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 .
Applicant’s response filed 02/12/2026 has been received and considered entered. This is a response to amendments and arguments filed 02/12/2026.
Claims Status
Claims 4, 6-8, 10-11, 13-14, 23-33, 36-38, 41, 44, 46-48, 50, 52, 54-57, 59-60, 63, 65-101, 103-109, 112 is/are cancelled. Claims 1-3, 5, 9, 12, 15-22, 34-35, 39-40, 42-43, 45, 49, 51, 53, 58, 61-62, 64, 102, 110-111 is/are currently pending. Claims 1-3, 5, 9, 12, 15-22, 34-35, 39-40, 42-43, 45, 49, 51, 53, 58, 61-62, 64, 102, 110-111 is/are under examination.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 5, 9, 15-16, 35, 40, 43, 45, 49, 53, 58, 61-62, 64, 102 is/are rejected under 35 U.S.C. 103 as being unpatentable over Burns (WO2020077295A1; published 04/16/2020, provided by applicant with IDS filed 07/08/2024), in view of Nishio (2015), GenBank (2019) (NCBI Reference Sequence: NG_008323.1), and Essenfelder (2005). This is a new grounds of rejection.
Regarding claim 1, Burns teaches a construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes GJB2 (connexin-26) and the promoter is selective for a supporting cell (claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
Regarding claim 5, Burns teaches that the GJB2 mRNA has the sequence of NCBI accession number NM_004004, which comprises a sequence 100% identical to SEQ ID NO:1 (see alignment below; Burns page 49).
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Regarding claim 9, Burns teaches that the GJB2 mRNA has the sequence of NCBI accession number NM_004004, which encodes a protein of accession number QAU32547.1, which is 100% identical to the amino acid sequence of SEQ ID NO:7 (see alignment below; Burns page 49).
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Regarding claim 15, Burns teaches that the promoter sequence is capable of expressing the coding sequence in an IPhC, IPC, OPC, Deiters’ cells, Hensen’s cells, Claudius cells, interdental cells (Table 5 pages 54-55; claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
Regarding claim 35, Burns teaches that the construct further comprises a 5’ UTR and a 3’ UTR (page 57 lines 12-16).
Regarding claim 40, Burns teaches that the construct further comprises a polyadenylation tail (polyadenylation signal) (page 57 lines 12-16).
Regarding claim 43, Burns teaches that the promoter and coding sequence are flanked by 5’ and 3’ ITRs (page 58 line 35-page 59 line 11; claims 89, 94).
Regarding claim 45, Burns teaches that the 5’ and 3’ ITRs are AAV2 ITRs (claim 94).
Regarding claim 49, Burns teaches that the construct comprises the gene GJB2 and 5’ and 3’ UTR sequences (page 57 lines 12-16; page 49; claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85) (the known GJB2 mRNA sequence comprises the 5’ UTR sequence of SEQ ID NO:20 and the 3’ UTR sequence of SEQ ID NO:67, shown below, and SEQ ID NO:1, shown above).
Alignment of SEQ ID NO:20:
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Alignment of SEQ ID NO:67:
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Further regarding claim 49, Burns teaches that the construct comprises AAV ITR sequences known in the art (page 58 line 35-page 59 line 11; claims 89, 94). Alignments of SEQ ID NOs:8 and 9 to the known AAV2 reference sequence of accession number J01901.1, shown below, show that SEQ ID NOs:8 and 9 comprise the plus and minus strand of the AAV2 3’ ITR sequence. Burns teaches that the construct comprises AAV2 ITR sequences, specifically (claim 94). As such, the construct of Burns comprises SEQ ID NOs:8-9.
SEQ ID NO:8:
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SEQ ID NO:9:
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Regarding claims 53 and 58, Burns teaches an AAV viral vector comprising the construct (claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
Regarding claims 61-62, Burns teaches a pharmaceutical composition comprising the construct, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier (excipient) (claim 96).
Regarding claim 64, Burns teaches an ex vivo cell comprising the construct (page 51 lines 13-14).
