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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on 05/14/2026
Currently, claims 1-2, 4-7, 9-10, and 12-16 are pending in the instant application. Claim 1 has been amended to incorporate the elements of claims 3, 8, and 11, which have correspondingly been canceled. Accordingly, claims 1-2, 4-7, 9-10, and 12-16 are under examination on the merits in the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/14/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments and Amendments
Drawings
The drawings were received on 05/14/2026. The drawings are a replacement sheet of FIG. 6 to address the objection to drawings detailed in the non-final Office action dated 02/25/2026. These drawings are acceptable.
Withdrawn Rejections/objections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
New Rejections Necessitated by Amendment and/or newly filed IDS
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 4-7, 9-10, 13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Maguire CA, et. al., (WO-2020198737-A1) in view of Sena-Esteves M. et. al., (US-20180311290-A1) and Griffin JM et. al., (Gene Ther. 26(5):198–210; published 2019-04-08).
Regarding claim 1, Maguire teaches a method of genetically modifying retinal optic nerve head astrocytes, the method comprising: contacting a retinal optic nerve head astrocyte in an eye of a subject with an effective dose of a nucleic acid composition comprising [claim 10: “A method of delivering a transgene to a cell, the method comprising contacting the cell with the AAV of claims 1 -9;” claim 11: “wherein the cell is a … astrocyte…;” pg. 4 lns. 3-4: “the cell is in the eye of the subject, and the AAV is administered by subretinal or intravitreal injection;” pg. 11 lns. 13-15: “AAV transduction is a process involving multiple steps, from cell receptor binding and entry to nuclear transport, second-strand synthesis and finally gene and protein expression.”]: a first viral inverted terminal repeat sequence [see figures 1A and 3A and pg. 42 lns. 16-17: “we constructed an AAV library plasmid which consisted of an AAV2 ITR-flanked expression cassette”], a promoter [see figures 1A and 3A and pg. 25 lns. 23-24: “The virus can also include one or more sequences that promote expression of a transgene, e.g. one or more promoter sequences…”], a transgene [see figures 1A and 3A and pg. 23 lns. 19: “the AAV also includes a transgene sequence”], a posttranslational regulatory element [see figures 1A and 3A and pg. 26. lns. 3-4: “The woodchuck hepatitis virus posttranscriptional response element (WPRE) can also be used.” (it is noted that applicant refers to WPRE as a posttranslational element in the specification and claims while the field and prior art refers to WPRE as a posttranscriptional element)], a polyadenylation sequence [see figures 1A and 3A and pg. 14 lns. 9-10: “there are poly A signals after the … cassette …”], and a second viral inverted terminal repeat sequence [see figures 1A and 3A and pg. 42 lns. 16-17: “we constructed an AAV library plasmid which consisted of an AAV2 ITR-flanked expression cassette”]; wherein the nucleic acid composition is encapsulated by an AAV5 viral capsid to form a viral particle [pg. 25 lns. 23-24: “The virus can also include one or more sequences that promote expression of a transgene;” pg. 44. lns. 30-31: “All capsids packaged a single-stranded AAV2 ITR-flanked AAV-CBA-GFP-WPRE transgene cassette;” and pg. 18. lns. 2-3: “for CNS use, in some embodiments the AAV is AAV1, AAV2, AAV4, AAV5, AAV6, AAV8, or AAV9.”]
Regarding claim 2, Maguire teaches the first viral inverted terminal repeat sequence is AAV2 [see figures 1A and 3A and pg. 42 lns. 16-17 “we constructed an AAV library plasmid which consisted of an AAV2 ITR-flanked expression cassette”].
Regarding claim 4, Maguire teaches the posttranslational regulatory element is a woodchuck posttranslational regulatory element [see figures 1A and 3A and pg. 26. Lns. 3-4 “The woodchuck hepatitis virus posttranscriptional response element (WPRE) can also be used.” (it is noted that applicant refers to WPRE as a posttranslational element in the specification and claims while the field refers to WPRE as a posttranscriptional element)].
Regarding claim 5, Maguire teaches the polyadenylation sequence is a bovine growth hormone polyadenylation sequence [see figures 1A and 3A and pg. lns. 21-22 “pA, poly A signals (both SV 40 and bovine growth hormone derived)”].
Regarding claim 6, Maguire teaches the second viral inverted terminal repeat sequence is AAV2 [see figures 1A and 3A and pg. 42 lns. 16-17 “we constructed an AAV library plasmid which consisted of an AAV2 ITR-flanked expression cassette”].
