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 .
Status of Claims
Claims, 3-9, 11, 13-18, 20-43, 46-48, 50-52, 54-61, 64-68, 70-73, 78-80, 82-84, 91, 93, 95-97, 99-100, 102-103, 105-114, 116-117, and 112-125 are canceled.
Claims 1-2, 10, 12, 19, 44-45, 49, 53, 62-63, 69, 74, 77, 81, 85-90, 92, 94, 98, 101, 104, 115, 118, 121, and 126 are pending and are under examination on the merits.
Priority
This application claims priority to U.S. Provisional Patent Application Serial No. 63/494,453, filed April 5, 2023; and 63/589,417, filed October 11, 2023.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-2, 10, 12, 19, 44-45, 49, 53, 62-63, 69, 74, 77, 81, 85-90, 92, 94, 98, 101, 104, 115, and 126 are supported by the U.S. Provisional Patent Application Serial No. 63/494,453 disclosure, filed April 5, 2023; thus, are being considered with an effective filing date of April 5, 2023.
Claims 118 and 121 are supported by the U.S. Provisional Patent Application Serial No. 63/589,417 disclosure, filed October 11, 2023; thus, are being considered with an effective filing date of October 11, 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/27/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
Claims 2, 45, 104, 115, 121, and 126 recite alternative claim limitations using “or,” “and/or” or “one or more;” the examiner has considered only one from the lists in the alternative as being required, However, for compact prosecution and customer service, the examiner considered more than one alternative limitation when possible as applicable to cited prior art rejections.
Claims 2, 12, 19, 49, 53, 63, 69, 77, and 81 recite “optionally wherein” for alternative limitations. The examiner is not considering limitation that follow “optionally wherein” as being required; thus, such limitations will not be considered to further limit the claim and the broadest reasonable interpretation will be afforded based on the preceding limitation listed in the alternative. However, for compact prosecution and customer service, the examiner has considered as many of the optional limitations as possible with respect to the prior art.
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 45, 49, 85-90,and 101 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.
Claim 45 recites “one or more Byrne enhancer elements and/or one or more Paulin enhancer elements,” claims 85 and 88 recite “a Byrne desmin enhancer element” and “a Paulin desmin enhancer element,” and claims 86 and 89 recite “a Byrne desmin enhancer element comprising the polynucleotide sequence of SEQ ID NO:21” and “a Paulin desmin enhancer element comprising the polynucleotide sequence of SEQ ID NO:22.” However, the specification fails to provide a clear structural and/or functional distinction between these two elements, and therefore, the metes and bounds of the claims cannot be determined. Specifically, SEQ ID NO: 21 is provided as an example of the “Byrne enhance” and SEQ ID NO: 22 is provided as an example of the “Paulin enhancer.” However, unlike the Byrne enhancer, the Paulin enhancer is defined by the applicant’s citation of Li and Paulin’s NPL and by genomic positions upstream of the Desmin coding region. Furthermore, a sequence comparison reveals that the 277 bp SEQ ID NO: 22 “Paulin enhancer” is a direct sub-sequence of the 359 bp SEQ ID NO: 21 “Byrne enhancer” (aligningto bases 21-297).. While the term “Paulin enhancer” has recognized meaning in the gene regulation field based on the cited Li and Paulin NPL, the term “Byrne enhancer” does not appear to be a term of the art, and thus it is unclear the distinction between the two terms. Claims 87, 90, and 101 inherit based on respective claim dependency and do not resolve the issue.
A person of ordinary skill in the art would not be able to determine the metes and bounds of the claims when selecting between these alternatives for the following reasons: (a) lack of mutual exclusivity because the Byrne enhancer entirely encompasses the Paulin enhancer, and the use of the “and/or” connector creates a situation where a single physical sequence (the 359 bp Byrne enhancer) could simultaneously satisfy both alternatives. It is unclear if a construct containing the 359 bp sequence is intended to be “one Byrne enhancer,” “one Paulin enhancer plus additional nucleotides,” or “one of each.” (b) No objective standard for differentiation because the specification provides no standard or functional characteristic to distinguish the Byrne enhancer from the Paulin enhancer sequences other than a minor difference in length of two example sequences. Given that the field recognizes the “Paulin enhance” as the source of this regulatory activity, the use of a second, non-standard term (“Byrne enhancer”) to describe a slightly longer fragment of the same locus fails to provide the requisite degree of clarity. (c) Ambiguous boundaries because it is unclear whether a sequence that is longer than the 277 bp Paulin core but shorter than the 359 bp Byrne fragment would be classifies as one, the other, or neither. Without clear definitions of where the Byrne enhancer ends and the paulin identity begins, the public is unable to distinguish the metes and bound of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 45 recites the broad recitation once or more Bryne enhancer elements and/or one or more Paulin enhancer elements, and the claim also recites one or more enhance elements comprising the nucleotide sequence of SEQ ID NO: 21…and/or one or more enhance elements comprising the nucleotide sequence of SEQ ID NO: 22 … which is the narrower statement of the range/limitation. Also, in the present instance, claim 49 recites the broad recitation a rabbit β-globin intron, and the claim also recites in intron comprises the nucleotide sequence of SEQ ID NO: 13 which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 44-45, 49, 62, and 69 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Williams (WO 2022056291 A1).
Regarding claims 44-45, Williams teaches expression cassettes comprising “novel combinations of muscle-specific enhancers and promoters useful for achieving high and persistent expression in muscle tissue or myocytes,” see abstract. Williams further teaches “combining desmin muscle-specific promoters and desmin muscle-specific enhancers and MCK muscle-specific enhancers to provide hybrid promoters that drive transgene expression in muscle cells and tissues,” and that “the resulting hybrid promoters are useful for muscle cell and gene therapy,” see [0012]. Williams further teaches “a mammalian desmin promoter, a mammalian desmin enhancer, and one or more mammalian muscle creatine kinase (MCK) enhancers that are operably linked,” see [0013] and as in claim 1. Williams further teaches that “the mammalian desmin promoter is human, the mammalian desmin promoter can include a nucleic acid sequence having 80% or more identity to any of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10,” see claims 1-4 and [0066].
Further regarding claim 44-45, Williams teaches “the mammalian desmin enhancer comprises a nucleic acid sequence having at least 80% identity to the nucleic acid sequence of SEQ ID NO: 6,” see claims 9-10, which aligns with a 100% identity score to claimed SEQ ID NO: 22 of the instant case. Williams further teaches SEQ ID NO: 50, as the “Human Desmin Enhancer (hdesmin (-1008 to -558) enhancer),” which comprises the claimed SEQ ID NO: 21 with a 99.6% identity score (see Table 2 [0120] and sequence search results attached to the file wrapper). Wilson further teaches that “it should also be understood that there can be multiple mammalian desmin enhancers and that any combination of the mammalian desmin enhancer(s)…can be made in terms of the order of the elements,” see [0098], and that the Desmin enhancers can be 5’ to the Desmin promoter, see [0134]. Thus, when assembling the Desmin enhancer elements defined as SEQ ID NOs: 50 and 6 with the Desmin promoter element defined by SEQ ID NO: 9 taught by Williams, in the following order, SEQ ID NO: 50, SEQ ID NO: 6, and SEQ ID NO: 9, a Desmin enhancer/promoter sequence is assembled with a 97.4% identity score to claimed SEQ ID NO: 12 in the instant case, which meets the about 90% identity requirement claimed. See sequence alignment below:
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Regarding claim 49, Williams further teaches additional elements such as “an intron can be inserted in the muscle-specific regulatory nucleic acid sequence” and that the “transgene can be positioned downstream from the mammalian desmin promoter, possibly between the additional elements…,” see [0098]. Wilson further teaches the use of the “Bovine Growth Hormone derived polyadenylation signal” element, see [0126].
