DETAILED ACTION
Applicant’s response received on 5/18/26 has been entered. Claims 1-2, 5, 7-10, 15-34, and 36 are 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 Of these, claims 22-24 and 29-30 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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. 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 statements (IDS) submitted on 5/18/26 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 Rejections - 35 USC § 112
The rejection of previously pending claims 1-2, 5, and 7-10, 15-21, and 36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement, is withdrawn in view of applicant’s arguments, in particular the argument that the presence of each target peptide sequence in Tables I-III, was recovered from muscle tissue following the mRNA-based in vivo selection-its presence in the table is direct evidence of functional muscle-specific tropism, and that the selection system does not generate false positives because the sequences recovered via mRNA enrichment from muscle necessarily achieved transduction and capsid mRNA expression in muscle cells where lower enrichment score reflects a reduced degree of muscle enrichment relative to higher-scoring variants, not an absence of muscle tropism.
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, 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, is withdrawn over claim 36 and maintained over claims 25-28, and 31-34. Applicant’s 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 applicant argues that impermissible hindsight reasoning was used to combine the teachings of Grimm et al. and Adachi et al. because according to applicant Grimm et al. teaches away from screening a mixture because Grimm teaches that mixture-based screening is time-consuming and labor-intensive, and instead focuses on isolated screening of an AAV library that does not comprise a mixture. The applicant further argues that the methodology taught by Grimm uses visual detection using fluorescent signals which cannot be used with the Adachi et al. mixture-based biopanning with DNA method. The applicant also argues that Nonnemacher’s TRACER platform also operates with mixture-based screening which is incompatible with Grimm’s isolated visual detection approach. Finally, the applicant states that Stutika and Farris do not overcome the deficits in the combined teachings of Grimm, Adachi, and Nonnemacher.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). It is also noted one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In addition, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In the instant rejection, Grimm et al. was cited for 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.
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. Applicant’s argument that Grimm et al. teaches away from screening a mixture because Grimm criticizes using a mixture by teaching that mixture-based screening is time-consuming and labor-intensive, and instead focuses on isolated screening of an AAV library that does not comprise a mixture, is not persuasive. Grimm et al. does not teach that mixture-based screening doesn’t work. Grimm et al. teaches that their non-mixture screening method has advantages over the mixture based method. This preference for a non-mixture based screening method, however, does not erase the teachings in Grimm et al. for the mixture based method. Applicant is reminded that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed."). Also, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant's argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." 27 F.3d at 554, 31 USPQ2d at 1132.).
Furthermore, Grimm et al. is not read in a vacuum. Adachi et al. was cited to supplement 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. In regards to applicant’s argument that Grimm et al. uses a visual screening step whereas Adachi uses DNA screening, it is first noted that the claims are drawn to a product which is an AAV vector library, and not to a method of screening. Second, as noted above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). At issue are the structural components of the AAV vector library, and both Grimm et al. and Adachi et al. provide teachings for a library mixture of AAV vectors.
Stutika et al. and Farris, whose teachings concerning splice regulatory sequences were not argued by applicant, were cited because while Grimm et al. 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, it is maintained that 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.
Turning to Nonnemacher et al., the rejection noted that while Grimm et al. generally teaches to use a constitutive or inducible promoter to express the variant capsid protein, Grimm et al. does not teach to use a tissue specific promoter, and Nonnenmacher et al. was cited to supplement Grimm et al. and Adachi et al. by teaching that other promoters can be used to express AAV capsids, and in particular tissue specific promoters. As set forth in the rejection, 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 is maintained that 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.
Double Patenting
The provisional rejection of claims 1-2, 5, 7-10, 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 withdrawn over claims 1-2, 5, 7-10, and 15-21, and maintained over claims 25-28 and 31-33.
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 claims 25-28 and 31-33 remain rejected, see above, applicant’s traversal is not persuasive and the provisional rejection stands.
The provisional rejection of claims 1-2, 5, 7-10, 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, is withdrawn over claims 1-2, 5, 7-10, and 15-21, and maintained over claims 25-28 and 31-33.
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 claims 25-28 and 31-33 remain rejected, see above, applicant’s traversal is not persuasive and the provisional rejection stands.
Allowed Claims
Claims 1-2, 5, 7-10, 15-21, and 36 are considered free of the prior art and allowed.
THIS ACTION IS MADE FINAL. 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.
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
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