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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This Action is in response to the papers filed on November 21, 2025. Pursuant to the amendment filed on November 21, 2025, claims 1, 10-14, 16-18, 22-23 and 31-33 are currently pending of which claims 1 has been amended, claim 2 and 8 have been cancelled, and claim 33 is new.
Therefore, claims 1, 10-14, 16-18, 22-23 and 31-33 are currently under examination to which the following grounds of rejection are applicable.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment to the claims dated November 21, 2025, wherein claim 1 has been amended and claims 2 and 8 have been cancelled, the rejection to claims 1, 10, 14, 16-18, 22-23, and 31 rejected under 35 U.S.C. 103 as being unpatentable over Cepko et al. (US 2016/0279265; of record IDS filed on August 23, 2024 (US-10,980,896-B2)) in view of Choi et al. (US 2014/0017201; provided in the Office Action dated May 6, 2024), have been withdrawn. The rejection to now cancelled claim 2 is rendered moot.
In view of Applicants’ amendment to the claims dated November 21, 2025, wherein claim 1 has been amended and claims 2 and 8 have been cancelled, the rejection to claims 1 and 11-13 rejected under 35 U.S.C. 103 as being unpatentable over Cepko et al. (US 2016/0279265; of record IDS filed on August 23, 2024 (US-10,980,896-B2)) in view of Choi et al. (US 2014/0017201; provided in the Office Action dated May 6, 2024) and further in view of Choi et al. (Molecular Brain 2014, 7:17; hereinafter ‘Choi-2’; provided in the Office Action dated May 6, 2024), have been withdrawn. The rejection to now cancelled claim 8 is rendered moot.
In view of Applicants’ amendment to the claims dated November 21, 2025, wherein claim 1 has been amended and claims 2 and 8 have been cancelled, the rejection to claim 32 rejected under 35 U.S.C. 103 as being unpatentable over Cepko et al. (US 2016/0279265; of record IDS filed on August 23, 2024 (US-10,980,896-B2)) in view of Choi et al. (US 2014/0017201; provided in the Office Action dated May 6, 2024) further in view of Promega. (“pCI and pSI mammalian expression vectors." Promega Notes 49.7 (1994). Revised 2009), has been withdrawn.
The withdrawn rejections is in view of Choi not teaching “the expression cassette comprising a human bestrophin 1 (hBest1) promoter, a chimeric intron, and a nucleic acid molecule encoding nuclear factor erythroid 2-like 2 (Nrf2), wherein the hBest1 promoter comprises nucleotides 4885-5507 of the nucleotide sequence of SEO ID NO:9, and wherein the chimeric intron comprises a 5'-donor site from the first intron of the human B-globin gene and the branch and 3' -acceptor site from the intron that is between the leader and the body of an immunoglobulin gene heavy chain variable region” as now recited in the amended claim 1.
Applicants' arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
New Grounds of Rejection:
Claim Rejections - 35 USC § 103
Claims 1, 10, 14, 16-18, 22-23, and 31-33 are newly rejected under 35 U.S.C. 103 as being unpatentable over Cepko et al. (US 2016/0279265; of record IDS filed on August 23, 2024 (US-10,980,896-B2)) in view of Choi et al. (US 2014/0017201; provided in the Office Action dated May 6, 2024), Petrukhin et al. (US Pub. No. 2006/0105364 A1; of record IDS filed on August 23, 2024), and Promega (“pCI and pSI mammalian expression vectors." Promega Notes 49.7 (1994). Revised 2009). This is a new rejection necessitated by Applicants' amendments to the claims in the response filed on November 21, 2025.
Regarding claim 1 and claim 33, Cepko teaches a composition, comprising an adeno-associated virus (AAV) expression cassette (“compositions comprising a viral vector comprising a retinal cell-type specific promoter operably linked to a nucleic acid molecule encoding Nrf2.” (par 0029); “the viral vector is capable of directing expression of the nucleic acid preferentially in a particular cell type. (par 0149); “the viral vector for use in the methods of the present invention is an AAV vector.” (par 0147)), the expression cassette comprising a tissue specific promoter (“a tissue-specific promoter for use in the vectors and methods of the invention is a retinal cell-specific promoter. In one embodiment, a retinal cell-specific promoter is a rod-, cone-, and bipolar cell-specific promoter” (par 0149)), a chimeric intron (“include a CMV promoter and a beta-globin intron constructed with anti-oxidation genes” (par 0042); Instant specification describes “the chimeric intron comprises a 5' -donor site from the first intron of the human β-globin gene” (p 4, line7-8)), and a nucleic acid molecule encoding nuclear factor erythroid 2-like 2 (Nrf2) (“compositions comprising a viral vector comprising a retinal cell-type specific promoter operably linked to a nucleic acid molecule encoding Nrf2.” (par 0029)).
