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 .
Priority
The instant application is a national stage entry of PCT application PCT/US22/30264, filed 11/07/2023 under 35 USC 371. Acknowledgement is made of the applicant’s claim for benefit to prior-filed U.S. provisional patent applications 63/193,212, which was filed 05/26/2021.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-20, drawn to a method for treating Dent disease in a subject in need thereof or correcting a mutation in the CLCN5 gene in a cell using a nucleic acid vector encoding a CLCN5 protein, in the reply filed on 03/30/2026 is acknowledged. Accordingly, claims 1-20 have been considered on the merits. Claims 21-31 are withdrawn from consideration pursuant 37 CFR 1.142(b).
Claim Interpretation
Claims 1 recites preamble “for treating Dent disease in a subject in need thereof”, claim 12 recites preamble “for correcting a mutation in the CLCN5 gene in a cell”, both are intended use. The purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See MPEP 2111.02.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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 1-4 and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Imbrici et al. (Front Pharmacol. 2016 May 10;7:121, cited in IDS), in view of Davis et al. ( Physiol Genomics. 2019 Sep 1;51(9):449-461) and NCBI Reference Sequence: NM_000084.5 (Available in 1993, cited in IDS), as evidenced by Qin et al. (PLoS One. 2010 May 12;5(5):e10611).
Imbrici et al. summarize the main pharmacological strategies performed to treat major channelopathies caused by mutations in voltage-gated and inward rectifying ion channels (p2, right column).
Regarding claim 1, Imbrici et al. teach the main inherited ion channelopathies of CNS, PNS, skeletal muscle, heart, kidney, pancreas, and bone (p3, figure 1), which include Dent disease in kidney. Dent disease is caused by mutations in CLCN5 gene (p15, right column), the disease is essentially due to defective receptor-mediated endocytosis causing a generalized dysfunction of proximal tubule (PT) cells (p15-16). Imbrici et al. teach several therapies for this disease, including cell and gene therapy, stating that gene therapy is another strategy can be exploited, which has already been studied for neurological channelopathies (see p20, right column). The teaching of Imbrici et al. indicates (using gene therapy) for treating Dent disease. Imbrici et al. do not teach (the gene therapy) method comprising administering to the subject an effective amount of a nucleic acid vector encoding a CLCN5 protein. However, this was disclosed by Davis et al. and NCBI Reference Sequence: NM_000084.5 at the time of instant invention.
Davis et al. systematically review the pros and cons of the most commonly tested gene therapy vector systems derived from adenovirus, retrovirus, and adeno-associated virus and provide insight about their potential utility as a therapy for various types of genetic diseases in the kidney (Abstract).
Regarding claim 1, Davis et al. teach gene therapy can be used for genetic diseases in kidney (see Abstract), the most common replication-defective viral vector systems are based on either adenovirus, lentivirus, or adeno-associated virus for genetic modification of various cell types in the kidney (p449, left-right column). Davis et al. teach studies regarding administering viral vectors to animal models for treating kidney diseases (see Tables 1-4). The viral vectors comprise promoters and transgenes, and are administered via different administration routes to achieve treatment outcome (i.e., see the columns of transgene/marker gene expression and therapeutic effect). This teaching reads on “administering to a subject an effective amount of a nucleic acid vector with a transgene (encoding a protein), thereby treating the disease” in instant claim. Regarding CLCN5 gene which encodes CLCN5 protein, NCBI Reference Sequence: NM_000084.5 is Homo sapiens Cl-/H+ antiporter 5 (CLCN5), transcript variant 3, mRNA, which encodes functional CLCN5 protein.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Imbrici et al.’s strategy of treating Dent disease by gene therapy, use a viral vector comprising promoter and transgene for gene therapy as taught by Davis et al., and clone the CLCN5 gene provide by NCBI Reference Sequence: NM_000084.5 in the vector then administer the viral vector to the subject to express the transgene and achieve therapeutic effect. The skilled artisan would have been motivated to conduct such gene therapy by administering to a subject a viral vector comprising CLCN5 gene encoding a CLCN5 Protein since Imbrici et al. teach Dent disease is caused by CLCN5 gene mutation and suggest using gene therapy, Davis et al. teach gene therapy using viral vectors comprising promoter and transgene and administer the viral vectors to a subject for the treatment. There would be a reasonable expectation of success of the gene therapy using a viral vector comprising CLCN5 gene encoding a CLCN5 Protein, which produces a vector with wild type gene (CLCN5 gene) and delivers to target cells, since Davis et al. teach viral vectors comprising promoters and transgenes and vector delivery route (i.e., Tables 1-4), and NCBI Reference Sequence: NM_000084.5 provides the CLCN5 gene which encodes functional CLCN5 protein.
