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 .
Support for the amendments is within the instant application specification.
Applicant’s amendment to the claims filed on 11/28/2025 in response to the Non-Final Rejection mailed on 7/29/2025is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 40-44, 50, 55, 57, 60-65 are pending.
Claims 1-39, 45-49, 51-54, 56, 58-59 are canceled.
Applicant’s remarks filed on 11/28/2025 in response to the Non-Final Rejection mailed on 7/29/2025 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/28/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Rejections
The rejection of claims 45-49, 51-54, 56, 58 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement are withdrawn in view of Applicant’s cancellation of claims.
The rejection of claims 45-49, 51-54, 56, 58 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in view of Applicant’s cancellation of claims.
The rejection of claims 45-49, 51-54, 56, 58 under 35 U.S.C. 101 are withdrawn in view of Applicant’s cancellation of claims.
The rejection of claims 45-49, 51-54, 56, 58 under 35 U.S.C. 102(a)(1) as being anticipated by Thapa et al. (2019, BioEssays, cited in PTO-892 dated 7/29/2025) {herein Thapa) as evidenced by Iconomou et al (2016, Biochemical Journal, cited in PTO-892 dated 7/29/2025) {herein Iconomou}.
The rejection of claims 40-58 under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter is withdrawn in view of Applicant’s amendment of claim 40 to recite ‘a complex comprising a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins.’
Claim Rejections - 35 USC § 112
Modified Written Description
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.
The rejection of claims 40-44, 50, 55, 57, 61-65 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is maintained. The rejection has been modified in view of Applicant’s amendment of claim 40 to recite ‘modified polyribonucleotide; two or more modified nucleotides each comprising a functional group conjugated to a first chemical compound; two or more aptamers; two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound’ and newly added claims 62-65. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claims 40-44, 50, 55, 57, 61 are drawn to a complex comprising a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins , wherein: (a) the modified linear polyribonucleotide is bound to the two or more ubiquitin ligases by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a first chemical compound, wherein the first chemical compound binds one of the two or more ubiquitin ligases; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more ubiquitin ligases; and (b) the modified linear polyribonucleotide is bound to the two or more substrate proteins by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound, wherein the second chemical compound binds one of the two or more substrate proteins; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more substrate proteins; and wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins. The structure of the modified linear polyribonucleotide and modified nucleotide are a large number of modifications as it can encompass the entire polyribonucleotide. Furthermore, the structure of a first and second chemical compound encompasses an extremely large number of chemical compounds.
Claims 62-65 are drawn to a complex comprising a bifunctional modified linear polyribonucleotide bound to two or more ubiquitin ligases, wherein the bifunctional modified linear polyribonucleotide has the following structure: X1- linear polyribonucleotide-X2, wherein each of X1 and X2 comprises one or more ubiquitin ligase binding moiety (UBM), wherein each UBM is bound to a ubiquitin ligase by way of: (i) a modified nucleotide comprising a functional group conjugated to a chemical compound, wherein the chemical compound binds the ubiquitin ligase; or (ii) an aptamer, wherein the aptamer binds the ubiquitin ligase. The structure of the bifunctional modified linear polyribonucleotide and modified nucleotide are a large number of modifications as it can encompass the entire polyribonucleotide. Furthermore, the structure of a chemical compound encompasses an extremely large number of chemical compounds.
The specification discloses the following representative modified linear polyribonucleotide as the linear RNA has a 5' end or 3' end that is modified or protected from degradation (e.g., by a 5' end protectant or a 3' end protectant). The specification discloses the first and second modified nucleotides as comprising a click chemistry moiety, small molecule (Instant Application Specification: para 0008). The specification discloses the first and second chemical compound as a small molecule, target protein ligand, LCL161 derivative, VHL-1, pomalidomide, lenalidomide, thalidomide or a derivative thereof, a HIFIa-derived ®-hydroxyproline, VHL ligand 2, VL-296, a VH032 derivative, a hydroxyproline-based ligand, Heat Shock Protein 90 (HS90) inhibitor, Kinase and Phosphatase inhibitor, MDM2 inhibitor, HDAC inhibitor, Human Lysine Methyltransferase Inhibitor, Angiongenesis inhibitor, Immunosuppressive compound, dasatinib, lapatinib, gefitinib, foretinib, Sirt2 inhibitor 3b, Sirt2 inhibitor, SNS-032, AC220, ceritinib, ibrutinib, ibrutinib derivative, 4-OHT, Jql, PDE4 inhibitor, thiazolidinedione-based ligand, ripk2 inhibitor, bosutinib, OTX015, steel factor, TBK1 inhibitor, HJB97, aminopyrazole analog, RN486, AR antagonist, IACS-73, nutlin small molecule. The specification discloses the bifunctional linear modified polyribonucleotide as cytotoxic nucleosides incorporated into the linear polyribonucleotide. However, the breadth of the claims encompass any modified linear polyribonucleotide , bifunctional modified linear polyribonucleotide, modified nucleotides, chemical compounds. Additionally, the breadth of the claims encompass any nucleotide mutations via any modification technique such as deletion, mutation, etc. for the degradation of substrate protein.
