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 .
Claim Status
Claims 34-35, 40, 42, 44, 47, 55, 57, 63-64, 71, and 84-92 are currently pending in this application.
Election/Restrictions
Applicant's election without traverse of Group I, claims 34-35, 40, 42, 47, 51, 55, 57, 63-64, and 71 in the reply filed on Oct. 12, 2024 is acknowledged. Applicant's election is acknowledged of the hGAA780I species encoded by SEQ ID NO: 4, the fusion protein species comprising SEQ ID NO: 6, and the vIGF2 peptide species comprising SEQ ID NO: 44. Claims 34-35, 40, 42, 44, 47, 55, 57, 63-64, 71, and 84-92 have been considered on the merits and all arguments have been fully considered.
Previous Rejections
Status of the rejections:
The previous claim rejections under 112(b) are withdrawn in view of applicant’s claim amendments.
Benefit of Priority Claim
Acknowledgement is made of applicant’s claim for the benefit of the prior-filed applications US 62/840,0911 and US 62/913,401 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c). The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosures of US 62/840,0911 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application with regard to SEQ ID NOs: 30, 32, 44, 49-54, and 61, therefore the earliest effective filing date of claims 47, 57, 63, 84, and 86-92 is Oct. 10, 2019 based on US 62/913,401.
Claim Interpretation
The term “vIGF2 peptide” in the claims is interpreted as any peptide that binds a cation-independent mannose 6-phosphate receptor (CI-MPR) as indicated in the instant application at pg. 16, line 30.
Claim Rejections - 35 USC § 112(a), New Matter (new)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 44 and 91 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The phrase “miR-183 target sequences” lacks support in the application as filed and thus constitutes new matter.
37 CFR 1.118(a) states “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”. In the instant case, the recitation of the limitation “dorsal root ganglion (DRG)-specific miR-183 target sequences” is considered new matter. Upon review of the instant specification, examiner could not find explicit or implicit support for these limitations.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981) teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed…If a claim is amended to include subject matter, limitation or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes, “When an amendment is filed in reply to an objection or rejection based on U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendment made to the disclosure”. This is a new matter rejection.
Claim Rejections - 35 USC § 112(b) (new)
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 34-35, 40, 42, 44, 47, 55, 57, 63-64, 71, and 84-92 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.
Claims 34 and 86 each recites the term “acid-alpha glucosidase (GAA) peptide,” which encompasses polypeptides of lengths of at least 686 amino acids (e.g., amino acids 204-890, 204-952, 123-890, 70-952 or 70-890 of SEQ ID NO: 3 as in claim 35). However, the ordinary meaning of “peptide” is a shorter polypeptide not longer than 25-50 amino acids. If the applicant acts as her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). Thus, the terms “acid-alpha glucosidase peptide” and “GAA peptide” as used in the claims is incoherent for including much longer polypeptides. Claims 35, 40, 42, 44, 47, 55, 57, 63-64, 71, and 84-92 are included in this rejection for depending from indefinite claim 34 or 86.
Claims 34 and 86 each recites the term “vIGF2 peptide,” which encompasses polypeptides of lengths of 64-67 amino acids (e.g., SEQ ID NO: 32 or 44 as in claim 47 and 84). However, the ordinary meaning of “peptide” is a shorter polypeptide not longer than 25-50 amino acids. Claims 35, 40, 42, 44, 47, 55, 57, 63-64, 71, and 84-92 are included in this rejection for depending from indefinite claim 34 or 86.
Claim Rejections - 35 USC § 103 (new)
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 34-35, 40, 42, 55, 71, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Mingozzi (WO2018/046774; IDS ref.) in view of LeBowitz (US20120148556A1) and EMA (European Medicines Agency Guidelines 2019, EMA/CAT/852602/2018).
The claims are interpreted as provided in a previous section.
Mingozzi teaches a recombinant adeno-associated virus (rAAV) comprising: (a) an AAV capsid which targets muscle, heart, and/or central nervous system (e.g., AAV1 and AAV8) (pg. 4, lines 10-17); and (b) a vector genome packaged in the AAV capsid (pg.36, line 3, to pg. 37, line 17), said vector genome comprising a nucleic acid sequence encoding a chimeric fusion protein comprising a signal peptide fused to a human GAA sequence (“GAA peptide”) (pg. 9, lines 7-27) (hGAA-delta-8, hGAA-delta-42, hGAA-delta-29, hGAA-delta-43, and hGAA-delta-47 (SEQ ID NOs: 27-28 and 34-36)) comprising instant SEQ ID NO: 61 in the catalytically active site (as shown below for SEQ ID NO: 27) and under control of regulatory sequences that direct its expression (pg. 2, line 21, to pg. 3, line 30), such as for use in treating Pompe disease using enzyme-replacement via gene therapy delivery of recombinant human GAA constructs (pg. 3, lines 29-30; pg. 4, lines 19-21; pg. 34, line 10, to pg. 35, line 24; pg. 44, lines 19-36; pg. 47, line 11, to pg. 48, line, to pg. 51).
99.9% identity in 917 residues overlap; Score: 4920.0; Gap frequency: 0.0%
Ins. SEQ 3 36 LLVPRELSGSSPVLEETHPAHQQGASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPD
SEQ ID 27 1 LLVPRELSGSSPVLEETHPAHQQGASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPD
************************************************************
Ins. SEQ 3 96 KAITQEQCEARGCCYIPAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRT
SEQ ID 27 61 KAITQEQCEARGCCYIPAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRT
************************************************************
Ins. SEQ 3 156 TPTFFPKDILTLRLDVMMETENRLHFTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSE
SEQ ID 27 121 TPTFFPKDILTLRLDVMMETENRLHFTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSE
************************************************************
Ins. SEQ 3 216 EPFGVIVRRQLDGRVLLNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTR
SEQ ID 27 181 EPFGVIVRRQLDGRVLLNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTR
************************************************************
Ins. SEQ 3 276 ITLWNRDLAPTPGANLYGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGG
SEQ ID 27 241 ITLWNRDLAPTPGANLYGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGG
************************************************************
Ins. SEQ 3 336 ILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAH
SEQ ID 27 301 ILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAH
************************************************************
Ins. SEQ 3 396 FPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSY
SEQ ID 27 361 FPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSY
************************************************************
Ins. SEQ 3 456 RPYDEGLRRGVFITNETGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGM
SEQ ID 27 421 RPYDEGLRRGVFITNETGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGM
************************************************************
Ins. SEQ 3 516 WIDMNEPSNFIRGSEDGCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLY
SEQ ID 27 481 WIDMNEPSNFIRGSEDGCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLY
************************************************************
Ins. SEQ 3 576 GLTEAIA SHRALVKARGTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFN
SEQ ID 27 541 GLTEAIA SHRALVKARGTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFN
************************************************************
Ins. SEQ 3 636 LLGVPLVGADVCGFLGNTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAM
SEQ ID 27 601 LLGVPLVGADVCGFLGNTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAM
************************************************************
Ins. SEQ 3 696 RKALTLRYALLPHLYTLFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPV
SEQ ID 27 661 RKALTLRYALLPHLYTLFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPV
************************************************************
Ins. SEQ 3 756 LQAGKAEVTGYFPLGTWYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTIN
SEQ ID 27 721 LQAGKAEVTGYFPLGTWYDLQTVPVEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTIN
************************ ***********************************
Ins. SEQ 3 816 VHLRAGYIIPLQGPGLTTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQ
SEQ ID 27 781 VHLRAGYIIPLQGPGLTTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQ
************************************************************
Ins. SEQ 3 876 VIFLARNNTIVNELVRVTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVL
SEQ ID 27 841 VIFLARNNTIVNELVRVTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVL
************************************************************
Ins. SEQ 3 936 DICVSLLMGEQFLVSWC
SEQ ID 27 901 DICVSLLMGEQFLVSWC
*****************
Regarding claim 34, Mingozzi does not teach wherein the GAA fusion protein comprises a vIGF2 peptide and an isoleucine at position 780 based on the numbering of the sequence in SEQ ID NO: 3.
