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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 08/19/2025 is acknowledged. Claims 120 and 132 were cancelled. Claims 119,130 and 133 were amended. Claims 141-148 are new. Claims 119,121-131,133,136-148 are pending. Claims 119-129 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 treated without traverse in the reply filed on 01/08/2025. Claims 130,131,133 and 136-148 are directed to the elected invention and are under examination.
In the office action mailed 03/19/2025, the examiner indicated that SEQ ID NOs: 100-103 were free of the art. Upon further consideration, the examiner is issuing a second non-final rejection based on a case of obviousness regarding using SEQ ID NOs:100-103 in the recited methods.
Response to Arguments
Applicant’s arguments and amendments, see page 6, filed 08/19/2025, with respect to the objection to the Figures 16-18, and the objection to claim 130, have been fully considered and are persuasive. The objection to Figures 16-18 have been withdrawn due to the submission of replacement sheets for Figures 16-18 more clearly showing the content of the figures, and the objection to Claim 130 is withdrawn due to the amendment reciting the fully gene name, “rhodopsin”.
Applicant’s arguments and amendments, see pages 6-7, filed 08/19/2025, with respect to the Scope of Enablement rejection of claims 130-133 and 136-140 have been fully considered and are persuasive. Therefore, the 35 U.S.C. 112(a) Scope of Enablement rejection of claims 130-133 and 136-140 has been withdrawn, due to the amendments to claim 130 reciting the method occurring in vitro or ex vivo, and reciting the first targeting domain comprises a sequence that is the same as, or differs by no more than 3 nucleotides from, a sequence selected from the group consisting of SEQ ID NOs: 100-103.
Applicant’s arguments and amendments, see page 7, filed 08/19/2025, with respect to the 35 U.S.C. 102(a)(1) rejections of claims 130 and 131 as anticipated by Tsai et al. and claims 130 and 131 anticipated by WO 2015195621 and claims 130-132 as anticipated by WO 2014186585 have been fully considered and are persuasive. Therefore the rejections have been withdrawn, as applicant has amended claim 130 to recite the first targeting domain comprises a sequence that is the same as, or differs by no more than 3 nucleotides from, a sequence selected from the group consisting of SEQ ID NOs: 100-103 which is not taught in the above references. However, upon further consideration, a new ground(s) of rejection is made in view of a case of obviousness regarding the instantly claimed first targeting domain sequences of the gRNA molecule.
Applicant’s arguments and amendments, see page 8, filed 08/19/2025, with respect to the 35 U.S.C 103 rejection of claims 133 and 136-140 as unpatentable over WO 2014186585 in view of Tsai et al. have been fully considered and are persuasive. Therefore, the rejection has been withdrawn due to the amendment to claim 130 reciting the first targeting domain comprises a sequence that is the same as, or differs by no more than 3 nucleotides from, a sequence selected from the group consisting of SEQ ID NOs: 100-103 which is not taught in the above references. However, upon further consideration, a new ground(s) of rejection is made in view of a case of obviousness regarding the instantly claimed first targeting domain sequences of the gRNA molecule.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 130 and 131 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014186585 (‘585) in view of Guo et al. (Journal of Human Genetics (2010) 55, 571-576) as evidenced by NCBI Reference Sequence NM_000539.3.
Regarding claims 130-131, ‘585 teaches methods of modifying an endogenous gene which may be a rhodopsin (RHO) gene, comprising administering to the cell a first nucleic acid molecule comprising a single guide RNA that recognizes a target site in the endogenous gene and a second nucleic acid that encodes a functional domain which associates with the sgRNA on the target site, thereby modifying the endogenous gene (paragraph 0022). ‘585 teaches a CRISPR/Cas system that binds to a target site in a region of interest in an endogenous gene wherein the CRISPR/Cas system comprising one or more engineered sgRNAs that recognize the target gene and a functional domain (e.g. a nuclease domain) (paragraphs 0016,0018), and teach the Cas nucleases are Cas9 nucleases (paragraphs 0025-0027). ‘585 teaches the methods and compositions of the invention may be used to disrupt a RHO allele with a CRISPR/Cas system where the single guide RNA comprises sequences to target a human RHO gene, and that targeting specific locations are useful for gene correction, and preferred target locations include exon 1 and exon 5 (paragraph 0070).
