DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ response to restriction requirement filed on June 30, 2026, have been received and entered. Claims 1-3, 5-6, 8-911, 13, 16, 19,27, 30, 32, 32, 34, 37, 44-46, 48, 50,52, 57-58, 60, 63, 66, 74, 77, 79-81, 91-93, 105, 108-110 are pending in the instant application.
Election/Restrictions
Applicants’ election of Group I in the reply filed on June 30, 2026, is acknowledged. Because applicants did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicants’ election of following (a) SEQ ID NOs: 5-8, 10-26, 28-31, 33-47, 49-51, 53-77, 79-101, 103-124, 126-129, 131-167, 171-180, 182-183, 185-200, 202-238, 240-252, 255-262, 264-267, 270, 272-308, 311-317, 319- 324, 326-335, 337-347, 349-357, 359-365, 367-370, 372-374, 376-389, 391-399, 401-406, 408- 430, 432-438, 440-454, 456-465, 467-479, 481-484, 486, 488-490, 492-500, 501-507, 509, 511- 517, 519-526, 528, 532-546, 548-566, 568-574, 576-615, 617-620, 623-624, 626-631, 633-635, 638-640, 642, 645-652, 654-660, 662-687, 689-693, 695, 697, 699-701, 703-708, 710-711, 713- 727, 729, 732-733, 735-742, and 744-746 (665 sequences) (b) engineered AAV9 capsid polypeptide comprising mutations at position 267 and position 269 of the wild-type AAV9 capsid protein (SEQ ID NO: 1), wherein the mutation at position 267 is a G to A mutation and the mutation at position 269 is an S to T mutation (G267A/S269T double mutant), as recited in claim 19 and (a) a cell comprising a composition, as species for n-mer peptides, mutation in AAV capsid and cell respectively is acknowledged, However, upon further consideration, restriction between invention of group I-II and IV and the election of species requirement for then-mer peptide and AAV capsid mutation are withdrawn. Further claim 108 drawn to a pharmaceutical formulation is rejoined with the elected invention. The requirement is still deemed proper and is therefore made FINAL.
Claims 80-81 and 109-110 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 30, 2026.
Priority
This application is 371 of PCT/US22/77628 filed on 10/05/2022, which claims priority from US provisional application no 63/252,559 filed on 10/05/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/05/2024, 11/24/2025, 03/05/2026, 06/30/2026 and 07/21/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 1-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are under consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: a composition comprising
an engineered AAV9 capsid polypeptide comprising an RGD n-mer peptide set forth in Tables 4, or 5 inserted between amino acids 588-589 of wild type AAV9, and optionally, further comprising a cardiac muscle specific promoter operatively linked to one or more of a therapeutic polynucleotides, where the encoded engineered AA V capsid exhibits increased tropism for cardiac muscle cells, a vector encoding said engineered AA V capsid, a vector system comprising said vector, and a eukaryotic cell comprising said vector,
does not reasonably provide enablement for any composition comprising any other targeting moiety effective to target a cardiac muscle cell, any vector comprising any other engineered AAV capsid protein comprising any targeting peptide inserted anywhere else which imparts increased specificity for cardiac muscle cells, or for a vector encoding any other AAV capsid protein which does not comprise any cardiac muscle specific regulatory elements. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the invention
The claims are directed to a composition comprising: a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746);and optionally a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety. Dependent claims limit the here at least one of the one or more n-mer inserts comprises or consists of one or more RGD motifs, wherein at least one of the RGD motifs comprises or consists of XmRGDX., wherein m is 0-4 amino acids, wherein n is 0-15 amino acids, and wherein Xm, and X. are each independently selected from any amino acid, optionally wherein the one or more n-mer inserts are each 3-25 or 3-15 amino acids in length, wherein the targeting moiety comprises a polypeptide, a polynucleotide, a lipid, a polymer, a sugar, or a combination thereof subsequently limiting the viral protein is an adeno associated virus (AAV) protein, optionally wherein the AAV protein is an AAV capsid protein. Claims further limits the the AAV capsid protein is an engineered AAV capsid protein having reduced or eliminated uptake in a non-cardiac muscle cell as compared to a corresponding wild-type AAV capsid polypeptide, optionally wherein the non-cardiac muscle cell is a liver cell, and optionally wherein the wild-type AAV capsid polypeptide is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7,AAV8, AAV9, AAV rh.74, AAV rh.10, or Anc80 AAV capsid polypeptide. Claims are also directed to a vector system comprising :a vector comprising: one or more polynucleotides, and wherein at least one of the one or more polynucleotides encodes all or part of a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746). Claims are also directed to a cell comprising said composition as in claim 1.
Breadth of the claims
The claims broadly encompasses composition comprising any targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746 , wherein the targeting moiety comprises any polypeptide, any polynucleotide, any lipid, any polymer, any sugar, or a combination thereof subsequently limiting to any viral protein. Claims further encompass a vector system comprising a nucleotide sequence encoding all or part of a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts or any engineered viral protein subsequently limiting to an AAV capsid protein which comprises an n-mer target peptide of at least three amino acids inserted between two codons or inserted between any two amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 598-599, 704-714. The claims further limit then n-mer inserts comprises or consists of one or more RGD motifs, wherein at least one of the RGD motifs comprises or consists of XmRGDX, wherein m is 0-4 amino acids, wherein n is 0-15 amino acids, and wherein Xm, and X. are each independently selected from any amino acid, optionally wherein the one or more n-mer inserts are each 3-25 or 3-15 amino acids in length., or most specifically to any one of the peptides recited in Tables 4 or 5. Certain claims further recite where the engineered AAV capsid has increased specificity, increased cardiac muscle cell specificity.
