DETAILED ACTION
Applicant’s amendment and response received on 6/29/26 has been entered. Claims 5-6, 8, 10, 17-19, 23-24, 26-29, 33-36, 38-41, 45-52, 54-55, 58-60, 63-68, and 70-71 are now canceled, and new claims 72-74 have been added. Claims 1-4, 7, 9, 11-16, 20-22, 25, 30-32, 37, 42-44, 53-54, 56-57, 61-62, 69, and 72-74 are now pending in the instant application.
Of these, claims 37 and 42-43 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1/20/26. Claims 1-4, 7, 9, 11-16, 20-22, 25, 30-32, 44, 53-54, 56-57, 61-62, 69, and 72-74 are therefore currently under examination based on the species of an insertion site which is 581-593, and a cell which is a eukaryotic cell. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Those sections of Title 35, US code, not included I this action can be found in a previous office action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/29/26 and 7/9/26 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner, and initialed and signed copies of the 1449s are attached to this action.
Claim Objections
The objection to claims 15, 57, 62, and 71 for grammatical and typographical errors is withdrawn in view of either the cancelation of, or amendments to the claims.
Claim Rejections - 35 USC § 101
The rejection of claims 30, 61, and 70 under 35 U.S.C. 101 because the claimed invention is directed to judicial exception which is a product of nature without significantly more, is withdrawn over canceled 70, and further withdrawn over amended claims 30 and 61. Claim 61 as amended now recites an engineered AAV capsid library. Claim 30 as amended now recites a polypeptide encoded by a vector of claim 1, where claim 1 has been amended to recite an engineered AAV capsid polypeptide having a peptide inserted therein.
Claim Rejections - 35 USC § 112
The rejection of previously pending claims 3-4, 67, and 69-71 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, is withdrawn in view of either the cancellation of, or amendments to the claims.
Applicant’s amendments to the claims has necessitated the following new grounds of rejection.
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 9, 11-13, 16, 20, 22, 25, and 30 are newly 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.
Amended claim 9 depends on claim 1 and recites the limitation "the motif polynucleotide". There is insufficient antecedent basis for this limitation in the claim. Claim 1 refers to a “motif peptide”, not to a “motif polynucleotide”. As such, the metes and bounds of claim 9 cannot be determined. Claims 11-13, 16, and 20 depend on claim 9 and thus are included in this rejection.
Claim 22 recites the limitation, “wherein single promoter is operably coupled to both the AAV capsid protein polynucleotide and the AAV rep protein polynucleotide and the single promoter is the only promoter operably coupled to the AAV capsid protein polynucleotide and the AAV rep protein polynucleotide. This limitation regarding a “single promoter” is confusing as claim 1 limits the promoter operably linked to the AAV capsid protein polynucleotide to tissue-specific promoter. However, claim 22 does not refer to this promoter, or indicate that the “single promoter” is the same as the tissue-specific promoter in claim 1. As such, claim 22 appears to conflict with the limitation of claim 1 such that the metes and bounds of claim 22 cannot be determined. Claim 25 depends on claim 22 and thus is included in this rejection.
Amended claim 30 recites “[a] polypeptide encoded by a vector of claim 1”. However, claim 1 has been amended to recite that the vector encodes and “engineered AAV capsid polypeptide”. Thus, claim 30 appears to be attempting to claim a genus of polypeptide not specifically recited in claim 1, which is limited to an engineered AAV capsid polypeptide. Thus, the metes and bounds of claim 30 cannot be determined.
It is suggested that applicant amend claim 30 to recite, “[a]n engineered AAV capsid polypeptide encoded by the vector of claim 1”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is newly rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 7 depends on claim 1 and recites that the polyA sequence is an SV40 polyA sequence. However, claim 1 has been amended to include the limitation of an SV40 polyA sequence. As such, claim 7 does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The rejection of previously pending claims 2, 4, 9, 11-16, 18-20, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement, is maintained over claims 14-15, and withdrawn over the remaining claims in view of applicant’s cancellation of, amendments to the claims, or arguments.
