DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ amendments to the claims and response to restriction requirement filed on August 21, 2026, have been received and entered. Claims 1-12, 14-19 have been canceled. Claims 20-33 are newly added. Claims 13, 20-32 and 33 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claim 13, 20-33 (group II) in the reply filed on August 21, 2026, is acknowledged. Applicant further elect without traverse coding sequence of SEQ ID NO: 22, AAVhu68 and Ubc promoter as species of CDKL5 coding sequence, rAAV capsid and regulatory sequence. However, upon further consideration, election of species requirement is withdrawn, and all the withdrawn species are rejoined with the elected species.
Priority
This application is 371 of PCT/US22/78327 filed on 10/18/2022, which claims priority from US provisional application no 63/256,827 filed on 10/18/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/22/2024 and 08/21/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 13, 20-32 and 33 are under consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 13, 20-32 and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of improving hindlimb clasping and impaired cognitive function associated with CDKL5 deficiency disorder (CDD) in a infant (neonatal) subject, said method comprising intracerebroventricularly administering an effective amount of a rAAV to the subject in need thereof such that human CDKL5 protein is expressed in central nervous system (CNS) cells, wherein the rAAV comprises:(a) an AAVhu68 or AAVrh91 capsid; and(b) a vector genome in the AAV capsid of (a), wherein the vector genome comprises a 5' AAV inverted terminal repeat (ITR), an expression cassette comprising a human CDKL5 coding sequence consisting of nucleotides sequence of SEQ ID NO: 22 operably linked to a regulatory sequence, and a 3' AAV ITR, wherein the regulatory sequences comprise a UbC or a hSyn promoter and further comprising at least two miR183 targeting sequences,, wherein the miR183 targeting sequences consist of SEQ ID NO: 11,
does not reasonably provide enablement for delivering any amount of rAAV via any other route or site, to any other subject any development stage, any other human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22, using a non-CNS specific promoter or a sequence comprising miR183 targeting sequence. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
The nature of invention is directed to a gene therapy for CDKL5 Deficiency Disorder (CDD), a serious childhood brain disorder caused by loss of CDKL5 protein. The claims are drawn to a method for treating CDKL5 deficiency disorder comprising administering an rAAV., wherein the rAAV comprises (a) an AAVhu68 or AAVrh91 capsid; and(b) a vector genome in the AAV capsid of (a), wherein the vector genome comprises a 5' AAV inverted terminal repeat (ITR), an expression cassette comprising a human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22 operably linked to regulatory sequences which control expression thereof, wherein the regulatory sequences further comprise at least two miR183 targeting sequences operably linked to the CDLK5 sequence, and a 3' AAV ITR. Dependent claims limit the regulatory sequences further comprise a UbC promoter or a hSyn promoter and wherein the expression cassette comprises nucleic acid sequence of nucleotides 220 to 4609 of SEQ ID NO: 49 (or SEQ ID NO: 50), nucleic acid sequence of nucleotides 226 to 4608 of SEQ ID NO: 29 (or SEQ ID NO: 59) or the nucleic acid sequence of nt 224 to 4191 of SEQ ID NO: 31 (or SEQ ID NO: 60). Claims are also directed to a method for treating CDKL5 deficiency disorder comprising administering an rAAV, wherein the rAAV comprises:(a) an AAVhu68; and(b) a vector genome in the AAV capsid of (a), wherein the vector genome comprises a 5' AAV inverted terminal repeat (ITR), an expression cassette comprising a human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22 or a sequence at least 99% identical to SEQ ID NO: 22 operably linked to regulatory sequences which control expression thereof, and a 3' AAV ITR, wherein the regulatory sequences comprise a UbC promoter and further comprise at least two miR183 targeting sequences and a rabbit globin polyA signal. Dependent claim limit the rAAV is administered via an intra-cisterna magna injection at a total dose of: a) about 6.8 x 1012 GC, about 2.1 x 1013 GC, about 6.8 x 1013 GC, or about 2.0 x 1014 GC in a human infant subject of at least 6 months up to 8 months of age; b) about 8.7 x 1012 GC, about 2.6 x 1013 GC, about 8.7 x 1013 GC, or about 2.6 x 1014 GC in a human infant subject of at least 8 months up to 12 months of age;and/or c) about 1.1 x 1013 GC, about 3.2 x 1013 GC, about 1.0 x 1014 GC, or about 3.2 x 1014 GC in a human infant subject greater than 12 months of age.