Guidance of the Specification and The Existence of Working Examples:
The specification discloses an AAV vector comprising a capsid—with short, inserted peptide motifs that improve cardiac muscle targeting. The inserts are selected from identified sequence libraries and are positioned so they are displayed on the exterior of the viral particle It is further disclosed that the resulting particle can be paired with a therapeutic cargo for delivery to heart tissue (see para. 6, 18, 98-105, 441-445). The specification pertains entirely on the identification of AA V capsid proteins comprising a targeting peptide which are capable of conferring cardiac muscle cell tropism to the AA V9 virus. The specification does not disclose any other use of the engineered AAV capsid for targeting AA V particles comprising the capsid to cells other than cardiac muscle cells specific tropism. The specification teaches mRNA-based detection methods are more stringent for selection of AAV variants (example 1). Example 2 teaches mRNA-based detection methods that can be used to detect AAV capsid variants from a capsid variant library. FIGS. 3A-3B shows graphs that can demonstrate a correlation between the virus library and vector genome DNA (FIG. 3A) and mRNA (FIG. 3B) in the liver. FIGS. 4A-4F shows that capsid variants expressed at the mRNA level identified in different tissues. Example 3 teaches capsid mRNA expression that is driven by CMV, CK8 , MHCK7 or hSyn promoter. Example 4 teaches a schematic demonstrating generating an AAV capsid variant library, particularly insertion of a random n-mer (n=3-15 amino acids) into a wild-type AAV9. In this example, random 7-mers were inserted between aa588-589 of variable region VIII of AAV9 viral protein and used to form the viral genome containing vectors with one variant per vector. As shown in FIG. 8, the capsid variant vector library was used to generate AAV particles where each capsid variant encapsulated its coding sequence as the vector genome. FIG. 9 shows vector maps of representative AAV capsid plasmid library vectors (see e.g., FIG. 8) that can be used in an AAV vector system to generate an AAV capsid variant library. The library can be generated with the capsid variant polynucleotide under the control of a tissue specific promoter or constitutive promoter. Example 5 teaches cardiac specific inserts are generated via optimizing 7-mer inserts in an AAV9 capsid using a selection approach described in example 4. For these, none of the amino acids shown in the inserts replace any within the capsid prolylpeptide. Resulting insert variants in rank-order are shown in Table 4. Cardiac specific inserts were also generated using a fixed RGD-motif selection approach. For this, capsid variant selection was performed by insertion XXXRGDXXXX into the AAV9 capsid, where X is any amino acid and where the first three amino acids preceding "RGD" replace amino acids 586, 587 and 588 of the AAV9 capsid polypeptide such that "RGDXXXX" is inserted right before amino acid residue 589 of the AAV9 capsid polypeptide. Cardiac muscle specific variants from this selection method are shown in rank-order in Table 5.
It should be noted that while the specification provides general guidance for modifying the capsid protein of AAV9 in a number of specific positions, to include putative heterologous targeting peptides, the specification's working examples teach generating and testing of targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety is AAV comprising AAV9 capsid proteins in which a putative targeting 7-mer peptide has been inserted into the capsid protein between amino acids 588-589 (example 4 or 5). The specification only teaches that AAV comprising an AAV9 capsid modified at position 588 by insertion of 7 amino acid n-mer sequences including the peptides containing RDG motif but fails to specify any ordered rank to any of the peptide set forth in table 4 or 5. The specification discloses selection method are shown in rank-order in table 4 or 5, however, the scope of rank order is unclear. There is no baseline expression or mRNA expression of control is depicted, nor does there is any level of statistical relevance for an ordered rank is provided. There is no score for the highest ranked variant peptide in the context of the AAV9 or any other AAV serotype with target peptide insertion at different positions of different serotype of AAV encompassed by the claim that shows higher cardiac muscle specific tropism as compared to any other n-mer peptide inserted into AAV capsid.
Thus, based on the disclosure and working examples, it appears that at least the AAV9 capsids with RGD nmers listed in Table 4 or 5 inserted at position 588 appear to exhibit increased cardiac muscle tropism. However, as the specification fails to provide sufficient guidance as to the relevance of ordered scores from Table 4 or 5. It is further unclear whether AAV9 or any other serotype comprising the breadth of targeting peptides recited as Table 4 or 5 for example, inserted between position 588-589 can in fact confer or increase cardiac muscle specific tropism to AAV9 or any other AA V serotype. The specification also does not provide any working examples that show any of the other targeting peptides that comprises a polypeptide, lipid or polymer comprising n-mer insert ser forth in table 4 or 5 or when inserted between positions 588-589 or anywhere else in AAV capsid are capable of selectively transducing or have increased transduction of cardiac muscle cells. Further, neither the specification nor the working examples provide any teaching or specific data which indicate that any of the AA V capsids modified with one of the n-mer peptides disclosed in table 4 or 5 are cardiac cell specific. The working example at best shows a transduction of cardiac muscle cells using certain peptides obtained through screening that are ranked in order that is not clear for the reasons discussed above. Thus, upon consideration of the breadth of the claims, the guidance provided by the specification, and the working examples provided, the disclosure fails to provide sufficient specific guidance and/or evidence that the use of any n-mer peptide of at least three amino acids, when inserted between different positions of AAV or an equivalent position in any other AA V serotype would result in a functional capsid protein capable of redirecting the targeting of an AAV virus comprising the capsid to cardiac muscle cells, muscle tissue, or any other type of cell.