Regarding claim 7, Maguire teaches the first viral inverted terminal repeat sequence is the same as the second viral inverted terminal repeat [see figures 1A and 3A and pg. 42 lns. 16-17 “we constructed an AAV library plasmid which consisted of an AAV2 ITR-flanked expression cassette”].
Regarding claim 10, Maguire teaches the composition is administered via intravitreal (IVT) injection [pg. 29 lns. 17-19 “for delivery into the retina, subretinal or intravitreal injections can be used…”].
Regarding claim 13, Maguire teaches the transgene comprises a CRISPR/Cas system [pg. 25 lns. 19-22 “transgenes can include…CRISPR Cas9/casl2a and guide RNAs.”].
Regarding claim 15, Maguire teaches the subject has or is predicted to have an optic neuropathy [claim 15: “wherein the subject has… Leber Hereditary Optic Neuropathy…”].
Maguire does not teach the promoter of the nucleic acid is a gfaABC1D (SEQ ID NO:1) promoter or a variant thereof.
Sena-Esteves M. et. al., teach “An AAV vector carrying human synapsin-1 (also referred to as "Syn1") and GfaABC1D (also referred to as "GFAP") promoters for simultaneous dual expression of transgenes of interest in both neurons and astrocytes" (see figure 50 and para [0212]). Sena-Esteves M. et. al., further teach “the second promoter is specific for astrocytes, and optionally is a GfaABC1D (also referred to as GFAP) promoter" (claim 66); and "a GFAP promoter is represented by SEQ ID NO: 14,” which SEQ ID NO: 14 has 100% identity to the instantly claimed SEQ ID NO:1 (para [0019]).
Griffin also utilizes the GfaABC1D promoter. Griffin teaches that “the GfaABC1D promoter is a compact GFAP promoter with the size of 694 bp,” and that “GfaABC1D previously displayed expression properties in transgenic mice indistinguishable from the 2.2 kb promoter,” which “allows for greater flexibility in creating therapeutic AAV constructs with less transgene size restrictions…a drawback of using AAV for gene delivery” (see methods first section). Griffin further teaches an AAV expression cassettes in the following configuration: pAM/GfaABC1D-dYFP-WPRE-BGHpA. Griffin describes that “the AAV5 serotype has been previously shown to exhibit almost completely astrocyte-specific transduction (99%) when a GFAP promoter was used after infusion into the mouse hippocampus” (see discussion para 3). Griffin further illustrates that the “AAV5-GfaABC1D-dYFP transduction of cell cultures led to a far greater number of dYFP-positive cells compared with the full GFAP promoter in the same serotype, while transgene expression levels were comparable” (discussion para 4). Griffin further teaches “an absence of dYFP colocalization with the microglia marker, Iba1 indicates either an inability of AAV5-GFAP-dYFP and AAV5-GfaABC1D-dYFP to transduce microglia and/or inactivity of the GFAP promoter in microglia” (discussion para 6). However, unlike the observation in microglia, Griffin reports that neuronal cells have a varying degree of transduction with AAV5 and/or GfaABC1D promoter activity, “motor neurons in the ventral horn showed relatively high transgene expression, whereas other neurons showed weak transgene expression and no dYFP was observed in neuronal cell bodies in the dorsal horn,” concluding that “neurons in different regions within the spinal cord have a different repertoire of cell surface receptors or different transcriptional activity,” (discussion para 6).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to utilize the truncated GfaABC1D promoter sequence taught by Sena-Esteves M. et. al., and Griffin withing the AAV-based retinal gene therapy framework taught by Maguire, because this adaptation represents a combination of prior art elements according to known methods to yield predictable results, as described in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) and MPEP 2143. Maguire provides the general framework for retinal astrocyte targeting but utilizes the full-length GFAP promoter, which is a large 2.2Kb fragment. Since Maguire teaches that delivery to the retina can be via IVT injections, it is inherent that IVT injections can deliver therapies to retinal astrocytes and also astrocytes at the optic nerve head (ONH). There are no teachings on record that preclude ONH astrocytes from receiving therapies delivered by IVT injections. Sena-Esteves M. et. al., provides the exact truncated GfaABC1D promoter sequence with 100% identity to SEQ ID NO: 1 of the instant case. Griffin provides the critical motivation for the substitution, explaining that the 694bp GfaABC1D promoter provides “greater flexibility in creating therapeutic AAV constructs with less transgene size restrictions,” which is a known “drawback of using AAV for gene delivery” because larger AAV vectors have less transduction efficiency. A PHOSITA would have further been motivated by Griffin because he demonstrated that the GfaABC1D promoter exhibits expression properties “indistinguishable” from the full 2.2kb promoter while significantly increasing the number of positive cells. A PHOSITA would have been motivated to combine these teachings with a reasonable expectation of success to achieve efficient, astrocyte-specific gene expression while maximizing the available payload capacity for the transgene (such as the CRISPR system taught by Maguire) because the routes of delivery (i.e., subretinal and IVT injections) were commonly practiced to delivery AAV-mediated gene therapy compositions to cells of the eye.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Maguire CA, et. al., (WO-2020198737-A1) in view of Sena-Esteves M. et. al., (US-20180311290-A1) and Griffin JM et. al., (Gene Ther. 26(5):198–210; published 2019-04-08) as applied to claims 1-2, 4-7, 9-10, 13, and 15 above, and further in view of Parks RJ. Et. al., (Proc. Natl. Acad. Sci., Vol 93, pp 13565-13570, published Nov. 1996).
