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 the Claims
Claims 1-8, 10-12, and 14-20 were previously pending with claims 10, 14, 18, and 20 being independent claims. Claims 1-8, 12, 16-17, and 19 remain withdrawn from consideration as being drawn to a non-elected invention. Applicant elected the invention of a method of using a CRISPR-Cas system to treat a genetic disease in vivo and the species of Rett syndrome in the reply filed 12 March, 2025.
Receipt is acknowledged of the Amendments to the claims filed on 30 September, 2025. Claims 14, 19, and 20 are amended. Claim 11 is cancelled. Claims 21-25 are newly added.
Therefore, claims 10, 14-15, 18, and 20-25 are pending and under examination in the instant Official Action. Claim 10 is the only independent claim that is pending and under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2019085659, filed 17 December, 2019, which claims priority to Italian Application No. IT102018000020230, filed 19 December, 2018. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies of papers required by 37 CFR 1.55 have been filed in this application on 17 June, 2021.
The earliest possible priority for the instant application is 19 December, 2018. (please correct the PTO-326 to add the foreign priority claimed)
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10 October, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings filed on 17 June, 2021 are accepted by the Examiner.
Claim Interpretation
All instant claims are being interpreted consistent with the species election of Rett syndrome.
Claim Objections
Claim 18 is objected to because of the following informalities: it recites the wrong tense of the word administer. Claim 18 should read “administered”. Appropriate correction is required.
Withdrawn Objections/Rejections in view of Applicant’s Amendments/Arguments
Claim objection
The objections to claims 10, 14, 18, and 20 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claims 14, 18 and 20 to depend from claim 10 and has amended claim 10 to recite limitations previously contained within a non-elected claim.
Maintained Objections/Rejections in view of Applicant’s Amendments/Arguments
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.
Amended claim 10 now reads: “10. (Currently amended) A method of editing a mutant genomic target sequence carrying one or more mutations in a target cell of a subject affected by Rett syndrome, said method comprising administering to said subject a non-naturally occurring or engineered Clustered Regularly Interspersed Short Palindromic Repeat (CRISPR)-CRISPR associated(Cas) (CRISPR-Cas) system targeting a mutant genomic target sequence carrying one or more mutations in the target cell, the CRISPR-Cas system comprising a first viral expression vector and a second viral expression vector,
wherein the first viral expression vector comprises:
1) a nucleotide sequence encoding a guide RNA (gRNA) operably linked to a promoter sequence located on said first viral expression vector upstream of the 5' end of said nucleotide sequence encoding the gRNA, wherein said gRNA comprises a scaffold nucleotide sequence capable of binding an endonuclease enzyme and a guide nucleotide sequence capable of hybridizing to the mutant genomic target sequence; and
2) a donor nucleotide sequence consisting of the wild type sequence of the mutant genomic target sequence; and
wherein the second viral expression vector comprises:
3) a nucleotide sequence encoding an endonuclease enzyme, said nucleotide sequence being operably linked to a promoter sequence located on said second viral expression vector upstream of the 5' end of said nucleotide sequence encoding the endonuclease enzyme; and
4) a target nucleotide sequence consisting of the mutant genomic target sequence, said target nucleotide sequence being present on the second viral expression vector in one copy or, alternatively, in a first copy and a second copy, wherein, when said target nucleotide sequence is present in one copy, said one copy is located between the 3' end of the promoter sequence operably linked to the nucleotide sequence encoding the endonuclease enzyme and the 5' end of said nucleotide sequence encoding the endonuclease enzyme, or, when said target nucleotide sequence is present in a first copy and a second copy, said first copy is located upstream of the 5' end of the promoter sequence operably linked to the nucleotide sequence encoding the endonuclease enzyme and said second copy is located downstream of the 3' end of said nucleotide sequence encoding the endonuclease enzyme, each copy of the target nucleotide sequence being flanked at the 3' end by a Protospacer Adjacent Motif (PAM) sequence;
wherein the mutant genomic target sequence in the target cell is a mutant MECP2 gene, a mutant FOXG1 gene, or a mutant CDKL5 gene.”
