DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Art Unit location of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Art Unit 1656 and Examiner Paul Holland.
3. Claims 1-12 are pending.
Election/Restrictions
4. Applicant’s election without traverse of Group I, claims 1-6 and the species fumarylacetoacetate hydrolase in the reply filed on 10/29/2025 is acknowledged.
5. Claims 7-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/29/2025.
Claims 1-6 are pending and examined on the merits.
Priority
6. Acknowledgement is made of applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to Korea Patent Application No. 10-2020-0102636, filing date 08/14/2020. The certified copy has been filed in the present application, filed on 02/13/2023.
Information Disclosure Statement
7. The IDSs filed on 02/13/2023 and 03/15/2024 have been considered by the examiner and copies of the Form PTO/SB/08 are attached to the office action.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
8. 37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See Tables 1 and 2.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, 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.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. See Figures 3, 4, 5, and 6.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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.
Claim Rejections - 35 USC § 112(a)
9. 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.
A. Written Description
10. Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claims 1 and 3-6 are drawn to a method of preparing mutant gene-corrected cells, comprising: (a) isolating cells from a subject; (b) treating the isolated cells with a compound to prepare chemically-derived progenitor cells; and (c) correcting a mutant gene of the chemically-derived progenitor cells ex vivo.
Claim 2 is drawn to the method of claim 1, wherein the correcting of a gene is to correct a gene by an adenine base editor or prime editing.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of “compounds” to prepare chemically derived progenitor cells; and “correcting” a mutant gene of the chemically-derived progenitor cells ex vivo as encompassed by the claims (i.e. treating primary hepatocytes with a hepatic growth factor, A83-01 and CHIR99021 to reprogram hepatocytes to hepatic progenitor cells and correcting a mutant gene with a ABE6.3, ABE7.8, ABE7.10, NG-ABEmax, NG-ABE8e and ABEmax adenosine deaminases or a CRISPR/sgRNA/pegRNA complex). Other than the above disclosed species there is no other drawings or structural formulas disclosed of compounds that reprogram any cells to progenitor cells nor any other drawings or structural formulas of any method of correcting a mutant gene as encompassed by the claims.
The reprogramming of primary hepatocytes into hepatic progenitor cells by treatment of cells with hepatic growth factor, A83-01 and CHIR99021 was known in the art as taught by Choi et al. (WO2018/221904 A2; examiner cited with US Patent Application Publication 2020/0147143 A1, examiner cited, serving as a translation).
It is noted that ABE6.3, ABE7.8, ABE7.10, NG-ABEmax, NG-ABE8e and ABEmax are mutant adenosine deaminases that have been mutated in order to switch specificity from RNA to DNA as taught by Liu et al. (US Patent 10,113,163 B2; examiner cited), who further disclose mutant adenosine deaminase of E. coli TadA that deaminate a adenosine in DNA [see Abstract].
Prime editing compositions for targeted genetic modifications of correcting a mutant gene comprising a nucleic acid programmable DNA binding protein, a reverse transcriptase, and PEgRNA were known in the art as taught by Liu et al. (WO 2020/191171 A1, priority to 03/19/2019; examiner cited), hereinafter called Liu2.
To this end, there is no prior-art or disclosed teaching of the infinite number of compounds as encompassed by the claims that can treat any cell type and result in reprogrammed progenitor cells. Furthermore, other than the disclosed adenosine deaminases as taught by Liu et al., the prior art points to adenosine deaminases being specific for RNA as evidenced by Wolf et al. (EMBO Journal, 2002; examiner cited). To this end, there is no prior-art or disclosed teaching regarding which of the amino acids can vary in any adenosine deaminase by either conservative or non-conservative substitutions and still result in a protein that switches specificity from RNA to DNA for deamination and there is no disclosed or art-recognized correlation between any structure other than adenosine deaminase variants disclosed above and by Liu et al. to have DNA deaminase activity. Given what is known in the art about the likely outcome of substitutions on structure, conservation of structure is not necessarily a surrogate for conservation of function. In this case, there is no disclosed correlation between structure and function. Accordingly, one of skill in the art would not accept the disclosure of treating primary hepatocytes with a hepatic growth factor, A83-01 and CHIR99021 to reprogram hepatocytes to hepatic progenitor cells and correcting a mutant gene with a ABE6.3, ABE7.8, ABE7.10, NG-ABEmax, NG-ABE8e and ABEmax adenosine deaminases or a CRISPR/sgRNA/pegRNA complex as being representative of all methods of preparing chemically derived progenitor cells and correcting a mutant gene as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of molecular biology and gene editing, fails to satisfy the written description requirement of 35 U.S.C. 112(a).
B. Scope of Enablement
11. Claims 1-6 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 treating primary hepatocytes with a hepatic growth factor, A83-01 and CHIR99021 to reprogram hepatocytes to hepatic progenitor cells and correcting a mutant gene in said hepatic progenitor cells with a ABE6.3, ABE7.8, ABE7.10, NG-ABEmax, NG-ABE8e and ABEmax adenosine deaminases or a CRISPR/sgRNA/pegRNA complex, does not reasonably provide enablement for all methods of treating isolated cells with any compound to prepare progenitor cells and correcting any mutant gene in said progenitor cell by any method as encompassed by the claims.
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/or use the invention commensurate in scope with these claims.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A) The breadth of the claims: Claims 1 and 3-6 are drawn to a method of preparing mutant gene-corrected cells, comprising: (a) isolating cells from a subject; (b) treating the isolated cells with a compound to prepare chemically-derived progenitor cells; and (c) correcting a mutant gene of the chemically-derived progenitor cells ex vivo.