The teaching of Maguire, Sena-Esteves and Griffin regarding claims 1-2, 4-7, 9-10, 13, and 15 above are incorporated herein by reference to the first 103 rejection above.
Regarding claim 12, Maguire teaches the purification of AAV particles (pg. 33 lns. 22-23: “AAV was purified from the cell lysate using iodixanol density-gradient ultracentrifugation”).
Neither Maguire, Sena-Esteves or Griffin teach the final contamination percentage as <0.01% of the total composition
However, Parks teaches that viral vector preparations can be routinely purified to reach levels of <0.01% contamination using “cesium chloride buoyant density centrifugation,” as taught in the specification of the instant case. Parks further teaches that “large scale preparations of vector yielded…stocks…with <0.01% contamination by the E1-deleted helper virus,” and that this level of purity provides “increased cloning capacity, increased safety and reduced immunogenicity” (see abstract).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to apply the ultra-purification standards and density-gradient techniques taught by Parks to the AAV compositions of Maguire to achieve high purity (i.e., <0.01% contamination of the total composition) because this represents use of known technique to improve similar devices (viral vectors) in the same way, as described in as described in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) and MPEP 2143. A PHOSITA would have been motivated to combine these teachings because AAV and Adenovirus share similar physical properties (non-enveloped, icosahedral capsids) that allow them to be purified by the same density-gradient ultracentrifugation methods taught by Maguire and Parks. Parks establishes that <0.01% contamination is an achievable standard for clinical grade vectors to ensure patient safety. Thus, a PHOSITA would have been motivated to use these standard methods to provide compositions with the claimed purity level for the predictable benefit of reducing immunogenicity in vivo. Therefore, the limitation in claim 12 is merely a recitation of the expected purity level of a pharmaceutical-grade viral composition.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Maguire CA, et. al., (WO-2020198737-A1) in view of Sena-Esteves M. et. al., (US-20180311290-A1) and Griffin JM et. al., (Gene Ther. 26(5):198–210; published 2019-04-08) as applied to claims 1-2, 4-7, 9-10, 13, and 15 above, and further in view of Dalkara D, et. al., (Mol Ther.;17(12):2096-102, published 2009, provided in IDS).
The teaching of Maguire, Sena-Esteves and Griffin regarding claims 1-2, 4-7, 9-10, 13, and 15 above are incorporated herein by reference to the first 103 rejection above.
While Griffin does teach that the combination of AAV5 capsid with the GfaABC1D promoter does spare transduction and/or expression of transgenes in microglia, neither Maguire, Sena-Esteves or Griffin teach that retinal ganglion cells (RGCs) or photoreceptor cells (PRCs) are not genetically modified when using this combination.
Dalkara provides the explicit teaching that administering AAV5 virions via IVT injection spares RGCs and PRCs from transduction, as Dalkara states in the abstract:
“Adeno-associated viral gene therapy has shown great promise in treating retinal disorders, with three promising clinical trials in progress. Numerous adeno-associated virus (AAV) serotypes can infect various cells of the retina when administered subretinally, but the retinal detachment accompanying this injection induces changes that negatively impact the microenvironment and survival of retinal neurons. Intravitreal administration could circumvent this problem, but only AAV2 can infect retinal cells from the vitreous, and transduction is limited to the inner retina. We therefore sought to investigate and reduce barriers to transduction from the vitreous. We fluorescently labeled several AAV serotype capsids and followed their retinal distribution after intravitreal injection. AAV2, 8, and 9 accumulate at the vitreoretinal junction. AAV1 and 5 show no accumulation, indicating a lack of appropriate receptors at the inner limiting membrane (ILM). Importantly, mild digestion of the ILM with a nonspecific protease enabled substantially enhanced transduction of multiple retinal cell types from the vitreous, with AAV5 mediating particularly remarkable expression in all retinal layers.”
