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 .
Note this application has been assigned to a different examiner.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any rejection or objection not reiterated in this Action is withdrawn.
Election/Restrictions
Claims 54 and 69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 7, 2024.
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)(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 8, 34, 35, 38, 42, 55 and 57 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Koeberl et al. (US 2012/0276072 A1, of record).
Regarding claims 34, 42 and 57, Koeberl teaches a recombinant adeno-associated virus (AAV) vector comprising a nucleic acid sequence encoding an alpha-glucosidase (GAA) polypeptide operatively-linked to a liver-specific promoter (LSP promoter) [0017] [0037]. Koeberl further teaches in figure 9 SEQ ID 3, which is 100% identical to instant SEQ ID 73. The recombinant AAV vector further comprises 5’ and 3’ inverted terminal repeats (ITRs) [0164] and the source for the AV capsid gene includes AAV8 [0157].
Regarding claim 8 the promoter is a cell-specific promoter (liver-specific promoter) and also can be constitutive or inducible [0177].
Regarding claim 35, the recombinant AAV vector comprises a secretory signal peptide operably linked to GAA (located at the N-terminal of the GAA polypeptide) [0009].
Regarding claim 38, the secretory signal peptide is Alpha-1-antitrypsin (AAT), GAA signal peptide (endogenous signal peptide) or fibronectin signal peptide [0035] [0088] [0280].
Regarding claim 55, Koeberl teaches a pharmaceutical composition comprising a recombinant AAV vector in a pharmaceutically-acceptable carrier [0219].
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.
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.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Koeberl in view of Chuah et al. (US 2020/0407749).
Koeberl teaches the limitation of claim 34 as described in the previous rejection, including the use of a GAA transgene, but does not teach an AAV8 vector comprising SEQ ID NO: 75.
However, Chuah teaches a sequence designated as SEQ ID NO: 94. This sequence is 95% identical to instant SEQ ID NO: 75 and is taught at paragraph 14 as a preferred codon optimized hGAAco transgene.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the vector of Koeberl et al. to contain the sequence of Chuah et al. One of ordinary skill in the art would do so and would expect success because Chuah teach their SEQ ID NO: 94 is a preferred codon optimized version of GAA.
Claims 8, 34, 35-39, 41, 42, 49, 52, 55, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Koeberl et al. as applied to claims 8, 34, 35, 38, 42, 55 and 57 above, and further in view of LeBowitz et al. (US 2018/0125949 A1, of record), Monahan et al. (US 2013/0012574, of record) and Powell et al. (2015, Discovery Medicine, 19(102): 49-57, of record).
Koeberl et al. teach all limitations of claims 8, 34, 35, 38, 42, 55 and 57 as detailed above.
Regarding claim 36, Koeberl teaches a recombinant AAV vector, wherein the heterologous nucleic acid sequence comprises a secretory signal peptide and the GAA polypeptide and provides isolated nucleic acids encoding lysosomal polypeptides (e.g., GAA) that are fused to a signal peptide that enhances targeting of the polypeptide to the secretory pathway [0077]. Koeberl teaches that the recombinant AAV vector is applicable as gene therapy in Pompe disease [0297]. Regarding claim 52, the secretory signal peptide is a fibronectin signal peptide or a modification thereof [0088].
Regarding claim 37, Koeberl teaches wherein the AAV genome comprises, in the 5' to 3' direction:
a 5' ITR ("a recombinant AAV vector genome comprising the AAV 5' and 3' inverted terminal repeats (ITRs)" [0164])
a liver specific promoter sequence [0297] ("the AAV vector encoding the alpha-1-antitrypsin signal peptide linked to hGAA" [0296]; "the Ad E1 region the CB promoter+hGAA cDNA+polyA transgene cassette flanked by the AAV2 TR sequences")[0244].
d. a nucleic acid encoding a secretory signal peptide ("a chimeric polypeptide comprising a secretory signal sequence operably linked to a lysosomal polypeptide" claim 73; "peptide leader sequence (SEQ ID NO: 4, corresponding to amino acids 1-27, SEQ ID NO:2) of hGAA was replaced with the synthetic peptide leader sequence SP38 ...peptide leader sequences from erythropoietin, albumin, alpha-1-antitrypsin and factor IX")[0280].
