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 .
Applicant’s response of 02/20/2026, including a substitute specification, has been received and entered into the application file.
Claims 130, 131, 138, and 141-142 were amended in the claim set filed 02/20/2026.
Claim 136 was canceled in the claim set filed 02/20/2026.
Accordingly, claims 130-135 and 137-146 are pending and under consideration.
Information Disclosure Statement
Receipt of an information disclosure statement on 02/20/2026 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Status of Prior Objections/Rejections
RE: Specification
►The disclosure was previously objected to for various informalities.
The substitute specification filed 02/20/2026 has obviated the basis of the objection of record. The objection of record is hereby withdrawn. The Examiner thanks Applicant for their careful attention to correcting typographical errors throughout the instant specification.
RE: Claim Objections
►Claims 131, 138, 141, and 142 were previously objected to for various informalities.
The amendments to the instant claim set have obviated the basis of the objections of record.
The objections of record are hereby withdrawn.
RE: Claim Rejections - 35 USC § 101
►Claims 130-134, 138-139, 141-143, and 145-146 were previously rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomena without significantly more.
The amendments to instant claim 130, from which all other claims directly or indirectly depend or otherwise require the subject matter of, have obviated the basis of the rejection of record.
The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 102
►Claims 130-132, 134, 136, and 137 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by Winkler, 2013 (hereinafter Winkler).
Applicant has traversed the rejection of record, asserting that Winkler, as set forth in the prior action, does not teach the linker structure of amended instant claim 130.
In response, this is found persuasive in view of the claim amendments. Updated grounds of rejection necessitated by amendment are set forth in detail below.
►Claims 130-133, and 138-146 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/028857 A1 (hereinafter Subramanian), as evidenced by Gillams and Jia, 2018.
Applicant has traversed the rejection of record, asserting that Subramanian (as evidenced by Gillams and Jia, 2018), as set forth in the prior action, does not teach the linker structure of amended instant claim 130.
In response, this is found persuasive in view of the claim amendments. Updated grounds of rejection necessitated by amendment are set forth in detail below.
RE: Claim Rejections - 35 USC § 103
►Claim 135 was previously rejected under 35 U.S.C. 103 as being unpatentable over Winkler, 2013 (hereinafter Winkler) as applied to claim 130 above (see section Claim Rejections - 35 USC § 102), and further in view of US 2016/0339109 A1 (hereinafter Chang).
Applicant has traversed the rejection of record, asserting that Winkler and Chang, as set forth in the prior action, do not render the structure of instant claim 135 obvious.
In response, this is found persuasive in view of the claim amendments. Updated grounds of rejection necessitated by amendment are set forth in detail below.
New/Maintained Grounds of Objection/Rejection
Claim Interpretation
Regarding the interpretation of the instant claim set, the Examiner notes the following:
Amended instant claim 130 requires either Structure 1 or Structure 5. Therefore, any art that applies to one of the instantly claimed structures may be applied throughout the instant claim set, whether or not the art discloses both structures. For example, instant claim 135, which depends from instant claim 130, limits the identity of B, which is a component of Structure 5 but not of Structure 1. Therefore, any art that reads on Structure 1 must also anticipate the limitations of instant claim 135.
R and R’ are recited to each independently be a spacer group at amended instant claim 130. As set forth in the prior action, under broadest reasonable interpretation, spacer groups may themselves be nucleotides.
The recitation of “□” defined as “a covalent linker comprising at least one nucleotide” at amended instant claim 130 is considered to read on any covalent linking structure comprising at least one nucleotide. Put another way, any covalent linking structure comprising any linking species and at least one nucleotide is considered to read on the structure of “□,” as recited at amended instant claim 130.
Claim Rejections - 35 USC § 112(b)
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.