Thus, as Dalkara reiterated in the discussion: “Following subretinal delivery (emphasis added), AAV serotypes 1 and 4 primarily infect and mediate expression in RPE cells; AAV2, 5, 7, 8, and 9 transduce RPE and photoreceptors; and AAV8 and 9 also infect Müller glia”…however, only AAV2 has been found to efficiently transduce the inner retina after intravitreal injection, indicating that the vitreoretinal junction represents a tissue barrier to AAV gene delivery.” Dalkara further explain in the discussion that: “in contrast to AAV2, 8, and 9, we find that AAV serotypes 1 and 5 are unable to find attachment sites at the vitreoretinal junction”…and that, when administered via IVT injection, AAV5 transduced “various cells of the retina, including the RPE and photoreceptors, only when in “combination with Pronase E,” which digests the ILM. Thus, Dalkara explicitly teaches that “ILM digestion in conjunction with AAV5 delivery may allow for targeting of outer retinal cells without the need for subretinal injection,” see discussion. Dalkara, in a control experiment, confirmed these results by delivering AAV5 subretinally and observing robust transduction of retinal neurons, see results “Retinal penetration of Cy3-labeled viral particles following intravitreal injection:” (“The cryosections of retinas treated with AAV1-Cy3 did not exhibit any significant fluorescence (Supplementary Figure S2b,c). AAV5-Cy3 showed only very localized signal in displaced ganglion cells. To confirm that these results were not due to the difficulty of visualizing the Cy3 capsid label over tissue autofluorescence, AAV5-Cy3 was injected subretinally, and robust fluorescence was observed in the RPE and photoreceptors at the region of injection (Supplementary Figure S3)”).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to incorporate the explicit functional limitation that the AAV5-encapsidated nucleic acid composition does not genetically modify microglia, RGCs, and PRCs into the AAV-based eye gene therapy methods taught by Maguire, Sena-Esteves, and Griffin, specifically by implementing the intravitreal route of administration as taught by Maguire and further characterized by Dalkara.
A PHOSITA would have been motivated to do so because Dalkara establishes that wild-type AAV5 virions possess an inherent structural inability to attach to or traverse on intact vitreoretinal junction and inner limiting membrane (ILM) when introduced into the vitreous humor. This anatomical barrier physically confines the viral particles within the vitreous cavity and prevents them from accessing deeper neural retinal layers, and thus leaving only the astrocytes at the optic nerve head exposed to the viral particles. A PHOSITA seeking an efficient, non0invasive means of administering a therapeutic transgene to localized, vitreous-exposed ocular tissues without causing surgical trauma or retinal detachment, and specifically wishing to spare off-target deep retinal neurons (such as RGCs and PRCs) and non-astrocyte glia (such as microglia, which Griffin confirms are transcriptionally silent with respect to the GFAP promoter), would be motivated to exploit this inherent physical exclusion property of the AAV5 capsid via standard IVT delivery.
A PHOSITA would have had a reasonable expectation of success because Dalkara explicitly demonstrates that IVT delivery results in a total absence if viral accumulation or transduction in deeper retinal layers, cleanly restricting the vector pool away from PRCs and RGCs unless an exogenous protease is added to artificially digest the ILM. Furthermore, Griffin provides a reasonable expectation of success that the compact GFAP promoter sequence maintains absolute transcriptional fidelity within astrocyte lineages while remaining silent in microglia. Therefore, combining an IVT delivered AAV5 capsid with the truncated GFAP promoter represents the routine combination of prior art elements according to known methods to yield a predictable, cell-sparing functional profile driven by a combination or inherent anatomical barriers and promoter specificity.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Maguire CA, et. al., (WO-2020198737-A1) in view of Sena-Esteves M. et. al., (US-20180311290-A1) and Griffin JM et. al., (Gene Ther. 26(5):198–210; published 2019-04-08) as applied to claims 1-2, 4-7, 9-10, 13, and 15 above, and further in view of Boye SE. and Boye SL. herein “Boye” (US-20200405744-A1, published 2020-12-31).
