DETAILED ACTION
The examiner for your application at the USPTO has changed. Examiner Abigail VanHorn can be reached at 571-270-3502.
Election/Restrictions
Applicant's election with traverse in the reply filed on October 14 2025 is acknowledged. Without addressing the merits of the arguments, in light of the search, the species election as set forth in the restriction requirement mailed on July 14 2025 is withdrawn.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Acknowledgement is made of the amendments to the sequence listing as well as the specification filed October 14 2025.
Claims 2, 4-5, 7, 9-11, 13, 15-17, 19-20, 22, 25-26, 29, 31, 35, 38, 40-42 and 44-48 were/stand cancelled. Claims 1, 3, 6, 8, 12, 14, 18, 21, 23-24, 27-28, 30, 32-34, 36-37, 39 and 43 are pending in the application.
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 .
Priority
This application is a 371 of PCT/US21/37955 (06/17/2021) which claims benefit of 63/040,949 (06/18/2020) as reflected in the filing receipt issued on 10/17/2025.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 1 2023 and October 15 2025 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The examiner notes that paragraph 00468, example 4, of the instant specification discusses the UNA siRNA oligomers of Table 3 and that they were formulated using methods described in U.S. Application No. 16/232212, filed on March 18 2020. However, this application number corresponds to a smart resistance band, and corresponds to USPGPUB No. 20200206556 (cited on PTO Form 1449 filed 10/15/2025). This Application number does not appear to provide support for UNA siRNA oligomers. Applicants are encouraged to review the cited Application number.
Claim Objections
Claim 1 is objected to because of the following informalities: the abbreviations rA, rU, rG, rC (specifically the “r”) and UNA are not defined in the claim. When an abbreviation is used the first time it should be defined. Here “r” is interpreted as meaning a natural or modified ribonucleotide. The recitation “UNA” is interpreted as meaning an unlocked nucleic acid. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 27-28, 30, 32 and 34 are 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 27 in the definition of X1, X2 and X3 recites as a choice:
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. However, as pointed to by the arrow, the nitrogen only contains two bonds. Therefore, it isn’t clear if the incorrect structure is written and there should be an additional chemical group attached (see for example RN in the structure recited in USPGPUB No. 20210060168) or a negative charge is missing (since the N would have to be negatively charged if only two bonds are attached). Therefore, the scope of the species is unclear. It is noted that the instant specification also does not clarify the issue as the exact same language appears in the instant specification.
The same issue occurs for the following species in claim 1: in the definition of L1, L2 and L3:
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; in the definition of X4 :
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.
Claim 27 as currently written is vague and indefinite. The structure of Formula II includes A-X4-Q wherein one species for X4 as claimed is -NHC(O)R2 wherein R2 is C1-C10 alkyl, carbocycle, heterocyclyl, etc. and is optionally substituted. This definition of X4 includes only one point of attachment but the structure of Formula II requires two points of attachment. Therefore, it is unclear where in the structure the other point of attachment is located. This issue is further complicated by the recitation that the R2 can be optionally substituted. The scope of attachment of X4 to A and/or Q is unclear.
A similar issue occurs with L4 in claim 27. Numerous species only include one “-“ such as -C(O)NH-C2-C10alkenyl-phosphate but never indicate where the other point of attachment is on the molecule since L4 is required to connect Q and R1.
Claim 34 as currently written is vague and indefinite. The claim recites several compounds which include the variable W1 and W2 and v but the claim never indicates what these variables stand for. The same lack of description for the variables T and Y in the last claimed structure. Since the claim never provides a description of these variables the scope of the claimed structure is unclear.
Claims 28, 30 and 32 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues. The examiner notes that while claim 30 does clarify the issue of claim 27 with regards to X4, the claim is included because it does not clarify all the issues identified in claim 27.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 3, 6, 8, 12, 14, 18, 21, 23-24, 36 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Alba et al. (Biochemistry, 2013, cited on PTO Form 1449) in view of Snead et al. (Molecular Therapy Nucleic Acids, 2013).
