DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/US2022/073908 (filed 07/19/2022). Acknowledgement is made of Applicants’ claim for benefit of U.S. Application No. 63/223,494 (filed 07/19/2021).
Claim Interpretation
The following comments are made to establish broadest reasonable interpretation for the record.
Regarding claims 1, 11-15, 24: These claims recite the term microdystrophin. Under broadest reasonable interpretation, the term microdystrophin is interpreted as including both mini-dystrophin and microdystrophin constructs; this interpretation is supported by the instant specification (e.g., par. 00311).
Regarding claims 1, 28, 58: The preamble of claim 1 recites a use for the pharmaceutical composition of the instant claims (“…for use in treating a dystrophinopathy…”); claims 28 and 58 attempt to further define the composition by reciting specific dystrophinopathies treated by said composition. However, recited uses are considered intended use limitations. Intended use limitations only limit the product in so far as the product must be capable of being used as recited. See MPEP 2111.02. In the instant case, the pharmaceutical composition is capable of being administered to treat the recited dystrophinopathies; i.e., claims 28 and 58 do not further limit the structure of the composition of claim 1.
Regarding claim 4: This claims recites, “…wherein the nucleic acid molecule encodes one or more of human p37AUF1, p40AUF1, p42AUF1, or p45AUF1.” As disclosed by the instant specification, p37AUF1, p40AUF1, p42AUF1, and p45AUF1 are isoforms of AUF1 (par. 0018).
Regarding claims 12-15: These claims recite the term the microdystrophin protein. The lack of antecedent basis for the protein per se is discussed below as it pertains to 35 US.C. 112(b). However, in the interest of compact prosecution, this limitation is interpreted as referring to a microdystrophin protein encoded by the microdystrophin pharmaceutical composition of claim 11; this is supported by the instant specification, which recites, “…and the second therapeutic is a gene therapy vectors, including an rAAV gene therapy vector encoding a microdystrophin…” (par. 00307).
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 12-24 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.
Regarding claims 12-14: These claims recite the limitation the microdystrophin protein. There is insufficient antecedent basis for this limitation in these claims. As set forth in above, this limitation is interpreted as referring to a microdystrophin protein encoded by the microdystrophin pharmaceutical composition of claim 11. However, as claim 11 merely recites a microdystrophin pharmaceutical composition, it would not be immediately understood by a person having ordinary skill in the art if the instant claims are further defining the composition of claim 11 as directed to a composition which encodes a microdystrophin protein. Thus, the metes and bounds of claims 12-14 are not clearly or precisely defined, rendering the claims indefinite.
Regarding claim 15: Following the above discussion, the instant claim suffers from the same lack of clarity surrounding the microdystrophin protein set forth above, further compounded by line 5, which recites, “…which trans gene [sic] is flanked by ITRs…”. Without the indefiniteness issues of the preceding claims, this might be attributed to formatting or editing errors; as is, the invention of claim 15 would not be immediately understood by a person of ordinary skill in the art. Is the transgene referring to the gene which encodes the microdystrophin protein, or a different therapeutic gene? The metes and bound are not clearly or precisely defined, rendering the claim indefinite.
Claims 16-23 depend from claim 15, inherit its deficiencies, and are likewise rejected as indefinite.
Regarding claim 24: The instant claim is directed to specific microdystrophin pharmaceutical compositions. As evidenced by Mendell, et al., rAAVrh74.MHCK7.micro-dystrophin is the same composition as SRP-9001 (Neurology. 2021); the comma immediately following rAAVrh74.MHCK7 is presumed to be a typographical error. However, while parentheticals can be used for abbreviations, the use of parentheticals adjacent to terms which recite alternate names or isoforms renders the claim indefinite because it is not clear whether the items within the parentheticals are required or optional.
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 28 and 58 are 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.
Regarding claims 28, 58: Intended use limitations are set forth above. Following that discussion, claims 28 and 58 recite, “…wherein the dystrophinopathy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, or limb-girdle muscular dystrophy.” This intended use limitation does not introduce any further limitation to the structure of the pharmaceutical composition; i.e., the product of claim 1 is the same product of claims 28 and 58, and likewise suitable for any intended purposes recited therein. Thus, claims 28 and 58 have the same scope as claim 1, and do not further limit the product recited therein.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 8, 10-11, 14-17, 20-23, 28, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider and Chenette (US 2018/0163178) in view of Xiao, et al. (US 2017/0368198) and Rodino-Klapac, et al. (Hum Mol Genet. 2013), as evidenced by Chamberlain, et al. (Hum Gene Ther Methods. 2016) and Kim, et al. (Mol Ther Methods Clin Dev. 2020).