However LeBowitz teaches hGAA fusion proteins ([0014]) comprising a peptide at least 75% identical to a human IGF2 sequence (vIGF2 peptide) (SEQ ID NO: 1) for lysosomal targeting via binding CI-MPR wherein the human GAA polypeptide component (SEQ ID NO: 2) comprises an isoleucine at position 780 based on the numbering of the positions in instant SEQ ID NO: 3, as shown below, wherein the GAA has a sequence over 95% identical to 70-952 of instant SEQ ID NO: 3 ([0014]-[0016]; [0045]-[0046]; [0064]-[0066]; [0071]; [0002]).
99.7% identity in 885 residues overlap; Score: 4734.0; Gap frequency: 0.0%
Ins. SEQ 3 68 AQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGAQMGQPWC
SEQ ID 2 63 APAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGAQMGQPWC
* **********************************************************
Ins. SEQ 3 128 FFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLHFTIKDPA
SEQ ID 2 123 FFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLHFTIKDPA
************************************************************
Ins. SEQ 3 188 NRRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVLLNTTVAPLFFADQFLQ
SEQ ID 2 183 NRRYEVPLETPRVHSRAPSPLYSVEFSEEPFGVIVHRQLDGRVLLNTTVAPLFFADQFLQ
*********** *********************** ************************
Ins. SEQ 3 248 LSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLALEDGGSA
SEQ ID 2 243 LSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLALEDGGSA
************************************************************
Ins. SEQ 3 308 HGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYW
SEQ ID 2 303 HGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYW
************************************************************
Ins. SEQ 3 368 GLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAM
SEQ ID 2 363 GLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAM
************************************************************
Ins. SEQ 3 428 VQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKVWPGSTAF
SEQ ID 2 423 VQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKVWPGSTAF
************************************************************
Ins. SEQ 3 488 PDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELENPPYVPGV
SEQ ID 2 483 PDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELENPPYVPGV
************************************************************
Ins. SEQ 3 548 VGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SHRALVKARGTRPFVISRSTFAGHG
SEQ ID 2 543 VGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SHRALVKARGTRPFVISRSTFAGHG
************************************************************
Ins. SEQ 3 608 RYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVRWTQLGAF
SEQ ID 2 603 RYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVRWTQLGAF
************************************************************
Ins. SEQ 3 668 YPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVARPL
SEQ ID 2 663 YPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVARPL
************************************************************
Ins. SEQ 3 728 FLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPIEALGSLP
SEQ ID 2 723 FLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPIEALGSLP
************************************************************
Ins. SEQ 3 788 PPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAVAL
SEQ ID 2 783 PPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAVAL
************************************************************
Ins. SEQ 3 848 TKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKVTVL
SEQ ID 2 843 TKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKVTVL
************************************************************
Ins. SEQ 3 908 GVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC
SEQ ID 2 903 GVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC
*********************************************
LeBowitz teaches using these fusion proteins in enzyme replacement therapy to treat Pompe disease by administration to a subject ([0018]; [0047]; [0057]). Furthermore, EMA teaches using recombinant AAV viruses to infect human host cells in vitro to evaluate and confirm functionality of Gene Therapy Investigational Medicinal Products (GTIMPs) to characterize and quantify potency before moving on to investigating in vivo applications in human subjects (pg. 40, lines 1497-1511).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to use the GAA fusion protein taught by LeBowitz in an AAV viral delivery transgenic system taught by Mingozzi for testing potency preclinically in host cells as taught by EMA. One of ordinary skill in the art would be motivated to because LeBowitz teaches such fusion proteins have potential uses in enzyme replacement therapies for GAA-deficiencies but that further research is warranted on targeted lysosomal delivery and improved pharmacological formulations before in vivo gene therapy uses.
Regarding claim 35, the fusion proteins taught by LeBowitz have GAA sequences over 95% identical to 204-890, 204-952, 123-890, 70-952, and 70-890 of instant SEQ ID NO: 3 as shown above.
Regarding claim 40, Mingozzi teaches basing the GAA encoding construct on a wildtype human GAA coding sequence (SEQ ID NO: 8, Examples) that is over 95% identical to instant SEQ ID NO: 5, as shown below.