Claims 10, 14-15, 18, and 20 remain rejected and claims 21-25 are newly 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 editing a mutant genomic target sequence carrying one or more mutations in a target cell of a mouse model of Rett syndrome comprising administering to the mouse model of Rett syndrome the CRISPR-Cas system of claim 1,
wherein the viral expression vectors are adeno-associated virus serotype 2 (AAV2) vectors, wherein the mutant genomic target sequence is a mutant MECP2 gene, a mutant FOXG1 gene, or a mutant CDKL5 gene, and wherein the mouse model of Rett syndrome comprises a mutant MECP2 gene (claims 10 and 23) , a mutant FOXG1 gene (claims 10 and 24) , or a mutant CDKL5 gene (claims 10 and 25),
does not reasonably provide enablement for an in vivo method of treating Rett syndrome in any subject (mouse, dog, human, bird, fish, etc.) comprising administering any viral expression vectors (adenoviral, lentiviral, adeno-associated viral, etc.) comprising a CRISPR-Cas system as recited in claims 10, 14, 18 and 20 (e.g, a first viral expression vector and a second viral expression vector ) targeting a mutant MECP2 gene, a mutant FOXG1 gene, or a mutant CDKL5 gene. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Amended claim 10 still broadly reads on a method of editing a mutant genomic target sequence in a target cell of any subject (mouse, dog, human, bird, fish, etc.) comprising administering any viral vectors (adenoviral, lentiviral, adeno-associated viral, etc.) comprising a CRISPR-Cas system. None of the claims under examination further limit “subject”, “viral expression vector”, or “mutant genomic target sequence”. Further, as noted above, the elected invention is specifically the in vivo embodiment of the invention. Although Applicant has amended claim 10 to not explicitly recite a method of treating, claim 10 still encompasses such a method and is still directed, as amended, to an in vivo method. The method of treating and in vivo objectives are further exemplified by dependent claims 14-15 and 20 which require direct administration of a pharmaceutical composition comprising the CRISPR-Cas system to the subject. Also, amended claim 10 broadly encompasses any target cell as amended (encompassing every cell of the body, somatic and germline, and specifically encompasses editing only a particular cell type like osteoblasts for example). New claim 21 specifies that the viral vector is an AAV vector but continues to read on any of such vectors. No dependent claims sufficiently narrow the scope of claim 10 to render them enabled pursuant the identified enabled scope in the Non-Final Rejection mailed 02 April, 2025.
The specification does not provide sufficient guidance for determining whether any viral expression vector comprising a CRISPR-Cas system can be administered in vivo to any target cell of any subject targeting mutations in the MECP2, FOXG1, or CDKL5 genes to effectuate a treatment for Rett syndrome. The instant specification teaches CRISPR-Cas systems as a method of correcting mutant genes (Specification, page 4, lines 6-32). However, the instant specification teaches that “in vivo applications of the CRISPR-Cas system, particularly as a therapeutic tool, are still hampered by the inefficiency of precise base editing and high frequency of Cas9-induced genomic cleavages at sites that differ from the intended genomic target” (Specification, page 5, lines 7-9). Thus, the specification teaches that current applications of CRISPR-Cas systems have yet to become a therapeutically viable option for in vivo editing of mutant genes because the systems inefficiently edit intended sequences and have off-target effects. The specification prophetically announces that the CRISPR-Cas system employed by the inventors overcomes the limitations of CRISPR-Cas systems to enable “safely use of this system in therapeutic applications, particularly in gene therapy” (Specification, page 6, lines 24-27). However, as is discussed below, the working examples provided by Applicant supply scant evidence in support of such an achievement. The instant specification also teaches adeno-associated viral vectors (AAVs) and teaches that AAV2 exhibits higher tropism towards kidney parenchyma while AAV9 is particularly suitable for targeting brain or neuronal cells (Specification, page 11, lines 1-12). The specification broadens the suitable viral expression vectors by teaching “for example, a lentivirus, a retrovirus, a parvovirus, an adenovirus” and by teaching “preferably,…AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8 or AAV9” (Specification, page 12, lines 24-28). However, as is discussed below, the working examples provided by Applicant supply limited support of such a broad genus of viral expression vectors used to modify any cells in any subject as a treatment for Rett syndrome. The working examples disclose only two two-vector CRISPR-Cas system for treatment of Rett syndrome wherein an AAV2 donor vector is combined with a PX551 plasmid to supply SpCas9 enzyme, a