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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/09/2023, 10/18/2023, and 12/29/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
This application is a national stage filing under 35 U.S.C. # 371 of International PCT Application, PCT/US2021/050205, filed September 14, 2021, which claims priority under 35 U.S.C. 9 119(e) to U.S. Provisional Application, U.S.S.N. 63/161,6 19, filed March 16, 2021, and to U.S. Provisional Application, U.S.S.N. 63/078,233, filed September 14, 2020
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Election/Restrictions
Applicant’s election of Group I (claims: 1-2, 5, 10, 14, 23-24, 28-29, 32, 36, 38, 41, 44, 45, 48-50, 53, 55, 58, and 59), drawn to an isolated nucleic acid comprising an expression cassette, a vector comprising a GJB2 promoter, a recombinant adeno-associated virus (rAAV), a cell, and a pharmaceutical composition, in the reply filed on 12/29/2025 is acknowledged. Applicants’ election of species SEQ ID NO: 37, drawn to a human GJB2 promoter and an enhancer, in the reply filed on 12/29/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Status of Claims
Claims 3-4, 6-9, 11-13, 15-22, 25-27, 30-31, 33-35, 37, 39-40, 42-43, 46-47, 51-52, 54, 56-57, 60, 64-76 are cancelled. Claims 1-2, 5, 10, 14, 23-24, 28-29, 32, 36, 38, 41, 44, 45, 48-50, 53, 55, 58, 59, and 61-63 are currently pending. Claims 61-63 are withdrawn as being drawn to the nonelected method invention in view of the restriction requirement and applicant’s election.
CLAIM INTERPRETATION
Claims 5, 10, 14, 24, 29, 32, 36, 38, 41, 44-45, 53, 55, and 59 recite the term “optionally.” Elements or limitations that follow the term “optionally” are not required; however, for compact prosecution and customer service, one element/limitation will be considered if possible. Applicant is advised to appropriately amend by removing “optionally,” since any term(s) thereafter are not required and thus do not further limit. Terms following “optionally” will not be considered in future actions.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 14, 45, and 49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites a broad recitation, SEQ ID NO: 5, and the claim also recites SEQ ID NO: 102, which is a narrower statement of the range/limitation. The specification defines both SEQ ID NO: 5 and SEQ ID NO: 102 as being portions of the human GJB2 promoter, with SEQ ID NO: 5 being 500 bp consecutive nucleotides and SEQ ID NO: 102 being a “GJB2 proximal promoter” of 120 bp consecutive nucleotides. A nucleotide sequence alignment of SEQ ID NO: 5 to SEQ ID NO: 102 demonstrates that SEQ ID NO: 102 corresponds to nucleotide positions 73-192 of SEQ ID NO: 5 with 100% identity. Therefore, SEQ ID NO: 102 is a narrower recitation of SEQ ID NO: 5. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 14 recites the limitation "the promoter" in line 3 section “a)” of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 1, on which claim 14 depends, does not recite “a promoter.”
Claim 45 is not interpretable as written as the phrase, “claims 1-44,” was not properly deleted in the amendment to claims. Applicant may remedy by submitting a revised claim set. For examination purposes and customer service, the examiner is considering claim 45 to be dependent on claim 1.
Claim 49 recites the limitation "a 3’ ITR" in line 10 of the claim. Claim 49 depends from claim 48, which recites “a 3’ ITR.” It is unclear whether "a 3' ITR" in claim 49 is an additional 3' ITR, thus comprising two different 3' ITRs or whether "a 3' ITR" is meant to refer back to "a 3' ITR" in claim 48. For compact prosecution and customer service, the examiner will interpret "a 3' ITR" in claim 49 as referring back to "a 3' ITR" in claim 48. Applicant may remedy by submitting a revised claim set.
Claim Rejections - 35 USC § 112 Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 48 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The specification does not describe the claimed structure as amended and there is no evidence that the inventors contemplated the structure without a 5' ITR and only with a 3' ITR (see [0026-0027]). Furthermore, there is no art to support the claimed structure as amended (i.e., an rAAV vector without a 5’ ITR).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 58 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 58 recites a cell comprising the isolated nucleic acid of claim 1. The specification discloses “the host cell is a mammalian cell (e.g., a human cell) [00158], and that the isolated nucleic acid is a therapy for GRB2 related hearing loss in a subject, wherein “the subject is human” [0040]. Therefore, when the cell of claim 58 is present in vivo, it reads on a human organism, which is excluded from the scope of patentable subject matter under 35 U.S.C. 101 and section 33(a) of the America Invents Act. Amending “A cell” to an “An isolated cell” would be remedial if supported by the specification.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 5, 10, 14, 23-24, 28-29, 32, 36, 41, 45, 50, 53, 55, and 58-59 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bartolome C. et. al., (US-20210095313-A1).
Regarding claim 1, Bartolome teaches “an isolated polynucleotide comprising a nucleic acid sequence encoding GJB2” (see claim 1). Bartolome teaches “A transgene expression cassette comprising: the polynucleotide of claim 1; and minimal regulatory elements” (see claim 24). Wherein, “the term “minimal regulatory elements” is meant to refer to regulatory elements that are necessary for effective expression of a gene in a target cell and thus should be included in a transgene expression cassette. Such sequences could include, for example, promoter or enhancer sequences, a polylinker sequence facilitating the insertion of a DNA fragment within a plasmid vector, and sequences responsible for intron splicing and polyadenylation of mRNA transcripts.” See [0099].
Regarding claim 2, Bartolome teaches “the nucleic acid encoding the GJB2 protein is optimized for human expression, and/or is a human GJB2, or a functional fragment thereof.” See [0156]. Bartolome teaches “The polynucleotide of claim 1, wherein the nucleic acid sequence comprises SEQ ID NO: 10.” See claim 5. SEQ ID NO: 10 has 100% identity to SEQ ID NO: 2 of the instant case
Bartolome teaches “the nucleic acid sequence of the human wild-type GJB2 (hGJB2wt) (SEQ ID NO. 10)” see FIG. 10, and “the nucleic acid sequence of the human codon optimized GJB2 (hGJB2co3) (SEQ ID NO. 11)” see FIG 11, and “the nucleic acid sequence of the human codon optimized GJB2 (hGJB2co6) (SEQ ID NO. 12)” see FIG. 13, and “the nucleic acid sequence of the human codon optimized GJB2 (hGJB2co9) (SEQ ID NO. 13)” see FIG 13 and [0288].
Regarding claims 5 and 24, Bartolome teaches “the nucleic acid sequence is operably linked to a promoter; the promoter is…small GJB2 promoter, medium GJB2 promoter, large GJB2 promoter, or a sequential combination of 2-3 individual GJB2 expression-specific promoters.” See [0013]. Bartolome teaches “the promoter is an endogenous GJB2 promoter; the nucleic acid sequence of the GJB2 promoter (SEQ ID NO. 6).” See [0172] and figure 8. Bartolome teaches “various length versions of the endogenous mammalian GJB2 promoter, including the 128-bp-long basal promoter of GJB2 (GJB2(128)), GJB2(539), GJB2 (1000); the 1000 bp length promoter is estimated to contain all the known functional regions of the greater GJB2 promoter (primarily core promoter plus transcription factor binding sites).” See [0296]. Furthermore, positions 261-380 of Bartolome’s SEQ ID NO: 6 comprises the entire 120-mer sequence of SEQ ID NO: 102.