Regarding claim 102, Burns teaches a kit comprising the construct (page 65 line 30-page 66 line 3).
However, Burns does not teach that the supporting cell-specific promoter is the GJB6 promoter of SEQ ID NO:101. Instead, Burns teaches that the supporting cell-specific promoter is the GJB2 promoter (claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
Nishio and Essenfelder teach the GJB6 promoter of SEQ ID NO:101.
Regarding claims 1, 16, 49, Nishio teaches that expression of GJB6 is localized to pillar cells, supporting cells, Hensen’s cells, Claudius’ cells, external sulcus cells, spiral prominence cells, spiral ligament cells, stria vascularis, interdental cells, spiral limbus, and inner sulcus cells, and furthermore teaches that GJB6 is not expressed in inner or outer hair cells, spiral ganglion, Reisner’s membrane, and tectorial membrane (page 5). Nishio teaches that GJB6 has the same cell type-specific expression in the inner ear as GJB2 (page 5). Nishio also teaches that GJB2 and GJB6 have different tissue-specific expression profiles outside of the inner ear (see Table 4 page 29).
Essenfelder teaches that nucleotides -461 to +33 relative to the GJB6 gene sequence comprise an active GJB6 promoter region (Fig. 3). SEQ ID NO:101 is 100% identical to the genomic sequence upstream of the GJB6 gene (see genome alignment below), and comprises the promoter sequence taught by Essenfelder in Fig. 3.
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The GenBank record of NG_008323.1 describes the human GJB6 reference sequence and details that nucleotides 1-5076 are the 5’ UTR of the hGJB6 genomic sequence. Instant SEQ ID NO:101 is 100% identical to nucleotides 4296-5030 of NG_008323.1.
Given that the GJB2 promoter, used by Burns, has the same cell type specificity as the GJB6 promoter, as taught by Nishio, it would have been obvious to a person of ordinary skill in the art at the time of filing that the GJB6 promoter was an obvious alternative to the GJB2 promoter used by Burns for driving expression in inner ear supporting cells. While Essenfelder teaches that nucleotides -461 to +33 of the GJB6 gene sequence, which is 100% identical to nucleotides 323-735 of instant SEQ ID NO:101 (see alignment below).
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Essenfelder teaches that this promoter sequence is an active promoter region, comprising known transcription factor binding sites (see Fig. 3). However, this sequence, as shown by the GenBank record, is a fragment of the 5’ UTR of the GJB6 gene. It would have been obvious to an artisan at the time of filing that in order to place a transgene under the control of the GJB6 promoter, to exhibit the same tissue- or cell-specific expression pattern of the GJB6 gene, the minimum length of the GJB6 promoter, as taught by Essenfelder, must be included in the promoter region, and that the remainder, or any fragment of the remainder, of the 5’ UTR of the GJB6 gene, as described in the GenBank record of the full human GJB6 gene sequence, may be included. An expression cassette comprising a transgene operatively linked to the entire 5’ UTR of the human GJB6 gene as described by the GenBank record, including the active GJB6 promoter taught by Essenfelder, would comprise instant SEQ ID NO:101, as SEQ ID NO:101 is entirely comprised within the complete 5’ UTR of the GJB6 gene. Thus, the GJB6 promoter of SEQ ID NO:101 was known in the art, as taught by Essenfelder and GenBank, and thus the promoter sequence of SEQ ID NO:101 would have been an obvious alternative to the GJB2 promoter used by Burns.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Burns (WO2020077295A1; published 04/16/2020), Nishio (2015), GenBank (2019), and Essenfelder (2005), as applied to claim 1 above, and further in view of Tu (1998).
The teachings of Burns, Nishio, GenBank, and Essenfelder can be combined to render obvious the limitations of claim 1, as discussed above.
Regarding claim 12, Burns teaches that the construct comprises the GJB2 promoter sequence (claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
However, Burns does not teach that the construct comprises two promoters—the GJB6 and GJB2 promoters—nor that the GJB2 promoter is truncated.
Nishio, Essenfelder, and Tu teach that GJB2 and GJB6 promoters are regulated by different transcription factors and are active in different tissues.
