DETAILED ACTION
Claims 1-18 of the claim set filed March 7, 2025 are pending. Claims 14-16 are withdrawn. Claims 1-13 and 17-18 are being examined on the merits herein.
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 .
Election/Restrictions
Applicants’ election of Group I claims 1-13 and 17-18 in the reply filed on June 23, 2026 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Thus, claims 14-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-13 and 17-18 will be examined on the merits herein.
Priority
A claim for benefit of a prior-filed application under 35 U.S.C. 119(a)-(f) or under 35
U.S.C. 120, 121, 365(a)-(c), 386 (a) or 386(c) has been made. The effective filing date of the
present application is 9/16/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/13/2024 and 6/23/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Double Patenting
Claims 1, 2, 5, 8, 9, 10, 12, and 13 are rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 3, and 4 of Univ of Florida (U.S. Patent No. 2017/0356009 A1, published Dec 14, 2017; PTO 892) (i.e., reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1, 3, and 4 of Univ of Florida, in view of Ling (Ling et al., Journal of Virology (2015) 89(2); PTO 892), make obvious claims 1, 2, 5, 8, 9, 10, 12, and 13 of the instant application. Claim 9 is made unpatentable as being made obvious by Univ of Florida in view of Ling, as evidenced by Kuz (Kuz et al., Viruses (2024) 16, 1215; PTO 892).
Claim 1 of the instant application requires: An adeno-associated virus (AAV) particle comprising a nucleic acid vector, wherein the nucleic acid vector comprises a 5' inverted terminal repeat (ITR) comprising a myoblast determination protein (MyoD) binding site and/or myocyte enhancer factor (MEF) binding site.
Claim 1 of the reference application requires: A recombinant adeno-associated virus (rAAV) particle, comprising: a viral capsid encapsidating a nucleic acid vector, wherein the nucleic acid vector comprises a glucocorticoid receptor responsive element and/or a transcription factor binding site inserted within an inverted terminal repeat (ITR).
Claim 3 of the reference application requires: The rAAV particle of claim 1 or 2, wherein the transcription factor binding site is a transcription factor binding site for a transcription factor described in Table 1, i.e., MyoD and Mef.
Thus, the reference application differs in that the claims of said application do not per se teach of MyoD and/or MEF binding sites within the 5’ ITR. However, this is made obvious by the teachings of Ling.
Ling teaches enhanced transgene expression from recombinant single-stranded D-sequence-substituted AAV vectors (Abstract). Ling teaches of the removal of the D sequence and replacement with a sequence containing putative binding sites for transcription factors in single-stranded AAV vectors significantly augments transgene expression (Abstract).
Ling teaches both WT and rAAV genomes contain inverted terminal repeats (ITRs) of 145 nucleotides (nt) at both ends. The terminal 125 nucleotides in each ITR form a palindromic double-stranded T-shaped hairpin structure, in which the A-A′ palindrome forms the stem and the two smaller palindromes, B-B′ and C-C′, form the cross-arms of the T. The other 20 nucleotides (i.e., the D sequence) in the ITR remain single stranded. The ssD[−] sequence is always at the 3′ end, whereas the complementary one, the ssD[+] sequence is invariably at the 5′ end (p952 last paragraph – p953 1st paragraph).
Ling teaches of ssD+ (i.e., 5’) sequence substituted ssAAV genomes can be successfully packaged into rAAV vectors and that the transduction efficiency of these vectors is significantly higher than that of conventional ssAAV vectors (p953, 1st column, 1st full paragraph). Ling teaches of the insertion of binding sites for 2 transcription factors (p959, 1st column, 1st paragraph).
Thus, it would have been obvious to a POSITA, before the EFD of the claimed invention, to combine the teachings of Ling and Univ of Florida (i.e., reference application). As both teach of the inclusion of transcription factor binding sites within the ITR and Ling further teaches of significantly augmented transgene expression by inserting said transcription factor binding sites into the D+ sequence, i.e., the 5’ ITR, a POSITA would have been motivated to place said transcription factor binding sites within the 5’ ITR. A POSITA would have had a reasonable expectation of success in combining said teachings due to both Univ of Florida (reference application) and Ling teaching of ITRs with transcription factor binding sites incorporated within.
Thus, the reference application, in view of Ling, makes obvious claim 1 of the instant application.