Regarding claim 10, Bartolome teaches that “the gene may or may not include regions preceding and following the coding region, e.g., 5′ untranslated (5′UTR) or “leader” sequences and 3′ UTR or “trailer” sequences. The term “gene” means the nucleic acid sequence which is transcribed (DNA) to RNA in vitro or in vivo when operably linked to appropriate regulatory sequences.” See [0125]. Furthermore, Bartolome teaches SEQ ID NO: 6 which comprises SEQ ID NO: 30 of the instant case with 95.4% homology surpassing the “at least 80% identical” limitation recited in claim 10.
Regarding claim 14, Bartolome teaches the term “enhancer…refers to a cis-acting regulatory sequence (e.g., 50-1,500 base pairs) that binds one or more proteins (e.g., activator proteins, or transcription factor) to increase transcriptional activation of a nucleic acid sequence. Enhancers can be positioned up to 1,000,000 base pars upstream of the gene start site or downstream of the gene start site that they regulate.” See [0112]. Bartolome teaches analogous to a “GRE” of the instant case that “the term “minimal regulatory elements” is meant to refer to regulatory elements that are necessary for effective expression of a gene in a target cell and thus should be included in a transgene expression cassette. Such sequences could include, for example, promoter or enhancer sequences, a polylinker sequence facilitating the insertion of a DNA fragment within a plasmid vector, and sequences responsible for intron splicing and polyadenylation of mRNA transcripts.” See [0100].
Regarding claim 23, Bartolome teaches “an isolated polynucleotide comprising a nucleic acid sequence encoding GJB2.” See Claim 1. Bartolome teaches “a transgene expression cassette comprising: the polynucleotide of claim 1; and minimal regulatory elements.” See claim 24. Bartolome teaches that “the term “minimal regulatory elements” is meant to refer to regulatory elements that are necessary for effective expression of a gene in a target cell and thus should be included in a transgene expression cassette. Such sequences could include, for example, promoter or enhancer sequences, a polylinker sequence facilitating the insertion of a DNA fragment within a plasmid vector, and sequences responsible for intron splicing and polyadenylation of mRNA transcripts.” See [0099].
Regarding claim 28, Bartolome teaches that “a promoter can be one naturally associated with a gene or sequence, as can be obtained by isolating the 5′ non-coding sequences located upstream of the coding segment and/or exon of a given gene or sequence. Such a promoter can be referred to as “endogenous.”” See [0114]. Bartolome teaches that “the GJB2 promoter is a support-cell specific promoter and can transduce cells of the inner ear that express the GJB2 gene.” See [0172].
Regarding claim 29, Bartolome teaches that “the AAV vectors … are particularly suited to deliver and express GJB2 in the cochlear support cells; the AAV vectors … are particularly suited to deliver and express GJB2 in one or more of the external support cells and/or the organ of Corti support cells; suited to deliver and express GJB2 in one or more of the outer hair cells, the inner hair cells, hensen's cells, deiters' cells, pillar cells, inner phalangeal cells and/or outer phalangeal cells/ border cells.” See [0189]. Bartolome teaches that “the promoter is highly specific for support cell expression in the cochlea.” See [0111].
Regarding claim 32, Bartolome teaches “AAV vectors for expression of GJB2 protein contain nucleic acid, e.g., a GJB2 nucleic acid sequence (e.g., a codon optimized GJB2 nucleic acid sequence), positioned between two inverted terminal repeat (ITR) sequences.” See [0178]. Bartolome teaches “inverted terminal repeats (ITRs) flanking the AAV genomic cassette.” See [0187]. Bartolome teaches “the serotype of the ITRs of the AAV vector are independently selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAV12.” See [0180]. Bartolome teaches “the ITR is WT AAV2 ITR.” See [0095]. Bartolome shows “the nucleic acid sequences of the following ITRs (AAV2) 5′-3′” See figure 9 and [0183].
Regarding claim 36, Bartolome teaches “the nucleic acid sequence further comprises an operably linked 3′UTR regulatory region comprising a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE).” See [0130]. Bartolome shows the nucleic acid sequence of Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) (SEQ ID NO. 15).” See [0289] and FIG. 15.
Regarding claim 41, Bartolome teaches that the GJB2 transgene is “operably linked to a 3′-UTR regulatory region comprising the Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) followed by either a SV40 or human growth hormone (hGH) polyadenylation signal.” See [0013]. Bartolome shows “the nucleic acid sequence of SV40 poly(A) (SEQ ID NO. 16)” and “the nucleic acid sequence of a SV40/bGH terminator sequence (SEQ ID NO. 17).” See [0289] and FIG. 16 and FIG. 17.
Regarding claim 45, Bartolome teaches “an isolated polynucleotide comprising a nucleic acid sequence encoding GJB2.” See claim 1. Bartolome teaches “a recombinant adeno-associated (rAAV) expression vector comprising the polynucleotide of claim 1 and an AAV genomic cassette.” See Claim 32.
Regarding claim 50, Bartolome teaches “a recombinant adeno-associated (rAAV) expression vector comprising the polynucleotide of claim 1 and an AAV genomic cassette.” See claim 32. Bartolome teaches “the expression vector of claim 32 further comprising a protein capsid variant optimally suited for cochlear delivery.” See claim 35. Bartolome teaches “the term “rAAV viral particle” refers to a recombinant AAV virus particle, i.e., a particle that is infectious but replication defective. A rAAV viral particle comprises single stranded genome DNA packaged into AAV capsid proteins.” See [0070]. Bartolome teaches “the term a “rAAV virus” or “rAAV viral particle” is meant to refer to a viral particle composed of at least one AAV capsid protein and an encapsidated rAAV vector genome; As used herein, the term a “rAAV virus” or “rAAV viral particle” is meant to refer to a viral particle composed of at least one AAV capsid protein and an encapsidated rAAV vector genome.” See [0127-0128].
Regarding claim 53, Bartolome teaches “delivering a heterologous nucleic acid to cells of the inner ear of a subject comprising administering a recombinant adeno-associated virus (rAAV) vector.” See [0147]. Bartolome teaches “a protein capsid variant suitable for targeted cochlear delivery.” See [0022] and claim 35. Bartolome teaches “the term “inner ear cells” or “cells of the inner ear” refers to inner hair cells (IHCs) and outer hair cells (OHCs), spiral ganglion neurons, vestibular hair cells, vestibular ganglion neurons, supporting cells and cells in the stria vascularis. Supporting cells refer to cells in the ear that are not excitable, e.g., cells that are not hair cells or neurons.” See [0093].