Applicant Claims
The instant application claims an oligomer comprising a sense strand and an antisense strand that mediates RNA interference against a target RNA sequence having a trinucleotide repeat expansion, wherein: a) the antisense strand comprises a sequence having at least 80% identity to the sequence of Formula (I): rGrCrUrGrCrUrGrCX1X2rCrUrGrCrUrGrCrUrG (I) (SEQ ID NO: 15), wherein X1 and X2 are each independently selected from the group consisting of rA, rU, rG, rC, UNA-A, UNA-U, UNA-G, and UNA-C and at least one of X1 and X2 is a UNA monomer; b) the oligomer comprises a UNA monomer at the first position at the 5’-end of the sense strand; and c) the sense strand and the antisense strand each independently comprise 19-29 monomers.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Alba et al. is directed to allele-selective inhibition of expression of huntingtin and ataxin-3 by RNA duplexes containing unlocked nucleic acid substitutions. Unlocked nucleic acid (UNA) is an acyclic analogue of RNA that can be introduced into RNA or DNA oligonucleotides. The increased flexibility conferred by the acyclic structure fundamentally affects the strength of base pairing, creating opportunities for improved applications and new insights into molecular recognition (abstract). Tested the effect of UNA substitutions within duplexes which were either fully complementary relative to target mRNAs or in duplexes that contained a mismatch at position 9 of the antisense strand. As shown in Figure 2A were duplexes that contained a single UNA substitutions at position 9, 10 or 11 from the 5’ termini of the guide (antisense) strand. Shown in Figure 3 is duplexes with a mismatched base at position 9 and the introduction of UNA substitutions. It is taught that two duplexes P9U9 and P9U13 had outstanding potency (page 9333, left column, third paragraph).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Alba et al. teach an antisense sequence which is the same as instantly claimed and teaches a sense strand, Alba et al. does not teach the sense strand contains a UNA monomer at the first position of the 5’-end. However, this deficiency is cured by Snead et al.
Snead et al. is directed to 5’ unlocked nucleic acid modification improve siRNA targeting. It is taught that optimization of small interfering RNAs is important in RNA interference based therapeutic development (abstract). Optimal siRNAs are biased toward selection and usage of the antisense (AS) strand. Sub-optimal siRNAs may perform poorly due to significant selection of the undesired S (sense) strand (page 1 bridging paragraph). It is taught that the incorporation of UNA (unlocked nucleic acid) at the 5’ end of the S strand not only retained but improved silencing potency of the AS strands which Snead et al. comments is consistent with a previous report. The conclusion is that the results supports the general applicability of the 5’ UNA modification to block silencing by the modified strand and concomitantly improved the silencing ability of the unmodified strand (page 3, right column). 5’ UNA modified (d)siRNAs would have the additional benefit of reducing off-target effects mediated by the S strand (page 6, end of first paragraph).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Alba et al. and Snead et al. and utilize 5’-UNA modification on the sense strand of the RNA duplex of Alba et al. One skilled in the art would have been motivated to utilize a UNA at a 5’-end (i.e. the first position) of the sense strand in order to reduce off-target effects and improve the silencing potency of the antisense strand as suggested by Snead et al. There is a reasonable expectation of success as Snead et al. teaches that optimization of small interfering RNAs is important in RNA interference based therapeutic development and Alba et al. teaches the use of UNA modification to improve potency.
Regarding claim 1, as shown in Figure 1 of Alba et al., REP-U9 has the structure GCUGCUGCUGCUGCUGCUGdTdT which is mixed with an equimolar sense RNA strand (5′-CAGCAGCAGCAGCAGCAGCdTdT-3′) (page 9330, right column, first paragraph). As shown below the sequence in Alba et al. (Db) has 100% identity to the instantly claimed SEQ ID NO: 5 wherein X1 is U and X2 is G.
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As shown in Figure 3: the mismatch sequence P9U9 is GCUGCUGCAGCUGCUGCUGdTdT (Db) which contains an UNA-A
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Regarding claim 3, as shown above, the sequence taught in Alba et al. is the same as instantly claimed.
