DETAILED ACTION
This action is in reply to papers filed 12/15/2025.
Claims 16-18, 20-23, 27-30, and 32 are pending and examined herein.
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
Applicant elected without traverse of Group 1, and the species of SEQ ID NO: 3 and desmin promoter, in the reply filed on 04/22/2025. Claims 33-37 are withdrawn from consideration as being drawn to a non-elected inventive group (claims 33-35) or to a non-elected species (claims 36-37).
Withdrawn Objection(s) and/or Rejection(s)
The objection to the drawings filed 03/14/2022 are withdrawn in light of the amended drawings filed 12/15/2025, which overcome the basis of the prior objection regarding sheet margins, view number, and color drawings without a petition.
The objection to the specification is withdrawn in light of the amended specification, which includes the Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1).
The objections to claims 17, 18, 20, 23, and 29 regarding minor informalities are withdrawn in light of amendments to the claims.
The rejection of claim 16 under 35 U.S.C. 112(b) is withdrawn in light of amendments to the claim.
Claim Objections
Claim 16 remains objected to because of the following informalities: “mir208a” (line 6) should be corrected to the commonly used abbreviation in the art, which is “miR-208a,” as recited in line 3 of claim 16. Appropriate correction is required.
Claim Interpretation
Claim 16 recites the limitation “therapeutically acceptable level” (line 5). As Applicant noted in the Remark filed 12/15/2025, the phrase “therapeutically acceptable amount” is defined in the specification as referring to “an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition, including alleviating symptoms of such diseases” (para 38 of PGPUB US2022/0370640 A1). This definition is acknowledged and used for the purposes of examination.
Claim 23 is drawn to an expression system comprising nucleotides 146 to 3946 of SEQ ID NO: 3, or nucleotides 146 to 3974 of SEQ ID NO: 4. The specification maps the nucleotides in SEQ ID NOs: 3 and 4 to particular sequences or functions (p 34). Nucleotides 3175-3180 of SEQ ID NO: 4, which is has the sequence CTCGAG, is identified as a spacer sequence between the two miR-208 target sequences (p33). However, the specification is silent as to the identity of nucleotides 3147-3152 and 3175-3180 of SEQ ID NO: 3, and nucleotides 3147-3152 and 3203-3208 of SEQ ID NO: 4. In addition to being possible spacer sequences, as with nucleotides 3175-3180 of SEQ ID NO: 4, each of these 5-base pair sequences correspond to a recognition sequence for restriction enzymes, which are known in the art. In the absence of a clear definition in the specification, the identities of these nucleotide sequences are given their broadest reasonable interpretation, which includes spacer sequences and recognition sequences for restriction enzymes.
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 16-18, 21, 27-30, and 32 remain rejected under 35 U.S.C. 103 as being unpatentable over Roudaut (Circulation, 2013; main text cited as Reference No. 24 in IDS filed 03/14/2022), in view of Grimm (WO 2019/207132 A1; effective filing date 04/27/2018), as evidenced by UniProt ID: FKRP_HUMAN (earliest publication 03/01/2001);
Roudaut teaches the AAV2/9-desmin-CAPN3-miR208aT vector (p 1099, col 1, para 2; also referred to as the “pdes.C3-T vector”). This vector comprises AAV2/9-desmin-CAPN3, which is an AAV2/9 carrying the human CAPN3 cDNA under the control of the desmin promoter (p 1095, col 1, para 5; claims 21, 28-30). This vector further comprises miR208aT, which is a DNA fragment carrying 2 copies of miR208a target sequence in tandem (p 1096, col 1, para 2-3; claim 16).
Roudaut teaches injecting the pdes.C3-T vector in an 800µL volume of viral preparation (reads on pharmaceutical composition of claim 32; Supplementary materials, p 6) into the tail vein of C3-knockout mice (p 1101, col 2, para 2). Post-mortem anatomopathological examination showed an absence of toxicity in the heart (p 1101, col 2, para 2). Roudaut further teaches that the calpain3 protein was not detected in the heart (p 1101, col 2, para 2), but that high expression of CAPN3 transgene was detected in skeletal muscles (p 1101, col 2, para 2 – p 1102, col 1, para 1) (claims 16, 27). Roudaut teaches that the skeletal muscles injected with the pdes.C3-T vector displayed improved histological features compared muscles from control mice injected with PBS (p 1102, col 1, para 2; Fig 8A) (claim 16).
Roudaut further teaches that the molecular strategies presented in the paper, including the pdes.C3-T vector, can be used to prevent cardiac toxicity not only for calpainopathies caused by mutations in the CAPN3 gene, but also for any other transgene with potential toxicity in the heart (p 1103, col 1, para 3).
Roudaut does not teach an expression system comprising a sequence encoding FKRP.
Grimm teaches an AAV vector comprising a modified AAV capsid for use in treating and preventing muscular disease and muscle regeneration (p 2, ln 5-10). Grimm teaches that the muscular disease to be treated includes LGMD2A and LGMD2I, which are caused by mutations in CAPN3 and FKRP, respectively (p 11, ln 20-27). Grimm further teaches that a polynucleotide encoding a non-disease mediating variant, such as a wildtype variant, of either CAPN3 or FKRP can function as a pharmaceutically active agent in the AAV capsid (p 25, ln 32 – p 26, ln 2).
Given the teachings of Grimm, there was a reasonable expectation that a polynucleotide encoding CAPN3 or FKRP would work equivalently as a pharmaceutically active agent in a vector comprising an AAV capsid. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the CAPN3 cDNA in the pdes.C3-T vector taught in Roudaut with the FKRP cDNA with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Furthermore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pdes.C3-T vector taught in Roudaut by substituting the CAPN3 cDNA with the FKRP cDNA as the pharmaceutically active agent in the AAV vector, as taught in Grimm. One of ordinary skill in the art would have been motivated to make this modification to create vector to enable the delivery of FKRP to the skeletal muscles without toxicity in the heart. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Roudaut teaches that the pdes.C3-T vector can be used to prevent cardiac toxicity not only for calpainopathies caused by mutations in the CAPN3 gene, but also for any other transgene with potential toxicity in the heart (p 1103, col 1, para 3), and Grimm teaches that a polynucleotide encoding a non-disease mediating variant, such as a wildtype variant, of either CAPN3 or FKRP can function as a pharmaceutically active agent in an AAV capsid (p 25, ln 32 – p 26, ln 2).
The combination of prior art cited above in both rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 82 USPQ2d 1385 (US 2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) 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.
In the present situation, rationales B and G are applicable. The modification of Roudaut with the teachings of Grimm represent substitution for one known element for another, and 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. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Regarding claim 17: Grimm is silent as to the sequence of FKRP. UniProt ID: FKRP_HUMAN is the amino acid sequence of human FKRP. SEQ ID NO: 5 of the instant application is 100% identical to UniProt ID: FKRP_HUMAN. Alignment is attached.
Regarding claim 18: Nucleotides 1659 to 3146 of the sequences set forth in SEQ ID NOs 1: 3, and 4 are identical to each other. Translated nucleotides 1659 to 3146 of the sequences set forth in SEQ ID NOs 1: 3, and 4 are 100% identical to the amino acid sequence set forth in SEQ ID NO: 5. Alignments are attached.
Claims 16 and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over Roudaut (Circulation, 2013; main text cited as Reference No. 24 in IDS filed 03/14/2022), in view of Grimm (WO 2019/207132 A1; effective filing date 04/27/2018), as evidenced by UniProt ID: FKRP_HUMAN (earliest publication 03/01/2001), and further in view of Shyu (Canadian Journal of Cardiology, 2015).
The teachings of Roudaut and Grimm are set forth above.
Roudaut, in view of Grimm, as evidenced by UniProt ID: FKRP_HUMAN, renders obvious claim 16.