Claim 146 is 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 146 recites “a composition comprising a conjugate of claim 141, and a” This is not a complete sentence and does not comprise a period at the end; thus, the metes and bounds of what the claimed composition comprises are unclear. The previous claim set (dated 05/17/2023) recites “a composition comprising a conjugate of claim 141, and a pharmaceutically acceptable excipient.” For purposes of examination and in the interest of compact prosecution, the Examiner has interpreted instant claim 146 to recite “a composition comprising a conjugate of claim 141, and a pharmaceutically acceptable excipient” (underlined emphasis added), as in the previous claim set. It would be remedial to amend the claim set such that instant claim 146 recites a complete sentence, thereby clearly delineating the metes and bounds of protection sought by the instant claim set.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 130-132, 134, 135, and 137 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Winkler et al., 2013 (hereinafter Winkler; of record).
With regard to claim 130, which recites “a linker compound comprising Structure 1 or 5:…
wherein
B is a trivalent branch point;
each of L1, L2 and L3 is independently *-R-□-R’-X’ or X-R-□-R’-*, wherein * is the point of attachment to B;
X and X’ are independently a maleimide, azide, alklyne, activated carboxyl, or amine, and X and X’ are the same;
R and R’ are each independently a spacer group; and
□ is a covalent linker comprising at least one nucleotide,”
as previously set forth, Winkler discloses that while insufficient pharmokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents, covalent attachment of ligands designed to influence the biodistribution and cellular uptake can advance the therapeutic applications and development options regarding therapeutic oligonucleotides (abstract). Winkler further discloses that these ligands may be covalently attached to therapeutic oligonucleotides via linkers, such as those depicted in Figure 4. While Structure 1 has been amended such that it no longer reads on a nucleic acid or fragment thereof found in nature (as set forth above), the oligonucleotide structure with linkers depicted in Figure 4 of Winkler nonetheless reads on the structure of Structure 1 of amended instant claim 130.
Figure 4 of Winkler depicts an oligonucleotide structure with linkers, said structure comprising terminal amines (see top and bottom; reads on X and X’) immediately preceded by an alkyl group (reads on the spacer group of R and R’) and connected by a covalent linker structure that comprises at least one nucleotide (reads on □). While this structure comprises additional components, it does comprise all of the instantly claimed components of a linker compound comprising Structure 1.
Thus, it is considered that Winkler discloses each and every limitation of instant claim 130.
With regard to claim 131, which recites “the covalent linker □ [of the linker compound of claim 130] comprises Structure 2:
[R”-(p)a-N-(p)b]c (Structure 2)
wherein
c is an integer greater than or equal to 1; and
in each iteration of [R”]-(p)a-N-(p)b]:
R” is a spacer group or is absent;
each p is independently a derivative of phosphoric acid;
N is a nucleoside; and
a and b are each independently an integer greater than or equal to zero, with the proviso that a and b may not both be zero,”
as previously set forth, Structure 2 of instant claim 131 reads on a nucleotide, as the spacer group R” may comprise nucleotides or may be absent, while the claimed structure with phosphoric acid bound to a nucleoside reads on a nucleotide. Furthermore, as set forth above, Figure 4 of Winkler depicts an oligonucleotide structure with linkers, said structure comprising terminal amines (see top and bottom; reads on X and X’) immediately preceded by an alkyl group (reads on the spacer group of R and R’) and connected by a covalent linker structure that comprises at least one nucleotide (reads on □). Thus, Figure 4 of Winkler depicts a covalent linker comprising at least one nucleotide, which anticipates each and every additional limitation of instant claim 131.
With regard to claim 132, which recites “in each iteration of [R”-(p)a-N-(p)b], R” is independently an alkyl, alkyl ether, aryl, heteroaryl, heterocyclyl, alkyl-aryl, alkyl-heteroaryl, or alkyl-heterocyclyl, or is absent,” as set forth above, Figure 4 of Winkler depicts an oligonucleotide structure with linkers, said structure comprising terminal amines (see top and bottom; reads on X and X’) immediately preceded by an alkyl group (reads on the spacer group of R and R’) and connected by a covalent linker structure that comprises at least one nucleotide (reads on □). Thus, it is considered that Winkler discloses iterations of the instantly claimed structure in which R” is either an alkyl structure or is absent, as instantly claimed. Accordingly, it is considered that Winkler anticipates each and every additional limitation of instant claim 132.