99.7% identity in 2859 residues overlap; Score: 18573.0; Gap frequency: 0.0%
SEQ ID 5 1 ATGGGAGTGAGGCACCCGCCCTGCTCCCACCGGCTCCTGGCCGTCTGCGCCCTCGTGTCC
SEQ ID 8 1 ATGGGAGTGAGGCACCCGCCCTGCTCCCACCGGCTCCTGGCCGTCTGCGCCCTCGTGTCC
************************************************************
SEQ ID 5 61 TTGGCAACCGCTGCACTCCTGGGGCACATCCTACTCCATGATTTCCTGCTGGTTCCCCGA
SEQ ID 8 61 TTGGCAACCGCAGCGCTCCTGGGGCACATCCTACTCCATGATTTCCTGCTGGTTCCCCGA
*********** ** *********************************************
SEQ ID 5 121 GAGCTGAGTGGCTCCTCCCCAGTCCTGGAGGAGACTCACCCAGCTCACCAGCAGGGAGCC
SEQ ID 8 121 GAGCTGAGTGGCTCCTCCCCAGTCCTGGAGGAGACTCACCCAGCTCACCAGCAGGGAGCC
************************************************************
SEQ ID 5 181 AGTAGACCAGGGCCCCGGGATGCCCAGGCACACCCCGGCCGTCCCAGAGCAGTGCCCACA
SEQ ID 8 181 AGCAGACCAGGGCCCCGGGATGCCCAGGCACACCCCGGGCGGCCGCGAGCAGTGCCCACA
** *********************************** ** ** **************
SEQ ID 5 241 CAGTGCGACGTCCCCCCCAACAGCCGCTTCGATTGCGCCCCTGACAAGGCCATCACCCAG
SEQ ID 8 241 CAGTGCGACGTCCCCCCCAACAGCCGCTTCGATTGCGCCCCTGACAAGGCCATCACCCAG
************************************************************
SEQ ID 5 301 GAACAGTGCGAGGCCCGCGGCTGTTGCTACATCCCTGCAAAGCAGGGGCTGCAGGGAGCC
SEQ ID 8 301 GAACAGTGCGAGGCCCGCGGCTGTTGCTACATCCCTGCAAAGCAGGGGCTGCAGGGAGCC
************************************************************
SEQ ID 5 361 CAGATGGGGCAGCCCTGGTGCTTCTTCCCACCCAGCTACCCCAGCTACAAGCTGGAGAAC
SEQ ID 8 361 CAGATGGGGCAGCCCTGGTGCTTCTTCCCACCCAGCTACCCCAGCTACAAGCTGGAGAAC
************************************************************
SEQ ID 5 421 CTGAGCTCCTCTGAAATGGGCTACACGGCCACCCTGACCCGTACCACCCCCACCTTCTTC
SEQ ID 8 421 CTGAGCTCCTCTGAAATGGGCTACACGGCCACCCTGACCCGTACCACCCCCACCTTCTTC
************************************************************
SEQ ID 5 481 CCCAAGGACATCCTGACCCTGCGGCTGGACGTGATGATGGAGACTGAGAACCGCCTCCAC
SEQ ID 8 481 CCCAAGGACATCCTGACCCTGCGGCTGGACGTGATGATGGAGACTGAGAACCGCCTCCAC
************************************************************
SEQ ID 5 541 TTCACGATCAAAGATCCAGCTAACAGGCGCTACGAGGTGCCCTTGGAGACCCCGCATGTC
SEQ ID 8 541 TTCACGATCAAAGATCCAGCTAACAGGCGCTACGAGGTGCCCTTGGAGACCCCGCATGTC
************************************************************
SEQ ID 5 601 CACAGCCGGGCACCGTCCCCACTCTACAGCGTGGAGTTCTCCGAGGAGCCCTTCGGGGTG
SEQ ID 8 601 CACAGCCGGGCACCGTCCCCACTCTACAGCGTGGAGTTCTCCGAGGAGCCCTTCGGGGTG
************************************************************
SEQ ID 5 661 ATCGTGCGCCGGCAGCTGGACGGCCGCGTGCTGCTGAACACGACGGTGGCGCCCCTGTTC
SEQ ID 8 661 ATCGTGCGCCGGCAGCTGGACGGCCGCGTGCTGCTGAACACGACGGTGGCGCCCCTGTTC
************************************************************
SEQ ID 5 721 TTTGCGGACCAGTTCCTTCAGCTGTCCACCTCGCTGCCCTCGCAGTATATCACAGGCCTC
SEQ ID 8 721 TTTGCGGACCAGTTCCTTCAGCTGTCCACCTCGCTGCCCTCGCAGTATATCACAGGCCTC
************************************************************
SEQ ID 5 781 GCCGAGCACCTCAGTCCCCTGATGCTCAGCACCAGCTGGACCAGGATCACCCTGTGGAAC
SEQ ID 8 781 GCCGAGCACCTCAGTCCCCTGATGCTCAGCACCAGCTGGACCAGGATCACCCTGTGGAAC
************************************************************
SEQ ID 5 841 CGGGACCTTGCGCCCACGCCCGGTGCGAACCTCTACGGGTCTCACCCTTTCTACCTGGCG
SEQ ID 8 841 CGGGACCTTGCGCCCACGCCCGGTGCGAACCTCTACGGGTCTCACCCTTTCTACCTGGCG
************************************************************
SEQ ID 5 901 CTGGAGGACGGCGGGTCGGCACACGGGGTGTTCCTGCTAAACAGCAATGCCATGGATGTG
SEQ ID 8 901 CTGGAGGACGGCGGGTCGGCACACGGGGTGTTCCTGCTAAACAGCAATGCCATGGATGTG
************************************************************
SEQ ID 5 961 GTCCTGCAGCCGAGCCCTGCCCTTAGCTGGAGGTCGACAGGTGGGATCCTGGATGTCTAC
SEQ ID 8 961 GTCCTGCAGCCGAGCCCTGCCCTTAGCTGGAGGTCGACAGGTGGGATCCTGGATGTCTAC
************************************************************
SEQ ID 5 1021 ATCTTCCTGGGCCCAGAGCCCAAGAGCGTGGTGCAGCAGTACCTGGACGTTGTGGGATAC
SEQ ID 8 1021 ATCTTCCTGGGCCCAGAGCCCAAGAGCGTGGTGCAGCAGTACCTGGACGTTGTGGGATAC
************************************************************
SEQ ID 5 1081 CCGTTCATGCCGCCATACTGGGGCCTGGGCTTCCACCTGTGCCGCTGGGGCTACTCCTCC
SEQ ID 8 1081 CCGTTCATGCCGCCATACTGGGGCCTGGGCTTCCACCTGTGCCGCTGGGGCTACTCCTCC
************************************************************
SEQ ID 5 1141 ACCGCTATCACCCGCCAGGTGGTGGAGAACATGACCAGGGCCCACTTCCCCCTGGACGTC
SEQ ID 8 1141 ACCGCTATCACCCGCCAGGTGGTGGAGAACATGACCAGGGCCCACTTCCCCCTGGACGTC
************************************************************
SEQ ID 5 1201 CAGTGGAACGACCTGGACTACATGGACTCCCGGAGGGACTTCACGTTCAACAAGGATGGC
SEQ ID 8 1201 CAGTGGAACGACCTGGACTACATGGACTCCCGGAGGGACTTCACGTTCAACAAGGATGGC
************************************************************
SEQ ID 5 1261 TTCCGGGACTTCCCGGCCATGGTGCAGGAGCTGCACCAGGGCGGCCGGCGCTACATGATG
SEQ ID 8 1261 TTCCGGGACTTCCCGGCCATGGTGCAGGAGCTGCACCAGGGCGGCCGGCGCTACATGATG
************************************************************
SEQ ID 5 1321 ATCGTGGATCCTGCCATCAGCAGCTCGGGCCCTGCCGGGAGCTACAGGCCCTACGACGAG
SEQ ID 8 1321 ATCGTGGATCCTGCCATCAGCAGCTCGGGCCCTGCCGGGAGCTACAGGCCCTACGACGAG
************************************************************
SEQ ID 5 1381 GGTCTGCGGAGGGGGGTTTTCATCACCAACGAGACCGGCCAGCCGCTGATTGGGAAGGTA
SEQ ID 8 1381 GGTCTGCGGAGGGGGGTTTTCATCACCAACGAGACCGGCCAGCCGCTGATTGGGAAGGTA
************************************************************
SEQ ID 5 1441 TGGCCCGGGTCCACTGCCTTCCCCGACTTCACCAACCCCACAGCCCTGGCCTGGTGGGAG