f. A nucleic acid encoding an alpha-glucosidase (GAA) polypeptide ("a chimeric polypeptide comprising a secretory signal sequence operably linked to a lysosomal polypeptide" claim 73; "peptide leader sequence (SEQ ID NO: 4, corresponding to amino acids 1-27, SEQ ID NO: 2) of hGAA was replaced with the synthetic peptide leader sequence SP38 ... peptide leader sequences from erythropoietin, albumin, alpha-1-antitrypsin and factor IX" [0280]).
g. A poly A sequence ("It will be understood that the GAA 3' UTR can contain some heterologous sequence(s) (e.g., the polyA signal"; para [0244]- "Ad E1 region the CB promoter+hGAA cDNA+polyA transgene cassette flanked by the AAV2 TR sequences" [0107])
h. A 3' ITR ("a recombinant AAV vector genome comprising the AAV 5' and 3' inverted terminal repeats (ITRs)"; para [0244]" Ad E1 region the CB promoter+hGAA cDNA+polyA transgene cassette flanked by the AAV2 TR sequences"[0164]).
In addition, Koeberl teaches that a coding region encoding a GAA polypeptide may include intron sequences [0100]. However, Koeberl fails to teach an intron sequence between the liver specific promoter sequence and the nucleic acid encoding a secretory signal peptide as recited in claim 37c. and also does not disclose a nucleic acid encoding an IGF-2 sequence, as recited in claims 36 and 37e.
Koeberl fails to teach that the heterologous nucleic acid sequence further comprises an IGF-2 sequence located between the secretory signal peptide and the GAA polypeptide, as recited in claim 36.
However, regarding claims 36, 37e and 39, LeBowitz teaches a heterologous nucleic acid sequence encoding a targeted therapeutic fusion polypeptide, which comprises a IGF-2 sequence and a GAA sequence, for targeting lysosomal enzymes to lysosomes (claim 17; [0006]). The fusion polypeptide contains a GAA polypeptide and an IGF-2 mutein having an amino acid sequence at least 70% identical to mature human IGF-2 (SEQ ID NO: 1), and having diminished binding affinity for the insulin receptor relative to the affinity of naturally occurring human IGF-2 for the insulin receptor; wherein the IGF-2 mutein binds to the human cation-independent mannose-6-phosphate receptor (CI-MPR; also referred to as IGF-2 receptor) in a mannose-6-phosphate-independent manner [0011].
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LeBowitz’s mature IGF-2 sequence set forth in SEQ ID NO: 1 shares 100% identity with the claimed sequence set forth in SEQ ID NO: 5, corresponding to the claimed IGF-2 leader sequence (See sequence alignment of instant SEQ ID NO:5 and LeBowitz’s SEQ ID NO:1 - search results for SEQ ID NO: 5 - database Published Applications AA Main).
With respect to the limitation “an IGF-2 leader sequence located between secretory signal peptide and the GAA polypeptide” in claim 36, Lebowitz further teaches a chimeric protein, ZC-701, that contains a N-terminal IGF-2-based GILT (Glycosylation Independent Lysosomal Targeting) tag fused via a three amino acid spacer to hGAA (See Fig. 1; [0102]). The IGF-2-based GILT tag can be fused directly to the lysosomal enzyme polypeptide (GAA) or can be separated from the lysosomal enzyme polypeptide by a linker or a spacer [0077]. Figure 1 below shows a map of N-terminus of ZC-701, in which the IGF-2 tag is located between a signal peptide and the spacer upstream from the GAA sequence. Therefore, Lebowitz teaches an IGF-2 sequence located between the signal peptide and the GAA polypeptide, as recited in claims 36 and 37.
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Furthermore, LeBowitz discloses that the IGF-2 tag including its signal peptide fused to the N-terminus of GAA directs the production of a recombinant GAA enzyme that is secreted at high levels and that contains a high affinity ligand for the M6P/IGF-2 receptor [0034].