Regarding claim 20: The pdes.C3-T vector comprises miR208aT, which is a DNA fragment carrying 2 copies of miR208a target sequence in tandem (p 1096, col 1, para 2-3). The target sequence of miR208a used in Roudaut is ACAAGCTTTTGCTCGTCTTAT, which is a 21 base-pair sequence that differs from the sequence set forth in SEQ ID NO:2 (Supplementary materials, p 1, para 1) that differs from the 22-base pair sequence set forth in SEQ ID NO: 2 by one thymine base (ACAAGCTTTTTGCTCGTCTTAT).
Shyu teaches a sequence of human miR-208a antigomer (p 681, col 1, para 1), which is 100% identical to the sequence set forth in SEQ ID NO: 2 of the instant application:
Qy 1 ACAAGCTTTTTGCTCGTCTTAT 22
||||||||||||||||||||||
Db 1 ACAAGCTTTTTGCTCGTCTTAT 22
Given the teachings of Shyu, there was a reasonable expectation that the miR208a sequence taught in Roudaut and the miR208a sequence taught in Shyu would work equivalently. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the miR208a sequence taught in Roudaut with the miR208a sequence taught in Shyu with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claims 16 and 21-22 remain rejected under 35 U.S.C. 103 as being unpatentable over Roudaut (Circulation, 2013; main text cited as Reference No. 24 in IDS filed 03/14/2022), in view of Grimm (WO 2019/207132 A1; effective filing date 04/27/2018), as evidenced by UniProt ID: FKRP_HUMAN (earliest publication 03/01/2001), and further in view of Vandendriessche (US 2017/0275649 A1).
The teachings of Roudaut and Grimm are set forth above.
Roudaut, in view of Grimm, as evidenced by UniProt ID: FKRP_HUMAN, renders obvious claims 16 and 21.
Regarding claim 22: Roudaut is silent as to the sequence of the desmin promoter. Vandendriessche teaches a human desmin promoter having the sequence set forth in SEQ ID NO: 47 (para 29). The sequence set forth in SEQ ID NO: 6 of the instant application is 100% identical to bases 24-1084 of the sequence set forth in SEQ ID NO: 47 of Vandendriessche. Alignment is attached. Vandendriessche teaches that the desmin promoter having the sequence set forth in SEQ ID NO: 47 can be used in an AAV vector (para 35).
Given the teachings of Vandendriessche, there was a reasonable expectation that the desmin promoter having the sequence set forth in SEQ ID NO: 47 and the desmin promoter taught in Roudaut would work equivalently as a desmin promoter in an AAV vector. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the desmin promoter taught in Roudaut with the desmin promoter having the sequence set forth in SEQ ID NO: 47 of Vandendriessche with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claims 16 and 21-23 remain rejected under 35 U.S.C. 103 as being unpatentable over Roudaut (Circulation, 2013; main text cited as Reference No. 24 in IDS filed 03/14/2022), in view of Grimm (WO 2019/207132 A1; effective filing date 04/27/2018), as evidenced by UniProt ID: FKRP_HUMAN (earliest publication 03/01/2001), in view of Vandendriessche (US 2017/0275649 A1), and further in view of Gicquel (Human Molecular Genetics, 2017; cited as Reference No. 13 in IDS filed 03/14/2022), Charton (ESGCT and FSGT Collaborative Congress, 2015, P159; cited as Reference No. 11 in IDS filed 03/14/2022), Xu (Molecular Therapy, 2013), Olafsdottir (Acta Veterinaria Scandinavica, 2008), Karn (Gene, 1984), and Ford (Addgene Blog, 2016).
The teachings of Roudaut, Grimm, and Vandendriessche are set forth above.
Roudaut, in view of Grimm, as evidenced by UniProt ID: FKRP_HUMAN, renders obvious claims 16 and 21.
Roudaut, in view of Grimm, as evidenced by UniProt ID: FKRP_HUMAN, and further in view of Vandendriessche, renders obvious claims 16 and 21.
Regarding claim 23: Nucleotides 146-3946 of SEQ ID NO: 3 consists of the following:
Nucleotides 146-1206 of SEQ ID NO: 3 is 100% identical to the sequence set forth in SEQ ID NO: 6, which is the desmin promoter.
Nucleotides 1207-1652 of SEQ ID NO: 3 corresponds to the sequence of the HBB2 intron.
Nucleotides 1203-1658 of SEQ ID NO: 3 corresponds to the consensus Kozak sequence (GCCACC).
Nucleotides 1659-3146 of SEQ ID NO: 3 encode the human FKRP protein, the sequence of which is set forth in SEQ ID NO: 5.
Nucleotides 3147-3152 of SEQ ID NO: 3 is TCTAGA.
Nucleotides 3153-3174 of SEQ ID NO: 3 are 100% identical to the sequence set forth in SEQ ID NO: 2, which is the miR-208a target sequence.
Nucleotides 3175-3180 of SEQ ID NO: 3 is CTCGAG.
Nucleotides 3181-3946 of SEQ ID NO: 3 corresponds to the HBB2 polyA sequence.
Roudaut, in view of Grimm, as evidenced by UniProt ID: FKRP_HUMAN, and further in view of Vandendriessche, does not teach 1) Nucleotides 1207-1652 of SEQ ID NO: 3, corresponding to the sequence of the HBB2 intron; 2) Nucleotides 3181-3946 of SEQ ID NO: 3 corresponds to the HBB2 polyA sequence; 3) A single-copy miR-208a target sequence, corresponding to nucleotides 3153-3174 of SEQ ID NO: 3; 4) Nucleotides 1203-1658 of SEQ ID NO: 3, corresponding to the consensus Kozak sequence (GCCACC); 5) Nucleotides 3147-3152 of SEQ ID NO: 3 (TCTAGA), or 6) Nucleotides 3175-3180 of SEQ ID NO: 3 (CTCGAG).
Regarding differences 1-2: Gicquel teaches an rAAV2/9 vector comprising a desmin promoter, followed by the HBB2 intron (reads on nucleotides 1207-1652 of SEQ ID NO: 3), murine FKRP cDNA, and the HBB2 polyA signal (reads on nucleotides 3181-3946 of SEQ ID NO: 3) (Fig 3A; p 1962, col 1, para 1). This vector was injected intramuscularly into mice, where overexpression of FKRP was confirmed (p 1955, col 1, para 4 – p 1955, col 2, para 1).
Given the teachings of Gicquel, there was a reasonable expectation that the FKRP cargo placed between the HBB2 intron and the HBB2 polyA signal, as taught in Gicquel, and the FKRP cargo taught in Roudaut would work equivalently as an FKRP cargo under the control of a desmin promoter in an AAV vector. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the FKRP cargo taught in Roudaut with the FKRP cargo placed between the HBB2 intron and the HBB2 polyA signal, as taught in Gicquel, with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding difference 3: Charton teaches an AAV vector for the delivery of calpain 3 to mice, wherein the vector comprises a target sequence of miR208 in the AAV cassette to prevent cardiotoxicity of the vector (A74, P159, para 1). Charton teaches that systemic injection of this vector, comprising one target sequence of miR208, resulted in specific regulation of the calpain 3 transgene in the heart and prevention of cardiac events (A74, P159, para 1).
Given the teachings of Charton, there was a reasonable expectation that an AAV vector comprising one target sequence of miR208, as taught in Charton, and an AAV vector comprising a tandem target sequence of miR208, as taught in Roudaut, would work equivalently to prevent cardiotoxicity of the vector. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the tandem target sequence of miR208, as taught in Roudaut, with one target sequence of miR208, as taught in Charton, with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding difference 4: Xu teaches an AAV vector comprising the mouse FKRP, wherein the Kozak sequence GCCACC was placed in front of the N-terminus of the FKRP coding sequence (Materials and Methods; Supplementary Figure S1). Xu teaches that intraperitoneal administration of the AAV9-FKRP vector to mice resulted in systemic FKRP expression in all striated muscles (Abstract).
