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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 3, 2025 has been entered.
Application Status
This action is written in response to applicant' s correspondence received September 3, 2025. Claims 1, 5-7, and 12 are currently pending.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant's amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites, “ or a corresponding, reverse, complement, …”. The comma after “corresponding” should be removed.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5-7 and 12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for “a synthetic oligonucleotide having TDP-43 binding activity, wherein the synthetic oligonucleotide comprises at least one of SEQ ID NO: 6, SEQ ID NO: 7, … and SEQ ID NO: 9 or a corresponding reverse sequence…” does not reasonably provide enablement for “ … wherein the synthetic oligonucleotide comprises at least one of … SEQ ID NO: 8.. or … a corresponding … complement or reverse-complement nucleotide sequence of at least one of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Regarding Claims 1 and 12, the instant application fails to show how a complement or reverse complement of SEQ ID NO: 6-9 has TDP-43 binding activity. Regarding Claim 1, the instant applications fails to show SEQ ID NO: 8 prevents or reduces aggregation of TDP-43.
MPEP 2164.01(a) recites, “In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. See Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Breadth of the Claims and The Nature of the Invention
Claim 1 recites, “A method of preventing or reducing aggregation, misfolding, or intracellular seeding of TAR DNA-binding protein (TDP-43)” comprising “a synthetic oligonucleotide having TDP-43 binding activity” comprising of at least one of SEQ ID NO: 6-9 or at least one of their corresponding reverse, complement or reverse-complement nucleotide sequences.
Claim 12 recites, “A pharmaceutical composition comprising an isolated oligonucleotide having TDP-43 binding activity” comprising of at least one of SEQ ID NO: 6-9 or at least one of their corresponding reverse, complement or reverse-complement nucleotide sequences.
An oligonucleotide is interpreted to be a short nucleotide sequence. The oligonucleotide is interpreted to requiring TDP-43 biding activity.
SEQ ID NO: 8 has a sequence of A(GT)6. The use of the “T” nucleotide is interpreted as a DNA oligonucleotide.
The State of the Prior Art, The Level of One of Ordinary Skill, The Level of Predictability in the Art
This discussion cites the following prior art: Mann, J. et. al., Neuron, Vol. 102, (April 17, 2019) p. 321-338 and Lukavsky, P. et. al., Nature Structural & Molecular Biology, Vol. 20, No. 12 (November 17, 2013) p.1443-1451.
Mann teaches SEQ ID NO: 7, as Clip_34nt, binds TDP-43: “[W]e designed a 2’OMe-modified RNA oligonucleotide based on a well-characterized TDP-43 binding sequence (Clip_34nt) previously shown to exhibit a high affinity for TDP-43” (p. 330, col. 2).
Lukavsky teaches UG-rich RNA oligonucleotides including UG-repeats and AUG12 bind TDP-43 (p. 1444, col. 1 and 2). SEQ ID NO: 6 and 9 are GU repeats with 2’OMe and MOE modified oligonucleotides respectively.
The prior art failed to reveal any complement or reverse complement of SEQ ID NO: 6-9 binding TDP-43. One skilled in the art would not reasonably expect a complement or reverse complement of a nucleotide sequence to exhibit the same binding properties as the original sequences.
The prior art also failed to reveal the use of GT repeat sequences, or SEQ ID NO: 8, reduces TDP-43 aggregation. One skilled in the art would not reasonably expect a DNA sequence to exhibit the same chemical properties as a RNA sequence.
The Amount of Direction and Existence of Working Examples
The instant specification teaches GU repeats administered to cell lysate in vitro promotes liquid-liquid phase separation of TDP-43 (p. 44, line 21): “Consistently, addition of A(GU)18 led to an almost 4-fold increase in turbidity compared to control .. (see e.g., FIG 9C)” (p. 45, lines 6-8). This reads on the use of the sequences of SEQ ID NO: 6 and 9 to reduce aggregation of TDP-43. The instant specification also teaches the use of the sequence Clip_34nt, the same sequence as SEQ ID NO: 7, to reduce aggregation of TDP-43: “CLIP34 triggered spontaneous TDP-43 phase separation” (p. 44, lines 2-3).