‘585 teaches guide RNAs for use with the CRISPR/Cas system and that cells of interest are contacted with the sgRNAs in Table 1 (paragraph 0221, pages 81-82). ‘585 teaches sgRNA sequences targeting human RHO of SEQ ID NOs: 184-186 and which are 23 nucleotides in length (Table 2, page 84).
‘585 does not teach wherein the first targeting domain of the first gRNA molecule comprises a sequence that is the same as, or differs by no more than 3 nucleotides from a sequence selected from the group consisting of SEQ ID NOs: 100-103.
However, before the effective filing date, Guo et al. taught the mRNA sequence of the rhodopsin gene was publicly available as evidenced by NCBI Reference Sequence NM_000539.3. The human RHO gene sequence (NM_000539.3) was taught by Guo et al. (page 63, left column) more than one year prior to the effective filing date of the instant application. The human RHO mRNA sequence of NM_000539.3 is shown below.
PNG
media_image1.png
804
518
media_image1.png
Greyscale
As seen in the alignment below, a BLAST of instant SEQ ID:100 aligns with nucleotides 74-95 of the RHO mRNA sequence of NM_000539.3.
PNG
media_image2.png
216
478
media_image2.png
Greyscale
Alignment of instant SEQ ID NO: 101 to the sequence of NM_000539.3 (Qy is instant SEQ ID NO: 101, Db is NM_000539.3):
PNG
media_image3.png
69
307
media_image3.png
Greyscale
Alignment of instant SEQ ID NO: 102 to the sequence of NM_000539.3 (Qy is instant SEQ ID NO: 102, Db is NM_000539.3):
PNG
media_image4.png
82
304
media_image4.png
Greyscale
Alignment of instant SEQ ID NO: 103 to the sequence of NM_000539.3 (Qy is instant SEQ ID NO: 103, Db is NM_000539.3):
PNG
media_image5.png
76
304
media_image5.png
Greyscale
As shown above, instant SEQ ID NOs: 100-103 target different regions of the RHO sequence.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to choose any of the 22 nucleotide regions of the target RHO gene sequence and to produce gRNA target sequences that target these nucleotide regions to arrive at the gRNA sequences of instant SEQ ID NOs: 100-103 for use in the method of altering a cell with a reasonable expectation of success. There would be a reasonable expectation of success, because Guo et al. teach the RHO mRNA sequence was known before the effective filing date, and alignment of the instant sequences with the RHO mRNA sequences is shown to align with different regions of the RHO gene. One of ordinary skill in the art would have been motivated to provide a guide RNA of any of SEQ ID NOs: 100-103 for use in the method of ‘585, because ‘585 teaches the methods and compositions of the invention may be used to disrupt a RHO allele with a CRISPR/Cas system where the single guide RNA comprises sequences to target a human RHO gene, and that targeting specific locations are useful for gene correction, (paragraph 0070) and would make obvious the limitations of claims 130 and 131.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 133 and 136-148 are rejected under 35 U.S.C. 103 as being unpatentable over ‘585 and Guo et al. as evidenced by NCBI Reference Sequence NM_000539.3 as applied to claims 130 and 131 above, and further in view of Tsai et al. (Ophthalmol. 125(9): 1421-1430 September 2018), cited in prior office action.
The teachings of ‘585 and Guo et al. as evidenced by NCBI Ref. Seq. NM_000539.3 as applicable to claims 130 and 131 are described above.
In addition, ‘585 teaches “In relation to RP, more than 80 mutations in the rhodopsin gene have been identified that account for 30% of all Autosomal Dominant Retinitis Pigmentosa (ADRP) in humans. Three point mutations in the human rhodopsin gene (leading to P23H, Q64X and Q344X in the protein sequence) are known to cause ADRP in humans. The P23H mutation is the most common rhodopsin mutation in the United States. Due to problems with protein folding, P23H rhodopsin only partially reconstitutes with retinal in vitro, and mutant rhodopsin expressed in transgenics causes retinal degeneration. Thus, the methods and compositions of the invention may be used to disrupt a RHO allele with a CRISPR/Cas system where the single guide RNA comprises sequences to target a human RHO gene (paragraph 0070).