Olafsdottir teaches that a Kozak sequence adjacent to the ATG start codon greatly increases the efficiency of translation, and therefore overall expression, of the gene product (p 2, col 1, para 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV vector taught in Roudaut, in view of Grimm, as evidenced by UniProt ID: FKRP_HUMAN, and further in view of Vandendriessche, Gicquel, and Charton, by placing the GCCACC Kozak sequence in front of the N-terminus of the FKRP coding sequence, as taught in Xu. One of ordinary skill in the art would have been motivated to make this modification because Olafsdottir teaches that a Kozak sequence adjacent to the ATG start codon greatly increases the efficiency of translation, and therefore overall expression, of the gene product. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Xu teaches that a Kozak sequence can be was placed in front of the N-terminus of the FKRP coding sequence in an AAV vector intended for systemic delivery.
Regarding differences 5-6: Nucleotides 3147-3152 of SEQ ID NO: 3 is TCTAGA, which is a recognition sequence for the restriction enzyme XbaI, as evidenced by Karn (Fig 1). Nucleotides 3175-3180 of SEQ ID NO: 3 is CTCGAG, which is a recognition sequence for the restriction enzyme XhoI, as evidenced by Karn (Fig 1).
Karn teaches a phage cloning vector comprising a polylinker oligonucleotide, which introduces cleavage sites for XbaI and XhoI (abstract). Ford teaches that the ideal vector backbone contains a variety of restriction enzyme cut sites downstream of the promoter as part of a multiple cloning site, and that having multiple sites facilitates the orientation of gene insert with respect to the promoter (p 2, para 1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have placed the recognition sequences for XbaI and XhoI, which are taught in a single vector in Karn, in the AAV vector. The placement of restriction enzyme digest sites in a vector is a design choice, which is considered obvious. See MPEP 2144(VI)(C).
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 16-18, 20-22, 27-30, and 32 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 5-10 of U.S. Patent No. US 9,981,049 B2 in view of Grimm (WO 2019/207132 A1), as evidenced by UniProt ID: FKRP_HUMAN (earliest publication 03/01/2001), and further in view of Vandendriessche (US 2017/0275649 A1).
Regarding claims 16, 20, and 27: Reference claims 1 and 3 are drawn to an expression vector comprising a nucleic acid sequence encoding a myotubularin polypeptide, and at least one additional sequence, which consists of the target sequence of miR208a as set forth in SEQ ID NO: 10. SEQ ID NO: 10 of the reference application is 100% identical to SEQ ID NO: 2 of the instant application (claim 20). Alignment is attached.
The expression vector of reference claim 1 does not comprise a sequence encoding FKRP.
Grimm teaches an AAV vector comprising a modified AAV capsid for use in treating and preventing muscular disease and muscle generation (p 2, ln 5-10). Grimm teaches that the muscular disease to be treated includes myotubular myopathy and LGMD2I, which are caused by mutations in MTM1 and FKRP, respectively (p 11, ln 20-27; p 12, ln 20-21). Grimm further teaches that a polynucleotide encoding a non-disease mediating variant, such as a wildtype variant, of either MTM1 or FKRP can function as a pharmaceutically active agent in the AAV capsid (p 25, ln 32 – p 26, ln 2).
Given the teachings of Grimm, there was a reasonable expectation that a polynucleotide encoding MTM1 or FKRP would work equivalently as a pharmaceutically active agent in a vector comprising an AAV capsid. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the sequences set forth in SEQ ID NOs: 1, 2, or 3 with with a sequence encoding FKRP with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Furthermore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the expression vector of reference claim 1 by substituting the MTM1 cDNA with the FKRP cDNA as the pharmaceutically active agent in the AAV vector, as taught in Grimm. One of ordinary skill in the art would have been motivated to make this modification to create vector to enable the delivery of MTM1 to the skeletal muscles without toxicity in the heart. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Grimm teaches that a polynucleotide encoding a non-disease mediating variant, such as a wildtype variant, of either MTM1 or FKRP can function as a pharmaceutically active agent in an AAV capsid (p 25, ln 32 – p 26, ln 2).
Regarding claim 17: Grimm is silent as to the sequence of FKRP. UniProt ID: FKRP_HUMAN is the amino acid sequence of human FKRP. SEQ ID NO: 5 of the instant application is 100% identical to UniProt ID: FKRP_HUMAN. Alignment is attached.
Regarding claim 18: Nucleotides 1659 to 3146 of the sequences set forth in SEQ ID NOs 1: 3, and 4 are identical to each other. Translated nucleotides 1659 to 3146 of the sequences set forth in SEQ ID NOs 1: 3, and 4 are 100% identical to the amino acid sequence set forth in SEQ ID NO: 5. Alignments are attached.
The viral vector of reference claim 8 reads on claim 28. The AAV vector of reference claim 9 reads on claim 29. The AAV8 or AAV9 vector of reference claim 10 reads on claim 30. The pharmaceutical compositions of reference claims 5 and 6 read on claim 32.
Regarding claims 21-22: Reference claim 7 is drawn to the expression vector of reference claim 3, further comprising a desmin promoter consisting of the nucleic acid sequence set forth in SEQ ID NO: 11. SEQ ID NO: 11 of the reference application is not identical to SEQ ID NO: 6 of the instant application.
Vandendriessche teaches a human desmin promoter having the sequence set forth in SEQ ID NO: 47 (para 29). The sequence set forth in SEQ ID NO: 6 of the instant application is 100% identical to bases 24-1084 of the sequence set forth in SEQ ID NO: 47 of Vandendriessche. Alignment is attached. Vandendriessche teaches that the desmin promoter having the sequence set forth in SEQ ID NO: 47 can be used in an AAV vector (para 35).
Given the teachings of Vandendriessche, there was a reasonable expectation that the desmin promoter having the sequence set forth in SEQ ID NO 47 of Vandendriessche and the desmin promoter having the sequence set forth in SEQ ID NO: 11 of the reference application would work equivalently as a desmin promoter in an AAV vector. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the desmin promoter having the sequence set forth in SEQ ID NO: 11 of the reference application with the desmin promoter having the sequence set forth in SEQ ID NO: 47 of Vandendriessche, which is identical to the sequence set forth in SEQ ID NO: 6 of the instant application, with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claims 16-18, 20-22, 27-30, and 32 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-9, and 12 of U.S. Patent No. US 11,819,478 B2 in view of Grimm (WO 2019/207132 A1), Roudaut (Circulation, 2013; main text cited as Reference No. 24 in IDS filed 03/14/2022), and Vandendriessche (US 2017/0275649 A1), as evidenced by UniProt ID: FKRP_HUMAN (earliest publication 03/01/2001)
Regarding claims 16, 20-22, and 27: Reference claims 1 and 9 are drawn to an expression vector comprising a nucleic acid sequence encoding a calpain 3, a muscle-specific promoter sequence, and at least one target sequence of miR208a as set forth in SEQ ID NO: 10. SEQ ID NO: 10 of the reference application is 100% identical to SEQ ID NO: 2 of the instant application (claim 20). Alignment is attached.
The expression vector of reference claims 1 and 9 does not comprise 1) a sequence encoding FKRP, or 2) a desmin promoter.
Regarding difference 1: Grimm teaches an AAV vector comprising a modified AAV capsid for use in treating and preventing muscular disease and muscle generation (p 2, ln 5-10). Grimm teaches that the muscular disease to be treated includes myotubular myopathy and LGMD2I, which are caused by mutations in MTM1 and FKRP, respectively (p 11, ln 20-27; p 12, ln 20-21). Grimm further teaches that a polynucleotide encoding a non-disease mediating variant, such as a wildtype variant, of either MTM1 or FKRP can function as a pharmaceutically active agent in the AAV capsid (p 25, ln 32 – p 26, ln 2).
Given the teachings of Grimm, there was a reasonable expectation that a polynucleotide encoding CAPN3 or FKRP would work equivalently as a pharmaceutically active agent in a vector comprising an AAV capsid. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the sequences encoding CAPN3 in the vector of reference claim 1 with sequences encoding FKRP with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Furthermore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector of reference claim 1 by substituting the CAPN3 cDNA with the FKRP cDNA as the pharmaceutically active agent in the AAV vector, as taught in Grimm. One of ordinary skill in the art would have been motivated to make this modification to create vector to enable the delivery of FKRP to the skeletal muscles without toxicity in the heart. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Grimm teaches that a polynucleotide encoding a non-disease mediating variant, such as a wildtype variant, of either CAPN3 or FKRP can function as a pharmaceutically active agent in an AAV capsid (p 25, ln 32 – p 26, ln 2).