The teaching of Maguire, Sena-Esteves and Griffin regarding claims 1-2, 4-7, 9-10, 13, and 15 above are incorporated herein by reference to the first 103 rejection above.
Neither Maguire, Sena-Esteves or Griffin teach the optic neuropathy is pre-glaucoma, glaucoma, ischemic optic neuropathy, or diabetic retinopathy.
Boye teaches a method of genetically modifying retinal astrocytes, the method comprising: contacting a retinal astrocyte in an eye of a subject with an effective dose of a nucleic acid composition comprising [claim 52: “A method of delivering a cargo to an eye of a subject in need thereof, the method comprising administering to the eye of the subject a rAAV particle;” claim 62: “the method of claim 52, wherein the cargo comprises a polynucleotide comprising a heterologous nucleic acid sequence;” claim 63: “The method of claim 62, wherein the heterologous nucleic acid sequence is operably linked to a regulatory sequence that direct expression of the heterologous nucleic acid sequence in…an astrocyte cell.”]: a first viral inverted terminal repeat sequence [0074: “the one or more transgenes are flanked on each side with an ITR sequence], a promoter [0074: “the nucleic acid vector comprises one or more heterologous nucleic acids comprising a sequence encoding a protein or polypeptide of interest operably linked to a promoter], a transgene [0160: “ heterologous nucleic acid regions (e.g., transgenes)”], a posttranslational regulatory element [0124: “ the nucleic acid vector comprises a woodchuck hepatitis virus post-transcription regulatory element (WPRE)” (it is noted that applicant refers to WPRE as a posttranslational element in the specification and claims while the field and prior art refers to WPRE as a posttranscriptional element)], a polyadenylation sequence [0124: “ the nucleic acid vector comprises…a polyadenylation signal sequence…”], and a second viral inverted terminal repeat sequence [0074: “the one or more transgenes are flanked on each side with an ITR sequence]; wherein the nucleic acid sequence is encapsulated by a viral capsid to form a viral particle [0161: “an rAAV particle or rAAV preparation containing such particles comprises a viral capsid and a nucleic acid vector as described herein, which is encapsidated by the viral capsid”].
Boye further teaches the first viral inverted terminal repeat sequence is AAV2 [0069: “The ITR sequences can be derived from any AAV serotype (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) or can be derived from more than one serotype. In some embodiments, the ITR sequences are derived from AAV2 or AAV6.” 0070: “the nucleic acid vector comprises a pTR-UF-11 plasmid backbone, which is a plasmid that contains AAV2 ITRs. This plasmid is commercially available from the American Type Culture Collection (ATCC MBA-331).”].
Boye further teaches the posttranslational regulatory element is a woodchuck posttranslational regulatory element [0124: “ the nucleic acid vector comprises a woodchuck hepatitis virus post-transcription regulatory element (WPRE)” (it is noted that applicant refers to WPRE as a posttranslational element in the specification and claims while the field refers to WPRE as a posttranscriptional element)].
Boye further teaches the second viral inverted terminal repeat sequence is AAV2 [0069: “The ITR sequences can be derived from any AAV serotype (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) or can be derived from more than one serotype. In some embodiments, the ITR sequences are derived from AAV2 or AAV6.” 0070: “the nucleic acid vector comprises a pTR-UF-11 plasmid backbone, which is a plasmid that contains AAV2 ITRs. This plasmid is commercially available from the American Type Culture Collection (ATCC MBA-331).”].
Boye further teaches the first viral inverted terminal repeat sequence is the same as the second viral inverted terminal [0069: “The ITR sequences can be derived from any AAV serotype (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) or can be derived from more than one serotype. In some embodiments, the ITR sequences are derived from AAV2 or AAV6.” 0070: “the nucleic acid vector comprises a pTR-UF-11 plasmid backbone, which is a plasmid that contains AAV2 ITRs. This plasmid is commercially available from the American Type Culture Collection (ATCC MBA-331).”].
Boye further teaches the effective dose comprises at least 1x108 viral particles per ml [claim 62: “ The method of claim 52, wherein the rAAV particle is administered to the eye of the subject in a titer of less than 5×1011 vg/ml.” and claim 60: “The method of claim 52, wherein the rAAV particle is administered to the eye of the subject in a titer of about 1×1010 vector genomes (vg)/ml, 5×1010 vg/ml, 1×1011 vg/ml, 5×1011 vg/ml, 1×1012 vg/ml, 2×1012 vg/ml, 3×1012 vg/ml, 4×1012 vg/ml, about 5×1012 vg/ml, about 1×1013 vg/ml, or about 5×1013 vg/ml.”].