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004). Here, the disclosure fails to teach which modified linear polyribonucleotide, bifunctional modified polyribonucleotide, modified nucleotides, chemical compounds out of the numerous possibilities for the degradation of substrate protein.
Accordingly, one of skill in the art would not accept the disclosure of the modified linear polyribonucleotide as the linear RNA has a 5' end or 3' end that is modified or protected from degradation (e.g., by a 5' end protectant or a 3' end protectant); first and second modified nucleotides as comprising a click chemistry moiety as representative of all modified nucleotides and nucleosides; first and second chemical compound as a small molecule, target protein ligand, LCL161 derivative, VHL-1, pomalidomide, lenalidomide, thalidomide or a derivative thereof, a HIFIa-derived ®-hydroxyproline, VHL ligand 2, VL-296, a VH032 derivative, a hydroxyproline-based ligand, Heat Shock Protein 90 (HS90) inhibitor, Kinase and Phosphatase inhibitor, MDM2 inhibitor, HDAC inhibitor, Human Lysine Methyltransferase Inhibitor, Angiongenesis inhibitor, Immunosuppressive compound, dasatinib, lapatinib, gefitinib, foretinib, Sirt2 inhibitor 3b, Sirt2 inhibitor, SNS-032, AC220, ceritinib, ibrutinib, ibrutinib derivative, 4-OHT, Jql, PDE4 inhibitor, thiazolidinedione-based ligand, ripk2 inhibitor, bosutinib, OTX015, steel factor, TBK1 inhibitor, HJB97, aminopyrazole analog, RN486, AR antagonist, IACS-73, nutlin small molecule; the bifunctional linear modified polyribonucleotide as cytotoxic nucleosides incorporated into the linear polyribonucleotide as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of linear polyribonucleotide bound to two or more copies of a target protein and to two or more copies of a substrate protein, fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph.
RESPONSE TO REMARKS: Beginning on p. 6 of Applicant’s remarks, in summary, Applicant contends that amending claim to recite ‘to recite a complex that includes a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins, in which the two or more ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins’ necessitates withdrawal of the rejection. Applicant contends that claim 40 is further amended to specify that the modified linear polyribonucleotide binds the two or more ubiquitin ligases by way of a chemical compound or an aptamer and that the polyribonucleotide binds the two or more substrate proteins (e.g., proteins of interest for degradation) by way of a chemical compound or an aptamer. Applicant contends that chemical compounds such as small molecules that bind various ubiquitin ligases are well-known in the art.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that amending claim 40 to recite a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins does not necessitate withdrawal of the rejection as Applicant has not clearly defined a modified linear polyribonucleotide within the instant application claims. Applicant is reminded that the claims are read in-light of the specification. Examiner contends that Applicant’s assertion that chemical compounds such as small molecules that bind various ubiquitin ligases are well-known in the art does not negate the fact that a large number of chemical compounds encompass the instant application claim on ‘a first and second chemical compound.’ Examiner contends that although Applicant specified several species of chemical compounds within table 4 of the specification, there are a large number of chemical compounds that bind ubiquitin that are not included within table 4 of the specification. Supporting the Examiner’s position is the evidentiary reference of King et at (2014, Nature Chemical Biology, Examiner cited) which recites there are over 1,000 proteins (chemical compounds) that may function in the ubiquitin-proteasome system (page 871, column 1, para 1). Examiner contends that although Applicant has indicated a limited number of species of chemical compounds that bind ubiquitin in table 4 of the specification, Applicant is reminded that claims are read in-light of the specification. It is suggested that incorporating the limitations of claim 60 into independent claims would overcome this rejection.