Regarding claim 55, Bartolome teaches “the serotype of the capsid sequence and the serotype of the ITRs of said AAV vector are independently selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAV12.” See [0020]. Bartolome teaches “the capsid sequences are derived from one of the human serotypes AAV1-AAV12; Capsids suitable for this purpose comprise AAV2 and AAV2 variants including AAV2-tYF, AAV2-MeB, AAV2-P2V2, AAV2-MeStYFTV, AAV2-P2V6; as well as AAV5, AAV8, and Anc80L65.” See [0197].
Regarding claim 58, Bartolome teaches “a host cell comprising the polynucleotide of claim 1” (Claim 1: An isolated polynucleotide comprising a nucleic acid sequence encoding GJB2.). See Claim 19. Bartolome teaches “a host cell comprising the transgene expression cassette of claim 24” (Claim 24: A transgene expression cassette comprising: the polynucleotide of claim 1; and minimal regulatory elements.). See claim 27. Bartolome teaches “AAV and Gene Therapy; Gene therapy refers to treatment of inherited or acquired diseases by replacing, altering, or supplementing a gene responsible for the disease. It is achieved by introduction of a corrective gene or genes into a host cell, generally by means of a vehicle or vector.” See [0231-0232]. Bartolome teaches “the term “vector” is meant to refer to a recombinant plasmid or virus that comprises a nucleic acid to be delivered into a host cell, either in vitro or in vivo.” See [0124].
Regarding claim 59, Bartolome teaches “a composition comprising the polynucleotide of claim 1” (Claim 1: An isolated polynucleotide comprising a nucleic acid sequence encoding GJB2.). See claim 63. Bartolome teaches “a composition comprising the transgene expression cassette of claim 24” (Claim 24: A transgene expression cassette comprising: the polynucleotide of claim 1; and minimal regulatory elements.). See claim 66. Bartolome teaches “the composition is a pharmaceutical composition.” See [0032]. Bartolome teaches “the term “pharmaceutical composition” or “composition” is meant to refer to a composition or agent described herein (e.g. a recombinant adeno-associated (rAAV) expression vector), optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients and the like.” See [0109].
Claims 1-2, 5, 14, 23, 28-29, 32, 41, 45, 50, 53, 55, and 58-59 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Maguire CA. et. al., (WO-2019200016-A1, provided in IDS).
Regarding Claim 1, Maguire discloses an isolated nucleic acid (a vector including an isolated nucleic acid described herein, Pg. 2, lns.15-16) comprising an expression cassette (“recombinant adeno-associated viruses (rAAVs) ... comprising expression cassettes,” Pg. 8, Lns.5-6), wherein the expression cassette comprises a Gap Junction beta 2 (GJB2) gene regulatory element (GRE) (“configured for expression of ... gap junction beta 2 (GJB2),” Pg. 8, Ln. 7; “in a further embodiment, other native expression control elements, such as enhancer elements, ... may also be used to mimic the native expression,” Pg. 15, lns. 21-23), and a nucleotide sequence encoding a GJB2 protein (“configured for expression of ... gap junction beta 2 (GJB2),” Pg. 8, ln. 7). Also see claims 40-43.
Regarding Claim 2, Maguire discloses the isolated nucleic acid of claim 1, wherein the GJB2 protein is a human GJB2 protein (“In some aspects, the disclosure provides isolated nucleic acids that are useful for expressing ... human GJB2,” Pg. 8, lns. 10-11). Maguire further discloses SEQ ID NO: 4, which is 100% identical to SEQ ID NO: 2 in the instant case. Also see claims 40-42.
Regarding Claim 5, Maguire discloses the isolated nucleic acid of claim 1, wherein the expression cassette further comprises a promoter operably linked to the nucleotide sequence encoding a GJB2 protein (Claim 40: “an isolated nucleic acid, comprising: … (ii) a second region comprising a transgene encoding Gap Junction beta 2 (GJB2),” and claim 43: “the isolated nucleic acid of any one of claims 40-42, wherein the transgene further comprises a promoter.”). Maguire further teaches that “the native promoter for the transgene will be used. The native promoter may be preferred when it is desired that expression of the transgene should mimic the native expression. The native promoter may be used when expression of the transgene must be regulated temporally or developmentally, or in a tissue- specific manner, or in response to specific transcriptional stimuli.” See pg. 15, lns. 17-21.
Regarding claim 14, Maguire teaches “the vector also includes conventional control elements which are operably linked with elements of the transgene in a manner that permits its transcription, translation, and/or expression in a cell transfected with the vector or infected with the virus produced by the invention.” Maguire further teaches “regulatory sequences are said to be operably linked when they are covalently linked in such a way as to place the expression or transcription of the nucleic acid sequence under the influence or control of the regulatory sequences. If it is desired that the nucleic acid sequences be translated into a functional protein, two DNA sequences are said to be operably linked if induction of a promoter in the 5' regulatory sequences results in the transcription of the coding sequence.” See pg. 13, Lns. 14-20.
Regarding claims 23 and 28-29, Maguire teaches “an isolated nucleic acid, comprising: … (ii) a second region comprising a transgene encoding Gap Junction beta 2 (GJB2).” See claim 40. Maguire further teaches “the isolated nucleic acid of any one of claims 40-42, wherein the transgene further comprises a promoter.” See claim 43. Maguire further teaches that “the native promoter for the transgene will be used. The native promoter may be preferred when it is desired that expression of the transgene should mimic the native expression. The native promoter may be used when expression of the transgene must be regulated temporally or developmentally, or in a tissue- specific manner, or in response to specific transcriptional stimuli.” See pg. 15, lns. 17-21. Maguire further teaches “ the rAAV as provided herein, is capable of delivering the transgene (e.g., CLRN1 or GJB2 ) to the cells in the inner ear (e.g., cochlear). Non limiting examples of the cells in the cochlear are outer hair cells (OHC), inner hair cells (IHC), spiral ganglion neurons, stria vascularis, inner sulcus, spiral ligament, or vestibular system. In other examples, the cells in the cochlear are fibrocytes lining the inner ear.” See pg. 19, lns. 12-17.
Regarding claim 32, Maguire teaches “the selected transgene sequence and associated regulatory elements are flanked by the 5' and 3' AAV ITR sequences.” See pg. 12, lns. 10-15. Maguire further teaches “the AAV ITR sequences may be obtained from any known AAV, including presently identified mammalian AAV types. In some embodiments, the isolated nucleic acid comprises at least one ITR having a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV10, and AAV11. In some embodiments, the isolated nucleic acid comprises a region (e.g., a first region) encoding an AAV2 ITR.” Maguire teaches “the isolated nucleic acid further comprises…a second AAV ITR,” and that “the second AAV ITR has a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV 10, AAV11, and variants thereof.” See pg. 12, lns. 14-17 and 19-22.
Regarding claim 41, Maguire teaches that “the vector can further comprise certain regulatory elements (e.g., enhancers, kozak sequences, and poly adenylation sites).” See pg. 15, lns. 22-24.
Regarding claim 45, Maguire teaches “a vector comprising the isolated nucleic acid of any one of claims 40-46.” See claim 47. Maguire further teaches that “the vector is a plasmid.” See claim 48. Maguire further teaches that the vector is a viral AAV vector. See claims 46 and 50.