Regarding claims 62 and 69, Williams further teaches that “the various muscle-specific hybrid promoters … may be used for muscle-specific transgene expression in cultured cells or tissues from, by way of example but not limitation, episomal or integrated plasmid, Nanoplasmid, minicircle, Doggybone, MIDGE, adenoviral, adeno-associated viral (AAV), retroviral, and lentiviral vectors, see [0012][0101][0126].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-2, 10, 12, 19, 92, 94, 98, and 104 are rejected under 35 U.S.C. 103 as being unpatentable over Geall et. al., (US 20190298847 A1, in IDS) in view of Khvorova et al., (US20200385737A1) and Hou et. al., (US 20200377887 A1).
Claim 1, is directed to a recombinant adeno-associated virus (rAAV) particle comprising an RNAi molecule comprising a first strand and a second strand forming a duplex, wherein the first strand (guide) comprises nucleic acid with the sequence SEQ ID NO: 1 or with a sequence about 90% identical to SEQ ID NO: 1 and the second strand comprises a non-guide region. The examiner notes that the use of the open-ended transition “comprising” means the claim is to include any molecule that contains the recited 21-mer sequence, even if additional nucleotides are present.
Regarding claims 1-2, 19, 92, and 98 Geall teaches “polynucleic acid molecules, pharmaceutical compositions, and methods for treating muscle atrophy or myotonic dystrophy,” see abstract. Geall teaches a systematic “walking” library of polynucleic acid molecules designed to target the DMPK gene via RNA interference (RNAi). Geall teaches RNAi polynucleic acid molecules that target sequences set forth in SEQ ID NOs: 28-141, 370-480, or 703-3406, of which SEQ ID NOs: 2646-2648 are of particular relevance to the claimed SEQ ID NO: 1 in the instant case. SEQ ID NOs: 2646-2648 are 23-mer “target RNA” sequences, see claims 1 and 8 and [0118-0120]. In the field of RNAi and as taught by Geall, “the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof” (see [0186]). Therefore, a disclosure of a “target RNA” sequence is a disclosure of the sense/passenger strand of an RNAi. Because the 23-mers taught by Geall are 100% identical to the passenger-side complement of the claimed 21-mer of SEQ ID NO: 1, Geall’s disclosure of SEQ ID NOs: 2646-2648 anticipate the claimed RNAi guide sequence.
Further regarding claim 1, Geall explicitly teaches that the RNAi polynucleic acid comprises a sense strand (passenger) and an antisense (guide) strand, see [0126]. Geall further teaches that the sense and antisense strands are complimentary to one another and form a duplex (see [0186-0189]), and considering the well-established principle of Watson-Crick base pairing, the disclosure of a sense strand inherently discloses its complementary antisense strand. The antisense compliment of Geall’s SEQ ID NO: 2646-2648 is a 23-mer that contains the 21-nucleotide sequence of the claimed SEQ ID NO: 1 with 100% identity, see sequence results attached to the file wrapper. Under the “comprising” construction of the claim, the 23-mer antisense strand anticipates the claimed 21-mer guide sequence.
While the specific sequences cited above (2646-2648) are 23-mers, Geall provided a robust framework of overlapping length ranges that encompass the claimed 21-mer. Geall teaches, for example, that the molecules can be: “about 18 to about 25 nucleotides…about 19 to about 23 nucleotides…about 20 to about 22 nucleotides,” see [0124-0130]. A 21-mer falls squarely within these narrowly defined, nested ranges.
Furthermore, Geall teaches SEQ ID NO: 13,462, which is a 19-mer specifically categorized as an antisense/guide strand, see [0121]. This 19-mer is 100% identical to the first 19 nucleotide bases of the claimed SEQ ID NO: 1. Having 19 bases identical to the 21-mer sequence claimed provides a 90.4% identity, which falls within the claimed about 90% identity structural limitation.
Geall does not merely disclose a random list of sequences, rather Geall teaches: (1) the specific DMPK genetic targets; (2) the specific sequences (e.g., SEQ ID NOs: 2646-2648); and (3) the specific architecture and length (i.e., duplex comprising a 20-22 nucleotide antisense strand). Because Geall provides a 100% sequence match within a disclosed range of “about 20 to about 22” nucleotides for the purpose of targeting the same gene (DMPK), the prior art is in possession of the claimed invention.
Further regarding claim 2, Geall teaches the first strand and the second strand are linked by means of an RNA linker capable of forming a loop structure ([0167]: “the sense strand is connected to the antisense strand via a linker molecule, which … is a polynucleotide linker”). Geall teaches the RNAi is a small inhibitory RNA (siRNA), a microRNA (miRNA), or a small hairpin RNA (shRNA) ([0123]: “the polynucleic acid molecule comprises RNA…RNA comprises short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA)…”). Geall further teaches “an asymmetric hairpin is a linear polynucleic acid molecule comprising an antisense region, a loop portion that comprises nucleotides or non-nucleotides, and a sense region that comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complimentary nucleotides to base pair with the antisense region and form a duplex with loop. For example, an asymmetric hairpin polynucleic acid molecule comprises an antisense region having length sufficient to mediate RNAi in a cell or in vitro system (e.g. about 19 to about 22 nucleotides) and a loop region comprising about 4 to about 8 nucleotides, and a sense region having about 3 to about 18 nucleotides that are complementary to the antisense region.” See [0188].
Further regarding claim 19, Geall teaches “a polynucleic acid molecule that hybridizes to a target sequence of human DMPK and mediates RNA interference against the human DMPK” see claim 1, and that “mediation of RNA interference against the human DMPK modulates muscle atrophy or myotonic dystrophy in a subject” see claim 3. Geall further teaches “the myotonic dystrophy is DM1” see [0008], and that “DM1 is caused by a dominantly inherited “CTG” repeat expansion in the gene DM protein kinase (DMPK),” see [0310]. Geall teaches the polynucleic acid molecules comprising the RNAi may be delivered by a recombinant vector, which may be a viral vector “derived from adeno-associated virus, retrovirus, adenovirus, or alphavirus,” see [0345].
Regarding claim 92, Geall teaches the use of pharmaceutical compositions, see [0373].
Regarding claim 94, Geall teaches the use/production of kits, see “kits/Article of Manufacture” [0368]-[0371].
Further regarding claim 98, Geall teaches administering an effective amount of the RNAi for treating muscle atrophy or myotonic dystrophy, see [0008] and [0089].
