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 .
Applicant’s response to restriction requirement filed on December 23, 2025 have been received and entered. Claims 1-9, 15, 19, 21-23, 31, 35, 40, 46 and 60 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-9, 15 and 21 (group I) in the reply filed on December 23, 2025 is acknowledged.
Claims 21-23, 31, 35, 40, 46 and 60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 23, 2025.
Priority
This application is a 371 of PCT/US2021/032480 filed on 05/14/2021, which claims priority from US provisional application no 63/109,420 filed on 11/04/2020and application no 63/025,039 filed on 05/14/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/27/2023 and 06/13/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 1-9, 15 and 21 are under consideration.
Claim Rejections - 35 USC § 102
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.
Claims 1-9 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brough (USPGPUB 20160102320, dated 04/14/2016 or 9951351, dated 04/24/2018).
Claims are directed to a nucleic acid vector comprising a high expression supporting cell-specific promoter operably linked to a polynucleotide encoding atonal BHLH transcription factor 1 (Atoh1). Dependent claim limits the Atoh1 polypeptide having the sequence of SEQ ID NO: 10.
Claim interpretation: (i) The term "supporting cell" is interpreted as specialized epithelial cells in the cochlea and vestibur system of the inner ear that reside between hair cells.
(ii) Recitation of term optionally in claim 2 make the subsequent limitation optional and therefore terms following optionally are not given any patentable weight and not considered as part of nucleic acid vector.
(iii) The term comprises promoter has the sequence ID NO is interpreted to include additional nucleotide as term “has” is synonymous with comprises or have is open-ended and does not exclude additional, unrecited elements or method steps. (see MPEP 2111.03).
With respect to claims 1 and 9, Brough teaches vector comprising a nucleic acid sequence encoding a human atonal homolog-1 (Hath1) protein operably linked to a human glial fibrillary acidic protein (GFAP) promoter (abstract), wherein the GFAP expression n is primarily restricted to the supporting cells of the sensory organs (see para. 34).
PNG
media_image1.png
200
400
media_image1.png
Greyscale
It is relevant to note that the Brough teaches Hath-1 nucleic acid as set forth in SEQ ID NO: 1 encoding Atoh 1protein as set forth in NCBI accession no. AAV41305.1 that has 100% sequence identity to SEQ ID NO: 10 (see para. 32 see sequence alignment above).
With respect to claim 2, Brough teaches GFAP promoter as set forth in SEQ ID NO: 2 having the sequence comprising SEQ ID NO: 1, 2 and 3 (see claim 8 of ‘320 and page 29(.
Regarding claim 3, Brough teaches the vector comprising GFAP promoter comprises nucleotide 1114 to 1367 of SEQ ID NO: 2 that has 100% sequence identity to nucleotide 1-254 of B (SEQ ID NO: 2) (see below the sequence homology).
PNG
media_image2.png
200
400
media_image2.png
Greyscale
With respect to claim 4, Brough teaches the vector comprising GFAP promoter comprises nucleotide 230-483 of SEQ ID NO: 2 (B) that is present as nucleotide 1343 to 1595 of SEQ ID NO: 2 (see below the sequence homology).
PNG
media_image3.png
200
400
media_image3.png
Greyscale
Regarding claim 5, Brough teaches the vector comprising GFAP promoter comprises nucleotides 459-711 of SEQ ID NO: 2 (B) that is present as nucleotide 1572 to 1824 of SEQ ID NO: 2 (see below the sequence homology).
PNG
media_image4.png
200
400
media_image4.png
Greyscale
Regarding claim 6, Brough teaches the vector comprising GFAP promoter comprises nucleotide 687-917 of SEQ ID NO: 2 (B) that is present as nucleotide 1800 to 2030 of SEQ ID NO: 2 (see below the sequence homology).
PNG
media_image5.png
200
400
media_image5.png
Greyscale
Regarding claim 7, Brough teaches the vector, wherein the high expression supporting cell specific GFAP promoter comprises SEQ ID NO 2 that has 100% sequence identity to all of B as set forth in SEQ ID NO: 2 (see below the sequence homology).