Regarding claim 6, as shown above the sense and antisense strand both contain a dT at the first and second position from the 3’-end.
Regarding claim 8, as shown in Figure 3, X1 (position 9) is a UNA-A.
Regarding claim 12, incorporation of a UNA at the first position of the 5’-end of the sense strand of Alba et al. would result in a UNA-C.
Regarding claim 14, the oligomer has at least one blunt end.
Regarding claim 18, as taught by Snead et al. incorporation of the UNA at the first position of the sense strand results in reduced off-target effects.
Regarding claim 21, as shown in Figures 2 and 3 of Alba et al. the oligomer selective inhibitions expression of wt.
Regarding claim 23, as shown below the instantly claimed SEQ ID No: 2 (Qy) is the same as the sense strand of Alba et al. (Db):
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Regarding claim 24, as shown below P9U9 of Alba et al. (Db) is the same as instantly claimed SEQ ID No: 8 (Qy):
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Regarding claims 36 and 43, Alba et al. teaches transfecting the RNA duplexes into patient-derived fibroblast cells using a cationic lipid (page 9332) which reads on the oligomer (RNA duplex) and pharmaceutically acceptable carrier (cationic lipid) which reads on (i) in claim 43.
Claims 27-28, 30, 32-34, 37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Alba et al. in view of Snead et al. as applied to claims 1, 3, 6, 8, 12, 14, 18, 21, 23-24, 36 and 43 above and in further view of Rajappan et al. (USPGPUB No. 20210060168).
The applied reference, Rajappan et al., has a common Applicant and joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Applicant Claims
The oligomer is a conjugated oligomer of formula II. The instant application claims a pharmaceutical composition comprising the oligomer of claim 1 and a lipid of formula V.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Alba et al. and Snead et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Alba et al. and Snead et al. suggest the claimed oligomer with the instantly claimed UNA modifications, a conjugate of formula II is not taught. However, this deficiency is cured by Rajappan et al.
Rajappan et al. is directed to asialoglycoprotein receptor mediated delivery of therapeutically active conjugates. It is taught that the delivery of therapeutic agents into the cells or tissues of human subjects is important for its therapeutic effects and is usually impeded by a limited ability of the compound to reach targeted cells and tissues (paragraph 002). Taught are conjugates of therapeutically active molecules and an ASGP-R binding ligand that facilitates the hepatocyte selective delivery of the therapeutic molecule (paragraph 0005). As claimed the conjugate is of formula IA:
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wherein the difference between this structure and the instant claims is that R1 as claimed in Rajappan et al. is generally a biologically active molecule (claim 1). Specifically claimed R1 are antisense oligonucleotides (claims 19-20). Rajappan et al. teaches that a pharmaceutical composition comprising a compound of formula IA can be combined with a lipid of formula II:
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which is the same as instantly claimed (paragraph 0097). The lipids are taught as protecting it from enzymatic degradation (paragraph 0323).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Alba et al., Snead et al. and Rajappan et al. and utilize the conjugate of Formula IA of Rajappan et al. with the RNA duplex of Alba et al. One skilled in the art would have been motivated to utilize the conjugate in order to facilitate delivery of the RNA duplex into the cells or tissues as taught by Rajappan et al. Since Rajappan et al. teaches the conjugates can be used with antisense oligonucleotides and Alba et al. suggests the use of a lipid to deliver the RNA duplex there is a reasonable expectation of success.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Alba et al., Snead et al. and Rajappan et al. and utilize a lipid of formula II in combination with the conjugate of formula IA with the RNA duplex of Alba et al. One skilled in the art would have been motivated to utilize this additional lipid in order to help protect the compound from enzymatic degradation as taught by Rajappan et al. Since Rajappan et al. expressly teaches the combination of the lipid of Formula II with Formula IA there is a reasonable expectation of success.
Regarding claim 27, as set forth above Formula IA is the same as instantly claimed Formula II when R1 is an oligonucleotide.
Regarding claim 28, the same G1-G3 are claimed by Rajappan et al. (claim 9).