With regard to claim 134, which additionally recites “c [of the linker compound of claim 131] is an integer from 2-6,” Figure 4 of Winkler (set forth above) depicts 4 total nucleotides. Thus, Figure 4 of Winkler depicts 2 nucleotides linked by a covalent linker comprising 2 nucleotides, as instantly claimed. Thus, Winkler anticipates each and every additional limitation of instant claim 134.
With regard to claim 135, which recites “B [of the linker compound of claim 130] is methanetriyl…ethanetriyl…propanetriyl…tris(hydroxymethyl)aminomethane, trisubstituted aryl, or substituted ammonia,” as set forth above (see section Claim Interpretation), Winkler anticipates Structure 1 and is therefore considered to anticipate all the limitations of instant claim 135 as well, which is drawn to Structure 5 and is not required by the instant claim language. Thus, it is considered that Winkler anticipates each and every additional limitation of instant claim 135.
With regard to claim 137, which recites “R and R’ [of the linker compound of claim 130] are each independently an alkyl, alkyl ether, aryl, heteroaryl, heterocyclyl, alkyl-aryl, alkyl-heteroaryl, or alkyl-heterocyclyl,” as set forth above, Figure 4 of Winkler depicts an oligonucleotide structure with linkers, said structure comprising terminal amines (see top and bottom; reads on X and X’) immediately preceded by an alkyl group (reads on the spacer group of R and R’) and connected by a covalent linker structure that comprises at least one nucleotide (reads on □). Thus, it is considered that Winkler anticipates each and every additional limitation of instant claim 137.
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.
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 133 and 138-146 are rejected under 35 U.S.C. 103 as being unpatentable over Winkler et al., 2013 (hereinafter Winkler; of record) as applied to claims 130 and 131 above, and further in view of WO 2020/028857 A1 (hereinafter Subramanian; of record).
The disclosure of Winkler is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the additional limitations of instant claims 133 and 138-146.
With regard to claim 133, which recites “c [of the linker compound of claim 131] is greater than or equal to 2 and each N is uridine or each N is thymidime,” as previously set forth, polyT linkers are known in the art, as disclosed in Subramanian. Subramanian discloses, in part, multimeric oligonucleotides linked via an oligonucleotide-based linker such as a poly-dT linker (paragraph [000265]), which reads on the linker structure of instant claim 133. While Subramanian does not disclose the length of said poly-dT linker, as set forth above, Figure 4 of Winkler depicts 2 nucleotides linked by a covalent linker comprising 2 nucleotides. Therefore, as set forth in greater detail below, it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant application to utilize the poly-dT linker of Subramanian in the linked structure shown in Winkler to predictably link oligonucleotides, particularly for purposes of generating a multimeric structure, as disclosed in Subramanian. Thus, it is considered that Subramanian discloses each and every additional limitation of instant claim 133.
With regard to claim 138, which recites “a multimeric oligonucleotide comprising subunits, wherein each of the subunits is independently a single-stranded or double-stranded oligonucleotide, and one or more of the subunits is joined to another subunit via covalent bonds formed by a reaction with a compound of claim 130,” as set forth above, Subramanian discloses, in part, multimeric oligonucleotides connected by a linker in which said multimeric oligonucleotides comprise 2 to 5, 2 to 10, or 4 to 20 oligonucleotides linked together (paragraphs [000263] and [000264]) via multiple covalent bonds (paragraph [000292]). The oligonucleotides disclosed in Subramanian may be single-stranded or double-stranded (paragraph [00078]), as instantly claimed. Additionally, as set forth above, the linker structure recited in instant claim 130 is anticipated by Winkler. Furthermore, Winkler also discloses covalent linker attachment (abstract; page 794, column 1, paragraph 4) for purposes of generating multivalent compounds (page 802, column 2, paragraph 3) that improve the affinity thereof (page 803, column 2, paragraph 2). Thus, it is considered that Subramanian discloses each and every additional limitation of instant claim 138.