Schneider and Chenette (hereinafter Schneider) teaches compositions encoding AUF1 for muscle cell uptake (Abstract).
Xiao, et al. (hereinafter Xiao) teaches polynucleotides encoding mini-dystrophin proteins and vectors comprising the same (Abstract).
Rodino-Klapac, et al. (hereinafter Rodino-Klapac) teaches combinatorial therapy of micro-dystrophin and follistatin for Duchenne muscular dystrophy (Abstract).
Regarding claims 1, 11, 15-17, 28, 58: Schneider teaches a pharmaceutical composition comprising a nucleic acid molecule encoding an AUF1 protein and a targeting element which controls muscle satellite cell-specific uptake or expression (pars. 0037, 0108), wherein the targeting element is a muscle satellite cell-specific promoter, e.g., MyoD or myogenin promoter (par. 0051), and wherein the nucleic acid molecule is contained within an AAV vector (pars. 0052, 0057). The composition is useful for treating muscular dystrophy, such as limb girdle muscular dystrophy (par. 0125). As evidenced by Chamberlain, et al., the transgene and additional elements, e.g., promoters, of an rAAV cassette are flanked by ITRs (see e.g., pg. 2, par. 1; pg. 3, par. 2) Thus, the composition of Schneider reads on:
the pharmaceutical composition for use in treating a dystrophinopathy in a subject in need thereof, wherein said pharmaceutical composition comprises a first therapeutic, wherein the first therapeutic is a first rAAV particle comprising a nucleic acid molecule encoding an AU-rich mRNA binding factor 1 (AUF1) protein, or functional fragment thereof, operatively coupled to a muscle cell-specific promoter and flanked by inverted terminal repeat (ITR) sequences limitations recited in part a) of claim 1; and
the wherein the dystrophinopathy is limb-girdle muscular dystrophy limitation recited in claim 28.
Schneider teaches an embodiment wherein the composition is used in combination with other treatments, and may be administered together, separately, or sequentially (par. 0127), but does not explicitly teach the combination as set forth in the instant claims.
However, Xiao teaches a pharmaceutical composition which comprises an AAV viral vector with flanking ITRs comprising a polynucleotide encoding a mini-dystrophin protein (see e.g., pars. 0014, 0022-0023, 0054, 0088), wherein the polynucleotide is operably linked to a CK7 promoter (pars. 0045-0050). The rAAV particle is useful for treating Duchenne muscular dystrophy and Becker muscular dystrophy (par. 0092). This reads on:
the pharmaceutical composition for use in treating a dystrophinopathy in a subject in need thereof, wherein said pharmaceutical composition comprises a second therapeutic which is different from said first therapeutic, wherein the second therapeutic is a microdystrophin pharmaceutical composition limitations recited in part b) of claim 1;
the wherein the second therapeutic is a microdystrophin pharmaceutical composition limitation recited in claim 11;
the wherein the microdystrophin pharmaceutical composition comprises a therapeutically effective amount of a second rAAV particle comprising an artificial genome comprising a nucleic acid that encodes the microdystrophin protein operatively coupled to a regulatory sequence that promotes expression in muscle cells, which trans gene is flanked by ITRs; and a pharmaceutically acceptable carrier limitations recited in claim 15;
the wherein the regulatory sequence comprises a muscle-specific promoter limitation recited in claim 16;
the wherein the muscle-specific promoter is a CK7 promoter limitation recited in claim 17; and
the wherein the dystrophinopathy is Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) limitations recited in claim 58.