In regards to claim 2 (teaching the 5’ ITR comprises a MyoD binding site), claim 5 (teaching the 5’ ITR comprises a MEF binding site), and claim 8 (teaching wherein the 5’ ITR comprises a MyoD and MEF binding site), Examiner notes Univ of Florida (i.e., reference application) in view of Ling makes obvious said claims. As Univ of Florida (reference application) teaches of both MyoD and Mef transcription factor binding sites (i.e., Table 1 claim 3) and Ling teaches of 2 transcription factor binding sites being incorporated into the 5’ ITR D+ sequence as discussed supra, Univ of Florida (reference application) in view of Ling thus makes obvious claims 2, 5, and 8 of the instant application.
In regards to claim 9 (teaching wherein the MyoD and/or MEF binding site are comprised upstream from the trs of the ITR), said claim is made obvious by the reference application in view of Ling as evidenced by Kuz. As is evidenced by Kuz, Fig 2, the D sequence is upstream from (5’ relative to) the terminal resolution site (TRS) of the ITR.
Fig 2
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As Ling teaches substituting the D sequence with transcription factor binding sites, Ling thus teaches said binding sites are comprised upstream from (5’ relative to) the TRS of the ITR.
Claim 10 of the instant application further requires the nucleic acid vector comprises a transgene. Said claim is made obvious by reference application claim 4 which states: wherein the nucleic acid vector further comprises a heterologous nucleic acid region comprising a sequence encoding a protein or polypeptide of interest or RNA of interest (i.e., a transgene).
Claim 12 of the instant application is made obvious by the reference application in view of Ling as Ling teaches of AAV2 (i.e., serotype 2) (Abstract).
Claim 13 of the instant application is made obvious by the reference application in view of Ling as Ling teaches the AAV2 vectors were injected intravenously in a phosphate-buffered saline, i.e., a composition in a pharmaceutically acceptable carrier (p954, 5th paragraph).
Therefore, claims 1, 3, and 4 of Univ of Florida, in view of Ling, make obvious claims 1, 2, 5, 8, 9, 10, 12, and 13 of the instant application.
Claims 6 and 7 are rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 3 of Univ of Florida (U.S. Patent No. 2017/0356009 A1, published Dec 14, 2017; PTO 892) (i.e., reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1and 3 of Univ of Florida, in view of Ling (Ling et al., Journal of Virology (2015) 89(2); PTO 892) and The Board of Regents of the Univ of Texas System, hereinafter Univ of Texas (US 2014/0155460 A1, published June 5, 2014, EFD April 4, 2005; PTO 892), make obvious claims 6 and 7 of the instant application.
In regards to claim 6, as discussed supra, Univ of Florida (reference application) and Ling make obvious the AAV particle of claim 1. Further, Univ of Texas teaches MEF2 binding sites are highly conserved and teaches, as shown below in Fig 2C, the highly conserved binding site of MEF2 (underlined in red in Figure 2C) is CTAAAAATAG, i.e., SEQ ID NO: 4. Said sequence corresponds to SEQ ID NO: 14 of Univ of Texas.
Fig 2 C
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Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Univ of Florida (reference application), Ling and Univ of Texas. As Univ of Florida and Ling teach of MEF binding sites in the rAAV of claim 1 and Univ of Texas teaches MEF binding sites are highly conserved and teaches SEQ ID NO: 4 of the instant application as the highly conserved binding site sequence, a POSITA would have been motivated to use SEQ ID NO: 4 as the MEF binding site sequence in the rAAV of Univ of Florida and Ling. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying MEF sequences.
In regards to claim 7, Examiner notes SEQ ID NO: 33 is the complement of SEQ ID NO: 4 (claim 6). As discussed supra, it would have been obvious to a POSITA to incorporate SEQ ID NO: 4 into the rAAV of claim 1 due to SEQ ID NO: 4 being the conserved region of the MEF binding site. Further, Ling teaches complementary sequences within an ITR (p953, 1st paragraph).
Thus, it would have been obvious to a POSITA, before the EFD of the claimed invention, to combine the teachings of Univ of Florida, Ling and Univ of Texas. A POSITA would have been motivated to incorporate the complementary sequence of SEQ ID NO: 4, i.e., SEQ ID NO: 33, into the rAAV of claim 1 due to Ling teaching of complementary sequences within an ITR. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying MEF sequences.