Regarding claim 12, Nishio teaches that GJB2 and GJB6 have different tissue-specific expression profiles outside of the inner ear (see Table 4 page 29).
Regarding claim 12, Essenfelder teaches that the GJB6 promoter binds to Sp1 and Egr1 (page 36) and AP-2 (Fig. 3).
Regarding claim 12, Tu teaches that the GJB2 promoter binds to Sp1 and Sp3 (page 175).
Regarding claim 12, Tu teaches the core promoter sequence of the human GJB2 promoter, comprising the binding sites for necessary transcription factors (Fig. 2). SEQ ID NO:91 comprises the core promoter sequence taught by Tu (see alignment below). Tu further teaches that the activity of multiple transcription factors increases expression of a gene, compared to activity of a single transcription factor (page 180).
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As shown above, the promoter sequence taught by Tu encompasses nucleotides 1-124 of SEQ ID NO:91, described as being nucleotides -128 to -1 relative to the GJB2 gene (Fig. 2). An alignment of SEQ ID NO:91 to the known human GJB2 gene locus shows that nucleotides 125-128 of SEQ ID NO:91 constitute nucleotides 1-4 of the GJB2 gene sequence (see alignment below).
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The combination of the teachings of Tu, Nishio, and Essenfelder renders obvious that the GJB2 and GJB6 promoters are regulated by different but overlapping sets of transcription factors. These different sets of transcription factors result in different levels of expression of GJB2 and GJB6 in response to different stimuli. Furthermore, as taught by Tu, coadministration of different transcription factors results in greater expression of a gene than administration of a single transcription factor. Given these teachings, it would have been obvious to a person of ordinary skill in the art at the time of filing that the promoter regulating expression of the GJB2 coding sequence of Burns should comprise both the GJB6 promoter sequence, taught by Nishio and Essenfelder, and the core human GJB2 promoter sequence, taught by Tu, as this combination would restrict expression of the coding sequence to inner ear supporting cells and would allow for the binding of more transcriptional regulators than either promoter sequence alone, resulting in greater expression of the connexin-26 protein encoded by the construct of Burns. Furthermore, such a construct comprising pGJB6-pGJB2-GJB2 would naturally comprise nucleotides 125-128 of SEQ ID NO:91, as these nucleotides are nucleotides 1-4 of the GJB2 coding sequence.
Claim(s) 19-22, 34, 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Burns (WO2020077295A1; published 04/16/2020), Nishio (2015), GenBank (2019), and Essenfelder (2005), as applied to claim 1 above, and further in view of Sacheli (2009) and Brown (2007).
Burns, Nishio, GenBank, and Essenfelder can be combined to render obvious the limitations of claim 1, as discussed above. However, Burns, Nishio, GenBank, and Essenfelder do not teach the use of miRTS to regulate tissue specificity of construct expression.
Brown teaches the use of miRTS to regulate tissue specificity of transgene constructs, and Sacheli teaches inner ear-specific miRNA.
Regarding claim 19, Brown teaches that the insertion of a microRNA target site into a transgene expression vector (labeled “mirT” in Brown) (see Fig. 1a, Fig. 2c) can be used to restrict expression of the transgene to cells that do not endogenously express the miRNA which binds to the mirT (pages 1461, 1463-1464). Brown also teaches that mirT “perfectly complementary” to an miRNA provide greater transgene suppression than imperfectly complementary mirT sites (page 1465).
Regarding claim 39, Brown teaches that the mirT is inserted into the 3’ or 5’ UTR of a transgene, wherein the transgene construct comprises a 3’ UTR and a 5’ UTR (Fig. 1a, Fig. 2c).
However, Brown does not teach miRNA expressed in the inner ear.
Sacheli teaches miRNA expressed in the inner ear.
Regarding claims 20-22, Sacheli teaches that the microRNA miR-182 and miR-183 are expressed exclusively in inner ear hair cells in the mature ear (page 365).