Further, Rodino-Klapac teaches a combination of AAV-mediated micro-dystrophin and follistatin treatment via intramuscular injection in the mdx mouse model of Duchenne muscular dystrophy (DMD) results in full correction and optimized therapeutic effect in restoring skeletal muscle physiological responses to wild-type levels (pg. 4930; col. 2, par. 3); neither treatment restores function to wild-type levels as single therapies (pg. 4930; col. 2, par. 2).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the AUF1 composition of Schneider by combining it with the mini-dystrophin composition of Xiao. This conclusion of obviousness is based on the ‘combining known alternatives’ rationale. The combination of pharmaceutical compositions useful for treating muscular dystrophy is a predictable use of known alternatives for muscular dystrophy therapy, leading to the predictable result of treating said dystrophy. This rationale aligns with the principle of combining known prior art elements according to known methods to yield predictable results; see MPEP 2143(I)(A). Further, the skilled artisan would be motivated to combine the AUF1 and mini-dystrophin compositions with the expectation of increasing the therapeutic benefit due to an additive effect in view of the teachings of the Rodino-Klapac disclosure.
Regarding claim 4: Following the above discussion, Schneider teaches an embodiment wherein the AUF1 protein is p37AUF1, p40AUF1, p42AUF1, or p45AUF1 (par. 0043); this reads on the wherein the nucleic acid molecule encodes one or more of human p37AUF1, p40AUF1, p42AUF1, or p45AUF1 limitation recited in claim 4.
Regarding claim 8: Following the above discussion, as evidenced by Chamberlain, et al., AAVs are a nonenveloped, single-stranded DNA virus (pg. 1; par. 2). Thus, the composition of Schneider reads on the wherein the nucleic acid encoding the AUF1 protein is a single stranded or self-complementary recombinant artificial genome limitation recited in claim 8.
Regarding claim 10: Following the above discussion, Schneider does not teach the limitations recited in the instant claim. However, Schneider teaches the formulations for the composition may be presented in unit dosage form and prepared by any pharmacological methods known in the art (par. 0114); i.e., Schneider clearly teaches the composition is provided in a formulation, including dosage, effective to achieve a therapeutic effect. That means the conditions necessarily to achieve the therapeutic effect were result effective variables. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art; see MPEP 2144.05(II)(A). This renders obvious the wherein the rAAV is administered at a dose of 1E13 to 1E14 vg/kg or a dose of 2E13 vg/kg limitation recited in claim 10.
Regarding claim 14: Following the above discussion, Xiao teaches an embodiment wherein the mini-dystrophin protein comprises the amino acid sequence of SEQ ID NO: 7 (par. 0063), which shares 100% sequence identity to instant SEQ ID NO: 135; please see Office Action Appendix I for sequence alignments and percent identity (pgs. 4-6). This reads on the wherein the microdystrophin protein has an amino acid sequence of SEQ ID NO: 135 limitation recited in claim 14.
Regarding claim 20: Following the above discussion, Xiao teaches an embodiment wherein the AAV capsid is an AAV9 capsid comprising the amino acid sequence of SEQ ID NO: 13 (Table 13; pg. 66), which shares 100% sequence identity to instant SEQ ID NO: 115; please see Office Action Appendix I for sequence alignments and percent identity (pgs. 2-3). This reads on the wherein the AAV has a capsid that is 100% identical to SEQ ID NO: 115 (AAV9 capsid) limitation recited in claim 20.
Regarding claim 21: Following the above discussion, Xiao teaches an embodiment wherein the rAAV particle is administered intravenously or injected directly into the muscle (par. 0126); further disclosed are embodiments wherein the dose is 2, 3, 4, 5, 6, 7, 8, or 9x1013 vg/kg, or wherein the dose is 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, or 9x1014 vg/kg (par. 0127). This reads on the wherein the therapeutically effective amount of the second rAAV particle is administered intravenously or intramuscularly at dose of 2x1013 to 1x1015 genome copies/kg limitation recited in claim 21.
Regarding claim 22: It is set forth above Schneider teaches an embodiment wherein the composition is used in combination with another treatment and administered together (par. 0127); this reads on the wherein the first therapeutic and the second therapeutic are administered concurrently limitation recited in claim 22.