The applicant argues that the vectors are for screening as part of a vector library and do not require any functional tropism, cell-type specificity, or successful transduction result. The applicant argues that the issues raised in the rejection and cited evidence apply to functional effects which are not claimed. While applicant’s arguments have been found persuasive for pending and amended claims 2-4, 7, 9, 11-13, 16, 20-22, 25, 30-32, 37, 42-44, 53-54, 56-57, 61-62, and 69, applicant’s arguments are not found persuasive over claims 14 and 15 which continue to recite functional activities of the vector. Claim 14, recites the vector of claim 1, which has been amended to recite the limitation of an inserted motif peptide previously recited in claim 2, “wherein the vector is capable of producing AAV virus particles having increased specificity, reduced immunogenicity, or both”. Claim 15 depends on claim 14 and further recites, “wherein the vector is capable of producing AAV virus particles having increased muscle cell specificity, reduced immunogenicity, or both”. Thus, the vectors recited in claims 14 and 15 do in fact recite specific functional activities which, as discussed in detail in the rejection of record, are not enabled for the breadth of the claims. The applicant provides no arguments concerning the lack of enablement for the scope of engineered capsids encompassed by the claimed vector which exhibit these functional features. As such, the scope of enablement rejection over claims 14-15 is maintained.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 7, 9, 11-15, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 57, 59, 61-62, 65, 67, and 69 under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/189244 (April, 2018), hereafter referred to as Grimm et al., is maintained over claim 30, and withdrawn over the remaining claims in view of applicant’s cancellation of or amendments to those claims which now recite the presence of 5’ and 3’ ITR and a tissue specific promoter.
The applicant argues that the claimed vector required the presence of 5’ and 3’ ITR and a tissue specific promoter which are not taught by Grimm et al. However, claim 30 is drawn to a polypeptide encoded by the vector and not to the vector itself. Grimm et al. teaches an engineered AAV capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV capsid serotype AAV2 or AAV9 (Grimm et al., pages 25-28, and 30-31). As such, Grimm et al. continues to anticipate the polypeptide product claimed in claim 30.
The rejection of claims 1, 7, 9, 11-15, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 57, 59, 61-62, 65, 67, and 69-71 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017, is maintained over claim 30, and withdrawn over the remaining claims in view of applicant’s cancellation of, or amendments to these claims which now recite the presence of 5’ and 3’ ITR and a tissue specific promoter.
The applicant argues that the claimed vector required the presence of 5’ and 3’ ITR and a tissue specific promoter which are not taught by Li et al. However, claim 30 is drawn to a polypeptide encoded by the vector and not to the vector itself. Li et al. teaches modified AAV capsid protein with enhanced transduction of muscle cells, including skeletal, and cardiac muscle cells, and reduced transduction of the liver, where the AAV capsid polypeptide is modified by inserting 1-10 or more amino acids into amino acid position 585-590 of AAV2 or the corresponding positions of other AAV, including specifically amino acid positions 588-589 of AAV9 (Li et al., paragraphs 186, 188-190, and 232). As such, Li et al. continues to anticipate the polypeptide product claimed in claim 30.
Claim Rejections - 35 USC § 103
The rejection of claims 1 and 3 under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017, in view of Farris et al. (2008) Human Gene Therapy, Vol. 19, 1421-1427, is withdraw in view of applicant’s amendments to the claims which now recite the presence of 5’ and 3’ ITR and a tissue specific promoter.
Applicant’s amendments to the claims has necessitated the following new grounds of rejection.
Claims 1-4, 7, 9, 11-16, 20-22, 25, 30-32, 44, 53-54, 56-57, 61-62, 69, and 72-74 are newly rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/189244 (April, 2018), hereafter referred to as Grimm et al., in view of Adachi et al. (2010) Gene Ther. Regul., Vol. 5(1), 31-55, Stutika et al. (2016) J. Virol., Vol. 90(3), 1278-1289, Farris et al. (2008) Human Gene Ther., Vol. 19, 14221-1427, and U.S. Patent Application Publication 2021/0380969 (2021), hereafter referred to as Nonnenmacher et al., with an effective filing date of Oct. 2, 2018.