Maintained Scope of Enablement
The rejection of claims 40-44, 50, 55, 57, 6165 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained. The rejection has been modified in view of Applicant’s amendment of claim 40 to recite ‘modified polyribonucleotide; two or more modified nucleotides each comprising a functional group conjugated to a first chemical compound; two or more aptamers; two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound’ and newly added claims 62-65. The specification while being enabled for the first and second modified nucleotides as comprising two or more modified nucleotides that are modified 5-azido- C3-uridine-5'-triphosphate or 5-ethynyl-uridine-5'-triphosphate , it does not reasonably provide enablement for all first and second modified nucleotides, first and second chemical compounds and modified nucleotides as encompassed by the claims. 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 and/or use the invention commensurate in scope with these claims.
The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (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. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A)The breadth of the claims:
Claims 40-44, 50, 55, 57, 61 are drawn to a complex comprising a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins , wherein: (a) the modified linear polyribonucleotide is bound to the two or more ubiquitin ligases by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a first chemical compound, wherein the first chemical compound binds one of the two or more ubiquitin ligases; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more ubiquitin ligases; and (b) the modified linear polyribonucleotide is bound to the two or more substrate proteins by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound, wherein the second chemical compound binds one of the two or more substrate proteins; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more substrate proteins; and wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins. The structure of the modified linear polyribonucleotide and modified nucleotide are a large number of modifications as it can encompass the entire polyribonucleotide. Furthermore, the structure of a first and second chemical compound encompasses an extremely large number of chemical compounds.
Claims 62-65 are drawn to a complex comprising a bifunctional modified linear polyribonucleotide bound to two or more ubiquitin ligases, wherein the bifunctional modified linear polyribonucleotide has the following structure: X1- linear polyribonucleotide-X2, wherein each of X1 and X2 comprises one or more ubiquitin ligase binding moiety (UBM), wherein each UBM is bound to a ubiquitin ligase by way of: (i) a modified nucleotide comprising a functional group conjugated to a chemical compound, wherein the chemical compound binds the ubiquitin ligase; or (ii) an aptamer, wherein the aptamer binds the ubiquitin ligase. The structure of the bifunctional modified linear polyribonucleotide and modified nucleotide are a large number of modifications as it can encompass the entire polyribonucleotide. Furthermore, the structure of a chemical compound encompasses an extremely large number of chemical compounds.
B) The nature of the invention; C)The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: As noted above, the scope of the claimed modified linear polyribonucleotide, bifunctional modified linear polyribonucleotide, first and second modified nucleotides, first and second chemical compounds and modified nucleotides are a large number of compounds and sequences. The structure of the claimed modified linear polyribonucleotide, bifunctional modified linear polyribonucleotide, first and second modified nucleotides, first and second chemical compounds and modified nucleotides promoting degradation of the substrate protein are a large number of sequences and compounds.
It is well-known in the prior art that there are a large number of nucleotides sequences that bind ubiquitin. In this regard, the reference of Randles et al (2018, Front Biosci, Examiner cited) recites greater than 150 ubiquitin receptors have been found and their ubiquitin-binding domains (UBDs) are structurally diverse and include alpha-helical motifs, zinc fingers (ZnF), pleckstrin-homology (PH) domains, ubiquitin conjugating (Ubc)-related structures and src homology 3 (SH3) domains (abstract). As such, there are a large number of nucleotides that bind ubiquitin.
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of modified linear polyribonucleotide as the linear RNA has a 5' end or 3' end that is modified or protected from degradation (e.g., by a 5' end protectant or a 3' end protectant); first and second modified nucleotides, first and second chemical compounds (i.e. the first and second modified nucleotides as comprising two or more modified nucleotides which are modified 5-azido- C3-uridine-5'-triphosphate or 5-ethynyl-uridine-5'-triphosphate.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
RESPONSE TO REMARKS: Beginning on p. 7 of Applicants’ remarks, Applicants in summary contend that amending claim to recite ‘to recite a complex that includes a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins, in which the two or more ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins’ necessitates withdrawal of the rejection. Applicant contends that claim 40 is further amended to specify that the modified linear polyribonucleotide binds the two or more ubiquitin ligases by way of a chemical compound or an aptamer and that the polyribonucleotide binds the two or more substrate proteins (e.g., proteins of interest for degradation) by way of a chemical compound or an aptamer. Applicant contends that chemical compounds such as small molecules that bind various ubiquitin ligases are well-known in the art.
