single strands, not CpG sequences, where are only the loop structures attached to the branches thus the examiner’s “mischaracterization of Qu undermines the rejection.” Contrary to applicant’s assertions, the interpretation of Qu’s Figure 1 as provided by applicant is consistent with what the examiner set forth at page 10. That is, the CpG oligos are not present in the stem or branched oligonucleotides and are only present as being attached along with the TAT peptides to the branched oligonucleotides. The examiner fails to see the difference between the examiner’s interpretation of Qu’s Figure 1 and applicant’s interpretation.
Applicant argues that the examiner cannot rely on Radovic-Moreno’s nucleic acid structure for placing an immunostimulatory sequence on a stem sequence, which is not present in Radovic-Moreno’s structure. In response, it is noted that there is no statement in the rejection that Radovic-Moreno taught the instantly claimed structure having a stem comprising an immunostimulatory sequence. Hence, applicant’s argument is irrelevant and unpersuasive.
Applicant argues that the claims are not obvious because the examiner provided “no articulated reasoning” for modifying or deviating from Qu. In response, applicant’s attention is directed to the fact that the instant obviousness rationale is not established on modifying or deviating from Qu’s structure. The Qu reference is a secondary reference that is used to support the obviousness of some of the claimed structural limitations (e.g., CpG oligo, peptide, antigen), which are rendered obvious to be incorporated into the structure of Shchepinov. As such, a reasoning for deviating from Qu’s structure need not be articulated so as to establish the obviousness rationale for the instant claims rejected over Shchepinov et al. in view of Qu et al. and Radovic-Moreno et al.
Applicant argues that the examiner misinterpreted Shchepinov’s Figure 6, which does not show creating 6 or 9 branches and the examiner conflated functional groups with oligonucleotide branches thus Shchepinov does not teach a dendrimer structure comprising 6 or 9 branches. Contrary to applicant’s argument, the examiner did not confuse the number of branches with that of functional moieties. That is, the number of functional moieties in the 6-branched structure with 2 treblers is 18, and that in the 9-branched structure with 3 treblers is 27 in Figure 6 of Shchepinov. Applicant is advised to refer to the examiner’s detailed description added to Shchepinov’s Figure 6 in the last Office action (see page 8), which will not be reproduced herein. That is, applicant chose to completely dismiss the clear distinction the examiner set forth in the last Office action between the extended functionalities attached to dendrimer structure of Shchepinov and the number of branches (6 or 9) linked via treblers. The examiner will not further comment on the applicant’s argument as there is no merit. For applicant’s own edification, applicant is advised to refer to page 8 of the last Office action.
Applicant argues that the examiner failed to explain why one would have specifically selected 6 or 9 branches when there is “a vast array of possible branch numbers” including 27, 81, and 243 for treblers. Applicant also argues that there is “no known relationship between branch number and any result” thus selection of 6 or branches is “arbitrary” and therefore the examiner used “impermissible hindsight reconstruction” based on applicant’s disclosure. In response, it is noted that the oligomer dendrimers having 2 or 3 treblers, each forming 6 or 9 branches oligonucleotides, respectively, which can be attached with user-desired functional moieties were art-recognized, not “arbitrary”, design options as evidenced by Shchepinov, and as such, there is no rational or legal reason for the examiner to set forth a reason for a person of ordinary skill in the art to make a 6-mer or 9-mer branched oligonucleotide dendrimer structure instead of 27-mer, 81-mer or 243-mer branched oligonucleotide structures. 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).
Applicant argues that the claims are not obvious because of “unexpected results” such as “superior cellular uptake of 6BD and 9BD vs. 3BD and linear structures”. In response, applicant’s attention is directed to the fact that unexpected results must be compared with the closest prior art, which is Shchepinov’s 6 or 9 branched dendrimers.
“When unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).
Applicant argues that the “superior cellular uptake” does not depend on the stem sequence (T10 or immunostimulatory sequence) and the examiner failed to explain a scientific rationale. In response, applicant’s attention is directed to the fact that the T10 stem sequence was merely addressed in order to support that the alleged unexpected results pertaining to the 6BD or 9BD structure with the T10 stem sequence are not commensurate in scope with the rejected claims, because the structures relied on for evidence of nonobviousness do not possess the stem oligonucleotide being an immunostimulatory oligonucleotide or a TLR antagonist as expressly required by the rejected claims.
Applicant argues that the examiner’s position is “internally inconsistent” because the examiner set forth that it would have been obvious to use an immunostimulatory sequence as a stem sequence. In response, applicant’s attention is directed to the fact that legal requirement for the obviousness rationale is different and distinct from that for the secondary “evidence” applicant relies on for supporting nonobviousness of the rejected claims. Again, the T10 stem sequence was pointed out in the last Office action in order to show that not only did applicant’s evidence fail to compare with the closest prior art, but it also failed to be commensurate in scope with the claims, which expressly require that “the oligonucleotide stem comprises” “(ii) an immunostimulatory oligonucleotide” as in claim 1, thus in all dependent claims thereof, for instance claim 4 requiring that “the oligonucleotide stem comprises an immunostimulatory oligonucleotide.” That is, the T10 stem sequence shown in the evidence submitted by applicant to support the asserted nonobviousness of the rejected claims is not one of (i)-(iii) thus is not commensurate in scope with the rejected claims as written. Note that the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” See MPEP §716.02.
Applicant argues that the structures with the T10 stem sequence “are reasonably representative of the claimed invention”. In response, even if the T10 stem sequence, which is not a claimed sequence and is far from representing any of (i)-(iii) stem sequences claimed in the instant case, were to represent the claimed structure for the sake of argument, the evidence comparing a 6BD (and/or 9BD) with a 3BD (and/or linear) cannot support applicant’s asserted nonobviousness because the closest prior art’s structure is not a 3BD or a linear structure. Furthermore, the non-linear, semi-spherical oligonucleotide dendrimer structures formed by 6 branches or 9 branches were reasonably expected in the prior art to have an improved cellular uptake in immune cells (e.g., DCs) compared to the linear DNA or non-semi-spherical structure formed by 3 branches thus the results shown in the instant application or evidence of record submitted by applicant are not deemed unexpected, let alone “really unexpected.”
“Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” See MPEP §716.02.
Applicant argues that the examiner misapplied In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). In particular, applicant argues that “the closest existing structure is 3BD”. The examiner fails to understand where the 3BD structure is disclosed in the cited prior art and why applicant patently disregards and discredits the trebler-linked oligodendrimer structures of Shchepinov that do “exist in the prior art” as not being the closest prior art structures. Since applicant did not provide any substantial reasoning for dismissing Shchepinov’s structures while insisting that a 3BD structure is the closest prior art structure, the examiner is unable to properly address applicant’s argument. Again, even if the 3BD structure should be regarded as the closest prior art structure as alleged by applicant, which the examiner does not agree with, the improved cellular uptake provided by the 6BD or 9BD compared to the 3BD would have been reasonably expected, not unexpected, because nucleic acid structure resembling a sphere was suggested to enhance “rapid cellular up-take, predominant accumulation in endosomes, and increased resistance to nucleases” in view of Radovic-Moreno.
In view of the foregoing, applicant’s arguments are not found persuasive thus the instant rejection is hereby reapplied.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RAM SHUKLA can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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