SEQ ID 8 1441 TGGCCCGGGTCCACTGCCTTCCCCGACTTCACCAACCCCACAGCCCTGGCCTGGTGGGAG
************************************************************
SEQ ID 5 1501 GACATGGTGGCTGAGTTCCATGACCAGGTGCCCTTCGACGGCATGTGGATTGACATGAAC
SEQ ID 8 1501 GACATGGTGGCTGAGTTCCATGACCAGGTGCCCTTCGACGGCATGTGGATTGACATGAAC
************************************************************
SEQ ID 5 1561 GAGCCTTCCAACTTCATCAGGGGCTCTGAGGACGGCTGCCCCAACAATGAGCTGGAGAAC
SEQ ID 8 1561 GAGCCTTCCAACTTCATCAGGGGCTCTGAGGACGGCTGCCCCAACAATGAGCTGGAGAAC
************************************************************
SEQ ID 5 1621 CCACCCTACGTGCCTGGGGTGGTTGGGGGGACCCTCCAGGCGGCCACCATCTGTGCCTCC
SEQ ID 8 1621 CCACCCTACGTGCCTGGGGTGGTTGGGGGGACCCTCCAGGCGGCCACCATCTGTGCCTCC
************************************************************
SEQ ID 5 1681 AGCCACCAGTTTCTCTCCACACACTACAACCTGCACAACCTCTACGGCCTGACCGAAGCC
SEQ ID 8 1681 AGCCACCAGTTTCTCTCCACACACTACAACCTGCACAACCTCTACGGCCTGACCGAAGCC
************************************************************
SEQ ID 5 1741 ATCGCCTCCCACAGGGCGCTGGTGAAGGCTCGGGGGACACGCCCATTTGTGATCTCCCGC
SEQ ID 8 1741 ATCGCCTCCCACAGGGCGCTGGTGAAGGCTCGGGGGACACGCCCATTTGTGATCTCCCGC
************************************************************
SEQ ID 5 1801 TCGACCTTTGCTGGCCACGGCCGATACGCCGGCCACTGGACGGGGGACGTGTGGAGCTCC
SEQ ID 8 1801 TCGACCTTTGCTGGCCACGGCCGATACGCCGGCCACTGGACGGGGGACGTGTGGAGCTCC
************************************************************
SEQ ID 5 1861 TGGGAGCAGCTCGCCTCCTCCGTGCCAGAAATCCTGCAGTTTAACCTGCTGGGGGTGCCT
SEQ ID 8 1861 TGGGAGCAGCTCGCCTCCTCCGTGCCAGAAATCCTGCAGTTTAACCTGCTGGGGGTGCCT
************************************************************
SEQ ID 5 1921 CTGGTCGGGGCCGACGTCTGCGGCTTCCTGGGCAACACCTCAGAGGAGCTGTGTGTGCGC
SEQ ID 8 1921 CTGGTCGGGGCCGACGTCTGCGGCTTCCTGGGCAACACCTCAGAGGAGCTGTGTGTGCGC
************************************************************
SEQ ID 5 1981 TGGACCCAGCTGGGGGCCTTCTACCCCTTCATGCGGAACCACAACAGCCTGCTCAGTCTG
SEQ ID 8 1981 TGGACCCAGCTGGGGGCCTTCTACCCCTTCATGCGGAACCACAACAGCCTGCTCAGTCTG
************************************************************
SEQ ID 5 2041 CCCCAGGAGCCGTACAGCTTCAGCGAGCCGGCCCAGCAGGCCATGAGGAAGGCCCTCACC
SEQ ID 8 2041 CCCCAGGAGCCGTACAGCTTCAGCGAGCCGGCCCAGCAGGCCATGAGGAAGGCCCTCACC
************************************************************
SEQ ID 5 2101 CTGCGCTACGCACTCCTCCCCCACCTCTACACACTGTTCCACCAGGCCCACGTCGCGGGG
SEQ ID 8 2101 CTGCGCTACGCACTCCTCCCCCACCTCTACACACTGTTCCACCAGGCCCACGTCGCGGGG
************************************************************
SEQ ID 5 2161 GAGACCGTGGCCCGGCCCCTCTTCCTGGAGTTCCCCAAGGACTCTAGCACCTGGACTGTG
SEQ ID 8 2161 GAGACCGTGGCCCGGCCCCTCTTCCTGGAGTTCCCCAAGGACTCTAGCACCTGGACTGTG
************************************************************
SEQ ID 5 2221 GACCACCAGCTCCTGTGGGGGGAGGCCCTGCTCATCACCCCAGTGCTCCAGGCCGGGAAG
SEQ ID 8 2221 GACCACCAGCTCCTGTGGGGGGAGGCCCTGCTCATCACCCCAGTGCTCCAGGCCGGGAAG
************************************************************
SEQ ID 5 2281 GCCGAAGTGACTGGCTACTTCCCCTTGGGCACATGGTACGACCTGCAGACGGTGCCAATA
SEQ ID 8 2281 GCCGAAGTGACTGGCTACTTCCCCTTGGGCACATGGTACGACCTGCAGACGGTGCCAGTA
********************************************************* **
SEQ ID 5 2341 GAGGCCCTTGGCAGCCTCCCACCCCCACCTGCAGCTCCCCGTGAGCCAGCCATCCACAGC
SEQ ID 8 2341 GAGGCCCTTGGCAGCCTCCCACCCCCACCTGCAGCTCCCCGTGAGCCAGCCATCCACAGC
************************************************************
SEQ ID 5 2401 GAGGGGCAGTGGGTGACGCTGCCGGCCCCCCTGGACACCATCAACGTCCACCTCCGGGCT
SEQ ID 8 2401 GAGGGGCAGTGGGTGACGCTGCCGGCCCCCCTGGACACCATCAACGTCCACCTCCGGGCT
************************************************************
SEQ ID 5 2461 GGGTACATCATCCCCCTGCAGGGCCCTGGCCTCACAACCACAGAGTCCCGCCAGCAGCCC
SEQ ID 8 2461 GGGTACATCATCCCCCTGCAGGGCCCTGGCCTCACAACCACAGAGTCCCGCCAGCAGCCC
************************************************************
SEQ ID 5 2521 ATGGCCCTGGCTGTGGCCCTGACCAAGGGTGGGGAGGCCCGAGGGGAGCTTTTCTGGGAC
SEQ ID 8 2521 ATGGCCCTGGCTGTGGCCCTGACCAAGGGTGGGGAGGCCCGAGGGGAGCTGTTCTGGGAC
************************************************** *********
SEQ ID 5 2581 GATGGAGAGAGCCTGGAAGTGCTGGAGCGAGGGGCCTACACACAGGTCATCTTCCTGGCC
SEQ ID 8 2581 GATGGAGAGAGCCTGGAAGTGCTGGAGCGAGGGGCCTACACACAGGTCATCTTCCTGGCC
************************************************************
SEQ ID 5 2641 AGGAATAACACGATCGTGAATGAGCTGGTACGTGTGACCAGTGAGGGAGCTGGCCTGCAG
SEQ ID 8 2641 AGGAATAACACGATCGTGAATGAGCTGGTACGTGTGACCAGTGAGGGAGCTGGCCTGCAG
************************************************************
SEQ ID 5 2701 CTGCAGAAGGTGACTGTCCTGGGCGTGGCCACGGCGCCCCAGCAGGTCCTCTCCAACGGT
SEQ ID 8 2701 CTGCAGAAGGTGACTGTCCTGGGCGTGGCCACGGCGCCCCAGCAGGTCCTCTCCAACGGT
************************************************************
SEQ ID 5 2761 GTCCCTGTCTCCAACTTCACCTACAGCCCCGACACCAAGGTCCTGGACATCTGTGTCTCG
SEQ ID 8 2761 GTCCCTGTCTCCAACTTCACCTACAGCCCCGACACCAAGGTCCTGGACATCTGTGTCTCG
************************************************************
SEQ ID 5 2821 CTGTTGATGGGAGAGCAGTTTCTCGTCAGCTGGTGTTAG
SEQ ID 8 2821 CTGTTGATGGGAGAGCAGTTTCTCGTCAGCTGGTGTTAG
***************************************
Regarding claim 42, the fusion protein SEQ ID NO: 2 taught by LeBowitz comprises a sequence over 95% identical to instant SEQ ID NO: 6, as shown below.