This argument is found to be not persuasive because the structure of a modified linear polyribonucleotide and chemical compounds for promoting the degradation of ubiquitin tagged substrates is a large number of sequences and compounds and are not limited to those specific polyribonucleotides and chemical compounds disclosed in the specification. It was not routine in the art at the time of the invention to make and test all of the large number of possible modified linear polyribonucleotide and chemical compounds that promote the degradation of ubiquitin tagged substrates. It is suggest that incorporating the limitations of claim 60 into all independent claims would overcome this rejection.
Maintained 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.
The rejection of claims 40-44, 50, 55, 57, 61-65 under 35 U.S.C. 102(a)(1) as being anticipated Thapa et al. (2019, BioEssays, cited on PTO-892 dated 7/29/2025) {herein Thapa) as evidenced by Yao et al (2017, Cell, Examiner cited) {herein Yao}, Zhang et al (2018, Journal of Cancer Research and Clinical Oncology, Examiner cited) {herein Zhang}, Fote et al (2024, Medical Sciences, Examiner cited) {herein Fote} and Nguyen et al (2025, nature neuroscience, Examiner cited) {herein Nguyen} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 40 to recite ‘a modified linear polyribonucleotide’ and newly added claims 60-65. See MPEP 2131.01 regarding multiple reference 102 rejections.
As amended, claims 40-44, 50, 55, 61 are drawn to a complex comprising a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins , wherein: (a) the modified linear polyribonucleotide is bound to the two or more ubiquitin ligases by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a first chemical compound, wherein the first chemical compound binds one of the two or more ubiquitin ligases; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more ubiquitin ligases; and (b) the modified linear polyribonucleotide is bound to the two or more substrate proteins by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound, wherein the second chemical compound binds one of the two or more substrate proteins; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more substrate proteins; and wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins.
Previously presented claim 57 is drawn to a pharmaceutical composition comprising the complex according to claim 40.
New claims 62-65 are drawn to a complex comprising a bifunctional modified linear polyribonucleotide bound to two or more ubiquitin ligases, wherein the bifunctional modified linear polyribonucleotide has the following structure: X1- linear polyribonucleotide-X2, wherein each of X1 and X2 comprises one or more ubiquitin ligase binding moiety (UBM), wherein each UBM is bound to a ubiquitin ligase by way of: (i) a modified nucleotide comprising a functional group conjugated to a chemical compound, wherein the chemical compound binds the ubiquitin ligase; or (ii) an aptamer, wherein the aptamer binds the ubiquitin ligase.
With respect to claims 40-44, 50, 55, 57, 61-65, Thapa teaches an expanded CAG repeat motif in the mRNA (mRNA HTT) of individuals diagnosed with Huntington Disease (page 4, column 2, para 2). Said mRNA HTT is bifunctional since it promotes neurodegradation and the initiation of neurotoxic proteins (Fig 3), Evidentiary reference of Nguyen is cited to demonstrate that the CAG repeat expansion in the HTT gene contains m6A RNA modifications (abstract) which involves the methylation of adenosine at the nitrogen-6 position. As such, absent evidence, it is the Examiner’s position that mRNA HTT inherently possess modifications of 2 or more nucleotides. Evidentiary reference of Yau is cited to demonstrate that ubiquitin binds mRNA HTT heterotopically (branched and linear) (abstract). Furthermore, it is known by those of ordinary skill in the art that nucleotides natively contain the functional groups phosphate, a sugar and a nitrogenous base. The instant application defines ‘functional groups’ a being sugar nucleobase (Instant Application Specification: para 0092). As such, Examiner is interpreting the nucleotides CAG within the HHT mRNA as containing functional groups. Thapa further teaches RNA binding ubiquitin ligase MID1, S6 Kinase (S6K) and Protein phosphatase 2A (PP2A) bind to the HTT mRNA and in conjugation with other proteins, which initiates ubiquitination of the protein substrate PP2A and S6K (page 4, column 2, para 2 and