Regarding claim 30, the same X4 are claimed by Rajappan et al. (claim 11).
Regarding claim 32, Rajappan et al. claims a specific compound (claim 21) wherein R1 is an antisense oligonucleotide.
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Regarding claim 33, Rajappan et al. claims the following compound (claim 22). Exemplified compounds have the antisense oligonucleotide connected to the 5’ end (paragraph 0414; 0420).
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Regarding claim 34, Rajappan et al. the variable Q can be
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The same structures as instantly claimed 34 are taught (paragraph 0094).
Regarding claim 37, Rajappan et al. teaches that a pharmaceutical composition comprising a compound of formula IA can be combined with a lipid of formula II:
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which is the same as instantly claimed (paragraph 0097).
Regarding claim 39, the same lipids are taught (paragraph 0105) including:
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.
Claims 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Alba et al. in view of Snead et al. as applied to claims 1, 3, 6, 8, 12, 14, 18, 21, 23-24, 36 and 43 above and in further view of Cedillo et al. (WO 2018067900).
Applicant Claims
The oligomer is a conjugated oligomer of formula II.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Alba et al. and Snead et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Alba et al. and Snead et al. suggest the claimed oligomer with the instantly claimed UNA modifications, a conjugate of formula II is not taught. However, this deficiency is cured by Cedillo et al.
Cedillo et al. is directed to methods of conjugating oligomeric compounds. The conjugate when bound to a parent compound such as an oligonucleotide modifies one or more properties of the compound to which they are attached including pharmacokinetics, adsorption, cellular distribution, cellular uptake, etc. (page 14, lines 23-28). Taught are conjugated oligomeric compounds with the following structure (page 8; claim 15):
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Conjugate groups react with an oligomeric compound or an antisense oligonucleotide. The point of attachment is the 3’-end or 5’-end (paragraph bridging pages 15-16). Oligomeric compounds include RNAi compounds (page 17).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Alba et al., Snead et al. and Cedillo et al. and use the RNA duplex of Alba et al. in the conjugate of Cedillo et al. One skilled in the art would have been motivated to utilize the conjugate in order to improve properties of the RNA duplex as taught by Cedillo et al. There is a reasonable expectation of success as Alba et al. teaches the duplexes can be delivered with a lipid and Cedillo et al. suggests the use of the conjugate with antisense oligonucleotides.
Regarding claims 27-28,
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reads on instantly claimed G1-G3 being a monosaccharide i.e. galactosamine; L1-L3 is C6 alkyl; Y1-Y3 is NHC(O); X1-X3 is CH2-O-CH2 where m is 2 and n is 1; X4 is NHC(O) R2 wherein R2 is C3 alkyl; Q is C(O)NH-CH2 wherein j is 6 and L4 is phosphate or phosphorothioate.
Claims 37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Alba et al. in view of Snead et al. as applied to claims 1, 3, 6, 8, 12, 14, 18, 21, 23-24, 36 and 43 above and in further view of Payne et al. (USPGPUB No. 20180170866).
Applicant Claims
The instant application claims a pharmaceutical composition comprising the oligomer of claim 1 and a lipid of formula V.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Alba et al. and Snead et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Alba et al. suggests the use of a cationic lipid with the RNA duplex, Alba et al. does not expressly teach a lipid of formula V. However, this deficiency is cured by Payne et al.
Payne et al. is directed to ionizable cationic lipids for RNA delivery. Claimed is a compound of formula I:
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wherein a specific compound claimed is
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(claim 2). Taught are pharmaceutical composition comprising a lipid nanoparticle comprising a nucleic acid, preferably a RNA polynucleotide. The lipid nanoparticle increases the lifetime of RNA in circulation and delivers the nucleic acid to cells in the body. The cationic lipids are used in the pharmaceutical formulation (paragraph 0057).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Alba et al., Snead et al. and Payne et al. and utilize the cationic lipids of Payne et al. with the RNA duplex of Alba et al. One skilled in the art would have been motivated to utilize the cationic lipids in order to form pharmaceutical compositions which increase the lifetime of the RNA duplex in circulation and deliver the RNA to cells in the body as taught by Payne et al. There is a reasonable expectation of success as Alba et al. teaches the use of a cationic lipid for delivery of the RNA duplex and Payne et al. teaches the use of the cationic lipid with RNA.