Grimm et al. teaches the creation of a library of AAV vectors, where each vector component of the library comprises a polynucleotide encoding an engineered AAV capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV capsid serotype AAV2 or AAV9 (Grimm et al., pages 25-28, and 30-31). Grimm et al. further teaches that the targeting peptide comprises RGDCFC or RGDCFCA (Grimm et al., also SEQ ID NOS 3, and 9). In particular, Grimm et al. further teaches an AAV vector encoding the AAV2 rep gene together with the capsid gene coding for the engineered AAV capsid (Grimm et al., paragraph 158). Grimm et al. also teaches that the AAV vector can be used to identify an AAV variant infecting a target cell of interest (Grimm et al., pages 12-13). On page 19, Grimm et al. teaches that the vector can further comprise a polyA site such as SV40 polyA sequence downstream of the polynucleotide encoding the engineered AAV capsid (Grimm et al., page 19). Specifically Grimm on page 19 states:
More preferably, in the vector of the invention, the polynucleotide is operatively linked to expression control sequences allowing expression in eukaryotic cells or isolated fractions thereof. Expression of said polynucleotide comprises transcription of the polynucleotide, preferably into a translatable mRNA. Regulatory elements ensuring expression in eukaryotic cells, preferably mammalian cells, are well known in the art. They, preferably, comprise regulatory sequences ensuring initiation of transcription and, optionally, poly-A signals ensuring termination of transcription and stabilization of the transcript. Additional regulatory elements may include transcriptional as well as translational enhancers. Possible regulatory elements permitting expression in eukaryotic host cells are the AOX1 or GALI promoter in yeast or the CMV-, SV40-, RSV-promoter (Rous sarcoma virus), CMV-enhancer, SV40- enhancer or a globin intron in mammalian and other animal cells. Preferably, the regulatory element comprises the AAV p40 promoter. Moreover, inducible expression control sequences may be used in an expression vector encompassed by the present invention. Suitable expression control sequences are well known in the art. Beside elements which are responsible for the initiation of transcription such regulatory elements may also comprise transcription termination signals, such as the SV40-poly-A site, the tk-poly-A site, or the AAV poly-A site downstream of the polynucleotide (emphasis added by the examiner).
Note that Grimm et al. on page 15 clearly teaches, “[t]he polynucleotide of the present invention encodes a variant AAV capsid polypeptide of the present invention. Preferably, the polynucleotide comprises a sequence encoding an AAV capsid polypeptide as specified herein, wherein a nucleic acid sequence encoding a specific combination of (i) a strain-specific capsid polypeptide and (ii) a peptide inserted into said capsid polypeptide, preferably replacing the nucleic acid sequence encoding the naturally occurring capsid polypeptide”. Thus, the polynucleotide present in the vector, which is taught in page 19 to be operably linked to a promoter and, optionally, to a polyA sequence, is a polynucleotide encoding a variant AAV capsid polypeptide. Thus, Grimm et al. specifically teaches that inclusion of a polyA sequence downstream of a polynucleotide sequence encoding an AAV capsid in a vector constitutes one particular embodiment of the vector.
Grimm et al. teaches several embodiments of the AAV vector library, including a preferred embodiment where the AAV vectors present in the library are used in an “isolated manner”, or not as a mixture. However, Grimm et al. teachings are not limited to this preferred embodiment and encompass AAV vector libraries where the component vector variants are present together, as a mixture. Grimm et al. discloses the use of AAV vector libraries in this form which involves several rounds of enrichment and reinfection of cells with the AAV library vectors. Grimm et al. does differ from the instant claims by not teaching that the vectors comprise 5’ and 3’ ITR flanking the rep and cap coding sequences. Adachi et al. supplements Grimm et al. by providing a more detailed protocol for the enrichment and reinfection method disclosed by Grimm et al. Adachi et al. teaches an rAAV1.9-3 based random peptide display library comprising AAV1.9-3 vectors which each contain a random 7- or 12-mer peptide-coding sequence inserted between AAV1.9-3 amino acid positions 590-591 (Adachi et al., page 35). Adachi et al. teaches that the vectors comprise 5’-3’ a 5’ ITR, the rep coding sequence coupled to the cap coding sequence and a 3’ ITR (Adachi et al., page 35, Figure 2a). Adachi et al. further teaches selection of cell binding variants using biopanning selection where the AAV vector library as a whole, i.e. all vectors together as a mixture, is applied to target cells, for 3-5 rounds of selection (Adachi et al., page 35, Figure 2, and pages 37-38). Thus, as both Grimm et al. and Adachi provide the teachings and motivation to prepare an AAV vector library, as a mixture of individual vectors, rather than as a collection of individual, spatially separated AAV vectors, and Adachi et al. provides teaching and motivation to utilize a vector design for a library to screen for AAV capsids comprising inserted peptide variants capable of cell specific targeting, it would have been prima facia obvious to the skilled artisan at the time of filing to make a vector or mixture of vectors using a vector comprising 5’ and 3’ ITRs flanking a promoter, a rep coding sequence a cap coding sequence, an SV40 polyA, where the cap coding sequence encodes an engineered AAV capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV capsid serotype AAV2 or AAV9 with a reasonable expectation of success.