Cepko does not teach “wherein the hBest1 promoter comprises nucleotides 4885-5507 of the nucleotide sequence of SEO ID NO:9, and wherein the chimeric intron comprises a 5'-donor site from the first intron of the human B-globin gene and the branch and 3' -acceptor site from the intron that is between the leader and the body of an immunoglobulin gene heavy chain variable region”.
Choi teaches a composition comprising viral vectors, particularly recombinant adeno-associated viral vectors, that are capable of delivering a heterologous gene to the retina; wherein the promoter is a tissue specific promoter such as VMD2 (abstract, par 0029, 0033). The instant specification describes bestrophin 1(hBest1) is used interchangeably with VMD2 (p 16, line 28-30). Choi teaches expression of vectors comprising the VMD2 promoter revealed expression in RPE cells and photoreceptors (0162).
Choi teaches the promoter comprises 99% nucleotide identity to nucleotides 4885-5507 of SEQ ID NO:9 as seen in the alignment below between instant SEQ ID NO: 9 and Choi’s SEQ ID NO: 12 (the VMD2 Promoter).
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A STIC Sequence Search of nucleotides 4885-5507 of the nucleotide sequence of SEO ID NO:9 resulted in 100% similarity with Petrukhin et al. (US 2006/0105364 A1), particularly with SEQ ID NO: 1. The reference states, “CG1CE, which, when mutated, is responsible for Best's macular dystrophy.” (abstract). SEQ ID NO: 1 is the genomic DNA sequence of human CG1CE. A full search alignment listed as Result #27 is provided with the Office Action
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Cepko in view of Choi and Petrukhin teach a β-globin intron following the CMV promoter (para 0042).
Cepko in view of Choi and Petrukhin do not explicitly teach wherein the chimeric intron comprises a 5'-donor site from the first intron of the human B-globin gene and the branch and 3' -acceptor site from the intron that is between the leader and the body of an immunoglobulin gene heavy chain variable region, which is listed as nucleotides 1120-1252 of the nucleotide sequence of SEQ ID NO:21 based on Figure 19 and the Specification.
Promega teaches the pCI mammalian expression vector that comprises a chimeric intron at nucleotides 857-989 that is “composed of the 5´-donor site from the first intron of the human β-globin gene and the branch and 3´-acceptor site from the intron that is between the leader and the body of an immunoglobulin gene heavy chain variable region” (p 3; Sec. 5.8). The chimeric intron is described as being responsible for increasing gene expression by a high level for all cDNA inserts. (Sec. 5.8)
SEQ ID NO 21, nt 1120-1252 aligned to Promega plasmid vector, pCI (Accession ID: U47119.2):
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the promoter and chimeric intron of the AAV composition taught by Cepko to that of the promoter taught by Choi in view of Petrukhin, and the chimeric intron taught by Promega, particularly because (1) Choi teaches AAV vectors comprising the VMD2 promoter revealed expression in RPE cells and photoreceptors which are relevant for gene therapy treatment of degenerative ocular disorder, e.g., retinitis pigmentosa, and because (2) Promega teaching the chimeric intron as responsible for driving gene expression within a mammalian expression vector, and therefore there is a reasonable expectation such AAV vector would be expressed in mammalian cells. Moreover, the combination of elements which were all known prior to effective filing date of the claimed invention would have a reasonable expectation as functioning similarly when incorporated in the AAV vector taught by Cepko.
Regarding claim 10, dependent on claim 1, Cepko teaches wherein the expression cassette further comprises a post-transcriptional regulatory region (“contain numerous regulatory signals, including transcriptional control elements, polyadenylation signals, and sequences needed for replication and integration of the viral genome.” (par 0086).
Regarding claim 14, dependent on claim 1, Cepko teaches wherein the expression cassette is present in a vector (“the nucleic acid molecule is contained within a vector.” (par 0020); “the nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors.” (par 0154)).
Regarding claim 16, dependent on claim 1, Cepko teach an AAV particle comprising the composition of claim 1, as rejected above (“In a particular embodiment, the nucleic acid molecules and/or vectors are incorporated in a composition suitable for intraocular administration. … to effectively treat the retinal disorder.” (par 0167); “In one embodiment, nasal inhalants are used with an aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound” (0206)). See also para. [0231])
Regarding claim 17, dependent on claim 16, Cepko teaches an isolated cell comprising the AA V particle of claim 16 (par 0101).