State of the Art and Predictability of the Art and the Amount of Experimentation
Necessary:
The state of prior art before the effective filing of this application recognized that a peptide whose insertion that is enabled and works in one AAV capsid variant may be deleterious to another AAV serotype. In this regard, Shi (Hum Gene Ther. 2001;12(14):1697-1711) teaches generating a series of 38 virus capsid mutants containing peptide insertions at 25 unique sites within the AAV capsid protein. The art teaches 4 of 38 mutant viruses did not assemble particles; 14 of 38 assembled noninfectious particles; and only 20 of 38 assembled fully infectious particles (see abstract). The art further teaches surface of the mutant AAV particles was found to be highly dependent on the inclusion of appropriate scaffolding sequences and site of insertion of the peptide (see abstract). The claims broadly encompass a composition comprising: a targeting moiety effectively to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts set forth in Table 4 or 5 and comprises any polypeptide, polynucleotide, lipid or polymer. However, art teaches while ability to insert RGD m-mer into a targeting polypeptide could be accomplished, however, its cardiac muscle specificity is not predictable just because of insertion of n-mer sequence. This is because cardiac muscle cell specificity depends on the specific polypeptide scaffold, nucleic acid, its insertion site, conformation of RGD or another motif. Sonntag (Chem Bio Chem, 2017, 18,441–443) teaches generating and characterizing a library of fluorescent mCitrine proteins with RGD motifs incorporated at several positions in loops within the protein main chain (abstract). The amino acid sequence was either inserted into the mCitrine sequence, thus expanding the size of the loop, or replaced a five-residue loop stretch, thus retaining the size of the loop. The importance of the structure of the RGD mer (GRGDS) sequence for affinity is illustrated by the absence of binding by the two constructs with the RGD epitope in the flexible NorCterminus (0/1 and 240/241) (see page 442, col. 1, para. 2). Sonntag emphasizes on the loop selection, as shown by the inactivity in integrin binding by constructs with the RGD sequence in the flexible termini and in some other loops. The insertion of RGD motifs in mCitrine loops thus imposes a specific structure and microenvironment on the RGD motif (see page 442, col. 1, last para.). In view of foregoing, it is apparent that different insertion positions resulted in different binding characteristics. The guidance provided in the specification is limited to modifying the capsid protein of AAV9 in a number of specific positions, to include putative heterologous targeting peptides set forth in table 4 or 5 showing contemplated cardiac muscle cell specific targeting. The specification is silent on identifying any polypeptide, nucleic acid, or sugar or location of the insertion with in the protein or nucleic acid. There is no guidance on a composition comprising any other targeting moiety effective to target a cardiac muscle cell other than a composition comprising rAAV comprising an AAV9 capsid protein containing a heterologous targeting peptides set forth in table 4 or 5 at specified site. An artisan would have to perform undue experimentation to produce and characterize a library of polypeptide, nucleic acid containing RGD motifs to make and use the invention, without reasonable expectation of success.
Claims broadly encompass one or more of the one or more n-mer inserts are incorporated into the AAV protein at any site such that at least one or more of the one or more n-mer inserts and/or optional RGD motifs are each inserted between any two-amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 598-599, 704-714, or any combination thereof in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh. 10 capsid polypeptides, However, the art teaches that modifications to the capsid protein of AAV is not predictable since merely inserting or substituting at least one amino acid (alanine) into the capsid protein can result in structural changes of the capsid and/or loss of specific functions (see Wu et al. Journal of Virology (2000) 74, 18, 8635-8647). Wu teaches that mutants mut19, mut20, mut23, mut24, mut25, mut42, mut46, mut47 did not form capsid at all following their respective amino acid mutations (see Table I). Michelfelder et al. further teaches that the capsid region surrounding amino acid R588 is used for incorporation of peptides ligands into AAV because such peptide insertions are compatible with capsid assembly and allow for presentation of the target peptide near the top of the protruding capsid domains within the threefold spike region (Michelfelder et al. (2011) PLoS ONE, Vol. 6(8), 1-11, see page 2). Thus, the prior art before the effective filing date teaches that it was not predictable whether the modification of any residue in the any capsid would result in a functional capsid protein, and establishes that the state of the art for insertion of target peptides into AAV in particular was limited to insertion of target peptides into the AAV capsid at or near the heparin binding site, such as between residues 586-591. Additionally, Douar et al (Virology, 2003, 309(2), 203-208) teaches a dependent peptide alteration of virus formation essentially affecting the assembly and packaging of virus (see page 206, last para). This is further evident from the Korbelin (Gene Therapy, 2017, 24, 470-481) who reported AAV library screenings is variable, and the influence of the production procedure has not been thoroughly evaluated (abstract). Ying teaches that there are several methods for increasing the tropism of an AAV for a target tissue, many such modifications such as conjugation of ligands to the capsid can cause viral instability, higher immunogenicity, and reduced infectivity (Ying et al. Gene Therapy, 2010, 17, 980- 990, see page 980). Ying et al. teaches that they were able to identify two specific target peptide capable of increasing heart transduction and expression of modified AA V2 using three rounds of in vivo screening of an AA V2 peptide library and two additional peptides with putative increased heart cell targeting using four rounds of in vitro screening of the AAV2 library in heart cells (Ying et al., pages 981-983) However, it is clear from Table I that the majority of peptides identified in the first round of both types of screenings were not present in subsequent rounds (Ying page 982, Table I). Ying et al. also teaches that the in vitro selected peptides did not in fact significantly increase AA V2 targeting to cardiac tissue when tested in vivo (Ying page 983). Finally, Ying et al. clearly shows that even their 2 best targeting peptides from the in vivo screen, while demonstrating a statistically significant increase in cardiac tissue targeting of AA V2, continued to exhibit transduction of other tissues (Ying et al., page 984). Korbelin also utilized in vivo screening of an AA V2 target peptide library where a 7mer peptide was inserted at position 588, and found after 5 rounds of in vivo screening only 1 peptide which provided a significant increase in pulmonary targeting with a decrease in the targeting of other tissue types (Korbelin et al. Molecular Therapy, 2016, 24(6), 1050-1061, see page 1053, Figure 2, and page 1059). In view of foregoing, it is apparent that the prior art before the effective filing date teaches unpredictability and difficulty in generating modified AA V capsid with targeting peptides that confer increased specificity to a desired cardiac muscle specific expression.
