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 Application/Restriction/Claims
Claims 1-4, 6-12, 14-15, 30, 33, 37, 48-49 and 66-67 submitted on 6/21/2024 are pending and are the subject of the present Official action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 62/358,337, PCT/US2017/040745 and CON of 16/315,462 filed on 7/5/2016, 7/5/2017 and 1/4/2019, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 7/5/2016.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/24/2024 was received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement was considered by the examiner.
Notice of Non-Compliance
This application discloses nucleic acid and/or amino acid sequences that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821 through 1.825 (the “sequence rules”). However, this application discloses nucleotide and/or amino acid sequences which require labeling by accompanying sequence identifiers (i.e. SEQ ID NO:), but which are not so labeled. For example, at least Figs 53 and 57 of the instant application disclose nucleotide sequences in excess of 10 bp in length that are not identified by sequence identifier. Applicants should be aware that this may not comprise the only instance(s) of non-compliance. Applicant should carefully review the application for any further example(s) of failure to identify sequences by sequence identifier, and to otherwise verify that the application is in full compliance with the sequence rules. Please note that any sequences not already disclosed in the sequence listing or CRF will require amendment and resubmission of both the sequence listing and the CRF.
Applicant is required to comply with all sequence rules set forth in 37 CFR 1.821 through 1.825 in the next substantive response. This requirement will not be held in abeyance, and failure to comply with these requirements may result in ABANDONMENT of the application under 37 CFR 1.821(g). Direct the reply to the undersigned.
Claim Interpretation
Claim 1 describes a method for treating retinal degeneration comprising a vector which encodes a gRNA that hybridizes with a target sequence of a DNA molecule encoding “one or more gene products” expressed in a cell, wherein the one or more gene products comprise DLK and LZK. The broadest reasonable interpretation of these limitations reads on targeting one gene product or segment thereof like the target sequence disclosed in SEQ ID NO: 147 which corresponds to a known segment of the DLK gene.
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 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.
Claims 1-4, 6-12, 14-15, 30, 37, 48-49 and 66-67 are rejected under 35 U.S.C. 103 as being unpatentable over Ranganathan et al. US 2016/0074535, published 3/17/2016, priority date 6/16/2014 (hereinafter Ranganathan) in view of Welsbie et al. "Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death." Proceedings of the National Academy of Sciences 110.10 (2013): 4045-4050 (hereinafter Welsbie).
Claims 1 and 37: Ranganathan describes a method for treating retinal degeneration using a non-naturally occurring CRISPR-Cas system comprising one or more vectors comprising an H1 promoter operably linked to at least one nucleotide sequence encoding a CRISPR-Cas system guide RNA (gRNA) and a regulatory element operably linked to a nucleotide sequence encoding a Cas9 nuclease protein (Ranganathan, para 9, 11, 18, 50). Ranganathan provides embodiments wherein the gRNA hybridizes with a target sequence and the nuclease cleaves one or two strands of the target DNA molecule to alter gene expression (Ranganathan, para 18). Ranganathan provides a description of possible gene targets related to glaucoma in retinal neurons in humans (Ranganathan, para 18, 162, 163, 165, 166, 171). Ranganathan provides embodiments wherein the gRNA and Cas9 protein are located on the same or different vectors (Ranganathan, para 18). Although Ranganathan describes treating retinal degeneration like glaucoma, Ranganathan does not specifically describe targeting one or more gene products comprising dual leucine zipper kinase (DLK) and Leucine Zipper Kinase (LZK).
Claims 2, 4, 9, 10, 48, 49: Ranganathan describes preferred embodiments towards the use of codon optimized CRISPR-Cas systems which use a Cas9 protein for inactivating targeted gene products using programable gRNAs (Ranganathan, para 4-6 and 9).
Claim 3: Ranganathan describes administering CRISPR-Cas system to subjects using adeno-associated virus (AAV) particles (Ranganathan, para 18).
Claims 6-8 and 66-67: Ranganathan provides a description of the bidirectional H1 promoter (Ranganathan, para 13, 45 and Fig 10). Ranganathan describes the H1 promoter as providing transcription in one direction with respect to the gRNA and the opposite direction for the nuclease (Ranganathan, para 47-50). Ranganathan describes the advantages of using a single promoter for driving the expression of both components in reducing the vector size and improving packing efficiency.