single gRNA, and donor template for correction of one specific MECP2 mutation (the c.473C>T mutation) or one specific FOXG1 mutation (c.688C>T mutation) (Specification, Table 1., Table 2.; page 40, lines 20-32). It is noted that a person having ordinary skill in the art would recognize PX551 as an AAV vector despite instant applicant’s lack of such a designation because Swiech and Addgene teach this designation (Swiech et al. (Nature biotechnology 33.1 (2015): 102-106, hereinafter “Swiech”, Swiech, whole document) (Addgene Website, PX551, plasmid #60957, Addgene: PX551, Accessed: 26 March, 2025, hereinafter “Addgene”). The working examples describe in vitro off-target analysis (Specification, page 31, lines 7-25), in vitro editing efficiency analysis (Specification, page 32, lines 15-end; page 33, lines 1-18), and in vivo delivery protocols for mice and dogs (Specification, page 33, lines 20-end; page 34-36, whole pages; page 37, lines 1-10). However, no specific mention of the MECP2-specific CRISPR system or of any Rett syndrome model is made in this section. The working examples also prophetically describe how human studies may be performed but no support is given for actually administering anything to humans in vivo let alone a CRISPR-Cas system which, to-date, is “still hampered by the inefficiency of precise base editing and high frequency of Cas9-induced genomic cleavages at sites that differ from the intended genomic target” (Specification, page 5, lines 7-9; page 37, lines 12-30; page 38, whole page; page 39, lines 1-25). The working examples do disclose the use of the FOXG1, and MECP2 systems independently to transfect HEK293 cells in vitro and to edit 22% of mutant alleles for the FOXG1 system and 64% of mutant alleles for the MECP2 system (Specification, page 40, lines 20-32; page 41, lines 1-25), and disclose a frequency of off-target cuts of 1% in those HEK293 cells (Specification, page 41, lines 27-32; page 42, lines 1-4). However, the working examples for in vivo editing of mutant alleles in mice and dogs are limited to different diseases and different mutant alleles (Specification, page 43, lines 4-32; page 44, lines 1-5). Finally, the working examples further elaborate on the prophetic use of CRISPR-Cas systems to in vivo edit humans (Specification, page 44, lines 7-31, pages 45-47, whole pages). However, these prophetic examples of how one might edit humans in vivo with CRISPR do little to overcome the observed limitations of such a method to-date that in vivo CRISPR-Cas therapies are “still hampered by the inefficiency of precise base editing and high frequency of Cas9-induced genomic cleavages at sites that differ from the intended genomic target” (Specification, page 5, lines 7-9). Therefore, the specification does not provide sufficient guidance for determining whether any viral expression vector comprising a CRISPR-Cas system can be administered in vivo to any target cell of any subject targeting mutations in the MECP2, FOXG1, or CDKL5 genes to effectuate a treatment for Rett syndrome because of the limitation of the working examples to in vitro analysis of only two Rett syndrome specific genetic mutations, the complete lack of in vivo analysis of any CRISPR-Cas system specific to Rett syndrome, and the applicant observed limitations of making such a leap to utilize CRISPR-Cas systems in vivo in humans.
At the time of filing, it was known that Rett syndrome almost exclusively affects females because it is X-linked (Matijevic et al. (European Neurology 61.1 (2008): 3-10., hereinafter “Matjevic”, Abstract)). Matjevic also teaches that the genus of Rett syndrome-causing mutations within the MECP2 gene encompasses at least 8 different C>T mutations in the third and fourth exon, and that, in males, a disease-causing mutation usually leads to severe neonatal encephalopathy and death within 1-2 years of birth (Matjevic, page 5, first partial paragraph; page 6, sixth full paragraph). Thus, a person having ordinary skill in the art at the time of filing knew from the teachings of Matjevic that even within the MECP2 gene, there are a multitude of different mutations that give rise to the disease and that treatment in males significantly differs from treatment in females owing to the X-linked nature of the disease and the usual severity within males. At the time of filing, it was also known that while CRISPR systems have been extensively studied for in vitro and ex vivo applications, significant challenges still exist in the transition of CRISPR systems to in vivo applications