PNG
media_image6.png
200
400
media_image6.png
Greyscale
PNG
media_image7.png
200
400
media_image7.png
Greyscale
Regarding claim 8, Brough teaches the vector, wherein the high expression supporting cell specific GFAP promoter comprises has sequence of SEQ ID NO 2 that has 100% sequence identity to SEQ ID NO:8 (see below the sequence homology).
PNG
media_image8.png
200
400
media_image8.png
Greyscale
With respect to claim 9, Brough teaches a cell comprising the nucleic acid vector comprising a nucleic acid sequence encoding a human atonal homolog-1 (Hath1) protein operably linked to a human glial fibrillary acidic protein (GFAP) promoter (para.42, 63) (see para. 34).
Accordingly, claims 1-9 and 15 are anticipated by Brough.
Claim Rejections - 35 USC § 103
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.
Claims 1, 8 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Brough (USPGPUB 20160102320, dated 04/14/2016 or 9951351, dated 04/24/2018), Griffin et al (Gene Therapy (2019) 26:198–210) and Sena-Estevens (US20180311290, dated 11/1/2018)/Lee et al (Glia. 2008;56:481–93, abstract).
Claims are directed to a nucleic acid vector comprising a high expression supporting cell-specific promoter operably linked to a polynucleotide encoding atonal BHLH transcription factor 1 (Atoh1). Claims are also directed to a nucleic acid vector encoding a high expression promoter operably linked to a polynucleotide encoding Atoh1.
Claim interpretation: (i) The term "supporting cell" is interpreted as specialized epithelial cells in the cochlea and vestibur system of the inner ear that reside between hair cells.
(ii) the term “supporting cell-specific promoter” is interpreted as defined in the specification as promoter that leads to GFP immunolabeling above background in at least 50% of supporting cells (see page 10, lines 18-20) .
(iii) the term “a high expression promoter” is interpreted as defined in the specification as a promoter that drives transgene expression in supporting cells transformed with a vector encoding such promoter operably linked to the transgene at a level that is at least 0.25 log fold change higher than expression of the transgene in supporting cells transformed with the same amount (e.g., titer) of an equivalent vector encoding the long GFAP promoter operably linked to the transgene (see page 10, lines 11-15) .
The teaching of Brough has been described above and relied in same manner here. Briefly, Brough teaches vector comprising a nucleic acid sequence encoding a human atonal homolog-1 (Hath1) protein operably linked to a human glial fibrillary acidic protein (GFAP) promoter (abstract), wherein the GFAP expression n is primarily restricted to the supporting cells of the sensory organs (see para. 34).
Brough teaches supporting cell-specific long GFAP promoter, however, differs form claimed invention by not disclosing (i) a high expression promoter operably linked to Atoh1, wherein said promoter consist of nucleotide sequence of SEQ ID NO: 8.
However, before the effective filing date of instant application, Griffin teaches ~4.7 kb packaging limitation of AAV that severely imposes sequence length restriction on the therapeutic genes that could be cloned into the expression cassette. It is disclosed that long GFAP promoter effectively mediates transgene expression but its relatively larger promoter size occupies almost half of the packaging capacity (See Griffin page 207, col. 2, last para.). The art teaches a shorter GFAP promoter (of 681 bp GFAP as summarized by Lee) that showed greater transduction efficiency and transgene expression as compared to long GFAP promoter (see page 208, col. 1, para. 1 of Griffin).
PNG
media_image9.png
200
400
media_image9.png
Greyscale
Sena-Estevens provided requisite guidance regarding a short GFAP promoter as set forth in SEQ ID NO: 14 that has 100% sequence identity to SEQ ID NO: 8 (see above and sequence search results).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art by modifying the vector disclosed in Brough by substituting long GFAP promoter with a truncated 681bp GFAP promoter as suggested in Griffin and disclosed in Sena-Estevens/Lee, as instantly claimed, with a reasonable expectation of success, before the effective filing date of instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so as prior art recognized (i) using a truncated GFAP promoter instead of longer GFAP promoter that would occupies almost half of the packaging capacity of AAV and (ii) 681 bp truncated GFAP promoter is more efficient in transduction and gene expression as compared to longer GFAP promoter. Absent evidence of any unexpected and/or superior results, one of skill in the art would have been expected to have a reasonable expectation of success in substituting one long GFAP promoter with shorter GFAP promoter because the art successfully reported shorter GFAP promoter exhibits greater transduction efficiency and transgene expression as compared to long GFAP promoter (see above) . It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf.June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
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 1-9 and 15 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.