Regarding claims 12, as discussed above, Imbrici et al. teach the main inherited ion channelopathies of CNS, PNS, skeletal muscle, heart, kidney, pancreas, and bone (p3, figure 1), which include Dent disease in kidney. Dent disease is caused by mutations in CLCN5 gene (p15, right column), the disease is essentially due to defective receptor-mediated endocytosis causing a generalized dysfunction of proximal tubule (PT) cells (p15-16). Imbrici et al. teach several therapies for this disease, including cell and gene therapy, stating that gene therapy is another strategy can be exploited, which has already been studied for neurological channelopathies (see p20, right column). The teaching of Imbrici et al. indicates (using gene therapy) for treating Dent disease. Imbrici et al. do not teach the gene therapy comprising contacting the cell with a nucleic acid vector encoding a functional CLCN5 protein. However, Davis et al. teach gene therapy for genetic disease (in kidney) (see Abstract), the most common replication-defective viral vector systems based on either adenovirus, lentivirus, or adeno-associated virus for genetic modification of various cell types in the kidney (p449, left-right column). The teaching of “genetic modification of cells” indicates correcting the gene mutation by wild type and/or functional gene. Davis et al. teach studies regarding administering viral vectors to animal models for treating kidney diseases (see Tables 1-4). The viral vectors comprise promoters and transgenes, and are administered via different administration routes. After administration the viral vector would contact and transduce the target cells then express the transgenes (wild type and/or functional genes) in the cells. Moreover, Davis et al. teach ex vivo applications (see p453-454, Table 3) using lentiviral vector comprising transgenes to transduce cells. These teachings read on “a (gene therapy) method comprising contacting the cell with a nucleic acid vector (comprising a transgene) encoding a functional protein” in instant claim. Regarding CLCN5 gene which encodes CLCN5 protein, NCBI Reference Sequence: NM_000084.5 is Homo sapiens Cl-/H+ antiporter 5 (CLCN5), transcript variant 3, mRNA, which encodes functional CLCN5 protein.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Imbrici et al.’s strategy of treating Dent disease by gene therapy, use a viral vector comprising promoter and transgene as taught by Davis et al., and clone the CLCN5 gene provide by NCBI Reference Sequence: NM_000084.5 in the vector, then administer the viral vector to the subject, wherein the viral vector contacts and transduces target cells to express the transgene (encoding functional CLCN5 protein) or use ex vivo method to contact and transduce viral vectors to target cells. The skilled artisan would have been motivated to conduct such gene therapy using a viral vector comprising a nucleic acid vector comprising CLCN5 gene since Imbrici et al. teach Dent disease is caused by CLCN5 gene mutation and suggest using gene therapy, Davis et al. teach gene therapy using viral vectors comprising promoter and transgene and administer the viral vectors to a subject or cell and the transgene would express in the target cell (which corrects mutation gene in the target cell). There would be a reasonable expectation of success of using the gene therapy which having a viral vector with wild type gene (CLCN5 gene) and contact to target cells to express the gene, since Davis et al. teach viral vectors comprising promoters and transgenes and vector delivery route (i.e., Tables 1-4) as well as ex vivo gene therapy, and NCBI Reference Sequence: NM_000084.5 provides the CLCN5 gene which encodes functional CLCN5 protein.