97.9% identity in 961 residues overlap; Score: 4980.0; Gap frequency: 1.6%
SEQ ID 6 22 LCGGELVDTLQFVCGDRGFLFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPARSE
SEQ ID 2 2 LCGGELVDTLQFVCGDRGFYFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPAKSE
******************* ************************************* **
SEQ ID 6 82 GGGGSGGGGSRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYI
SEQ ID 2 62 G---------------APAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYI
* * ******************************************
SEQ ID 6 142 PAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDV
SEQ ID 2 107 PAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDV
************************************************************
SEQ ID 6 202 MMETENRLHFTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVL
SEQ ID 2 167 MMETENRLHFTIKDPANRRYEVPLETPRVHSRAPSPLYSVEFSEEPFGVIVHRQLDGRVL
*************************** *********************** ********
SEQ ID 6 262 LNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANL
SEQ ID 2 227 LNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANL
************************************************************
SEQ ID 6 322 YGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVV
SEQ ID 2 287 YGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVV
************************************************************
SEQ ID 6 382 QQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSR
SEQ ID 2 347 QQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSR
************************************************************
SEQ ID 6 442 RDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNE
SEQ ID 2 407 RDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNE
************************************************************
SEQ ID 6 502 TGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSED
SEQ ID 2 467 TGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSED
************************************************************
SEQ ID 6 562 GCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SHRALVKAR
SEQ ID 2 527 GCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SHRALVKAR
************************************************************
SEQ ID 6 622 GTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLG
SEQ ID 2 587 GTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLG
************************************************************
SEQ ID 6 682 NTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYT
SEQ ID 2 647 NTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYT
************************************************************
SEQ ID 6 742 LFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGT
SEQ ID 2 707 LFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGT
************************************************************
SEQ ID 6 802 WYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGL
SEQ ID 2 767 WYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGL
************************************************************
SEQ ID 6 862 TTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVR
SEQ ID 2 827 TTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVR
************************************************************
SEQ ID 6 922 VTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSW
SEQ ID 2 887 VTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSW
************************************************************
SEQ ID 6 982 C
SEQ ID 2 947 C
*
Regarding claim 55, LeBowitz teaches wherein the fusion protein has a linker peptide between the vIGF2 component (GILT tag) and the GAA component ([0071], [0054]; Example 1, [0065]-[0067]).
Regarding claim 71, Mingozzi teaches therapeutic compositions comprising a pharmaceutical acceptable carrier and excipient(s), such as the suspending agent that is a starch, serum albumin or glycerol (pg. 41).
Regarding claim 84, although LeBowitz does not expressly teach wherein the vIGF2 component expressly comprises instant SEQ ID NO: 44, LeBowitz teaches using any functional vIGF2 component (GILT tag) having an amino acid sequence at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to mature human IGF-II (SEQ ID NO: 1) and as shown below instant SEQ ID NO: 44 is 95.2% identical to SEQ ID NO: 1.
95.2% identity in 63 residues overlap; Score: 321.0; Gap frequency: 0.0%
SEQ ID 44 1 SRTLCGGELVDTLQFVCGDRGFLFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPA
SEQ ID 1 5 SETLCGGELVDTLQFVCGDRGFYFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPA
* ******************** *************************************
SEQ ID 44 61 RSE
SEQ ID 1 65 KSE
**
Therefore, the claimed invention as a whole would have been prima facie obvious to a person of ordinary skill before the earliest effective filing date absent evidence to the contrary.
Claims 34-35, 40, 42, 44, 55, 71, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Mingozzi in view of LeBowitz and EMA as applied above, and further in view of Lieber (US20170037431A1; IDS ref.).
Regarding claim 44, the combination of Mingozzi, LeBowitz, and EMA does not teach wherein the nucleic acid vector comprises at least two tandem repeats of DRG-specific miR-183 target sequences operably linked 3’ to the sequence encoding the fusion protein.
However Lieber teaches a miRNA-based gene regulation system to suppress a potential cytotoxicity of high level of transgene expression from a viral vector (para. 155) by using multiple tandem repeats (at least 4) of miR-183 targeting site that binds to a miR-183 sequence ([0010], [0053], [0061], [0138] and [0167]), e.g., SEQ ID NO: 7 (5'- AGUGAAUUCUACCAGUGCCAUA -3') of Lieber which is a reverse complement targeting miR-183 at SEQ ID NO: 14 (5'-UAUGGCACUGGUAGAAUUCACU-3').
It would have been obvious to a person skilled in the art to use multiple tandem repeats of miR-183 targeting site as taught by Lieber et al. for the purpose of silencing cytotoxicity during recombinant AAV virus production. Therefore, the claimed invention as a whole would have been prima facie obvious to a person of ordinary skill before the earliest effective filing date absent evidence to the contrary.
Claims 34-35, 40, 42, 55, 64, 71, and 84-85 are rejected under 35 U.S.C. 103 as being unpatentable over Mingozzi in view of LeBowitz and EMA as applied above, and further in view of Wilson (WO2018160582A1; IDS ref.).
The invention of claims 34-35, 40, 42, 55, 71, and 84 would have been prima facie obvious to a person of ordinary skill before the earliest effective filing date as set forth fully above.
Regarding claim 64, the combination of Mingozzi, LeBowitz, and EMA does not expressly teach wherein the AAV capsid is a clade F capsid. However Mingozzi teaches wherein the AAV capsid is an AAV9 capsid, such as for target muscle cells (pg. 36, lines 25-26) and AAV9 is a clade F capsid as evidenced by Wilson (pg. 76, lines 12-13).
Regarding claim 85, the combination of Mingozzi, LeBowitz, and EMA does not teach wherein the AAV capsid is an AAVhu68 capsid.
However Wilson teaches AVV gene therapy vectors based on the clade F AAVhu68 capsid have significantly higher yields than AAV9 while providing tropism to motor cortex like AAV9 but with improved transduction efficiency over AAV9, e.g. to the cerebellum and motor cortex (pg. 10, lines 32-33; Examples 2-4; FIG. 3-6; pg. 29, lines 6-11), and Wilson teaches uses in treating Pompe disease by expressing recombinant GAA (pg. 38, line 28).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to specifically choose the AAVhu68 capsid taught by Wilson for use in the AAV viral delivery GAA-transgenic approach taught by Mingozzi wherein the ultimate goal is to treat Pompe disease. One of ordinary skill in the art would be motivated to because Wilson teaches AAVhu68 has higher yields while providing efficient transduction.
