DETAILED ACTION
This action is in reply to papers filed 9/30/2025. Claims 57, 60-63 and 65 -77 are pending and examined herein.
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20180100165A1, Published 4/12/2018.
Maintained Rejection(s)
The nonstatutory double patenting rejection of instant claims over claims 1-7 of U.S. Patent No. U.S. Patent 9816108 is maintained. Applicant’s arguments will be addressed following maintained rejection.
Withdrawn/Moot Rejection(s)
The 35 U.S.C. 103(a) rejection of claims 57-63, 65-70 and 72-75 as being unpatentable over Acland et al. in view of Hildinger and Eliasof et al. is withdrawn in view of amendments made to independent claim 57.
The 35 U.S.C. 103(a) rejection of claim 64 as being unpatentable over Acland et al. in view of Hildinger and Eliasof et al. as applied to claims 57-63, 65-70 and 72-75 and further in view of Young et al. is moot in view of the cancellation of the claim.
The 35 U.S.C. 103(a) rejection of claim 71 as being unpatentable over Acland et al. in view of Hildinger and Eliasof et al. as applied to claims 57-63, 65-70 and 72-75 and further in view of Gao et al. is withdrawn in view of amendments made to independent claim 57.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 57, 60-63, 66 -70 and 72-75 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Acland et al. (PgPub US20040022766A1, Published 2/5/2004; Reference in IDS filed 3/9/3022, previously cited) in view of Hildinger (PgPub US20070042462A1, Published 2/22/2007; Reference in IDS filed 3/9/3022, previously cited), Eliasof et al. (WO2004065576A2, Published 8/5/2004; Reference in IDS filed 3/9/3022, previously cited) and Young et al. (Investigative Ophthalmology & Visual Science September 2003, Vol.44, 4076-4085., previously cited).
Claim interpretation: Para. 151 of the PgPub teaches the terms “identical” or percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence (Examiner’s emphasis). Para. 158 teaches “subsequence” means any consecutive stretch of amino acids within a sequence, e.g., at least 3 consecutive amino acids within a given protein or polypeptide sequence.
Acland teaches a method for treating an ocular disorder characterized by the defect or absence of a normal gene in the ocular cells of a human or animal subject, wherein said method involves administering to the subject by subretinal injection an effective amount of a recombinant adeno-associated virus carrying a nucleic acid sequence encoding the normal gene (as in claim 75, in-part) under the control of a promoter sequence which expresses the product of the gene in the ocular cells (Abstract). To this end, Acland teaches introducing into at a first population of human retinal cells (Pg. 3, Para. 29, Lines 1-5) an rAAV vector (Pg. 3, Para. 25, Lines 1-4), such as an rAAV5 vector (as in claim 63) (Pg. 2, para. 20; Pg. 3, para. 23), comprising a polynucleotide that comprises a promoter operably linked (Pg. 4, Para. 35,Lines 1-9 , Pg. 4, Para. 40, Lines 1-4 and Pg. 5, Para. 41, Lines 1-4) to at a first nucleic acid segment that encodes a biologically-active, retinal-specific human guanylate cyclase polypeptide (GUCY2D) (Pg. 3, Para. 28, Lines 1-8 and Pg. 4, Para. 30, Lines 1-4 and 6-9) (as in claim 57, in-part and as in claim 75).
Regarding claim 66, Acland teaches the rAAV vector further comprises an intron sequence operably linked to the at least a first nucleic segment (Pg. 4, Para. 35, lines 1-4 and Pg. 4, Para. 38), which is operably linked to the promoter. Regarding claim 67, claim 68 and claim 69, Acland teaches the rAAV is comprised within an infectious adeno-associated viral particle, virion, or a plurality of infectious AAV particles (Pg. 3, Para. 24, lines 1-4 and Pg. 7, Col. 2, Para. 65, lines 11-15). Regarding claim 70, Acland teaches a composition comprising an rAAV vector and a pharmaceutically-acceptable buffer, carrier, vehicle (Pg. 6, Para. 56, lines 6-10). Regarding claim 72, claim 73 and claim 74, Acland teaches the human has a defect in at least one eye (Pg. 1, Para. 8, lines 1-4). Furthermore, Acland teaches the human is a child that has Leber congenital amaurosis- 1 (LCA- 1) (Pg. 1, Para. 10, lines 1-10 and Pg. 2, Para. 16, lines 1-7).