Regarding SEQ ID NO: 8, the instant specification teaches “ssDNA composed of GT repeats …, which binds TDP-43 …, did not induced TDP-43 droplet formation at concentrations that strongly promoted phase separation” (p. 43, 16-19). This reads as SEQ ID NO: 8 does not prevent or reduce aggregation of TDP-43 in vitro.
The instant specification does not teach the use of complement or reverse complement sequences of SEQ ID NO: 6-9 to prevent or reduce aggregation of TDP-43. The instant specification does teach that “RNA-driven TDP-43 phase separation is sequence-dependent” (p. 45, line 25).
The Quantity of Experimentation Needed
The reverse, complements and reverse complements of SEQ ID NO: 6-9 would require testing 12 additional sequences, which would not be undue. For one skilled in the art, the reverse sequences of SEQ ID NO: 6, 7 and 9 would have a reasonable expectation of success because the reverse of UG-rich sequences are still UG-rich sequences. However, for complement and reverse complement sequences of SEQ ID NO: 6-9, one skilled in the art would not have a reasonable expectation of success as the sequences would no longer be UG-rich but rather AC-rich sequences. In addition, the instant specification teaches a GT rich sequence, SEQ ID NO: 8 or its reverse sequence, does not prevent or reduce TDP-43 aggregation.
Conclusion
Regarding Claims 1 and 12, the prior art and instant specification fail to teach the complement and reverse complement nucleotide sequences of SEQ ID NO: 6-9 bind TDP-43. Both the prior art and instant specification teach TDP-43 binding is sequence specific, and therefore one skilled in the art would not have a reasonable expectation of success.
Regarding Claim 1, the prior art and instant specification fail to teach SEQ ID NO: 8 or its reverse sequence prevent or reduce TDP-43 aggregation. The instant specification teaches GT repeats did not strongly promote phase separation of TDP-43.
Therefore, Claims 1 and 12 are rejected under 35 U.S.C. 112(a) for scope of enablement over the complement and reverse complement sequences of SEQ ID NO: 6-9. Additionally, Claim 1 is rejected under 35 U.S.C. 112(a) for scope of enablement for SEQ ID NO: 8 and its reverse sequence.
Regarding Claims 5-7, the dependent claims fail to limit the independent claim, Claim 1, to overcome the scope of enablement rejection.
Claim Rejections - 35 USC § 102
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 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.
Claims 1, 6, 7 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mann, J. et. al., Neuron, Vol. 102, (April 17, 2019) p. 321-338.
Regarding Claim 1, Mann teaches a method of reducing aggregation of TDP-43 in a cell in vitro in which the method comprises administering an effective amount of synthetic oligonucleotide: “Cells [HEK293 cells] expressing optoTDP43 were treated with either Clip_34nt or a scrambled oligonucleotide… treatment with the bONs [bait oligonucleotides] resulted in a dose dependent reduction in cytoplasmic optoTDP43 assemblies” (p. 330, col. 2).
Mann further teaches a synthetic oligonucleotide having TDP-43 binding activity and comprising of a sequence identical to SEQ ID NO. 7: “[W]e designed a 2’OMe-modified RNA oligonucleotide based on a well-characterized TDP-43 binding sequence (Clip_34nt) previously shown to exhibit a high affinity for TDP-43” (p. 330, col. 2). SEQ ID NO. 7, as described in the instant specification (p. 15), is Clip_34nt with a 2’OMe modification.
Therefore, Mann teaches “a method of … reducing aggregation … of TDP-43 in a cell in vitro, the method comprising administering a therapeutically effective amount of a synthetic oligonucleotide having TDP-43 binding activity, wherein the synthetic oligonucleotide comprises … at least one of SEQ ID NO: 7”, and Claim 1 is anticipated by Mann.
Regarding Claim 6, Mann teaches a method used on human cells that have TDP-43 proteinopathy, a symptom of neurodegenerative diseases (p. 333, col. 1). Therefore, Claim 6 is anticipated by Mann.
Regarding Claim 7, Mann teaches that TDP-43 proteinopathy correlates with ALS/FTD (p. 330, col. 1). Therefore, Claim 7 is anticipated by Mann.