(Luther et al. (Expert opinion on drug delivery 15.9 (Published online: 12 September, 2018): 905-913., hereinafter “Luther”, Luther, page 906, only full paragraph)). Luther teaches that adenoviral vectors elicit host-immune responses that hamper its efficacy as an in vivo CRISPR-Cas delivery system (Luther, page 908, first partial paragraph), and lentiviral vectors nonspecifically integrate into host-genome and cause insertional mutagenesis or even tumorigenesis which hampers their efficacy as in vivo CRISPR-Cas delivery systems (Luther, page 908, first full paragraph). Luther also teaches that immunogenicity, off-target effects, and potential mutagenesis of various delivery vectors are important considerations and that, while AAV vectors avoid random integration, they still may simply be too dangerous for clinical application because of immunogenicity of the viral components and of Cas protein itself (Luther, page 910, last full paragraph). Thus, a person having ordinary skill in the art before the effective filing date of the claimed invention knew from the teachings of Luther that different viral vectors have different drawbacks for clinical application of CRISPR-Cas systems and that, although AAV vectors avoid insertional mutagenesis concerns, they still may simply be too dangerous for clinical applications. At the time of filing, it was also known that there are still hurdles that need to be overcome to achieve in vivo genome editing in a therapeutic context with CRISPR-Cas systems (Mout et al. (Bioconjugate chemistry 28.4 (2017): 880-884., hereinafter “Mout”, Mout, Abstract)). Mout specifically discusses the challenges associated with translation of CRISPR-Cas systems to in vivo therapeutic contexts and teaches that off-target effects and immunogenicity are two of the major hurdles to achieving such a translation (Mout, page 882, “CHALLENGES” subheading; page 883, first partial and first and second full paragraphs). Mout teaches that even though the gRNA is designed to target a specific gene of interest, often a significant number of nonspecific genes are targeted by the same Cas9/gRNA and that off-target effects of CRISPR systems in vivo have not been explored (Mout, page 882, last partial paragraph; page 883, first partial paragraph). Mout also teaches that gene-based delivery of CRISPR elements can permanently integrate Cas9 gene into host cells leading to immunogenicity and elimination of Cas9 expressing cells, and that AAV-based CRISPR systems delivered in vivo can suffer and has in fact suffered this fate (Mout, page 883, first full paragraph). Thus, a person having ordinary skill in the art at the time of filing knew from the teachings of Mout that off-target effects of CRISPR-Cas systems have yet to be fully explored in vivo and that immunogenicity and off-target effects remain significant hurdles to applying CRISPR-Cas systems in an in vivo therapeutic context.
Therefore, in view of the breadth of the claims, the lack of sufficient guidance in the specification for determining whether any viral expression vector comprising a CRISPR-Cas system can be administered in vivo to any target cell of any subject targeting mutations in the MECP2, FOXG1, or CDKL5 genes to effectuate a treatment for Rett syndrome to effectuate a treatment for Rett syndrome, the limitation of the working examples to in vitro analysis of only two Rett syndrome specific genetic mutations, the complete lack of in vivo analysis of any CRISPR-Cas system specific to Rett syndrome, the applicant observed limitations of making such a leap to utilize CRISPR-Cas systems in vivo in humans, and the unpredictability evidenced by the prior art at the time of filing with respect to viral vector selection, Rett syndrome-specific mutational and phenotypic diversity, and the in vivo application of CRISPR-Cas systems, it would require undue experimentation for a skilled artisan to use the invention commensurate in scope with the claims.
Response to Arguments
Applicant argues that the amendments to claim 10 render the scope of the pending claims under examination fully enabled because (1) claim 10 has been amended to recite a method of editing a mutant genomic target sequence carrying one or more mutations in a target cell of a subject affected by Rett syndrome, and (2) claim 10 has been further amended to specify that the mutant genomic target sequence in the target cell is a mutant MECP2 gene, a mutant FOXG1 gene, or a mutant CDKL5 gene. These arguments have been fully considered but are not found persuasive for the following reasons:
(1)/(2) Applicant argues “Example 2.2 of the present application (paragraphs [0152] and [0153]) provides experimental evidence showing that the CRISPR- Cas system is effective in correcting defective MECP2 and FOXG1 genes in primary fibroblasts derived from patients affected by Rett syndrome. Following transfection, next generation sequencing (NGS) was used to confirm CRISPR-Cas editing within the targeted gene sequencing, and showed a significant reduction of mutant alleles proportion to about 15%. As is well known in the art, fibroblasts obtained from patients are a well-established model for studying genetic diseases of the nervous system and evaluating new therapeutic strategies like gene editing, due to their metabolic and biochemical relationships with neurons. Additionally, it is well known to the person skilled in the art that fibroblasts can be reprogrammed to create induced Pluripotent Stem Cells (iPSCs), which can subsequently be differentiated into neurons (see Juopperi TA, Modeling neurological diseases using patient-derived induced pluripotent stem cells. Future Neurol. 