While Geall teaches the RNAi may be delivered via an rAAV vector, Geal does not teach per se rAAV particles comprising an AAVrh74 capsid (with about 90% identity to wild type) or administering the rAAV particles at a dose of about 1 x 108 to about 2 x 1013 genome copies/mL and/or a dose of about 1 x 108 to about 2 x 1014 genome copies/kg of body weight. Geall further does not teach the RNAi further comprises a scaffold and that the RNAi comprises a passenger strand comprising nucleic acid with the sequence of SEQ ID NO: 2 or with a sequence with about 90% identity to the sequence of SEQ ID NO: 2, nucleic acid with the sequence of SEQ ID NO:7 or with a sequence with about 90% identity to the sequence of SEQ ID NO:7.
Khvorova teaches asymmetric RNA silencing agents such that the guide stand and the passenger strand are not perfect complement to one another. Khvorova teaches that “the capacity of a siRNA-like duplex to mediate RNAi or translational repression may be predicted by the distribution of non-identical nucleotides between the target gene sequence and the nucleotide sequence of the silencing agent at the site of complementarity,” and that “where gene silencing by translational repression is desired, at least one non-identical nucleotide is present in the central portion of the complementarity site so that duplex formed by the miRNA guide strand and the target mRNA contains a central “bulge”. Khvorova further teaches that “ the “bulge” is centered at nucleotide positions 12 and 13 from the 5′ end of the miRNA molecule.” See [0306]. Khvorova teaches that the bulge is for by “extra nucleotides that create a single nucleotide “loop” in one portion of the stem, and/or one or more unpaired nucleotides that create a gap in the hybridization of the two portions of the stem to each other,” see [0309]. Khvorova further teaches “to facilitate entry of the antisense strand into RISC (and thus increase or improve the efficiency of target cleavage and silencing), the base pair strength between the 5′ end of the sense strand and 3′ end of the antisense strand can be altered;” for example, where there “is at least one wobble base pair, e.g., G:U, between the 5′ end of the first or antisense strand and the 3′ end of the sense strand portion,” which enhances “entry into RISC,” see [0316][0340]. Khvorova teaches that applying these “asymmetry design rules” to RNAi silencing agents facilitates “enhanced efficacy and specificity in mediating RNAi,” because such alterations “facilitate entry of the antisense strand of the siRNA… into RISC in favor of the sense strand, such that the antisense strand preferentially guides cleavage or translational repression of a target mRNA, and thus increasing or improving the efficiency of target cleavage and silencing,” see [0339].
Hou teaches gene therapy tools for Huntington’s disease using adeno-associated virus (AAV) particles to deliver RNA molecules that silence the huntingtin (HTT) gene, see entire claim set. In particle Hou teaches using rAAV particles comprising an AAV capsid comprising an amino acid sequence with about 90% identity to a wildtype AAVrh74 capsid, see claim 10. Hou further teaches administering the rAAV particles at a dose of about 1 x 108 to about 2 x 1013 genome copies/mL and/or a dose of about 1 x 108 to about 2 x 1014 genome copies/kg of body weight, see [0528]-[0531].
Hou further teaches that “a “modulatory polynucleotide” is any nucleic acid sequence(s) which functions to modulate (either increase or decrease) the level or amount of a target gene, e.g., mRNA or protein levels,” see [0205]. Hou further teaches that “at least one siRNA, miRNA or other RNAi agent described herein, may be encoded by a modulatory polynucleotide which may also comprise at least one molecular seq ID No,” see [0300]. Hou further teaches methods of designing the modulatory polynucleotides encoding novel double stranded RNAi constructs, see [0008]. Hou further teaches that a “modulatory polynucleotide comprises in the 5′ to 3′ direction, a 5′ flanking sequence, a 5′ arm, a loop motif, a 3′ arm and a 3′ flanking sequence,” and that “ the 5′ arm may comprise a nucleic acid sequence encoding a sense sequence and the 3′ arm comprises a nucleic acid sequence encoding the antisense sequence” or “the 5′ arm comprises a nucleic acid sequence encoding the antisense sequence and the 3′ arm comprises a nucleic acid sequence encoding the sense sequence,” see [0314]. Hou further teaches that Hou further teaches “separating the sense and antisense sequence of the stem loop structure of the modulatory polynucleotide is a loop sequence (also known as a loop motif, linker or linker motif). The loop sequence may be of any length, between 4-30 nucleotides, between 4-20 nucleotides, between 4-15 nucleotides, between 5-15 nucleotides, between 6-12 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, and/or 15 nucleotides,” see [0307]. Hou further teaches the use miR155 scaffold, see [0209][0211][0342]. Hou further teaches that “ the 5′ arm, sense and/or antisense sequence, loop motif and/or 3′ arm sequence may be altered (e.g., substituting 1 or more nucleotides, adding nucleotides and/or deleting nucleotides). The alteration may cause a beneficial change in the function of the construct (e.g., increase knock-down of the target sequence, reduce degradation of the construct, reduce off target effect, increase efficiency of the payload, and reduce degradation of the payload),” see [0315]. Hou further teaches SEQ ID NO: 12 corresponding to a 5’ miR155 scaffold portion, which aligns with 100% identity to SEQ ID NO: 9 of the instant case. Hou further teaches SEQ ID NO: 21 corresponding to a 3’ miR155 scaffold portion, which aligns with 100% identity to SEQ ID NO: 10 of the instant case. Hou further teaches SEQ ID NO: 17 corresponding to a miR155 loop structure, which aligns with 100% identity to SEQ ID NO: 3 of the instant case. See sequence search results attached to the file wrapper.
Hou further teaches that “the modulatory polynucleotide is designed using at least one of the following properties: loop variant, seed mismatch/bulge/wobble variant, stem mismatch, loop variant and vassal stem mismatch variant, seed mismatch and basal stem mismatch variant, stem mismatch and basal stem mismatch variant, seed wobble and basal stem wobble variant, or a stem sequence variant,” see [0216].
Hou further teaches the use of pharmaceutical compositions and kits, see claim 11 and [0009].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to incorporate the asymmetric DMPK targeting RNAi of Geall comprising a modified passenger strand consistent with the structure taught by Khvorova into the microRNA scaffold of Hou and further package it into an rAAV particle with a AAVrh74 capsid in order to treat a mammal suffering from myotonic dystrophy-1 (DM1) by administering the virus comprising the DMPK targeting microRNA in the claimed dosing ranges.