Regarding claim 39, ATX-0083 is the same structure as instantly claimed, specifically the first structure in the right column on page 15 of the claim set.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 6, 8, 12, 14, 18, 21, 23-24, 27-28, 30, 32-33, 36 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12290567 in view of Alba et al. and Snead et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims an oligomer comprising a sense and antisense strand wherein the oligomer is conjugated to an oligomer of formula II.
Patent ‘567 claims a compound of formula IA
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wherein R1 is a biologically active molecule (claim 1). Specific compounds claimed include:
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(claim 17) and
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(claim 18). Specific R1 claimed include antisense oligonucleotides (claim 17, 18).
While Patent ‘567 claims an oligonucleotide, Patent ‘567 does not expressly claim the instantly claimed oligomer. However, this deficiency is cured by Alba et al. and Snead et al.
Alba et al. is directed to allele-selective inhibition of expression of huntingtin and ataxin-3 by RNA duplexes containing unlocked nucleic acid substitutions. Unlocked nucleic acid (UNA) is an acyclic analogue of RNA that can be introduced into RNA or DNA oligonucleotides. The increased flexibility conferred by the acyclic structure fundamentally affects the strength of base pairing, creating opportunities for improved applications and new insights into molecular recognition (abstract). Tested the effect of UNA substitutions within duplexes which were either fully complementary relative to target mRNAs or in duplexes that contained a mismatch at position 9 of the antisense strand. As shown in Figure 2A were duplexes that contained a single UNA substitutions at position 9, 10 or 11 from the 5’ termini of the guide (antisense) strand. Shown in Figure 3 is duplexes with a mismatched base at position 9 and the introduction of ulna substitutions. It is taught that two duplexes P9U9 and P9U13 had outstanding potency (page 9333, left column, third paragraph).
Snead et al. is directed to 5’ unlocked nucleic acid modification improvise siRNA targeting. It is taught that optimization of small interfering RNAs is important in RNA interference based therapeutic development (abstract). Optimal siRNAs are biased toward selection and usage of the antisense (AS) strand. Sub-optimal siRNAs may perform poorly due to significant selection of the undesired S (sense) strand (page 1 bridging paragraph). It is taught that the incorporation of UNA (unlocked nucleic acid) at the 5’ end of the S or strand not only retained but improved silencing potency of the AS strands which Snead et al. comments is consistent with a previous report. The conclusion is that the results supports the general applicability of the 5’ UNA modification to block silencing by the modified strand and concomitantly improved the silencing ability of the unmodified strand (page 3, right column). 5’ UNA modified (d)siRNAs would have the additional benefit of reducing off-target effects mediated by the S strand (page 6, end of first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘567, Alba et al. and Snead et al. and utilize the RNA duplex of Alba et al. with the conjugate of Formula IA of Patent ‘567. Since Patent ‘567 claims the biologically active agent is an oligonucleotide including antisense oligonucleotides and Alba et al. suggests the use of a lipid to deliver the RNA duplex there is a reasonable expectation of success in using the oligonucleotide of Alba et al. with the conjugate of Patent ‘567.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘567, Alba et al. and Snead et al. and utilize 5’-UNA modification on the sense strand of the RNA duplex of Alba et al. One skilled in the art would have been motivated to utilize a UNA modification at the 5’-end (i.e. the first position) of the sense strand in order to reduce off-target effects and improve the silencing potency of the antisense strand as suggested by Snead et al. There is a reasonable expectation of success as Snead et al. teaches that optimization of small interfering RNAs is important in RNA interference based therapeutic development and Alba et al. teaches the use of UNA modification to improve potency.