Regarding claims 2 and 13, following the discussion above, Davis et al. teach the most common replication-defective viral vector systems based on either adenovirus, lentivirus, or adeno-associated virus for genetic modification of various cell types in the kidney (p9, right column), reads on “lentiviral vector” for gene therapy in instant claims.
Regarding claims 3 and 14, Davis et al. teach viral vectors comprising promoters and transgenes, and shows that the promoters drive expression of transgene, for instance, viral vector comprises promoters (CAG, Npt2a, NKCC, AQP2) and transgenes (GFP), selective GFP staining was observed using the segment-specific promoters, CAG was observed in all cell types (see p451, Table 2). This teaching indicates “the vector is operably linked to a promoter that drives the expression of the CLCN5 protein” as recited in instant claims.
Regarding claims 4 and 15, Davis et al. teach promoters in the vectors, which includes promoters such as CMV promoter. CMV promoter is a constitute promoter, which is evidenced by Qin et al.. Qin et al. teach commonly used constitutive promoters SV40, CMV, UBC, EF1A, PGK and CAGG for mammalian systems (Abstract), indicates that CMV promoter is a constitute promoter.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Imbrici et al.’s strategy of treating Dent disease by gene therapy, and use a lentiviral vector comprising a constitute promoter (i.e., CMV) and transgene for gene therapy as taught by Davis et al., then clone the CLCN5 gene provide by NCBI Reference Sequence: NM_000084.5 in the vector and administer the viral vector to the subject to express the transgene and achieve therapeutic effect. The skilled artisan would have been motivated to have such lentiviral vector comprising a constitute promoter (i.e., CMV) and CLCN5 gene for gene therapy since Imbrici et al. teach Dent disease is caused by CLCN5 gene mutation and suggest using gene therapy, Davis et al. teach gene therapy using viral vectors (i.e., lentiviral vectors) comprising a constitute promoter (i.e., CMV) and transgene and administer the viral vectors to a subject for gene modification. There would be a reasonable expectation of success of the gene therapy using viral vectors (i.e., lentiviral vectors) comprising a constitute promoter (i.e., CMV) and CLCN5 gene encoding a CLCN5 Protein since Davis et al. teach viral vectors comprising promoters and transgenes (i.e., Tables 1-4), and NCBI Reference Sequence: NM_000084.5 provides the CLCN5 gene which encodes functional CLCN5 protein.
Regarding claims 10 and 11, Davis et al. teach route of administration of viral vectors can be retrograde ureter administration (see, i.e., p451, Table 2), reads on “delivered locally to the kidney” and “retrograde ureteral injection” in instant claims.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Imbrici et al.’s strategy of treating Dent disease by gene therapy, use the gene therapy as taught by Davis et al. and clone the CLCN5 gene provide by NCBI Reference Sequence: NM_000084.5 in the viral vector, and administer the viral vector locally using retrograde ureteral injection to the subject to express the transgene in target cells. The skilled artisan would have been motivated to conduct such gene therapy using a lentiviral vector comprising a nucleic acid vector comprising CLCN5 gene and retrograde ureteral injection the viral vector since Imbrici et al. teach Dent disease is caused by CLCN5 gene mutation and suggest using gene therapy, Davis et al. teach gene therapy using viral vectors comprising promoters and transgenes and administer the viral vectors to a subject by local injection (i.e., retrograde ureter administration). There would be a reasonable expectation of success of administering the viral vector with wild type gene (CLCN5 gene) to target cells (i.e., via retrograde ureter administration), since Davis et al. teach viral vectors comprising promoters and transgenes, as well as vector delivery route (i.e., retrograde ureter administration), and NCBI Reference Sequence: NM_000084.5 provides the CLCN5 gene which encodes functional CLCN5 protein.
Claims 1-5 and 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Imbrici et al. (Front Pharmacol. 2016 May 10;7:121, cited in IDS), in view of Davis et al. ( Physiol Genomics. 2019 Sep 1;51(9):449-461) and NCBI Reference Sequence: NM_000084.5 (Available in 1993), as evidenced by Qin et al. (PLoS One. 2010 May 12;5(5):e10611), as applied to claims 1-4 and 10-15 above, and further in view of NOVOPro (online in 2020).