Regarding claim 50, Maguire teaches a recombinant adeno-associated virus (rAAV), comprising: (i) a capsid protein; and (ii) the isolated nucleic acid of claim 1. See claim 50 of Maguire and Maguire applied to claim 1 above.
Regarding claim 53, Maguire teaches “the rAAV is formulated for delivery to the ear, the rAAV is formulated for delivery to the inner ear, the rAAV is formatted for delivery to the cochlea of the inner ear, and the rAAV is formulated for delivery to a fibrocyte lining the fluid space of the cochlea.” See claims 59-62.
Regarding claim 55, Maguire teaches “the capsid protein is AAV9 capsid protein, or a variant there of,” and “the AAV9 capsid variant is AAV9.PHP.B.” See claims 51-52. Maguire further teaches the “AAV capsid protein is of an AAV serotype selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrhlO, and AAV.PHP.B.” See pg. 16, lns. 31-33 and Maguire applied to claim 1 above.
Regarding claim 58, Maguire teaches a cell comprising the nucleic acid of claim 1. See claim 49 and Maguire applied to claim 1 above.
Regarding claim 59, Maguire teaches “a pharmaceutical composition, comprising the rAAV” comprising the isolated nucleic acid of claim 1. See claim 63 and Maguire applied to claim 1 above.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5, 10, 14, 23-24, 28-29, 32, 36, 38, 41, 44-45, 48-50, 53, 55, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Bartolome C. et. al., (US-20210095313-A1) in view of, Simons et. al., (US-20230183743-A1), Ng R. et. al., (US-20210277417-A1), Genkin D. et. al. (US-20190241908-A1), and Mastroyiannopoulos et. al., (EMBO reports, 6(5), 458-463, published 4/15/2005).
The teachings of Bartolome regarding claims 1-2, 5, 10, 14, 23-24, 28-29, 32, 36, 41, 45, 50, 53, 55, and 58-59 are incorporated herein by reference to the corresponding 102 rejection above.
Regarding claims 24, 44, and 48-49, Bartolome teaches that SEQ ID NO: 6 is a full length GJB2 promoter which comprises the GJB2 minimal promoter corresponding with 100% homology to SEQ ID NO: 102 and the GJB2 5’ UTR corresponding with 100% homology to SEQ ID NO: 103 of the instant case. Bartolome further teaches SEQ ID NO: 10, which corresponds with 100% homology to the hGJB2 coding region, SEQ ID NO: 2 in the instant case.
Regarding claims 36 and 38, Bartolome teaches the use of a WPRE: “3′-UTR regulatory region comprising the Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) followed by either a SV40 or human growth hormone (hGH) polyadenylation signal.” See [0187].
Regarding claim 44, Bartolome teaches “AAV vectors for expressing an isolated polynucleotides in a subject or cell.” See [0003]. Bartolome teaches “an isolated polynucleotide comprising a nucleic acid sequence encoding GJB2.” See claim 1. Bartolome teaches “a transgene expression cassette comprising: the polynucleotide of claim 1; and minimal regulatory elements.” See claim 24. Bartolome teaches “a nucleic acid vector comprising the expression cassette of claim 24.” See claim 25. Bartolome teaches “the vector of claim 25, wherein the vector is an adeno-associated viral (AAV) vector.” See claim 26.
Bartolome does not teach:
1) a 5’-ITR comprising a nucleotide sequence comprising SEQ ID NO: 106 or a 3’-ITR comprising a nucleotide sequence comprising SEQ ID NO: 107;
2) a WPRE comprising a nucleotide sequence comprising SEQ ID NO: 108;
3) a bGH poly(A) signal comprising a nucleotide sequence comprising SEQ ID NO: 109;
4) a 5’ UTR comprising a first nucleotide sequence comprising SEQ ID NO: 103 and a second nucleotide sequence comprising SEQ ID NO: 104;
5) a 3’ UTR comprising a nucleotide sequence comprising SEQ ID NO: 32; and
6) a nucleotide sequence comprising SEQ ID NO: 110 or 111.
Simons teaches “compositions and methods for treating gjb2-associated hearing loss.” See title. Simons teaches an “rAAV construct comprising a 5' ITR, a promoter comprising a hGJB2 enhancer and a hGJB2 promoter, a 5' UTR, a nucleic acid encoding a hGJB2 gene, a FLAG tag, a 3' UTR, a bGH polyA, and a 3' ITR.” See [0009] and FIG. 2. It is noted Simons’ vector configuration is the same configuration of the vector in the instant case minus the WPRE. Simons teaches “constructs comprising hGJB2 coding sequences with GJB2 5' UTR and 3'UTR sequences.” See [0010] and FIG. 2. Simons teaches SEQ ID NO: 3 is “GJB2 cDNA with untranslated rejoins,” SEQ ID NO: 4 is “spliced Human GJB2 isoform X1 cDNA including untranslated regions Sequence,” SEQ ID NO: 5 is “Human GJB2 Genomic DNA Sequence,” and SEQ ID NO: 6 is “expanded Human GJB2 Genomic DNA Sequence including certain regulatory regions.” The above GJB2 sequences taught by Simons comprise with 100% homology the GJB2 UTRs, SEQ ID NO: 32, SEQ ID NO: 103, and SEQ ID NO: 104, claimed in the instant case. See sequence listing and [0099]. Simons further teaches SEQ ID NO: 35 is an “exemplary cloning site,” which comprises with 100% homology SEQ ID NO: 104 of the instant case. See sequence listing. Simons teaches SEQ ID NO: 8 is an “exemplary 5' AAV ITR,” which has 100% homology to SEQ ID NOs: 106 and 107 in the instant case. See sequence listing. Simons teaches SEQ ID NO: 9 is an “exemplary 3' AAV ITR,” which has 100% homology to SEQ ID NOs: 106 and 107 in the instant case. See sequence listing. Simons teaches “there are several poly(A) signal sequences that can be used, including those derived from bovine growth hormone (bGH)” see [0222] and FIG. 2. Simons teaches “those of ordinary skill in the art will readily understand that similar constructs can be made in accordance” to the examples provided.
Simons teaches the incorporation of “regulatory element” or “regulatory sequence” into the GJB2 expression cassettes and that they refer “to non-coding regions of DNA that regulate, in some way, expression of one or more particular genes. … In some embodiments, a regulatory element impairs or enhances transcription of one or more genes. In some embodiments, a regulatory element may be located in cis to a gene being regulated. … For example, in some embodiments, a regulatory sequence refers to a nucleic acid sequence which is regulates expression of a gene product operably linked to a regulatory sequence. In some such embodiments, this sequence may be an enhancer sequence and other regulatory elements which regulate expression of a gene product.” See [0069]. Simons teaches “regulatory elements facilitate tissue specific expression at physiologically suitable levels.” See [0006].