Thus, claims 1and 3 of Univ of Florida (reference application), in view of Ling and Univ of Texas, make obvious claims 6 and 7 of the instant application.
Claim 11 is rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 3 of Univ of Florida (U.S. Patent No. 2017/0356009 A1, published Dec 14, 2017; PTO 892) (i.e., reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1and 3 of Univ of Florida, in view of Ling (Ling et al., Journal of Virology (2015) 89(2); PTO 892) and Asher (Asher et al., Expert Opinion on Biological Therapy (2020) 20(3): 263-274; PTO 892), make obvious claim 11 of the instant application.
In regards to claim 11, Univ of Florida and Ling teach the AAV particle of claim 1 but do not teach AAVrh74.
Asher teaches AAVrh74 and further teaches AAVrh74 is of non-human origin and thus avoids prior human infection which minimizes the potential for preexisting immunity (bottom of page 267- 1st paragraph p268).
Therefore, it would have been obvious to a POSITA before the effective filing date of the claimed invention, to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the AAV serotype of Univ of Florida and Ling (i.e., AAV2) for the AAVrh74 serotype of Asher in order to minimize the potential for preexisting immunity.
The skilled artisan would have had a reasonable expectation of successfully substituting one well studied AAV serotype for another well studied AAV serotype. Substitution of one element for another known in the field is obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, claims 1and 3 of Univ of Florida, in view of Ling and Asher, make obvious claim 11 of the instant application.
Claim 17 is rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 3 of Univ of Florida (U.S. Patent No. 2017/0356009 A1, published Dec 14, 2017; PTO 892) (i.e., reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1and 3 of Univ of Florida, in view of Ling (Ling et al., Journal of Virology (2015) 89(2); PTO 892) and Fickett (Fickett, J.W. Gene (1996) 172; PTO 892), make obvious claim 17 of the instant application.
In regards to claim 17, Univ of Florida and Ling teach the AAV particle of claim 8 but do not teach wherein the MEF binding site is upstream of the MyoD binding site.
Fickett teaches coordinate positioning of MEF2 and MyoD binding sites and teaches MEF2 and MyoD families of transcriptional regulatory factors both play central roles in the terminal differentiation of skeletal muscle. Fickett teaches binding sites for the 2 families often occur nearby and with precise geometric restrictions (Abstract). Fickett teaches in the sense strand order, i.e., 5’ to 3’, in the MCK 5’ enhancer, there are 2 MEF2 and 2 myogenin sites. Fickett teaches MyoD binds to the myogenin sites and thus the “myogenin sites” of Fickett are MyoD binding sites. As is seen below, Fickett teaches in the sense strand order, i.e., 5’ to 3’ order, there is a MEF2 site followed by a myogenin, i.e., MyoD, binding site. Fickett teaches the placement of a MEF2 binding sites 5’ to a myogenin, i.e., MyoD, binding sites is found in human, mouse, rat and rabbit (p22, point 3.1).
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Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of the Univ of Florida and Ling with the teachings of Fickett. Univ of Florida and Ling teach a nucleic acid vector comprising MEF2 and MyoD binding sites but do not teach a specific arrangement of said MEF2 and MyoD binding sites. Fickett teaches 5’ to 3’ positioning of MEF2 to MyoD binding sites in the MCK enhancer in human, mouse, rat and rabbit. Thus, a POSITA would have been motivated to place the MEF2 binding site upstream of (5’ relative to) the MyoD binding site in the nucleic acid vector of Univ of Florida and Ling due to Fickett teaching of the natural placement of said binding sites in multiple species. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying MEF2 and MyoD.
Thus, claims 1and 3 of Univ of Florida, in view of Ling and Fickett, make obvious claim 17 of the instant application.
The nonstatutory obviousness-type 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 obviousness-type 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 obviousness-type 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 obviousness-type 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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 5, 8, 9, 10, 12, and 13 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Univ of Florida Research Foundation Inc, hereinafter Univ of Florida (US 2017/0356009 A1, published Dec 14, 2017, EFD Nov 21, 2014; IDS filed 6/13/2024; PTO 892). Claim 9 is rejected under 102(a)(1) and 102(a)(2) as being anticipated by Univ of Florida, as evidenced by Kuz (Kuz et al., Viruses (2024) 16, 1215; PTO 892).