The teaching of Imbrici et al., Davis et al. and NCBI Reference Sequence: NM_000084. is set forth above.
Regarding claims 5 and 16, Imbrici et al., Davis et al. and NCBI Reference Sequence: NM_000084.5 do not teach the promoter is an EF-1 alpha promoter. However, this was disclosed by NOVOPro at the time of instant invention.
NOVOPro teaches the difference between EF-1 alpha and the CMV promoter (see Title).
Regarding claims 5 and 16, NOVOPro teaches EF-1 alpha is a constitutive promoter of human origin that can be used to drive ectopic gene expression in various in vitro and in vivo contexts (parag 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Imbrici et al.’s strategy of treating Dent disease by gene therapy, use the gene therapy as taught by Davis et al. and clone the CLCN5 gene provide by NCBI Reference Sequence: NM_000084.5 in the vector, further use a constitutive promoter EF-1 alpha promoter in the vector as taught by NOVOPro. The only difference between instant claim and Imbrici et al.’ in view of Davis et al.’s viral vector for gene therapy is instant claim uses EF-1 alpha promoter in the vector. Since NOVOPro teaches EF-1 alpha promoter can be used to drive ectopic gene expression in various in vitro and in vivo contexts (parag 1), one of ordinary skill in the art would have substituted other promoters such as CMV promoter for EF-1 alpha promoter depends on their research interest. This simple substitution of one known element (EF-1 alpha promoter) for another known element (CMV promoter) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Claims 1-4, 6-8, 10-15 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Imbrici et al. (Front Pharmacol. 2016 May 10;7:121, cited in IDS), in view of Davis et al. ( Physiol Genomics. 2019 Sep 1;51(9):449-461) and NCBI Reference Sequence: NM_000084.5 (Available in 1993, cited in IDS), evidenced by Qin et al. (PLoS One. 2010 May 12;5(5):e10611), as applied to claims 1-4 and 10-15 above, further in view of Shunya et al. (WO2019045049, published in 2019).
The teaching of Imbrici et al., Davis et al. and NCBI Reference Sequence: NM_000084.5 is set forth above.
Regarding claims 6-8 and 17-19, Davis et al. teach the viral vector comprising promoters such as Npt2a (see p451, Table 2), but the Npt2a promoter is used in adenoviral vector but not lentiviral vector. However, tissue-specific promoters such as Npt2a can also be expressed in lentiviral vectors, such was disclosed by Shunya et al..
Shunya et al. teach a renal tubule cell specific expression vector (parag 0001).
Regarding claims 6-8 and 17-19, Shunya et al. teach a renal tubule cell specific promoter (see parag 0029), which may be a promoter of a gene selected from the group consisting of NPT2a, NKCC2, AQP2, NCC, and ENaC (parag 0032). The promoters are specific for renal tubule, therefore is a tissue-specific promoter (claims 6 and 17), the promoters would be specific for renal tubule proximal cells (which belongs to renal tubule cells, claims 7 and 18), and specifically, the promoter can be NPT2a (claims 8 and 19).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Imbrici et al.’s strategy of treating Dent disease by gene therapy, use the gene therapy as taught by Davis et al. and clone the CLCN5 gene provide by NCBI Reference Sequence: NM_000084.5 in the vector, further use a tissue-specific promoter such as Npt2a promoter which is specific for renal tubule proximal cells as taught by Shunya et al.. The skilled artisan would have been motivated to use the tissue-specific promoter such as Npt2a promoter which is specific for renal tubule proximal cells since Shunya et al. teach such operation with the specific promoter can be used to specifically expressing a gene in the target cells (i.e., renal tubule cells) (parag 0007). There would be a reasonable expectation of success of using the tissue-specific promoter such as Npt2a promoter since Shunya et al. teach the tissue-specific promoter is Npt2a promoter (see parag 0038) and the location of Npt2a promoter is upstream of the transgene (i.e., CLCN5 gene).
Allowable Subject Matter
Claims 9 and 20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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