While Grimm et al. and Adachi et al., as noted above, both teach an AAV vector comprising a rep gene together with the capsid gene coding for the engineered AAV capsid, Grimm et al. and Adachi et al. differ from the claimed AAV vector by not teaching that the AAV vector also includes a splice regulatory sequence which is either a splice donor or splice acceptor sequence present either within the rep gene or between the rep and cap gene sequences. Grimm et al. further does not teach that the splice regulatory sequence is a modified sequence. Stutika et al. supplements Grimm et al. by teaching an AAV vector comprising the rep coding sequence followed by a cap coding sequence where a polyA sequence is present at the 3’ end of the cap coding sequence (Stutika et al., Figure 2). Stutika et al. also shows the presence of several splice regulatory sequence both within the coding sequence of rep and between the coding sequences of rep and cap, including both splice donor and splice acceptor sequences (Stutika et al., Figure 2). In addition, Stutika et al. teaches two modifications to the splice donor sequence at position 527 of rep, where the modifications inactivate this donor sequence (Stutika et al., page 1283 and Figure 2B). Figure 5 of Stutika et al. also shows that a number of the splice donor and acceptor sequences present in various AAV serotypes appear to qualify as splice regulatory sequences as they show less correspondence to the consensus splice donor sequence, or the consensus splice acceptor sequence, and/or are less active than other splice regulatory sequences present in rep sequence (Stutika et al., Table 3 and Figure 5). Farris et al. also teaches modification of splice donor sequences present in the rep polynucleotide sequence, where the modified splice donor sequences result in improved rAAV production vs wild-type donor RepCap constructs (Farris et al., Figure 1 and pages 1421 -442).
Therefore, in view of the teachings of both Grimm et al. and Adachi et al. for AAV vector libraries where the individual vector are present together, i.e. as a “mixture”, the teachings of both Stutika et al. and Farris et al. that the AAV rep polynucleotide sequence comprises several splice donor sequences, that the sequence between the rep and cap polynucleotides also includes a splice acceptor sequence, that the splice regulatory sequences present in the wild type AAV constitute functional splice regulatory sequences, the motivation provided by both Stutika et al. and Farris et al. to modify a splice donor sequence to either inactivate or improve the activity of the splice donor sequence in order to either observe the effects of the changes on AAV production, or to improve AAV production, it would have been prima facie obvious to the skilled artisan at the time of filing to modify at least one splice donor sequence present in the AAV rep sequence of a vector according to Grimm et al. in view of Adachi et al. in order to produce an AAV vector or AAV vector library present as a mixture of vectors with a reasonable expectation of success.