‘585 and Guo et al. as evidenced by NCBI Ref. Seq. NM_000539.3 do not teach wherein the nucleic acid of (a) or (b) further comprises (c) a RHO cDNA molecule, and do not teach a method of altering a retinal cell in vivo comprising delivering to the cell via subretinal injection an AAV vector comprising the nucleic acid sequence that encodes a first gRNA molecule and a nucleic acid comprising a sequence that encodes an RNA-guided nuclease molecule operably linked to a rod-specific promoter.
However, before the effective filing date, Tsai et al. teach an “ablate and replace” strategy that destroys expression of all endogenous chromosomal Rho genes in a mutation independent manner using an improved CRISPR/Cas9 based gene ablation technique, and enables expression of wild-type protein through exogenous cDNA (page 3, second paragraph). Tsai et al. teach using an expression cassette, AAV-GR, which comprises two gRNA expressing cassettes and an mRho promoter-driven hRHO cDNA expressing cassette cloned into a vector, and an AAV-Cas9 expression cassette (page 3), in which the gRNAs target sequences in exon 1 of mouse Rho (Results pg 5). Tsai et al. teach all components were cloned into two AAV vectors, where Cas9 was packaged into one vector and the dual gRNA expression cassettes and human RHO cDNA driven by an mRho promoter were cloned in another AAV vector, and gene ablation could only occur in any cells that took up both vectors, while gene replacement could occur in any rod photoreceptors that took up just the hRHO cDNA containing vector, and teach subretinal injection into the eye (page 6). Tsai et al. teach that the in vivo AAVs-Cas9+GR-mediated gene ablation leads to decreased endogenous mRho levels in photoreceptors and rod cells, and that dual AAV ablate-and-replace combination system has therapeutic efficacy in treating dominant retinal degenerative disorders (page 7), and the ablate-and-replace combination leads to significantly greater survival of functioning photoreceptors, and is mutation-independent (page 8). Tsai et al. teach gene replacement driven by a native Rho promoter has higher safety and durability in patients compared to using a ubiquitous promoter (page 9, first paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the nucleic acid molecule used in the method of ‘585 and Guo et al. as evidenced by NM_000539.3, with the teachings of Tsai et al. regarding the RHO cDNA and arrangement of the AAV vectors to arrive at the instant claims with a reasonable expectation of success, as it would have amounted to applying a known technique (the method of Tsai et al.) to a known method (the method of ‘585) ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to modify the nucleic acid molecule used in the method of ‘585 and Guo et al. as evidenced by NM_000539.3, to comprise an RHO cDNA molecule in the nucleic acid molecule comprising the sequence encoding the gRNA molecule and that the nucleic acid molecules are AAV vectors, and that the cell is a retinal cell, because Tsai et al. teach an ablate-and-replace method using one AAV vector encoding Cas9 and another AAV vector encoding gRNA and RHO cDNA, and that the ablate-and-replace combination leads to significantly greater survival of functioning photoreceptors, and is mutation-independent, and has therapeutic efficacy in treating dominant retinal degenerative disorders and would make obvious the limitations of claims 133 and 136-138.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have to have modified the nucleic acid molecule used in the method of ‘585 and Guo et al. as evidenced by NM_000539.3, with the teachings of Tsai et al. to arrive at the instant claims with a reasonable expectation of success, as it would have amounted to applying a known technique (the method of Tsai et al.) to a known method (the method of ‘585) for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to modify the nucleic acid molecule used in the method of ‘585 to comprise a promoter operably linked to either the RNA-guided nuclease molecule, the RHO cDNA molecule or both, and for the promoter to be a rod-specific promoter, because Tsai et al. teach two AAV vectors, where Cas9 was packaged into one vector and the dual gRNA expression cassettes and human RHO cDNA driven by an mRho promoter were cloned in another AAV vector, and that gene ablation could only occur in any cells that took up both vectors, while gene replacement could occur in any rod photoreceptors that took up just the hRHO cDNA containing vector, and would make obvious the limitations of claims 139 and 140.