In regards to claims 1, 2, 5, 8, 10, 12, and 13, Univ of Florida teaches of recombinant AAV (rAAV) nucleic acid vectors that comprise one or more modifications within at least one inverted terminal repeat (ITR) region. Univ of Florida teaches exemplary modifications include ITR sequences comprising a transcription factor binding site (Abstract).
Univ of Florida teaches of rAAV vector genomes that comprise one or more modifications within the ITR regions, such as within the D-sequences, which resulted in improved transduction efficiency. Univ of Florida teaches in some embodiments, a rAAV particle comprises a viral capsid encapsulating a nucleic acid vector, wherein the nucleic acid vector comprises an ITR comprising a transcription factor binding site [0003].
Univ of Florida teaches in some embodiments, the D-sequence that is removed (i.e., D+ or D- sequence) is replaced with a sequence that comprises one or more transcription factor binding sites that bind positive regulators of transcription [0005]. Univ of Florida teaches the ssD- sequence is at the 3’ end of the rAAV genome whereas the complementary ssD+ sequence is at the 5’ end of the rAAV genome. Thus, Univ of Florida teaches the 3’ or the 5’ D sequence may be removed and replaced with transcription factor binding site sequences [0127].
Univ of Florida teaches (Fig 6A; [0016]) of schematic structures of rAAV genomes. As can be seen in Fig 6A, Univ of Florida teaches a nucleic acid vector which comprises a 5’ ITR (i.e., the ITR farthest to the left) comprising a substitute sequence in place of the D sequence. Univ of Florida additionally teaches a substitute sequence replacing the D-sequence within the 3’ ITR (i.e., farthest to the right).
Figure Legend: HP = hairpin structure; D= D-sequence; S= substitute sequence; CMVp= cytomegalovirus promoter; hrGFP =humanized recombinant GFP; hGH (A)n= human growth hormone polyA signal
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Univ of Florida teaches the transcription factor binding site is a tissue-specific transcription factor binding site and exemplary transcription factors and their binding sites are shown in Table 1 ([0038]; Table 1). MyoD (claim 2) and MEF-2 (claim 5) are provided as exemplary transcription factors per Table 1, with the binding site consensus sequence also being provided. Univ of Florida additionally teaches the removed D sequence(s) may be replaced with one or more sequences as described herein, i.e., one or more transcription factor binding sites, i.e., MyoD and MEF-2 (claim 8) [0038].
Thus, Univ of Florida teaches a AAV particle comprising a nucleic acid vector, wherein the nucleic acid vector comprises a 5’ ITR comprising a MyoD and/or MEF binding site (claim 1).
Moreover, Univ of Florida teaches wherein the nucleic acid vector further comprises a transgene (claim 10). As shown in Fig 6A, Univ of Florida teaches of the GFP transgene. Additionally, Univ of Florida teaches the nucleic acid vector may further comprise a heterologous nucleic acid region comprising a sequence encoding a protein or polypeptide of interest or an RNA of interest and further teaches said nucleic acid region may be for a therapeutic protein [0042].
Univ of Florida teaches the ITR sequences and thus the nucleic acid vector is of serotype 2, i.e., AAV2 (claim 12) [0047].
Univ of Florida teaches a composition comprising the AAV particle of claim 1 [0060] and a pharmaceutically acceptable carrier (claim 13) [0065].
Thus, Univ of Florida anticipates claims 1, 2, 5, 8, 10, 12, and 13, therefore said claims are properly rejected.
In regards to claim 9, Univ of Florida teaches the AAV particle of claim 9. Further,
Univ of Florida teaches both the WT and rAAV genomes contain ITRs of 145 nucleotides at both ends. The terminal 125 nucleotides in each ITR form a palindromic double-stranded T-shaped hairpin structure in which the A-A’ palindrome forms the stem and the two smaller palindromes, B-B’ and the C-C’, form the cross-arms of the T. The other 20 nucleotides (D-sequence) in the ITR remain single stranded [0127]. Univ of Florida does not per se teach the D sequence is upstream of the TRS, however, as a POSITA will appreciate, and as is evidenced by Kuz, it is inherent the D sequence is upstream of the TRS.
As is evidenced by Kuz, Fig 2, the D sequence is upstream from (5’ relative to) the terminal resolution site (TRS) of the ITR.