Regarding claim 34, Sacheli teaches a sequence 100% complementary to miR-183 (aligned to SEQ ID NO:79 below, is 100% complementary to SEQ ID NO:79).
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The combination of Burns, Nishio, and Essenfelder renders obvious a polynucleotide construct comprising a promoter specific to inner ear support cells, as discussed above. As taught by Nishio, discussed above, the GJB6 and GJB2 genes are not significantly expressed in hair cells. The selection of the GJB2 promoter for expression in inner ear supporting cell types in Burns renders obvious that expression of the construct in hair cells is not desired by Burns in these methods. The teachings of Brown and Sacheli render obvious a method of further suppressing the expression of the construct of Burns in hair cells. Brown teaches that microRNA target sites, perfectly complementary to their corresponding miRNA, can be used to suppress expression of a transgene in specific cell types which endogenously express the miRNA; Sacheli teaches that miR-182 and miR-183 are specifically expressed in inner ear supporting cell types but not in hair cells. As such, it would have been obvious to a person of ordinary skill in the art at the time of filing that, in order to further suppress undesired expression of the transgene of Burns in hair cells while promoting desired expression in inner ear supporting cell types, in addition to the use of a supporting cell-specific promoter, an miR-182 and/or miR-183 target site, perfectly complementary to miR-182 and/or miR-183, should be inserted into an untranslated region of the transgene expression vector, as taught by the combination of Brown and Sacheli.
Claim(s) 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Burns (WO2020077295A1; published 04/16/2020), Nishio (2015), GenBank (2019), and Essenfelder (2005), as applied to claim 1 above, and further in view of Post (US5122458A).
The teachings of Burns, Nishio, GenBank, and Essenfelder can be combined to render obvious the limitations of claim 1, as discussed above. However, Burns, Nishio, GenBank, and Essenfelder do not teach the use of a bovine growth hormone polyadenylation signal (bGHpA).
Post teaches that the bGHpA was known to be an effective polyadenylation signal for expression of transgenes in eukaryotes.
Regarding claim 42, Post teaches that bGHpA was an effective polyadenylation signal for use in eukaryotes, to enhance expression of a transgene (claim 1; abstract).
Burns teaches that a polyadenylation signal is comprised in the polynucleotide construct. However, Burns does not specify the particular polyadenylation signal to be used. Post teaches that the bovine growth hormone polyadenylation signal is effective in enhancing expression of genes in eukaryotes; such a polyadenylation signal would be beneficial to use as the polyadenylation signal of Burns, as the methods of Burns are methods of expressing the polynucleotide construct in eukaryotic cells. As such, it would have been obvious to a person of ordinary skill in the art at the time of filing that the bGHpA of Post would be an optimal polyadenylation signal for use with the methods of Burns.
Claim(s) 110-111 is/are rejected under 35 U.S.C. 103 as being unpatentable over Burns (WO2020077295A1; published 04/16/2020), in view of Nishio (2015), Sacheli (2009), and Brown (2007).
Regarding claim 110, Burns teaches a construct comprising a coding sequence operably linked to a promoter (GJB2 promoter), wherein the coding sequence encodes a connexin 26 protein, and wherein the construct is introduced into inner ear support cells (claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
However, Burns does not teach that the construct further comprises an miRTS for a microRNA expressed in an inner ear cell.
Brown teaches the use of miRTS to regulate tissue specificity of transgene constructs, and Sacheli teaches inner ear-specific miRNA.
Regarding claim 110, Brown teaches that the insertion of a microRNA target site into a transgene expression vector (labeled “mirT” in Brown) (see Fig. 1a, Fig. 2c) can be used to restrict expression of the transgene to cells that do not endogenously express the miRNA which binds to the mirT (pages 1461, 1463-1464). Brown also teaches that mirT “perfectly complementary” to an miRNA provide greater transgene suppression than imperfectly complementary mirT sites (page 1465).
However, Brown does not teach miRNA expressed in the inner ear.
Sacheli teaches miRNA expressed in the inner ear.
Regarding claims 110-111, Sacheli teaches that the microRNA miR-182 and miR-183 are expressed exclusively in inner ear hair cells in the mature ear (page 365).