Breadth of the claims:
The claims are broadly directed to a method of treating any CDKL5 deficiency disorder comprising administering via any route an rAAV comprising an AAVhu68 or AAVrh91 capsid and a vector genome comprising an expression cassette comprising any human CDKL5 sequence of nucleotides 1to 2883 of SEQ ID NO: 22 operably linked to any regulatory sequence and further comprises at least two miR 183 targeting sequence. The claim as presented encompasses administering via any route an AAV comprising any human CDKL5 sequence of nucleotides 1to 2883 of SEQ ID NO: 22 operably linked to any regulatory sequence to a subject possibly in need thereof. It is noted that while claims are directed to an active method of administering via any means any amount of adeno-associated virus (AAV) anywhere at any site the claims in part are interpreted as method of treating CDKL5 deficiency disorder in a subject in need thereof in view of disclosure of the specification (see page 2, lines 31-32).
It is emphasized that instant rejection is based on four separate issues: 1) administering via any route any amount of recombinant adeno-associated virus (rAAV) comprising a human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 5 of SEQ ID NO: 22 to have an effect on treating CDKL5 deficiency disorder of different etiology and pathology, 2) the absence of an enabling disclosure of correlating the local expression of human CDKL5 protein in diseased cells/organ of CNS at a level sufficient to treat genus of CDKL5 deficiency disorder of different etiology and pathology in a subject in need thereof; (3) delivering an rAAV encoding human CDKL5 polypeptide in any predictable animal model of treating genus of CDKL5 deficiency disorder of different etiology and pathology; and 4) nexus between cellular pathology associated with genus of CDKL5 deficiency disorder to local expression in cells of CNS. The deficiencies were identified by the Office after analysis of the disclosure provided in the instant application. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404.
Guidance of the Specification and The Existence of Working Examples:
The specification teaches CDKL5 Deficiency Disorder (CDD) is a severe disorder with early seizures, developmental delay, hypotonia, and other neurologic symptoms, and there is currently no cure. Example teachers a single ICV injection of AAVhu68hSynHCDKL5 at a dose of 5x1010 GC into a neonatal male Cdk15KO/Y mouse and female Cdk15 KO/X mice. The results show AAV-treated male and female mice exhibited reduced hyperactivity (significantly reduced horizontal activity and rearing, and trending reduction in center activity) compared to vehicle-treated male Cdk15 Cdk15KO/Y mice and female Cdk15 KO/X mice, respectively, The correction in the hyperactivity phenotype was most evident in male Cdk15 mice, as males exhibited a generally more severe hyperactivity phenotype for all three parameters evaluated when compared to that of female Cdk15 KO/X mice (Fig. 15A-F, See also, Example 3). It is further disclosed that AAV-treated male Cdk15KO/Y mouse mice and female Cdk15KO/YX mouse mice displayed an improved quality of nests, as evidenced by a significant increase in nest building quality scores and a significant decrease in the percent of intact nestlets compared to that of vehicle-treated male Cdk15KO/Y mice and female Cdk15KO/X mice, respectively (see fig. 10A and 10F). The specification further teaches AAV-treated male Cdk15 mice and female Cdk15 mice displayed significantly reduced hindlimb clasping scores compared to that of vehicle-treated male Cdk15 mice and female Cdk15 mice (see fig. 14A and B)). On the Y maze test, AAV-treated female Cdk15KO/X mice exhibited an increase in the percent of spontaneous