Fig 2
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As noted supra in the previously discussed rejections, Univ of Florida teaches removing the D sequence and replacing said sequence with MyoD and/or MEF binding sites. Thus, Univ of Florida teaches wherein the MyoD and/or MEF binding sites are comprised upstream from (5’ relative to) the TRS of the ITR.
Thus, the claim is anticipated and is properly rejected.
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 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Univ of Florida in view of The Board of Regents of the Univ of Texas System, hereinafter Univ of Texas (US 2014/0155460 A1, published June 5, 2014, EFD April 4, 2005; PTO 892).
In regards to claim 6, Univ of Florida teaches the AAV particle of claim 1 but does not teach wherein the MEF binding site comprises SEQ ID NO: 4, i.e., CTAAAAATAG.
Univ of Texas teaches MEF2 binding sites are highly conserved and teaches, as shown below in Fig 2C, the highly conserved binding site of MEF2 (underlined in red in Figure 2C) is CTAAAAATAG, i.e., SEQ ID NO: 4. Said sequence corresponds to SEQ ID NO: 14 of Univ of Texas.
Fig 2 C
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Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Univ of Florida and Univ of Texas. As Univ of Florida teaches of MEF binding sites in the rAAV of claim 1 and Univ of Texas teaches MEF binding sites are highly conserved and teaches SEQ ID NO: 4 of the instant application as the highly conserved binding site sequence, a POSITA would have been motivated to use SEQ ID NO: 4 as the MEF binding site sequence in the rAAV of Univ of Florida. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying MEF sequences.
Thus, the claim is obvious and is properly rejected.
In regards to claim 7, Examiner notes SEQ ID NO: 33 is the complement of SEQ ID NO: 4 (claim 6). As discussed supra, it would have been obvious to a POSITA to incorporate SEQ ID NO: 4 into the rAAV of claim 1 due to SEQ ID NO: 4 being the conserved region of the MEF binding site. Further, Univ of Florida teaches in some embodiments, the nucleic acid vector is self-complementary ([0004], claim 10).
Thus, it would have been obvious to a POSITA, before the EFD of the claimed invention, to combine the teachings of Univ of Florida and Univ of Texas. A POSITA would have been motivated to incorporate the complementary sequence of SEQ ID NO: 4, i.e., SEQ ID NO: 33, into the rAAV of claim 1 due to Univ of Florida teaching in some embodiments, the nucleic acid vector is self-complementary. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying MEF sequences.
Thus, the claim is obvious and is properly rejected.
Claims 11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Univ of Florida in view of Asher (Asher et al., Expert Opinion on Biological Therapy (2020) 20(3): 263-274; PTO 892).
In regards to claim 11, Univ of Florida teaches the AAV particle of claim 1. Univ of Florida teaches the rAAV particle may be of any AAV serotype but does not per se teach of AAVrh74 [0055].
Asher teaches AAVrh74 and further teaches AAVrh74 is of non-human origin and thus avoids prior human infection which minimizes the potential for preexisting immunity (bottom of page 267- 1st paragraph p268).
Therefore, it would have been obvious to a POSITA before the effective filing date of the claimed invention, to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the AAV serotype of Univ of Florida for the AAVrh74 serotype of Asher to minimize the potential for preexisting immunity.
The skilled artisan would have had a reasonable expectation of successfully substituting one well studied AAV serotype for another well studied AAV serotype. Substitution of one element for another known in the field is obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the claim is obvious and is properly rejected.
In regards to claim 18, Univ of Florida teaches the AAV particle of claim 10. Further, Univ of Florida teaches any number of promoters are suitable for use in the selected host cell and such examples include tissue-specific promoters [0050]. Univ of Florida does not teach per se of a muscle-specific promoter.
Asher teaches gene therapy for Duchenne muscular dystrophy (Abstract). Asher teaches optimal treatment of DMD requires selection of an AAV vector with high tropism for skeletal, diaphragm and cardiac muscles. To reach these muscles the vector must be administered systemically. This requires high doses, making the safety profile of the vector selected critical. The focus on skeletal and cardiac muscle also necessitates the selection of a promoter that expresses at high levels in these tissues, and minimally in off-target organs (p267, 1st paragraph). Asher teaches use of AAVrh74 as the vector and a muscle-specific MHCK7 promoter (p267, Case Study 5).