Burns teaches a polynucleotide construct comprising a promoter specific to inner ear support cells, as discussed above. As taught by Nishio, the GJB6 and GJB2 genes are not significantly expressed in hair cells (page 5). The selection of the GJB2 promoter for expression in inner ear supporting cell types in Burns renders obvious that expression of the construct in hair cells is not desired by Burns in these methods. The teachings of Brown and Sacheli render obvious a method of further suppressing the expression of the construct of Burns in hair cells. Brown teaches that microRNA target sites, perfectly complementary to their corresponding miRNA, can be used to suppress expression of a transgene in specific cell types which endogenously express the miRNA; Sacheli teaches that miR-182 and miR-183 are specifically expressed in inner ear supporting cell types but not in hair cells. As such, it would have been obvious to a person of ordinary skill in the art at the time of filing that, in order to further suppress undesired expression of the transgene of Burns in hair cells while promoting desired expression in inner ear supporting cell types, in addition to the use of a supporting cell-specific promoter, an miR-182 and/or miR-183 target site, perfectly complementary to miR-182 and/or miR-183, should be inserted into an untranslated region of the transgene expression vector, as taught by the combination of Brown and Sacheli.
However, regarding claim 112, Burns does not teach that the promoter is the GJB6 promoter.
Nishio teaches that the GJB2 and GJB6 are expressed in the same cell populations of the inner ear (page 5).
Given that the GJB2 promoter, used by Burns, has the same cell type specificity as the GJB6 promoter, as taught by Nishio, it would have been obvious to a person of ordinary skill in the art at the time of filing that the GJB6 promoter was an obvious alternative to the GJB2 promoter used by Burns for driving expression in inner ear supporting cells.
Response to Arguments
Applicant's arguments filed 02/12/2026 have been fully considered but they are not persuasive.
The above rejection is a new grounds of rejection, relying on the GenBank record of the human genomic GJB6 gene sequence. Applicant argued that:
Essenfelder’s Figure 3 disclosed a 494-nucleotide sequence. The GJB6 genomic sequence provided by the Examiner is a 17,434-nucleotide sequence. The claimed promoter sequence of SEQ ID NO:101 is a 735-nucleotide sequence. Thus, Essenfelder does not disclose a promoter sequence according to SEQ ID NO: 101, as the Essenfelder Figure 3 sequence is 322-nucleotides too short. And the GJB6 genomic sequence is almost 24 times the length of the claimed SEQ ID NO: 101. Thus Essenfelder does not remedy the deficiencies of Burns.
The prior office action merely presented the BLAST alignment of the GJB6 genomic sequence and SEQ ID NO:101, without providing the full GenBank record or discussing the teachings therein. The full GenBank record, provided herein and thus necessitating a new grounds of rejection, describes the coding sequence as starting at nucleotide 5077, and as such, the preceding 5076 nucleotides constitute a 5’ untranslated region associated with the GJB6 gene. The GenBank record thus does not teach that all 17,434 nucleotides of NG_008323.1 form part of a promoter sequence or other 5’ UTR; the GenBank record teaches that 5076 of the nucleotides form a 5’ UTR, 10,358 of the nucleotides form the coding sequence (including both exons and introns), and 2,001 of the nucleotides form an associated 3’ UTR. Essenfelder describes the function of 322 nucleotides of the 369 nucleotides 5’ of and most proximal to the GJB6 coding sequence as having the function of a promoter, and teaches the specific transcription factors which bind within that segment. However, all 5076 nucleotides of that 5’ noncoding sequence are clearly associated with the GJB6 coding sequence in the GenBank record. As discussed in the rejection above, an artisan would recognize that the entire 5’ UTR taught by the GenBank record could be used to confer upon a transgene the tissue- and cell type-specific expression pattern of GJB6, as this region comprises the entirety of the promoter region taught by Essenfelder. Such an artisan would recognize that the promoter sequence taught by Essenfelder would constitute a functional GJB6 promoter sequence to be used in such applications, as this is a fragment of the 5’ noncoding genomic sequence that Essenfelder teaches as conferring cell type-specific expression patterns consistent with known GJB6 expression patterns. It would be obvious to such an artisan that any fragment of the 5’ untranslated region associated with the GJB6 gene, as described in the GenBank record, and which includes the GJB6 promoter sequence taught by Essenfelder, would serve as a GJB6 promoter sequence and would only include noncoding sequences known to be part of the human GJB6 gene’s 5’ UTR region. An expression cassette comprising such a sequence would comprise instant SEQ ID NO:101. Instant claim 1 merely requires that the promoter comprise SEQ ID NO:101.