Regarding Claim 12, Mann teaches a composition comprising an isolated oligonucleotide having TDP-43 binding activity with a sequence identical to SEQ ID NO: 7 as described above (p. 330, col. 2). Therefore, Claim 12 is anticipated by Mann.
RE: Applicant’s Arguments, 35 USC § 102
Applicant argues in remarks filed September 3, 2025, “Mann’s disclosure is simply directed to the known Clip_34nt oligonucleotide and a single 2’OMe-modified version thereof. Consequently, Mann fails to disclose each and every element of amended claim 1 and the claims depending therefrom”. This argument is not persuasive as shown in the rejections above. The instant specification defines SEQ ID NO: 7 as “CLIP-34 2OMe modified” (p. 15) Mann teaches a synthetic oligonucleotide having TDP-43 binding activity which is a 2’OMe-modified RNA oligonucleotide of Clip_34nt as well as the method of Claim 1 in a cell in vitro.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Mann, J. et. al., Neuron, Vol. 102, (April 17, 2019) p. 321-338 as applied to Claims 1, 6, 7, and 12 above, and further in view of Lukavsky, P. et. al., Nature Structural & Molecular Biology, Vol. 20, No. 12 (November 17, 2013) p.1443-1451 and Khvorova, A. and Watts, J. Nature Biotechnology, Vol. 35, No. 3 (February 27, 2017) p. 238-248.
Regarding Claim 1, Claim 1 with respect to SEQ ID NO: 7 is taught by Mann. Mann further teaches that bait nucleic acids “can inhibit aberrant phase transitions of TDP-43, providing a potential therapeutic approach for future study” (p. 336, col. 1).
Mann does not teach the use of SEQ ID NO: 6 or 9. SEQ ID NO: 6 is described in the instant specification as a 6 GU repeat 2’OMe modified oligonucleotide (p. 15). SEQ ID NO: 9 is described in the instant specification as a 6 GU repeat mixed MOE modified oligonucleotide (p. 15).
Lukavsky teaches at least six GU repeats are needed to bind TDP-43 twice across both RRMs: “Of the 10 nt in contact with the protein surface, 6 nt are recognized sequence specifically (G1, G3, U4, G5, U8 and G9). All are Us or Gs, and this explains the binding preference of TDP-43 for UG-rich sequences” (p. 1445, Col. 1) and “Both RRMs [of TDP-43] are required for high-affinity binding of single-stranded RNA containing a minimum of six UG repeats” (p. 1443, Col. 2).
Khvorova teaches the 2’OMe and MOE modifications, “The 2′-O-methyl modification of RNA (2′OMe-RNA), which occurs in nature, improves binding affinity and nuclease resistance and reduces immune stimulation. Using 2′-O-methyl as a starting point, medicinal chemists worked to find an ideal 2′-O-alkyl substituent. Among dozens of variants tested, 2′-methoxyethyl (MOE) emerged as one of the most useful analogs, providing a further increase in nuclease resistance and a jump in binding affinity … per modified nucleotide” (p. 239, Col. 1). Khvorova recites, “Combining modifications of the oligonucleotide backbone, sugars, bases and the 5′-phosphate are necessary to develop compounds with optimal activity” (p. 240, Figure 2) providing a motivation for using modified oligonucleotides.
Regarding Claim 1, Mann teaches Claim 1 with respect to SEQ ID NO: 7. It would be obvious to one skilled in the art to combine the GU repeats taught by Lukavsky and the RNA modifications of taught by Khvorova to create SEQ ID NO: 6, a 6 GU repeat 2’OMe modified oligonucleotide, and SEQ ID NO: 9, a 6 GU repeat mixed MOE modified oligonucleotide and substitute the modified nucleotide for SEQ ID NO: 7 in the method of Mann. The substitution into the method of Mann would be predictable as Lukavsky teaches GU repeats bind TDP-43, and Mann teaches bait oligonucleotides that bind to TDP-43 would be appropriate for their method. It would also be predictable that the modifications taught by Khovrova would work with the method of Mann as Mann uses 2’OMe modified RNA and Khovrova teaches the modifications are well studied. One skilled in the art would be motivated to perform the substitution as Lukavsky teaches TDP-43 binds preferentially to GU rich sequences, binds both RRM domains, and Mann teaches that other bait oligonucleotides should be studied for therapeutic use. Therefore, Claim 1 is obvious over Mann, Lukavsky, and Khvorova.