Therefore, the claimed invention as a whole would have been prima facie obvious to a person of ordinary skill before the earliest effective filing date absent evidence to the contrary.
Claims 47, 57, 84, 86-88, 90, and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Amicus (WO2019213180A1, priority to 2019-04-03; IDS ref.) in view of LeBowitz (US20120148556A1).
Regarding claim 47, Amicus teaches a gene therapy vector comprising a recombinant AAV vector comprising an AAV capsid and a vector genome carrying a nucleic acid construct having regulatory sequences operably linked to a sequence encoding a therapeutic protein (positioned 30-110 bp upstream of a start site) ([00111]-[00115]) wherein the protein is a fusion protein comprising a signal peptide ([0004]-[0005]), vIGF2 component (a peptide that selectively binds to the CI-MPR), and human alpha-glucosidase (GAA) (or enzymatically active fragment thereof) component ([0007]) comprising an active site at 516-521 relative to instant SEQ ID NO: 3 (Example 4, SEQ ID NO: 23; FIG. 12) as shown below, and wherein the vIGF2 peptide is at least 90% identical to instant SEQ ID NO: 32, as shown below, with at least one substitution at any one of positions 6, 26, 27, 43, 48-50, 55 and 65 ([0009], SEQ ID NO: 1), such as having E6R, Y27L, and K65R as in Example 4 (SEQ ID NO: 31).
98.5% identity in 908 residues overlap; Score: 4799.0; Gap frequency: 0.0%
SEQ ID 3 45 SSPVLEETHPAHQQGASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCE
SEQ ID 23 75 ATPARSEGGGGSGGGGSRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCE
* * * ********************************************
SEQ ID 3 105 ARGCCYIPAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDI
SEQ ID 23 135 ARGCCYIPAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDI
************************************************************
SEQ ID 3 165 LTLRLDVMMETENRLHFTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRR
SEQ ID 23 195 LTLRLDVMMETENRLHFTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRR
************************************************************
SEQ ID 3 225 QLDGRVLLNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLA
SEQ ID 23 255 QLDGRVLLNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLA
************************************************************
SEQ ID 3 285 PTPGANLYGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLG
SEQ ID 23 315 PTPGANLYGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLG
************************************************************
SEQ ID 3 345 PEPKSVVQQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWND
SEQ ID 23 375 PEPKSVVQQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWND
************************************************************
SEQ ID 3 405 LDYMDSRRDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRR
SEQ ID 23 435 LDYMDSRRDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRR
************************************************************
SEQ ID 3 465 GVFITNETGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSN
SEQ ID 23 495 GVFITNETGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSN
************************************************************
SEQ ID 3 525 FIRGSEDGCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SH
SEQ ID 23 555 FIRGSEDGCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SH
************************************************************
SEQ ID 3 585 RALVKARGTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGA
SEQ ID 23 615 RALVKARGTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGA
************************************************************
SEQ ID 3 645 DVCGFLGNTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYA
SEQ ID 23 675 DVCGFLGNTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYA
************************************************************
SEQ ID 3 705 LLPHLYTLFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVT
SEQ ID 23 735 LLPHLYTLFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVT
************************************************************
SEQ ID 3 765 GYFPLGTWYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYII
SEQ ID 23 795 GYFPLGTWYDLQTVPVEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYII
*************** ********************************************
SEQ ID 3 825 PLQGPGLTTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNT
SEQ ID 23 855 PLQGPGLTTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNT
************************************************************
SEQ ID 3 885 IVNELVRVTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMG
SEQ ID 23 915 IVNELVRVTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMG
************************************************************
SEQ ID 3 945 EQFLVSWC
SEQ ID 23 975 EQFLVSWC
********
100.0% identity in 67 residues overlap; Score: 360.0; Gap frequency: 0.0%
SEQ ID 32 1 AYRPSETLCGGELVDTLQFVCGDRGFYFSRPASRVSRRSRGIVEECCFRSCDLALLETYC
SEQ ID 1 1 AYRPSETLCGGELVDTLQFVCGDRGFYFSRPASRVSRRSRGIVEECCFRSCDLALLETYC
************************************************************
SEQ ID 32 61 ATPAKSE
SEQ ID 1 61 ATPAKSE
*******
Amicus does not teach wherein the GAA component comprises an isoleucine at position 780.
However LeBowitz teaches hGAA fusion proteins ([0014]) for use in enzyme replacement therapy to treat Pompe disease comprising a polypeptide at least 75% identical to a human IGF2 sequence (vIGF2 peptide) (SEQ ID NO: 1) for lysosomal targeting via binding CI-MPR wherein the human GAA polypeptide component (SEQ ID NO: 2) comprises an isoleucine at position 780 based on the numbering of the positions in instant SEQ ID NO: 3, as shown above ([0014]-[0016], [0018]; [0045]-[0047]; [0057]; [0064]-[0066]; [0071]; [0002]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to use the GAA fusion protein taught by LeBowitz in an AAV viral delivery transgenic system taught by Amicus for activity testing in CHO host cells as taught by Amicus (Example 5, FIG. 15). One of ordinary skill in the art would be motivated to because LeBowitz teaches such fusion proteins have potential uses in enzyme replacement therapies for GAA-deficiencies.
Regarding claim 57, Amicus taches wherein the signal peptide is a BiP or Gaussia signal peptide ([0004]-[0005]).
Regarding claim 84, Amicus teaches wherein the vIGF2 component consists of instant SEQ ID NO: 44 (Example 4, SEQ ID NO: 31).
100.0% identity in 63 residues overlap; Score: 334.0; Gap frequency: 0.0%
SEQ ID 44 1 SRTLCGGELVDTLQFVCGDRGFLFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPA
SEQ ID 31 1 SRTLCGGELVDTLQFVCGDRGFLFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPA
************************************************************
SEQ ID 44 61 RSE
SEQ ID 33 61 RSE
***
Regarding claim 86, Amicus teaches a gene therapy vector comprising a recombinant AAV vector comprising an AAV capsid and a vector genome carrying a nucleic acid construct having regulatory sequences operably linked to a sequence encoding a therapeutic protein (positioned 30-110 bp upstream of a start site) ([00111]-[00115]) wherein the protein is a fusion protein comprising a BiP signal peptide comprising instant SEQ ID NO: 49 ([0004]-[0005], [0013]; SEQ ID NO: 13) as shown below, a vIGF2 component comprising instant SEQ ID NO: 44 as shown above, and a human alpha-glucosidase (GAA) (or enzymatically active fragment thereof) component ([0007]) comprising an active site at 516-521 relative to instant SEQ ID NO: 3 (Example 4, SEQ ID NOs: 23 and 31; FIG. 12) as shown above.
100.0% identity in 18 residues overlap; Score: 76.0; Gap frequency: 0.0%
SEQ ID 44 1 MKLSLVAAMLLLLSAARA
SEQ ID 13 1 MKLSLVAAMLLLLSAARA
******************
Regarding claims 87-88, Amicus teaches wherein the AAV has the clade F AAVhu68 capsid ([0007]).