Limitations Not Found in the Prior Art
SEQ ID NOs:90 and 104 are described in the disclosure as corresponding to the human GDF6 promoter and the human PARM1 promoter, respectively. However, a search of the art did not produce evidence that the PARM1 promoter was known in the art to be a supporting cell-selective promoter. As such, it would not be obvious to design an expression cassette comprising a GJB2 gene—important for inner ear function—operatively linked to a promoter not known to drive expression in the inner ear (pPARM1). Moreover, Bademci (2020) (published after the effective filing date) teaches that GDF6 is expressed in the entire cochlea, inherently including supporting cells. However, a search of SEQ ID NO:90 in BLAST shows that SEQ ID NO:90 comprises segments which in aggregate are at least 95% identical to segments of the human GDF6 5’ UTR, but that SEQ ID NO:90 as a whole is not at least 85% identical to one contiguous segment of the human GDF6 5’ UTR (see alignments below). Likewise, a BLAST search of SEQ ID NO:104 showed that SEQ ID NO:104 is not at least 85% identical to a continuous segment of the human genome. Thus, claims 2-3, which require SEQ ID NOs:90 and 104 respectively, are not rendered obvious by the prior art at the time of filing.
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Claim 51 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: SEQ ID NOs:94, 97, 100, 103, and 106 comprise a GJB2 exon 2 fragment with two mismatches to the known GJB2 gene sequence and a GJB2 exon 2 fragment with 17 mismatches relative to the known GJB2 gene sequence, wherein 25 nucleotides of the human GJB2 gene sequence are unaccounted for (see BLAST alignments below of SEQ ID NO:103).
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A BLASTx search shows that nucleotides 1401-2078 of SEQ ID NO:103 encode a protein comprising a single amino acid alteration relative to the known human (and P. troglodytes) GJB2 protein, with the single alteration being M102K (see alignment below).
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Kenneson (2002) teaches known mutations of GJB2 (page 259). However, no mutation of amino acid residue 102 is described by Kenneson, or otherwise found in the prior art. It would not have been obvious to an artisan whether an M102K alteration would be benign (and thus an obvious alternative to the known reference GJB2 exon 2 sequence) or pathogenic (and thus obvious to introduce into an expression cassette used to investigate or model a pathogenic GJB2 variant). An artisan, without knowing the function of such an alteration, or having any indication as to the functional or structural implications of such an alteration, would have no motivation to introduce the alteration. SEQ ID NOs:94, 97, 100, and 106 each comprise a sequence 100% identical to nucleotides 1401-2078 of SEQ ID NO:103. As claim 51 requires sequences 100% identical to SEQ ID NOs:94, 97, 100, 103, or 106, claim 51 is free of the art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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18314671:
Claims 1-3, 5, 9, 12, 15-22, 34-35, 39-40, 43, 45, 49, 53, 58, 61-62, 64, 102, 110-111 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-10, 12-17, 87, 91-92, 106, 109, 113-114, 117-118, 120, 129, 131, 133, 142, 157, 167 of copending Application No. 18314671 (reference application), in view of Burns (WO2020077295A1; published 04/16/2020).
The copending claims recite all of the same limitations as the pending instant claims except for the AAV serotype from which the 5’ and 3’ ITRs are derived, and the sequence of the polynucleotide encoding a polypeptide.
