DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/18/25 has been entered.
Claims 4 and 6 have been canceled. Claims 1-2, 5, 7-10, 15-34, and 36 are now pending in the instant application. Of these, claims 22-24 and 29-30 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/3/22. It is noted that applicant has requested rejoinder of withdrawn claims 22-24 and 29-20; however, this request is premature as no generic or linking claims have been found allowable. Claims 1-2, 4-10, 15-21, 25-28, 31-34, and 36 are therefore currently under examination. 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 in this action can be found in a previous office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/18/25 in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner, and an initialed and signed copy of the 1449 is attached to this action.
Claim Rejections - 35 USC § 112
The rejection of previously pending claims 1-2, 4-10, 15-21, and 36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement, is withdrawn over canceled claims 4 and 6, and maintained in part over amended claims 1-2, 6, 7-10, 15-21, and 36. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The rejection of record identified the following scope of enablement: the specification, while enabling for an engineered AAV capsid genetically modified by insertion of a muscle cell targeting peptide comprising an RGDnmer peptide (see sequences set forth in claim 2) between amino acids 588-589 of wild type AAV9 or an equivalent position in a wild type AAV of a different serotype, a polynucleotide encoding the engineered AAV capsid, an AAV comprising said engineered capsid, a vector system encoding said engineered AAV capsid, and a cell comprising said vector, does not provide an enabling disclosure for making and using any AAV capsid protein comprising any targeting peptide as set forth in claim 1 inserted into and further wherein the capsid protein is capable of targeting a muscle cell or any other cell type.
While applicant’s amendments to the claims have overcome issues regarding the site of insertion of the targeting peptide as the claims are now limited to insertion of the n-mer motif between amino acids 588-589 of a wild-type AAV-9 capsid polypeptide or an equivalent position in a wild-type AAV capsid polypeptide of a different serotype, the claims continue to read on non-RGDnmr peptides.
As set forth in MPEP 2164.01(a), there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: A) the breadth of the claims; B) the nature of the invention; C) the state of the prior art; D) the level of one of ordinary skill; E) The level of predictability in the art; (F) the amount of direction provided by the inventor; G) the existence of working examples; and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) and Ex parte Forman, 230 USPQ 546,547 (BPAI 1986).It is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above factors while ignoring one or more of the others. The examiner’s analysis must consider all the evidence related to each of these factors, and any conclusion of nonenablement must be based on the evidence as a whole. In re Wands 858 F.2d at 737, 740, 8 USPQ2d at 1404, 1407. Further, a conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). MPEP 2164.01(a). In regards to the full scope of the claimed invention, it is noted that the specification must teach those of skill in the art how to make and how to use the invention as broadly claimed. In re Goodman, 29 USPQ2d at 2013 (Fed. Cir. 1994), citing In re Vaeck, 20 USPQ2d at 1445 (Fed. Cir. 1991).
The previous office action analyzed the specification in direct accordance to the factors outlined in In re Wands, namely 1) the nature of the invention, 2) the state of the prior art, 3) the predictability of the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the quantity of experimentation necessary, 7) the relative skill of the skilled artisan, and 8) the breadth of the claims, and presented detailed scientific reasons supported by publications from the prior art for the finding of a lack of enablement for invention as claimed. Note that case law including the Marzocchi decision sanctions both the use of sound scientific reasoning and printed publications to support a holding of non-enablement (see In re Marzocchi 169 USPQ 367, and Ex parte Sudilovsky 21 USPQ2d 1702). Further, the unpredictability of a particular art area may alone provide reasonable doubt as to the accuracy of the broad statement made in support of enablement of claims. See Ex parte Singh, 17 USPQ2d 1714 (BPAI 1991). 35 U.S.C. 112 also requires that the scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art. In re Fisher, 166 USPQ 18, 24 (CCPA 1970).