Finally, in regards to the promoter operably linked to the nucleotide encoding the variant capsid polypeptides, while Grimm et al. generally teaches to use a constitutive or inducible promoter to express the variant capsid protein, Nonnenmacher et al. teaches that other promoters can be used to express AAV capsids, and in particular tissue specific promoters. Nonnenmacher et al. supplements Grimm et al., Adachi et al., Stutika et al. and Farris et al. by teachings the development of a broadly-applicable functional AAV capsid library screening platform referred to as the TRACER (Tropism Redirection of AAV by Cell type-specific Expression of RNA) platform system (Nonnenmacher et al., paragraph 10). Nonnenmacher teaches that the capsid gene present in the AAV capsid library vector is placed under the control of a cell type-specific promoter to drive capsid mRNA expression in the absence of helper virus co-infection, and that this RNA-driven screen increases the selective pressure in favor of capsid variants which transduce a specific cell type (Nonnenmacher et al., paragraph 10). Nonnenmacher et al. further teaches that the TRACER platform allows generation of AAV capsid libraries whereby specific recovery and subcloning of capsid mRNA expressed in transduced cells is achieved with no need for transgenic animals or helper virus co-infection and with increased stringency (Nonnenmacher et al., paragraph 11). In particular, Nonnenmacher et al. teaches libraries designed to express CAP mRNA under the control of any cell-specific promoter such as, but not limited to, synapsin-1 promoter (neurons), GFAP promoter (astrocytes), TBG promoter (liver), CAMK promoter (skeletal muscle), or MYH6 promoter (cardiomyocytes) (Nonnenmacher et al., paragraph 11 and Figure 4A). Therefore, by teaching that the use of a cell specific promoter to drive expression of a variant AAV capsid in AAV capsid vector libraries increases the selective pressure in favor of capsid variants which transduce a specific cell type, allowing for the identification of AAV capsid variants with high tropism for the target cell type with high stringency, Nonnenmacher et al. provides substantial motivation to utilize a cell specific promoter operatively linked to an AAV capsid variant in AAV capsid library vectors.
Thus, based on the substantial benefits to using a cell specific promoter in operative linkage to a nucleotide sequence encoding a variant CAP polypeptide over a constitutive promoter in AAV capsid libraries as taught by Nonnenmacher et al., it would have been prima facie obvious to the skilled artisan at the time of filing to utilize a cell specific promoter instead of a constitutive promoter in the AAV capsid variant vectors of the vector library taught by Grimm et al. in view of Adachi et al., Stutika et al. and Farris et al. to drive expression of a variant AAV capsid with a reasonable expectation of success.
Double Patenting
The rejection of previously pending claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,920,150, hereafter referred to as the ‘150 patent, in view of US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017, is withdrawn in view of applicant’s amendments to the claims.
The previously provisional rejection of claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 on the ground of nonstatutory double patenting as being unpatentable over claims 1-26, and 31-41 of copending application 17/707,944, hereafter referred to as the ‘944 application, in view of US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017, is withdrawn in view of new grounds of rejection based on the issuance of U.S. Patent 12,628,082 and the amendments to the instant claims.
Applicant’s amendments to the claims has necessitated the following new grounds of rejection.
Claims 1-4, 7, 9, 11-16, 20-22, 25, 30-32, 44, 53-54, 56-57, 61-62, 69, and 72-74 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over 1) claims 1-30 of U.S. Patent No. 11,920,150, hereafter referred to as the ‘150 patent, OR 2) claims 1-28 of U.S. Patent No. 12,618,082, hereafter referred to as the ‘082 patent, in view of WO 2018/189244 (April, 2018), hereafter referred to as Grimm et al., in view of Adachi et al. (2010) Gene Ther. Regul., Vol. 5(1), 31-55, Stutika et al. (2016) J. Virol., Vol. 90(3), 1278-1289, Farris et al. (2008) Human Gene Ther., Vol. 19, 14221-1427, and U.S. Patent Application Publication 2021/0380969 (2021), hereafter referred to as Nonnenmacher et al., with an effective filing date of Oct. 2, 2018.
The ‘150 patent claims recite vector/vector systems, capsid polypeptides, cell comprising the vectors, AAV particles comprising the capsid and methods of administering the vector or AAV particle which are both broader than the instant claims. The ‘150 patent claims recite in certain dependent claims a number of limitations set forth in the instant claims with the exception that the ‘150 patent claims do not specifically recite additional particulars of the capsid vector, such as the presence of flanking 5’ and ‘3 ITRS, an SV40 polyA, a rep protein, a tissue-specific promoter, or the presence or absence of a splice regulatory element. However, it is noted that the ‘150 patent claims do encompass these embodiment and do broadly recite in claim 12 that the vector comprises one more regulatory element operatively linked to the capsid sequence.