Regarding the claimed oligomer, as shown in Figure 1 of Alba et al., REP-U9 has the structure GCUGCUGCUGCUGCUGCUGdTdT is mixed with an equimolar sense RNA strand (5′-CAGCAGCAGCAGCAGCAGCdTdT-3′) (page 9330, right column, first paragraph). As shown below the sequence in Alba et al. (Db) has 100% similarity to the instantly claimed SEQ ID NO: 5 wherein X1 is U and X2 is G.
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As shown in Figure 3: the mismatch sequence P9U9 is GCUGCUGCAGCUGCUGCUGdTdT (Db) which contains an UNA-A
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Regarding claim 3, as shown above, the sequence taught in Alba et al. is the same as instantly claimed.
Regarding claim 6, as shown above the sense and antisense strand both contain a dT at the first and second position from the 3’-end.
Regarding claim 8, as shown in Figure 3, X1 (position 9) is a UNA-A.
Regarding claim 12, incorporation of a UNA at the first position of the 5’-end of the sense strand of Alba et al. would result in a UNA-C.
Regarding claim 14, the oligomer has at least one blunt end.
Regarding claim 18, as taught by Snead et al. incorporation of the UNA at the first position of the sense strand results in reduced off-target effects.
Regarding claim 21, as shown in Figures 2 and 3 of Alba et al. the oligomer selective inhibitions expression of wt.
Regarding claim 23, as shown below the instantly claimed SEQ ID No: 2 (Qy) is the same as the sense strand of Alba et al. (Db):
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Regarding claim 24, as shown below P9U9 of Alba et al. (Db) is the same as instantly claimed SEQ ID No: 8 (Qy):
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Regarding claim 27-28, 30 and 32-33, Patent ‘567 claims the same structure as set forth above.
Regarding claims 36 and 43, Alba et al. teaches transfecting the RNA duplexes into patient-derived fibroblast cells using a cationic lipid (page 9332) which reads on the oligomer (RNA duplex) and pharmaceutically acceptable carrier (cationic lipid) which reads on (i) in claim 43.
Claims 1, 3, 6, 8, 12, 14, 18, 21, 23-24, 27-28, 30, 32-34, 36-37, 39 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8, 11, 13, 19, 22, 25, 28, 30-31, 34-35, 37, 39-41, 43-44, 46-47, 49, 51 and 56 of copending Application No. 18001574 (USPGPUB No. 20230227826). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, Copending ‘574 claims a method for inhibiting expression of a protein encoded by an mRNA having an expanded trinucleotide repeat region comprising administering to a subject an oligomer comprising a sense strand and an antisense strand wherein: a) the antisense strand comprises a sequence having at least 80% identity to the sequence of Formula (I): rGrCrUrGrCrUrGrCX1X2rCrUrGrCrUrGrCrUrG (I), wherein X and X2 are each independently selected from the group consisting of rA, rU, rG, rC, UNA-A, UNA-U, UNA-G, and UNA-C and wherein at least one of X and X2 is a UNA monomer; b) the oligomer comprises a UNA monomer at the first position at the 5'-end of the sense strand; and c) the sense strand and the antisense strand each independently comprise 19-29 monomers.
Therefore, copending ‘574 claims the same oligomer as instantly claimed as formula I is the same as instantly claimed.
Regarding claim 3, copending ‘574 claims the same limitations (claim 8).
Regarding claim 6, copending ‘574 claims the same limitations (claim 11).
Regarding claim 8, copending ‘574 claims the same limitations (claim 13)
Regarding claim 12, copending ‘574 claims the same limitations (claim 19).
Regarding claim 14, copending ‘574 claims the same limitations (claim 22).
Regarding claim 18, copending ‘574 claims the same limitations (claim 25).
Regarding claim 21, copending ‘574 claims the same limitations (claim 28).
Regarding claim 23, copending ‘574 claims the same limitations (claim 30).
Regarding claim 24, copending ‘574 claims the same limitations (claim 31).
Regarding claims 27-28, 30 and 32-34, copending ‘574 claims the same limitations (claims 34-35, 37, 39 and 40-41).
Regarding claims 36 and 43, copending ‘574 claims the same limitations (claim 43 and 51).