Therefore, in view of the state of the prior art at the time of filing and in particular the art recognized unpredictability in modifying AAV capsid proteins, including the modification of the AAV capsid to comprise a targeting peptide, the art recognized unpredictability in obtaining a peptide which confers increased tropism to a desired cell type, the art recognized importance of splice regulatory elements for expressing AA V capsid from a vector, the lack of guidance in the specification for n-mer peptides which confer increased tropism to any type of cell, the limitation of the working examples to insertion of target peptides at position 588 of the AAV9 capsid for increasing the tropism of an AAV capsid for muscle cells, the lack of guidance for any peptide capable of conferring cell-specific AA V transduction where other non-target cells are not transduced, the lack of guidance for removing all splice regulatory elements from a vector comprising a nucleotide sequence encoding the three subunits of AA V capsid while retaining the capacity to express a functional AA V capsid, and the breadth of the claims, an artisan of skill would have to have perform undue experimentation to make and use the invention as supported by the observations in the art record.
Claim Rejections - 35 USC § 112
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 1-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 44, 79, 91 recite the phrase “wherein at least one of the one or more n-mer inserts is selected from Table 4 or Table 5 (see claims 1 and 44)”. MPEP 21373.05(s) states ‘where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608. 1609 (Bd. Pat. App. & Inter. 1993). In the instant ease, listing of n-mer comprising or consisting of SEQ ID NO in the claim is not difficult and it is suggested that applicants should delete the recitation of Table and incorporate the requisite peptide SEQ ID NO in the claim. Please note limitations within parenthesis are used in claims to delineate an abbreviation of a term that is recited just prior to the parentheses and does not impart further limitations to the claim. Claims 2-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 45-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 92-93, 105 and 108 are included in the rejection because they directly or indirectly depend from the rejected base claims. A direct recitation of all the m-mer insert sequence would be remedial. Appropriate correction and/or clarification is required.
Claim Rejections - 35 USC § 112
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.
Claim 3 is 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. In the instant case, claim 3 recites a limitation “targeting moiety is effective to target a cardiac muscle cell”, which is already part of claim 1. Applicants 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. Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5-6, 8-9, 11, 13, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 74, 77, 79, 91-93, 105 and 108 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tabebordbar et al., (Cell September 2021, 184, 4919–4938).
Claim interpretation: Recitation of limitations following the term "optionally" in the claims have been interpreted as being not required. As such, "optional" elements recited by a claim do not need to be disclosed by prior art of record.
With respect to claims 1-3, 5-6, 8-9, 11, 44-45, 46, 48, 50, 57-58, 79, 91; Tabebordbar teaches a composition comprising AAV comprising a polynucleotide encoding an engineered AAV9 capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV9 capsid (pages 4920, col. 2, para. 1, Fig. 5B, e4). Tabebordbar. teaches that the targeting peptide comprises or consists of GPGRGDQTTL or ASTRGDHGVL that has 100% sequence identity to SEQ ID NO: 530 and SEQ ID NO: 637. (see table S5). It is noted that each of the one or more n-mer inserts comprises at least one RGD motif and insert is from 3-15 amino acid. (see table S5). It is further disclosed that the targeting moiety is effective to target muscle fibers and cardiomyocytes (see fig. 1C and ID).
Regarding claim 13, 60, 63, Tabebordba teaches engineered MyoAAV 2A capsid comprises one or more mutation that transduces mouse skeletal muscles 10–80 times more efficiently and transduces the heart 17 times more efficiently than wild type AAV9. Furthermore, transgene mRNA expression was 2.5 times lower in the liver of MyoAAV 2A-injected animals compared to AAV9-injected mice (Figure 5E).
With respect to claim 27, 50, 52, Tabebordbar teaches the composition is an engineered vial particle that contains micro dystrophin gene (see page e4 and e5).
Regarding claims 30, 32, 34, 37 and 92-93, Tabebordbar teaches that the optional cargo is capable of inducing exon skipping a micro dystrophin gene capable of treating or preventing cardiac muscle disease or disorder such as DMD (table S2, figure 6, e5 last para).
With respect to claim 105 and 108, Tabebordbar teaches mouse skeletal muscle cells comprising said AAV vector (see fig. 2, S2G-S2K). It is further disclosed that a composition comprising the AAV comprising an engineered AAV9 capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV9 capsid (pages 4920, col. 2, para. 1, Fig. 5B, e4), wherein the targeting peptide comprises or consists of XmRGDXn such as GPGRGDQTTL or ASTRGDHGVL that has 100% sequence identity to SEQ ID NO: 530 and SEQ ID NO: 637 is formulated in saline and could be used for therapeutic purposes after injection of a low dose of virus (see fig. 6).
Accordingly, Tabebordbar anticipates claims 1-3, 5-6, 8-9, 11, 13, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 74, 77, 79, 91-93, 105 and 108.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 13, 16, 19, 44, 52, 58, 63, 66 are rejected under 35 U.S.C. 103 as being unpatentable over Tabebordbar et al., (Cell September 2021, 184, 4919–4938) and Vandenberghe (WO2019217911, dated 11/14/2019).
The teaching of Tabebordbar has been described above and relied on in same manner here. Briefly Tabebordbar teaches a composition comprising AAV comprising a polynucleotide encoding an engineered AAV9 capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV9 capsid (pages 4920, col. 2, para. 1, Fig. 5B, e4). Tabebordbar. teaches that the targeting peptide comprises or consists of GPGRGDQTTL or ASTRGDHGVL that has 100% sequence identity to SEQ ID NO: 530 and SEQ ID NO: 637. (see table S5). It is noted that each of the one or more n-mer inserts comprises at least one RGD motif and insert is from 3-15 amino acid. (see table S5). It is further disclosed that the targeting moiety is effective to target muscle fibers and cardiomyocytes (see fig. 1C and ID).
