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 .
DETAILED ACTION
Application status
Claims 1-20 are pending in this application.
Priority
It is acknowledged that the instant application is a DIV of US Application No. 17858758 (now US PAT 12060588) filed on 07/06/2022, which is a DIV of 16326700 (now US PAT 11434476) filed on 02/19/2019, which is the 371 national stage entry of PCT/US17/47674, filed on 08/18/2017, which claims benefit of 62377520 filed on 08/19/2016.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/26/2024, 03/24/2025, 11/14/2025 and 05/12/2026 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “fused to an effector domain have methylation activity” which can be substantially improved with respect to grammar (italicized for added emphasis). The Examiner suggests replacing the noted phrase with ---fused to an effector domain having methylation activity---.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 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.
Claims 1-20 are rejected under 35 U.S.C. § 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1, 9, 11 and 12 (2-8, 10, 13-20 dependent therefrom) recite a phrase “a patient in need thereof”, “a disease or disorder in a subject”, “associated or produced by a genetic modification” or “involved in pathogenesis of the disease or disorder”, respectively, which lack clear metes and bounds. A person of ordinary skill in the art (POSITA) cannot determine with reasonable certainty which patients, diseases, disorders or genomic modifications fall within the claimed scope without additional criteria or definitions. In the interest of advancing prosecution, the Examiner has interpreted these terms as involving any patient, any disease or disorder, any genetic modification and any pathogenesis.
The following is a quotation 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.
Claims 1-20 are rejected under 35 U.S.C. § 112(a), written description, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to a method of treating a patient in need thereof, the method comprising administering to the patient: a) a nucleic acid that encodes a polypeptide comprising a catalytically inactive site specific nuclease fused to an effector domain have methylation activity; and b) a guide sequence or a nucleic acid that encodes a guide sequence; and a method of treating a disease or disorder in a subject comprising administering to the subject: a) a polypeptide comprising a catalytically inactive site specific nuclease fused to an effector domain having methylation or demethylation activity, or a nucleic acid encoding the polypeptide; and b) a guide sequence or a nucleic acid that encodes a guide sequence, wherein the guide sequence targets a genomic sequence comprising a CTCF binding site.
To satisfy the written description aspect of 35 U.S.C. § 112(a) for a claimed genus of [compositions or methods], it must be clear that: (1) the identifying characteristics of the claimed [compositions or methods] have been disclosed, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these; and (2) a representative number of species within the genus must be disclosed.
University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lily and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description as noted from Enzo Biochemical (see above).
The specification discloses only two representative species of the genus of claimed methods, i.e. dCas9-Tet1 having demethylation activity or dCas9-Dnmt3a having methylation activity at CTCF sites in miR290/Pou5f1. However, these two disclosed species fails to provide adequate written description for an extremely genus of claimed methods encompassing a method of treating any patient in need thereof, the method comprising administering to the patient: a) any nucleic acid that encodes any polypeptide comprising any catalytically inactive site specific nuclease fused to any effector domain have methylation activity; and b) any guide sequence or any nucleic acid that encodes any guide sequence; and a method of treating any disease or disorder in any subject comprising administering to the subject: a) any polypeptide comprising any catalytically inactive site specific nuclease fused to any effector domain having methylation or demethylation activity, or any nucleic acid encoding the polypeptide; and b) any guide sequence or any nucleic acid that encodes any guide sequence, wherein the guide sequence targets a genomic sequence comprising a CTCF binding site.
Moreover, the specification fails to provide a representative number of species across the extremely broad genus of:
[1] any patient having any diseases or disorders associated with or produced by any genetic modification in any genomic sequence optionally involved in any pathogenesis;
[2] any nucleic acid encoding any polypeptide with catalytically inactive site fused to any effector domain having methylation or demethylation activity; and
[3] any guide sequence.
It is noted by the Examiner that none of the dependent claims remedy the deficiencies noted above regarding 35 U.S.C. § 112(a) written description.
While M.P.E.P. section 2163 acknowledges that a single species can describe a genus, it also acknowledges that for a genus that encompasses widely variant species, disclosure of a single species within the genus fails to adequately describe all members of the genus. Please refer to the M.P.E.P. section 2163.05 [R-7.2022] under I, B for more details with respect to sufficient number of representative species that should be disclosed to describe a widely variant genus.