Regarding claim 1, Burns teaches a construct, similar to that of the copending claims, comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes GJB2 (connexin-26) and the promoter is selective for a supporting cell (claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
Regarding claim 5, Burns teaches that the GJB2 mRNA has the sequence of NCBI accession number NM_004004, which is comprises a sequence 100% identical to SEQ ID NO:1 (see alignment below; Burns page 49).
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213
553
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Regarding claim 9, Burns teaches that the GJB2 mRNA has the sequence of NCBI accession number NM_004004, which encodes a protein of accession number QAU32547.1, which is 100% identical to the amino acid sequence of SEQ ID NO:7 (see alignment below; Burns page 49).
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208
566
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Regarding claim 45, Burns teaches that the 5’ and 3’ ITRs are AAV2 ITRs (claim 94).
Regarding claim 49, Burns teaches that the construct comprises the gene GJB2 and 5’ and 3’ UTR sequences (page 57 lines 12-16; page 49; claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85) (the known GJB2 mRNA sequence comprises the 5’ UTR sequence of SEQ ID NO:20 and the 3’ UTR sequence of SEQ ID NO:67, shown below, and SEQ ID NO:1, shown above).
Alignment of SEQ ID NO:20:
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328
678
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Alignment of SEQ ID NO:67:
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262
691
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Further regarding claim 49, Burns teaches that the construct comprises AAV ITR sequences known in the art (page 58 line 35-page 59 line 11; claims 89, 94). Alignments of SEQ ID NOs:8 and 9 to the known AAV2 reference sequence of accession number J01901.1, shown below, show that SEQ ID NOs:8 and 9 comprise the plus and minus strand of the AAV2 3’ ITR sequence. Burns teaches that the construct comprises AAV2 ITR sequences, specifically (claim 94). As such, the construct of Burns comprises SEQ ID NOs:8-9.
SEQ ID NO:8:
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342
679
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SEQ ID NO:9:
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323
683
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Regarding claim 110, Burns teaches that the coding sequence of a similar expression cassette encodes connexin 26 (claims 24-25, 28-37, 40-41, 46-47, 62-63, 66-75, 78-79, 84-85).
Given that the structure and function of the construct of Burns and of the copending claims overlap significantly (an expression construct, comprising a polynucleotide under the control of a supporting cell-specific promoter, used in methods of treating hearing loss), the use of specifically GJB2 as the coding sequence of the construct, to treat hearing loss associated with GJB2, as taught by Burns, would be an obvious modification to the copending claims. Furthermore, the teachings of Burns detailed above render obvious additional limitations to the copending claims which then render obvious the specific sequences of the 5’ and 3’ UTRs and ITRs of the polynucleotide construct of the pending instant claims, as the 5’ and 3’ UTR sequences are the non-coding regions of the GJB2 gene, and the 5’ and 3’ ITR sequences are known AAV2 ITR sequences. Burns teaches constructs in which the entirety of the GJB2 gene is comprised in the construct, and as such, the constructs of Burns comprise the 5’ and 3’ UTR sequences of the GJB2 gene. Burns also specifically teaches that the AAV2 ITR sequences allow for versatility in AAV vector serotype selection; as the copending claims require packaging of the construct in an AAV and require that the construct comprise AAV ITR sequences, it would be obvious for the AAV ITR sequences of the copending claims to be AAV2 ITR sequences, allowing for the selection of multiple different AAV vectors with different tropisms.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 42 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 8-10, 13, 92 of copending Application No. 18314671 and Burns (WO2020077295A1; published 04/16/2020), as applied to claims 1 and 40 above, and further in view of Post (US5122458A) and copending claims 129 and 131.
The claim limitations of the copending application render obvious the limitations of claims 1 and 40. However, the copending application does not require that the polyadenylation tail is bovine growth hormone polyA.
Post teaches that the bGHpA was known to be an effective polyadenylation signal for expression of transgenes in eukaryotes.
Regarding claim 42, Post teaches that bGHpA was an effective polyadenylation signal for use in eukaryotes, to enhance expression of a transgene (claim 1; abstract).
