DETAILED ACTION
Notice of 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
Claims 1-9, 11-13 and 16-25 are pending and subject to examination on the merits.
Priority
The instant application is a 371 of PCT/EP2023/057313 filed 22 March 2023 which claims benefit of foreign priority document EP 22163850.5 filed 23 March 2022 is acknowledged. Said document has been received.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 18 August 2026 and 06 November 2025 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Drawings
The drawings of Figures 8-18 are objected to because pursuant to MPEP 2412.06 and 37 C.F.R. 1.83(a), sequences that are included in the sequence listing (XML) should not be duplicated in the drawings if they do not depict any special feature or characteristic. Here nothing has been done to the sequences (e.g. showing additional details, specifical features, alignments, etc.) and are a duplication of the sequences in the sequence listing represented by SEQ ID NOs: 1-11.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: in paragraph 0148, it is stated that N10T is expected to show similar phenotype to N10S due to the structural similarity of the amino acids Serine and Tyrosine. The single amino acid symbol of “T” represents Threonine, not Tyrosine (whose single amino acid symbol is Y). Threonine would be expected to have a similar structure to Serine whereas Tyrosine is an aromatic amino acid having little to no structural similarity to Serine.
Appropriate correction is required.
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.
Claim 24 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 24 is deemed indefinite because it depends upon canceled claim 10.
Claims 1-9, 11-13 and 16-25 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 the inventor or join inventor regards as the invention.
Claims 1, 11 and 20 a modified mammalian glutamine synthetase comprising a mutation at amino acid position 10 and/or 298 in a mammalian glutamine synthetase having an amino acid sequence of SEQ ID NO: 1, 2, 3 or 4 or an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 1, 2, 3 or 4, wherein the mutation is selected from the group consisting of R298K, N10S, N10T and N10Q. However, it not clear if the glutamine synthetase has 95% identity to SEQ ID NO: 1-4 before the recited mutations or if it has 95% identity (and higher) after/inclusive of the recited mutations are made in SEQ ID NO: 1-4.
For examination purposes, it will be construed that the glutamine synthetase has the 95% identity to SEQ ID NO: 1-4 prior to the mutations being introduced. However, clarification is requested.
It is unclear whether the breadth of the claims is intended to encompass the full length sequence or fragments of any size or length of an amino acid sequence of SEQ ID NO: 1, 2, 3 or 4. Accordingly, the metes and bounds of the phrase cannot be ascertained from the claims.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-9, 11-13 and 16-25 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
Claims 1, 11 and 20 are drawn to a modified mammalian glutamine synthetase comprising a mutation at amino acid position 10 and/or 298 in a mammalian glutamine synthetase having an amino acid sequence of SEQ ID NO: 1, 2, 3 or 4 or an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 1, 2, 3 or 4, wherein the mutation is selected from the group consisting of R298K, N10S, N10T and N10Q. However, it not clear if the glutamine synthetase has 95% identity to SEQ ID NO: 1-4 before the recited mutations or if it has 95% identity (and higher) after/inclusive of the recited mutations are made in SEQ ID NO: 1-4.
Thus the modified glutamine synthetase has at least two mutations introduced into any of SEQ ID NO: 1, 2, 3 or 4; or any sequence having at least 95% identity thereto. As such, one skilled in the art knows the starting sequence into which the mutations are made, however, given the claims recite that the mutations are comprising, this leaves the end glutamine synthetase sequences unknown and is open ended with the exception of requiring at least or of R298K, N10S, N10T and N10Q. Thus, the claims are drawn to an enormous genus of glutamine synthetases having an unlimited number of substitutions.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
Fransceus (J Ind Microbiol Biotechnol. 2017 - cited herein) reviews protein engineering techniques, such as random mutagenesis and recombination, directed evolution and iterative or combinatory saturation “hotspots”. Fransceus states that “a recurring problem, however, is choosing which amino acid positions should be targeted. Answering this question is not an easy feat and requires substantial insight in the relationship between an enzyme’s sequence or structure and its properties.” (See p. 687, 2nd col., 2nd paragraph). Sanavia et al. (Computational and Structural Biotechnology Journal, 2020 – cited herein) discloses challenges in the prediction of protein stability in the occurrence of multiple mutations. “Multiple-point mutations are common variations of the protein sequence that may be needed in protein engineering when a single-point mutation is not enough to yield the desired stability change. Dealing with multiple-site variations adds another level of complexity beyond the prediction of the effect of a single variant on protein stability, since it requires the learning of many types of combinatorial effects”. (See Section 3.2, p. 1974, 1st paragraph therein).
The specification is limited to specific variants of glutamine synthetase from SEQ ID NO:1 Cricetulus griseus, wherein the variants consist of single substitutions of R298K or N10S/Q/W/F/Y/G, and wherein only R298K showed increased significantly higher productivity whereas and N10S/Q showed increased phenotypic stability compared to SEQ ID NO:1. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the above example described above is not enough and does not constitute a representative number of species to describe the whole genus. Therefore, the specification fails to describe sufficient representative species of the claimed genus.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 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) 1-9, 11-13 and 16-25 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Shao et al. (US 2025/0101402 – cited herein, with an effectively filed date of 03 August 2021).
