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 .
Application Status and Election
Claims 1-14 and 16-18 are pending.
Applicant’s election of Group I (claims 1-14) and the species below in the reply filed 03/03/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Species elected:
Claim 2: the monogenic muscular disease as limb-girdle muscular dystrophy (LGMD)
Claim 3: Point mutation
Claim 4: SGCA. Examiner includes DYSF dysferlin gene.
Claim 5: Crispr/Cas based tool for adenine base editing (ABE)
Claim 7: muscle density range between 40,000 and 90,000 cells/9.5 cm2
Claims 16-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 1-14.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
Specifically, the sequence disclosures in the Drawings filed 9/1/23 in Figures 1-5 and 8 contain enumerated sequences of at least 10 nucleotides yet lack a SEQ ID NO designation.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Rejections - 35 USC § 112(b)
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.
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites, “…such as 55,000 and 75,000 cells/9.5 cm2.” However, the phrase “such as” is indefinite exemplary language. MPEP 2173.05(d) states "Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made.”
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-6, 8-11, and 14 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Glucksmann (Glucksmann, A., WO-2015048577-A2).
Regarding claim 1, Glucksmann teaches methods and compositions of a Cas9 molecule complexed with a gRNA molecule which can be used to target a specific location in a target DNA for specific editing of a target gene with the delivery of a payload via an ex vivo method [0005] and where the method includes the CRISPR/Cas knockdown [0600]. Glucksmann teaches the cell is one of a variety of cells including a human stem cells [0105] and where in some embodiments that cell is manipulated by editing (e.g., introducing a mutation or correcting) one or more target genes, where the expression of the target gene is modulated is also modulated ex vivo [0766]. Glucksmann teaches the method is performed in cultured cells, isolated ex vivo from a subject, and then further comprises administering the cell to a patient. The modified cell may be, for example, an induced pluripotent stem cell, a bone marrow derived progenitor, a skeletal muscle progenitor, a CD 133+ cell, a mesoangioblast, or a MyoD-transduced dermal fibroblast [1033]. Glucksmann teaches in some embodiments, the manipulated cell is a stem cell or progenitor cell [0770] where the cell is converted or differentiated into muscle cells [0772-0775], i.e. primary human muscle stem cell. Glucksmann teaches the Cas9- and/or gRNA-encoding DNA delivered by a vector and/or plasmids [0647]. Glucksmann teaches the target gene includes the dystrophin gene, mutated in DMD, as well as the dysferlin gene in Limb-Girdle Muscular Dystrophy type 2B [1032] as identified as a monogenic one gene disorder (Table IX-2), i.e. targeted modification of the at least one mutation of a monogenic disorder.
Regarding claim 2, Glucksmann teaches the target gene includes the dystrophin gene, mutated in DMD, as well as the dysferlin gene in the elected disease Limb-Girdle Muscular Dystrophy type 2B [1032].
Regarding claim 3, Glucksmann teaches the genetic signature, e.g., a premature stop codon, results from a point mutation [1011].
Regarding claim 4, Glucksmann teaches the target gene includes the dysferlin and SGCA gene in the elected disease Limb-Girdle Muscular Dystrophy type 2B [1032] (Table IX-2).
Regarding claim 5, Glucksmann teaches the modified nucleosides and modified nucleotides can be incorporated into a modified nucleic acid, can include a modified nucleobase. Examples of nucleobases include adenine (A), guanine (G), cytosine (C), and uracil (U). These nucleobases can be modified or wholly replaced to provide modified nucleosides and modified nucleotides that can be incorporated into modified nucleic acids [0939].
Regarding claim 6, Glucksmann teaches the Cas9- and/or gRNA-encoding DNA delivered by a vector and/or plasmids [0647].
Regarding claim 8, Glucksmann teaches the composition further comprises mRNA that encodes the Cas9 molecule [0082].
Regarding claim 9, Glucksmann teaches the Cas9- and/or gRNA-encoding DNA can be delivered, e.g., by electroporation, sonoporation, and/or lipid-mediated transfection (i.e., a carrier for delivery) [0660].
Regarding claim 10, Glucksmann teaches methods and compositions of a Cas9 molecule complexed with a gRNA molecule which can be used to target a specific location in a target DNA for specific editing of a target gene with the delivery of a payload via an ex vivo method [0005] and where the method includes the CRISPR/Cas knockdown [0600], i.e. a recombinant protein transport system.
Regarding claim 11, Glucksmann teaches the Cas9- and/or gRNA-encoding DNA can be delivered, e.g., by electroporation, sonoporation, and/or lipid-mediated transfection (i.e., a carrier for delivery) [0660].
Regarding claim 14, Glucksmann teaches the above applied to claim 1.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 7, 12, and 13, is/are rejected under 35 U.S.C. 103 as being unpatentable over Glucksmann (Glucksmann, A., WO-2015048577-A2) as applied to claim 1, in view of Haque (Haque, Nazmul, et al. "Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy." The Scientific World Journal 2013.1 (2013): 632972.) and Mehrabani (Mehrabani, Davood, et al. "Growth kinetics, characterization, and plasticity of human menstrual blood stem cells." Iranian Journal of Medical Sciences 41.2 (2016): 132.) and Freitas-Ribeiro (Freitas-Ribeiro, Sara, et al. "Strategies for the hypothermic preservation of cell sheets of human adipose stem cells." PLoS One 14.10 (2019): e0222597.).
Regarding claim 7, 12, and 13, the teachings above as applied for claim 1 are incorporated here.
Glucksmann does not teach transfection cell density protocols, or stem cell cultivation parameters, or temperature/oxygen content of the culture parameters.
Regarding claims 12 and 13, Haque teaches hypoxic culture environment of 2–9% O2 can greatly improve growth kinetics, genetic stability, and expression of chemokine receptors during in vitro expansion and eventually can increase efficiency of MSC-based regenerative therapies (abstract). Freitas-Ribeiro teaches pausing cells at hypothermic temperatures such as at 4 degrees Celsius for up to seven days is a short-term and simplified alternative to cryopreservation and is capable of slowing metabolic activity, protein synthesis, transport systems and cell cycle progression and prevents cell damage from ice nucleation and changes in solute concentration caused by severe temperature changes as the ones experienced by cells during cryopreservation (pg 2 para 2-4). Regarding claim 7, Mehrabani teaches culturing stem cells at 5×104 cells per well, i.e. 50,000 cells (pg 133 col 2 para 4).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have cultured the cells of Glucksmann with the cell culture parameters known in the art taught by Mehrabani, Freitas-Ribeiro, and Haque in order to optimize transfection efficiency for enhanced crispr mediated gene editing, given the parameter advantages described. Examiner also notes that optimization of doses/concentrations and culture parameters would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Therefore, claims 7, 12, and 13 are obvious and is properly rejected under 35 U.S.C. 103.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Jennifer Dunston can be reached on (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
Prosecution Insights