Regarding difference 2: Roudaut teaches the AAV2/9-desmin-CAPN3-miR208aT vector (p 1099, col 1, para 2; also referred to as the “pdes.C3-T vector”). This vector comprises AAV2/9-desmin-CAPN3, which is an AAV2/9 carrying the human CAPN3 cDNA under the control of the desmin promoter (p 1095, col 1, para 5). This vector further comprises miR208aT, which is a DNA fragment carrying 2 copies of miR208a target sequence in tandem (p 1096, col 1, para 2-3).
Roudaut further teaches the AAV2/9-pmiR206-CAPN3 vector (also referred to as the “p206.C3 vector”), which was created by exchanging the desmin promoter of the pdes.C3-T vector with a miR-206 promoter (p 1099, col 1, para 2 – col 2, para 1). Roudaut teaches that both vectors did not induce cardiac fibrosis in mice upon injection (p 1099, col 2, para 1), and that the skeletal muscles injected with the vectors displayed improved histological features compared muscles from control mice injected with PBS (p 1102, col 1, para 2; Fig 8A).
Given the teachings of Roudaut, there was a reasonable expectation that a desmin promoter and miR-206 promoter would work equivalently as a promoter in an AAV vector comprising a target sequence to be expressed in the skeletal muscles and a target sequence for miR-208. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted miR-208 promoter, as recited in reference claim 1, with the desmin promoter, as taught in Roudaut, with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding claim 17: Grimm is silent as to the sequence of FKRP. UniProt ID: FKRP_HUMAN is the amino acid sequence of human FKRP. SEQ ID NO: 5 of the instant application is 100% identical to UniProt ID: FKRP_HUMAN. Alignment is attached.
Regarding claim 18: Nucleotides 1659 to 3146 of the sequences set forth in SEQ ID NOs 1: 3, and 4 are identical to each other. Translated nucleotides 1659 to 3146 of the sequences set forth in SEQ ID NOs 1: 3, and 4 are 100% identical to the amino acid sequence set forth in SEQ ID NO: 5. Alignments are attached.
The viral vector of reference claim 5 reads on claim 28. The AAV vector of reference claim 6 reads on claim 29. The AAV8 or AAV9 vector of reference claim 7 reads on claim 30. The pharmaceutical compositions of reference claims 8 and 12 read on claim 32.
Response to Arguments
Any reference cited below is provided solely to rebut Applicant’s arguments.
Claim Rejections Under 35 U.S.C. § 103
Applicant argues: Roudaut relates to calpain 3 and/or myotubularin, which are unrelated to FKRP and are associated with different pathologies (XLMTM and LGMD2A). As disclosed in the specification as filed, patients having pathologies linked to a FKRP deficiency such as Limb-Girdle Muscular Dystrophy type 21 (LGMD21) often display cardiac abnormalities. Therefore, according to the common knowledge in the art when the present application was filed, a sustained level of FKRP expression in the heart was considered beneficial, especially to alleviate the cardiac symptoms of FKRP-associated diseases. The skilled artisan therefore would not have considered the vectors of Roudaut to prevent cardiac expression of FKRP as doing so would have eliminated what the skilled artisan would have understood to be beneficial effects of such expression. Moreover, Applicant respectfully submits that the skilled artisan would understand that tissue-specific toxicity depends strongly on the gene expressed. While Roudaut generally and broadly hypothesizes that their molecular strategies may be used to prevent cardiac toxicity for any transgene with potential toxicity in the heart, Roudaut does not mention FKRP or any additional transgenes. Given that the skilled artisan would have understood FKRP transgene to be expression in the heart to be beneficial, the skilled artisan would not have understood Roudaut' s broad hypothesis to relate to FKRP expression since cardiac toxicity of FKRP was unknown.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Importantly, Roudat teaches that the vector taught therein can be used to prevent cardiac toxicity “for any other transgene with potential toxicity in the heart” (p 1103, col 1, para 3; emphasis added); the teachings of Roudat does not require that the transgene has confirmed toxicity in the heart. Gicquel (Human Molecular Genetics, 2017, 26(10): 1952-1965; cited in IDS filed 03/14/2022), for example, teaches that injection of high doses of an rAAV2/9 vector expressing Fkrp induced a decrease of αDG glycosylation and laminin binding, and that intravenous injection of said vector into an Fkrp-knockout mouse model indicated dose-dependent toxicity (Abstract), indicating potential cardiac toxicity as a consequence of Fkrp overexpression. Therefore, the potential cardiac toxicity of FKRP overexpression was known in the art before the effective filing date of the claimed invention.
Applicant argues: Grimm is generally related to AAV capsids having increased transduction efficiencies and cell specificities using modified AAV capsids. While Grimm broadly discloses modified AAV vectors encoding various human genes, including FKRP, for use in treating and/or preventing a muscular disease and/or in muscle regeneration, Grimm merely includes FKRP among a laundry list of potential transgenes that can be used with Grimm's modified AAVs. Grimm does not call out FKRP or otherwise place any importance on its inclusion in the list. Rather, Grimm is focused on AAV capsids comprising a specific peptide insertion, which is meant to increase transduction efficiencies of the AAV capsid into muscle cells. The vectors of Roudaut do not contain such a peptide and Grimm does not address control of transgene expression or cardiac safety concerns that may potentially arise from expression of any transgene, let alone expression of FKRP specifically. The skilled artisan would therefore have no reason to select FKRP out of Grimm's list and insert it into a vector that does not comprise the capsid modification that is the focus of Grimm's disclosure in order to reduce cardiac toxicity of FKRP expression that was previously unrecognized in the art. Given that, as disclosed in the specification as filed, the skilled artisan would have understood FKRP expression in the heart to be beneficial rather than toxic, as well as Roudaut and Grimms failure to teach or suggest that such expression may be toxic, the skilled artisan would have had no reason to modify the vectors of Roudaut and Grimm to express FKRP and at least one miR-208a target sequence as required by the present claims. Claim 16 is therefore non-obvious over Roudaut and Grimm.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Both Roudat and Grimm teach AAV vectors for use in treating muscular disease. That Grimm teaches FKRP and CAPN3 among a multitude of muscular dystrophy-associated genes, and that Grimm does not teach FKRP as the preferred embodiment, does not render the use of a FKRP transgene in the vector of Roudat less obvious. Furthermore, as set forth in the response to the previous argument, the teachings of Roudat does not require that the transgene used in the vector taught therein has confirmed toxicity in the heart, but merely potential toxicity, and the potential cardiac toxicity of FKRP overexpression was known in the art before the effective filing date of the claimed invention (e.g., Gicquel 2017).
Applicant argues: Shyu shows that microRNA miR-208a plays a key role in cardiac fibrosis following myocardial infarction (MI) in rats. MI increases the expression of miR-208a, which activates the production of endoglin and ß-MHC, two markers of pathological cardiac remodeling. Increased miR-208a leads to cardiac fibrosis, while its inhibition (with an antagomir) or treatment with atorvastatin and valsartan reduces this fibrosis. Thus, miR-208a is a central regulator of cardiac fibrosis via endoglin. Shyu does not provide any disclosure related to gene expression de-targeting in specific muscles. Nor does Shyu provide any teaching related to muscular dystrophies and FKRP, even more to the potential cardiac toxicity of FKRP. Nothing in Shyu would lead the skilled artisan to include a miR-208a target sequence in an expression vector that selectively expresses FKRP in skeletal muscle and at a non-toxic level in cardiac muscle. Claim 20 is therefore nonobvious over Roudaut, Grimm, and Shyu.