Shao et al. teach a modified mammalian (platypus/Ornithorhynchidae) glutamine synthetase (SEQ ID NO: 1) comprising a chimeric glutamine synthetase between platypus and rat, and comprises SEQ ID NO: 38 which has an N10S substitution and 95.4% sequence identity compared to instant SEQ ID NO: 1 (See Experimental Example 4). See also, Supplemental Content, 20260630_100830_us-18-848-533-1.rapbm2file, Result #42; alignment reproduced below.
Said SEQ ID NO: 38 with the N10S substitution also has 95.5% sequence identity to instant SEQ ID NO: 2 (See Supplemental Content, 20261014_121218_us-18-848-533-2.align150.rapbm, Result # 51).
Said SEQ ID NO: 38 with the N10S substitution also has 95.7% sequence identity to instant SEQ ID NO: 3 (See Supplemental Content, 20260630_100830_us-18-848-533-3.rapbm file, Result #43).
Said SEQ ID NO: 38 with the N10S substitution also has 96.6% sequence identity to instant SEQ ID NO: 4 (See Supplemental Content, 20260630_100830_us-18-848-533-4.rapbm, Result #29).
In addition, additional modified glutamine synthetase from Cricetulus griseus (SEQ ID NO: 4), which is the same species as instant SEQ ID NO: 1, is taught specifically with an N10S substitution in paragraphs 0120-0121; Claims 26-27, 43.
Nucleic acids encoding the same and vectors comprising the nucleic acids are also taught (See Section 5.2); host cells comprising the same (See Section 5.3); methods of making/expressing using the modified mammalian glutamine synthetase to make a protein of interest by culturing host cells in a culture medium having no glutamine and expressing said protein of interest and isolating said protein of interest are also taught (See Sections 5.4 and 5.5; Sections 5.6 and subsections thereof; and Example 4; claims 54-141, especially claims 54-57, 85-88, 121-122, 134).
RESULT 42
US-18-294-528-38
Sequence 38, US/18294528
Publication No. US20250101402A1
GENERAL INFORMATION
APPLICANT: Shanghai ZhenGe Biotechnology Co., Ltd. (en)
TITLE OF INVENTION: SELECTABLE MARKERS FOR EUKARYOTIC EXPRESSION SYSTEM (en)
FILE REFERENCE: 817A001WO02
CURRENT APPLICATION NUMBER: US/18/294,528
CURRENT FILING DATE: 2024-02-01
NUMBER OF SEQ ID NOS: 85
SEQ ID NO 38
LENGTH: 373
TYPE: PRT
FEATURE:
NAME/KEY: source
LOCATION: 1..373
QUALIFIERS: mol_type = protein
organism = synthetic construct
Query Match 95.4%; Score 1968; Length 373;
Best Local Similarity 94.6%;
Matches 353; Conservative 12; Mismatches 8; Indels 0; Gaps 0;
Qy 1 MATSASSHLNKNIKQMYLCLPQGEKVQAMYIWVDGTGEGLRCKTRTLDCEPKCVEELPEW 60
| |||||||:|||||||: |||||||||||||:||||||||||||||| ||| :||||||
Db 1 MTTSASSHLSKNIKQMYMDLPQGEKVQAMYIWIDGTGEGLRCKTRTLDSEPKSIEELPEW 60
Qy 61 NFDGSSTFQSEGSNSDMYLSPVAMFRDPFRRDPNKLVFCEVFKYNRKPAETNLRHSCKRI 120
||||||||||||||||||| | ||||||||:|||||:|||||||||||||||||||||||
Db 61 NFDGSSTFQSEGSNSDMYLVPAAMFRDPFRKDPNKLIFCEVFKYNRKPAETNLRHSCKRI 120
Qy 121 MDMVSNQHPWFGMEQEYTLMGTDGHPFGWPSNGFPGPQGPYYCGVGADKAYGRDIVEAHY 180
|||||:||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 MDMVSSQHPWFGMEQEYTLMGTDGHPFGWPSNGFPGPQGPYYCGVGADKAYGRDIVEAHY 180
Qy 181 RACLYAGVKITGTNAEVMPAQWEFQIGPCEGIRMGDHLWVARFILHRVCEDFGVIATFDP 240
|||||||:||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RACLYAGIKITGTNAEVMPAQWEFQIGPCEGIRMGDHLWVARFILHRVCEDFGVIATFDP 240
Qy 241 KPIPGNWNGAGCHTNFSTKAMREENGLKHIEEAIEKLSKRHRYHIRAYDPKGGLDNARRL 300
|||||||||||||||||||||||||||: |||||:||||||:||||||||||||||||||
Db 241 KPIPGNWNGAGCHTNFSTKAMREENGLRCIEEAIDKLSKRHQYHIRAYDPKGGLDNARRL 300
Qy 301 TGFHETSNINDFSAGVANRSASIRIPRTVGQEKKGYFEDRRPSANCDPFAVTEAIVRTCL 360
||||||||||||||||||||||||||| ||||||||||||||||||||:|||||||||||
Db 301 TGFHETSNINDFSAGVANRSASIRIPRIVGQEKKGYFEDRRPSANCDPYAVTEAIVRTCL 360
Qy 361 LNETGDEPFQYKN 373
|||||||||||||
Db 361 LNETGDEPFQYKN 373
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUZANNE M NOAKES whose telephone number is (571)272-2924. The examiner can normally be reached M-F (7-4).
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.
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.
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 14 October 2026