alternations when compared to vehicle-treated female Cdk15KO/X mice. This result indicated that AAV treatment increased the tendency of female Cdk15KO/X mice to explore less recently visited arms of the maze, which is suggestive of an improvement in spatial learning/memory. In contrast, this phenotype was not evident in male Cdk15KO/Y mice (emphasis added) (fig. 42A and 42B). In the instant case, the claims fail to specify where and whom the rAAV is administered. Is it administered to a subject having CDKL4 deficiency disorder or predisposed to have said disorder or is it administered to a zebrafish, fruit fly or roundworm. The specification is silent on treating CDD in any non-mammalian species. The claim encompasses administering any amount of rAAV, delivered via any route to any site at any stage of development of any subject to treat CDKL5 deficiency disorder. Thus, based on the disclosure and working examples, it appears that at least an ICV or ICM injection of an effective amount of rAAV comprising (a) AAVhu68 capsids and a vector genome in the AAV capsid of (a), wherein the vector genome comprises a 5' AAV inverted terminal repeat (ITR), an expression cassette comprising a human CDKL5 coding sequence consisting of nucleic acid of SEQ ID NO: 22 operably linked to hSyn promoter comprising two miR183 targeting sequence and a 3’ITR, into CNS of a subject in need thereof , wherein said injection into CNS exhibits (i) CDKL5 protein expression in the cortex and hippocampus tissue and (ii) reduced hyperactivity. The specification also does not provide any working examples that show delivering any other rAAV, delivered via any other route, or using a fragment of human CDKL5 codon optimized sequence are capable of transducing cells of CNS to thereby have an effect on treating CDKL5 deficiency disorder.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The prior art summarized by the references of Amendola (PLoS One. 2014 16;9(5): e91613, 1-12) teaches mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome (abstract). The art teaches the primary clinical features of CDKL5 disorder are seizures initiating in the first few months of life, stereotypical hand movements, motor rigidity, and deficient language acquisition. Several additional features have been noted in some carriers, including gastrointestinal problems, bruxism, and a characteristic sideways glance (see page, col. 1, para. 1). The art teaches phenotypes of Cdk5 knockout mouse as exemplified in the instant application show hind-limb claspin, hypoactivity and reduced dendritic branching of cortical neuron and abnormal EEF responses to convulsant feature that may model the stereotypic hand movements, hpotonia. However, art teaches early onset seizers are key feature of CDKL15 disorder was not detected and authors failed to detect any spontaneous seizer or epileptiform activity in mutant mice on two different genetic backgrounds (see page 8, col. 2, last para. to page 9, col. 1, para. 1). Amendola concludes the findings as an indication that Cdkl5 impacts on the development of epilepsy in humans in a manner significantly different from mice (see page 9, col. 2, para. 1). In view of foregoing, it is apparent that results observed in male Cdk15KO/Y mice or female Cdk15KO/X mice could not be extended to study treating all the CDKL5 deficiency disorder (CDD) as embraced by the breadth of the claim particularly since prior art teaches Cdk15KO/X or Cdk15KO/Y fails to detect any spontaneous seizer or epileptiform activity. An artisan would have to perform undue experimentation to first establish a predictable animal model that fully exhibits all the features including early onset seizers to make and use the invention, without reasonable expectation of success.