However, Acland fails to teach the promoter is a photoreceptor-specific human rhodopsin kinase promoter (as further in claim 57).
Before the effective filing date of the claimed invention, Hildinger taught contrary to many prior-art publications, it was discovered that the effective packaging capacity of AAV is larger than 5.7 kb. Particularly, Hildinger discovered that the capsid of AAV5 seems to be able to accommodate larger genomes, even beyond 6.5 kb and up to 8 kb with high efficacy (Pg. 3, para. 38). To this end, Hildinger teaches said vector comprises a rhodopsin kinase promoter for photoreceptor-directed gene expression (as further in claim 57) (Pg. 12, Para. 152).
And although Hildinger et al. teach a rhodopsin kinase promoter for photoreceptor-directed gene expression, Hildinger fails to teach said promoter comprises at least 90% sequence identity to SEQ ID NO: 12 (as further in claim 57) or at least about 95% sequence identity to SEQ ID NO: 12 (as in claim 62).
Before the effective filing date of the claimed invention, Young taught the human Rk gene (GenBank Acc. No. AY327580) (Pg. 4078, Col. 2). Young teaches the 2.0-kb region flanking the 5′ end of the human Rk gene was isolated, mapped, and sequenced. The sequence was fused upstream of the luciferase gene and was tested for promoter activity in retinoblastoma cells by transient transfection. SEQ ID NO: 12 is 98% (as further in claim 57 and as in claim 62) identical to nucleotides 1793-2087 (i.e. a subsequence) of the human Rk gene taught by Young. See below.
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However, none of Acland, Hildinger or Young teach a nucleic acid encoding a human guanylate cyclase polypeptide comprising at least 90% identical to SEQ ID NO: 1 (as further in claim 57 and as in claim 61).
These deficiencies are cured by Eliasof et al.
Eliasof teaches a retinal-specific human guanylate cyclase protein, that comprises an amino acid sequence that is 100% identical to claimed SEQ ID NO: 1 (as further in claim 57, as in claim 60 and as in claim 61). Eliasof teaches said retinal guanylyl cyclase 1 (retGC or guanylate cyclase 2D) is expressed in DRG followed by brain, prostate and breast (see Eliasof, Pg. 10, Para. 39-40). The alignment between SEQ ID NO: 1 (Qy, query) and the retinal-specific human guanylate cyclase protein taught by Karicheti et al. (Db, database) is provided below.
RESULT 1
ADQ89060
ID ADQ89060 standard; protein; 1103 AA.
XX
AC ADQ89060;
XX
DT 15-JUN-2007 (revised)
DT 21-OCT-2004 (first entry)
XX
DE Human urological disorder related protein 1405 SEQ: 12.
XX
KW urological disorder; uropathic; cytostatic; urinary incontinence;
KW benign prostatic hyperplasia; human; BOND_PC;
KW guanylate cyclase 2D, membrane (retina-specific); unnamed;
KW guanylate cyclase 2D, membrane (retina-specific) [Homo sapiens]; GUCY2D;
KW LCA; CYGD; LCA1; CORD6; GUC2D; retGC; GUC1A4; RETGC-1; ROS-GC1;
KW CORD6, LCA, GUC2D, GUC1A4; cone rod dystrophy 5/6; CORD5;
KW guanylyl cyclase; guanylyl cyclase [Homo sapiens]; GO4383; GO4672;
KW GO4872; GO5524; GO5640; GO5887; GO6182; GO6468; GO7168; GO7242; GO7601;
KW GO16020; GO50896.