Tabebordbar differs from claimed invention by not disclosing AAV9 capsid polypeptide comprising mutations at position 267 and position 269 of the wild-type AAV9 capsid protein (SEQ ID NO: 1), wherein the mutation at position 267 is a G to A mutation and the mutation at position 269 is an S to T mutation (G267A/S269T double mutant).
Vandenberghe cures the deficiency by disclosing superior performance of the double mutant AAV9 G267A S269T versus the mutant AAV9 G267A. Vandenberghe teaches double mutant not only exhibits the liver "off' phenotype, but the results suggest a benefit of gene delivery to the heart and skeletal muscle (see page 24, lines 14-16).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the composition of Tabebordbar.by incorporating single or double mutant as disclosed by Vandenberghe, in order to reduce uptake in liver cells and improve expression in heart and skeletal muscle cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so in order to improve the expression of cargo in cardiac muscle and reduce expression in non-cardiac cells (see page 24, lines 14-16) . One of skill in the art would have been expected to have a reasonable expectation of success in because prior art successfully reported superior tropism of AAV9 G267A S269T towards cardiac tropism as compared to single mutant AAV9 or wild type AAV9. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support the finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-6, 8-9, 11, 13, 16, 19, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of USP. 11920150. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. In the instant case, claims are directed to a composition comprising: a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746);and optionally a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety, wherein the targeting moiety is effective to target a cardiac muscle cell. Dependent claims limit he wherein the targeting moiety comprises a viral protein, optionally wherein the viral protein is a capsid protein, wherein the the viral protein is an adeno associated virus (AAV) protein, optionally wherein the AAV protein is an AAV capsid protein (claim 9). Claim 11 limits herein one or more of the one or more n-mer inserts are incorporated into the AAV protein such that at least one or more of the one or more n-mer inserts and/or optional RGD motifs are each inserted between any two-amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 598-599, 704-714, or any combination thereof in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide. Claims further limits the cargo is capable of inducing exon skipping in a gene, optionally a dystrophin gene, optionally, wherein the cargo is a mini- or micro-dystrophin gene. Claims 44-46, 48, 50, 52, 57-58, 60, 63, 66, 74, 77, 79, 91-93 are directed to a vector system comprising :a vector comprising: one or more polynucleotides, wherein at least one of the one or more polynucleotides encodes all or part of a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746). Claims 105 and 108 are directed to a cell comprising said composition as in claim 1 and said vector system. In contrast, claims in ‘150 is directed to A composition comprising: a targeting moiety effective to target a muscle cell, wherein the targeting moiety comprises an n-mer motif, wherein the n-mer motif is an RGD motif, wherein the RGD motif has a formula of X.mRGDXn, wherein each instance of X is independently selected from any amino acid, m is 0-4 amino acids and n is 1-15 amino acids or m is 1-4 amino acids and n is 0-15 amino acids, wherein the targeting moiety comprises a viral capsid protein, wherein the n-mer motif is (a) inserted between any two contiguous amino acids of the viral capsid protein, (b) replaces one or more native viral capsid protein amino acids, or both (a) and (b); and a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety. Dependent claims limit the n-mer motif is any one of SEQ ID NO: 13-50, 1277-2493, 3737-4979, 6647-8313, 8314-8502, or 8692-8889. It is noted that RGDHGQL (SEQ ID NO 8704) is encompassed within Table 4 or 5 of the instant application. The '150 patent claims recite vector/vector systems, capsid polypeptides, cell comprising the vectors, AA V particles comprising the capsid and methods of administering the vector or AAV particle that encompass the nmer insertion claimed in the instant application. Thus, claims in the instant application are encompassed by the claims in '150 patent claims.
.
Claims 1-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7, 10-11, 13-14, 16,32, 48-4954, 57, 59-61, 63, 66-67. 88-89, 98, 116 and 117 of copending Application No. 18689897. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. In the instant case, claims are directed to a composition comprising: a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746);and optionally a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety, wherein the targeting moiety is effective to target a cardiac muscle cell. Dependent claims limit he wherein the targeting moiety comprises a viral protein, optionally wherein the viral protein is a capsid protein, wherein the the viral protein is an adeno associated virus (AAV) protein, optionally wherein the AAV protein is an AAV capsid protein (claim 9). Claim 11 limits herein one or more of the one or more n-mer inserts are incorporated into the AAV protein such that at least one or more of the one or more n-mer inserts and/or optional RGD motifs are each inserted between any two-amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 598-599, 704-714, or any combination thereof in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide. Claims further limits the cargo is capable of inducing exon skipping in a gene, optionally a dystrophin gene, optionally, wherein the cargo is a mini- or micro-dystrophin gene. Claims 44-46, 48, 50, 52, 57-58, 60, 63, 66, 74, 77, 79, 91-93 are directed to a vector system comprising :a vector comprising: one or more polynucleotides, wherein at least one of the one or more polynucleotides encodes all or part of a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746). Claims 105 and 108 are directed to a cell comprising said composition as in claim 1 and said vector system. In contrast, claims in ‘897 are directed to a composition comprising: a targeting moiety effective to target a muscle cell or both a muscle cell and a central nervous system (CNS) cell, wherein the targeting moiety comprises one or more n-mer inserts each comprising: one or more P-motifs, wherein at least one