In response: Applicant’s arguments have been fully considered, but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Shyu is relied upon for teaching a sequence of human miR-208a antigomer, which is 100% identical to the sequence set forth in SEQ ID NO: 2 of the instant application. As set forth above in the rejection of claim 16 under 35 USC 103, Roudat, in view of Grimm teaches a miR-208a target sequence in an expression vector that selectively expresses FKRP in skeletal muscle and at a non-toxic level in cardiac muscle.
Applicant argues: Vandendriessche is related to nucleic acid regulatory elements (i.e., specific DNA sequences) to enhance expression in skeletal muscle or in both skeletal and cardiac muscle. Consistently, Vandendriessche teaches that its preferred promoter is a desmin promoter, which is expressed in both skeletal and cardiac muscle. Vandendriessche does not mention FKRP or FKRP expression. Vandendriessche also does not teach or suggest that expression of any transgene, let alone FKRP specifically, could be toxic when expressed in cardiac muscle. Nothing in Vandendriessche would motivate the skilled artisan looking to selectively express FKRP in skeletal muscle while limiting toxicity in cardiac muscle to select a promoter that is expressed in both tissues. Claim 23 is therefore non-obvious over Roudaut, Grimm, Uniprot ID: FKRP HUMAN, and Vandendriessche.
In response: Applicant’s arguments have been fully considered, but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Vandendriessche is relied upon for teaching a sequence of a desmin promoter, which is 100% identical to the sequence set forth in SEQ ID NO: 6 of the instant application. As set forth above in the rejection of claim 16 under 35 USC 103, Roudat, in view of Grimm teaches an expression vector that selectively expresses FKRP in skeletal muscle and at a non-toxic level in cardiac muscle.
Applicant argues: Gicquel reports the systemic administration of an AAV9 comprising an FKRP-coding sequence under the control of the desmin promoter, with a reported beneficial effect on muscle function. Gicquel recommends controlling the level of transgene expression due to potentially harmful effects on muscle or an immune response. However, Gicquel does not investigate effect on cardiac tissue nor suggest potential toxicity.
In response: Applicant’s arguments have been fully considered, but are not persuasive because Applicant’s arguments regarding Gicquel are unclear. As set forth above in the rejection of claim 23 under 35 USC 103, Gicquel is cited for its teaching regarding nucleotides 1207-1652 of SEQ ID NO: 3, corresponding to the sequence of the HBB2 intron, and nucleotides 3181-3946 of SEQ ID NO: 3, corresponding to the HBB2 polyA sequence. As set forth above in the rejections under 35 USC 103, Roudat, in view of Grimm, renders obvious claim 16. Gicquel is not relied upon for the rejection of claim 16.
Applicant argues: Charton demonstrates that AAV vectors incorporating target sequences for specific microRNAs can regulate transgene expression to improve safety and efficacy in gene therapy for LGMD. By including miRNA142-3p or miR-208 target sequences, immune responses in antigen-presenting cells and cardiac toxicity were reduced. This enabled long-term, tissue-specific therapeutic expression of alpha-sarcoglycan or calpain 3. Charton does not relate to FKRP or expression systems for targeted expression of FKRP. There is nothing in Charton that would teach or suggest to the ordinarily skilled artisan that inclusion of a miR-208a target sequence in an expression system for targeted expression of FKRP would be effective at reducing cardiac toxicity of FKRP expression. This is especially true given the teaching in the specification as filed that the cardiac toxicity of FKRP overexpression was previously unknown. The skilled artisan would therefore have no reason to look to Charton or to otherwise combine the teachings of Charton with Roudaut, Grimm, UniProt ID: FKRP HUMAN, Vandendriessche, Gicquel, Xu, Olafsdottir, Karn, and Ford, as asserted in the Office Action.
In response: Applicant’s arguments have been fully considered, but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Charton is relied upon for teaching a sequence of an AAV vector for the delivery of calpain 3 to mice, wherein the vector comprises a target sequence of miR208 in the AAV cassette to prevent cardiotoxicity of the vector (A74, P159, para 1). As set forth above in the rejection of claim 16 under 35 USC 103, Roudat, in view of Grimm, teaches an expression vector that selectively expresses FKRP in skeletal muscle and at a non-toxic level in cardiac muscle.
Applicant argues: Xu describes that AAV9-mediated gene therapy efficiently restores FKRP expression in skeletal and cardiac muscles of FKRP-mutant mice. The vector of Xu shows strong cardiac tropism and minimal liver expression with no observed toxicity. However, Xu's vectors used a beta-actin chicken promoter coupled with the CMV enhancer. Olafsdottir merely describes that adding a full Kozak sequence to expression vectors greatly improved HAS protein production in horse cells. The W2 vector of Olafsdottir, with both a Kozak sequence and intron A, showed the highest expression and is a strong candidate for developing Th1-focused vaccines against insect bite hypersensitivity in horses. This supports the importance of expression regulation but is unrelated to FKRP or cardiac safety. Nothing in Xu or Olafsdottir teach or suggest the inclusion of a FKRP sequence and a miR-208a target sequence in an expression system for the targeted expression of FKRP as required by claim 16. Nor would the skilled artisan have any reason to look to Xu or Olafsdottir and arbitrarily utilize only the Kozak sequence in combination with random specific components taught in Roudaut, Grimm, UniProt ID: FKRP HUMAN, Vandendriessche, Gicquel, Charton, Karn, and Ford, as asserted in the Office Action.
In response: Applicant’s arguments have been fully considered, but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As set forth above in the rejection of claim 16 under 35 USC 103, Roudat, in view of Grimm, renders obvious the inclusion of a FKRP sequence and a miR-208a target sequence in an expression system for the targeted expression of FKRP. Neither Xu nor Olafsdottir is relied upon for said limitations in claim 16. As set forth above in the rejection of claim 23 under 35 USC 103, Xu teaches an AAV vector comprising FKRP, wherein the Kozak sequence GCCACC was placed in front of the N-terminus of the FKRP coding sequence, and Olafsdottir teaches that a Kozak sequence adjacent to the ATG start codon greatly increases the efficiency of translation, and therefore overall expression, of the gene product. Therefore, one of ordinary skill in the art would have been motivated to have modified the AAV vector taught in Roudaut, in view of Grimm, and further in view of Vandendriessche, Gicquel, and Charton, by placing the GCCACC Kozak sequence in front of the N-terminus of the FKRP coding sequence, as taught in Xu because Olafsdottir teaches that a Kozak sequence adjacent to the ATG start codon greatly increases the efficiency of translation and overall expression of the gene product.
Applicant argues: Karn describes the lambda 2001 vector in an improved phage cloning system with a 34-bp polylinker allowing insertion of 10-23 kb DNA fragments and selectable Spi-recombinants. Ford describes standard molecular cloning techniques and emphasizes the importance of positioning the insert properly with respect to the promoter, but it does not discuss gene therapy applications or tissue specificity. Nothing in Karn nor Ford teaches or reasonably suggests the inclusion of a FKRP sequence and a miR-208a target sequence in an expression system for the targeted expression of FKRP as required by claim 16. Nor would the skilled artisan have any reason to look to Karn or Ford and arbitrarily utilize only the restriction sequence in combination with random specific components taught in Roudaut, Grimm, UniProt ID, Vandendriessche, Gicquel, Charton, Xu, and Olafsdottir, as asserted in the Office Action.
In response: Applicant’s arguments have been fully considered, but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As set forth above in the rejection of claim 16 under 35 USC 103, Roudat, in view of Grimm, renders obvious the inclusion of a FKRP sequence and a miR-208a target sequence in an expression system for the targeted expression of FKRP. Neither Karn nor Ford is relied upon for said limitations in claim 16. As set forth above in the rejection of claim 23 under 35 USC 103, given the teachings of Karn and Ford, the placement of restriction enzyme digest sites in a vector is a design choice, which is considered obvious.