Regarding claim 41, the IGF-2 mutein contains a deletion of amino acids corresponding to positions 2-7 of SEQ ID NO:1 [0015]. LeBowitz teaches an amino acid sequence set forth in SEQ ID NO: 8 which shares 100% identity with the instantly claimed SEQ ID NO:6, corresponding to the claimed sequence of IGF-2 comprising an amino acid deletion in positions 2-7 (Shown below sequence alignment of instant SEQ ID NO: 6 and LeBowitz’s SEQ ID NO:8- search results from database Published Applications AA Main) (regarding claim 52).
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In addition, the targeted therapeutic fusion polypeptide of LeBowitz can be administered to treat Pompe Disease [0019] [0052]. LeBowitz does not disclose an intron sequence between the liver specific promoter sequence and the nucleic acid encoding a secretory signal peptide, as recited in claim 37c.
However, regarding claim 37c., Monahan teaches compositions for enhanced transduction of an AAV vector comprising a heterologous nucleic acid of interest (abstract). Monahan teaches an expression vector containing a canine B domain deleted FVIII cDNA driven by a liver-specific promoter/enhancer, followed by a chimeric intron [0123].
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While Monahan does not explicitly teach that the intron is between the liver specific promoter and a nucleic acid encoding a secretory signal peptide, as instantly claimed, Powell remedies Monahan’s deficiency. Powell teaches the general organization of an AAV expression cassette design and shows that an intron is generally located between the promoter and the transgene (See Figure 1 below).
Powell discusses that placing an intron between the promoter and the transgene in an AAV expression cassette increases transgene expression (pg. 6, section “Introns”). Furthermore, Powell discusses that a variety of introns placed between the promoter and transgene were compared using AAV2 for liver transgene expression, and the MVM intron increased transgene expression more than any other intron tested and more than 80-fold over no intron (pg. 6, section “Introns”) (regarding claim 49).
Since Koeberl and LeBowitz teach a fusion polypeptide comprising the transgene of interest, GAA, with a signal peptide and an IGF-2 sequence, it would have been obvious to a person of ordinary skill in the art at the effective filing date of the claimed invention to combine the teachings of Koeberl regarding a recombinant AAV vector comprising a heterologous nucleic acid sequence encoding a fusion polypeptide that includes a secretory signal peptide and a GAA polypeptide for treating Pompe Disease, with the teachings of LeBowitz regarding a fusion polypeptide comprising an IGF-2 mutein fused to a GAA polypeptide for treating Pompe Disease, and the teachings of Monahan and Powell regarding the use and location of an intron in an AAV vector, to arrive at the claimed invention. A person of skill would have been motivated to make the combination since Koeberl teaches that fusing a signal peptide to GAA polypeptide enhances targeting of the polypeptide to the secretory pathway, and LeBowitz teaches that including an IGF-2 tag fused with GAA directs the production and high secretion levels of GAA in the lysosome. Therefore, a skilled artisan would have combined Koeberl and LeBowitz to produce an AAV recombinant vector comprising a fusion polypeptide having a signal peptide, IGF-2 sequence and GAA polypeptide as the transgene with the purpose of efficiently targeting GAA enzyme to lysosomes for the treatment of lysosomal diseases such as Pompe disease.
Furthermore, one of ordinary skill would have been motivated to further combine Koeberl and Lebowitz with Monahan and Powell to include an intron between the liver-specific promoter sequence and a nucleic acid encoding a secretory signal peptide since expression cassettes for AAV vectors have introns placed after a liver-specific promoter sequence, as taught by Monahan, and the use of introns, such as MVM, between the promoter and transgene for liver transgene expression was shown to increase transgene expression.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Claims 34 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Koeberl et al. (US 2012/0276072 A1) (ref. of record) in view of Doering et al. (US 2017/0326256 A1).
Koeberl meets the limitations of claim 34 as set forth above.
Regarding claim 45, Koeberl does not teach that the nucleic acid sequence encoding the GAA polypeptide is codon optimized.