Regarding claim 23: Following the above discussion, Schneider and Rodino-Klapac are silent in regards to the vector genome ratio for combined rAAV therapeutics. However, as evidenced by Kim, et al., the art recognized the ratio of two AAV vectors in combination gene therapy as an optimizable variable for determining the optimal ratio for gene expression (Fig. 2; pg. 475, par. 2). As such, determining said ratio would have been a matter of routine optimization; see MPEP 2144.05(II)(A). This renders obvious the wherein the ratio of the vector genomes of the first rAAV particle in the first therapeutic to the vector genomes of the second rAAV particle in the second therapeutic is 0.5 to 1; 0.25 to 1; 0.2 to 1; 0.1 to 1; 1 to 1; 1 to 2; 1 to 5; 1 to 10; 1 to 20; 1 to 100; or 1 to 1000 limitations recited in claim 23.
Claims 2-3 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider and Chenette (US 2018/0163178) in view of Xiao, et al. (US 2017/0368198) and Rodino-Klapac, et al. (Hum Mol Genet. 2013), further in view of Escobar, et al. (Mol Ther Nucleic Acids. 2016); as evidenced by Chamberlain, et al. (Hum Gene Ther Methods. 2016).
The teachings of Schneider, Xiao, and Rodino-Klapac are set forth above.
Escobar, et al. (hereinafter Escobar) teaches Sleeping Beauty transposon-based vector delivery of dysferlin for muscular dystrophy (Abstract).
Regarding claims 2-3, 18: Following the above discussion, Schneider does not teach the promoter limitations recited in claims 2 or 3, nor does Xiao teach the promoter limitations recited in claim 18.
However, Escobar teaches the Spc5-12 promoter provides tissue specificity in skeletal muscle and drives strong transgene expression in myoblasts, myotubes, and myofibers (pg. 2; col. 1, par. 1).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the AUF1 composition of Schneider and the mini-dystrophin composition of Xiao by substituting the Spc5-12 promoter of Escobar for both the muscle satellite cell-specific promoter of Schneider and the CK7 promoter of Xiao. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so for the skeletal muscle tissue specificity and strong transgene expression conferred by the Spc5-12 promoter, as disclosed by Escobar (pg. 2). Further, as the three promoters are all muscle cell-specific promoters, and as Escobar additionally teaches use of the Spc5-12 promoter in AAVs (pg. 6; par. 1), the skilled artisan would have more than a reasonable expectation of success.
This renders obvious the wherein the muscle cell-specific promoter is a Spc5-12 promoter limitations recited in claims 2, 3, and 18.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider and Chenette (US 2018/0163178) in view of Xiao, et al. (US 2017/0368198) and Rodino-Klapac, et al. (Hum Mol Genet. 2013), further in view of Wilson, et al. (US 2007/0036760); as evidenced by Chamberlain, et al. (Hum Gene Ther Methods. 2016).
The teachings of Schneider, Xiao, and Rodino-Klapac are set forth above.
Wilson, et al. (hereinafter Wilson) teaches sequences of novel adeno-associated virus capsids (Abstract).
Regarding claim 9: As evidenced by Chamberlain, the genome of rAAVs are encapsidated within a serotype-specific capsid (pg. 2; par. 2); however, Schneider is silent in regards to the AAV capsid or its amino acid sequence of the AUF1 composition.
Wilson teaches an amino acid sequence of a capsid for a novel serotype AAV9.hu14 serotype comprising SEQ ID NO: 123 (pars. 0079, 0091, 0103); this capsid is useful for gene therapy vectors (par. 0074), highly efficient in transduction of muscle tissue (par. 0063), and advantageous if rAAV re-administration or repeat gene therapy is required (par. 0076). SEQ ID NO: 123 shares 100% sequence identity with instant SEQ ID NO: 115; please see Office Action Appendix I for sequence alignment and percent identity (pgs. 2-3).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the AUF1 composition of Schneider by using SEQ ID NO: 123 for the AAV capsid, as taught by Wilson. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so for highly efficient transduction of muscle tissue as well as its advantage if re-administration thereof or repeat gene therapy is required, as disclosed by Wilson (pars. 0063, 0076); further, as Wilson teaches its utility for gene therapy vectors (par. 0074), the skilled artisan would have more than a reasonable expectation of success.
Thus, the modification set forth above renders obvious the wherein the AAV has a capsid that is 100% identical to SEQ ID NO: 115 (AAV9 capsid) limitation recited in claim 9.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider and Chenette (US 2018/0163178) in view of Xiao, et al. (US 2017/0368198) and Rodino-Klapac, et al. (Hum Mol Genet. 2013), further in view of Zhao, et al. (Hum Mol Genet. 2016) and Koo, et al. (Hum Gene Ther. 2011); as evidenced by Chamberlain, et al. (Hum Gene Ther Methods. 2016).
