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 .
Election/Restrictions
Applicant’s election of Group I (claims 4 and 6) in the reply filed on 05/19/2026 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)).
Claims 8,9,11,13,15-19,21,26,27,31,34 and 37-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. 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)).
Claims 4 and 6 are under examination.
Priority
This application is a 371 of PCT/US2022/025916, filed 04/22/2022 which claims benefit of 63/327,410, filed 04/05/2022 and claims benefit of 63/179,097, filed 04/23/2021 as reflected by the most recent filing receipt.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See page 17, paragraph 0049.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites, “optionally wherein the GRE comprises, consists essentially of, or consists of the nucleotide sequence AGAACANNNTGTTCT (SEQ ID NO: 18), or its reverse or reverse complement, wherein each N is independently a T,C,G or A”. The metes and bounds of the claim are not clear because of “comprises, consists essentially of, or consists of”. It is not clear if additional nucleotides can be included in the nucleotide sequence of SEQ ID NO: 18 because "comprising" or “consisting essentially of” would allow additional nucleotides (SEQ ID NO: 18 could be within a larger nucleotide sequence), but "consisting of" would not.
Claim 6 is included in the rejection because it depends on claim 4 and does not correct the issue.
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.
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.
Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Philadelphia (WO 2015013313, Published 29 Jan 2015) in view of Ling #1 (J Virol. 29 Oct 2014; 89(2): 952-961), cited on an IDS, and Ling #2 (Molecular Therapy, Vol 23, Supp 1, May 2015), cited on an IDS.
Claim Interpretation: Regarding the limitations following “optionally” in claim 4, this is not being considered as a required claim limitation. Regarding claim 6, the preamble recites “a composition” but the body of the claim only recites the AAVrh74 particle of claim 4 and no additional elements, and therefore art reading on claim 4 also reads on claim 6.
Regarding claims 4 and 6, Philadelphia teaches recombinant AAV-Rh74 vectors and related AAV vectors such as AAV-Rh74 variants such as capsid variants particles that include (encapsidate, package) AAV vector genomes (paragraph 0012). Philadelphia teaches AAV-Rh74 and related AAV vector mediated polynucleotide transfer produced protein expression levels that were significantly higher than several other serotypes currently studied in preclinical and clinical settings. In particular, AAV-Rh74 targets polynucleotides to the liver with efficiency at least comparable or superior to the gold standard for liver transduction, AAV8, both in mice and in hemophilia B dogs (paragraph 0009). Philadelphia teaches that the recombinant AAV-Rh74 vector particle has one or more ITR sequences that flank the 5’ or 3’ terminus of the heterologous polynucleotide sequence (paragraph 0017).
Philadelphia does not teach the AAVrh74 particle comprising a first ITR comprises a first D-sequence and a second ITR comprises a second D-sequence, wherein the first D-sequence and/or second D-sequence is substituted with a glucocorticoid receptor-binding element (GRE).
Ling #1 taught both WT and rAAV genomes contain inverted terminal repeats (ITRs) of 145 nucleotides (nt) at both ends, and 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 (D sequence) in the ITR remain single stranded (pages 952-953). The ssD[-] sequence is always at the 3’ end, whereas the complementary one, the ssD[+] sequence is invariably at the 5’ end (page 953, first paragraph). Therefore, Ling #1 teach AAVs comprise a first and second D-sequence in each ITR. Ling #1 taught that removal of the D sequences from the viral genome impairs rescue, replication and encapsidation of AAV DNA, and that restoration of one D sequence (ssD[+] sequence) in the ssAAV genome and which is substituted with a sequence containing putative binding sites for transcriptions factors in ssAAV vectors, had significantly higher transduction efficiencies than conventional ssAAV vectors (page 953, 2nd paragraph, Abstract).
Ling #2 taught capsid-modified next generation AAV serotype vectors that transduce cells and tissues more efficiently at reduced vector doses as well as genome-modified generation X AAV vectors that also transduce cells and tissues more efficiently (First paragraph). Ling #2 taught the recombinant AAV genome contains inverted terminal repeats (ITRs) of 145 nucleotides at both ends, and a 20-nucleotide sequence called the D-sequence was replaced with a substitute sequence. Ling #2 taught the hypothesis that replacement of the D-sequence with a full GRE binding-site in the ITR might further increase transgene expression from these GenX AAV genomes, and that recombinant AAV vectors were generated in which the D-sequence was replaced with a fully functional GRE site. Insertion of a full GRE binding-site in the ITR significantly increased the transgene expression from these GenX AAV genomes following encapsidation in the wild-type (WT) AAV2 capsid vectors in human cell lines in vitro (page S125).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the AAVrh74 vector particle of Philadelphia to comprise a first and second D-sequence in each ITR according to Ling #1, and to substitute a first and/or second D-sequence with a GRE site according to the teachings of Ling #2 to arrive at the instant invention with a reasonable expectation of success. There would be a reasonable expectation of success because Philadelphia, Ling #1 and Ling #2 all pertain to AAV vectors and variants. One of ordinary skill in the art would have been motivated to do so because Philadelphia teach AAV-Rh74 and related AAV vector mediated polynucleotide transfer produced protein expression levels that were significantly higher than several other serotypes currently studied in preclinical and clinical settings. In particular, AAV-Rh74 targets polynucleotides to the liver with efficiency at least comparable or superior to the gold standard for liver transduction, AAV8, and Ling #1 taught that removal of the D sequences from the viral genome impairs rescue, replication and encapsidation of AAV DNA, and that restoration of one D sequence (ssD[+] sequence) in the ssAAV genome and which is substituted with a sequence containing putative binding sites for transcriptions factors in ssAAV vectors, had significantly higher transduction efficiencies than conventional ssAAV vectors and Ling #2 taught that replacement of the D-sequence in AAV with a full GRE binding-site in the ITR might further increase transgene expression from these GenX AAV genomes, and that recombinant AAV vectors were generated in which the D-sequence was replaced with a fully functional GRE site and insertion of a full GRE binding-site in the ITR significantly increased the transgene expression from these GenX AAV genomes following encapsidation in the wild-type (WT) AAV2 capsid vectors in human cell lines in vitro.