Boye further teaches the composition is administered via intravitreal injection [claim 52 “the rAAV particle is administered intravitreally”].
Boye further teaches the subject has or is predicted to have an optic neuropathy [0004-0005: “a cargo is administered to treat a disease selected from the group consisting of: …diabetic retinopathy…, or glaucoma.”]. Both diabetic retinopathy and glaucoma are classified as optic neuropathies.
Boye further teaches the optic neuropathy is pre-glaucoma, glaucoma, ischemic optic neuropathy, or diabetic retinopathy [0004-0005: “a cargo is administered to treat a disease selected from the group consisting of: …diabetic retinopathy…, or glaucoma.”].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to select the specific optic neuropathies taught by Boye, namely pre-glaucoma, glaucoma, ischemic optic neuropathy, or diabetic retinopathy, as the clinical indication for astrocyte-specific AAV therapeutic methods taught by Maguire, Sena-Esteves, and Griffin.
A PHOSITA would have been motivated to do so because Maguire establishes a general framework for targeting retinal and optic nerve head astrocytes to treat blinding conditions, but does not exhaustively list all subsets of optic neuropathies. Boye explicitly identifies both glaucoma and diabetic retinopathy as sever ocular pathologies characterized by cellular distress where gene therapy payloads must be successfully directed to ocular astrocytes. Since ocular and optic nerve head astrocytes undergo significant changes during the progression of glaucoma and diabetic retinopathy, a PHOSITA would be motivated to apply the construct of Griffin (AAV5-gfaABC1D) to these specific diseases to maximize transgene expression in the relevant target cell type while minimizing vector size constraints.
A PHOSITA would have had a reasonable expectation of success because Boye demonstrates that standard IVT delivery routes successfully introduce AAV particles to ocular tissues to treat glaucoma and diabetic retinopathy at predictable clinical titers. Furthermore, because the fundamental structural anatomy of the eye and the cellular transcription profiles of retinal astrocytes remain constant across these designated optic neuropathies, a PHOSITA would reasonably expect that swapping the genialized disease target of Maguire with the specific indications of Boye would yield the predictable therapeutic result of targeted genetic modification.
Claim Rejections - 35 USC § 112
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 14 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of genetically modifying retinal optic nerve head astrocytes, the method comprising: administering intravitreally to a retinal optic nerve head astrocyte in an eye of a subject an effective dose of a nucleic acid viral vector comprising: a first viral inverted terminal repeat sequence, a gfaABC1D (SEQ ID NO:1) promoter or a variant thereof, a transgene, a posttranslational regulatory element, a polyadenylation sequence and a second viral inverted terminal repeat sequence; wherein the nucleic acid viral vector is encapsulated by an AAV5 viral capsid to form a viral particle and wherein the viral particle does not genetically modify microglia, retinal ganglion cells (RGCs) or photoreceptors (PRCs), does not reasonably provide enablement for a method as instantly claimed where microglia, RGCs and PRCs are not genetically modified when employing subretinal injection to deliver the viral particle of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The disclosure of the specification is sufficient to enable a person skilled in the art to practice a method where microglia, RGCs, and PRCs are spared only when the viral particles of claim 1 are administered by IVT injectoin, such that the physical barrier of an intact ILM prevents the AAV5 capsid from penetrating the deeper layers of the neural retina. However, claim 14 depends from claim 1 and does not incorporate the IVT limitation of parallel dependent claim 10. Under Broadest Reasonable Interpretation (BRI), the method of claim 14 encompasses any and all routes of administration including subretinal injections.
To determine whether a claim is enabled, it is evaluated using the factors set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). An analysis of the Wands factors indicated that enabling a cell-sparing profile across the scope of claim 14, specifically including subretinal injections, would require undue experimentation:
The Breath of the Claim(s): The scope of claim 14 is broad because it recites a negative functional limitation (“does not genetically modify microglia, RGCs, or PRCs”) across any undisclosed physical route of ocular contact.
Nature of the Invention: The application says there are no good methods to deliver gene therapies specifically to retinal and optic nerve head astrocytes for glaucoma and related disorders. The invention solves the delivery problem by pairing an astrocyte-selective promoter (gfaABC1D) with an AAV5 capsid so that an injected vector preferentially expresses its transgene in optic nerve head astrocytes. Intravitreal administration then places the viral particles in position to transduce the target cells, while sparing optic nerve cells.