Specifically, the ‘150 patent claims OR the ‘082 patent claims recite engineered AAV capsids, or AAV viral particles, or vector systems comprising engineered AAV capsids where the capsid comprises an RGD motif which is 3-18 amino acids in length and which more specifically is a peptide sequence set forth in Table I of the instant application (’150 claims 1, 3 and 12-13, and ‘082 claim 17), and where the RGD motif is inserted between amino acids 588-589 (‘150 claims 5 and 17, and ‘082 claim 20). The ‘150 patent claims OR the ‘082 patent claims also recites cells comprising the engineered AAV capsids. Thus, while not identical in scope, the ’150 patent claims OR the ‘082 patent claims encompass the instant claimed products.
While for example claim 12 of the ‘150 patent OR claim 17 of the ‘082 patent does recite the presence of one or more regulatory sequences in the vector, none of either set of patent claims specifically recites that the regulatory sequences are a polyA sequence and a tissue-specific promoter sequence, that the vector further encodes a rep protein, that the vector comprises flanking 5’ and 3’ ITR, or that the vector comprises splice regulatory sequences. However, such embodiments are encompassed by the ‘150 patent claims or the ‘082 patent claims, and further the inclusion of such elements in an AAV vector encoding a modified capsid were known in the prior art.
Grimm et al. supplements the ‘150 patent claims OR the ‘082 patent claims by teaching the creation of a library of AAV vectors, where each vector component of the library comprises a polynucleotide encoding an engineered AAV capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV capsid serotype AAV2 or AAV9 (Grimm et al., pages 25-28, and 30-31). Grimm et al. further teaches that the targeting peptide comprises RGDCFC or RGDCFCA (Grimm et al., also SEQ ID NOS 3, and 9). In particular, Grimm et al. further teaches an AAV vector encoding the AAV2 rep gene together with the capsid gene coding for the engineered AAV capsid (Grimm et al., paragraph 158). Grimm et al. also teaches that the AAV vector can be used to identify an AAV variant infecting a target cell of interest (Grimm et al., pages 12-13). On page 19, Grimm et al. teaches that the vector can further comprise a polyA site such as SV40 polyA sequence downstream of the polynucleotide encoding the engineered AAV capsid (Grimm et al., page 19). Specifically Grimm on page 19 states:
More preferably, in the vector of the invention, the polynucleotide is operatively linked to expression control sequences allowing expression in eukaryotic cells or isolated fractions thereof. Expression of said polynucleotide comprises transcription of the polynucleotide, preferably into a translatable mRNA. Regulatory elements ensuring expression in eukaryotic cells, preferably mammalian cells, are well known in the art. They, preferably, comprise regulatory sequences ensuring initiation of transcription and, optionally, poly-A signals ensuring termination of transcription and stabilization of the transcript. Additional regulatory elements may include transcriptional as well as translational enhancers. Possible regulatory elements permitting expression in eukaryotic host cells are the AOX1 or GALI promoter in yeast or the CMV-, SV40-, RSV-promoter (Rous sarcoma virus), CMV-enhancer, SV40- enhancer or a globin intron in mammalian and other animal cells. Preferably, the regulatory element comprises the AAV p40 promoter. Moreover, inducible expression control sequences may be used in an expression vector encompassed by the present invention. Suitable expression control sequences are well known in the art. Beside elements which are responsible for the initiation of transcription such regulatory elements may also comprise transcription termination signals, such as the SV40-poly-A site, the tk-poly-A site, or the AAV poly-A site downstream of the polynucleotide (emphasis added by the examiner).
Note that Grimm et al. on page 15 clearly teaches, “[t]he polynucleotide of the present invention encodes a variant AAV capsid polypeptide of the present invention. Preferably, the polynucleotide comprises a sequence encoding an AAV capsid polypeptide as specified herein, wherein a nucleic acid sequence encoding a specific combination of (i) a strain-specific capsid polypeptide and (ii) a peptide inserted into said capsid polypeptide, preferably replacing the nucleic acid sequence encoding the naturally occurring capsid polypeptide”. Thus, the polynucleotide present in the vector, which is taught in page 19 to be operably linked to a promoter and, optionally, to a polyA sequence, is a polynucleotide encoding a variant AAV capsid polypeptide. Thus, Grimm et al. specifically teaches that inclusion of a polyA sequence downstream of a polynucleotide sequence encoding an AAV capsid in a vector constitutes one particular embodiment of the vector.