The teachings of Schneider, Xiao, and Rodino-Klapac are set forth above.
Zhao, et al. (hereinafter Zhao) teaches membrane-binding domains of dystrophin (Abstract).
Koo, et al. (hereinafter Koo) teaches an AAV vector for delivery of microdystrophin (Abstract).
Regarding claim 12: Following the above discussion, Xiao teaches an embodiment wherein the mini-dystrophin protein consists of the N-terminus, hinge H1, rods R1 and R2, hinge H3, rods R22, R23, and R24, hinge H4, the cysteine-rich domain (CR domain), and all of the carboxy-terminal domain (CT domain) (par. 0289).
For clarity of record: Xiao teaches the N-terminus (NT) and actin binding domain (ABD) together comprise amino acid residues 1-240 of the mini-dystrophin protein (par. 0015); Xiao subsequently teaches embodiments wherein the NT and ABD are seemingly separate domains due to a comma (see e.g. pars. 0015, 0289), as well as embodiments wherein the NT and ABD are referred to as seemingly the same domain due to the lack of said comma (see e.g. pars. 0301, 0302).
As evidenced by Zhao and Koo, it is accepted in the art the N-terminal domain of dystrophin comprises the actin binding domain. Zhao: “[Dystrophin] contains four functional domains including N-terminus (NT)…”; “Dystrophin NT and spectrin-like repeats R11-17 bind to cytoskeletal filamentous actin…” (par. 1 of pg. 3647 to pg. 3648). Koo: “Dystrophin protein is defined by four structural regions: an actin-binding N-terminal (NT) domain…” (pg. 1379; par. 1). Therefore, it is reasonable to interpret the NT of Xiao as the actin binding domain.
The Examiner acknowledges the closed claim language of the limitation set forth in claim 12; however, absent any definition in the instant disclosure, it is reasonable to interpret the ABD as recited in the instant claim as equivalent to the NT of Xiao.
Thus, Xiao teaches an embodiment wherein the mini-dystrophin protein consists of ABD-H1-R1-R2-H3-R22-R23-R24-H4-CR-CT (par. 0289). Xiao does not teach inclusion of the spectrin 3 (R3) region of dystrophin, nor the exclusion of spectrin 22 and 23 regions (R22 and R23).
Regarding the inclusion of R3:
Zhao teaches dystrophin is an essential cytoskeletal protein in muscle, providing a primary linkage between the ECM and the actin cytoskeleton; loss of dystrophin leads to sarcolemmal leakage, myofiber degeneration, and necrosis (pg. 3647, par. 1). The R1-3 subdomain is exclusively restricted at the muscle cell membrane, independently interacts with the sarcolemma (pg. 3648; col. 2, par. 2), and is an alternative membrane binding domain (MBD) via a CR domain-independent mechanism (pg. 3648; col. 1, pars. 2-3). Further, R1-3 shows exclusive membrane binding in skeletal muscle, while R10-12 only demonstrates partial membrane localization in skeletal muscle (pg. 3649; col. 2, par. 2). Interaction with the sarcolemma is central to how dystrophin protects the muscle (pg. 3649; col. 2, par. 3).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the mini-dystrophin composition of Xiao by including R3 after R1 and R2. This conclusion of obviousness is based on the ‘teaching, suggestion, and motivation rationale’. One would have been motivated to do so to strengthen the interaction of the mini-dystrophin protein to the sarcolemma to increase its protective property of the muscle, as taught by Zhao (pgs. 3648-3649). Further, as evidenced by both the Xiao and Zhao disclosure, techniques for the generation of specific protein configurations (i.e., the ability to include R3 in the mini-dystrophin construct), are well known in the art; thus, the skilled artisan would have more than a reasonable expectation of success.