The claims require administering via any route to any site a rAAV of the invention to treat CDD. The art teaches while this gene therapy approach offers a promising strategy for the treatment of CDD as deficiency of CDKL5 causes CDD, however, overexpressing the exogenous CDKL5 gene could lead to an abnormal or pathogenic phenotype (see page 2, col. 1, para. 2, Medici et al Neurotherapeutics 22 (2025) e00727, 1-19 and references therein). The timing and duration of the gene therapy is also critical as art reputed gene restoration at later ages may have limitations. It is relevant to note that gene therapy is administered at a single time point (10 months of age). This timing could be a critical factor influencing the extent of the therapeutic effect, as earlier intervention has been shown to yield stronger therapeutic outcomes compared to treatment at older ages 9see page 18, col. 1, para. 2). In view of foregoing, it is apparent that timing and age are key variables influencing the success of gene therapy in CDD, particularly in the context of older females with mosaic CDKL5 expression. The guidance provided in the specification is limited to an ICV or ICM injection of AAVhu68hSynHCDKL5 at a dose of 5x1010 GC into a neonatal male Cdk15KO/Y mouse and female Cdk15 KO/X mice. The specification is silent on amount of AAV delivered via any other route or site to any other subject of different development stage including to an older subject. Absent any evidence of using any dose of rAAV, timing and age of the subject, each of which are deemed to be critical influencing factor in the success of gene therapy in CDD, one of skill in the art would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
The breadth of the claims encompasses administering via any route, any amount of an rAAV to any subject, wherein the rAAV comprises (a) an AAVhu68 or AAVrh91 capsid; and(b) a vector genome in the AAV capsid of (a the vector genome comprises an expression cassette comprising a human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22. The art teaches intricacy of the human CNS and the blood–brain barrier, it is difficult to deliver genes, particularly since the expression of any given gene may be required in a particular CNS structure or cell type at a specific time during development (see abstract, Daci et al Int J Mol Sci, 2024, 25(2):1050, 1-19 and references therein). It is disclosed that the intravenous delivery of AAV vectors carries the risk of hepatotoxicity. Thus far, hepatotoxicity has resulted in the tragic death of eight patients treated with AAV gene therapy, including four patients treated for X-linked myotubular myopathy and four patients treated for spinal muscular atrophy (see section 2.2.3). It is further disclosed that two new AAV-related immunotoxicities emerged in the last few years. These included dorsal route ganglia toxicity and a syndrome of thrombocytopenia, hepatic and renal toxicity, referred to as thrombotic microangiopathy. It is emphasized that art reported that the preclinical evidence suggests that ICM and ICV routes of delivery are both promising alternatives to direct parenchymal injection for broad CNS transduction. The guidance provided in the specification is limited to an ICV injection into CNS of subject in need thereof to treat CDD. There is evidence on record that delivering of rAAV via any route to any site of a subject would not be enabling for the reasons discussed above to make and use the invention.
The claims encompasses delivering an expression cassette comprising any human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22. As written claim encompass short fragment of few human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22. The guidance provided in the specification is limited to hCDKL5 coding sequence that is set forth in SEQ ID NO: 22. The specification contemplates a fragment of at least 70% identical to SEQ ID NO: 22. There is no evidence on record that any fragment other than human CDKL5 coding sequence as set forth in SEQ ID NO: 22 is enabled to treat CDD in any subject. Hordeaux (Human Gene Therapy, 2020, 31, 808- 818) teaches administration of adeno-associated virus (AAV) vectors to nonhuman primates (NHP) via the blood or cerebrospinal fluid (CSF) can lead to dorsal root ganglion (DRG) pathology. Hordeaux discloses data from five different capsids, five different promoters, and 20 different transgenes suggesting that DRG pathology is almost universal after AAV gene therapy (abstract) following administration of said AAV via blood or cerebrospinal fluid (CSF) (abstract). The specification teaches regulatory sequences further comprise at least two miR183 targeting sequences operably linked to the CDLK5 sequence, primarily reducing DRG toxicity. The claimed genus of at least two miRNA miR-183 targeting sequence subsequently limiting to miR targeting sequence comprises the nucleotide sequence of SEQ ID NOL 11. . It is emphasized that adding nucleotide sequence to miRNA binding site could alter the transcript and miRNA mediated regulation. Liu et al (Nucleic Acids Res. 2014 Jul 31;42(15):9543–9552) teaches genetic variants within flanking regions of miRNA binding sites may also alter local target structure, affecting the potential of miRNA: targe hybridization (see page 6, col. 1, para. 2). The specification, however, has not disclosed any of the other sequence other than polynucleotide consisting of SEQ ID NO: 11. There is no evidence on the record of a relationship between at least one of miR- 183 consisting of the nucleic acid sequence of SEQ ID NO: 11 and any other miR-183 DRG de-targeting miRNA targeting site having additional sequences upstream or downstream of the miRNA targeting site that would provide any reliable information about the structure of miR 183 targeting sequence within the genus. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. Given, the variable and unpredictable expression pattern of AAV delivered via any route to any site and the lack of guidance provided by the specification with respect to determine the extent of transduction of AAV particle in cell types present in the CNS of a subject having a genus of CDD embraced by the breadth of the claim would require undue experimentation for one of skill in the art to make and use the invention, without a reasonable expectation of success. An artisan would have to carry out extensive experimentation to make use of the invention without reasonable expectation of success, and such experimentation would have been undue because of the treatment of CDD by delivering rAAV via any other route other than ICV into CNS in a subject in need thereof is unpredictable and specification fails to provide any guidance as to how the claimed method would have been practiced commensurate with full scope of the claims. In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled for the full scope of the claimed inventions.