Regarding the passenger strand, SEQ ID NO: 2, of instant claim 2, Geal’s disclosed sense strand, SEQ ID NO: 2647, which is the direct complement of the instantly claimed guide/antisense strand of SEQ ID NO: 1, does not, without modification satisfy the claimed limitation that the passenger/sense strand comprise nucleic acid with sequence of SEQ ID NO: 2 or a sequence with about 90% identity thereto. However, applying Khvorova’s teachings to the passenger strand of Geall, a PHOSITA would have: (1) introduced a two-nucleotide deletion into Geall’s passenger strand at the position corresponding to a bulge centered at positions 12-13 of the guide strand, per Khvorova’s teaching regarding RNAi repression and (2) substituted a nucleotide at the 3′ end of the sense strand portion to form a G:U wobble, per Khvorova’s teaching regarding enhanced asymmetry. The resulting modified passenger strand aligns to the claimed SEQ ID NO: 2 with 100% identity, see sequence alignment:
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Regarding the SEQ ID NO: 7 of claim 10, assembling (a) the guide strand of Geall corresponding to instant SEQ ID NO: 1, (b) the loop/linker sequence of Hou corresponding to instant SEQ ID NO: 3, and (c) the modified passenger stand corresponding to instant SEQ ID NO: 2 arrived at by applying Khvorova’s bulge and wobble teachings to Geall’s passenger strand results in an assembled RNAi duplex aligning to the claimed SEQ ID NO: 7 with 100% identity, see sequence alignment:
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A PHOSITA would have been motivated to modify Geall’s passenger strand according to Khvorova’s bulge and wobble teachings because asymmetric modifications bias RISC loading towards the intended guide strand and away from the passenger strand, thereby improving the efficiency of target cleavage and silencing. A PHOSITA seeking to optimize the DMPK-silencing efficacy and strand selection fidelity of Geall’s RNAi construct would have looked to Khvorova’s asymmetry enhancing design principles as routine, art-recognized tools and would have been motivated to apply one or more such features (i.e., bulges ad wobbles) because Khvorova teaches both embodiments enhance duplex asymmetry to bias stand selection, such that combining them represents the predictable stacking of complementary modifications rather than the combination of unrelated or competing teachings. A PHOSITA would have further been motivated to incorporated this asymmetric RNAi molecule into the miR155 scaffold and loop architecture to promote efficient Drosha/Dicer processing and reliable liberation of a guide strand for target transcript silencing. Ultimately, a PHOSITA would have been motivated to package the asymmetric RNAi molecule with the miR155 architecture into an rAAV with a AAVrh74 capsid to provide enhanced transduction efficiency for AAV delivered RNAi transgenes when administering within the dosing ranges taught by Hou because those ranges were already established in the art as effective for AAV-mediated RNAi gene therapy delivery.
A PHOSITA would have had a reasonable expectation of success in arriving at the claimed passenger strand (SEQ ID NO: 2) and assembled duplex (SEQ ID NO: 7 because Khvorova demonstrated that RNA silencing agents bearing a central bulge at positions 12-13 and/or a terminal wobble pair retain silencing function relative to a perfectly complementary duplex indicating that such modifications are compatible with RNAi activity and because Hou demonstrated the successful use of the miR155 scaffold elements with asymmetric RNAi molecules comprising bulges and/or wobbles without loss of function and in fact cause a beneficial change in the function of the construct. Because AAV vector components, i.e., capsid, scaffold, and transgene, are recognized in the art a modular and interchangeable, substituting Geall’s DMPK RNAi sequence for Hou’s RNAi sequences with Hou’s microRNA platform would have been expected to succeed predictably.
Claims 49, 53, 62-63, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Williams (WO 2022056291 A1) as applied to claims 44-45, 49, 62, and 69 above, and further in view of O'Riordan (US 20170173183 A1), Hou et. al., (US 20200377887 A1), and Yao (US 20200172928 A1).
The teachings of Williams are incorporated herein by reference to the 102 rejection above.
Williams does not teach the expression cassette’s transgene is embedded in the intron such that the transgene is flanks at its 5’ and 3’ end by a 5’ arm and a 3’ arm of the intron, respectively. Williams further does not teach that the expression cassette is flanked by one or more stuffer nucleic acid sequence.
O'Riordan teaches embedding nucleic acid sequences encoding miRNA constructs “in an intron,” see claim 24. O'Riordan further teaches miRNA “sequence embedded in the beta globin intron,” such that there is a 5’ arm of the beta globin intron located 5’ to the miR-708 transgene and a 3’ arm of the beta globin intron located 3’ to the miR-708 transgene, see [0184] and FIG. 23A. O'Riordan further teaches that “FIG. 24 shows the evaluation of candidate vectors harboring the miR-708 sequence, either in the miR-155 or the miR-708 scaffold (embedded in the beta-globin intron),” see [0059]. O'Riordan further teaches that such vectors comprising miRNA embedded in the beta globin intron “resulted in…expression in human cells in vivo, as compared to vectors driving expression of a control miR from either the opsin or the rhodopsin kinase promoter (Ops miR-Cont and RK miR-Cont, respectively),” and that “these results demonstrate the successful validation of several vectors that may be used for suppression/replacement strategies (such as those described above) in human cells,” see [0185].
O'Riordan teaches rAAV vectors with two stuffer sequences, one positioned 3’ to the 5’ ITR and the other positioned 3’ to the BGH PolyA and 5’ to the 3’ ATR. For example, O'Riordan teaches “the nucleic acid in the AAV comprises 5′ to 3′ nucleic acid encoding the following: an AAV ITR, a stuffer fragment (e.g., SEQ ID NO:11), an RK promoter, a chimeric intron (e.g., SEQ ID NO:10), a human rhodopsin, a β-globin intron, a miR-708 embedded in a β-globin intron, a bovine growth hormone polyadenylation sequence, a stuffer fragment, and an AAV ITR,” see [0121].
O'Riordan teaches rAAV vectors wherein “the AAV vector comprises an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrh10, AAV11, AAV12, AAV2R471A, AAV DJ, a goat AAV, bovine AAV, or mouse AAV serotype ITR,” see [0014]. O'Riordan further teaches and claims the AAV ITRs are AAV2 ITRs, see [0015] and claims 46 and 49-50. O'Riordan further teaches “self-Complementary AAV Viral Genomes,” see [0123].
Hou teaches “the viral genome comprises one or more filler sequences in order to have the length of the viral genome be the optimal size for packaging,” and that “ in order to have the length of the viral genome be about 4.6 kb.,” see [0178]. Hou further teaches “the viral genome comprises two filler sequences, and the first filler sequence is located 3′ to the 5′ ITR sequence and the second filler sequence is located 3′ to the polyadenylation signal sequence,” see [0183]; “the filler sequence is located 5′ to the 3′ ITR sequence,” see [0184]; and “a filler sequence may be located between two regions, such as …the polyadenylation signal sequence region and the 3′ ITR,” see [0196]. Hou further teaches that “ the vectors with a 5′ or 3′ filler sequence vectors presented the highest titers,” see [0665]. Hou further teaches SEQ ID NOs: 45, 62, and 64, which are defined as respectively: (45) construct HT106 ITR to ITR sequence (see [0351]); (62) Filler002 (see [0357]); and (64) Filler004 (see [0357]. Each of these three sequences align to SEQ ID NO: 18 of the instant case with 92.4% identity score, thereby salifying the claimed “with about 90% identity to the sequence of SEQ ID NO: 18” optional limitation. Hou further teaches SEQ ID NOs: 45, 49, 62, and 66, which are defined as respectively: (45) construct HT106 ITR to ITR sequence (see [0351]); (49) construct HT110 ITR to ITR sequence (see [0351]); (62) Filler002 (see [0357]); and (65) Filler005 (see [0357]. Each of these four sequences align to SEQ ID NO: 19 of the instant case with 96.7% identity score, thereby satisfying the claimed “with about 90% identity to the sequence of SEQ ID NO: 19” optional limitation. Furthermore, Hou teaches SEQ ID NOs: 46 and 63, which are defined as respectively: (46) construct HT107 ITR to ITR sequence (see [0351]) and (63) Filler003 (see [0357]). Each of these two sequences align to SEQ ID NO: 19 of the instant case with 95.5% identity score, thereby salifying the claimed “with about 90% identity to the sequence of SEQ ID NO: 19” optional limitation. Hou teaches “the AAV particle viral genome comprises at least one filler sequence region,” see [0360]. It is noted that the term “filler sequence” is synonymous with the instantly claimed term “stuffer sequence.”