Regarding claims 37 and 39, copending ‘574 claims the same limitations (claim 44 and 46).
The examiner notes that the instant application and copending ‘574 have the same patent term filing date. Note: MPEP 804.
Claims 1, 3, 6, 8, 12, 14, 18, 21, 23-24, 36-37, 39 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-40 of copending Application No. 18457090 (USPGPUB No. 20230398076) in view of Alba et al. and Snead et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1 and 37, copending ‘090 claims an apparatus for producing a lipid-encapsulated RNA nanoparticle wherein the lipid is of formula I which is the same as instantly claimed formula V (claim 1). Cationic lipids are claimed (claim 36). RNA claimed include antisense RNA, small interfering RNA, etc. (claim 40).
While copending ‘090 claims an apparatus which produces a lipid encapsulated RNA nanoparticle which contains the same lipid as instant claim 37 and an RNA, copending ‘090 does not claim the oligomer of claim 1. However, this deficiency is cured by Alba et al. and Snead et al.
The teachings of Alba et al. and Snead et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘090, Alba et al. and Snead et al. and utilize the RNA duplex of Alba et al. with the lipid of formula I of copending ‘090. Since copending ‘090 claims the RNA is an antisense RNA or small interfering RNA and Alba et al. suggests the use of a lipid to deliver the RNA duplex there is a reasonable expectation of success in using the oligonucleotide of Alba et al. with the lipid of copending ‘090 to conjugate and deliver the RNA.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘090, Alba et al. and Snead et al. and utilize 5’-UNA modification on the sense strand of the RNA duplex of Alba et al. One skilled in the art would have been motivated to utilize a 5’-end (i.e. the first position) of the sense strand in order to reduce off-target effects and improve the silencing potency of the antisense strand as suggested by Snead et al. There is a reasonable expectation of success as Snead et al. teaches that optimization of small interfering RNAs is important in RNA interference based therapeutic development and Alba et al. teaches the use of UNA modification to improve potency.
Regarding the claimed oligomer, as shown in Figure 1 of Alba et al., REP-U9 has the structure GCUGCUGCUGCUGCUGCUGdTdT is mixed with an equimolar sense RNA strand (5′-CAGCAGCAGCAGCAGCAGCdTdT-3′) (page 9330, right column, first paragraph). As shown below the sequence in Alba et al. (Db) has 100% similarity to the instantly claimed SEQ ID NO: 5 wherein X1 is U and X2 is G.
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As shown in Figure 3: the mismatch sequence P9U9 is GCUGCUGCAGCUGCUGCUGdTdT (Db) which contains an UNA-A
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Regarding claim 3, as shown above, the sequence taught in Alba et al. is the same as instantly claimed.
Regarding claim 6, as shown above the sense and antisense strand both contain a dT at the first and second position from the 3’-end.
Regarding claim 8, as shown in Figure 3, X1 (position 9) is a UNA-A.
Regarding claim 12, incorporation of a UNA at the first position of the 5’-end of the sense strand of Alba et al. would result in a UNA-C.
Regarding claim 14, the oligomer has at least one blunt end.
Regarding claim 18, as taught by Snead et al. incorporation of the UNA at the first position of the sense strand results in reduced off-target effects.
Regarding claim 21, as shown in Figures 2 and 3 of Alba et al. the oligomer selective inhibitions expression of wt.
Regarding claim 23, as shown below the instantly claimed SEQ ID No: 2 (Qy) is the same as the sense strand of Alba et al. (Db):
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Regarding claim 24, as shown below P9U9 of Alba et al. (Db) is the same as instantly claimed SEQ ID No: 8 (Qy):
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Regarding claims 36 and 43, Alba et al. teaches transfecting the RNA duplexes into patient-derived fibroblast cells using a cationic lipid (page 9332) which reads on the oligomer (RNA duplex) and pharmaceutically acceptable carrier (cationic lipid) which reads on (i) in claim 43.
Regarding claims 37 and 39, Copending ‘090 claims the same structure as set forth above.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636