fig 3). MID1 is a E3 ubiquitin ligase that binds to two binding moieties on the HTT mRNA. Evidentiary reference of Zhang is cited to demonstrate that MID1 is an inhibitor of apoptosis (page 856, column 2, para 1). As such, absent evidence otherwise, it is the Examiner’s position that said property is an inherent characteristic of the ubiquitinase. Additionally, absent evidence otherwise, it is the Examiner’s position that the nucleotide that allows for the binding of MID1 to the modified linear polyribonucleotide is interpreted as being a first chemical compound that binds MID1 ubiquitin ligases (page 4, column 2, para 2 and fig. 3, Table 1). Evidentiary reference of Fote is cited to demonstrate that HTT mRNA binds to ten or more ubiquitin ligases (Fig 3) and substrates (S4). As such, absent evidence otherwise, it is the Examiner’s position that ten or more ubiquitin and substrates inherently binds to HTT mRNA. As such, said property is not inventive. Furthermore, absent evidence otherwise, it is the Examiner’s position that PP2A and S6K are substrate proteins that bind the modified linear polyribonucleotide. In addition, absent evidence otherwise, it is the Examiner’s position that the nucleotide that allows for the binding of the substrate to the modified linear polyribonucleotide is a second chemical compound. Thapa further teaches that Furamidine can be utilized as a therapeutic for the treatment of Huntington Disease as it affects the binding of HTT mRNA to MID1, thereby stimulating neuroprotection (page 4, column 2, para 2). As such, absent evidence otherwise, it is the Examiner’s position that furamidine, HTT mRNA, MID1, PP2A , S6Kto be a pharmaceutical composition as said composition stimulates neuroprotection. Additionally, the instant application specification defines a pharmaceutical as the linear RNA (para 0279 and para 0286). As such, absent evidence otherwise, it is the Examiner’s position that the furamidine, HTT mRNA, MID1, PP2A, S6K is a pharmaceutical composition as it contains modified linear RNA in the version of HTT mRNA. Regarding the limitation “wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins,” this language does not require steps to be performed or limit the claim to a particular structure and does not limit the scope of the claim. See MPEP 2106.C and 2111.04. Instead, the “wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins” clause merely recites a correlation between ubiquitin and its usefulness in degrading substrates. It is unclear by the recitation ‘…X1- linear polyribonucleotide-X2...’ if Applicant intends on the ubiquitin ligases to bind the 5’ and 3’ ends of the linear polyribonucleotide since Applicant did not specify 3’ and/or 5’. As such, absent evidence otherwise, it is the Examiner’s position that the teaching of MID1 bound to the bifunctional modified linear polyribonucleotide meets the limitations of the instant application claim 62.
For the reasons stated herein, the teachings of Thapa anticipates claims 40-44, 50, 55, 57, 61-65.
RESPONSE TO REMARKS: Beginning on p. 5 of Applicant’s remarks, in summary, Applicant contends that Thapa fails to anticipate the amended claims at least because Thapa does not recite each and every aspect of amended claim 40. Applicant contends that Thapa is silent with respect to modified linear polyribonucleotides that include any combination of conjugated small molecules or aptamers for forming a complex by which the modified polyribonucleotide directly binds ubiquitin ligases or substrate proteins.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Thapa teaches an expanded CAG repeat motif in the mRNA (mRNA HTT) of individuals diagnosed with Huntington Disease (page 4, column 2, para 2). Absent evidence otherwise, it is the Examiner’s position that mRNA HTT inherently comprises mutations in two or more nucleotides. Supporting the Examiner’s position if the evidentiary reference of Nguyen which is cited to demonstrate that the CAG repeat expansion in the HTT gene contains m6A RNA modifications (abstract) and involves the methylation of adenosine at the nitrogen-6 position. Examiner contends that Thapa further teaches RNA binding ubiquitin ligase MID1, S6 Kinase (S6K) and Protein phosphatase 2A (PP2A) bind to the HTT mRNA and in conjugation with other proteins, which initiates ubiquitination of the protein substrate PP2A and S6K (page 4, column 2, para 2 and fig 3).
New 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.