Claim 2 is drawn to the method of claim 1, wherein the correcting of a gene is to correct a gene by an adenine base editor or prime editing.
(C) The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: The scope of the claimed methods of treating any cell with any compound to reprogram said cell to a progenitor cell is unlimited. The scope of all methods of correcting any mutant gene in progenitor cell is unlimited.
The reprogramming of primary hepatocytes into hepatic progenitor cells by treatment of cells with hepatic growth factor, A83-01 and CHIR99021 was known in the art as taught by Choi et al. (WO2018/221904 A2; examiner cited with US Patent Application Publication 2020/0147143 A1, examiner cited, serving as a translation).
It is noted that ABE6.3, ABE7.8, ABE7.10, NG-ABEmax, NG-ABE8e and ABEmax are mutant adenosine deaminases that have been mutated in order to switch specificity from RNA to DNA as taught by Liu et al. (US Patent 10,113,163 B2; examiner), who further disclose mutant adenosine deaminase of E. coli TadA that deaminate a adenosine in DNA [see Abstract].
Furthermore, other than the disclosed adenosine deaminases as taught by Liu et al., the prior art points to adenosine deaminases being specific for RNA as evidenced by Wolf et al. (EMBO Journal, 2002; examiner cited).
Prime editing compositions for targeted genetic modifications of correcting a mutant gene comprising a nucleic acid programmable DNA binding protein, a reverse transcriptase, and PEgRNA were known in the art as taught by Liu et al. (WO 2020/191171 A1, priority to 03/19/2019; examiner cited), hereinafter called Liu2.
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of “compounds” to prepare chemically derived progenitor cells; and “correcting” a mutant gene of the chemically-derived progenitor cells ex vivo as encompassed by the claims, i.e. treating primary hepatocytes with a hepatic growth factor, A83-01 and CHIR99021 to reprogram hepatocytes to hepatic progenitor cells and correcting a mutant gene with a ABE6.3, ABE7.8, ABE7.10, NG-ABEmax, NG-ABE8e and ABEmax adenosine deaminases or a CRISPR/sgRNA/pegRNA complex. Other than these working examples, the specification fails to disclose any other working examples of compounds capable of reprogramming cells to progenitor cells and any other working examples of methods of correcting a mutant gene in said progenitor cells.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Claim Rejections - 35 USC § 103
12. 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.
13. Claim(s) 1-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (WO2018/221904 A2; examiner cited with US Patent Application Publication 2020/0147143 A1, examiner cited, serving as a translation) in view of Yu et al. (Human Gene Therapy, 2016; cited on IDS filed on 02/13/2023) and Musunuru et al. (WO 2019/213183 A1; examiner cited).
14. Claims 1-6 are drawn to a method of preparing mutant gene-corrected cells, comprising: (a) isolating cells from a subject; (b) treating the isolated cells with a compound to prepare chemically-derived progenitor cells; and (c) correcting a mutant gene of the chemically-derived progenitor cells ex vivo.
15. With respect to claim 1, Choi et al. teach methods for treating liver disease by reprogramming primary human adult hepatocytes by isolating the cells from a subject, and treating the isolated cells with a chemical compound such as HGF, A83-01 and CHIR99021 to produce chemically-derived progenitor cells [see Abstract; paragraphs 0005-0014].
With respect to claim 4, Choi et al. teach the method wherein the isolated cells are primary hepatocytes [see paragraphs 0005-0014; 0042-0043].
With respect to claim 5, Choi et al. teach the method wherein the compounds are HGF, A83-01 and CHIR99021 [see Abstract; paragraphs 0005-0014].
With respect to claim 6, Choi et al. teach the method wherein the chemically-derived progenitor cells are chemically derived hepatic progenitor cells [see paragraphs 0005-0014; 0042-0043].
However, Choi et al. does not teach the method of claim 1 of correcting a mutant gene of the chemically-derived progenitor cells ex vivo; the method of claim 2, wherein the correcting of a gene is to correct a gene by an adenine base editor or prime editing; and the method of claim 3, wherein the corrected gene is fumarylacetoacetate hydrolase (Fah).
Yu et al. teach that progenitor cells have great therapeutic potential because of heir ability to self-renew and differentiate, and targeted gene editing technologies using engineered nucleases such as zinc finger nucleases, TALENs, and CRISPR/Cas9 show great clinical promise allowing for the site-specific correction of diseases causing mutations [see Abstract; p. 732-734].
Musunuru et al. teach ex vivo methods of correcting mutant gene mutations in hepatic cells comprising a site specific mutation in fumarylacetoacetate hydrolase using adenosine deaminase base editors to treat the hereditary disorder tyrosinemia type I [see p. 20, bottom; p. 25; p. 29, bottom].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Choi et al., Yu et al., and Musunuru et al. to use the hepatic progenitor cells of Choi et al. to correct a mutant gene because Choi et al. teach methods for preparing chemically-derived hepatic progenitor cells from primary hepatocytes for treatment of various liver diseases. Yu et al. teach that progenitor cells hold clinical promise for site specific correction of mutations that cause diseases. Musunuru et al. teach that base editors can be designed to target mutant gene mutations in hepatic cells to treat hereditary disorder tyrosinemia type I. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability, and would have been motivated to combine the teachings of Choi et al., Yu et al., and Musunuru et al. because Yu et al. acknowledges that progenitor cells hold clinical promise for site specific correction of mutations that cause diseases, and Musunuru et al. acknowledges that base editors can be designed to target mutant gene mutations in hepatic cells to treat hereditary disorder tyrosinemia type I. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
16. Status of the claims:
Claims 1-12 are pending.
Claims 7-12 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 1-6 are rejected.
No claims are in condition for an allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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, Manjunath Rao can be reached at 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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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656