XX
OS Homo sapiens.
XX
CC PN WO2004065576-A2.
XX
CC PD 05-AUG-2004.
XX
CC PF 14-JAN-2004; 2004WO-US000750.
XX
Query Match 100.0%; Score 5730; DB 5; Length 1103;
Best Local Similarity 100.0%;
Matches 1103; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTACARRAGGLPDPGLCGPAWWAPSLPRLPRALPRLPLLLLLLLLQPPALSAVFTVGVLG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTACARRAGGLPDPGLCGPAWWAPSLPRLPRALPRLPLLLLLLLLQPPALSAVFTVGVLG 60
Qy 61 PWACDPIFSRARPDLAARLAAARLNRDPGLAGGPRFEVALLPEPCRTPGSLGAVSSALAR120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PWACDPIFSRARPDLAARLAAARLNRDPGLAGGPRFEVALLPEPCRTPGSLGAVSSALAR120
Qy 121 VSGLVGPVNPAACRPAELLAEEAGIALVPWGCPWTQAEGTTAPAVTPAADALYALLRAFG180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VSGLVGPVNPAACRPAELLAEEAGIALVPWGCPWTQAEGTTAPAVTPAADALYALLRAFG180
Qy 181 WARVALVTAPQDLWVEAGRSLSTALRARGLPVASVTSMEPLDLSGAREALRKVRDGPRVT240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 WARVALVTAPQDLWVEAGRSLSTALRARGLPVASVTSMEPLDLSGAREALRKVRDGPRVT240
Qy 241 AVIMVMHSVLLGGEEQRYLLEAAEELGLTDGSLVFLPFDTIHYALSPGPEALAALANSSQ300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 AVIMVMHSVLLGGEEQRYLLEAAEELGLTDGSLVFLPFDTIHYALSPGPEALAALANSSQ300
Qy 301 LRRAHDAVLTLTRHCPSEGSVLDSLRRAQERRELPSDLNLQQVSPLFGTIYDAVFLLARG360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LRRAHDAVLTLTRHCPSEGSVLDSLRRAQERRELPSDLNLQQVSPLFGTIYDAVFLLARG360
Qy 361 VAEARAAAGGRWVSGAAVARHIRDAQVPGFCGDLGGDEEPPFVLLDTDAAGDRLFATYML420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 VAEARAAAGGRWVSGAAVARHIRDAQVPGFCGDLGGDEEPPFVLLDTDAAGDRLFATYML420
Qy 421 DPARGSFLSAGTRMHFPRGGSAPGPDPSCWFDPNNICGGGLEPGLVFLGFLLVVGMGLAG480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 DPARGSFLSAGTRMHFPRGGSAPGPDPSCWFDPNNICGGGLEPGLVFLGFLLVVGMGLAG480
Qy 481 AFLAHYVRHRLLHMQMVSGPNKIILTVDDITFLHPHGGTSRKVAQGSRSSLGARSMSDIR540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 AFLAHYVRHRLLHMQMVSGPNKIILTVDDITFLHPHGGTSRKVAQGSRSSLGARSMSDIR540
Qy 541 SGPSQHLDSPNIGVYEGDRVWLKKFPGDQHIAIRPATKTAFSKLQELRHENVALYLGLFL600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 SGPSQHLDSPNIGVYEGDRVWLKKFPGDQHIAIRPATKTAFSKLQELRHENVALYLGLFL600
Qy 601 ARGAEGPAALWEGNLAVVSEHCTRGSLQDLLAQREIKLDWMFKSSLLLDLIKGIRYLHHR660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ARGAEGPAALWEGNLAVVSEHCTRGSLQDLLAQREIKLDWMFKSSLLLDLIKGIRYLHHR660
Qy 661 GVAHGRLKSRNCIVDGRFVLKITDHGHGRLLEAQKVLPEPPRAEDQLWTAPELLRDPALE720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 GVAHGRLKSRNCIVDGRFVLKITDHGHGRLLEAQKVLPEPPRAEDQLWTAPELLRDPALE720
Qy 721 RRGTLAGDVFSLAIIMQEVVCRSAPYAMLELTPEEVVQRVRSPPPLCRPLVSMDQAPVEC780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 RRGTLAGDVFSLAIIMQEVVCRSAPYAMLELTPEEVVQRVRSPPPLCRPLVSMDQAPVEC780
Qy 781 ILLMKQCWAEQPELRPSMDHTFDLFKNINKGRKTNIIDSMLRMLEQYSSNLEDLIRERTE840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 ILLMKQCWAEQPELRPSMDHTFDLFKNINKGRKTNIIDSMLRMLEQYSSNLEDLIRERTE840