Applicant argues: The present invention relates to a combination of a promoter allowing expression at a therapeutically acceptable level of FKRP in the skeletal muscles and at least one target sequence of mir208a. The expression system according to the invention avoids undesired (excessive) "leakages" of FKRP expression into cardiac tissue, resulting in harmful effects, i.e. a potential toxicity. The cited prior art (i) does not recognize the potential toxicity of FKRP in cardiac tissue, (ii) does not suggest or motivate combining a specific promoter as listed with miR-208a target sequence(s) to control cardiac expression, and (iii) provides no teaching or expectation that this combination would yield a safe and effective gene therapy for LGMD2I. Claims 16-18, 20-23, 27-30, and 32, are thus non-obvious over the cited art.
In response: Applicant’s arguments have been fully considered, but are not persuasive. The responses to (i) and (ii) have been addressed above. Regarding (iii), the primary reference, Roudat, teaches that the AAV vector taught therein can be used to prevent cardiac toxicity for any other transgene with potential toxicity in the heart” (p 1103, col 1, para 3), indicating the efficacy of said vector for gene therapy.
Double Patenting Rejections
Regarding U.S. Patent No. US 9,981,049 B2, Applicant argues: As discussed above with respect to the obviousness rejection, the skilled artisan would have understood FKRP transgene to be expression in the heart to be beneficial. Grimm merely includes FKRP among a laundry list of potential transgenes that can be used with Grimm's modified AAVs. Grimm does not call out FKRP or otherwise place any importance on its inclusion in the list. Rather, Grimm is focused on AAV capsids comprising a specific peptide insertion, which is meant to increase transduction efficiencies of the AAV capsid into muscle cells. The skilled artisan would therefore have no reason to select FKRP out of Grimm's list and insert it into a vector that does not comprise the capsid modification that is the focus of Grimm's disclosure in order to reduce cardiac toxicity of FKRP expression that was previously unrecognized in the art. The present claims are therefore novel and non-obvious over the issued claims of the '049 patent.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Both the ‘049 patent and Grimm teach viral vectors for use in treating muscular disease. That Grimm teaches FKRP and MTM1 among a multitude of muscular dystrophy-associated genes, and that Grimm does not teach FKRP as the preferred embodiment, does not render the use of a FKRP transgene in the vector of ‘049 less obvious.
Regarding U.S. Patent No. US 11,819,478 B2, Applicant argues: In addition, as discussed above, the skilled artisan would not have considered modifying the vectors of Roudaut to prevent cardiac expression of FKRP as doing so would have eliminated what the skilled artisan would have understood to be beneficial effects of such expression. Moreover, Applicant respectfully submits that the skilled artisan would understand that tissue-specific toxicity depends strongly on the gene expressed. While Roudaut generally and broadly hypothesizes that their molecular strategies may be used to prevent cardiac toxicity for any transgene with potential toxicity in the heart, Roudaut does not mention FKRP or any additional transgenes. The' 478 patent is likewise silent regarding FKRP. Given that the skilled artisan would have understood FKRP transgene to be expression in the heart to be beneficial, the skilled artisan would not have understood Roudaut's broad hypothesis to relate to FKRP expression. Grimm merely includes FKRP among a laundry list of potential transgenes that can be used with Grimm's modified AAVs. Grimm does not call out FKRP or otherwise place any importance on its inclusion in the list. Rather, Grimm is focused on AA V capsids comprising a specific peptide insertion, which is meant to increase transduction efficiencies of the AAV capsid into muscle cells. The skilled artisan would therefore have no reason to select FKRP out of Grimm's list and insert it into a vector that does not comprise the capsid modification that is the focus of Grimm's disclosure in order to reduce cardiac toxicity of FKRP expression that was previously unrecognized in the art. The present claims are therefore novel and non-obvious over the issued claims of the '478 patent.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Roudat, Grimm, and the ‘478 patent teach viral vectors for use in treating muscular disease. That Grimm teaches FKRP and CAPN3 among a multitude of muscular dystrophy-associated genes, and that Grimm does not teach FKRP as the preferred embodiment, does not render the use of a FKRP transgene in the vector of the ‘478 patent less obvious. As set forth in the body of the rejection, given the teachings of Grimm, there was a reasonable expectation that a polynucleotide encoding CAPN3 or FKRP would work equivalently as a pharmaceutically active agent in the vector of the ‘478 patent.
Sequence Alignments
SEQ ID NO: 9 aligned to UniProt ID: FKRP_HUMAN
Query Match 100.0%; Score 2598; Length 495;
Best Local Similarity 100.0%;
Matches 495; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRLTRCQAALAAAITLNLLVLFYVSWLQHQPRNSRARGPRRASAAGPRVTVLVREFEAFD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRLTRCQAALAAAITLNLLVLFYVSWLQHQPRNSRARGPRRASAAGPRVTVLVREFEAFD 60
Qy 61 NAVPELVDSFLQQDPAQPVVVAADTLPYPPLALPRIPNVRLALLQPALDRPAAASRPETY 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NAVPELVDSFLQQDPAQPVVVAADTLPYPPLALPRIPNVRLALLQPALDRPAAASRPETY 120
Qy 121 VATEFVALVPDGARAEAPGLLERMVEALRAGSARLVAAPVATANPARCLALNVSLREWTA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VATEFVALVPDGARAEAPGLLERMVEALRAGSARLVAAPVATANPARCLALNVSLREWTA 180
