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 .
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show in FIG. 5 cells expressing green and red fluorophores as described in the specification: “IBA+ cells (green; open arrows) do not colocalize with tdTomato (solid arrows; red).” Applicant has provided black and white drawings only, and thus the green and red expressing cells are Indistinguishable from one another. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Applicant may remedy by submitting color drawings.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: “A.” as it occurs in FIG. 6. Applicant may remedy by providing new drawings that remove “A.” from FIG. 6.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claim 1 is 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.
Claim 1 recites the limitation "the nucleic acid sequence" in line 10 of claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites “a nucleic acid composition” earlier in lines 2-3, but nowhere preceding “the nucleic acid sequence” does the claim recite a nucleic acid sequence.
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, 4-8, 10-11, 13, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maguire CA, et. al., (WO-2020198737-A1).
Regarding claim 1, Maguire 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 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. 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 sequence is encapsulated by a 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” and pg. 44. lns. 30-31 “All capsids packaged a single-stranded AAV2 ITR-flanked AAV-CBA-GFP-WPRE transgene cassette].
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 8, Maguire teaches the viral capsid is AAV5 [pg. 18. lns. 2-3 “for CNS use, in some embodiments the AAV is AAV1, AAV2, AAV4, AAV5, AAV6, AAV8, or AAV9.”].
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 11, Maguire teaches the retinal astrocyte is an optic nerve head astrocyte. Since Maguire teaches that delivery to the retina can be via IVT injections as explained above in claim 10, 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.
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…”].
Claims 1-2, 4, 6-7, 9-10, 15-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Boye SE. and Boye SL. herein “Boye” (US-20200405744-A1, published 2020-12-31).
Regarding claim 1, 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”].
Regarding claim 2, Boye 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).”].
Regarding claim 4, Boye 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)].
Regarding claim 6, Boye 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).”].
Regarding claim 7, Boye 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).”].
Regarding claim 9, Boye 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.”].
Regarding claim 10, Boye teaches the composition is administered via intravitreal injection [claim 52 “the rAAV particle is administered intravitreally”].
Regarding claim 15, Boye 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.
Regarding claim 16, Boye 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.”].
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.
Claims 3 and 14 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 in further view of Griffin JM et. al., (Gene Ther. 26(5):198–210; published 2019-04-08).
The teaching of Maguire regarding claim 1 are incorporated herein by reference to the 102 rejection above.
Regarding claim 3 and 14, Maguire teaches expression of the transgene can also be driven by a tissue specific promoter, e.g., a tissue specific promoter for retina; namely, the use of an astrocyte promoter, glial fibrillary acidic protein (GFAP) (pg. 15 lns. 15-25).
Maguire does not teach the truncated form of GFAP, gfaABC1D, with identifier, SEQ ID NO:1, nor does Maguire teach microglia, retinal ganglion cells (RGCs) or photoreceptor cells (PRCs) are not genetically modified.
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 claimed SEQ ID NO:1 (para [0019]).
However, Sena-Esteves M. et. al., does not teach sparing microglia, retinal ganglion cells (RGCs) or photoreceptor cells (PRCs) from genetic modification.
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).
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. 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 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). 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. Furthermore, a PHOSITA would have been motivated to adopt the AAV5/GfaABC1D combination taught by Griffin to specifically achieve the negative limitation of claim 14 (no genetic modification of microglia, RGCs, or PRCs), as Griffin confirms that this specific composition avoids microglia transduction/expression and shifts targeting away from the “neuron centric” (RGCs/PRCs) transduction typical of other AAV configurations. Thus, claim 14 merely recites the intended result of the specific AAV5/GfaABC1D combination taught by Griffin.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Maguire CA, et. al., (WO-2020198737-A1) in view of Parks RJ. Et. al., (Proc. Natl. Acad. Sci., Vol 93, pp 13565-13570, published Nov. 1996).
The teaching of Maguire regarding claim 1 are incorporated herein by reference to the 102 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”).
Maguire does not 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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 9am-5pm EST.
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/COREY LANE BRETZ/ Patent Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635