Qy 841 ELELEKQKTDRLLTQMLPPSVAEALKTGTPVEPEYFEQVTLYFSDIVGFTTISAMSEPIE900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 ELELEKQKTDRLLTQMLPPSVAEALKTGTPVEPEYFEQVTLYFSDIVGFTTISAMSEPIE900
Qy 901 VVDLLNDLYTLFDAIIGSHDVYKVETIGDAYMVASGLPQRNGQRHAAEIANMSLDILSAV960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 VVDLLNDLYTLFDAIIGSHDVYKVETIGDAYMVASGLPQRNGQRHAAEIANMSLDILSAV960
Qy 961 GTFRMRHMPEVPVRIRIGLHSGPCVAGVVGLTMPRYCLFGDTVNTASRMESTGLPYRIHV 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 GTFRMRHMPEVPVRIRIGLHSGPCVAGVVGLTMPRYCLFGDTVNTASRMESTGLPYRIHV 1020
Qy 1021 NLSTVGILRALDSGYQVELRGRTELKGKGAEDTFWLVGRRGFNKPIPKPPDLQPGSSNHG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 NLSTVGILRALDSGYQVELRGRTELKGKGAEDTFWLVGRRGFNKPIPKPPDLQPGSSNHG 1080
Qy 1081 ISLQEIPPERRRKLEKARPGQFS 1103
|||||||||||||||||||||||
Db 1081 ISLQEIPPERRRKLEKARPGQFS 1103
The combination of prior art cited above in all 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), 550 U.S. 389, 82 USPQ2d 1385 (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 A, E and G are applicable. At the time of invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Acland et al., wherein Acland teaches introducing into human retinal cells an rAAV vector comprising a polynucleotide that comprises a photoreceptor promoter operably linked to a nucleic acid segment that encodes a retinal-specific human guanylate cyclase polypeptide with the teachings of Hildinger, wherein Hildinger teaches an rAAV vector comprising a rhodopsin kinase promoter for photoreceptor-directed gene expression with the teachings of Eliasof et al, wherein Eliasof teaches a retinal-specific human guanylate cyclase polypeptide with 100% sequence identity to claimed SEQ ID NO: 1, with a reasonable expectation of arriving at the claimed invention.
A person of skill in the art would have been motivated to modify the method of Acland in order to determine the efficacy of the retinal-specific human guanylate cyclase polypeptide taught by Eliasof in producing a biologically-active human retGC1 polypeptide in the retinal cells of a human. A reasonable expectation of success is present because Acland achieved an rAAV nearly the same as that claimed and the relevant expression in vivo. The only difference is the nucleic acid sequence encoding human guanylate cyclase polypeptide. Thus, there is every expectation that the claimed vector and methods could be reached given the combined teachings of Acland, Hildinger and Eliasof. Moreover, one of ordinary skill in the art would have found it prima facie obvious to substitute the generic rhodopsin kinase promoter of Hildinger et al. for the rhodopsin kinase promoter due to its’ suitability as Young observed no promoter in non-photoreceptor cells (see Young at Pg. 4080, Col. 1).