Accordingly, the limitations of claims 4 and 6 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Philadelphia (WO 2015013313, Published 29 Jan 2015) in view of Lu et al. (US 20170356009, Published 14 Dec 2017), cited on an IDS.
Claim Interpretation: Regarding claim 6, the preamble recites “a composition” but the body of the claim only recites the AAVrh74 particle of claim 4 and no additional elements, and therefore art reading on claim 4 also reads on claim 6.
Regarding claims 4 and 6, Philadelphia teaches recombinant AAV-Rh74 vectors and related AAV vectors such as AAV-Rh74 variants such as capsid variants particles that include (encapsidate, package) AAV vector genomes (paragraph 0012). Philadelphia teaches AAV-Rh74 and related AAV vector mediated polynucleotide transfer produced protein expression levels that were significantly higher than several other serotypes currently studied in preclinical and clinical settings. In particular, AAV-Rh74 targets polynucleotides to the liver with efficiency at least comparable or superior to the gold standard for liver transduction, AAV8, both in mice and in hemophilia B dogs (paragraph 0009). Philadelphia teaches that the recombinant AAV-Rh74 vector particle has one or more ITR sequences that flank the 5’ or 3’ terminus of the heterologous polynucleotide sequence (paragraph 0017).
Philadelphia does not teach the AAVrh74 particle comprising a first ITR comprises a first D-sequence and a second ITR comprises a second D-sequence, wherein the first D-sequence and/or second D-sequence is substituted with a glucocorticoid receptor-binding element (GRE).
Lu et al. taught the development 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, and which may be used to generate rAAV particles, comprising a viral capsid encapsidating a nucleic acid vector comprising a first ITR sequence comprising a glucocorticoid receptor responsive element and/or a second ITR sequence comprising a transcription factor binding site (paragraph 0003). Lu et al. taught both wild-type and rAAV genomes contain inverted terminal repeats (ITRs) of about 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 ITR remain single-stranded. The ssD[−] sequence is at the 3′ end, whereas the complementary one, ssD[+] sequence is at the 5′ end. Once in cells, the single-stranded virus undergoes second-strand DNA synthesis, which turns both ssD[−] and ssD[+] sequences into a double-stranded (ds) D [±] sequence (paragraph 0028), and that modifications within the ITRs, more specifically within or involving the D-sequences were shown to increase transduction efficiency and/or allow for regulatory control of one or more genes encoded by the nucleic acid vector… In another case, replacement of a partial glucocorticoid receptor responsive element (GRE) sequence within a D-sequence with a full GRE sequence enhanced transduction efficiency (paragraph 0028). Lu et al. taught a D-sequence within the first and/or second ITR sequence is replaced, in whole or in part, with the glucocorticoid receptor responsive element and/or the transcription factor binding site (paragraph 0035), and that exemplary glucocorticoid receptor responsive elements include 5′-AGAACAnnnTGTTCT-3′ (SEQ ID NO: 8) (paragraph 0036). SEQ ID NO: 8 of Lu et al. is the 100% identical to the GRE of instant SEQ ID NO: 18 recited in claim 4.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the AAVrh74 vector particle of Philadelphia to comprise a first and second D-sequence in each ITR and to substitute a first and/or second D-sequence with a GRE element according to the teachings of Lu et al. to arrive at the instant invention with a reasonable expectation of success. There would be a reasonable expectation of success because Philadelphia and Lu et al. pertain to AAV vectors and variants. One of ordinary skill in the art would have been motivated to do so because Philadelphia teach AAV-Rh74 and related AAV vector mediated polynucleotide transfer produced protein expression levels that were significantly higher than several other serotypes currently studied in preclinical and clinical settings. In particular, AAV-Rh74 targets polynucleotides to the liver with efficiency at least comparable or superior to the gold standard for liver transduction, AAV8, and Lu et al. taught both wild-type and rAAV genomes contain inverted terminal repeats (ITRs) comprising a D-sequence and that modifications within the ITRs, more specifically within or involving the D-sequences were shown to increase transduction efficiency and/or allow for regulatory control of one or more genes encoded by the nucleic acid vector. Lu et al. taught replacement of a partial glucocorticoid receptor responsive element (GRE) sequence within a D-sequence with a full GRE sequence enhanced transduction efficiency (paragraph 0028) and that a D-sequence within the first and/or second ITR sequence is replaced, in whole or in part, with the glucocorticoid receptor responsive element and/or the transcription factor binding site (paragraph 0035), and that exemplary glucocorticoid receptor responsive elements include 5′-AGAACAnnnTGTTCT-3′ (SEQ ID NO: 8) (paragraph 0036) which is 100% identical to the GRE of instant SEQ ID NO: 18 recited in claim 4.