P-motif comprises or consists of the amino acid sequence XmPX1QGTX2RXn (SEQ ID NO: 1699), wherein X1, X2, Xm, and Xn are each independently selected from any amino acid, wherein m is O, 1, 2, or 3, and wherein n. is 0, 1, 2, 3, 4, 5, 6, or 7; or one or more RGD motifs, wherein at least one of the RGD motifs comprises or consists of XmRGDXn, wherein m is 0-4 amino acids, wherein n is 0-15 amino acids, and wherein Xm, and Xn are each independently selected from any amino acid; or both, and optionally a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety; and optionally wherein the targeting moiety is effective target (a) a skeletal muscle ell, (b) a cardiac muscle cell, (c) a skeletal muscle cell and a CNS cell, or (d) a cardiac muscle cell and a CNS cell (instant claim 1). The composition of claim 1, wherein the one or more of the one or more P-motifs and one or more of the RGD motifs are (a) each independently selected from any one set forth in one or more of SEQ ID NOs: 4-1698 (Tables 4-1 It (b) (i) SEO ID NOs: 4-250 (Table 4); (ii) SEO ID NOs: 497-647 (Table 6); (iii) SEO ID NOs: 799-1074 (Table 8); (iv) SEO ID NOs: 1301-1497 (Table 10); or any combination of (i)-(iv); (c) (v) SEO ID NOs: 251-496 (Table 5); (vi) SEO ID NOs: 648-798 (Table 7); (vii) SEO ID NOs: 1498-1698 (Table 9); (viii) SEO ID NOs: 1075-1300 (Table 11); or any combination of (v)- (viii); or (d) (ix) SEO ID NOs: 4-250 (Table 4) and/or SEO ID NOs: 251-496 (Table 5); (x) SEO ID NOs: 497-647 (Table 6) and/or SEO ID NOs: 648-798 (Table 7); (xi) SEO ID NOs: 799-1074 (Table 8) and/or SEO ID NOs: 1498-1698 (Table 9); (xii) SEO ID NOs: 1301-1497 (Table 10) and/or SEO ID NOs: 1075-1300 (Table 11) (instant claim 1). 7. The composition of claim 1, wherein (a) the one or more n-mer inserts are each 3-25 or 3-15 amino acids in length; (b) (i) X1 is S, T, or A, (ii) X2 is L, V, F, or I, or (iii) both (i) and (ii); (c) the one or more RGD motifs and/or one or more P-motifs is/are immediately preceded by AQ or DG in the targeting moiety; or (d) any combination of (a)-(c) (instant claim 1). 10. The composition of claim 1, wherein the targeting moiety comprises a polypeptide, a polynucleotide, a lipid, a polymer, a sugar, or a combination thereof (instant claim 1). The composition of claim 1, wherein the targeting moiety comprises a viral protein, optionally wherein the viral protein is a capsid protein. 13. The composition of claim 11, wherein one or more of the n-mer inserts are incorporated into the viral protein such that at least one of the one or more RGD motifs, at least one of the one or more P motifs, or both is/are located between two amino acids of the viral protein such that at least one of the one or more RGD motifs and/or one or more P-motifs is external to a viral capsid (instant claims 1 and 6). 14. The composition of claim 11, wherein the viral protein is an adeno-associated virus (AAV) protein, optionally wherein the AAV protein is an AAV capsid protein (instant claim 1). 16. The composition of claim 14, wherein one or more of the one or more n-mer inserts are incorporated into the AAV protein such that at least one or more of the one more RGD motifs and/or at least one or more of the one or more P motifs are each inserted between any two contiguous amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545- 558, 581-593, 598-599, 704-714, or any combination thereof in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh. 10 capsid polypeptide; or wherein at least one of the one or more n-mer inserts is incorporated into the AA V protein such that at least one of the one more RGD motifs and/or at least one of the one or more P motifs is inserted between amino acids 588 and 589 in an AA V9 capsid polypeptide or in an analogous position in an AAV1, AA V2, AA V3, AA V 4, AA VS, AA V6, AA V7, AAV8, AAV 74, AAV rh. 10 capsid polypeptide (instant claims 1-7 and 11). Claims are also drawn to a vector system and a cell comprising said compotation. In the instant case, there is no patentable difference between the claimed compositions and the claims in copending Application no. 18/689,897. The copending Application no. 18/689,897 discloses a composition comprising an adeno-associated virus (AAV) which comprises a targeting moiety effective to target a muscle cell and a polynucleotide encoding a cargo (cargo polynucleotide), wherein the targeting moiety comprises a viral capsid protein comprising an n-mer motif; which comprises XmRGDXn, wherein X is any amino acid, m is 1 or 2, and n is 4, and wherein the n-mer motif is (a) inserted between any two amino acids of the viral capsid protein similar to one claimed in the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 6- 8, 11, 13, 16, 18-19, 21 23, 31-34 37-39 42, 44-45, 47-48, 52 56, 59, 61-62, 64, 74, 77 and 78 of copending Application No. 17764509 in view of Tabebordbar et al., (Cell September 2021, 184, 4919–4938). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. In the instant case, claims are directed to a composition comprising: a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746);and optionally a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety, wherein the targeting moiety is effective to target a cardiac muscle cell. Dependent claims limit he wherein the targeting moiety comprises a viral protein, optionally wherein the viral protein is a capsid protein, wherein the the viral protein is an adeno associated virus (AAV) protein, optionally wherein the AAV protein is an AAV capsid protein (claim 9). Claim 11 limits herein one or more of the one or more n-mer inserts are incorporated into the AAV protein such that at least one or more of the one or more n-mer inserts and/or optional RGD motifs are each inserted between any two-amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 598-599, 704-714, or any combination thereof in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide. Claims further limits the cargo is capable of inducing exon skipping in a gene, optionally a dystrophin gene, optionally, wherein the cargo is a mini- or micro-dystrophin gene. Claims 44-46, 48, 50, 52, 57-58, 60, 63, 66, 74, 77, 79, 91-93 are directed to a vector system comprising :a vector comprising: one or more polynucleotides, wherein at least one of the one or more polynucleotides encodes all or part of a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746). Claims 105 and 108 are directed to a cell comprising said composition as in claim 1 and said vector system. In contrast, claims in ‘509 are directed to a opposition comprising: a