DETAILED ACTION
Status of Application
Claims 1-8 are pending
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of Group 1, claim 1, drawn to a modified protein glutaminase, as submitted in communication filed on 06/04/2026 is acknowledged.
Upon further consideration, the previous restriction requirement between Groups I and IV is hereby withdrawn. Claim 6 will be rejoined for examination on the merits. Claims 2-5, 7-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 06/04/2026.
Species Election was made without traverse of Polypeptide (I) with residue substitution (A) in the reply filed on 06/04/2026.
Claims 1 and 6 are at issue and will be examined to the extent it encompasses the elected invention.
Priority
Acknowledgment is made of a claim for foreign priority under 35 U.S.C. 119(a)-(d) to JAPAN 2022-036683 filed on 03/09/2022. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
This is the US national application which entered the national stage from
Application No. PCT/JP2023/ 009183 filed on 03/09/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/06/2024 and 04/23/2026 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings submitted on 09/06/2024 have been reviewed and are accepted by
the examiner for examination purposes.
Claim Objections
Claim 1 is objected to due to the recitation of “A modified protein glutaminase comprising…”. It should be amended to recite “A modified glutaminase protein comprising…”. Appropriate correction is required.
Claim 6 is objected to due to the recitation of “the modified protein glutaminase…”. It should be amended to recite “the modified glutaminase protein…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
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.
Claims 1 and 6 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.
Claim 1 (claim 6 dependent thereon) is indefinite in the recitation of “a polypeptide consisting of an amino acid sequence obtained by introducing at least one of (A) a substitution of the amino acid residue at position 38…”, for the following reason: The term “position 38” is unclear in the absence of the reference glutaminase amino acid sequence identifier associated with position 38. For examination purposes, the polypeptide will be interpreted as a polypeptide that comprises a substitution at a position corresponding to position 38 of the polypeptide of SEQ ID NO: 1. Correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claims encompass a naturally occurring polypeptide/product as evidenced by Mah et al. (Uniprot ID: A0A1N7P918_9FLAO 03/15/2017; hereby Mah), which teaches a naturally occurring protein produced by C. gambrini that meets the recited structural and functional features. See sequence alignment below. The intracellular content of C. gambrini is a naturally occurring composition that comprises the glutaminase. This judicial exception is not integrated into a practical application because the claims encompass a naturally occurring polypeptide and do not apply or use the product in a manner that pose a meaningful limit on the judicial exception. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not recite additional elements that provide an inventive concept sufficient enough to make the polypeptide patent-eligible.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
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.
Claims 1 and 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow.
Claims 1 and 6 are directed in part to a genus of proteins having any structure, where the only structural limitation is the presence of one of the amino acid residues of part I (A) at the position corresponding to position 38 of the polypeptide of SEQ ID NO: 1. See claim rejections under 35 usc 112(b) for claim interpretation.
While the specification in the instant application discloses glutaminase polypeptides with various substitutions, it provides no clue as to the structural elements required in any SEQ ID: 1 polypeptide variant having substitutions at position 38 with any structure that can have glutaminase activity. Please note that the claimed protein encompasses a genus of proteins having any structure where the only structural limitation is the presence of one of the amino acid residues of part I (A) at the position corresponding to position 38 of the polypeptide of SEQ ID NO: 1. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which amino acid residues of part I (A) at the position corresponding to position 38 of the polypeptide of SEQ ID NO: 1 would provide a polypeptide structure that has glutaminase activity.
A sufficient written description of a genus of proteins may be achieved by a recitation of a representative number of proteins a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is no recited structural feature which is representative of all the members of the genus of proteins recited in the claims, and there is no information as to which are the structural elements of the proteins that are essential for the recited glutaminase activity, or a correlation between structure and function which would provide those unknown structural features. Furthermore, while one could argue that the species disclosed is representative of the structure of all the members of the genus of proteins required, it is noted that the art teaches examples of how even highly structurally homologous polypeptides can have different enzymatic activities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999) teach that one conservative amino acid substitution transforms a β-ketoacyl synthase into a malonyl decarboxylase and completely eliminates β-ketoacyl synthase activity. Tang et al. (Phil Trans R Soc B 368:20120318, 1-10, 2013) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrate (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001) teach that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the species disclosed is representative of the structure of all the glutaminase polypeptides required by the claims.