Simons teaches that the GJB2 expression cassettes are designed to target “support cell,” “supporting cell,” “inner ear support cell,” or “inner ear supporting cell” and that these cells refer “to cells of the inner ear that maintain the structure of the inner ear and maintain the environment of the sensory epithelium of the inner ear. In some aspects, inner ear supporting cells include, but are not limited to, inner phalangeal cells/border cells (IPhC), inner pillar cells (IPC), outer pillar cells (OPC), Deiters’ cells rows 1 and 2 (DC1/2), Deiters’ cells row 3 (DC3), Hensen’s cells (Hec), Claudius cells/outer sulcus cells (CC/OSC), interdental cells (Idc), inner sulcus cells (ISC), Kolliker’s organ cells (KO), greater ridge epithelial ridge cells (GER) (including lateral greater epithelial ridge cells (LGER)), and OC90+ cells (OC90), fibroblasts, and other cells of the lateral wall.” See [0074]. Simons teaches “constructs comprising microRNA regulatory target site (miRTS) which can be used to regulate (e.g., reduce) expression of connexin 26 in a cell (e.g., an inner ear cell, e.g., a hair cell).” See [0196-0213].
Simons teaches the role of GJB2 in the inner ear cells and that “there are over 200 defined mutations of GJB2, which show some level of pathogenicity, and various mutations in the GJB2 gene have been associated with hearing loss (e.g., non-syndromic sensorineural hearing loss or syndromic sensorineural hearing loss).” Thus, Simons provides rAAV constructs comprising WT hGJB2 that “can be useful for administration of compositions that result in expression of gene products involved in the development, function, and/or maintenance of inner ear cells, and/or the treatment of hearing loss, or diseases or conditions associated with hearing loss.” See entire publication. Simons teaches “there remains a need for effective treatments, such as gene therapy, which can repair and/or mitigate a source of a hearing problem.” See [0079].
However, Simons does not explicitly disclose the nucleic acid sequence of the bGH poly(A) signal. Simons also does not teach constructs comprising WPRE.
Ng teaches a bGH poly(A) signal comprising a nucleotide sequence with 100% homology to SEQ ID NO: 109 in the instant case. See SEQ ID NO: 20. Ng similarly to Simons teaches an AAV2 5’-ITR comprising a nucleotide sequence with 100% homology to SEQ ID NO: 106 and an AAV2 3’-ITR comprising a nucleotide sequence with 100% homology to SEQ ID NO: 107. See SEQ ID NOs: 24 and 25.
However, Ng does not teach constructs comprising WPRE.
Genkin teaches “an exemplary post-transcriptional regulatory element is the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). For example, a sequence from the WPRE is shown in SEQ ID NO: 16. The WPRE may be effective to increase expression of the protein.” See [0167]. Genkin further teaches the arrangement of the WPRE and that such arrangement stabilized the mRNA: “One or more sequences may be selected to stabilize mRNA. An example of such a sequence is a modified WPRE sequence, which may be engineered upstream of the polyA sequence and downstream of the coding sequence.” See [0164]. Genkin also teaches a construct comprising a transgene (DNAse I), WPRE, and bGH polyA signal in the 5’ to 3’ orientation. See Figure 9. Hence, this orientation was an art-recognized construct design: having WPRE positioned between the transgene and the polyA signal sequence. Lastly, SEQ ID NO: 16 corresponding to the WPRE taught by Genkin has 100% homology to SEQ ID NO: 108, the WPRE of the instant application.
Genkin does not expressly teach that the transgene comprises its 3’UTR sequence.
Mastroyiannopoulos teaches EGFP transgene constructs comprising a DMPK 3’ UTR either with or without a downstream WPRE. See figure 1. Mastroyiannopoulos reports “the addition of the WPRE sequence downstream of the DMPK 3’ UTR stimulates the transport of mutant transcripts to the cytoplasm and repairs myoblast differentiation.” Therefore, Mastroyiannopoulos explicitly teaches that placement of the WPRE between a 3’ UTR and PolyA signal increases expression of a transgene. See introduction and results.
Regarding claims 24, 32, 36, 38, and 41, it would have been obvious to one of ordinary skill in the art before the effective filing date to select the claimed polynucleotide sequences corresponding to the 5’-and-3’-AAV2 ITRs (as taught by Bartolome, Simons, and Ng), 5’-and-3’ GJB2 UTRs (as taught by Bartolome and Simons), the WPRE (as taught by Bartolome, Genkin, and Mastroyiannopoulos), and the bGH poly(A) signal (as taught by Bartolome, Simons, Ng, and Genkin) as the ITRs and expression regulatory elements in the expression cassette/rAAV constructs taught Bartolome. The nucleotide sequences for each element were disclosed with 100% alignment in their respective prior art references to the nucleotide sequences claimed in the instant case. A person of ordinary skill in the art would have been motivated to do so in order to avoid adverse effects of traditional non-targeted AAV gene therapy by directing expression of the hGJB2 transgene to the specific cell types of the inner ear and to maximize expression of the hGJB2 transgene within the desired cells needing therapy. The AAV2 ITRs, UTRs, WPRE, bGH poly(A) signal are all standard regulatory elements commonly used in the art to respectively target cell types, increase expression of a transgene, and terminate transcription. The placement of such elements when designing gene therapy constructs was well known in the art as evidenced by the teachings of Bartolome, Simmons, Ng, Genkin, and Mastroyiannopoulos. For example, regarding the WPRE, while Bartolome describes WPRE utility in the 3’ UTR region and Genkin describes WPRE placement between the transgene and polyA signal, Mastroyiannopoulos provides experimental data that explicitly support its placement between a 3’ UTR of a transgene and a polyA signal. One would have a reasonable expectation of success because using each of these construct elements represents a simple substitution of known elements with known functions and known optimal arrangements in relation to one another within AAV gene therapy constructs.
Regarding claims 44 and 48-49, it would have further been obvious to modify the gene therapy vectors taught by Bartolome to arrive at vectors comprising claimed SEQ ID NO: 110 (comprising the vector layout of claim 48) or SEQ ID NO: 111 (comprising the layout of claim 49). Each element of SEQ ID NO: 110, as detailed in claim 48, and SEQ ID NO: 111, as detailed in claim 49, were taught in the prior art with 100% identity. By assembling each known element and their respective known nucleotide sequence according to standard practices and teachings of vector arrangement in the art, one of ordinary skill in the art would have arrived at vectors comprising SEQ ID NO: 110 or SEQ ID NO: 111 (i.e., vector compositions as claimed in claims 48 and 49, respectively) with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so in order to generate an rAAV vector system that could target specific cell types in the inner ear and increase GJB2 protein expression and function, restoring GJB2 function, thereby treating GJB2 related hearing loss while avoiding the adverse effects of non-targeted AAV gene therapy.
Claims 1-2, 5, 10, 14, 23-24, 28-29, 32, 36, 38, 41, 44-45, 48-50, 53, 55, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Maguire C. et. al., (WO-2019200016-A1, provided in IDS) in view of, Simons et. al., (US-20230183743-A1), Ng R. et. al., (US-20210277417-A1), Genkin D. et. al. (US-20190241908-A1), and Mastroyiannopoulos et. al., (EMBO reports, 6(5), 458-463, published 4/15/2005).
The teachings of Maguire regarding claims 1-2, 5, 14, 23, 28-29, 32, 41, 45, 50, 53, 55, and 58-59 are incorporated herein by reference to the corresponding 102 rejection above.