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 13, 20-32 and 33 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 13 and 28 are vague and indefinite to the extent the active method step is unclear and incomplete. This active step of administering an rAAV is silent to target subject. It is unclear active step of administering is to a site, place, subject having disease, subject, cell or organ predisposed to disease, a host cell, an adult subject, an infant or any other eukaryotic subject. The metes and bounds of step of administering an rAAV could not be ascertained. Claims 20-27, 29-32 and 33 are included in the rejection because they directly or indirectly depend from the rejected base claims. Appropriate correction and clarifications are required.
Claims 23 is vague and indefinite because it is unclear whether vector genome comprises additional AAV5’ITR, an hCDKL5 coding sequence, a AAV 3ITR, which is different from one recited in the base claim. . 3. Recitation of genome comprises the AAV 5’ ITR etc.. providing antecedent to a AAV5’ ITR, .. of base claim 13 would be remedial. Appropriate correction and/or clarification is required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13, 20-32 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,-3, 13, 15-19, 23-30, 42-45of copending Application No. 17997301. Although the claims at issue are not identical, they are not patentably distinct from each other because claims in both application encompass same rAAV useful for treating CDD and for the following reasons. In the instant case, claims are directed to a method for treating CDKL5 deficiency disorder comprising administering an rAAV.,wherein the rAAV comprises (a) an AAVhu68 or AAVrh91 capsid; and(b) a vector genome in the AAV capsid of (a), wherein the vector genome comprises a 5' AAV inverted terminal repeat (ITR), an expression cassette comprising a human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22 operably linked to regulatory sequences which control expression thereof, wherein the regulatory sequences further comprise at least two miR183 targeting sequences operably linked to the CDLK5 sequence, and a 3' AAV ITR. Dependent claims limit the he regulatory sequences further comprise a UbC promoter or a hSyn promoter (claim 20), wherein the cassette comprises nucleic acid sequence of nucleotides 220 to 4609 of SEQ ID NO: 49 (or SEQ ID NO: 50), nucleic acid sequence of nucleotides 226 to 4608 of SEQ ID NO: 29 (or SEQ ID NO: 59) or the nucleic acid sequence of nt 224 to 4191 of SEQ ID NO: 31 (or SEQ ID NO: 60). Claims 22 limits the AAV capsid is an AAVhu68 capsid. Claim 23 limits the method of claim 13, wherein the vector genome comprises an AAV 5' ITR, a UbC promoter, an hCDKL5 coding sequence, at least two miR 183 targeting sequences, a rabbit globin polyA signal, and an AAV 3' ITR. Claim 24 limits the method of claim 23, wherein the vector genome further comprises a Kozak sequence, wherein the UbC promoter has the sequence of SEQ ID NO: 52 (claim 25) and wherein the miR 183 targeting sequence has the sequence of SEQ ID NO: 11 (claim 26). Claim 27 limits the claim 13, which has an AAVhu68 capsid comprising a nucleic acid molecule comprising the vector genome of SEQ ID NO: 49. Claim 28 is directed to a method for treating CDKL5 deficiency disorder comprising administering an rAAV, wherein the rAAV comprises:(a) an AAVhu68; and(b) a vector genome in the AAV capsid of (a), wherein the vector genome comprises a 5' AAV inverted terminal repeat (ITR), an expression cassette comprising a human CDKL5 sequence of nucleotides 1 to 2883 of SEQ ID NO: 22 or a sequence at least 99% identical to SEQ ID NO: 22 operably linked to regulatory sequences which control expression thereof, and a 3' AAV ITR, wherein the regulatory sequences comprise a UbC promoter and further comprise at least two miR183 targeting sequences and a rabbit globin polyA signal. Dependent claims limit the expression cassette comprises a Kozak sequence. Claim 