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 .
Election/Restrictions
Claims 1-9, 13, 17, 24-26 are pending.
Applicant’s election without traverse of Group I in the reply filed on 08/05/2026 is acknowledged.
Applicant’s election of following species of SEQ ID NO: 33 and T moiety illustrated below:
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Claims 9, 13, 25-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/05/2026.
Claims 1-8, 17 and 24 read on the elected group and species and are examined here.
Priority
The benefit to 62/663,162, filed on 04/26/2018, via a 371 of PCT/US2019/028613, filed on 04/23/2019, and 17/048,163, filed on 10/16/2020, is recognized.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/15/2025 was filed before the mailing date of this first Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 1-8, 17, 24 is rejected under 35 U.S.C. 103 as being unpatentable over Watanabe et al. (US20130211062, pub. 08/15/2013, “Watanabe”) and Hanson (WO2012150960, pub. 11/8/2012, in IDS).
Claim 1 recites a group of dystrophin pre-mRNA annealing site coordinates, e.g. “H53A(+32+56)”, the H represents human, 53 represents exon number, A represents exon acceptor site, the +32+56 represents annealing coordinates between the 32nd and 56th nucleotide from the start of the exon (pg. 31, line 16-31).
Second, it should be pointed out that Formula III of cl. 5 is a bit different from Formula I of claim 1. For Formula III, the T moiety and repeating Z PMO structures are not separated by a PMO with a base (Nu) as it is in Formula I.
Regarding instant cl. 1, 5, Watanabe discloses pharmaceutical composition which causes skipping of the 53rd exon in the human dystrophin gene with a high efficiency (abstract). Watanabe discloses two related diseases associated with mutation in dystrophin gene: Duchenne muscular dystrophy (DMD) and Becker’s muscular dystrophy (BMD; par. 4). DMD is the most frequent form of hereditary progressive muscular dystrophy that affects one in about 3,500 newborn boys, progressively resulting in muscle weakness, loss of ambulation, cardiac failure and then eventually early death (par. 2). The cause of DMD is due to a mutation in the dystrophin gene resulting in shifting of the transcript’s reading frame and abolishing its expression, while for BMD the mutation results in expression of a dystrophin protein but functions imperfectly due to some of the exons being deleted (par. 4). Thus, one suggested treatment for DMD is to skip exons with mutations by modifying splicing to restore the reading frame by bypassing the region with the mutation (par. 5). The produced protein is shorter than wild-type but the patients would retain partial stability of muscle cells and would have milder symptoms, similar to patients with BMD (par. 5).
Watanabe discloses “approximately 8% of all DMD patients may be treated by skipping the 53rd exon” and discloses a morpholino based oligomer that binds to the region of exon 53 of the pre-mRNA and causes the skipping of the exon by blocking the splicing machinery from binding to the region during intron excision (par. 5-6, 9, 74). Watanabe targets various regions of exon 53 with various sizes of morpholino oligomers and identifying morpholino oligomers that are successful in skipping exon 53 (see Fig. 1, Table 1, par. 72). Watanabe discloses a PMO No. 8 (phosphorodiamidate morpholino oligomer, which comprises dimethyl amino, par. 101) exon 53 skipping oligomer, which when tested in cultured cells from DMD patients “caused exon 53 skipping with an efficiency as high as more than 80% in the cells from DMD patients with deletion of exons 45-52 (Fig. 4) or deletions of exons 48-52 (Fig. 5)” (par. 280). The PMO No. 8 corresponds to SEQ ID NO: 35 that targets position 36-56 of Exon 53, see Table 2 (par. 191) and Table 1 discloses its sequence (see below for excerpt of Table 1, par. 71).
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SEQ ID NO: 35 of Watanabe is 100% identical to instant elected SEQ ID NO: 33; see below:
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and X is T or U.
Watanabe discloses a structure of “group 1” bound to 5’ end of a PMO oligomer (par. 162; see structure below of group 1), which is identical to the instant elected T moiety.
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Watanabe links the group 1 structure to the 5’ end of a PMO (PMO No. 14, also SEQ ID NO: 35 corresponding to H53A (36-56) see Table 2) and demonstrates that it has ~70% skipping efficiency, a little less than skipping efficiency of No. 8, which lacks the TEG moiety (Fig. 8)
Watanabe does not disclose the 6-arginine peptide at the 3’ end of the PMO oligomer.
Hanson discloses a cell-penetrating peptide (aka – carrier peptide) conjugated to the 3’ end of the PMO oligomer thus aiding in delivery of the PMO oligomer (provided below, see cover page).