Qy 181 RYGAAPAAPRCDALDGDAVVLLRARDLFNLSAPLARPVGTSLFLQTALRGWAVQLLDLTF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RYGAAPAAPRCDALDGDAVVLLRARDLFNLSAPLARPVGTSLFLQTALRGWAVQLLDLTF 240
Qy 241 AAARQPPLATAHARWKAEREGRARRAALLRALGIRLVSWEGGRLEWFGCNKETTRCFGTV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 AAARQPPLATAHARWKAEREGRARRAALLRALGIRLVSWEGGRLEWFGCNKETTRCFGTV 300
Qy 301 VGDTPAYLYEERWTPPCCLRALRETARYVVGVLEAAGVRYWLEGGSLLGAARHGDIIPWD 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VGDTPAYLYEERWTPPCCLRALRETARYVVGVLEAAGVRYWLEGGSLLGAARHGDIIPWD 360
Qy 361 YDVDLGIYLEDVGNCEQLRGAEAGSVVDERGFVWEKAVEGDFFRVQYSESNHLHVDLWPF 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 YDVDLGIYLEDVGNCEQLRGAEAGSVVDERGFVWEKAVEGDFFRVQYSESNHLHVDLWPF 420
Qy 421 YPRNGVMTKDTWLDHRQDVEFPEHFLQPLVPLPFAGFVAQAPNNYRRFLELKFGPGVIEN 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 YPRNGVMTKDTWLDHRQDVEFPEHFLQPLVPLPFAGFVAQAPNNYRRFLELKFGPGVIEN 480
Qy 481 PQYPNPALLSLTGSG 495
|||||||||||||||
Db 481 PQYPNPALLSLTGSG 495
Nucleotides 1659-3146 of SEQ ID NO: 3 aligned to nucleotides 1659-3146 of SEQ ID NO: 4
Nucleotides 1659-3146 of SEQ ID NO: 3 aligned to nucleotides 1659-3146 of SEQ ID NO: 1
Query Match 100.0%; Score 1488; DB 1; Length 1488;
Best Local Similarity 100.0%;
Matches 1488; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGAGACTGACCAGGTGCCAGGCTGCCCTGGCTGCTGCCATCACCCTGAACCTGCTGGTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ATGAGACTGACCAGGTGCCAGGCTGCCCTGGCTGCTGCCATCACCCTGAACCTGCTGGTG 60
Qy 61 CTGTTCTATGTGAGCTGGCTGCAGCACCAGCCCAGGAACAGCAGGGCCAGGGGCCCCAGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CTGTTCTATGTGAGCTGGCTGCAGCACCAGCCCAGGAACAGCAGGGCCAGGGGCCCCAGG 120
Qy 121 AGGGCCTCTGCTGCTGGCCCCAGGGTGACAGTGCTGGTGAGGGAGTTTGAGGCCTTTGAC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AGGGCCTCTGCTGCTGGCCCCAGGGTGACAGTGCTGGTGAGGGAGTTTGAGGCCTTTGAC 180
Qy 181 AATGCTGTGCCTGAGCTGGTGGACAGCTTCCTGCAGCAGGACCCTGCCCAGCCTGTGGTG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AATGCTGTGCCTGAGCTGGTGGACAGCTTCCTGCAGCAGGACCCTGCCCAGCCTGTGGTG 240
Qy 241 GTGGCTGCTGATACCCTGCCCTACCCCCCCCTGGCCCTGCCCAGGATCCCCAATGTGAGG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GTGGCTGCTGATACCCTGCCCTACCCCCCCCTGGCCCTGCCCAGGATCCCCAATGTGAGG 300
Qy 301 CTGGCCCTGCTGCAGCCTGCCCTGGACAGGCCTGCTGCTGCCAGCAGGCCTGAGACCTAT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CTGGCCCTGCTGCAGCCTGCCCTGGACAGGCCTGCTGCTGCCAGCAGGCCTGAGACCTAT 360
Qy 361 GTGGCCACAGAGTTTGTGGCCCTGGTGCCTGATGGGGCCAGGGCTGAGGCCCCTGGCCTG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GTGGCCACAGAGTTTGTGGCCCTGGTGCCTGATGGGGCCAGGGCTGAGGCCCCTGGCCTG 420
Qy 421 CTGGAGAGGATGGTGGAGGCCCTGAGGGCTGGCTCTGCCAGGCTGGTGGCTGCCCCTGTG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 CTGGAGAGGATGGTGGAGGCCCTGAGGGCTGGCTCTGCCAGGCTGGTGGCTGCCCCTGTG 480
Qy 481 GCCACAGCCAACCCTGCCAGGTGCCTGGCCCTGAATGTGAGCCTGAGAGAGTGGACAGCC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GCCACAGCCAACCCTGCCAGGTGCCTGGCCCTGAATGTGAGCCTGAGAGAGTGGACAGCC 540
Qy 541 AGGTATGGGGCTGCCCCTGCTGCCCCCAGGTGTGATGCCCTGGATGGAGATGCTGTGGTG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 AGGTATGGGGCTGCCCCTGCTGCCCCCAGGTGTGATGCCCTGGATGGAGATGCTGTGGTG 600
Qy 601 CTGCTGAGGGCCAGGGACCTGTTCAACCTGTCTGCCCCCCTGGCCAGGCCTGTGGGGACC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 CTGCTGAGGGCCAGGGACCTGTTCAACCTGTCTGCCCCCCTGGCCAGGCCTGTGGGGACC 660
Qy 661 AGCCTGTTTCTGCAGACAGCCCTGAGGGGCTGGGCTGTGCAGCTGCTGGACCTGACCTTT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AGCCTGTTTCTGCAGACAGCCCTGAGGGGCTGGGCTGTGCAGCTGCTGGACCTGACCTTT 720
Qy 721 GCTGCTGCCAGGCAGCCCCCCCTGGCTACAGCCCACGCCAGGTGGAAGGCTGAGAGGGAG 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 GCTGCTGCCAGGCAGCCCCCCCTGGCTACAGCCCACGCCAGGTGGAAGGCTGAGAGGGAG 780
Qy 781 GGCAGGGCCAGGAGGGCTGCCCTGCTGAGGGCCCTGGGGATCAGGCTGGTGAGCTGGGAG 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 GGCAGGGCCAGGAGGGCTGCCCTGCTGAGGGCCCTGGGGATCAGGCTGGTGAGCTGGGAG 840
Qy 841 GGGGGCAGGCTGGAGTGGTTTGGCTGCAACAAGGAGACAACCAGGTGCTTTGGGACAGTG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 GGGGGCAGGCTGGAGTGGTTTGGCTGCAACAAGGAGACAACCAGGTGCTTTGGGACAGTG 900
Qy 901 GTGGGGGATACCCCTGCCTACCTGTATGAGGAGAGGTGGACCCCCCCCTGCTGCCTGAGG 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 GTGGGGGATACCCCTGCCTACCTGTATGAGGAGAGGTGGACCCCCCCCTGCTGCCTGAGG 960
Qy 961 GCCCTGAGGGAGACAGCCAGGTATGTGGTGGGGGTGCTGGAGGCTGCTGGGGTGAGGTAC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 GCCCTGAGGGAGACAGCCAGGTATGTGGTGGGGGTGCTGGAGGCTGCTGGGGTGAGGTAC 1020
Qy 1021 TGGCTGGAGGGGGGCAGCCTGCTGGGGGCTGCCAGGCACGGGGACATTATCCCCTGGGAC 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 TGGCTGGAGGGGGGCAGCCTGCTGGGGGCTGCCAGGCACGGGGACATTATCCCCTGGGAC 1080
Qy 1081 TATGATGTGGACCTGGGCATCTACCTGGAGGATGTGGGCAACTGTGAGCAGCTGAGGGGG 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 TATGATGTGGACCTGGGCATCTACCTGGAGGATGTGGGCAACTGTGAGCAGCTGAGGGGG 1140
Qy 1141 GCTGAGGCTGGCTCTGTGGTGGATGAGAGGGGCTTTGTGTGGGAGAAGGCTGTGGAGGGG 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 GCTGAGGCTGGCTCTGTGGTGGATGAGAGGGGCTTTGTGTGGGAGAAGGCTGTGGAGGGG 1200
Qy 1201 GACTTTTTCAGGGTGCAGTACTCTGAGAGCAACCACCTGCACGTGGACCTGTGGCCCTTC 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 GACTTTTTCAGGGTGCAGTACTCTGAGAGCAACCACCTGCACGTGGACCTGTGGCCCTTC 1260
Qy 1261 TACCCCAGGAATGGGGTGATGACCAAGGACACCTGGCTGGACCACAGGCAGGATGTGGAG 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 TACCCCAGGAATGGGGTGATGACCAAGGACACCTGGCTGGACCACAGGCAGGATGTGGAG 1320
Qy 1321 TTCCCTGAGCACTTCCTGCAGCCCCTGGTGCCCCTGCCCTTTGCTGGCTTTGTGGCCCAG 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 TTCCCTGAGCACTTCCTGCAGCCCCTGGTGCCCCTGCCCTTTGCTGGCTTTGTGGCCCAG 1380
Qy 1381 GCCCCCAACAACTACAGGAGGTTCCTGGAGCTGAAGTTTGGCCCTGGGGTGATTGAGAAC 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 GCCCCCAACAACTACAGGAGGTTCCTGGAGCTGAAGTTTGGCCCTGGGGTGATTGAGAAC 1440
Qy 1441 CCCCAGTACCCCAACCCTGCCCTGCTGAGCCTGACAGGCTCTGGCTGA 1488
