DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 8-13-25.
Claims 1, 2, 4, 5, 7, 37, 44, 53, 58, 69, 70, 114, 118, 119, 124 and 125 are pending in the instant application.
Claims 69, 70, 114, 118, 119, 124 and 125 are withdrawn as being drawn to a non-elected invention or species.
Claims 1, 2, 4, 5, 7, 37, 44, 53, 58 have been examined on their merits as set forth below.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections not repeated in this Office action are hereby withdrawn.
New Rejections
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 1, 2, 4, 5, 7, 37, 44, 53, 58 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.
In claim 1, lines 3 and 4, the metes and bounds of “a portion thereof” with respect to the protein hDlx2 or the nucleic acid sequence encoding the protein are unclear.
In claim 4, lines 4 and 6, the metes and bounds of “a portion thereof” with respect to the protein hDlx2 or the nucleic acid sequence encoding the protein are unclear.
Appropriate correction or clarification is required.
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.
Claims 1, 2, 4, 5, 7, 37, 44, 53, 58 are 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims:
The claims are broadly drawn to adeno-associated virus (AAV) vectors comprising a human distal-less homeobox 2 (hDlx2) sequence comprising SEQ ID NO: 6 or a portion thereof, or which hDlx2 sequence encodes the amino acid sequence of SEQ ID NO: 10 or a portion thereof, which hDlx2 sequence is operably linked, in any order, to regulatory elements comprising:(a) a glial fibrillary acidic protein (GFAP) promoter comprising a nucleic acid sequence at least 95% identical to SEQ ID NO:3;(b) an enhancer from a human elongation factor-1 alpha (EF1-a) promoter or a cytomegalovirus (CMV) enhancer comprising a nucleic acid sequence at least 95% identical to SEQ ID NO:11;(c) a chimeric intron comprising a nucleic acid sequence at least 95% identical to SEQ ID NO:19;(d) a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) comprising the nucleic acid sequence of SEQ ID NO:18; and(e) a SV40 polyadenylation signal, a hGH polyadenylation signal, or a bGH polyadenylation signal comprising a nucleic acid sequence at least 95% identical to SEQ ID NO:20, AAV vectors optionally comprise an AAV serotype 2, AAV serotype 5, or AAV serotype 9, and which vectors convert a glial cell to a functional neuron in a subject in need thereof, which subject has a neurological condition optionally comprising Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), Huntington's Disease, epilepsy, physical injury, stroke, cerebral aneurysm, traumatic brain injury, concussion, a tumor, inflammation, infection, ataxia, brain atrophy, spinal cord atrophy, multiple sclerosis, traumatic spinal cord injury, ischemic or hemorrhagic myelopathy (myelopathy), global ischemia, hypoxic ischemic encephalopathy, embolism, fibrocartilage embolism myelopathy, thrombosis, nephropathy, chronic inflammatory disease, meningitis, and cerebral venous sinus thrombosis, which glial cell optionally is an astrocyte, a reactive astrocyte, or an NG2 cell, and which functional neurons optionally comprise glutamatergic neurons, GABAergic neurons, dopaminergic neurons, cholinergic neurons, seratonergic neurons, epinephrinergic neurons, motor neurons, or peptidergic neurons.
Teachings in the specification:
The specification teaches the following nucleic acid constructs:
[0024] Figure 1A depicts a map of a CE:Gfa681:Dlx2:WPRE:SV40.
[0025] Figure 1B depicts a map of a EF-1α:Gfa681:Dlx2:WPRE:SV40.
[0026] Figure 1C depicts a map of a CE:Gfa681:Dlx2:WPRE:hGH.
[0027] Figure 1D depicts a map of a EF-1α:Gfa681: Dlx2:WPRE:hGH.
[0028] Figure 2A depicts a map of a CE:Gfa1.6p:DIx2:WPRE:SV40.
[0029] Figure 2B depicts a map of a EF-1q:Gfa1.6p:Dlx2:WPRE:SV40.
[0030] Figure 2C depicts a map of a CE: Gfa1.6p:Dlx2:WPRE:hGH.
[0031] Figure 2D depicts a map of a EF-1α: Gfa1.6p:Dlx2:WPRE:hGH.
[0032] Figure 3A depicts a map of a CE:Gfa2.2:D1x2:WPRE:SV40.
[0033] Figure 3B depicts a map of a EF-1α: Gfa2.2: Dlx2:WPRE:SV40.
[0034] Figure 3C depicts a map of a CE: Gfa2.2:Dlx2:WPRE:hGH.
[0035] Figure 3D depicts a map of a EF-1α: Gfa2.2:Dlx2:WPRE:hGH.
[0036] Figure 4 depicts a map of a U6:shRNA1:H1:shRNA2:7SK:shRNA3.
[0037] Figure 5A depicts a map of a U6:shRNA:CE:Gfa681:Dlx2:WPRE:SV40.
[0038] Figure 5B depicts a map of a U6:shRNA: EF-1α:Gfa681:Dlx2:WPRE:SV40.