With regard to claim 139, which recites "each subunit [of the multimeric oligonucleotide of claim 138] is 15-30, 17-27, 19-26, or 20-25 nucleotides in length," Subramanian discloses that the oligonucleotides taught therein may be of a variety of different lengths, such as 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more nucleotides in length (paragraph [000214]). Subramanian further discloses that in some embodiments, the oligonucleotide may be 15 to 25 nucleotides in length, 21 to 23 nucleotides in length, or other such length ranges (paragraph [000214]). Thus, Subramanian discloses each and every limitation of claim 139.
With regard to claim 140, which recites "the multimeric oligonucleotide of claim 138, further comprising a targeting agent," as set forth above, Subramanian discloses, in part, therapeutic molecular payloads comprising multimeric oligonucleotides connected by a linker such as an oligonucleotide-based linker (i.e. as disclosed in Figure 4 of Winkler) that further comprise a targeting agent (paragraphs [00074], [00076], [00084], and [000263]-[000265]) to specifically target certain cells (disclosed to be muscle cells). Thus, Subramanian discloses a multimeric oligonucleotide further comprising a targeting agent, as instantly claimed, thereby disclosing each and every additional limitation of instant claim 140.
With regard to claim 141, which recites "a conjugate comprising a first bioactive compound joined to a second bioactive compound by [a] reaction with a linker compound of claim 130," the instant specification defines a bioactive compound as any molecule or agent that has a biological effect, such as proteins, peptides, amino acids, nucleic acids, oligonucleotides, targeting agents, carbohydrates, polysaccharides, lipids, organic compounds, inorganic chemical compounds, organometallic compounds, small molecule drugs, detectable labels, and derivatives of any of the foregoing (paragraph [00181 ]). Additionally, the instant specification discloses that conjugates of bioactive compounds of the instant application may include an antibody or an antibody fragment conjugated to an oligonucleotide or a multimeric oligonucleotide (paragraph [00186]). Thus, the multimeric oligonucleotide comprising oligonucleotide subunits disclosed in Subramanian joined via oligonucleotide-based linkers disclosed in Winkler (Figure 4 reads on Structure 1, as set forth above) reads on the instantly claimed first bioactive compound joined to a second bioactive compound by a reaction with a linker compound of claim 130. Additionally, Subramanian discloses, in part, therapeutic molecular payloads comprising multimeric oligonucleotides connected by a linker such as an oligonucleotide-based linker (i.e. as disclosed in Winkler and set forth above) that further comprise a targeting agent (paragraphs [00074], [00076], [00084], and [000263]-[000265]) to specifically target certain cells (disclosed to be muscle cells). This targeting agent is disclosed to be (among other agents) an antibody covalently linked to the molecular payload (paragraph [00084]), which reads on the instantly claimed conjugate comprising a first bioactive compound joined to a second bioactive compound. Finally, Subramanian discloses that linkers are conjugated to the disclosed molecular payload via chemical reactions, such as those taught in paragraphs [000302]-[000306]. Thus, Subramanian discloses each and every additional limitation of instant claim 141.
With regard to claim 142, which recites "the conjugate of claim 141, further compris[es] a third bioactive compound joined together with the first and second bioactive compounds by a reaction with a linker compound of claim 130," as set forth above regarding instant claim 138, Subramanian discloses, in part, therapeutic molecular payloads comprising multimeric oligonucleotides connected by a linker such as an oligonucleotide-based linker that further comprise a targeting agent (paragraphs [00074], [00076], [00084], and [000263]-[000265]) to specifically target certain cells (disclosed to be muscle cells). Subramanian discloses that the multimeric oligonucleotides taught therein may comprise 3 oligonucleotides linked together (paragraph [000264]) and that the targeting agent may be (among other agents) an antibody covalently linked to the molecular payload (paragraph [00084]), which reads on the instantly claimed conjugate comprising three bioactive compounds. Finally, Subramanian discloses that linkers are conjugated to the disclosed molecular payload via chemical reactions, such as those taught in paragraphs [000302]-[000306]. Thus, Subramanian discloses each and every additional limitation of instant claim 142.