||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 CCCCAGTACCCCAACCCTGCCCTGCTGAGCCTGACAGGCTCTGGCTGA 1488
Translation of nucleotides 1659-3146 of SEQ ID NO: 3 aligned to SEQ ID NO: 5
Query Match 100.0%; Score 2598; DB 1; Length 495;
Best Local Similarity 100.0%;
Matches 495; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRLTRCQAALAAAITLNLLVLFYVSWLQHQPRNSRARGPRRASAAGPRVTVLVREFEAFD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRLTRCQAALAAAITLNLLVLFYVSWLQHQPRNSRARGPRRASAAGPRVTVLVREFEAFD 60
Qy 61 NAVPELVDSFLQQDPAQPVVVAADTLPYPPLALPRIPNVRLALLQPALDRPAAASRPETY 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NAVPELVDSFLQQDPAQPVVVAADTLPYPPLALPRIPNVRLALLQPALDRPAAASRPETY 120
Qy 121 VATEFVALVPDGARAEAPGLLERMVEALRAGSARLVAAPVATANPARCLALNVSLREWTA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VATEFVALVPDGARAEAPGLLERMVEALRAGSARLVAAPVATANPARCLALNVSLREWTA 180
Qy 181 RYGAAPAAPRCDALDGDAVVLLRARDLFNLSAPLARPVGTSLFLQTALRGWAVQLLDLTF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RYGAAPAAPRCDALDGDAVVLLRARDLFNLSAPLARPVGTSLFLQTALRGWAVQLLDLTF 240
Qy 241 AAARQPPLATAHARWKAEREGRARRAALLRALGIRLVSWEGGRLEWFGCNKETTRCFGTV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 AAARQPPLATAHARWKAEREGRARRAALLRALGIRLVSWEGGRLEWFGCNKETTRCFGTV 300
Qy 301 VGDTPAYLYEERWTPPCCLRALRETARYVVGVLEAAGVRYWLEGGSLLGAARHGDIIPWD 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VGDTPAYLYEERWTPPCCLRALRETARYVVGVLEAAGVRYWLEGGSLLGAARHGDIIPWD 360
Qy 361 YDVDLGIYLEDVGNCEQLRGAEAGSVVDERGFVWEKAVEGDFFRVQYSESNHLHVDLWPF 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 YDVDLGIYLEDVGNCEQLRGAEAGSVVDERGFVWEKAVEGDFFRVQYSESNHLHVDLWPF 420
Qy 421 YPRNGVMTKDTWLDHRQDVEFPEHFLQPLVPLPFAGFVAQAPNNYRRFLELKFGPGVIEN 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 YPRNGVMTKDTWLDHRQDVEFPEHFLQPLVPLPFAGFVAQAPNNYRRFLELKFGPGVIEN 480
Qy 481 PQYPNPALLSLTGSG 495
|||||||||||||||
Db 481 PQYPNPALLSLTGSG 495
SEQ ID NO: 6 aligned to SEQ ID NO: 47 of Vandendriessche (US 2017/0275649 A1)
Query Match 100.0%; Score 1061; Length 1099;
Best Local Similarity 100.0%;
Matches 1061; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TACCCCCTGCCCCCCACAGCTCCTCTCCTGTGCCTTGTTTCCCAGCCATGCGTTCTCCTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 24 TACCCCCTGCCCCCCACAGCTCCTCTCCTGTGCCTTGTTTCCCAGCCATGCGTTCTCCTC 83
Qy 61 TATAAATACCCGCTCTGGTATTTGGGGTTGGCAGCTGTTGCTGCCAGGGAGATGGTTGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 84 TATAAATACCCGCTCTGGTATTTGGGGTTGGCAGCTGTTGCTGCCAGGGAGATGGTTGGG 143
Qy 121 TTGACATGCGGCTCCTGACAAAACACAAACCCCTGGTGTGTGTGGGCGTGGGTGGTGTGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 144 TTGACATGCGGCTCCTGACAAAACACAAACCCCTGGTGTGTGTGGGCGTGGGTGGTGTGA 203
Qy 181 GTAGGGGGATGAATCAGGGAGGGGGCGGGGGACCCAGGGGGCAGGAGCCACACAAAGTCT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 204 GTAGGGGGATGAATCAGGGAGGGGGCGGGGGACCCAGGGGGCAGGAGCCACACAAAGTCT 263
Qy 241 GTGCGGGGGTGGGAGCGCACATAGCAATTGGAAACTGAAAGCTTATCAGACCCTTTCTGG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 264 GTGCGGGGGTGGGAGCGCACATAGCAATTGGAAACTGAAAGCTTATCAGACCCTTTCTGG 323
Qy 301 AAATCAGCCCACTGTTTATAAACTTGAGGCCCCACCCTCGACAGTACCGGGGAGGAAGAG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 324 AAATCAGCCCACTGTTTATAAACTTGAGGCCCCACCCTCGACAGTACCGGGGAGGAAGAG 383
Qy 361 GGCCTGCACTAGTCCAGAGGGAAACTGAGGCTCAGGGCTAGCTCGCCCATAGACATACAT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 384 GGCCTGCACTAGTCCAGAGGGAAACTGAGGCTCAGGGCTAGCTCGCCCATAGACATACAT 443
Qy 421 GGCAGGCAGGCTTTGGCCAGGATCCCTCCGCCTGCCAGGCGTCTCCCTGCCCTCCCTTCC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 444 GGCAGGCAGGCTTTGGCCAGGATCCCTCCGCCTGCCAGGCGTCTCCCTGCCCTCCCTTCC 503
Qy 481 TGCCTAGAGACCCCCACCCTCAAGCCTGGCTGGTCTTTGCCTGAGACCCAAACCTCTTCG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 504 TGCCTAGAGACCCCCACCCTCAAGCCTGGCTGGTCTTTGCCTGAGACCCAAACCTCTTCG 563
Qy 541 ACTTCAAGAGAATATTTAGGAACAAGGTGGTTTAGGGCCTTTCCTGGGAACAGGCCTTGA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 564 ACTTCAAGAGAATATTTAGGAACAAGGTGGTTTAGGGCCTTTCCTGGGAACAGGCCTTGA 623
Qy 601 CCCTTTAAGAAATGACCCAAAGTCTCTCCTTGACCAAAAAGGGGACCCTCAAACTAAAGG 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 624 CCCTTTAAGAAATGACCCAAAGTCTCTCCTTGACCAAAAAGGGGACCCTCAAACTAAAGG 683
Qy 661 GAAGCCTCTCTTCTGCTGTCTCCCCTGACCCCACTCCCCCCCACCCCAGGACGAGGAGAT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 684 GAAGCCTCTCTTCTGCTGTCTCCCCTGACCCCACTCCCCCCCACCCCAGGACGAGGAGAT 743
Qy 721 AACCAGGGCTGAAAGAGGCCCGCCTGGGGGCTGCAGACATGCTTGCTGCCTGCCCTGGCG 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 744 AACCAGGGCTGAAAGAGGCCCGCCTGGGGGCTGCAGACATGCTTGCTGCCTGCCCTGGCG 803
Qy 781 AAGGATTGGCAGGCTTGCCCGTCACAGGACCCCCGCTGGCTGACTCAGGGGCGCAGGCCT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 804 AAGGATTGGCAGGCTTGCCCGTCACAGGACCCCCGCTGGCTGACTCAGGGGCGCAGGCCT 863
Qy 841 CTTGCGGGGGAGCTGGCCTCCCCGCCCCCACGGCCACGGGCCGCCCTTTCCTGGCAGGAC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 864 CTTGCGGGGGAGCTGGCCTCCCCGCCCCCACGGCCACGGGCCGCCCTTTCCTGGCAGGAC 923
Qy 901 AGCGGGATCTTGCAGCTGTCAGGGGAGGGGAGGCGGGGGCTGATGTCAGGAGGGATACAA 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 924 AGCGGGATCTTGCAGCTGTCAGGGGAGGGGAGGCGGGGGCTGATGTCAGGAGGGATACAA 983
Qy 961 ATAGTGCCGACGGCTGGGGGCCCTGTCTCCCCTCGCCGCATCCACTCTCCGGCCGGCCGC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 984 ATAGTGCCGACGGCTGGGGGCCCTGTCTCCCCTCGCCGCATCCACTCTCCGGCCGGCCGC 1043
Qy 1021 CTGCCCGCCGCCTCCTCCGTGCGCCCGCCAGCCTCGCCCGC 1061
|||||||||||||||||||||||||||||||||||||||||
Db 1044 CTGCCCGCCGCCTCCTCCGTGCGCCCGCCAGCCTCGCCCGC 1084
SEQ ID NO: 2 aligned to SEQ ID NO: 10 of US 9,981,049 B2
SEQ ID NO: 2 aligned to SEQ ID NO: 10 of US 11,819,478 B2
Query Match 100.0%; Score 22; DB 1; Length 22;
Best Local Similarity 100.0%;
Matches 22; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ACAAGCTTTTTGCTCGTCTTAT 22
||||||||||||||||||||||
Db 1 ACAAGCTTTTTGCTCGTCTTAT 22
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632