Regarding claim 18, dependent on claim 1, Cepko teaches a pharmaceutical composition comprising the AAV composition of claim 1 or particle of claim 16 (par 0165).
Regarding claim 22, Cepko teaches a method for prolonging the viability of a photoreceptor cell compromised by a degenerative ocular disorder, comprising contacting said cell with the composition of claim 1 thereby prolonging the viability of the photoreceptor cell compromised by the degenerative ocular disorder (Cepko claim 2).
Regarding claim 23, Cepko teaches a method for treating or preventing a degenerative ocular disorder in a subject, comprising administering to said subject a therapeutically effective amount of the composition of claim 1 thereby treating or preventing said degenerative ocular disorder (Cepko claim 3).
Regarding claim 31, dependent on claim 16, Cepko teaches a pharmaceutical composition comprising the AAV composition of claim 1 or particle of claim 16 (par 0165).
Regarding claim 32, dependent on claim 1, the rejection to claim 1 makes obvious wherein the chimeric intron comprises nucleotides 1120-1252 of the nucleotide sequence of SEQ ID NO:21, particularly Promega teaches this sequence and related function.
Claims 1, 11-13 are newly rejected under 35 U.S.C. 103 as being unpatentable over Cepko et al. (US 2016/0279265; of record IDS filed on August 23, 2024 (US-10,980,896-B2)) in view of Choi et al. (US 2014/0017201; provided in the Office Action dated May 6, 2024), Petrukhin et al. (US Pub. No. 2006/0105364 A1; of record IDS filed on August 23, 2024), and Promega (“pCI and pSI mammalian expression vectors." Promega Notes 49.7 (1994). Revised 2009), as applied to claim 1, and further in view of Choi et al. (Molecular Brain 2014, 7:17; hereinafter ‘Choi-2’; provided in the Office Action dated May 6, 2024). This is a new rejection necessitated by Applicants' amendments to the claims in the response filed on November 21, 2025.
Regarding claim 1, the disclosure of Cepko in view of Choi, Petrukhin, and Promega is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 11-13, dependent on claim 1, Cepko in view of Choi, Petrukhin, and Promega teach post-transcriptional control elements (“LTRs contain numerous regulatory signals, including transcriptional control elements, polyadenylation signals, and sequences needed for replication and integration of the viral genome.” (Cepko par 0086); “the gene cassette may include regulatory elements operably linked to the heterologous gene. These regulatory elements may include appropriate transcription initiation, termination, promoter and enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation (polyA) signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency; sequences that enhance protein stability;” (Choi par 0075)).
Cepko in view of Choi, Petrukhin, and Promega do not teach wherein the expression cassette further comprises a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) [in reference to claim 11]; wherein the expression cassette further comprises a post-transcriptional regulatory region comprising nucleotides 3110-3651 of the nucleotide sequence in Figure 19 (SEQ ID NO:21) that is about 99% identical [in reference to claim 12]; and wherein the expression cassette further comprises a post-transcriptional regulatory region comprising the nucleotide sequence of SEQ ID NO: 18 [in reference to claim 13].
Choi-2 teaches adeno-associated virus (AAV) vectors for the delivery of transgenes for specific cell types for use in gene therapy (abstract), in which the AAV expression cassette utilizes a woodchuck hepatitis post-transcriptional regulatory element (WPRE) (Figure 1). The reference teaches the “WPRE is a 600 bp long tripartite element containing gamma, alpha, and beta elements, in the given order and contributes to the strong expression of transgenes in AAV systems” (p 2, col 1, par 3). Choi-2 teaches an expression cassette that comprises a post-transcriptional regulatory region that is 99% identical to nucleotides 3110-3651 of the nucleotide sequence in Figure 19 (SEQ ID NO:21) as seen below. Lastly, Choi-2 teaches an expression cassette that comprises a post-transcriptional regulatory region that is 99% identical to SEQ ID NO:18 as seen below.
SEQ ID NO 21, nt 3110-3651 aligned to Choi-2 plasmid vector, KJ411911.1:
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SEQ ID NO 18 aligned to Choi-2 plasmid vector, KJ411911.1:
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV composition comprising post-transcriptional regulatory elements (PREs) taught by Cepko in view of Choi, Petrukhin, and Promega to further describe the PREs as comprising WPRE, based on the teaching by Choi-2 that WPREs contributes to strong transgene expression.