2011 May;6(3):363- 373, submitted concurrently herewith as part of an information disclosure statement). As of the priority date of the present application, fibroblast models were already widely used in medical and genetic research for Rett syndrome. By using fibroblasts from Rett syndrome patients, Li et al. showed that a disrupted molecular clockwork underlies the sleep-wake cycle disturbances typical of the Rett condition (Li Q., et al. Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT. Neurobiol Dis. 2015 May; 77:155-64, submitted concurrently herewith as part of the IDS) . Additionally, a genome-wide DNA methylation study utilizing a fibroblast model derived from discordant Rett syndrome twins carrying a MECP2 mutation allowed for the identification of the genetic or epigenetic factors underlying the variations in clinical severity observed between the twins (see Miyake K., et al. (2013) Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome. PLoS ONE 8(6): e66729, submitted concurrently herewith as part of an information disclosure statement). Clonal fibroblasts from patients with Rett syndrome have also been used as a reliable ex vivo platform to screen and validate potential therapeutic compounds (see Yu D., et al. Clonal Rett Syndrome cell lines to test compounds for activation of wild-type MeCP2 expression. Bioorganic & Medicinal Chemistry Letters (21) 2011: 5202-5205, submitted concurrently herewith as part of an information disclosure statement). This has been particularly effective for identifying and validating compounds that can suppress the gene mutations linked to the syndrome (see Vecsler M., et al. (2011) Ex Vivo Treatment with a Novel Synthetic Aminoglycoside NB54 in Primary Fibroblasts from Rett Syndrome Patients Suppresses MECP2 Nonsense Mutations. PLoS ONE 6(6): e20733, submitted concurrently herewith as part of an information disclosure statement). Juopperi et al. teaches an in vitro model of Rett syndrome based on iPSCs derived from patient fibroblasts (id. at paragraph bridging pages 367 and 368). To provide additional evidence of the claimed CRISPR system's editing efficiency, further experimental data obtained by the inventors is submitted herewith, which was published in the articles herewith enclosed (Croci S., et al. High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot. Eur J Hum Genet. 2020 Sep;28(9):1231-1242. doi: 10.1038/s41431-020-0624-x. Epub 2020 Apr 24. Erratum in: Eur J Hum Genet. 2024 Jan;32(1) :134. doi: 10.1038/s41431-023-01290-3, hereinafter referred to as "Croci S et al. 1".; Croci S., et al. AAV-mediated FOXG1 gene editing in human Rett primary cells. Eur J Hum Genet. 2020 Oct;28(10):1446- 1458. doi: 10.1038/s41431-020-0652-6, hereinafter referred to as "Croci S et al. 2", both submitted herewith as part of the IDS). Both articles illustrate the results of experiments conducted by the inventors on primary fibroblasts and neuronal cells that were differentiated from induced Pluripotent Stem Cells (iPSCs) from Rett syndrome patients, and demonstrate that the dual vector CRISPR system of the present invention can achieve efficient gene editing in these cellular models. More specifically, the studies by Croci S et al. 1 show the successful editing of the MECP2 mutation c.473C>T (p. (Thr158Met) ) with the CRISPR system of the present invention in both Rett syndrome fibroblasts and iPSC-derived neurons (correction efficiency ranging from 14% to 80% with a negligible percentage of indels), thereby confirming that the MECP2 gene can be efficiently modified in different cell types (see page 1235, section "Gene correction in patient's cells", Figure 4 and Table 2). Similarly, the studies of Croci S et al. 2 confirmed that both mutations c.688C>T (p. (Arg230Cys) ) and c.765G>A (p. (Trp255*) ) in the FOXG1 gene can be effectively corrected in the aforementioned cell-based models using the CRISPR-Cas system of the present invention (see page 1452, section "Gene editing efficiency", Fig. 3a-c). Applicant respectfully submits that the specification of the present patent application provides clear experimental evidence proving the ability of the claimed CRISPR-Cas system to correct gene variants associated with Rett syndrome in a target cell of a patient.” (Remarks, pages 10-13).
At the outset it should be noted that the Examiner is not challenging the editing efficiency of the disclosed CRISPR-Cas system, nor its ability to edit genes of target cells in vitro. The Examiner is challenging whether the supporting disclosure provides sufficient guidance when combined with the art at the time of filing to enable a skilled artisan to be able to predictably determine whether any viral expression vector comprising a CRISPR-Cas system can be administered in vivo to any target cell of any subject by any route of administration targeting mutations in the MECP2, FOXG1, or CDKL5 genes to effectuate a treatment for Rett syndrome.