Thus, 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.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 2
Claim 65 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Acland et al. (PgPub US20040022766A1, Published 2/5/2004; Reference in IDS filed 3/9/3022, previously cited) in view of Hildinger (PgPub US20070042462A1, Published 2/22/2007; Reference in IDS filed 3/9/3022, previously cited), Eliasof et al. (WO2004065576A2, Published 8/5/2004; Reference in IDS filed 3/9/3022, previously cited) and Young et al. (Investigative Ophthalmology & Visual Science September 2003, Vol.44, 4076-4085., previously cited) as applied to claims 57, 60-63, 66 -70 and 72-75 and further in view of Wilson et al. (WO1998009657A2, Published 4/23/1998).
The teachings of Acland et al., Hildinger et al., Eliasof et al., Young et al. are relied upon as detailed above. And although Acland teaches expression control sequences operably linked to the promoter includes an SV40 T intron (Pg. 4,para. 38), none of the aforementioned references teach an SV40 SD-SA sequence(as in claim 65).
Before the effective filing date of the claimed invention, Wilson teaches use of a recombinant adeno-associated virus (rAAV) comprising a heterologous gene operably linked to sequences which control expression thereof in a cell for the manufacture of a medicament. In one embodiment, Wilson teaches the sequence is an intron with functional splice donor and acceptor sites (as in claim 64) (Pg. 13, lines 14-29). A common intron sequence is also derived from SV-40, and is referred to as the SV-40 T intron sequence (Pg. 13, lines 24-25).
When taken with the teachings of Wilson et al., one of ordinary skill in the art would have found it prima facie obvious to select an SV40 T intron, comprising splice donor and acceptor sites, to be operably linked to the rhodopsin kinase promoter of Acland et al., Hildinger et al., Eliasof et al. and Young et al. The skilled artisan would have found it prima facie obvious to do so because Wilson teaches the SV40 T intron operably controls expression in a cell. Thus, for the purposes of regulating expression of SEQ ID NO: 1 in a cell, the combination would have been prima facie obvious.
Prior Art Rejection 3
Claim 71 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Acland et al. (PgPub US20040022766A1, Published 2/5/2004; Reference in IDS filed 3/9/3022, previously cited) in view of Hildinger (PgPub US20070042462A1, Published 2/22/2007; Reference in IDS filed 3/9/3022, previously cited), Eliasof et al. (WO2004065576A2, Published 8/5/2004; Reference in IDS filed 3/9/3022, previously cited) and Young et al. (Investigative Ophthalmology & Visual Science September 2003, Vol.44, 4076-4085., previously cited) as applied to claims 57, 60-63, 66 -70 and 72-75 and further in view of Gao et al. (PgPub US20050014262A1, Published 1/20/2005, previously cited).
The teachings of Acland et al., Hildinger et al. and Eliasof et al. are relied upon as detailed above. However, none of the references teach the composition further comprises a liposome (as in claim 71).
Before the effective filing date of the claimed invention, Gao et al. taught compositions particularly well suited for use in compositions requiring re-administration of rAAV for therapeutic or prophylactic purposes (Pg. 1, para. 4). Gao teaches introduction into the host cell of the vector may be achieved by any means known in the art or as disclosed above, including liposome delivery (as in claim 71) (Pg. 8, para. 82).
When taken with the teachings to Acland et al., Hildinger et al., Eliasof et al. and Young et al., one of ordinary skill in the art would have found it prima facie obvious to use the liposome of Gao et al. to deliver the AAV vector Acland et al., Hildinger et al., Eliasof et al. and Young et al. with a reasonable expectation of success. The skilled artisan would have found it prima facie to do so in order to deliver the AAV vector to the eye of patient having LCA-1.
Thus, the claimed invention would have been prima facie obvious.