Maguire does not teach:
1) a 5’-ITR comprising a nucleotide sequence comprising SEQ ID NO: 106 or a 3’-ITR comprising a nucleotide sequence comprising SEQ ID NO: 107;
2) a WPRE comprising a nucleotide sequence comprising SEQ ID NO: 108;
3) a bGH poly(A) signal comprising a nucleotide sequence comprising SEQ ID NO: 109;
4) a 5’ UTR comprising a first nucleotide sequence comprising SEQ ID NO: 103 and/or a second nucleotide sequence comprising SEQ ID NO: 104;
5) a 3’ UTR comprising a nucleotide sequence comprising SEQ ID NO: 32; and
6) a nucleotide sequence comprising SEQ ID NO: 110 or 111.
Simons teaches “compositions and methods for treating gjb2-associated hearing loss.” See title. Simons teaches an “rAAV construct comprising a 5' ITR, a promoter comprising a hGJB2 enhancer and a hGJB2 promoter, a 5' UTR, a nucleic acid encoding a hGJB2 gene, a FLAG tag, a 3' UTR, a bGH polyA, and a 3' ITR.” See [0009] and FIG. 2. It is noted this is the same configuration of the vector in the instant case minus the WPRE. Simons teaches “constructs comprising hGJB2 coding sequences with GJB2 5' UTR and 3'UTR sequences.” See [0010] and FIG. 2. Simons teaches SEQ ID NO: 3 is “GJB2 cDNA with untranslated rejoins,” SEQ ID NO: 4 is “spliced Human GJB2 isoform X1 cDNA including untranslated regions Sequence,” SEQ ID NO: 5 is “Human GJB2 Genomic DNA Sequence,” and SEQ ID NO: 6 is “expanded Human GJB2 Genomic DNA Sequence including certain regulatory regions.” The GJB2 sequences taught by Simons comprise with 100% homology the GJB2 UTRs, SEQ ID NO: 32, SEQ ID NO: 103, and SEQ ID NO: 104, claimed in the instant case. See sequence listing and [0099]. Simons further teaches SEQ ID NO: 35 is an “exemplary cloning site,” which comprises with 100% homology SEQ ID NO: 104 of the instant case. See sequence listing. Simons teaches SEQ ID NO: 8 is an “exemplary 5' AAV ITR,” which has 100% homology to SEQ ID NOs: 106 and 107 in the instant case. See sequence listing. Simons teaches SEQ ID NO: 9 is an “exemplary 3' AAV ITR,” which has 100% homology to SEQ ID NOs: 106 and 107 in the instant case. See sequence listing. Simons teaches “there are several poly(A) signal sequences that can be used, including those derived from bovine growth hormone (bGH)” see [0222] and FIG. 2. Simons teaches “those of ordinary skill in the art will readily understand that similar constructs can be made in accordance” to the examples provided.
Simons teaches the incorporation of “regulatory element” or “regulatory sequence” into the GJB2 expression cassettes and that they refer “to non-coding regions of DNA that regulate, in some way, expression of one or more particular genes. … In some embodiments, a regulatory element impairs or enhances transcription of one or more genes. In some embodiments, a regulatory element may be located in cis to a gene being regulated. … For example, in some embodiments, a regulatory sequence refers to a nucleic acid sequence which is regulates expression of a gene product operably linked to a regulatory sequence. In some such embodiments, this sequence may be an enhancer sequence and other regulatory elements which regulate expression of a gene product.” See [0069]. Simons teaches “regulatory elements facilitate tissue specific expression at physiologically suitable levels.” See [0006].
Simons teaches that the GJB2 expression cassettes are designed to target “support cell,” “supporting cell,” “inner ear support cell,” or “inner ear supporting cell” and that these cells refer “to cells of the inner ear that maintain the structure of the inner ear and maintain the environment of the sensory epithelium of the inner ear. In some aspects, inner ear supporting cells include, but are not limited to, inner phalangeal cells/border cells (IPhC), inner pillar cells (IPC), outer pillar cells (OPC), Deiters’ cells rows 1 and 2 (DC1/2), Deiters’ cells row 3 (DC3), Hensen’s cells (Hec), Claudius cells/outer sulcus cells (CC/OSC), interdental cells (Idc), inner sulcus cells (ISC), Kolliker’s organ cells (KO), greater ridge epithelial ridge cells (GER) (including lateral greater epithelial ridge cells (LGER)), and OC90+ cells (OC90), fibroblasts, and other cells of the lateral wall.” See [0074]. Simons teaches “constructs comprising microRNA regulatory target site (miRTS) which can be used to regulate (e.g., reduce) expression of connexin 26 in a cell (e.g., an inner ear cell, e.g., a hair cell).” See [0196-0213].
Simons teaches the role of GJB2 in the inner ear cells and that “there are over 200 defined mutations of GJB2, which show some level of pathogenicity, and various mutations in the GJB2 gene have been associated with hearing loss (e.g., non-syndromic sensorineural hearing loss or syndromic sensorineural hearing loss).” Thus, Simons provides rAAV constructs comprising WT hGJB2 that “can be useful for administration of compositions that result in expression of gene products involved in the development, function, and/or maintenance of inner ear cells, and/or the treatment of hearing loss, or diseases or conditions associated with hearing loss.” See entire publication. Simons teaches “there remains a need for effective treatments, such as gene therapy, which can repair and/or mitigate a source of a hearing problem.” See [0079].
However, Simons does not explicitly disclose the nucleic acid sequence of the bGH poly(A) signal. Simons also does not teach constructs comprising WPRE.
Ng teaches a bGH poly(A) signal comprising a nucleotide sequence with 100% homology to SEQ ID NO: 109 in the instant case. See SEQ ID NO: 20. Ng similarly to Simons teaches an AAV2 5’-ITR comprising a nucleotide sequence with 100% homology to SEQ ID NO: 106 and an AAV2 3’-ITR comprising a nucleotide sequence with 100% homology to SEQ ID NO: 107. See SEQ ID NOs: 24 and 25.
However, Ng does not teach constructs comprising WPRE.
Genkin teaches “an exemplary post-transcriptional regulatory element is the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). For example, a sequence from the WPRE is shown in SEQ ID NO: 16. The WPRE may be effective to increase expression of the protein.” See [0167]. Genkin further teaches the arrangement of the WPRE and that such arrangement stabilized the mRNA: “One or more sequences may be selected to stabilize mRNA. An example of such a sequence is a modified WPRE sequence, which may be engineered upstream of the polyA sequence and downstream of the coding sequence.” Genkin also teaches a construct comprising a transgene (DNAse I), WPRE, and bGH polyA signal in the 5’ to 3’ orientation. See Figure 9. Hence, this orientation was an art-recognized construct design: having WPRE positioned between the transgene and the polyA signal sequence. Lastly, SEQ ID NO: 16 corresponding to the WPRE taught by Genkin has 100% homology to SEQ ID NO: 108 of the instant application.
Genkin does not expressly teach that the transgene comprises its 3’UTR sequence.