Adachi et al. supplements the ‘150 patent claims OR the ‘082 patent claims and Grimm et al. by teaching an rAAV1.9-3 based random peptide display library comprising AAV1.9-3 vectors which each contain a random 7- or 12-mer peptide-coding sequence inserted between AAV1.9-3 amino acid positions 590-591 (Adachi et al., page 35). Adachi et al. teaches that the vectors comprise 5’-3’ a 5’ ITR, the rep coding sequence coupled to the cap coding sequence and a 3’ ITR (Adachi et al., page 35, Figure 2a). Adachi et al. further teaches selection of cell binding variants using biopanning selection where the AAV vector library as a whole, i.e. all vectors together as a mixture, is applied to target cells, for 3-5 rounds of selection (Adachi et al., page 35, Figure 2, and pages 37-38). Thus, as both Grimm et al. and Adachi provide the teachings and motivation to prepare an AAV vector or AAV vector library, with particular genetic elements such as a promoter and polyA operatively linked to the capsid sequence, the inclusion of a rep sequence, and Adachi et al. provides teaching and motivation to utilize a vector design which comprises 5’ and 3’ ITRs, it would have been prima facia obvious to the skilled artisan at the time of filing to make a vector or mixture of vectors using a vector library according to the ‘150 patent claims OR the ‘082 patent claims comprising 5’ and 3’ ITRs flanking a promoter, a rep coding sequence and a cap coding sequence, and a SV40 polyA, where the cap coding sequence encodes an engineered AAV capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV capsid serotype AAV2 or AAV9 with a reasonable expectation of success.
While Grimm et al. and Adachi et al., as noted above, both teach an AAV vector comprising a rep gene together with the capsid gene coding for the engineered AAV capsid, the ‘150 patent claims OR the ‘082 patent claims, Grimm et al. and Adachi et al. differ from the claimed AAV vector by not teaching that the AAV vector also includes a splice regulatory sequence which is either a splice donor or splice acceptor sequence present either within the rep gene or between the rep and cap gene sequences. Stutika et al. supplements the ‘150 patent claims OR the ‘082 patent claims, Grimm et al., and Adachi et al. by teaching an AAV vector comprising the rep coding sequence followed by a cap coding sequence where a polyA sequence is present at the 3’ end of the cap coding sequence (Stutika et al., Figure 2). Stutika et al. also shows the presence of several splice regulatory sequence both within the coding sequence of rep and between the coding sequences of rep and cap, including both splice donor and splice acceptor sequences (Stutika et al., Figure 2). In addition, Stutika et al. teaches two modifications to the splice donor sequence at position 527 of rep, where the modifications inactivate this donor sequence (Stutika et al., page 1283 and Figure 2B). Figure 5 of Stutika et al. also shows that a number of the splice donor and acceptor sequences present in various AAV serotypes appear to qualify as splice regulatory sequences as they show less correspondence to the consensus splice donor sequence, or the consensus splice acceptor sequence, and/or are less active than other splice regulatory sequences present in rep sequence (Stutika et al., Table 3 and Figure 5). Farris et al. also teaches modification of splice donor sequences present in the rep polynucleotide sequence, where the modified splice donor sequences result in improved rAAV production vs wild-type donor RepCap constructs (Farris et al., Figure 1 and pages 1421 -442).
Therefore, in view of the teachings of Stutika et al. and Farris et al. that the AAV rep polynucleotide sequence comprises several splice donor sequences, that the sequence between the rep and cap polynucleotides also includes a splice acceptor sequence, that the splice regulatory sequences present in the wild type AAV constitute functional splice regulatory sequences, the motivation provided by both Stutika et al. and Farris et al. to modify a splice donor sequence to either inactivate or improve the activity of the splice donor sequence in order to either observe the effects of the changes on AAV production, or to improve AAV production, it would have been prima facie obvious to the skilled artisan at the time of filing to modify the vectors of the ‘150 patent claims OR the ‘082 patent claims in view of Grimm et al. and Adachi et al. to further comprise at least one splice donor sequence present in the AAV rep sequence of in order to produce an AAV vector or AAV vector library with a reasonable expectation of success.