Claims 40-44, 50, 55, 57, 60-65 are newly rejected under 35 U.S.C. 103 as being unpatentable over Thapa et al. (2019, BioEssays, cited on PTO-892 dated 7/29/2025) {herein Thapa) in view of Woody et al (1988, Biochemical and Biophysical Research Communications, Examiner cited) {herein Woody} as evidenced by Yao et al (2017, Cell, Examiner cited) {herein Yao}, Zhang et al (Journal of Cancer Research and Clinical Oncology, Examiner cited) {herein Zhang}, Fote et al (2024, Medical Sciences, Examiner cited) {herein Fote}. The new rejection is necessitated by Applicant amendment of claim 40 to recite ‘two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound’ and new claim 60.
As amended, claims 40-44, 50, 55, 60-61 are drawn to a complex comprising a modified linear polyribonucleotide bound to two or more ubiquitin ligases and to two or more substrate proteins , wherein: (a) the modified linear polyribonucleotide is bound to the two or more ubiquitin ligases by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a first chemical compound, wherein the first chemical compound binds one of the two or more ubiquitin ligases; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more ubiquitin ligases; and (b) the modified linear polyribonucleotide is bound to the two or more substrate proteins by way of: (i) two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound, wherein the second chemical compound binds one of the two or more substrate proteins; or (ii) two or more aptamers, wherein each aptamer binds one of the two or more substrate proteins; and wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins.
Previously presented claim 57 is drawn to a pharmaceutical composition comprising the complex according to claim 40.
New claims 62-65 are drawn to a complex comprising a bifunctional modified linear polyribonucleotide bound to two or more ubiquitin ligases, wherein the bifunctional modified linear polyribonucleotide has the following structure: X1- linear polyribonucleotide-X2, wherein each of X1 and X2 comprises one or more ubiquitin ligase binding moiety (UBM), wherein each UBM is bound to a ubiquitin ligase by way of: (i) a modified nucleotide comprising a functional group conjugated to a chemical compound, wherein the chemical compound binds the ubiquitin ligase; or (ii) an aptamer, wherein the aptamer binds the ubiquitin ligase.
With respect to claims 40-44, 50, 55, 57, 61-65, Thapa teaches an expanded CAG repeat motif in the mRNA (mRNA HTT) of individuals diagnosed with Huntington Disease (page 4, column 2, para 2). Said mRNA HTT is bifunctional since it promotes neurodegradation and the initiation of neurotoxic proteins (Fig 3), Evidentiary reference of Yau is cited to demonstrate that ubiquitin binds mRNA HTT heterotopically (branched and linear) (abstract). Furthermore, it is known by those of ordinary skill in the art that nucleotides natively contain the functional groups phosphate, a sugar and a nitrogenous base. The instant application defines ‘functional groups’ a being sugar nucleobase (Instant Application Specification: para 0092). As such, Examiner is interpreting the nucleotides CAG within the HHT mRNA as containing functional groups. Thapa further teaches RNA binding ubiquitin ligase MID1, S6 Kinase (S6K) and Protein phosphatase 2A (PP2A) bind to the HTT mRNA and in conjugation with other proteins, which initiates ubiquitination of the protein substrate PP2A and S6K (page 4, column 2, para 2 and fig 3). MID1 is a E3 ubiquitin ligase that binds to two binding moieties on the HTT mRNA. Evidentiary reference of Zhang is cited to demonstrate that MID1 is an inhibitor of apoptosis (page 856, column 2, para 1). As such, absent evidence otherwise, it is the Examiner’s position that said property is an inherent characteristic of the ubiquitinase. Additionally, absent evidence otherwise, it is the Examiner’s position that the nucleotide that allows for the binding of MID1 to the modified linear polyribonucleotide is interpreted as being a first chemical compound that binds MID1 ubiquitin ligases (page 4, column 2, para 2 and fig. 3, Table 1). Evidentiary reference of Fote is cited to demonstrate that HTT mRNA binds to ten or more ubiquitin ligases (Fig 3) and substrates (S4). As such, absent evidence otherwise, it is the Examiner’s position that ten or more ubiquitin and substrates inherently binds to HTT mRNA. As such, said property is not inventive. Furthermore, absent evidence otherwise, it is the Examiner’s position that PP2A and S6K are substrate proteins that bind the modified linear polyribonucleotide. In addition, absent evidence otherwise, it is the Examiner’s position that the nucleotide that allows for the binding of the substrate to the modified linear polyribonucleotide is a second chemical compound. Thapa further teaches that Furamidine can be utilized as a therapeutic for the treatment of