Regarding claim 90, Amicus teaches wherein the fusion protein comprises a sequence at least identical to instant SEQ ID NO: 6 (SEQ ID NO: 32) but for I780 and LeBowitz teaches wherein the chimeric fusion protein comprises a sequence (SEQ ID NO: 2) at least 95% identical to instant SEQ ID NO: 6, as shown below.
97.9% identity in 961 residues overlap; Score: 4980.0; Gap frequency: 1.6%
SEQ ID 6 22 LCGGELVDTLQFVCGDRGFLFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPARSE
SEQ ID 2 2 LCGGELVDTLQFVCGDRGFYFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPAKSE
******************* ************************************* **
SEQ ID 6 82 GGGGSGGGGSRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYI
SEQ ID 2 62 G---------------APAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYI
* * ******************************************
SEQ ID 6 142 PAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDV
SEQ ID 2 107 PAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDV
************************************************************
SEQ ID 6 202 MMETENRLHFTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVL
SEQ ID 2 167 MMETENRLHFTIKDPANRRYEVPLETPRVHSRAPSPLYSVEFSEEPFGVIVHRQLDGRVL
*************************** *********************** ********
SEQ ID 6 262 LNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANL
SEQ ID 2 227 LNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANL
************************************************************
SEQ ID 6 322 YGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVV
SEQ ID 2 287 YGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVV
************************************************************
SEQ ID 6 382 QQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSR
SEQ ID 2 347 QQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSR
************************************************************
SEQ ID 6 442 RDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNE
SEQ ID 2 407 RDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNE
************************************************************
SEQ ID 6 502 TGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSED
SEQ ID 2 467 TGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSED
************************************************************
SEQ ID 6 562 GCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SHRALVKAR
SEQ ID 2 527 GCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIA SHRALVKAR
************************************************************
SEQ ID 6 622 GTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLG
SEQ ID 2 587 GTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLG
************************************************************
SEQ ID 6 682 NTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYT
SEQ ID 2 647 NTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYT
************************************************************
SEQ ID 6 742 LFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGT
SEQ ID 2 707 LFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGT
************************************************************
SEQ ID 6 802 WYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGL
SEQ ID 2 767 WYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGL
************************************************************
SEQ ID 6 862 TTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVR
SEQ ID 2 827 TTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVR
************************************************************
SEQ ID 6 922 VTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSW
SEQ ID 2 887 VTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSW
************************************************************
SEQ ID 6 982 C
SEQ ID 2 947 C
*
Regarding claim 92, Amicus teaches wherein the AAV vector is in a composition comprising a pharmaceutically acceptable carrier, excipient, and suspending agent (e.g., a polymer), such as a non-ionic, low-osmolar compound, buffer, and polymer ([0010]).
Therefore, the claimed invention as a whole would have been prima facie obvious to a person of ordinary skill before the earliest effective filing date absent evidence to the contrary.
Claims 47, 57, 84, 86-90, and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Amicus in view of LeBowitz as applied above, and further as evidenced by Nitta (Nitta et al., J Gene Med 7: 1348-55 (2005); IDS ref.).
Regarding claim 89, Amicus teaches wherein the transgene is driven by a CAG promoter, which inherently comprises a CMV early enhancer, chicken beta -actin promoter and rabbit beta-globin intron sequence as evidenced by Nitta (Abstract: Methods; pg.1349, 1st col., 1st para.). Therefore, the claimed invention as a whole would have been prima facie obvious to a person of ordinary skill before the earliest effective filing date absent evidence to the contrary.
Claims 47, 57, 84, 86-88, and 90-92 are rejected under 35 U.S.C. 103 as being unpatentable over Amicus in view of LeBowitz as applied above, and further in view of Lieber.
Regarding claim 91, Amicus and LeBowitz does not teach wherein the construct comprises at least two tandem repeats of DRG-specific miR-183 target sequences operably linked 3’ of the sequence encoding the fusion protein.
However Lieber teaches a miRNA-based gene regulation system to suppress a potential cytotoxicity of high level of transgene expression from a viral vector (para. 155) by using multiple tandem repeats (at least 4) of miR-183 targeting site that binds to a miR-183 sequence ([0010], [0053], [0061], [0138] and [0167]), e.g., SEQ ID NO: 7 (5'- AGUGAAUUCUACCAGUGCCAUA -3') of Lieber which is a reverse complement targeting miR-183 at SEQ ID NO: 14 (5'-UAUGGCACUGGUAGAAUUCACU-3').
It would have been obvious to a person skilled in the art to use multiple tandem repeats of an miR-183 targeting site as taught by Lieber for the purpose of silencing cytotoxicity during recombinant AAV virus production. Therefore, the claimed invention as a whole would have been prima facie obvious to a person of ordinary skill before the earliest effective filing date absent evidence to the contrary.
Double Patenting (new)
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 34-35, 42, 57, 64, 84-88, and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 14-18, and 24-26 of copending Application No. 17/998,371 (the reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 and 14 of the reference application disclose compositions for treating a subject having Pompe disease comprising a recombinant AAV comprising (a) an AAV capsid that targets muscle and (b) a genomic nucleic acid (vector) expressing a chimeric fusion protein comprising a signal peptide, vIGF2 peptide, and hGAA-780I fused together, wherein the hGAA active site comprises 516-521 relative to instant SEQ ID NO: 3 and has a sequence at least 95% identical to 1-982 of instant SEQ ID NO: 6 (as in instant claim 42); and wherein the nucleic acid encoding the chimeric hGAA-780I fusion protein is operably linked to regulatory sequences that direct its expression (including a promoter). Although reference claim 1 does not expressly recite the rAAV targets muscle, this is implied by the phrases “reducing the progression of abnormal muscle pathology” and “reversing abnormal muscle pathology” in reference claim 1. Although reference claim 14 does not expressly recite the rAAV targets muscle, this is implied by reference claims 25-26 reciting “reversing abnormal muscle pathology.” Furthermore, reference claims 7 and 17 each teaches wherein the capsid is an AAVhu68 capsid, which inherently targets muscle cells.
Regarding instant claim 42, reference claims 1 and 14 encompass wherein the hGAA encoding component has a sequence at least 95% identical to instant SEQ ID NO: 7 and the hGAA fusion protein component has at least 95% sequence identity to instant SEQ ID NO: 6 (1-982 of reference SEQ ID NO: 6). Regarding instant claim 35, reference claims 1 and 14 encompass wherein the fusion protein consists of instant SEQ ID NO: 6, i.e., 100% identity.
Regarding instant claims 57, reference claims 1 and 14 encompass wherein the signal peptide is a BiP signal peptide comprises instant SEQ ID NO: 49, as shown below.
100.0% identity in 18 residues overlap; Score: 76.0; Gap frequency: 0.0%
Ref. SEQ 7 1 MKLSLVAAMLLLLSAARA
Ins. SEQ 44 1 MKLSLVAAMLLLLSAARA
******************
Regarding instant claims 64 and 85, reference claims 7 and 17 teach wherein the AAV capsid is the F clade capsid AAVhu68.
Regarding instant claim 84, reference claims 1 and 14 encompass wherein the vIGF2 component comprises instant SEQ ID NO: 44, as shown below.