The copending claims recite that a polyadenylation signal is comprised in the polynucleotide construct. However, the copending claims do not specify the particular polyadenylation signal to be used. Post teaches that the bovine growth hormone polyadenylation signal is effective in enhancing expression of genes in eukaryotes; such a polyadenylation signal would be beneficial to use as the polyadenylation signal of the copending claims, as the methods of the copending claims (claims 129 and 131) are methods of expressing the polynucleotide construct in eukaryotic cells. As such, it would have been obvious to a person of ordinary skill in the art at the time of filing that the bGHpA of Post would be an optimal polyadenylation signal for use with the methods and compositions of the copending claims.
This is a provisional nonstatutory double patenting rejection.
18560064:
Claims 1-3, 5, 9, 12, 15-22, 34-35, 39-40, 42-43, 45, 49, 53, 58, 61-62, 64, 102, 110-111 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, 19-22, 62, 66, 69, 71, 81, 84-88, 90, 94, 98-99, 101, 111, 139, 144, 147, 149-150, 154, 177, 190, 241, 249, 263 of copending Application No. 18560064 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because, while the scope of the instant claims and the scope of the copending claims are different, the required limitations of the instant claims are recited or encompassed by the recited limitations of the copending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 42 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, 19, 22, 66 of copending Application No. 18560064, as applied to claims 1 and 40 above, and further in view of Post (US5122458A) and copending claims 249 and 263.
The claim limitations of the copending application render obvious the limitations of claims 1 and 40. However, the copending application does not require that the polyadenylation tail is bovine growth hormone polyA.
Post teaches that the bGHpA was known to be an effective polyadenylation signal for expression of transgenes in eukaryotes.
Regarding claim 42, Post teaches that bGHpA was an effective polyadenylation signal for use in eukaryotes, to enhance expression of a transgene (claim 1; abstract).
The copending claims recite that a polyadenylation signal is comprised in the polynucleotide construct. However, the copending claims do not specify the particular polyadenylation signal to be used. Post teaches that the bovine growth hormone polyadenylation signal is effective in enhancing expression of genes in eukaryotes; such a polyadenylation signal would be beneficial to use as the polyadenylation signal of the copending claims, as the methods of the copending claims 249 and 263 are methods of expressing the polynucleotide construct in eukaryotic cells. As such, it would have been obvious to a person of ordinary skill in the art at the time of filing that the bGHpA of Post would be an optimal polyadenylation signal for use with the methods and compositions of the copending claims.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 02/12/2026 have been fully considered but they are not persuasive.
Applicant argues that because the copending applications 18314671 and 18560064 have later filing dates, they are not proper ODP references, in view of Allergans USA, Inc. v MSN Labs. Pvt. Ltd. The MPEP is silent as to this case law. MPEP §804(I)(B)(1) states that “If two (or more) pending applications are filed, in each of which a rejection of one claimed invention over the other on the ground of provisional nonstatutory double patenting (NSDP) is proper, the provisional NSDP rejection will be made in each application.” MPEP §804(I)(B)(1)(b)(iii) states that if the application under examination has the earlier filing date, and the provisional nonstatutory double patenting rejection is the only rejection remaining, the NSDP rejection should be withdrawn. Thus the MPEP recognizes provisional NSDP rejections against later-filed applications as valid, and provides guidance for withdrawing such provisional NSDP rejections if the provisional NSDP rejections against later-filed applications are the only rejections remaining. Moreover, while Applicant argues that these provisional NSDP rejections are improper solely because the later-filed applications would not extend the patent term of the present application if issued, MPEP §804.02(IV) states that “Each one of the commonly owned conflicting nonstatutory double patenting references must be included in the terminal disclaimer to avoid the problem of dual ownership of patents to patentably indistinct inventions in the event that the patent issuing from the application being examined ceases to be commonly owned with any one of the double patenting references that have issued or may issue as a patent.” This makes clear that NSDP rejections serve to both prevent unjustified extension of patent exclusivity and conflicts of ownership and patent exclusivity rights. The above NSDP rejections will be maintained until such time as the pending claims and the copending claims are patentably distinct or the pending claims are in condition for allowance.
Conclusion
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636