Hou further teaches using promoters, enhancers, introns, and polyA signals to improve expression. Hou teaches “the nucleic acid sequence comprising the payload region may comprise one or more of a promoter region, an intron, a Kozak sequence, an enhancer or a polyadenylation sequence,” see [0039][0067-0069]. Hou further teaches “elements to enhance the transgene target specificity and expression include promoters, endogenous miRNAs, post-transcriptional regulatory elements (PREs), polyadenylation (PolyA) signal sequences and upstream enhancers (USEs), CMV enhancers and introns,” see [0086]. Hou further teaches “the viral genome comprises an enhancer element, a promoter and/or a 5′UTR intron,” see [0121]. Hou further teaches “the payload region comprises at least one element to enhance the expression such as one or more introns or portions thereof,” see [0166]. Hou further teaches the use of introns such as MVM (67-97 bps), FIX truncated intron 1 (300 bps), 0-globin SD/immunoglobulin heavy chain splice acceptor (250 bps), adenovirus splice donor/immunoglobin splice acceptor (500 bps), SV40 late splice donor/splice acceptor (19S/16S) (180 bps) and hybrid adenovirus splice donor/IgG splice acceptor (230 bps),” see [0166], or “others known in the art,” see [0179]. Hou also teaches the use of “a chimeric intron,” see [0174]. Hou further teaches the use of an “SV40…a human beta globin intron in an expression vector,” or “or others known in the art,” see [0161 and 0175].
Hou further teaches that the “…modulatory polynucleotides encoding the RNAi molecules may be inserted into recombinant AAV vectors,” see [0003]. Hou further teaches “the AAV particles…comprise a viral genome with at least one ITR region and a payload region,” or that “the viral genome has two ITRs,” wherein “these two ITRs flank the payload region at the 5′ and 3′ ends,” see [0081]. Hou further teaches that “the AAV serotype may be, but is not limited to” AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrh10, AAV11, AAV12, etc., see [0058]. Hou further teaches self-complementary AAV viral genomes (scAAVs)…contain DNA strands which anneal together to form double stranded DNA.,” and “by skipping second strand synthesis, scAAVs allow for rapid expression in the cell,” see [0051].
Hou further teaches the use of pharmaceutical compositions and kits, see claim 11 and [0009].
Yao teaches the “beta-globin intron (SEQ ID NO: 10),” see [0099], which aligns to the rabbit β-globin intron sequences, SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, of the instant case, with 89.3%, 89.5% and 100% identity score, respectively.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the desmin driven expression cassette of Williams to embed the transgene within an intron such that the transgene is flanked at its 5’ and 3’ ends by a 5’ arm and 3’ arm of the intron, respectively, as taught by O'Riordan and to further flank the resulting expression cassette with stuffer nucleic acid sequences and package it within a rAAV vector bounded by AAV ITRs, as taught by Hou and O’Riordan. A PHOSITA would have been motivated to embed the transgene in an intron in order to ensure robust expression in human cells and to utilize stuffer sequences to bring an AAV vector genome to its optimal packaging size ensuring highest titers. A PHOSITA would have had a reasonable expectation of success because AAV genomes are assembled from modular functionally independent components such as promoters, enhancers, introns, stuffer sequences, and ITS that were demonstrated in the art to function predictably regardless of the specific transgene. Hou, O’Riordan, and Yao each demonstrate successful use of these elements in functional AAV gene therapy constructs, such that a PHOSITA would have expected the same elements to function predictably when applied to the desmin drive expression cassette.
Claims 77, 81, 85, 87-88, and 101 are rejected under 35 U.S.C. 103 as being unpatentable over Geall et. al., (US 20190298847 A1, in IDS) in view of Khvorova et al., (US20200385737A1) and Hou et. al., (US 20200377887 A1) as applied to claims 1-2, 10, 12, 19, 92, 94, 98, and 104 above, further in view of Williams (WO 2022056291 A1), O'Riordan (US 20170173183 A1), Hou et. al., (US 20200377887 A1), and Yao (US 20200172928 A1) as applied to claims 44-45, 49, 53, 62-63, 69, and further in view of Loiler (WO2020047472A1) and Wahbi et. al., (Trends Cardiovasc Med. 2020 May; 30(4):232-238).
The teachings of Geall, Khvorova, Hou, Williams, O’Riordan, and Yao are incorporated herein by reference to the respective 102 and 103 rejections above.
Regarding the ordered arrangement of claims 85 and 88, Hou teaches an AAV viral genome comprising, in general 5’ to 3’ arrangement, “a) a 5’ inverted terminal repeat (ITR) sequence region…; b) an enhancer sequence region…; c) a promoter sequence region…; d) a modulatory polynucleotide sequence region…; e) a polyadenylation (polyA) signal sequence region…; and f) a 3’ ITR sequence region,” see claim 1. O’Riordan independently teaches the same general skeleton with additional resolution as to filler placement and intron embedding, teaching a construct comprising, 5’ to 3’, “an AAV ITR, a stuffer fragment…, an RK promoter, a chimeric intron…, a human rhodopsin, a β-globin intron, a miR-708 embedded in a β-globin intron, a bovine growth hormone polyadenylation sequence, a stuffer fragment, and an AAV ITR,” see [0121]. Thus, both Hou and O’Riordan, independently, teach that a functional rAAV vector genome is conventionally assembled in the order: 5’ ITR → stuffer/filler sequence → enhancer/promoter → intron (optionally with an embedded modulatory polynucleotide/miRNA scaffold flanked by intron arms) → polyadenylation signal → stuffer/filler sequence → 3’ ITR.