targeting moiety effective to target a muscle cell, wherein the targeting moiety comprises a motif, wherein the motif comprises any one of SEQ ID NO: 8319, 8324, 8331-8332, 8334, 8336-8337, 8341-8344, 8348, 8352-8354, 8356, 8358-8359, 8361, 8365-8366, 8368, 8370, 8372, 8374-8375, 8377-8378, 8385-8386, 8388, 8390, 8392- 8393, 8396-8398, 8400, 8403-8404, 8406-8411, 8413, 8416-8424, 8427-8428, 8430- 8431, 8433-8437, 8440-8443, 8445-8446, 8448, 8450-8451, 8453, 8456, 8458-8459, 8461, 8464, 8466-8470, 8472-8477, 8479, 8481-8491, 8493-8495, 8497-8501, 8503- 8691, 8719, 8721, 8747, 8773, 8801, 8808, 8825, 8838, 8849, 8851, 8856, 8861, 8865- 8866, 8876, 8878, 8880, 8884, 8887, 8891, 8893, 8900, 8902, 8905, 8908-8909, 8913- 8915, 8917-8919, 8927, 8929-8930, 8932-8937, 8940-8946, 8949-8951, 8954-8963, 8965-8968, 8970-8980, 8982-8985, 8987-8988, 8991-9003, 9006-9013, 9015-9016, 9018-9019, 9021-9026, 9028-9030, 9032, 9034-9036, 9038-9039, 9041-9047, 9049- 9060, 9062-9064, 9067-9069, 9072-9074, 9076-9080, or 9082-9087; and a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety. Dependent claims limit the motif comprise an RGD motif having a formula of XmRGDXₙ, wherein m is 0-4 amino acids, wherein n is 0-15 amino acids, wherein X is any amino acid, and wherein each X amino acid present is independently selected from the others from the group consisting of: any amino acid, wherein the RGD motif has a formula of XmRGDXₙ, wherein m is 0-4 amino acids, wherein n is 0-15 amino acids, wherein X is any amino acid, and wherein each X amino acid present is independently selected from the others from the group consisting of any amino acid. In the instant case, there is no patentable difference between the claimed compositions and the claims in copending Application no’509. The copending Application no. 17764509 discloses a composition, host cells, a pharmaceutical composition or a vector system comprising a targeting moiety effective to target a muscle cell and a polynucleotide encoding a cargo (cargo polynucleotide), wherein the targeting moiety comprises a viral capsid protein comprising an n-mer motif; which comprises XmRGDXn, wherein X is any amino acid, m is 1 or 2, and n is 4. The ‘509 differs from claimed invention by not disclosing that the n-mer motif set forth in table 4 or 5 and is (a) inserted between any two amino acids of the viral capsid protein similar to one claimed in the instant application. Tabebordbar cure the deficiency by disclosing s a composition comprising AAV comprising a polynucleotide encoding an engineered AAV9 capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV9 capsid (pages 4920, col. 2, para. 1, Fig. 5B, e4). Tabebordbar. teaches that the targeting peptide comprises or consists of GPGRGDQTTL or ASTRGDHGVL that has 100% sequence identity to SEQ ID NO: 530 and SEQ ID NO: 637. (see table S5). It is noted that each of the one or more n-mer inserts comprises at least one RGD motif and insert is from 3-15 amino acid. (see table S5). It is further disclosed that the targeting moiety is effective to target muscle fibers and cardiomyocytes (see fig. 1C and ID). Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the composition of ‘509 by substituting the n.mer RGD motif with one disclosed in Tabebordbar., in order to reduce uptake in liver cells and improve expression in heart and skeletal muscle cells, as instantly claimed, with a reasonable expectation of success,
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 11, 14-18, 19-26 of copending Application No. 19390032 in view of Tabebordbar et al., (Cell September 2021, 184, 4919–4938). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. In the instant case, claims are directed to a composition comprising: a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746);and optionally a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety, wherein the targeting moiety is effective to target a cardiac muscle cell. Dependent claims limit he wherein the targeting moiety comprises a viral protein, optionally wherein the viral protein is a capsid protein, wherein the the viral protein is an adeno associated virus (AAV) protein, optionally wherein the AAV protein is an AAV capsid protein (claim 9). Claim 11 limits herein one or more of the one or more n-mer inserts are incorporated into the AAV protein such that at least one or more of the one or more n-mer inserts and/or optional RGD motifs are each inserted between any two-amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 598-599, 704-714, or any combination thereof in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide. Claims further limits the cargo is capable of inducing exon skipping in a gene, optionally a dystrophin gene, optionally, wherein the cargo is a mini- or micro-dystrophin gene. Claims 44-46, 48, 50, 52, 57-58, 60, 63, 66, 74, 77, 79, 91-93 are directed to a vector system comprising :a vector comprising: one or more polynucleotides, wherein at least one of the one or more polynucleotides encodes all or part of a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746). Claims 105 and 108 are directed to a cell comprising said composition as in claim 1 and said vector system. In contrast, claims in ‘032 are directed to a composition comprising an adeno-associated virus (AAV) which comprises a targeting moiety effective to target a muscle cell and a polynucleotide encoding a cargo polynucleotide wherein the targeting moiety comprises a viral capsid protein comprising a an n-mer motif, which comprises XmRGDXn, wherein X is any amino acid, m is 3, and n is 4, and wherein the motif is (a) inserted between any two native amino acids of the viral capsid protein, (b) replaces one or more native viral capsid protein amino acids, or both (a) and (b). Dependent claims limit the motif is inserted in the N or C terminus of any amino acid in amino acids 581 to 593 corresponding to the wild type AAV9 capsid protein, wherein the viral capsid protein comprises an AAV9 capsid protein with one, two, or three additional amino acid substitution, insertion or deletion, wherein the cargo polynucleotide is operably linked to a promoter or a muscle specific promoter. Claims 19-24 are directed to a method that uses said AAV. In the instant case, there is no patentable difference between the claimed compositions and the claims in copending Application no. ‘032. The copending Application no. ‘032 discloses a composition, comprising a targeting moiety effective to target a muscle cell and a polynucleotide encoding a cargo (cargo polynucleotide), wherein the