Finally, in regards to the promoter operably linked to the nucleotide encoding the variant capsid polypeptides, while Grimm et al. generally teaches to use a constitutive or inducible promoter to express the variant capsid protein, Nonnenmacher et al. teaches that other promoters can be used to express AAV capsids, and in particular tissue specific promoters. Nonnenmacher et al. supplements the ‘150 patent claims OR the ‘082 patent claims, Grimm et al., Adachi et al., Stutika et al. and Farris et al. by teachings the development of a broadly-applicable functional AAV capsid library screening platform referred to as the TRACER (Tropism Redirection of AAV by Cell type-specific Expression of RNA) platform system (Nonnenmacher et al., paragraph 10). Nonnenmacher teaches that the capsid gene present in the AAV capsid library vector is placed under the control of a cell type-specific promoter to drive capsid mRNA expression in the absence of helper virus co-infection, and that this RNA-driven screen increases the selective pressure in favor of capsid variants which transduce a specific cell type (Nonnenmacher et al., paragraph 10). Nonnenmacher et al. further teaches that the TRACER platform allows generation of AAV capsid libraries whereby specific recovery and subcloning of capsid mRNA expressed in transduced cells is achieved with no need for transgenic animals or helper virus co-infection and with increased stringency (Nonnenmacher et al., paragraph 11). In particular, Nonnenmacher et al. teaches libraries designed to express CAP mRNA under the control of any cell-specific promoter such as, but not limited to, synapsin-1 promoter (neurons), GFAP promoter (astrocytes), TBG promoter (liver), CAMK promoter (skeletal muscle), or MYH6 promoter (cardiomyocytes) (Nonnenmacher et al., paragraph 11 and Figure 4A). Therefore, by teaching that the use of a cell specific promoter to drive expression of a variant AAV capsid in AAV capsid vector libraries increases the selective pressure in favor of capsid variants which transduce a specific cell type, allowing for the identification of AAV capsid variants with high tropism for the target cell type with high stringency, Nonnenmacher et al. provides substantial motivation to utilize a cell specific promoter operatively linked to an AAV capsid variant in AAV capsid library vectors.
Thus, based on the substantial benefits to using a cell specific promoter in operative linkage to a nucleotide sequence encoding a variant CAP polypeptide over a constitutive promoter in AAV capsid libraries as taught by Nonnenmacher et al., it would have been prima facie obvious to the skilled artisan at the time of filing to utilize a cell specific promoter instead of a constitutive promoter in the AAV capsid variant vectors of the vector library taught by the ‘150 patent claims OR the ‘082 patent claims in view of Grimm et al., Adachi et al., Stutika et al. and Farris et al. to drive expression of a variant AAV capsid with a reasonable expectation of success.
The provisional rejection of pending claims 1-4, 7, 9, 11-16, 20-22, 25, 30-32, 44, 53-54, 56-57, 61-62, 69, and 72-74 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 7-10, 15-34, and 36 of copending application 17/707,951, hereafter referred to as the ‘951 application, is maintained. The applicant argues that the filing of a terminal disclaimer will be considered upon the indication of allowable subject matter. However, as applicant has not traversed the grounds for rejection, and as no allowable subject matter has been indicated, the rejection stands.
The provisional rejection of pending claims 1-4, 7, 9, 11-16, 20-22, 25, 30-32, 44, 53-54, 56-57, 61-62, 69, and 72-74 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-8, 11, 13, 16, 18-19, 21, 23, 31-35, 37-39, 42, 44-45, 47-48, 52, 58-59, 61-62, 64, 74, 77, and 88-89 of copending application 17/764,509, hereafter referred to as the ‘509 application, in view of US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017, is maintained. The applicant states that this provisional rejection should be withdrawn if it is the only remaining rejection of the claims as the ‘509 application has a later filing date than the instant application. However, as the claims remain rejected, see above, applicant’s traversal is not persuasive and the provisional rejection stands.
No claims are allowed.
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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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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