Mapping the specific elements taught by the combined references onto this art-recognized skeleton: Williams teaches the Byrne and Paulin desmin enhancer elements positioned 5’ to the desmin promoter, see [0098], [0134] (applied above to claims 44-45); O’Riordan and Yao together teach a 5’ arm and 3’ arm of a rabbit β-globin intron flanking an embedded miRNA construct, see O’Riordan [0184], FIG. 23A and Yao [0099] (applied above to claims 49, 53); Hou and O’Riordan together teach a 5’ and 3’ miR-155 scaffold sequence flanking a guide-loop-passenger miRNA cassette, see Hou [0209], [0211], [0342] and O’Riordan [0038], [0058], [0118] (applied above to claim 12); Geall teaches the DMPK204 guide sequence and, as modified per Khvorova’s bulge and wobble teachings, the DMPK204 passenger sequence (applied above to claims 1, 2, and 10); Hou teaches the miR-155 loop sequence (SEQ ID NO:17, aligning to claimed SEQ ID NO:3 with 100% identity) positioned between the guide and passenger sequences, see [0307] (applied above to claim 2); Hou further teaches a BGH polyadenylation sequence (SEQ ID NO:67, aligning to claimed SEQ ID NO:16 with 100% identity) positioned 3’ to the modulatory polynucleotide region, see claim 1; and Hou further teaches 5’ and 3’ filler/stuffer sequences flanking the expression cassette and positioned adjacent to the ITRs, see [0178], [0183]-[0184], [0196] (applied above to claim 63). Assembling each of these individually-taught elements into the single conventional vector skeleton taught by both Hou and O’Riordan, in the specific 5’ to 3’ positions each reference assigns to its corresponding element type, results in the identical ordered arrangement recited in claims 85 and 88: AAV2 ITR, SerpinA1 stuffer, Byrne desmin enhancer, Paulin desmin enhancer, desmin promoter, 5’ arm of rabbit β-globin intron, 5’ miR155 scaffold, DMPK204 guide, miR155 loop, DMPK204 passenger, 3’ miR155 scaffold, 3’ arm of rabbit β-globin intron, BGH polyA, SerpinA1 stuffer, and AAV2 ITR.
Neither Geall, Khvorova, Hou, Williams, O’Riordan, and Yao teach the AAV capsid comprises an amino acid sequence comprising an amino acid substitution at position 502 or 505.
Loiler teaches “Non- limiting examples of recombinant AAV backbones to create the vector include AAV vector serotypes from the group of AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV 12, AAV13, AAV PHP.B, or AAV rh74. In a further aspect, the vector backbone is an AAV9 serotype, an AAVrh74 serotype, or a modified AAVrh74 serotype. Also provided is a polynucleotide encoding a modified AAVrh74 VP1 capsid protein comprising one or more modifications selected from the group of a substitution of isoleucine for asparagine at amino acid position 502, and an optional substitution of tryptophan to arginine at amino acid 505 of the VP1 of AAVrh74…” see [0008].
Loiler teaches that “one of the mutants (AAVmut4, asparagine to lsoleucine at amino acid 502 of VP1 capsid) increases gene delivery globally to all tissues tested up to 56-fold (between 3 and 56-fold increase depending on tissue) higher transduction efficiency,” see [0135][0137]. Loiler further teaches “AAV rh74 Consensus Sequence Alignment vs. AAVrh74 vs. AAVrh74-N502I-capsid vs. Rh74 YIG591 cap protein,” see “AAV rh74 Consensus Sequence Alignment” pages 55-56. Loiler further teaches SEQ ID NO: 11, which when aligning SEQ ID NO:50 of the instant case to SEQ ID NO: 11 of Loiter, there is 100% homology. See pages 55-56, [0135][0137], and sequence search results attached to the file wrapper.
Loiler teaches that “another mutant (AAVmut5, tryptophan to arginine at amino acid 505 of VP1 capsid) increases gene delivery to the heart almost 50-fold over AAVrh74,” see [0135]. Loiler teaches “AAV rh74 Consensus Sequence Alignment vs. AAVrh74 vs. AAVrh74-N502I-capsid vs. Rh74 YIG591 cap protein” see paged 55-56. When comparing SEQ ID NO:52 to the alignment of wild-type AAVrh74 taught by Loiter, there is a single amino acid difference, tryptophan to arginine substitution at position 505, which Loiler explicitly teaches as another mutant that exemplified enhanced gene delivery to the heart. SEQ ID NO: 52 is arrived at with 100% identity by applying the tryptophan to arginine substitution to the wild-type AAVrh74. See pages 55-56 and [0135][1037]. Loiler teaches that “the sequence of the AAV rh.74 genome is provided in U.S. Patent 9,434,928…” [0086].
Wahbi teaches “patients with myotonic dystrophy, the most common neuromuscular dystrophy in adults, have a high prevalence of arrhythmic complications with increased cardiovascular mortality and high risk for sudden death,” see abstract.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the rAAV particle comprising the DMPK-targeting expression cassette of Geall in view of Williams, Khvorova, Hou, O'Riordan, and Yao to utilize a modified AAVrh74 capsid comprising the N502I substitution or the W505R substitution, as taught by Loiler, including capsids corresponding to SEQ ID NO: 50 and SEQ ID NO: 52. One of ordinary skill in the art would have been motivated because Loiler explicitly teaches that substitution of isoleucine for asparagine at position 502 of the AAVrh74 VP1 capsid increases gene delivery globally to tissues by up to 56-fold and that substitution of tryptophan to arginine at position 505 increases gene delivery to the heart by nearly 50-fold, thereby identifying these mutations as advantageous capsid modifications for enhancing in vivo transduction efficiency, particularly in muscle and cardiac tissues relevant to treatment of DMPK-associated myotonic dystrophy as further supported by Wahbi describing the cardiac involvement in DM1. One would have had a reasonable expectation of success because Loiler demonstrates successful generation and functional use of these specific AAVrh74 mutant capsids and teaches that such modified capsids can be used with conventional rAAV vector genomes, and Hou and O'Riordan teach that rAAV genomes may be packaged into a variety of interchangeable AAV capsid serotypes, indicating that substitution of one known functional capsid variant for another would have predictably resulted in an rAAV particle capable of delivering the DMPK-targeting expression cassette.
Claim 115 is rejected under 35 U.S.C. 103 as being unpatentable over Geall et. al., (US 20190298847 A1, in IDS) in view of Khvorova et al., (US20200385737A1) and Hou et. al., (US 20200377887 A1) as applied to claims 1-2, 10, 12, 19, 92, 94, 98, and 104 above, and further in view of Anguela (WO2023004437A1, published 01/26/2023).
The teachings of Geall and Hou are incorporated herein by reference to the respective 103 rejection above.
Geall and Hou do not teach the RNAi is administered in combination with an immunosuppressive agent, wherein the immunosuppressive agent is administered before, at the same time, and/or after administration of the RNAi.
Anguela teaches “a method of intracellular delivery of a DNA to a subject comprising administration of: a. at least one of a cytosolic DNA-sensing inhibitor selected from the group consisting of a cyclic GMP-AMP synthase - stimulator of interferon genes (cGAS - STING) pathway inhibitor and an inflammasome pathway inhibitor; and b. a first nanoparticle comprising said DNA wherein step (b) can be performed prior to, concomitantly with, or after step (a),” see claim 1. Anguela further teaches that “an immunosuppressant is an anti-inflammatory agent,” see [0175]. Anguela further teaches that “ said DNA is a DNA vector comprising a transgene operatively linked to a regulatory element,” and that “said transgene is operatively linked to a promoter; and said DNA vector comprises 5’ to 3’ said promoter, said transgene, and a polyadenylation and termination signal,” see claims 3-4. Anguela teaches improved transgene expression when an immunosuppressant is administered along with the DNA vector encoding the transgene because of reduced interferon and cytokine release, thereby mitigating inflammation and the body’s immune response to the introduce DNA vector, see [0006]-[0009], [0011]-[0016], [0217]-[0241]
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to administer the rAAV particle packaged with the RNAi of Geall in view of Khvorova and Hou in combination with an immunosuppressive agent. A PHOSITA would have been motivated so the RNAi can reach cells while immune sensing of foreign DNA is dampened, thereby allowing for increased RNAi transgene expression and thus greater DMPK knockdown efficiency. A PHOSITA would have had a reasonable expectation of success because Anguela demonstrated that co-administration of an immunosuppressive/cytosolic DNA-sensing inhibitor alongside a delivered transgene predictably increases transgene expression by reducing the interferon and cytokine release that otherwise interfered with transgene delivery/expression. Because immunosuppressive pre-treatment, co-treatment, and post-treatment regimens were already established in the art as routine strategies for mitigating transgene induced innate immune responses in gene therapy, a PHOSITA would have reasonably expected that applying this same strategy to the DMPK-targeting rAAV particle of Geall in view of Khvorova and Hou would predictably yield the same benefit.