Regarding the exclusion of R22 and R23:
Now, as evidenced by Chamberlain, et al., it is well known in the art AAV vectors have a limited packaging capacity, with estimates for the maximum capacity ranging from 4.5 to 5.5 kb (pg. 2; col. 1, par. 3). Koo teaches a AAV constructs MD1 and MD2 for delivery of microdystrophin to muscle cells, comprising deletions of spectrin-like repeat domains 4-23 (pg. 1380; col. 1, par. 3). Intramuscular injection of AAV2/9-MD1 or -MD2 into the tibialis anterior muscles of neonatal mdx mice leads to stable and long-term microdystrophin expression up to 4 months post-delivery (pg. 1382; col. 1, par. 1).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the mini-dystrophin composition of Xiao by deleting R22 and R23 from the construct. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so to compensate for the inclusion of R3, due to the limited packaging capacity of AAV vectors. Further, the skilled artisan would have a reasonable expectation of success in doing so, as Koo teaches R22 and R23 are not required for microdystrophin expression.
The modifications set forth above render obvious the wherein the microdystrophin protein consists of dystrophin domains arranged from amino-terminus to the carboxy terminus: ABDH1-R1-R2-R3-H3-R24-H4-CR-CT, wherein ABD is an actin-binding domain of dystrophin, H1 is a hinge 1 region of dystrophin, R1 is a spectrin 1 region of dystrophin, R2 is a spectrin 2 region of dystrophin, R3 is a spectrin 3 region of dystrophin, H3 is a hinge 3 region of dystrophin, R24 is a spectrin 24 region of dystrophin, H4 is hinge 4 region of dystrophin, CR is the cysteine-rich region of dystrophin, and CT comprises at least the portion of the CT comprising an α1-syntrophin binding site limitations recited in claim 12.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Schneider and Chenette (US 2018/0163178) in view of Xiao, et al. (US 2017/0368198) and Rodino-Klapac, et al. (Hum Mol Genet. 2013), further in view of Sabeti, et al. (WO 2021/077000); as evidenced by Chamberlain, et al. (Hum Gene Ther Methods. 2016).
The teachings of Schneider, Xiao, and Rodino-Klapac are set forth above.
Sabeti, et al. (hereinafter Sabeti) teaches targeting moieties capable of specifically targeting muscle cells (Abstract).
Regarding claim 24: Following the above discussion, Xiao does not teach the particular microdystrophin compositions recited in the instant claim. However, Sabeti teaches the rAAV agent known as AAVrh74.MHCK7.microdystrophin, or SRP-9001 (par. 0327).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the mini-dystrophin composition of Xiao by substituting the rAAV encoding the mini-dystrophin protein of Xiao with the SRP-9001 composition of Sabeti. This conclusion of obviousness is based on the ‘substitution rationale’. The use of SRP-9001 in place of the mini-dystrophin composition of Xiao is a predictable use of prior art elements according to their established functions as rAAVs encoding miniaturized, synthetic versions of dystrophin, leading to the predictable result of the expression of microdystrophin in muscle cells. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B).
Claim Objections
Claims 10, 12, 15, and 21 are objected to because of the following informalities:
Regarding claims 10, 21: These claims recite limitations directed to the rAAV dose. However, the claim language is inconsistent. Claim 10 uses “E notation”, while claim 21 uses
traditional scientific notation. For consistency: lines 2-3 of claim 10 reads “wherein the rAAV is administered at a dose of 1E13 to 1E14 vg/kg or a dose of 2E13 vg/kg”; this should read “wherein the rAAV is administered at a dose of [[1E13]]1x1013 to [[1E14]]1x1014 vg/kg or a dose of [[2E13]]2x1013 vg/kg”.
Regarding claim 12: There is a presumed typographical error in line 3; the “ABDH1” of “…ABDH1-R1-R2-R3…” should read “ABD-H1”.
Regarding claim 15: Line 5 of this claims recites “ trans gene”; this should read “transgene”. Additionally, the grammar requires correction; e.g., “…wherein the transgene .
Appropriate correction is required.
Claims 5, 7, 13, and 19 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Allowable Subject Matter
Claims 29-30, 32, and 37 are allowed.
For clarity of record, SEQ ID NO: 17 (claims 5, 29), SEQ ID NOs: 31-36 (claims 7, 37), SEQ ID NOs: 52 and 54 (claim 13), and SEQ ID NOs: 94, 96, 130, and 132 (claim 19) are free from the prior art.
Conclusion
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
Prosecution Insights