[0039] Figure 5C depicts a map of a U6:shRNA:CE:Gfa1.6p:Dlx2:WPRE:SV40.
[0040] Figure 5D depicts a map of a U6:shRNA: EF-1α: Gfa1.6p:Dlx2:WPRE:SV40.
[0041] Figure 5E depicts a map of a U6:shRNA:CE:Gfa2.2:Dlx2:WPRE:SV40.
[0042] Figure 5F depicts a map of a U6:shRNA: EF-1α: Gfa2.2:Dlx2:WPRE:SV40.
[0043] Figure 6A depicts a map of a U6:shRNA:CE:Gfa681:D1x2:WPRE:hGH.
[0044] Figure 6B depicts a map of a U6:shRNA: EF-1α:Gfa681:D1x2:WPRE:hGH.
[0045] Figure 6C depicts a map of a U6:shRNA:CE:Gfa1.6p:Dlx2:WPRE:hGH.
[0046] Figure 6D depicts a map of a U6:shRNA: EF-1α: Gfa1.6p:Dlx2:WPRE:hGH.
[0047] Figure 6E depicts a map of a U6:shRNA:CE:Gfa2.2:D1x2:WPRE:hGH.
[0048] Figure 6F depicts a map of a U6:shRNA: EF-1α: Gfa2.2:Dlx2:WPRE:hGH.
[0049] Figure 7 depicts establishment of rat astrocyte primary culture from 3 day post-natal Sprague-Dawley rat brains. Upper left panel presents an image of GFAP stained cells. Upper right panel presents an image of SOX9 stained cells. Lower left panel presents an image of DAPI stained cells. Lower right panel presents a merged image of GFAP, SOX9, and DAPI stained cells.
[0050] Figure 8 depicts comparison of Dlx2 plasmid efficiency. Primary rat astrocyte cells are transfected with either the P44 (pEF-1α:Gfa681:Dlx2:WPRE:SV40), P60 (pEF 1α:Gfa681:Dlx2:shortened chimeric intron: WPRE:SV40), and P75 (CE:Gfa681:Dlx2:WPRE:SV40). Top panels show Dlx2 staining of cells, bottom panels show merged Dlx2 and DAPI staining of cells.
[0051] Figure 9A and 9B depicts quantitative analysis of AAV particle transduction into primary rat astrocytes. Figure 9A presents the percentage transduction rate of AAV9-P12 (pGfa681:GFP) and AAV5-P7 (pEF-1α:GFP) at MOI of 5 X 10⁵ vg/cell, 2 x10⁵ vg/cell, and 5 X 10⁴ ug/cell. Figure 9B presents the percentage transduction rate of AAV9-P12 (pGfa681:GFP) in cells seeded at a series of densities of 2 x10⁴ cell /well, 1.5 X 10⁴ cell /well, 1 x10⁴ cell /well, and 5 X 10³ cell /well and infected with virus at a series of amounts of 2µl, 1 µl, 0.5 µl, 0.25 µl, 0.125 µl of 1 X 10¹³ ug/ml virus in 100 µl of medium.
[0052] Figure 10 depicts rat cortical astrocytes (RCAs) immunostained with an anti-Dlx2 antibody and DAPI (nuclear stain) 24 hours post transfection with NXL-P104 (CE-pGfa681-CGRI-Dlx2-bGHpA) or NXL-P105 (CE-pGfa681-CI-DIx2-oPRE-bGHpA)
[0053] Figure 11 depicts rat cortical astrocytes (RCAs) immunostained with an anti-Dlx2 antibody and DAPI (nuclear stain) 24 hours post transfection with NXL-P133 (EE-pGfa681-CGRI-Dlx2-oPRE-bGHpA), NXL-P137 (EE-pGfa681-CGRI-Dlx2-oPRE-bGHpA), or NXL-P131 (EE-pGfa681-CI-D1x2-oPRE-bGHpA).
[0054] Figure 12 depicts rat cortical astrocytes (RCAs) immunostained with an anti-Dlx2 antibody and DAPI (nuclear stain) 6 days post transduction with AAV9-P133 (CE-pGfa681-CGRI-Dlx2-oPRE-bGHpA).
[Citations omitted] [Emphases added].
The examples provided in the instant specification, of the particular nucleic acid constructs synthesized, and the in vitro transfection of rat cortical astrocytes with the particularly described constructs, and transduction of rat cortical astrocytes in vitro with AAV9-P133 (CE-pGfa681-CGRI-Dlx2-oPRE-bGHpA), are not representative or correlative of the ability to convert glial cells to functional neurons in a subject using the broad genus of nucleic acid constructs claimed.
The specification fails to provide adequate description or reasonable representation of the broad genus of nucleic acid constructs claimed, and further whereby treatment effects are provided in a subject. The specification fails to provide a representative number of species, and do not indicate what distinguishing attributes are concisely shared by the members of the genus of AAV vectors claimed.
For the reasons stated above, the instant rejection for lacking adequate written description is proper.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
6-23-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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