Claims 118 and 121 are rejected under 35 U.S.C. 103 as being unpatentable over Geall et. al., (US 20190298847 A1, in IDS) in view of Khvorova et al., (US20200385737A1) and Hou et. al., (US 20200377887 A1) as applied to claims 1-2, 10, 12, 19, 92, 94, 98, and 104 above, and further in view of Tanner et al. (Nucleic Acids Res., Feb. 26, 2021, 49(4): 2240- 2254).
The teaching of Geall, Khvorova, and Hou are incorporated herein by reference to the respective 103 rejection above.
Neither Geall, Khvorova, nor Hou teach the splicing of gene transcripts, particularly MBNL1, SOS1, PKM, zTTN, GOGLA4, CLASP1, LDB3, MBNL2, SPAG9, DNAseI, TNNT3 and ZBTB49, are measured after administration of the rAAV particle.
Tanner teaches that “splicing changes in DM1 mice could be attributed to myotonia as an indirect consequence of Mbnl loss” and that measuring splicing changes via “targeted RNA splice sequencing provides a reliable indicator of RNA toxicity that responds rapidly to treatment” with antisense oligonucleotides targeting the DM1 CUG expansion transcript, see abstract and introduction. Of the splicing changes measures, Tanner explicitly teaches measuring “35 DM1-affected splice events,” of which, for example, MBNL1, TTN, CLASP1, LDB3, MBNL2, and TNNT3 among many others are taught by Tanner as exemplary genes to measure splicing in response to DM1 treatment.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to measure the splicing of gene transcripts, such as MBNL1, TTN, CLASP1, LDB3, MBNL2, and TNNT3, in addition to the administration of the rAAV particle as taught in the methods Geall, Khvorova, and Hou. A PHOSITA would have been motivated to do so in order to reliably determine if the DM-1 Myotonic Dystrophy RNAi therapy effectively knocked down the DM1 CUG expansion transcript. A PHOSITA would have had a reasonable expectation of success because this DM-1 biomarker method was already a standard procedure and represents addition of a known method to other known methods.
Claim 126 is rejected under 35 U.S.C. 103 as being unpatentable over Williams (WO 2022056291 A1) in view of O'Riordan (US 20170173183 A1), Hou et. al., (US 20200377887 A1), and Yao (US 20200172928 A1) as applied to claims 44-45, 49, 53, 62-63, and 69 above, and in further view of Geall et. al., (US 20190298847 A1, in IDS), Khvorova et al., (US20200385737A1) and Hou et. al., (US 20200377887 A1) as applied to claims 1-2, 10, 12, 19, 92, 94, 98, and 104 above.
The teaching of Williams, O'Riordan, Hou, and Yao are incorporated herein by reference to the respective 102 and 103 rejections above.
Neither Williams, O'Riordan, Hou, or Yao teach a DMPK204 guide sequence comprising a polynucleotide sequence of SEQ ID NO: 4 and a DMPK204 passenger sequence comprising a polynucleotide sequence of SEQ ID NO: 5.
The teachings of Geall, Khvorova, and Hou regarding the DMPK guide and passenger sequences and scaffolds are incorporated herein by refence to the respective 103 rejection above. SEQ ID NOs: 4 and 5 of the instant application are identical nucleic acid sequences to SEQ ID NOs 1 and 2, respectively, of the instant application, the difference being mere presentation as either the DNA form (SEQ ID NOs: 4 and 5) vs the transcribed RNA form (SEQ ID NOs: 1 and 2).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to incorporate the RNAi of Geall in view of Khvorova into the miR155 scaffold taught by Hou as the transgene incorporated into the expression cassette of Williams. A PHOSITA would have been motivated to do so in order to generate a therapeutic for DM-1 Myotonic Dystrophy that targets DMPK more efficiently and specifically in human muscle cells. A PHOSITA would have had a reasonable expectation of success because the scaffold, RNAi, and regulatory elements were all successfully used in making therapeutics for DM-1 Myotonic Dystrophy and/or other clinical indications, and thus represents a combination of known elements accordingly to their known functions.
Double Patenting
STATUTORY (35 USC 101)
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 74, 85, 87-88, and 90 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 69, 86, 88-89, and 91 of copending Application No. 18/296,283 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Instant claim 74 recites an rAAV vector comprising the nucleotide sequence of SEQ ID NO: 20 or a sequence with about 90% identity thereto. Reference claim 69(d) recites the identical limitation. Although instant claim 74 depends from claim 44, which recites the expression cassette in generic terms as “comprising a nucleic acid encoding a transgene,” the specific sequence recitation of SEQ ID NO: 29 in claim 74 necessarily narrows and fixes the claimed transgene to the specific DMPK-targeting RNAi construct encoded within that sequence, since SEQ ID NO: 20 is defined as the complete assembled vector sequence. Reference claim 69 depends from claim 62, which depends from claim 23, which explicitly recites “nucleic acid encoding the RNAi of claim 1.” Because both instant claim 74 and reference claim 69 require the identical structural limitation, the two claims are drawn to identical subject matter and thus the same invention.
Instant claim 86 is identical in scope to claim 86 of the reference application, as both claims recite an rAAV particle comprising an rAAV vector having the same ordered nucleic acid elements (AAV2 ITR, serpinA1 stuffer, Byrne desmin enhancer, Paulin desmin enhancer, desmin promoter, 5′ arm of rabbit β-globin intron, 5′ miR155 scaffold, DMPK204 guide, miR155 loop, DMPK204 passenger, 3′ miR155 scaffold, 3′ arm of rabbit β-globin intron, minimal BGH polyA, serpinA1 stuffer, AAV2 ITR) and further reciting the same AAVrh74 N502I capsid. Accordingly, instant claim 85 and reference claim 86 are drawn to identical subject matter.
Instant claim 87 depends from claim 85 and recites that the AAVrh74 N502I capsid comprises capsid proteins comprising the amino acid sequence of SEQ ID NO:50. Reference claim 88 depends from claim 86 and recites the identical limitation. Thus, instant claim 87 and reference claim 88 are drawn to identical subject matter.
Instant claim 88 is identical in scope to reference claim 89, as both claims recite the same rAAV vector architecture and further recite that the capsid is an AAVrh74 W505R capsid. Therefore, instant claim 88 and reference claim 89 are drawn to identical subject matter.
