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. Applicants’ amendment to the claims filed on 12/23/2025 in response to the Restriction Requirement mailed on 10/24/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 34-35 and 37-54 are pending.
Election/Restrictions
4. Applicant’s election of Group II, claims 34-35 and 37-54 in the reply filed on 12/23/2025 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)).
5. Claims 1-2, 5, 11, 14, 18, 22, and 24 have been cancelled by amendment to the claims filed on 12/23/2025.
Claims 34-35 and 37-54 are pending and examined on the merits.
Priority
6. Acknowledgement is made of applicants’ claimed domestic priority to U.S. Provisional Application No. 63/013665, filed on 04/22/2020.
Information Disclosure Statement
7. The IDSs filed on 03/03/2025 and 08/19/2025 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
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 patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), 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 the USPTO patent electronic filing system 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 the USPTO patent electronic filing system 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 – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. See Figure 9.
Required response – Applicant must provide:
Replacement and annotated 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 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
8. 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.
9. Claims 34-35 and 37-54 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.
The term "substantially maintained" is a relative term which renders the claim indefinite. The term "substantially maintained" is a term of degree and the examiner has reviewed the specification and while it is acknowledged that paragraph 00123 of the specification discloses “[i]n some embodiments, ‘substantially maintained’ comprises +1%, +2%, +4%, +5%, +7%, +8%, +10%, +12%,…”, such disclosure is exemplary and non-limiting. Moreover, there is nothing in the prior art of record to indicate that one of ordinary skill in the art could have ascertain the scope of the recited degree. It is suggested that applicant clarify the meaning of the claims. See Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. §112 and for Treatment of Related Issues in Patent Applications, 76 FR 7162 (Feb. 9, 2011), page 7165.
Further regarding claim 43, the term “reduced” is a relative term which renders the claim indefinite. The term "reduced" is a term of degree and the examiner has reviewed the specification and the examiner has reviewed the specification and found no disclosure to ascertain the scope of the recited degree. It is suggested that applicant clarify the meaning of the claims. See Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. §112 and for Treatment of Related Issues in Patent Applications, 76 FR 7162 (Feb. 9, 2011), page 7165.
Claim Rejections - 35 USC § 112(a)
10. 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
11. Claims 34-35 and 37-54 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 34 and 38-54 are drawn in relevant part to a method for genetically optimizing the expression of a polypeptide of interest such that it is substantially maintained in least 10% of a plurality of transgenic cells after a period of at least 80 generations of said cell comprising generating a coding sequence encoding a chimeric polypeptide comprising the polypeptide of interest and an essential gene of a target cell optimized thereto for the generation of a chimeric polypeptide in the target cell, wherein said optimized comprises: a modified GC content, at least one less mutation hotspot, a modified codon usage for optimized expression of said coding sequence in said target cell, at least on less epigenetic hotspot, or any combination thereof, comparted to a wildtype nucleic acid sequence encoding any one of: said polypeptide of interest, said essential gene of said target cell, and both; and wherein said chimeric polypeptide retains an essential function of said essential gene in said target cell.
Claims 35-36 are drawn in relevant part to the method wherein a selected linker provides optimal folding of both the polypeptide of interest and essential gene of said target cell.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of “chimeric polypeptides comprising the polypeptide of interest and an essential gene of a target cell” wherein when expressed in a transgenic cell substantially maintains expression in at least 10% of transgenic cells as encompassed by the claims (i.e. a Saccharomyces cerevisiae expressing a coding sequence having the host essential genes Fol3, Nus1, Dfr1, Sec2, Ram2, Tsc13, Ceg1, Sqt1, Kap95 and Cdc9). The specification discloses an actual reduction to practice of the following representative species of the genus of “linkers that provide optimal folding of both the polypeptide of interest and essential gene of said target cell as encompassed by the claims (i.e. a 2A linker). Other than the above disclosed species there is no other drawings or structural formulas disclosed of the infinite number of transgenic cells and optimized essential genes that expressed in a transgenic cell substantially maintains expression of a polypeptide of interest in at least 10% of transgenic cells after a period of 90 generations. There is no other drawings or structural formulas of the infinite number of linkers that provide optimal folding of both the polypeptide of interest and essential gene.
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 of any essential gene of any target cell that can be optimized by GC content, one less mutation hotspot or modified codon usage that results in a transgenic cell that expresses a polypeptide of interest in at least 10% of said cells after at least 80 generations. Accordingly, one of skill in the art would not accept the disclosure of a Saccharomyces cerevisiae expressing a coding sequence having the host essential genes Fol3, Nus1, Dfr1, Sec2, Ram2, Tsc13, Ceg1, Sqt1, Kap95 and Cdc9 as being representative of all methods of genetically optimizing the expression of a polypeptide 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
12. Claims 34-35 and 37-54 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 a method for genetically optimizing the expression of a polypeptide in a Saccharomyces cerevisiae expressing a coding sequence having the host essential genes Fol3, Nus1, Dfr1, Sec2, Ram2, Tsc13, Ceg1, Sqt1, Kap95 and Cdc9 and a 2A linker, does not reasonably provide enablement for all methods of optimizing expression of a polypeptide of interest in any transgenic cell 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 34 and 38-54 are drawn in relevant part to a method for genetically optimizing the expression of a polypeptide of interest such that it is substantially maintained in least 10% of a plurality of transgenic cells after a period of at least 80 generations of said cell comprising generating a coding sequence encoding a chimeric polypeptide comprising the polypeptide of interest and an essential gene of a target cell optimized thereto for the generation of a chimeric polypeptide in the target cell, wherein said optimized comprises: a modified GC content, at least one less mutation hotspot, a modified codon usage for optimized expression of said coding sequence in said target cell, at least on less epigenetic hotspot, or any combination thereof, comparted to a wildtype nucleic acid sequence encoding any one of: said polypeptide of interest, said essential gene of said target cell, and both; and wherein said chimeric polypeptide retains an essential function of said essential gene in said target cell.
Claims 35-36 are drawn in relevant part to the method wherein a selected linker provides optimal folding of both the polypeptide of interest and essential gene of said target cell.
(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 for genetically optimizing the expression of a polypeptide of interest such that it is substantially maintained in at least 10% of a plurality of transgenic cells after a period of at least 80 generations is unlimited. The scope of the linkers that provide optimal folding of both the polypeptide of interest and essential gene of the target cell is unlimited.
Methods for stabilizing genetically engineered functions in E. coli by overlapping a sequence with an essential gene was known in the art as taught by Blazejewski et al. (Science, 2019; examiner cited).
Rogozin et al. (Mutation Research, 2003; examiner cited) teach analysis of the nucleotide sequence context of hotspots can provide information on the molecular mechanisms of mutagenesis. However, the determinants of mutation frequency and specificity are complex [see Abstract].
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of chimeric polypeptides comprising the polypeptide of interest and an essential gene of a target cell wherein when expressed in a transgenic cell substantially maintains expression in at least 10% of transgenic cells, i.e. a Saccharomyces cerevisiae expressing a coding sequence having the host essential genes Fol3, Nus1, Dfr1, Sec2, Ram2, Tsc13, Ceg1, Sqt1, Kap95 and Cdc9. The specification disclose the following working examples of linkers that provide optimal folding of both the polypeptide of interest and essential gene of said target cell, i.e. a 2A linker. Other than these working examples, the specification fails to disclose any other working examples of transgenic cells, essential genes, and linkers.
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).
Conclusion
13. Status of the claims:
Claims 34-35 and 37-54 are pending.
Claims 34-35 and 37-54 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