Univ of Florida teaches the rAAV particle of the invention may be used to treat such diseases as muscular dystrophy [0066] and further teaches the use of tissue-specific promoters.
Therefore, it would have been obvious to a POSITA before the effective filing date of the claimed invention, to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the unspecified tissue specific promoter of Univ of Florida for the specified muscle specific promoter MHCK7 of Asher to treat DMD as taught by both Univ of Florida and Asher.
The skilled artisan would have had a reasonable expectation of successfully substituting one tissue specific promoter for another well studied muscle specific promoter. Substitution of one element for another known in the field is obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the claim is obvious and is properly rejected.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Univ of Florida in view of Fickett (Fickett, J.W. Gene (1996) 172; PTO 892).
In regards to claim 17, Univ of Florida teaches the AAV particle of claim 8. Univ of Florida does not teach wherein the MEF binding site is upstream of the MyoD binding site.
Fickett teaches coordinate positioning of MEF2 and MyoD binding sites and teaches MEF2 and MyoD families of transcriptional regulatory factors both play central roles in the terminal differentiation of skeletal muscle. Fickett teaches binding sites for the 2 families often occur nearby and with precise geometric restrictions (Abstract). Fickett teaches in the sense strand order, i.e., 5’ to 3’, in the MCK 5’ enhancer, there are 2 MEF2 and 2 myogenin sites. Fickett teaches MyoD binds to the myogenin sites and thus the “myogenin sites” of Fickett are MyoD binding sites. As is seen below, Fickett teaches in the sense strand order, i.e., 5’ to 3’ order, there is a MEF2 site followed by a myogenin, i.e., MyoD, binding site. Fickett teaches the placement of a MEF2 binding site 5’ to a myogenin, i.e., MyoD, binding site is found in human, mouse, rat and rabbit (p22, point 3.1).
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Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of the Univ of Florida with the teachings of Fickett. Univ of Florida teaches a nucleic acid vector comprising MEF2 and MyoD binding sites but does not teach a specific arrangement of said MEF2 and MyoD binding sites. Fickett teaches 5’ to 3’ positioning of MEF2 to MyoD binding sites in the MCK enhancer in human, mouse, rat and rabbit. Thus, a POSITA would have been motivated to place the MEF2 binding site upstream of (5’ relative to) the MyoD binding site in the nucleic acid vector of Univ of Florida due to Fickett teaching of the natural placement of said binding sites in multiple species. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying MEF2 and MyoD.
Thus, the claim is obvious and is properly rejected.
Allowable Subject Matter
Claims 3 and 4 are 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.
In regards to claim 3, examiner acknowledges, after a thorough SEQ ID search, that while there is prior art teaching 100% identity to SEQ ID NO: 1, the prior art does not per se teach said sequence is a MyoD binding site. Thus, a POSITA would not have been motivated to use said sequence in the rAAV of claim 1 as a MyoD binding site. In addition, Cao (Cao, et al., Dev Cell (2010) 18(4); PTO 892) teaches MyoD binds to thousands of genomic sites across the genome as identified by genome-wide ChIP-seq studies (Abstract). Cao further teaches of a consensus E-box motif which is present in 96% of the MyoD binding regions, with 89% of MyoD binding regions containing either CACCTG or CAGCTG sites (Discussion, 5th paragraph). Examiner notes CAGCTG is comprised within SEQ ID NO: 1. However, the full length of SEQ ID NO: 1 is AGCAGCTGCT. After a thorough search of art, Examiner has not found a motivation to make obvious the use of SEQ ID NO: 1 as a MyoD binding site to be included in the rAAV of claim 1.
In regards to claim 4, Examiner acknowledges, after a thorough SEQ ID search, that there is no close prior art for the 2 sequences shown in claim 4 as the MyoD binding site. Examiner notes, as noted supra, there is no prior art for SEQ ID NO: 1. TCGTCGACG is one nucleotide short of the complement of SEQ ID NO: 1, i.e., said sequence is lacking the last nucleotide, i.e., “T”, from SEQ ID NO: 1. AGCAGCTGC is one nucleotide short of being identical to SEQ ID NO: 1, i.e., said sequence is lacking the last nucleotide, i.e., “T”, from SEQ ID NO: 1.
Conclusion
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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