Huntington Disease as it affects the binding of HTT mRNA to MID1, thereby stimulating neuroprotection (page 4, column 2, para 2). As such, absent evidence otherwise, it is the Examiner’s position that furamidine, HTT mRNA, MID1, PP2A , S6Kto be a pharmaceutical composition as said composition stimulates neuroprotection. Additionally, the instant application specification defines a pharmaceutical as the linear RNA (para 0279 and para 0286). As such, absent evidence otherwise, it is the Examiner’s position that the furamidine, HTT mRNA, MID1, PP2A, S6K is a pharmaceutical composition as it contains modified linear RNA in the version of HTT mRNA. Regarding the limitation “wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins,” this language does not require steps to be performed or limit the claim to a particular structure and does not limit the scope of the claim. See MPEP 2106.C and 2111.04. Instead, the “wherein the ubiquitin ligases modulates the two or more substrate proteins, thereby promoting degradation of the two or more substrate proteins” clause merely recites a correlation between ubiquitin and its usefulness in degrading substrates. It is unclear by the recitation ‘…X1- linear polyribonucleotide-X2...’ if Applicant intends on the ubiquitin ligases to bind the 5’ and 3’ ends of the linear polyribonucleotide since Applicant did not specify 3’ and/or 5’. As such, absent evidence otherwise, it is the Examiner’s position that the teaching of MID1 bound to the bifunctional modified linear polyribonucleotide meets the limitations of the instant application claim 62.
However, Thapa does not teach the product of two or more modified nucleotides each comprising a functional group conjugated to a second chemical compound (claim 40). Thapa does not teach wherein the two or more modified nucleotides are each modified 5-azido- C3-uridine-5'-triphosphate or 5-ethynyl-uridine-5'-triphosphate (claim 60).
With respect to claim 60, Woody teaches the utilization of 5-azido- C3-uridine-5'-triphosphate for analysis of RNA substrate binding (abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to apply the teachings of Thapa et al of a modified linear polyribonucleotide (mRNA HHT) that binds more than 10 ubiquitin ligases and substrates (page 4, column 2, para 2) or combine the teachings of Woody of the utilization of 5-azido- C3-uridine-5'-triphosphate for analysis of RNA substrate binding (abstract).
One of ordinary skill in the art would be motivated to either use the teachings of Thapa et al. by itself or combine the teachings of Woody because Woody provides the motivation for Thapa to utilize 5-azido- C3-uridine-5'-triphosphate for crosslinking experiments into RNA since 5-azido- C3-uridine-5'-triphosphate is a substrate for RNA polymerase (Woody: page 923, para 1) and would provide an accurate representation of the interaction between ubiquitin ligase and the modified linear polyribonucleotide. One of ordinary skill in the art would have a reasonable expectation of success to try utilizing 5-azido- C3-uridine-5'-triphosphate as a photolabeling molecule as it has been utilized in the art as far back as 1988 in the accurate detection of protein-RNA interactions (Woody). Furthermore, since it relies upon the cellular RNA polymerase for incorporation, it also serves as a mechanism for measuring cellular activity.
One of skill in the art would have a reasonable expectation of success to make and use the claimed modified linear polyribonucleotide because Thapa teaches a modified linear polyribonucleotide (mRNA HHT) that binds more than 10 ubiquitin ligases and substrates (page 4, column 2, para 2). Whereas Woody teaches the utilization of 5-azido- C3-uridine-5'-triphosphate for analysis of RNA substrate binding (abstract). Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: applicants remarks filed on 11/28/2025 have been fully considered; however, they are rendered moot in view of the new rejection set forth above, which is necessitated by applicants’ amendment to the claims. Examiner contends that Woody et al teaches the utilization of 5-azido- C3-uridine-5'-triphosphate for analysis of RNA substrate binding (abstract), of which would be obvious to one of ordinary skill in the art to utilize for measuring the ubiquitination of mRNA by ubiquitin ligase as it has been utilized in the art as far back as 1988 in the accurate detection of protein-RNA interactions (Woody) and can serve as a mechanism for measuring cellular activity.
Conclusion
Status of Claims
Claims 40-44, 50, 55, 57, 60-65 are pending.
Claims 1-39, 45-49, 51-54, 56, 58-59 are canceled.
Claims 40-44, 50, 55, 57, 60-65 are rejected.
No claims are in condition for allowance.
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.
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/ERICA NICOLE JONES-FOSTER/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656