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Table 1 discloses numerous carrier peptide (pg. 31). Testing various arginine peptide lengths (from 5-8 arginines) conjugated to a PMO in a DMD mouse model, Hanson demonstrates that “[a]mongst the arginine series, the R6G peptide (R6 is 6-arginines, the G is glycine) has the highest efficacy in quadriceps and diaphragm and was similar to the other arginine series peptides in heart” (Ex. 30, pg. 147, lines 12-14). Although Hanson does not disclose the exact structure of -GR6; the structures of glycine and arginine are known, and the instant Formula III uses glycine to link the 6 arginine to the PMO (relevant to instant cl. 1, 5).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teaching of the PMO No.8 of Watanabe in view of Hanson and arrive at the claimed invention with a reasonable expectation of success. Based on success of Watanabe’s PMO No. 8 being a highly efficient oligomer in skipping exon 53 of dystrophin pre-mRNA transcript and Hanson noting that R6G peptide has a very high efficacy in quadriceps, diaphragm and heart, a skilled artisan would reasonably expect success in modifying the PMO No. 8 of Watanabe with R6G of Hanson to have the PMO be delivered in vivo to a specific target tissue, such as quadriceps, diaphragm or the cardiac tissue. Thus, claims 1 and 5 are prima facie obvious.
Regarding instant cl. 2, Watanabe discloses that H53(+36+56) was a preferred annealing site of exon 53 of dystrophin (see Fig. 1) and discloses SEQ ID NO: 35, which is a 21-monomer sequence in length. SEQ ID NO: 35 of Watanabe has a Z value of 19 with flanking PMOs with a Nu at 5’ end and at 3’ end (see SEQ ID NO: 35 below).
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Regarding instant cl. 3, Watanabe discloses SEQ ID NO: 35 bound to a TEG moiety, thus reads on elected instant SEQ ID NO: 33 of 21 nt., with X is T or U.
Regarding instant cl. 4, 5, Watanabe discloses each X is a T, see above.
Regarding instant cl. 6, 7, here Z value is interpreted to be amended due to the lack of PMO between the T moiety (i.e. the elected TEG moiety) and the repeating Z PMOs of Formula III of cl. 5.
Watanabe discloses SEQ ID NO: 35 with a TEG moiety, a 21-nt. sequence with a TEG moiety, which reads on Z of 20 with one PMO with a Nu base at 3’ end (i.e. a 21-nt. sequence) of elected SEQ ID NO: 33.
Regarding instant cl. 17, 24, Watanabe discloses administering a pharmaceutical composition comprising the oligomer of present invention (par. 164-166) and preferably contains a carrier to promote delivery to muscle tissue (par. 168).
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, 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 6, 24, 56, 63, 66, 74, 78, of copending Application No. 19/112,897 (‘897).
This is a provisional nonstatutory double patenting rejection.
Claim 1 of ‘897 teaches a 18-40 subunits in length targeting sequence complementary to a target region of a DMD gene with a PMO backbone in a 5’-3’ order and the target region is within an exon of human dystrophin pre-mRNA with upstream splice site with a slower intron compared to downstream of a slow intron.
Claim 6 teaches wherein the exon is exon 53. Claim 24 recites wherein the targeting sequence is SEQ ID NO: 65, which shares a 17-base sequence with instant elected SEQ ID NO: 33.
Qy 5 CGGNNCNGAAGGNGNNC 21 (instant SEQ ID NO: 33)
Db 1 CGGTTCTGAAGGTGTTC 17 (SEQ ID NO: 65, where X is T or U).
Claim 56 teaches a genus of PMO of Formula I (see below) and targeting sequence of SEQ ID NO: 65 (see above).
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Claim 63 teaches that Formula I is Formula (Ia):
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Claim 66 teaches L is glycine, claim 74 teaches that J is R6, and claim 78 teaches G is C(O)CH3 (corresponding to the TEG structure and R6 targeting peptide of instant cl. 1). Claim 56 teaches R2 is a nucleobase and R1 is N(R3)(R4) and R3 and R4 are C1-6 alkyl and z is 8-40 (thus, reading on instant internucleotide structure of cl. 1). Instant Internucleotide linkage of dimethyl group of R3 and R4 fall within the range of ‘897 genus, thus is prima facie obvious.
SEQ ID NO: 65 shares a 17-base sequence with instant elected SEQ ID NO: 33. Here, there is sufficient overlap between the two nucleobase sequences as instant claim requires Z is an integer 16 to 23 nucleobases (corresponding to instant H53A(+36+56); thus there is an overlap and the claim is prima facie obvious.
Claim 79 teaches a pharmaceutical composition and one carrier, corresponding to instant cl. 17.
Conclusion
No claim allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
Prosecution Insights