It would have been obvious to use the nucleic acid molecule of ‘585 and Guo et al. as evidenced by NM_000539.3 in an in vivo method as taught by Tsai et al. to arrive at the instant claims with a reasonable expectation of success, as it would have amounted to applying a known technique (the method of Tsai et al.) to a known method (the method of ‘585) for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to alter a retinal cell in vivo comprising delivering to the cell via subretinal injection an AAV vector comprising the nucleic acid molecules of ‘585 and Guo et al. as evidenced by NM_000539.3, because ‘585 teaches the methods and compositions of the invention may be used to disrupt a RHO allele with a CRISPR/Cas system where the single guide RNA comprises sequences to target a human RHO gene, and that targeting specific locations are useful for gene correction, (paragraph 0070). In addition, Tsai et al. teach two AAV vectors, where Cas9 was packaged into one vector and the dual gRNA expression cassettes and human RHO cDNA driven by an mRho promoter were cloned in another AAV vector subretinal injection into the eye (page 6). Tsai et al. teach that the in vivo AAVs-Cas9+GR-mediated gene ablation leads to decreased endogenous mRho levels in photoreceptors and rod cells, and that dual AAV ablate-and-replace combination system has therapeutic efficacy in treating dominant retinal degenerative disorders (page 7), and the ablate-and-replace combination leads to significantly greater survival of functioning photoreceptors, and is mutation-independent (page 8). One of ordinary skill in the art would be motivated to carry out the method wherein a RHO cDNA is operably linked to a rod-specific promoter because Tsai et al. teach gene replacement driven by a native Rho promoter has higher safety and durability in patients compared to using a ubiquitous promoter (page 9, first paragraph).
Accordingly, the limitations of claims 140-148 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 130-133 and 136-148 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 183-188 of copending Application No. 18/555,716 (‘716) (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 130 recites a method of altering a cell in vitro or ex vivo comprising contacting the cell with (a) a nucleic acid comprising a sequence that encodes a first gRNA molecule comprising a first targeting domain sequence that is complementary to a first target domain sequence of a RHO gene wherein the first targeting domain comprises a sequence that is the same as or differs by no more than 3 nucleotides from a sequence selected from the group consisting of SEQ ID NOs: 100-103 and (b) a nucleic acid comprising a sequence that encodes an RNA-guided nuclease molecule and instant claim 131 recites the RNA-guided nuclease is a Cas9 molecule. Claim 183 of ‘716 recites a method of altering a cell comprising contacting the cell with a pharmaceutical composition comprising a first nucleic acid comprising a sequence encoding an RNA-guided nuclease; and a second nucleic acid comprising a sequence encoding a first guide RNA comprising a first targeting domain that is complementary to a target domain in the RHO gene and a RHO complementary DNA, and claim 184 of ‘716 recites SEQ ID NOs: 100-502 which are the same sequences as SEQ ID NOs: 100-103 recited in claim 130 of ‘716.
Instant claims 133 and 143 recite the nucleic acid of (a) or (b) further comprises (c) a RHO cDNA molecule and instant claims 136 and 144 recite that (b) is present in the first nucleic acid molecule and (a) and (c) are present on the second nucleic acid molecule, while claim 183 of ‘716 as described above recites the RHO cDNA is in the second nucleic comprising the targeting domain complementary to a target domain in the RHO gene. Both instant claims 137 and 146 and claim 186 of ‘716 recite viral vectors.
Instant claims 139-140 and 145 recite the sequence encoding the RNA-guided nuclease, the RHO cDNA molecule, or both are operably linked to a promoter, and wherein the promoter is a rod-specific promoter, while claim 187 of ‘716 recites the first nucleic acid comprises a promoter operably linked to the sequence encoding the RNA-guided nuclease, and claim 188 recites the second nucleic acid comprises a promoter linked to the RHO cDNA.
Therefore the instant methods of claims 130-133 and 136-148 are not patentably distinct from the methods of claims 183-188 of ‘716.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues on page 8 of the response that claim 130 has been amended to recite “wherein the first targeting domain comprises a sequence that is the same as, or differs by no more than 3 nucleotide from, a sequence selected from the group consisting of SEQ ID NOs: 100-103”, thereby rendering the rejection moot.
This is not found persuasive, because the copending ‘716 application still has claims reciting SEQ ID NOs: 100-103. While the examiner indicated SEQ ID NOs: 1-3 were free of the art, the examiner meant free of the prior art, but this does not pertain to the double patenting rejection which recites the same sequences that are instantly claimed. Therefore, the rejection is maintained.
Conclusion
Claims 130,131,133 and 136-148 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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, Ram R Shukla can be reached on 571-272-0735. 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.
/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636