Prior Art Rejection 4
Claims 76-77 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Acland et al. (PgPub US20040022766A1, Published 2/5/2004; Reference in IDS filed 3/9/3022, previously cited) in view of Hildinger (PgPub US20070042462A1, Published 2/22/2007; Reference in IDS filed 3/9/3022, previously cited), Eliasof et al. (WO2004065576A2, Published 8/5/2004; Reference in IDS filed 3/9/3022, previously cited) and Young et al. (Investigative Ophthalmology & Visual Science September 2003, Vol.44, 4076-4085., previously cited) as applied to claims 57, 60-63, 66 -70 and 72-75 and further in view of Wilson et al. (U.S. Patent 6261551B1, Published 7/17/2001).
The teachings of Acland et al., Hildinger et al., Eliasof et al., and Young et al. are relied upon as detailed above. And although (1) Acland teaches the rAAV minigene contains AAV 5′ ITRs and 3′ ITRs located 5′ and 3′ to the heterologous molecule (as in claim 76a and claim 76f) and operably linked expression control sequences, such as promoters and introns that are contiguous with the coding sequences, wherein said vector is administered to the eye of a subject that has Leber congenital amaurosis- 1 (LCA- 1) (Pg. 1, Para. 10, lines 1-10 and Pg. 2, Para. 16, lines 1-7) (as in claim 77) and (2) Young teaches the rhodopsin kinase promoter for photoreceptor-directed gene expression comprising that has 98% sequence identity to SEQ ID NO: 12 (as in claim 76b) and (3) Eliasof teaches SEQ ID NO: 1 (as in claim 76d); None of Acland et al., Hildinger et al., Eliasof et al., and Young et al. teach in a 5' to 3' direction, b) the photoreceptor-specific human rhodopsin kinase promoter comprising SEQ ID NO: 12; c) an SV40 SD-SA sequence; d) the nucleic acid encoding the human guanylate cyclase polypeptide of SEQ ID NO: 1 and e) a polyadenylation site.
Before the effective filing date of the claimed invention, Wilson et al. taught a method for enhancing the efficiency of transduction of a recombinant AAV into a target cell is provided by infecting a target cell with a recombinant AAV comprising a selected transgene under the control of regulatory sequences. Wilson teaches the rAAV comprises AAV ITRs flanking a suitable promoter (as further in claim 76b), SV40 splice donor-splice acceptor (SD/SA) (as in claim 76c), a transgene (as further in claim 76d), and SV40 polyA signal (pA) (as in claim 76e).
When taken with the teachings to Acland et al., Hildinger et al., Eliasof et al. and Young et al., one of ordinary skill in the art would have found it prima facie obvious to arrange the rhodopsin kinase promoter, the SV40 SD-SA, the nucleic acid encoding the human guanylate cyclase polypeptide of SEQ ID NO: 1, and a polyadenylation site in 5’ to 3’ order and flanked by 5’ and 3’ AAV ITRs, respectively, because Wilson this configuration is efficient in transducing a target cell.
Thus, the claimed invention would have been prima facie obvious.
Applicant’s Arguments/Response to Arguments
In order to practice compact prosecution, Applicant’s arguments drawn to any of Acland et al., Hildinger et al., Eliasof et al., Young et al. and Gao et al. are addressed below.
Applicant argues: Acland does not teach the claimed photoreceptor-specific human
rhodopsin kinase promoter, which is different from the Acland promoters in that the claimed
promoter drives expression evenly in all photoreceptors, instead of only a subset of photoreceptors, such as rods and cones, as the promoters of Acland. See Acland at [0043]. As such, a person of skill in the art provided with Acland would have no indication how to select a promoter that has the technical effect of the promoter of the present claims.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. This is because the claims do not require an even expression in all photoreceptors. Rather, the claim 57 simply requires a photoreceptor-specific human rhodopsin kinase promoter. As acknowledged by Applicant, Acland teaches such.