The State of the Prior Art: The prior art, as exemplified by Dalkara D, et. al., (Mol Ther.;17(12):2096-102, published 2009, provided in IDS), establishes that the biological and physical behavior of AAV5 capsids is highly dependent on the sub-anatomical compartment into which they are delivered. The prior art explicitly teaches that when AAV5 virions are delivered via a subretinal injection, circumventing the ILM barrier, sit in direct contact with the retinal layer and robustly modify PRCs and RGCs. However, when administered via intravitreal injection, the ILM prevents the AAV5 viral particles from transducing RGCs and PRCs.
The level of Ordinary Skill in the Art: A person of ordinary skill in the art is a highly trained PhD level scientist, with deep understandings of AAV vector biology, gene therapy expressing constructs, ocular anatomy, and refined surgical skills at minimum in mammalian models such as mouse.
The Level of Predictability in the Art: Biotechnology and in vivo viral gene delivery are highly unpredictable arts. Altering the physical placement of a viral vector dramatically alters cell-surface receptor availability and structural tissue barriers.
The Amount of Direction Provided by the Inventor: The specification provides zero guidance or protocols demonstrating how a PHOSITA could inject the claimed AAV5-encapsidated vector subretinally while successfully preventing the genetic modification of RGCs and PRCs.
The Existence of Working Examples: The specification and the state of the art provides zero working examples.
The Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure: a PHOSITA would have to undergo extremely rigorous and exploratory research to achieve sparing RGCs and PRCs when delivering an AAV5 via subretinal injection. There would be no clear end in sight and the experimentation could perhaps consume a PHOSITA’s career with only negative data to show for it.
Because the prior art confirms that subretinal administration of AAV5 naturally drives the genetic modification of PRCs and RGCs, and because the specification provides no corresponding structural modification or steps to block this outcome during subretinal delivery, a PHOSITA would be required to perform vast, open-ended, and undue experimentation to achieve the negative functional limitation recited in claim 14. Consequently, the specification fails to enable the full scope of the invention across non-IVT delivery routes encompassed by the breadth of the claim.
Rejection under 35 U.S.C. 103 Stands Unrebutted as to Claim 12
Applicant’s remarks state that the presented arguments “address both rejections as they apply to the presently amended claims.” However, a review of the Remarks/Arguments section reveals that applicant has failed to present a single specific argument, data point, or legal traversal addressing the 35 U.S.C 103 rejection of dependent claim 12 over Maguire in view of Parks.
Applicant has made no attempt to traverse the obviousness of achieving a viral composition purity standard of less than 0.01% contamination using the density-gradient ultracentrifugation techniques taught by Parks. Because an applicant must distinctly and specifically traverse each ground of rejection to avoid waiver, the rejection of dependent claim 12 stands unrebutted and is maintained. Due to amendment of independent base claim 1, this rejection is set forth as a New Ground of Rejection Necessitated by Amendment in this section.
Applicant’s Arguments Regarding Claims 1-2, 4-7, 9-10, and 13-16.
Applicant’s argument that the combination of an AAV5 capsid and a modified/truncated gfaABC1D promoter yields unexpected results [referencing Crocs, Inc. v. U.S. Int'l Trade Comm'n., 598 F.3d 1294, 93 USPQ2d 1777 (Fed. Cir. 2010) and In re Soni, 54 F.3d 746, 34 USPQ2d 1684 (Fed. Cir. 1995)] by specifically and preferentially transducing retinal optic nerve head (ONH) astrocytes while unexpectedly “sparing” transduction of neuronal cell types (i.e., retinal ganglion cells [RGCs] and photoreceptors [PRCs] and other glial cells (microglia), is not persuasive.