Mastroyiannopoulos teaches EGFP transgene constructs comprising a DMPK 3’ UTR either with or without a downstream WPRE. See figure 1. Mastroyiannopoulos reports “the addition of the WPRE sequence downstream of the DMPK 3’ UTR stimulates the transport of mutant transcripts to the cytoplasm and repairs myoblast differentiation.” Therefore, Mastroyiannopoulos explicitly teaches that placement of the WPRE between a 3’ UTR and PolyA signal increases expression of a transgene. See introduction and results.
Regarding claims 10, 24, 32, 36, 38, and 41, it would have been obvious to one of ordinary skill in the art before the effective filing date to select the claimed polynucleotide sequences corresponding the 5’-and-3’-AAV2 ITRs (as taught by Maguire, Simons, and Ng), 5’-and-3’ GJB2 UTRs (as taught by Simons), the WPRE (as taught by Genkin, and Mastroyiannopoulos), and the bGH poly(A) signal (as taught by Bartolome, Simons, Ng, and Genkin) as the ITRs and expression regulatory elements in the expression cassette/rAAV constructs taught by Maguire. The nucleotide sequences for each element were disclosed with 100% alignment in their respective prior art references to the nucleotide sequences claimed in the instant case. A person of ordinary skill in the art would have been motivated to do so in order to avoid adverse effects of traditional non-targeted AAV gene therapy by directing expression of the hGJB2 transgene to the specific cell types of the inner ear and to maximize expression of the hGJB2 transgene within the desired cells needing therapy. The AAV2 ITRs, UTRs, WPRE, bGH poly(A) signal are all standard regulatory elements commonly used in the art to respectively target cell types, increase expression of a transgene, and terminate transcription. The placement of such elements when designing gene therapy constructs was well known in the art as evidenced by the teachings of Maguire, Simmons, Ng, Genkin, and Mastroyiannopoulos. For example, regarding the WPRE, while Bartolome describes WPRE utility in the 3’ UTR region and Genkin describes WPRE placement between the transgene and polyA signal, Mastroyiannopoulos provides experimental data that explicitly support its placement between a 3’ UTR of a transgene and a polyA signal. One would have a reasonable expectation of success because using each of these construct elements represents a simple substitution of known elements with known functions and known optimal arrangements in relation to one another within AAV gene therapy constructs.
Regarding claims 44 and 48-49, it would have further been obvious to modify the gene therapy vectors taught by Maguire to arrive at vectors comprising claimed SEQ ID NO: 110 (comprising the vector layout of claim 48) or SEQ ID NO: 111 (comprising the layout of claim 49). Each element of SEQ ID NO: 110, as detailed in claim 48, and SEQ ID NO: 111, as detailed in claim 49, were taught in the prior art with 100% identity. By assembling each known element and their respective known nucleotide sequence according to standard practices and teachings of vector arrangement/design in the art, one of ordinary skill in the art would have arrived at vectors comprising SEQ ID NO: 110 or SEQ ID NO: 111 (i.e., vector compositions as claimed in claims 48 and 49, respectively) with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so in order to generate an rAAV vector system that could target specific cell types in the inner ear and increase GJB2 protein expression and function, restoring GJB2 function, thereby treating GJB2 related hearing loss while avoiding the adverse effects of non-targeted AAV gene therapy.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5, 10, 14, 23-24, 28-29, 32, 36, 38, 41, 44-45, 48-50, 53, 55, and 58-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 12-16 of U.S. Patent No. US12054724B2 (provided in IDS) in view of Simons et. al., (US-20230183743-A1), Ng R et. al., (US-20210277417-A1), Genkin D et. al. (US-20190241908-A1), and Mastroyiannopoulos et. al., (EMBO reports, 6(5), 458-463, published 4/15/2005).
The teachings of Maguire regarding claims 1-2, 5, 14, 23, 28-29, 32, 41, 45, 50, 53, 55, and 58-59 are incorporated herein by reference to the corresponding 102 rejection above.
Maguire does not teach:
1) a 5’-ITR comprising a nucleotide sequence comprising SEQ ID NO: 106 or a 3’-ITR comprising a nucleotide sequence comprising SEQ ID NO: 107;
2) a WPRE comprising a nucleotide sequence comprising SEQ ID NO: 108;
3) a bGH poly(A) signal comprising a nucleotide sequence comprising SEQ ID NO: 109;
4) a 5’ UTR comprising a first nucleotide sequence comprising SEQ ID NO: 103 and a second nucleotide sequence comprising SEQ ID NO: 104;
5) a 3’ UTR comprising a nucleotide sequence comprising SEQ ID NO: 32; and
6) a nucleotide sequence comprising SEQ ID NO: 110 or 111.
Simons teaches “compositions and methods for treating gjb2-associated hearing loss.” See title. Simons teaches an “rAAV construct comprising a 5' ITR, a promoter comprising a hGJB2 enhancer and a hGJB2 promoter, a 5' UTR, a nucleic acid encoding a hGJB2 gene, a FLAG tag, a 3' UTR, a bGH polyA, and a 3' ITR.” See [0009] and FIG. 2. It is noted this is the same configuration of the vector of the instant case minus the WPRE. Simons teaches “constructs comprising hGJB2 coding sequences with GJB2 5' UTR and 3'UTR sequences.” See [0010] and FIG. 2. Simons teaches SEQ ID NO: 3 is “GJB2 cDNA with untranslated rejoins,” SEQ ID NO: 4 is “spliced Human GJB2 isoform X1 cDNA including untranslated regions Sequence,” SEQ ID NO: 5 is “Human GJB2 Genomic DNA Sequence,” and SEQ ID NO: 6 is “expanded Human GJB2 Genomic DNA Sequence including certain regulatory regions.” The GJB2 sequences taught by Simons comprise with 100% homology the GJB2 UTRs, SEQ ID NO: 32, SEQ ID NO: 103, and SEQ ID NO: 104, claimed in the instant case. See sequence listing and [0099]. Simons further teaches SEQ ID NO: 35 is an “exemplary cloning site,” which comprises with 100% homology SEQ ID NO: 104 of the instant case. See sequence listing. Simons teaches SEQ ID NO: 8 is an “exemplary 5' AAV ITR,” which has 100% homology to SEQ ID NOs: 106 and 107 in the instant case. See sequence listing. Simons teaches SEQ ID NO: 9 is an “exemplary 3' AAV ITR,” which has 100% homology to SEQ ID NOs: 106 and 107 in the instant case. See sequence listing. Simons teaches “there are several poly(A) signal sequences that can be used, including those derived from bovine growth hormone (bGH)” see [0222] and FIG. 2. Simons teaches “those of ordinary skill in the art will readily understand that similar constructs can be made in accordance” to the examples provided.
Simons teaches the incorporation of “regulatory element” or “regulatory sequence” into the GJB2 expression cassettes and that they refer “to non-coding regions of DNA that regulate, in some way, expression of one or more particular genes. … In some embodiments, a regulatory element impairs or enhances transcription of one or more genes. In some embodiments, a regulatory element may be located in cis to a gene being regulated. … For example, in some embodiments, a regulatory sequence refers to a nucleic acid sequence which is regulates expression of a gene product operably linked to a regulatory sequence. In some such embodiments, this sequence may be an enhancer sequence and other regulatory elements which regulate expression of a gene product.” See [0069]. Simons teaches “regulatory elements facilitate tissue specific expression at physiologically suitable levels.” See [0006].