However, Doering teaches an AAV-based transgene delivery system that uses improvements for the expression of clotting factor fVIII gene in the context of liver-directed AAV gene transfer, such as improved codon usage bias (codon-optimization) for the human liver cell compared to the naturally occurring nucleotide sequence of fVIII; and 2) Optimization of the codon usage to remove 5 ' - CG - 3 ' dinucleotides and other deleterious cis-acting DNA motifs [0037]. Furthermore, Doering discloses CpG motifs are removed since their occurrence may inhibit efficient expression of the transgene [0146], they may lead to gene methylation and silencing, and that CpG removal can reduce any immune response to a vector including the modified transgene, thus enhancing the safety and efficacy of the vector [0139]. In addition, Doering teaches that liver specific codon optimization improves expression for the HSQ and ET3 variants of the fVIII protein ([0019] [0022]; Fig. 3A).
Accordingly, it would have been obvious to one of ordinary skill in the art at the effective filing date to combine the teachings of Koeberl with the teachings of Doering by modifying Koeberl’s recombinant AAV vector comprising a heterologous nucleic acid sequence encoding a GAA polypeptide by performing codon optimization and reduction or elimination of CpG islands, as taught by Doering, since Doering teaches that CpG islands inhibit efficient expression of the transgene and may lead to gene methylation and silencing. Therefore, a person of ordinary skill in the art would have been motivated to make the combination with the purpose of improving the expression of GAA polypeptide and reducing the immune response against the vector, as a result of codon-optimization and reduction of CpG islands, thus increasing the safety and efficacy of the vector. Furthermore, one of ordinary skill would have had a reasonable expectation of success since AAV-based, tissue-specific transgene delivery systems that had been improved by performing such modifications were known in the art before the effective filing date of the claimed invention, as taught by Doering.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Claims 34 and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Koeberl et al. (US 2012/0276072 A1) (ref. of record) in view of Rabinowitz et al. (US 2014/0271550 A1, of record).
Koeberl meets the limitations of claim 34 as set forth above.
Koeberl does not teach an AAV vector comprising an ITR having an insertion, deletion or substitution, wherein one or more CpG islands are removed, as recited in claims 50 and 51.
However, Rabinowitz remedies Koeberl’s deficiency. Rabinowitz teaches a CpG-modified recombinant AAV vector carrying a nucleic acid molecule comprising AAV ITR sequences that may be CpG-modified or CpG-depleted ITRs (abstract; [0011] [0062] Figs. 15A-15C; [0030]). Rabinowitz teaches that CpG modified vectors comprising CpG depleted ITRs reduce innate immune responses toward the vector and/or transgene [0007] [0008] and CpG structures are reduced or removed without significantly impairing the function of the ITRs [0042].
Accordingly, it would have been obvious to a person of ordinary skill in the art at the effective filing date of the claimed invention to combine the teachings of Koeberl regarding a recombinant AAV vector comprising a heterologous nucleic acid sequence encoding a GAA polypeptide between 5’ and 3’ ITRs with the teachings of Rabinowitz regarding the removal of CpG islands in the ITRs of an AAV vector, to arrive at the claimed invention. One of ordinary skill would have been motivated to make the combination since Rabinowitz teaches that removing CpG in an AAV vector, including removing CpG in ITRs, does not affect their function and reduces or eliminates innate immune responses against the vector. Thus, a skilled artisan would have modified Koeberl’s vector to remove CpG islands in the ITR with the purpose of enhancing the delivery and expression of the transgene carried by the AAV vector and improving the safety of the vector.
Furthermore, a person of skill would have had a reasonable expectation of success since removal of CpG islands is a known technique in the field of AAV vector engineering, as taught by Rabinowitz.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Response to Arguments
Applicants traverse the rejections of record by arguing that Koeberl does not teach the claims as amended. This argument is not persuasive because Koeberl does teach a sequence corresponding to instant SEQ ID NO: 73. Additionally, a new rejection is made with Chuah et al. to address SEQ ID NO: 75.
Allowable Subject Matter
SEQ ID NOs: 74 and 76 are free of the art.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638