Applicant argues: While this reference provides a promoter sequence that partially overlaps with a human rhodopsin kinase promoter (cited as SEQ ID NO: 12), Hildinger does not disclose a promoter having at least 90% sequence identity to the 292 nucleotides of the human rhodopsin kinase promoter of the present claims, nor does it provide a person of skill in the art any reason for arriving at such claimed promoter.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Notably, Hildinger was not cited for teaching SEQ ID NO: 12. Indeed, Hildinger was cited for teaching a photoreceptor-specific human rhodopsin kinase promoter.
Applicant argues: Young includes a sequence of the human Rk gene (QA at p. 10), the promoter is described as a 0.11 kb region of the human Rk gene, not the promoter of the amended claims. See Young at Abstract ("Transgenic mice that carried the 0.11-kb DNA segment with the GFP gene linked downstream showed GFP transcript, fluorescence, and immunoreactivity that were restricted to photoreceptors"). Furthermore, although Young mentions a rhodopsin kinase promoter, the promoter of Young differs in that it is half the size of the claimed promoter. See Id. at Abstract. Because of the limited size of the genomes of AAV vectors, a person of skill in the art would not be motivated to increase the size of a promoter for delivery in an AAV vector.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. To study the transcriptional activity of the 5′ flanking region, Young teaches they generated a series of plasmids carrying the Rk flanking sequences upstream of the luciferase gene and analyzed their activity by transient transfection (Fig. 2) . WERI-RB1 retinoblastoma cells transfected with p-2.0Luc carrying the full 2.0-kb flanking sequence showed luciferase activities on average 50 times higher than those transfected with pLuc. Truncated constructs missing as few as 24 bases from the 3′ end of the 2.0-kb region (p-2.0/0.03Luc) conferred only a fraction of the luciferase activity (0.2×) whereas those without the proximal segment altogether with positions between +63 and −217 missing (p-2.0/0.2Luc) showed no activity at all. In contrast substantial enhancement in activity was observed with truncation from the 5′ direction. Both p-0.5Luc and p-0.11Luc were five to six times as active as p-2.0Luc.
It is well settled that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See MPEP 2123.
With respect to the size of the vector, Applicant’s arguments are not found persuasive as the claims do not restrict the size of the AAV vector. Moreover, Hildinger specifically teaches AAV5 vectors can accommodate up to 8 kb with high efficacy.
Applicant’s arguments: Specifically, Acland provides no data showing targeting of photoreceptors, and it would be incorrect to conflate transduction of retinal pigment epithelium (RPE) as reported in Acland with transduction of photoreceptors. See Acland at [0084]. While RPE cells are highly phagocytic and easy to transducer transfect, it was known at the time of filing that photoreceptor cells do not easily uptake vectors. Hildinger likewise shows no transfection of photoreceptor cells, while Young and Eliasof are silent as to AAV transfection.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Notably, Acland teaches the targeted cells are photoreceptors (see at least para. 30). None of Hildinger, Young and Eliasof were cited for teaching transfection of photoreceptor cells.
Applicant argues: In view of the unpredictability of the promoter of the present claims for driving expression specifically in photoreceptor cells from an AAV delivery vector, the data present in the instant specification, is unexpected. Applicant cites para. 187+ of the PgPub.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Critically, Applicant’s argument of unexpected results in the promoter of the present claims driving expression specifically in photoreceptor cells is unclear as this is an inherent property of a cell-specific promoter. Also of note, the Examples specifically use AAV5. Independent claim 57 is drawn to a generic AAV vector.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Maintained Rejection
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 57, 60-63 and 65 -75 remain and new claims 76-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. U.S. Patent 9816108. Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons expressed in the previous office action.
Applicant’s Arguments/Response to Arguments
Applicant argues: At least in view of the amendment requiring a human rhodopsin kinase promoter at least 90% identical to SEQ ID NO: 1, and the remarks with respect to the previous obviousness rejection, the double patenting rejection should be withdrawn.
In Response: Remarks drawn to the obviousness rejection have been previously addressed, and will not be addressed herein. None of the claims require a human rhodopsin kinase promoter that is at least 90% identical to SEQ ID NO: 1.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
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/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632