Instant claim 90 depends from claim 88 and recites that the AAVrh74 W505R capsid comprises capsid proteins comprising the amino acid sequence of SEQ ID NO:52. Reference claim 91 depends from claim 89 and recites the identical limitation. Accordingly, instant claim 90 and reference claim 91 are drawn to identical subject matter.
NON-STATUTORY
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.
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Claim 10 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18/626,784 in view of claim 78 of the same copending application. Although the claims at issue are not identical, they are not patentably distinct from each other because reference claim 2(d) recites “the RNAi comprises nucleic acid with the sequence of SEQ ID NO:7 or with a sequence with about 90% identity to the sequence of SEQ ID NO:7,” and reference claim 78 recites a recombinant AAV particle comprising the RNAi of claim 1 packaged with a capsid, optionally an AAVrh74 N502I or AAVrh74 W505R serotype capsid. It would have been obvious to a person of ordinary skill in the art to combine the SEQ ID NO:7 RNAi construct recited in reference claim 2 with the AAVrh74-family capsid particle recited in reference claim 78, both directed to the same DMPK-targeting RNAi platform disclosed in the same reference application, to arrive at instant claim 10’s rAAV particle comprising an AAVrh74-family capsid and an RNAi with the sequence of SEQ ID NO:7. A person of ordinary skill would have had a reasonable expectation of success because the reference application’s own claim set and specification disclose both elements as applicable components of the same construct. This is a provisional nonstatutory double patenting rejection.
Claims 86 and 89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 86 and 89, respectively, of copending Application No. 18/626,784 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because reference claims 86 and 89 recites the same 15 ordered nucleic acid elements (AAV2 ITR, SerpinA1 stuffer, Byrne desmin enhancer, Paulin desmin enhancer, desmin promoter, 5’ rabbit β-globin intron arm, 5’ miR155 scaffold, DMPK204 guide, miR155 loop, DMPK204 passenger, 3’ miR155 scaffold, 3’ rabbit β-globin intron arm, BGH polyA, SerpinA1 stuffer, AAV2 ITR) generically, without reciting the specific SEQ ID NOs for each element, whereas instant claims 86 and 89 recite the identical ordered arrangement with each element further limited to the specific polynucleotide sequence of SEQ ID NO:43, 18, 21, 22, 23, 14, 40, 4, 6, 5, 41, 15, 16, 19, and 49, respectively. Instant claims 86 and 89 are thus directed to a species falling entirely within the genus recited in reference claims 86 and 89. Because the reference application’s own specification and sequence listing define the identical specific sequences for each corresponding element as those recited in instant claims 86 and 89, practicing reference claims 86 and 89 as defined by its own specification necessarily practices instant claims 86 and 89, such that the two claims are not patentably distinct. With regard to the respective capsid variants of instant claims 86 and 89, reference application’s claims 86 and 89 require the exact same capsid mutants, respectively. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 98, 101, and 104 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 89 and 92 of copending Application No. 18/626,784 in view of Hou et al. (US 20200377887 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because reference claim 92 recites a composition comprising the rAAV particle of reference claim 78 (an AAVrh74-family capsid particle comprising RNAi targeting DMPK). However, reference claim 89 recites the same rAAV particle as instant claim 88. Hou teaches administering AAV particles comprising a modulatory-polynucleotide/RNAi payload, packaged with an AAVrh74-family capsid, to a mammal for the treatment of a neuromuscular/neurologic condition, see, e.g., [0528]-[0531] and claim set. It would have been obvious to a person of ordinary skill in the art to administer, in the claimed dose ranges, the composition of reference claim 92 or the rAAV particle of claim 89 to a mammal suffering from myotonic dystrophy-1 for the treatment thereof, since Hou establishes that administering in the same dose ranges an AAVrh74-family-capsid RNAi composition to a mammal for treatment of an underlying targeted condition was a routine, art-recognized use of such a composition, and the reference application’s own disclosure identifies DM1/DMPK as the intended therapeutic target of its claimed composition. A person of ordinary skill would have had a reasonable expectation of success because Hou demonstrates that AAVrh74-family-capsid RNAi compositions were already known to be effective for in vivo delivery and gene silencing when administered by this route. This is a provisional nonstatutory double patenting rejection.
Claim 115 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 92 of copending Application No. 18/626,784 in view of Hou et al. (US 20200377887 A1) and Anguela (WO2023004437A1, published 01/26/2023).
The teachings of Hou are incorporated herein by reference to the double patenting rejection of claim 98 above. Reference claim 92 in view of Hou renders obvious a method of administering the pharmaceutical composition of reference claim 92 to a mammal to treat myotonic dystrophy-1, as set forth above. Neither reference claim 92 nor Hou teach that the RNAi is administered in combination with an immunosuppressive agent, administered before, at the same time, and/or after administration of the RNAi.
The teachings of Anguela are incorporated herein by reference to the respective103 rejection above.
It would have been obvious to a person of ordinary skill in the art to administer the rAAV particle of reference claim 92, rendered obvious for the treatment of DM1 as set forth above, in combination with an immunosuppressive agent as taught by Anguela. A person of ordinary skill would have been motivated to do so because reducing immune-mediated silencing of the introduced RNAi transgene would be expected to increase DMPK knockdown efficiency. A person of ordinary skill would have had a reasonable expectation of success because Anguela demonstrates that such co-administration predictably improves transgene expression for vector-delivered constructs generally, and immunosuppressive regimens were already routine in AAV gene therapy to mitigate vector- and transgene-induced immune responses. This is a provisional nonstatutory double patenting rejection.
Claims 118 and 121 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 92 of copending Application No. 18/626,784 in view of Hou et al. (US 20200377887 A1) and Tanner et al. (Nucleic Acids Res., Feb. 26, 2021, 49(4): 2240-2254).
The teachings of Hou are incorporated herein by reference to the double patenting rejection of claim 98 above and the 103 rejections above. Reference claim 92 in view of Hou renders obvious a method of administering the composition of reference claim 92 to a mammal to treat myotonic dystrophy-1, as set forth above. Neither reference claim 92 nor Hou teach measuring the splicing of gene transcripts, particularly MBNL1, SOS1, PKM, TTN, GOGLA4, CLASP1, LDB3, MBNL2, SPAG9, DNAse1, TNNT3, and ZBTB49, after administration of the rAAV particle.
The teachings of Tanner are incorporated herein by reference to the respective103 rejection above.
It would have been obvious to a person of ordinary skill in the art to measure the splicing of gene transcripts, such as MBNL1, TTN, CLASP1, LDB3, MBNL2, and TNNT3, in addition to administering the rAAV particle rendered obvious by reference claim 92 in view of Hou. A person of ordinary skill would have been motivated to do so in order to reliably determine whether the DM1 myotonic dystrophy RNAi therapy effectively knocked down the DM1 CUG expansion transcript. A person of ordinary skill would have had a reasonable expectation of success because this DM1 biomarker method was already a standard, art-recognized procedure, representing the addition of a known method to a known method of treatment with predictable results. This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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