Regarding Claim 5, Claim 5 is an improper dependent claim. For compact prosecution, Claim 5 is interpreted as the synthetic oligonucleotide comprises at least two TDP-43 binding sites and is SEQ ID NO: 6 or 9. Lukavsky teaches GU-rich sequences with at least 6 repeats bind TDP-43 twice. Therefore, Claim 5 is obvious over Mann, Lukavsky, and Khvorova.
Regarding Claim 6, Mann teaches a method used on human cells that have TDP-43 proteinopathy, a symptom of neurodegenerative diseases (p. 333, col. 1). Therefore, Claim 6 is obvious over Mann, Lukavsky, and Khvorova.
Regarding Claim 7, Mann teaches that TDP-43 proteinopathy correlates with ALS/FTD (p. 330, col. 1). Therefore, Claim 7 is obvious over Mann, Lukavsky, and Khvorova.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Lukavsky, P. et. al., Nature Structural & Molecular Biology, Vol. 20, No. 12 (November 17, 2013) p.1443-1451 and Khvorova, A. and Watts, J. Nature Biotechnology, Vol. 35, No. 3 (February 27, 2017) p. 238-248.
Regarding Claim 12, Lukavsky teaches at least six GU repeats are needed to bind TDP-43 twice across both RRMs: “Of the 10 nt in contact with the protein surface, 6 nt are recognized sequence specifically (G1, G3, U4, G5, U8 and G9). All are Us or Gs, and this explains the binding preference of TDP-43 for UG-rich sequences” (p. 1445, Col. 1) and “Both RRMs [of TDP-43] are required for high-affinity binding of single-stranded RNA containing a minimum of six UG repeats” (p. 1443, Col. 2).
Lukavsky does not teach 2’ OMe or MOE modifications.
Khvorova teaches the 2’OMe and MOE modifications, “The 2′-O-methyl modification of RNA (2′OMe-RNA), which occurs in nature, improves binding affinity and nuclease resistance and reduces immune stimulation. Using 2′-O-methyl as a starting point, medicinal chemists worked to find an ideal 2′-O-alkyl substituent. Among dozens of variants tested, 2′-methoxyethyl (MOE) emerged as one of the most useful analogs, providing a further increase in nuclease resistance and a jump in binding affinity … per modified nucleotide” (p. 239, Col. 1). Khvorova recites, “Combining modifications of the oligonucleotide backbone, sugars, bases and the 5′-phosphate are necessary to develop compounds with optimal activity” (p. 240, Figure 2) providing a motivation for using modified oligonucleotides.
Regarding Claim 12, SEQ ID NO: 6 is described in the instant specification as a 6 GU repeat 2’OMe modified oligonucleotide (p. 15) and SEQ ID NO: 9 is described in the instant specification as a 6 GU repeat mixed MOE modified oligonucleotide (p. 15). It would be obvious to one skilled in the art to combine the teachings of Lukavsky and Khvorova to create a 6 GU repeat sequence with 2’OMe modifications to create SEQ ID NO: 6 or a 6 GU repeat sequence with MOE modifications to create SEQ ID NO: 9. The results would be predictable as Khvorova teaches these modifications are well studied and commonly used for optimal activity. Therefore, Claim 12 is obvious over Lukavsky and Khvorova.
RE: Applicant’s Arguments, 35 USC § 103
Applicant argues in remarks filed September 3, 2025, “The combinations of Mann + Lukavsky, Mann + Khvorova, and Mann + Lukavsky + Khvorova each fail to cure the deficiencies of Mann. Moreover, when viewed as a whole, each reference combination fails to provide disclosure, suggesting or teaching .. including Applicants’ claimed oligonucleotide sequence requirements” (p. 5). This argument is not persuasive as shown in the rejections above. Mann teaches SEQ ID NO: 7, and Lukavsky and Khvorova together teach SEQ ID NO: 6 and 9.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Krishna Nuggehalli Ravindra whose telephone number is (571)272-2758. The examiner can normally be reached M-Th, alternate F, 8a-5p est.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N.R./Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636