targeting moiety comprises a viral capsid protein comprising an n-mer motif, which comprises XmRGDXn. The ‘032 differs from claimed invention by not disclosing that the n-mer motif set forth in table 4 or 5 and is (a) inserted between any two amino acids of the viral capsid protein similar to one claimed in the instant application. Tabebordbar cure the deficiency by disclosing s a composition comprising AAV comprising a polynucleotide encoding an engineered AAV9 capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV9 capsid (pages 4920, col. 2, para. 1, Fig. 5B, e4). Tabebordbar. teaches that the targeting peptide comprises or consists of GPGRGDQTTL or ASTRGDHGVL that has 100% sequence identity to SEQ ID NO: 530 and SEQ ID NO: 637. (see table S5). It is noted that each of the one or more n-mer inserts comprises at least one RGD motif and insert is from 3-15 amino acid. (see table S5). It is further disclosed that the targeting moiety is effective to target muscle fibers and cardiomyocytes (see fig. 1C and ID). Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the composition of ‘032 by substituting the n.mer RGD motif with one disclosed in Tabebordbar, in order to improve expression in heart and skeletal muscle cells, as instantly claimed, with a reasonable expectation of success,
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 5-6, 8-9, 11, 13, 16, 19, 27, 30, 32, 34, 37, 44-46, 48, 50, 57-58, 60, 63, 66, 74, 77, 79, 91-93, 105 and 108 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 19390070 in view of Tabebordbar et al., (Cell September 2021, 184, 4919–4938). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. In the instant case, claims are directed to a composition comprising: a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746);and optionally a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety, wherein the targeting moiety is effective to target a cardiac muscle cell. Dependent claims limit he wherein the targeting moiety comprises a viral protein, optionally wherein the viral protein is a capsid protein, wherein the the viral protein is an adeno associated virus (AAV) protein, optionally wherein the AAV protein is an AAV capsid protein (claim 9). Claim 11 limits herein one or more of the one or more n-mer inserts are incorporated into the AAV protein such that at least one or more of the one or more n-mer inserts and/or optional RGD motifs are each inserted between any two-amino acids independently selected from amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 598-599, 704-714, or any combination thereof in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide. Claims further limits the cargo is capable of inducing exon skipping in a gene, optionally a dystrophin gene, optionally, wherein the cargo is a mini- or micro-dystrophin gene. Claims 44-46, 48, 50, 52, 57-58, 60, 63, 66, 74, 77, 79, 91-93 are directed to a vector system comprising :a vector comprising: one or more polynucleotides, wherein at least one of the one or more polynucleotides encodes all or part of a targeting moiety effective to target a cardiac muscle cell, wherein the targeting moiety comprises one or more n-mer inserts, wherein at least one of the one or more n-mer inserts is selected from Table 4 (SEQ ID NO: 4-500) or Table 5 (SEQ ID NO: 501-746). Claims 105 and 108 are directed to a cell comprising said composition as in claim 1 and said vector system. In contrast, claims in ‘70 are directed to composition comprising an adeno-associated virus (AAV) which comprises a targeting moiety effective to target a muscle cell and a polynucleotide encoding a cargo, wherein the targeting moiety comprises a viral capsid protein comprising an n-mer amotif; which comprises XmRGDXn, wherein X is any amino acid, m is 1 or 2, and n is 4, and wherein the n-mer motif is (a) inserted between any two amino acids of the viral capsid protein, (b) replaces one or more native viral capsid protein amino acids, or both (a) and (b), wherein the motif is 8 or 9 amino acid in length. Dependent claims limit the composition wherein the n motif is located at the N or C terminal of any amino acid in amino acids 581 to 593 corresponding to the wild type AAV9 capsid protein. Claims further limit the cargo comprises a micro-dystrophin protein and , wherein the cargo polynucleotide is operably linked to a promoter that is a muscle-specific promoter. Claims 20-29 are directed to a method that uses the composition of claim 1. The ‘070 differs from claimed invention by not disclosing that the n-mer motif set forth in table 4 or 5 and is (a) inserted between any two amino acids of the viral capsid protein similar to one claimed in the instant application. Tabebordbar cure the deficiency by disclosing s a composition comprising AAV comprising a polynucleotide encoding an engineered AAV9 capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV9 capsid (pages 4920, col. 2, para. 1, Fig. 5B, e4). Tabebordbar. teaches that the targeting peptide comprises or consists of GPGRGDQTTL or ASTRGDHGVL that has 100% sequence identity to SEQ ID NO: 530 and SEQ ID NO: 637. (see table S5). It is noted that each of the one or more n-mer inserts comprises at least one RGD motif and insert is from 3-15 amino acid. (see table S5). It is further disclosed that the targeting moiety is effective to target muscle fibers and cardiomyocytes (see fig. 1C and ID). Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the composition of ‘70 by substituting the n.mer RGD motif with one disclosed in Tabebordbar, in order to improve expression in heart and skeletal muscle cells, as instantly claimed, with a reasonable expectation of success,
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WO2021077000, IDS is not applied as prior under as invention is obtained from the inventor, and the publication is commonly owned and therefore 102(b)(1) (A) and (102(b) (2) (A) and 102(b)(2) (C) exception applies.
Grimm et al (WO2018189244, IDS). 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, a polynucleotide encoding the engineered capsid, a vector comprising the polynucleotide encoding the engineered AAV capsid, an AAV virus vector comprising the engineered capsid, and cells comprising the polynucleotide (pages 25-28, and 30-31). Grimm et al. further teaches that the targeting peptide comprises RGDCFC or RGDCFCA. Grimm is not applied as prior art because it fails to teach recited peptide sequence set forth in Table 4 or 5.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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