Dependent claim 14 depends directly from independent claim 1, and claim 1 does not require any limitation that would satisfy the intended result of the viral particle does not genetically modify microglia, retinal ganglion cells (RGCs) or photoreceptors (PRCs). As explained in the prior art and enablement rejections above, the intravitreal administration requirement of parallel dependent claim 10 provides the necessary additional limitation that would result in the viral particle of claim 1 to spare RGCs and PRCs. Thus, due to claim dependency and B.R.I., the method of claim 14 encompasses any and all routes of ocular tissue contact, including subretinal injection. To support the unexpected result argument, applicant explicitly cites in their remarks that Dalkara, Yang, and Lotery show that subretinal injection of AAV5 results in robust, widespread transduction of PRCs and retinal pigment epithelium cells (RPEs). Furthermore, as presented by the applicant in an additional supportive argument for unexpected result, the teachings of Griffin establish “that the combination of the AAV5 capsid with the modified GFAP promoter genetically modifies neurons,” see applicant’s remarks pgs. 2-3. Therefore, the nucleic acid viral vector of claim 1 does not have a structural limitation that will produce the intended result of claim 14. Because the broad scope of claim 14 encompasses subretinal delivery methods where these neuronal cells are aggressively modified in the prior art, applicant’s cell-sparing unexpected results argument cannot establish non-obviousness across the full scope of the claim. Accordingly, the full scope of claim 14 is now rejected under 35 U.S.C. 112(a) for Lack of Enablement, as detailed in the rejection above.
As established in the 103 rejection of claim 14, the recited cell-sparing profile represents a predictable execution of known prior art elements operating within known anatomical constraints, not an unexpected synergy. As taught by Griffin, the truncated gfaABC1D promoter sequence exhibits strict transcriptional fidelity, driving robust expression in astrocytes while remaining transcriptionally silent in microglia. The lack of microglia modification is thus a known, fully predictable property of the promoter sequence taught by Sena-Esteves and Griffin. Regarding sparing deep retinal neurons, applicant misrepresents the teachings of Dalkara by selectively presenting results reported from a control experiment to argue that AAV5 inherently targets photoreceptors. However, Dalkara explicitly teaches that when AAV5 is delivered via the intravitreal space, it “shows no accumulation at the vitreoretinal junction, indicating a lack of appropriate receptors at the inner limiting membrane (ILM).” Across the main body of the retina, the dense, continuous ILM acts as physical barrier that traps wild-type AAV5 within the vitreous humor, blocking it from penetrating the layers where RGCs and PRCs reside. Dalkara proves that AAV5 administered via IVT injection can only modify RGCs and PRCs if an exogenous protease (Pronase E) is actively co-administered to digest this physical barrier. Thus, the sparing of deeper retinal neurons during IVT administration is the inherent, predictable physical result of an intact ILM barrier, as explicitly taught by applicant’s own cited art.
Applicant uses Griffin’s data regarding spinal cord neurons to argue that the vector combination is unpredictable in the eye. However, Griffin explicitly notes that regional variations occur because “neurons in different regions…have a different repertoire of cell surface receptors or different transcriptional activity” (Griffin, pg. 209). Anatomically, the ONH is the precise structural site where the retinal nerve fibers exit the globe and where the continuous, dense retinal ILM membrane invaginates, as depicted in FIG. 3A, 4A and 4B of the instant application. This distinct structural opening deprives the ONH interface of the ILM present across the rest of the fundus, leaving the ONH astrocytes in direct contact with the vitreous humor containing the injected AAV5 viral particles. A PHOSITA combining the known astrocyte transcriptional profile of the gfaABC1D promoter (from Sena-Esteves and Griffin) with the known physical containment properties of an intravitreally injected AAV5 vector (from Dalkara) would fully expect gene expression to be restricted to the ONH astrocytes.
Applicant quotes Cameron et al. (2024), which is a post-filing journal article stemming from the inventors of the instant application, to argue that the combination had not been previously reported for targeting inner retinal or ONH astrocytes. While objective evidence of non-obviousness (secondary considerations) must be considered, a statement in a post-filing publication that a specific combination “had not been reported” does not overcome a prima facie case of obviousness built upon clear prior art suggestions. The question under 35 U.S.C. 103 is not whether the exact combination had been previously printed in a peer-reviewed journal for the exact sub-tissue, but whether a PHOSITA would have been motivated to combine the clear structural and transcriptional pieces taught by Maguire, Sena-Esteves, Griffin, and Dalkara with a reasonable expectation of success. Applying a known, astrocyte-specific promoter to an established ocular astrocyte-targeting protocol via an administration pathway known to physically restrict vector access represents routine combination of prior art elements according to known methods to yield predictable results.
Thus, applicant’s arguments regarding unexpected results are not persuasive.
Conclusion
No claims are allowed.
Applicant's amendment and submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 05/14/2026 necessitated/prompted the new ground(s) of rejection presented in this Office action, see MPEP § 706.07(a) and MPEP § 609.04(b).
Accordingly, THIS ACTION IS MADE FINAL.
Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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