Simons teaches that the GJB2 expression cassettes are designed to target “support cell,” “supporting cell,” “inner ear support cell,” or “inner ear supporting cell” and that these cells refer “to cells of the inner ear that maintain the structure of the inner ear and maintain the environment of the sensory epithelium of the inner ear. In some aspects, inner ear supporting cells include, but are not limited to, inner phalangeal cells/border cells (IPhC), inner pillar cells (IPC), outer pillar cells (OPC), Deiters’ cells rows 1 and 2 (DC1/2), Deiters’ cells row 3 (DC3), Hensen’s cells (Hec), Claudius cells/outer sulcus cells (CC/OSC), interdental cells (Idc), inner sulcus cells (ISC), Kolliker’s organ cells (KO), greater ridge epithelial ridge cells (GER) (including lateral greater epithelial ridge cells (LGER)), and OC90+ cells (OC90), fibroblasts, and other cells of the lateral wall.” See [0074]. Simons teaches “constructs comprising microRNA regulatory target site (miRTS) which can be used to regulate (e.g., reduce) expression of connexin 26 in a cell (e.g., an inner ear cell, e.g., a hair cell).” See [0196-0213].
Simons teaches the role of GJB2 in the inner ear cells and that “there are over 200 defined mutations of GJB2, which show some level of pathogenicity, and various mutations in the GJB2 gene have been associated with hearing loss (e.g., non-syndromic sensorineural hearing loss or syndromic sensorineural hearing loss).” Thus, Simons provides rAAV constructs comprising WT hGJB2 that “can be useful for administration of compositions that result in expression of gene products involved in the development, function, and/or maintenance of inner ear cells, and/or the treatment of hearing loss, or diseases or conditions associated with hearing loss.” See entire publication. Simons teaches “there remains a need for effective treatments, such as gene therapy, which can repair and/or mitigate a source of a hearing problem.” See [0079].
However, Simons does not explicitly disclose the nucleic acid sequence of the bGH poly(A) signal. Simons also does not teach constructs comprising WPRE.
Ng teaches a bGH poly(A) signal comprising a nucleotide sequence with 100% homology to SEQ ID NO: 109 in the instant case. See SEQ ID NO: 20. Ng similarly to Simons teaches an AAV2 5’-ITR comprising a nucleotide sequence with 100% homology to SEQ ID NO: 106 and an AAV2 3’-ITR comprising a nucleotide sequence with 100% homology to SEQ ID NO: 107. See SEQ ID NOs: 24 and 25.
However, Ng does not teach constructs comprising WPRE.
Genkin teaches “an exemplary post-transcriptional regulatory element is the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). For example, a sequence from the WPRE is shown in SEQ ID NO: 16. The WPRE may be effective to increase expression of the protein.” See [0167]. Genkin further teaches the arrangement of the WPRE and that such arrangement stabilized the mRNA: “One or more sequences may be selected to stabilize mRNA. An example of such a sequence is a modified WPRE sequence, which may be engineered upstream of the polyA sequence and downstream of the coding sequence.” Genkin also teaches a construct comprising a transgene (DNAse I), WPRE, and bGH polyA signal in the 5’ to 3’ orientation. See Figure 9. Hence, this orientation was an art-recognized construct design: having WPRE positioned between the transgene and the polyA signal sequence. Lastly, SEQ ID NO: 16 corresponding to the WPRE taught by Genkin has 100% homology to SEQ ID NO: 108 of the instant application.
Genkin does not expressly teach that the transgene comprises its 3’UTR sequence.
Mastroyiannopoulos teaches EGFP transgene constructs comprising a DMPK 3’ UTR either with or without a downstream WPRE. See figure 1. Mastroyiannopoulos reports “the addition of the WPRE sequence downstream of the DMPK 3’ UTR stimulates the transport of mutant transcripts to the cytoplasm and repairs myoblast differentiation.” Therefore, Mastroyiannopoulos explicitly teaches that placement of the WPRE between a 3’ UTR and PolyA signal increases expression of a transgene. See introduction and results.
Regarding claims 10, 24, 32, 36, 38, and 41, it would have been obvious to one of ordinary skill in the art before the effective filing date to select the claimed polynucleotide sequences corresponding the 5’-and-3’-AAV2 ITRs (as taught by Maguire, Simons, and Ng), 5’-and-3’ GJB2 UTRs (as taught by Simons), the WPRE (as taught by Genkin, and Mastroyiannopoulos), and the bGH poly(A) signal (as taught by Bartolome, Simons, Ng, and Genkin) as the ITRs and expression regulatory elements in the expression cassette/rAAV constructs taught by Maguire. The nucleotide sequences for each element were disclosed with 100% alignment in their respective prior art references to the nucleotide sequences claimed in the instant case. A person of ordinary skill in the art would have been motivated to do so in order to avoid adverse effects of traditional non-targeted AAV gene therapy by directing expression of the hGJB2 transgene to the specific cell types of the inner ear and to maximize expression of the hGJB2 transgene within the desired cells needing therapy. The AAV2 ITRs, UTRs, WPRE, bGH poly(A) signal are all standard regulatory elements commonly used in the art to respectively target cell types, increase expression of a transgene, and terminate transcription. The placement of such elements when designing gene therapy constructs was well known in the art as evidenced by the teachings of Maguire, Simmons, Ng, Genkin, and Mastroyiannopoulos. For example, regarding the WPRE, while Bartolome describes WPRE utility in the 3’ UTR region and Genkin describes WPRE placement between the transgene and polyA signal,Mastroyiannopoulos provides experimental data that explicitly support its placement between a 3’ UTR of a transgene and a polyA signal. One would have a reasonable expectation of success because using each of these construct elements represents a simple substitution of known elements with known functions and known optimal arrangements in relation to one another within AAV gene therapy constructs.
Regarding claims 44 and 48-49, it would have further been obvious to modify the gene therapy vectors taught by Maguire to arrive at vectors comprising claimed SEQ ID NO: 110 (comprising the vector layout of claim 48) or SEQ ID NO: 111 (comprising the layout of claim 49). Each element of SEQ ID NO: 110, as detailed in claim 48, and SEQ ID NO: 111, as detailed in claim 49, were taught in the prior art with 100% identity. By assembling each known element and their respective known nucleotide sequence according to standard practices and teachings of vector arrangement/design in the art, one of ordinary skill in the art would have arrived at vectors comprising SEQ ID NO: 110 or SEQ ID NO: 111 (i.e., vector compositions as claimed in claims 48 and 49, respectively) with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so in order to generate an rAAV vector system that could target specific cell types in the inner ear and increase GJB2 protein expression and function, restoring GJB2 function, thereby treating GJB2 related hearing loss while avoiding the adverse effects of non-targeted AAV gene therapy.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/ Patent Examiner, Art Unit 1635
/DANA H SHIN/Primary Examiner, Art Unit 1635