With regard to claim 143, which recites "each of the first, the second and the third bioactive compounds [of the conjugate of claim 142] is independently a peptide, a protein, an oligonucleotide, an organometallic compound, or a small molecule drug," as set forth above regarding instant claim 142, Subramanian discloses that the multimeric oligonucleotides taught therein may comprise 3 oligonucleotides linked together (paragraph [000264]) and that the targeting agent may be (among other agents) an antibody covalently linked to the molecular payload (paragraph [00084]), which reads on the instantly claimed conjugate comprising three bioactive compounds in which each bioactive compound is independently an oligonucleotide. Additionally, Subramanian discloses not only that the molecular payloads taught therein may comprise multimeric oligonucleotides connected by a linker such as an oligonucleotide-based linker that further comprise a targeting agent (paragraphs [00074], [00076], [00084], and [000263]-[000265]) to specifically target certain cells (disclosed to be muscle cells), but that the molecular payloads taught therein may alternatively and/or additionally comprise a small molecule, a protein, a peptide, a nucleic acid, or an oligonucleotide (paragraph [00074]), as instantly claimed. Thus, Subramanian discloses each and every additional limitation of instant claim 143.
With regard to claim 144, which recites “the conjugate of claim 143, further compris[es] a targeting agent,” as set forth above regarding instant claims 140 and 143, Subramanian discloses, in part, therapeutic molecular payloads comprising multimeric oligonucleotides connected by a linker such as an oligonucleotide-based linker that further comprise a targeting agent (paragraphs [00074], [00076], [00084], and [000263]-[000265]) to specifically target certain cells (disclosed to be muscle cells). These multimeric oligonucleotides may comprise 3 oligonucleotides linked together (paragraph [000264]). Thus, Subramanian discloses each and every additional limitation of instant claim 144.
With regard to claim 145, which recites "a composition comprising a multimeric oligonucleotide of claim 138 and a pharmaceutically acceptable excipient," as set forth above, Subramanian and Winkler collectively disclose the multimeric oligonucleotide of claim 138. Subramanian further discloses pharmaceutical compositions comprising the molecular payloads taught therein, as well as pharmaceutically acceptable excipients (paragraphs [000322]-[000326]). Thus, Subramanian discloses each and every additional limitation of instant claim 145.
With regard to claim 146, which recites "a composition comprising a conjugate of claim 141, and a [pharmaceutically acceptable excipient (see section Claim Rejections - 35 USC § 112(b))]," as set forth above, Subramanian and Winkler collectively disclose the conjugate of claim 141. Subramanian further discloses pharmaceutical compositions comprising the molecular payloads taught therein, as well as pharmaceutically acceptable excipients (paragraphs [000322]-[000326]). Thus, Subramanian anticipates each and every limitation of instant claim 146.
Given that Winkler discloses linker Structure 1 (see section Claim Rejections - 35 USC § 102) and further that multivalent compounds generated via covalent linker attachment display improved affinity, and that Subramanian discloses poly-dT linkers, as well as muscle-targeting multimeric oligonucleotides and conjugates and compositions thereof, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to generate multimeric oligonucleotides and conjugates and compositions thereof (as disclosed in Subramanian) using the linker structures disclosed in Winkler to predictably generate multimeric oligonucleotides and conjugates and compositions thereof that effectively target specified tissues for therapeutic purposes. One would have been motivated to make such a modification in order to receive the expected benefit of effectively targeting specified tissues with multimeric oligonucleotides and conjugates and compositions thereof for therapeutic purposes.
Conclusion
No claims are allowed.
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 Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
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