The rejection of record pointed out that the specification, as discussed in previous office actions, is focused exclusively on the identification of AAV capsid proteins comprising a targeting peptide which are capable of conferring muscle tropism to an AAV virus comprising the capsid. The specification does not disclose the use of the modified AAV capsid for targeting AAV to cells other than muscle cells. The specification thus clearly identifies the “use” of the disclosed modified AAV capsid protein for generating an modified AAV virus with muscle specific tropism. Applicant is reminded that 35 U.S.C. 112(a) requires that the specification provide, “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”. Further, as discussed in previous office actions, while the specification provides general guidance for modifying the capsid protein of AAV, particularly AAV9, in a number of specific positions, to include putative heterologous targeting peptides, the specification’s working examples are limited to the generation and testing of AAV comprising AAV9 capsid proteins in which a putative targeting peptide has been inserted into the capsid protein between amino acids 588-589. The specification teaches that AAV virus comprising an AAV9 capsid modified at position 588 by insertion of sequences including the SEQ ID NOS listed in claim 1 passed a score of “100” as a threshold for muscle cell tropism. The specification does not provide a discussion of what a score of “100” represents. In Table I, it appears to be related to the “sum of muscle mRNA”. However, as no baseline mRNA control is shown, or level of statistical relevance for a score of “100”, it is unclear what level of muscle infection, or muscle specific infection, this data represents. From Tables I-III, the majority of putative targeting peptides have scores barely above 100. It is noted, however, that the highest scoring peptides, for example Variant ID Nos 1-13 in Table I, are all RGDnmers with scores above 300. Table IV-VI, which list the highest ranked peptides for muscle expression in the context of the AAV9 capsid with target peptide insertion at position 588, again show that all the highest ranked peptides are RGDnmers. Thus, based on the disclosure and working examples, it appears that AAV9 capsids with RGDnmers inserted at position 588 appear to exhibit muscle tropism. However, as the specification fails to provide sufficient guidance as to the relevance of scores from Tables I-III which are near 100, or even 200, it is unclear whether AAV9 or any other serotype comprising the breadth of targeting peptides recited as SEQ ID NOS in claim 1, for example, inserted between positions 588-589 can in fact confer muscle specific tropism to AAV9 or any other AAV serotype. The specification also does not provide any working examples which demonstrate that any of the targeting peptides recited as SEQ ID NOS in claim 1, for example, when inserted between positions 588-589 are capable of transducing any other types of cells, such as fibroblasts, neurons, or epithelial cells etc. Thus, upon consideration of the breadth of the claims, the guidance provided by the specification, and the working examples provided, it is maintained that the disclosure fails to provide sufficient specific guidance and/or evidence that all of the specific targeting peptides recited in the instant claims, when inserted between positions 588-589 of AAV or an equivalent position in any other AAV serotype would result in a functional capsid protein capable of redirecting the targeting of an AAV virus comprising the capsid to muscle cells, muscle tissue, or any other type of cell.
Therefore, it is maintained that in view of the state of the prior art at the time of filing and in particular the art-recognized unpredictability in modifying capsid proteins, including AAV capsid proteins, and in producing infectious virus particles, the limitation of the working examples to insertion of target peptides at position 588 of the AAV9 capsid, and the breadth of the claims, it would have required undue experimentation to make and/or use the scope of capsids proteins, and AAV viruses encompassed by the instant claims as written.
Applicant’s response does not address this issue, as such, the rejection of record stands.
Claim Rejections - 35 USC § 102
The rejection of previously pending claims 25-28, 31, 33, and 36 under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/189244 (April, 2018), hereafter referred to as Grimm et al. as evidenced by Stutika et al. (2016) J. Virol., Vol. 90(3), 1278-1289, is withdrawn in view of applicant’s amendments to the claims which now recite that the vectors in the vector library have a cell type-specific promoter operably linked to the AAV variant capsid protein polynucleotide.
The rejection of claim 36 under 35 U.S.C. 102(a)(1) as being anticipated by Adachi et al. (2010) Gene Ther. Regul., Vol. 5(1), 31-55, is withdrawn in view of applicant’s amendments to the claims which now recite that the vectors in the vector library have a cell type-specific promoter operably linked to the AAV variant capsid protein polynucleotide.
Claim Rejections - 35 USC § 103
The rejection of claims 25-28, 31-34, and 36 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, and Farris et al. (2008) Human Gene Ther., Vol. 19, 14221-1427, is withdrawn in view of applicant’s amendments to the claims which now recite that the vectors in the vector library have a cell type-specific promoter operably linked to the AAV variant capsid protein polynucleotide.
Claims 25-28, 31-34, and 36 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.
It is noted that the claims have been amended to recite that the vectors in the vector library have a cell type-specific promoter operably linked to the AAV variant capsid protein polynucleotide.
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. 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. 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, 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.
While Grimm et al., as noted above, does teach an AAV vector comprising a rep gene together with the capsid gene coding for the engineered AAV capsid, Grimm et al. differs 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 such as a minimal sequence or an inactivated 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 order to produce an AAV vector library present as a mixture of vectors according to both Grimm et al. and Adachi et al. 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 la. 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 vector 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.
Applicant’s arguments, in so far as they apply to the new grounds of rejection set forth above, have been considered but have not been found persuasive. The applicant argues that Grimm et al. does not teach the use of a cell specific promoter to express the variant AAV capsid polypeptide and that the secondary references to remedy this deficiency. However, the rejection set forth above cites Nonnenmacher et al. for providing substantial motivation to use a cell specific promoter operatively linked to the nucleotide sequence encoding the variant AAV capsid polypeptide in order to improve the identification and selection of capsid variant with high tropism for the target cell type. As such, applicant’s arguments concerning Grimm et al. are not persuasive as Nonnenmacher et al. supplements the teachings of Grimm et al. by providing the teachings and motivation to use a cell specific promoter over a constitutive promoter with a reasonable expectation of success.
Double Patenting
The rejection of claims 1-2, 4-10, 15-21, 25-28, and 31-33 on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,920,150 (the ‘150 patent) is withdrawn in view of applicant’s submission of a terminal disclaimer on 9/18/25.
The terminal disclaimer filed on 9/18/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,920,150 has been reviewed and is accepted. The terminal disclaimer has been recorded.
The provisional rejection of claims 1-2, 4-10, 15-21, 25-28, and 31-33 on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of copending application 17/707,944, hereafter referred to as the ‘944 application, is maintained. The applicant states that this provisional rejection should be withdrawn if it is the only remaining rejection of the claims as the ‘944 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.
The provisional rejection of claims 1-2, 4-10, 15-21, 25-28, and 31-33 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. 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 argument is not persuasive and the provisional rejection stands.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634