Given the lack of additional representative species of the extremely broad genus of claimed methods as noted above, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112(a) published in the Official Gazette and also available at www.uspto.gov.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Qi et al. (Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression, Cell 152, 1173–1183, February 28, 2013) in view of Zetsche et al. (Cpf1 Is a Single RNA-Guided Endonuclease of a Class 2 CRISPR-Cas System, Cell, Volume 163, Issue 3, p759-771, October 22, 2015), Maeder et al. (Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins, Nature Biotechnology, volume 31, number 12, DECEMBER 2013, pages 1137-1142), Siddique et al. (Targeted Methylation and Gene Silencing of VEGF-A in Human Cells by Using a Designed Dnmt3a–Dnmt3L Single-Chain Fusion Protein with Increased DNA Methylation Activity, J. Mol. Biol. Volume 425, Issue 3, 8 February 2013, Pages 479-491), Kemp et al. (CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer, Cell Reports, Volume 7, Issue 4, p1020-1029, May 22, 2014), Medzhitov et al. (Transcriptional control of the inflammatory response, Nature Reviews Immunology volume 9, pages 692–703 (2009)) and Abraham et al. (US Patent Application Publication No. 2016/0362705 with an effective filing date of 06/12/2015)
The instant claims are drawn to a method of treating a patient in need thereof, the method comprising administering to the patient: a) a nucleic acid that encodes a polypeptide comprising a catalytically inactive site specific nuclease fused to an effector domain have methylation activity; and b) a guide sequence or a nucleic acid that encodes a guide sequence; and a method of treating a disease or disorder in a subject comprising administering to the subject: a) a polypeptide comprising a catalytically inactive site specific nuclease fused to an effector domain having methylation or demethylation activity, or a nucleic acid encoding the polypeptide; and b) a guide sequence or a nucleic acid that encodes a guide sequence, wherein the guide sequence targets a genomic sequence comprising a CTCF binding site. (see above 112(b) rejection for claim interpretation)
Qi et al. teach a modular, RNA-guided platform using catalytically inactive Cas9 (dCas9) that can be fused to effector domains and targeted to specific genomic loci via gRNAs (sgRNAs, which is 20-nucleotide targeting sequence fused to the tracrRNA scaffold, making it ~100 nucleotides long). This platform is explicitly disclosed as a general tool for recruiting various effector domains to DNA, which is highly programmable and works in mammalian cells (see Abstract; pg. 1174, “Results – CRISPRi: RNA-guided transcriptional repression; Figure 1; pg. 1175-1176 Figure 2 and related discussion of dCas9-KRAB fusions; and methods section).
Qi et al. do not teach an effector domain, TET1 or Dnmt3a, having methylation or demethylation activity, and the use of inactive Cpf1.
Zetsche et al. teach catalytically inactive dCpf1 (RuvC domain mutants: D917A and E1006A mutations) (see pg. 762, para under “The RuvC-like Domain of Cpf1 Mediates RNA-Guided DNA Cleavage”), which are also used for DNA binding/cleavage studies (see Figures 4-5).
Maeder et al. teach the concept of fusing a programmable DNA-binding domain (TALE) to the TET1 catalytic domain having demethylation activity, which enables locus-specific demethylation of CpG sites in promoters of genes (see Abstract; pg. 1138; Figure 1). Maeder et al. further teach that such targeted demethylation leads to activation of endogenous genes (see pg. 1139-1140; Figures 2-3) showing demethylation and transcriptional upregulation at specific loci such as KLF4 and SOX2).
Siddique et al. teach a fusion of designed zinc-finger protein fused to aDnmt3a-Dnmt3L single-chain fusion protein for targeted DNA methylation at a specific promoter (VEGF-A) leading to gene silencing in human cells (see Abstract; pg. 480-482; Figures 1-2; pg. 483-486; Figures 3-4).
Kemp et al. teach that CTCF binding sites contain aberrant methylation, i.e., hypo- or -hyper-methylated (see last para on pg. 1023) in human cancer, and it serves to bind to target DNA sequences in DNA-methylation-dependent manner, and that CTCF (CCCTC-binding factor) plays important roles in maintaining proper chromatin architecture and preventing oncogenic gene expression (see Abstract and Introduction).
Medzhitov et al. teach that DNA methylation is an epigenetic mechanism that regulates inflammatory gene expression (see Abstract; pg. 695 under “Dynamic chromatin remodeling”).
Abraham et al. teach a general methodology of administering a nucleic acid vector encoding dCas9-effector fusion with gRNA to a patient in need thereof (see all claims).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to practice a method of administering nucleic acid vector comprising the dCas9 fusion/gRNA platform taught by Qi et al. and [i] replace dCas9 with dCpf1 as taught by Zetsche et al., and/or [ii] replace the effector domain with TET1 as taught by Maeder et al. or Dnmt3a as taught by Siddique et al., while targeting CTCF binding sites for cancer patients as taught by Kemp et al. or alternatively for a patient with inflammatory disorder as taught by Medzhitov et al. A POSITA would have been motivated to practice such methods because dCas9 platform taught by Qi et al. provides simpler and superior design for targeting a specific genomic sequence for delivering TET1 or Dnmt3a for controlling methylation/demethylation while allowing alternative use of dCpf1 similar to dCas9, to any sites are regulated by DNA methylation/demethylation for gene expression control, in any patients with cancer and/or inflammation, especially for CTCF binding sites for maintaining proper chromatin architecture and preventing oncogenic gene expression as taught by Kemp et al. and Medzhitov et al. A POSITA would have had a reasonable expectation of success to practice such methods because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Qi et al., Zetsche et al., Maeder et al., Siddique et al., Kemp et al., Medzhitov et al. and Abraham et al. prior to the filing of the instant application.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 1-20 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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