This rejection was borne of Applicant’s limited disclosure of only in vitro experimental results with AAV2 vectors, solidified by Applicant’s election of the in vivo method with all of its breadth and substantiated by the field recognized unpredictability amounting to a gap between in vitro findings for CRISPR-Cas systems and their therapeutic application in vivo to any organism as well as the unpredictability evidenced by the prior art at the time of filing with respect to different viral vectors. Applicant has amended claim 10 to be specific to the three specific mutant genes identified in the Non-final Rejection mailed 02 April, 2025 to be enabled. However, Applicant has neglected to address the other issues of enablement raised in that same action. Here, Applicant asserts that amending claim 10 to recite a method of editing a mutant genomic target sequence carrying one or more mutations in a target cell of a subject affected by Rett syndrome somehow overcomes all other outstanding issues of enablement. Applicant supports this assertion by first pointing to Example 2.2 of the instant specification. This example is titled “Correction of Mutant FOXG1 and MECP2 genes in cell systems” and, as that title suggests, it is limited to in vitro experimental results. Applicant then turns to the art and provides Juopperi to state that it is “well known in the art [that] fibroblasts obtained from patients are a well-established model for studying genetic diseases of the nervous system…” Again, this is not what the Examiner is challenging here. It is conceded that ex vivo/in vitro applications for CRISPR/Cas system are well known in the art. What is also well known in the art is that significant challenges still exist in the transition of CRISPR systems to in vivo applications (Luther et al. (Expert opinion on drug delivery 15.9 (Published online: 12 September, 2018): 905-913., hereinafter “Luther”, Luther, page 906, only full paragraph)). Thus, Applicant’s providing Juopperi appears to miss the thrust of the rejection here. Applicant continues this logic with the provision of the Li, Miyake, Yu, and Vecsler references, and a publication by the instant inventors (Croci) to support ex vivo applications of CRISPR/Cas systems used in fibroblasts. Again, this appears to miss the thrust of the rejection as ex vivo applications are not challenged. Applicant has claimed such an in vitro/ex vivo application in withdrawn claim 6 but Applicant did not elect withdrawn claim 6, Applicant elected claim 10 directed to an in vivo method utilizing any viral vector to deliver a CRISPR/Cas system to any cell of any subject affected by Rett syndrome. Applicant has not amended and does not attempt to argue for enablement of any viral expression vector comprising a CRISPR-Cas system administered in vivo to any target cell of any subject targeting mutations in the MECP2, FOXG1, or CDKL5 genes to effectuate a treatment for Rett syndrome. Accordingly, these arguments have been considered but, respectfully, have not been found persuasive.
New Rejections Necessitated by Applicant’s Amendments/Arguments
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 14-15, 18, and 20-25 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.
Amended claim 10 recites the limitation "a mutant genomic target sequence" in the second, and eighth lines of the claim and “the mutant genomic target sequence” in the 19th, 21st, 28th, and 45th lines of the claim. There is insufficient antecedent basis for these limitation in the claim. It is unclear if the multiple recitations of “a mutant genomic target sequence” are referring to the same or different sequences. Thus, in having multiple antecedents, each recitation of “the mutant genomic target sequence” lacks antecedent basis. This rejection can be overcome by amending the second “a mutant genomic target sequence” to instead read “the mutant genomic target sequence”. Claims 14-15, 18, and 20-25 are further rejected for their dependency on a rejected base claim.
Claim 14 is unclear in its recitation of “and/or”. It is unclear whether Applicant intends the scope of claim 14 to encompass all of a vehicle, excipient and diluent or whether Applicant intends to encompass only one of these in the alternative. Accordingly, the scope of claim 14 is unclear.
Claim 21 is unclear in its recitation of “and/or”. It is unclear whether Applicant intends the scope of claim 21 to encompass both of the viral expression vectors being AAV vectors or whether Applicant intends to encompass only one of these in the alternative. Accordingly, the scope of claim 21 is unclear.
Claims 23-25 are indefinite because each recite “the mutant genomic target sequence” in the first line of each claim. This recitation lacks sufficient antecedent basis for the same reasons discussed above with claim 10. The proposed amendment to overcome the rejection of claim 10 would also obviate these rejections.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634