100.0% identity in 63 residues overlap; Score: 334.0; Gap frequency: 0.0%
Ref. SEQ 7 19 SRTLCGGELVDTLQFVCGDRGFLFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPA
Ins. SEQ 44 1 SRTLCGGELVDTLQFVCGDRGFLFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPA
************************************************************
Ref. SEQ 7 79 RSE
Ins. SEQ 44 61 RSE
***
Regarding instant claim 86, as shown above reference claims 1 and 14 encompass wherein the signal peptide is a BiP signal peptide comprising instant SEQ ID NO: 49 and the vIGF2 component comprises instant SEQ ID NO: 44. Regarding instant claims 87-88, reference claims 7 and 17 teach wherein the capsid is the F clade capsid AAVhu68. Regarding instant claims 90, as noted above reference claims 1 and 14 encompass wherein the fusion protein comprises instant SEQ ID NO: 6 and is encoded by instant SEQ ID NO: 7 or a sequence at last 95% identical thereto.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 34-35, 42, 44, 57, 64, 84-88, and 90-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 14-18, and 24-26 of copending Application No. 17/998,371 (reference application) as applied above, and further in view of Reid (Reid et al., Gene Ther 24: 462-9 (2017); IDS ref.).
Regarding instant claims 44 and 91, reference claims 6 and 16 teach wherein the vector genome comprises four or more miR-183 target sequences operably linked to the nucleic acid encoding the fusion protein. While the reference claims do not particularly teach the repeats are tandem or placed 3’ of the fusion protein under the same promoter (operably linked), it is known in the art to place miRNA target sequences in tandem repeats at a position 3’ of a protein coding region of interest (3’ UTR) for functional use according to Reid (Fig. 1), such as to improve yields of transgenic AAVs (Abstract).
Thus, the claims of the ‘371 application in view of Reid render these claims of the instant application obvious. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 34-35, 42, 55, 57, 64, 84-88, and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 14-18, and 24-26 of copending Application No. 17/998,371 (the reference application) as applied above, and further in view of Chen (Chen et al., Adv Drug Deliv Rev 65: 1357-69 (2013)).
Regarding claim 55, Chen teaches including linkers between functional domains of a chimeric fusion protein, such as to reduce the risks of misfolding , impaired bioactivity, and/or low yield (pg. 1358, left col., 2nd para.; Abstract). Thus, it would have been prima facie obvious to one of ordinary skill in the art to include a linker between the vIGF2 component and the hGAA component of the fusion protein and sequence encoding it, such as to improve protein folding and/or biological activity of each domain in the fused context. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 34-35, 42, 57, 64, 71, 84-90, and 92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 14-18, and 24-26 of copending Application No. 17/998,371 (reference application) as applied above, and further in view of Maclaren (US20140107185A1; IDS ref.).
Regarding instant claim 71, while the reference claims 1-4 and 6-8 do not expressly teach what additional components are included in the rAAV composition administered to the patient and, similarly, reference claims 14-18 and 24-26 do not teach what pharmaceutically acceptable components are included in the pharmaceutical composition suitable for administering an AAV vector to a patient with Pompe disease, it would have been obvious in view of the prior art to include a carrier, excipient and suspending agent as taught by Maclaren, e.g., a saccharide suspending agent and a surfactant/preservative/stabilizer/antioxidant in an isotonic aqueous carrier, such as saline, Ringer’s or Lactated Ringer’s ([0096]-[0098]).
Regarding instant claim 89, while the reference claims do not teach what wherein the regulatory sequences expressly comprise a CAG promoter comprising a cytomegalovirus early enhancer element, chicken beta-actin promoter (CBA), and rabbit beta-globin intron sequence, it would have been obvious in view of the prior art to use such a configuration of regulatory sequences in view of Maclaren teaching a CAG promoter or hybrid CBA/CAG are preferred promoters for AAV-delivered transgene expression, e.g., stable and long-term expression ([0074]).
Thus, the claims of the ‘371 application in view of Maclaren render these claims of the instant application obvious. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 34-35, 40, 42, 44, 55, 64, 71, and 84-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 29-30, 33, 40, 43, 46, and 55-56 of copending Application No. 17/606,410 (reference application) in view of Mingozzi (WO2018/046774) and LeBowitz (US20120148556A1).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 30 of the reference application discloses a recombinant AAV for use in treating Pompe disease comprising (a) an AAV capsid that targets at least one of muscle, heart, and CNS and (b) a genomic nucleic acid (vector genome) comprising (1) a nucleic acid sequence at least 95% identical to instant SEQ ID NO: 4 encoding an hGAA comprising 780I based on instant SEQ ID NO: 3 and 95% identical to SEQ ID NO: 3; and (2) operably linked regulatory sequences comprising a CAG promoter comprising a CMV early enhancer, chicken beta-actin promoter, and rabbit beta-globin intron sequences. Although reference claim 30 does not disclose wherein the hGAA is a chimeric fusion protein also comprising a signal peptide and a vIGF2 peptide, including these features is obvious in view of Mingozzi teaching adding a signal peptide enhanced hGAA secretion and reduced humoral responses in vivo (pg. 49, lines 9-17; FIG. 3-5) and LeBowitz teaching adding a vIGF2 component that binds to CI-MPR in a M6P-dependent manner targets a fusion protein for lysosomal delivery ([0064]-[0066]; [0002]; [0045]-[0046]). Thus reference claim 30 in view Mingozzi and LeBowitz teaches instant claims 34 and 40.
Regarding instant claim 35, the nucleic acid sequence encoding a polypeptide at least 95% identical to 1-952 of SEQ ID NO: 3 taught by the reference claims inherently comprises amino acids 204-890, 204, 952, 123-890, 70-952, and 70-890 of instant SEQ ID NO: 3, such as taught by reference claim 57.
Regarding claim 42, LeBowitz teaches using such chimeric fusion proteins in enzyme replacement therapy to treat Pompe disease by administration to a subject ([0018]; [0047]; [0057]) and specifically teaches such a fusion protein SEQ ID NO: 2 comprising a sequence over 95% identical to instant SEQ ID NO: 6, as shown above.
Regarding claim 44, reference claims 33 and 13 teaches an hGAA transgene expression construct in the vector genome comprising several tandem repeats of DRG-specific miR-183 target sequences operably linked 3’ to the sequence encoding the hGAA.
Regarding claim 55, LeBowitz teaches wherein the chimeric fusion protein has a linker peptide between the vIGF2 component (GILT tag) and the GAA component ([0071], [0054]; Example 1, [0065]-[0067]).
Regarding claim 64, reference claim 29 teaches wherein the capsid is an AAVhu.68 or AAV9 capsid, both of which are clade F capsids.
Regarding claim 71, reference claim 40 teaches therapeutic compositions comprising a pharmaceutical acceptable carrier, an excipient, and a suspending agent.
Regarding claim 84, LeBowitz teaches using any functional vIGF2 component (GILT tag) having an amino acid sequence at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to mature human IGF-II (SEQ ID NO: 1) and as shown above instant SEQ ID NO: 44 is 95.2% identical to SEQ ID NO: 1 of LeBowitz.
Thus, the claims of the ‘410 application in view of Mingozzi and LeBowitz render these claims of the instant application obvious. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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