Claims 11, 48: Ranganathan states that the bidirectional H1 promoter may be operably linked to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or more guide sequences (Ranganathan, para 81).
Claim 12, 14, 15, 30: Ranganathan provides a description of possible gene targets related to glaucoma in retinal neurons in humans (Ranganathan, para 18, 162, 163, 165, 166, 171). Ranganathan describes administration routes into the retinal area (Ranganathan, para 224, 226, 229).
Claims 1 and 37: Welsbie provides a description of glaucoma and the neurodegenerative process by which the loss of retinal ganglion cells leads to vision loss (Welsbie, abstract and intro para 1). Welsbie identified DLK as a key neuroprotective target in retinal ganglion cells. Welsbie used a conditional knockout approach to confirm that DLK is required for retinal ganglion cell JNK activation and cell death in a rodent model for optic neuropathy (Welsbie, abstract, pg 4046 and Fig 1 and 2). Welsbie found that DLK down-regulation promotes long-term survival and function of retinal ganglion cells in vitro and in vivo (Welsbie, pg 4046). Welsbie suggests that the genetic or pharmacological inhibition of DLK could provide a therapeutic approach for treating glaucoma and other forms of CNS neurodegeneration (Welsbie, Discussion last para).
It would have been prima facie obvious to one of ordinary skill in the art to apply the CRISPR-Cas9 system described by Ranganathan to decrease DLK gene expression as a therapy for glaucoma as described by Welsbie. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Welsbie identified DLK as a key neuroprotective target in retinal ganglion cells and showed data that DLK down-regulation promotes long-term survival and function of retinal ganglion cells in vitro and in vivo. Welsbie used small interfering RNA oligonucleotides (siRNAs) to alter DLK gene expression. However, one of ordinary skill could readily apply the CRISPR-Cas9 methods described by Ranganathan to alter DLK gene expression with a higher level of precision and clinical efficacy than through the use of siRNAs. One would be motivated to use the CRISPR-Cas methods described by Ranganathan to target the DLK gene rather than siRNAs since CRISPR offers a higher degree of specificity, efficiency and versatility. One would have a reasonable expectation of success given that DLK is a known gene target implicated in glaucoma and there exist predictable methods for designing CRISPR gRNAs toward known genes like DLK. Furthermore, the bidirectional H1 promoter used by Ranganathan provides expression of both gRNA and Cas9 components, thereby reducing the vector size and improving vector packing efficiency. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1-4, 6-12, 14-15, 30, 37, 48-49 and 66-67 to have been prima facie obvious to at the time the invention was made.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Ranganathan (supra) and Welsbie (supra) as applied to claims 1-4, 6-12, 14-15, 30, 37, 48-49 and 66-67 above in further view of Strausberg et al. Mammalian Gene Collection (MGC) Program Team*. "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences." Proceedings of the National Academy of Sciences 99.26 (2002): 16899-16903 (hereinafter Strausberg).
A description of Ranganathan and Welsbie can be found above. Neither Ranganathan nor Welsbie describe a target sequence consisting of the nucleotide sequence set forth in any one of SEQ ID Nos: 143-163 as described in claim 33.
Claim 33: However, the 23 bp target sequence identified in SEQ ID NO: 147 corresponds to a known segment of the DLK gene as show by Strausberg (sequence search results shown below).
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It would have been prima facie obvious to one of ordinary skill in the art to design a gRNA which targets the DLK gene segment disclosed by Strausberg using the CRISPR-Cas9 system described by Ranganathan to decrease DLK gene expression as a therapy for glaucoma as described by Welsbie. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Welsbie identified DLK as a key neuroprotective target in retinal ganglion cells and showed data that DLK down-regulation promotes long-term survival and function of retinal ganglion cells in vitro and in vivo. One of ordinary skill would be motivated to experiment with different gRNA targets within the DLK gene in order to improve DLK gene knockout efficiency as a therapy for glaucoma. One would have a reasonable expectation of success given that the sequence of the DLK gene is known in the art and there exists predictable methods for reprogramming gRNA targets using the CRISPR-Cas9 system described by Ranganathan to decrease DLK gene expression as a therapy for glaucoma. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634