Response to Applicants’ Arguments as they apply to rejections of:
Claims 1, 2, 10, 14, 16-18, 22, 23, and 31 rejected under 35 USC § 103 for being obvious over Cepko in view of Choi.
Claims 1, 8, 11-13 rejected under 35 USC § 103 for being obvious over Cepko in view of Choi, as applied to claim 1, and further in view of Choi et al (Choi-2).
Claims 32 rejected under 35 USC § 103 for being obvious over Cepko in view of Choi, as applied to claim 1, and further in view of Promega.
Starting on page 5 of the remarks filed on November 21, 2025, Applicants essentially argue the following:
“Applicants respectfully submit that the amended claims are not obvious in view of Cepko and Choi at least because the combination of references fails to teach or suggest every element of the amended claims. In particular, neither of the cited references teach or suggest an hBest1 promoter comprising nucleotides 4885-5507 of the nucleotide sequence of SEQ ID NO:9. As noted in MPEP § 2143.03, "[e]xaminers must consider all claim limitations when determining patentability of an invention over the prior art."”.
Applicant argues for unexpected results and unexpected advantages when the invention is put into practice: “In particular, Applicants have shown that there is a strong correlation between toxicity and the promoter used in the AAV vectors. Specifically, Applicants have shown that AAVs incorporating an RPE-specific promoter, the human Best1 promoter, were found to induce RPE toxicity in mice (see, e.g., Figures 3A-3C), while none of the photoreceptor-specific promoters induced RPE toxicity (see, e.g., Figure 2B). To overcome the toxicity associated with the hBestl promoter, Applicants have made the efforts to identify the critical elements that reduce this toxicity while maintaining pharmacological activity and, have developed the specifically claimed AAV vector comprising the specific combination of elements, i.e., a hBest1 promoter, a chimeric intron and Nrf2 (see, e.g., Example 3, Figures 14 and 15). Specifically, Applicants have shown that administration of this AAV construct to B6.CXB1-Pde6brd10/J, rd10 mice, i.e., one of the most used models of retinitis pigmentosa, delayed progression of loss of functional vision as assessed by optomotor response (Figure 18A), photopic ERG (Figure 18B), and cone marker (Figure 18C) as compared with the vehicle group.”
In response to the argument it has been fully considered but is not persuasive due to the following reasons:
Response to the first argument: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Cepko teaches all the limitations presented in claim 1, except the hBest1 promoter as seen in Cepko teaching using a CMV promoter. The second reference of Choi remedies the lack of teaching of the claimed hBest1 promoter of Cepko, wherein Choi teaches the hBest1 promoter that comprises 99% nucleotide identity to the nucleotides -585 to +38 of the hBest1 gene as seen in the alignment provided above between instant SEQ ID NO: 9 and Choi SEQ ID NO: 12 (the VMD2 Promoter). The new rejection set forth includes Petrukhin et al. that teaches the full sequence claimed, and states this version is related to a mutated version responsible for Best's macular dystrophy. Furthermore, the amended claim 1 has incorporated the chimeric intron recited in claim 32 albeit without sequence alignments, yet Promega teaches this chimeric intron as described in previous Office Action. Altogether, the combination of these references make obvious the limitations presented in claim 1.
Response to second argument, as it concerns unexpected results, MPEP 716.02 states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).” In the instant case, the claim has not identified the critical elements of the hBest1 promoter and chimeric intron that reduce toxicity while maintaining pharmacological activity of the AAV8 expression cassette as illustrated in Figure 2B, e.g., AAV8-hRK-Zs Green. The examiner acknowledges the claim has been amended to fully recite the human bestrophin 1 (hBest1) promoter as listed in SEQ ID NO: 9 at nucleotides 4885-5507. However, the chimeric intron is not fully elucidated in the claim. Applicants’ states, “Applicants have shown that administration of this AAV construct to B6.CXB1-Pde6brdl0/J, rdlO mice, i.e., one of the most used models of retinitis pigmentosa, delayed progression of loss of functional vision as assessed by optomotor response (Figure 18A), photopic ERG (Figure 18B), and cone marker (Figure 18C) as compared with the vehicle group.” (Remarks p 10). In order for the unexpected results to be persuasive they must be commensurate in scope with the claims, and as the claims are currently recited without the identification of the critical elements on the hBest1 promoter and chimeric intron they are not persuasive.
Conclusion
Claims 1, 10-14, 16-18, 22-23 and 31-33 are rejected. No claims are allowed. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634