The term “high expression ” in claim 1 is a relative term which renders the claim indefinite. The term “high expression” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the instant case, it is unclear if the high expression supporting cell-specific promoter (i) is relative to the expression of transgene in a greater number of support cells or (ii) is relative to transgene expression in support cells that is higher than in cells using long GFAP promoter. The metes and bounds of the phrase high expression could not be ascertained. A direct recitation of support cells specific promoter would obviate the basis of the rejection. Claims 2-9 and 15 directly or indirectly depend from the rejected base claim,
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.
Claims 1-, 15, 21 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 claims embrace a genus of high expression promoter or a high expression supporting cell-specific promoter. The specification defines the term “ high expression promoter” as a promoter that drives transgene expression in supporting cells transformed with a vector encoding such promoter operably linked to the transgene at a level that is at least 0.25 log fold change higher than expression of the transgene in supporting cells transformed with the same amount (e.g., titer) of an equivalent vector encoding the long GFAP promoter operably linked to the transgene (see page 10, lines 11-15 of the specification) . The term support cells refer specialized epithelial cells in the cochlea and vestibur system of the inner ear that reside between hair cells. Supporting cells maintain the structural integrity of the sensory organs during sound stimulation and head movements and help to maintain an environment in the epithelium that allows hair cells to function (see page 12 of the specification).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1117. The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The DNA sequences of all high expression promoter that drives transgene expression in supporting cells (specialized epithelial cells in the cochlea and vestibur system), other than the truncated GFAP promoter as set forth in SEQ ID NO: 8 that is at least 0.25 log fold change higher than expression of the transgene in supporting cells transformed with the same amount of an equivalent vector encoding the long GFAP promoter, encompassed within the genus of high expression promoter that drives transgene expression in supporting cells have not been disclosed. Based upon the prior art there is expected to be sequence variation among the species of DNA sequences of high expression supporting cells specific promoter . The specification has provided the sequences of the truncated GFAP promoter as set forth in SEQ ID NO: 8. The specification however has not disclosed the sequences of any of the other high expression supporting cell promoter embraced by the claims. There is no evidence on the record of a relationship between the structures of the DNA molecules of any of the embraced high expression supporting cells specific promoter sequences that would provide any reliable information about the structure of DNA molecules within the genus. There is no evidence on the record that embraced high expression supporting cells specific promoter had known structural relationships to each other; the art indicated that there is variation between DNA sequences of various high expression supporting cells specific promoter. The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998).
In the instant case, the claimed embodiments of high expression supporting cells specific promoter, other than the truncated GFAP promoter as set forth in SEQ ID NO: 8 encompassed within the genus of high expression supporting cells specific promoter lack a written description. The specification fails to describe what DNA molecules fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed high expression supporting cells specific promoter that show contemplated level of expression in support cells as compared to long GFAP promoter , and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of the above considerations, one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of high expression supporting cells specific promoter showing contemplated level of expression in support cells that specialized epithelial cells in the cochlea and vestibur system of the inner ear that reside between hair cells , other than the truncated GFAP promoter as set forth in SEQ ID NO: 8. Moreover, the art has recognized that there would be variation among the species of the genus of DNA sequences of high expression supporting cells specific promoter showing contemplated level of expression in support cells specialized epithelial cells in the cochlea and vestibur system of the inner ear that reside between hair cells. Therefore, Applicant was not in possession of the genus of high expression supporting cells specific promoter as encompassed by the claims. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention."
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
Prosecution Insights