32 limits the method, wherein the rAAV is administered via an intra-cisterna magna injection at a total dose set forth in the claims to an infant, In contrast, claims in 17997301 is directed to a recombinant adeno-associated virus (rAAV) useful for treating CDKL5 deficiency disorder (CDD), wherein the rAAV comprises:(a) an AAV capsid; and(b) a vector genome packaged in the AAV capsid of (a), wherein the vector genome comprises inverted terminal repeats (ITR) and a hCDKL5-coding sequence, which is a nucleic acid sequence encoding a functional human CDKL5 (hCDKL5), operably linked to sequences which regulate the hCDKL5 expression in central nervous system cells, and wherein the hCDKL5-coding sequence is nt 699 to 3581 of SEQ ID NO: 3 (SEQ ID NO: 22) or a sequence at least about 95% identical to nt 699 to 3581 of SEQ ID NO: 3 (SEQ ID NO: 22). Dependent claims limit the vector genome further comprises four miR183 targeting sequences operably linked to a 3' untranslated region of the hCDKL5 coding sequence, wherein the miR183 targeting sequences downregulate expression in the dorsal root ganglia. Claim 19 limits the rAAV, wherein at least one of the four miRNA target sequences for the at least first and/or at least second miRNA target sequence for the expression cassette mRNA is SEQ ID NO:11, wherein the capsid is an AAVhu68 capsid, an AAV9 capsid, or AAVrh91 capsid. Claims are also directed to a method of treating CDD, comprising administrating an effective amount of the rAAV according to claim 1 to a subject in need thereof. The '301 claims recite a rAAV and method of using rAAV in treating CDD in subject that is explicitly used in method as claimed in the instant application. Thus, claims in the instant application are encompassed by the claims in '301 patent application claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Objections
Claim 21 is objected to because of the following informalities: In the instant case, recitation of term “or” within the parenthesis should be deleted because SEQ ID NO: within parenthesis is essentially SEQ ID NO identifying the specific nucleotide fragment recited outside the parenthesis. Appropriate correction is required.
Claim 26 is objected to because of the following informalities: In the instant case, recitation of nucleotide sequence “ AGTGAA…ATA,” is redundant and should be deleted. Appropriate correction is required.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Schmid (Molecular Therapy, 2020, 28, page 49) teaches a method of treating CDD in an infant in need thereof, said method comprising intracerebroventricularly administering the rAAV comprises (a) an AAVhu68 capsid; and(b) a vector genome in the AAV capsid of (a), wherein the vector genome comprises a AAV comprising a codon optimized human CDKL5 coding operably linked to syn promoter , wherein said administration exhibits robust expression of CDKL5 in the 50% of the neuron and also improved neuro behavioral test as compared to wild type. While Schmid teaches use of a codon optimized human CDKL5 coding that appears to be same as one claimed in the instant application, however, no prior art rejection is made due to scope indicated in the office action for specific CDKL5 coding sequence of SEQ ID NO: 22 that is free of prior art.
Gao et al (Brain 143.3 (2020): 811-832.) teaches a vector comprising an expression cassette, wherein the expression cassette comprises a hCDKL5-coding sequence, which is a nucleic acid sequence encoding a functional human CDKL5 (hCDKL5), under control of regulatory sequences which direct the hCDKL5 expression (abstract). Guo fails to teach a coding sequence as set forth in SEQ ID NO: 22.
Fotin (US20190241633A1). teaches the coding sequence of a therapeutic protein SEQ ID NO: 15012 have about 75.8% sequence identity to instant SEQ ID NO: 22. Prior art fails to teach a coding sequence set forth in SEQ ID NO: 22.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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