Accordingly, the limitations of claims 4 and 6 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.
Claim 4 and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12,17-23,27,28 and 30 of U.S. Patent No. 10,900,053 (‘053) in view of Philadelphia (WO 2015013313, Published 29 Jan 2015).
Claims 1-12,17-23 of ‘053 recites 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), with claims 27-28 and 30 reciting the glucocorticoid receptor responsive element and/or the transcription factor binding site replaces a D-sequence or a portion thereof within the inverted terminal repeat (ITR) or wherein the glucocorticoid receptor responsive element and/or the transcription factor binding site replaces a D-sequence or a portion thereof within the inverted terminal repeat (ITR). Claims 2 and 10 of ‘053 also recite wherein the glucocorticoid receptor responsive element comprises AGAACANNNTGTTCT (SEQ ID NO: 8), which is the same GRE sequence that is optionally claimed in instant claim 4.
‘053 does not recite that the AAV particle is an AAVrh74 particle.
Philadelphia cures this deficiency, the teachings of which have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to replace the recombinant AAV particle comprising a viral capsid of ‘053 with the AAV serotype AAV-Rh74 based on the teachings of Philadelphia to arrive at the instant claims with a reasonable expectation of success as both ‘053 and Philadelphia pertain to recombinant AAVs. One of ordinary skill in the art would have been motivated to do so because Philadelphia teaches AAV-Rh74 and related AAV vector mediated polynucleotide transfer produced protein expression levels that were significantly higher than several other serotypes currently studied in preclinical and clinical settings. In particular, AAV-Rh74 targets polynucleotides to the liver with efficiency at least comparable or superior to the gold standard for liver transduction, AAV8, both in mice and in hemophilia B dogs (paragraph 0009) and that the recombinant AAV-Rh74 vector particle has one or more ITR sequences that flank the 5’ or 3’ terminus of the heterologous polynucleotide sequence (paragraph 0017).
Claims 4 and 6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/692,438 (‘438) in view of Lu et al. (US 20170356009, Published 14 Dec 2017).
Claims 1-8 of ‘438 recite an AAVrh74 capsid protein comprising an amino acid substitution or deletion at a position corresponding to T265 of wild-type AAVrh74 capsid protein of SEQ ID NO: 1, and nucleic acid encoding the capsid protein, and claims 9-12 recite an AAV particle comprising the AAVrh74 capsid protein and a nucleic acid comprising a gene of interest. Claim 13 recites a composition comprising the AAV particle and a pharmaceutically acceptable carrier, and claims 14-16 recite a method of administering to a subject the composition of claim 13.
‘438 does not recite that the AAVrh74 particle comprises a first ITR comprising a first D-sequence and a second ITR comprising a second D-sequence, wherein the first D-sequence and/or the sequence D-sequence is substituted with a glucocorticoid receptor-binding element (GRE), optionally wherein the GRE comprises, consists essentially of, or consists of the nucleotide sequence of SEQ ID NO: 18 or its reverse or reverse complement, wherein each N is independently a T,C,G or A.
Lu et al. cures these deficiencies, the teachings of which have been described above in the 103 rejections.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the AAVrh74 capsid protein and AAV particle comprising the AAVrh74 capsid protein of ‘438 to comprise a first and second D-sequence in each ITR and to substitute a first and/or second D-sequence with a GRE element according to the teachings of Lu et al. to arrive at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success because ‘438 and Lu et al. pertain to AAV vectors and variants. One of ordinary skill in the art would have been motivated to do so because Lu et al. taught both wild-type and rAAV genomes contain inverted terminal repeats (ITRs) comprising a D-sequence and that modifications within the ITRs, more specifically within or involving the D-sequences were shown to increase transduction efficiency and/or allow for regulatory control of one or more genes encoded by the nucleic acid vector. Lu et al. taught replacement of a partial glucocorticoid receptor responsive element (GRE) sequence within a D-sequence with a full GRE sequence enhanced transduction efficiency (paragraph 0028) and that a D-sequence within the first and/or second ITR sequence is replaced, in whole or in part, with the glucocorticoid receptor responsive element and/or the transcription factor binding site (paragraph 0035), and that exemplary glucocorticoid receptor responsive elements include 5′-AGAACAnnnTGTTCT-3′ (SEQ ID NO: 8) (paragraph 0036) which is 100% identical to the GRE of instant SEQ ID NO: 18 recited in claim 4.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 4 and 6 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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