Due to the fact that the specification only discloses a limited amount of amino acid sequences of glutaminase and amino acid substitutions required by the claimed composition, and the lack of description of any additional relevant structural elements, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 1 and 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 glutaminase proteins having the polypeptide sequence of SEQ ID NO: 1, does not reasonably provide enablement for a genus of proteins having any structure where the only structural limitation is the presence of one of the amino acid residues of part I (A) at the position corresponding to position 38 of the polypeptide of SEQ ID NO: 1. 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.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 1 and 6 broadly encompass a genus of proteins having any structure where the only structural limitation is the presence of one of the amino acid residues of part (A) at the position corresponding to position 38 of the polypeptide of SEQ ID NO: 1. The enablement provided is not commensurate in scope with the claims due to the lack of knowledge regarding the structure required for any glutaminase with the recited substitutions In the instant case, the specification enables for having glutaminase proteins having the polypeptide sequence of SEQ ID NO: 1.
The amount of direction or guidance presented and the existence of working examples. The specification fails to provide any clue as to the structural elements required in proteins having any structure where the only structural limitation is the presence of one of the amino acid residues of part I (A) at the position corresponding to position 38 of the polypeptide of SEQ ID NO: 1. No correlation between structure and function has been presented.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a polypeptide determines its structural and functional properties. While the art discloses a limited number of glutaminase polypeptides, neither the specification nor the art provides a correlation between structure and function such that one of skill in the art can envision the structure of any glutaminase polypeptide that can be used in the claimed product. In addition, the art does not provide any teaching or guidance as to which changes can be made to the glutaminase polypeptide such that the resulting variant would display the desired functional characteristics, or the general tolerance of glutaminase polypeptides to structural modifications and the extent of such tolerance. The art clearly teaches that (a) determining function based solely on structural homology, and (b) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved are highly unpredictable. For example, Singh et al. (Current Protein and Peptide Science 19(1):5-15, 2018) disclose different protein engineering approaches and state that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility and conformational changes (page 11, left column, last paragraph). Sadowski et al. (Current Opinion in Structural Biology 19:357-362, 2009) teach that much of the problem in assigning function from structure comes from functional convergence, where although a stable structure is required to perform many functions it is not always necessary to adopt a particular structure to carry out a particular function (page 357, right column, first full paragraph). Sadowski et al. further explain that the unexpected and significant difficulties of predicting function from structure show that the potential of structural models for providing novel functional annotations has not yet fully realized. Sadowski et al. also states that while a few successes have been achieved which required manual intervention, the ability to vary the requirements for specificity in prediction means that it is difficult to determine how useful the end result may be for the user (page 361, left column, first full paragraph). The teachings of Singh et al. and Sadowski et al. are further supported by the teachings of Witkowski et al., Tang et al. and Seffernick et al. already discussed above, where it is shown that even small amino acid changes result in enzymatic activity changes.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a polypeptide and enzymatic assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins having SEQ ID NO: 1 with the recited substitutions and any structure to find a polypeptide that has glutaminase activity. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, and/or (ii) a correlation between structure and glutaminase activity, one of skill in the art would have to test an essentially infinite number of proteins having SEQ ID NO: 1 with the recited substitutions and any structure to determine which ones have the desired functional characteristics.
Therefore, taking into consideration the extremely broad scope of the claims, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Claim Rejections - 35 USC § 102 (AIA )
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.
Claims 1 and 6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mah et al. (Uniprot ID: A0A1N7P918_9FLAO 03/15/2017; hereinafter “Mah”)
Claims 1 and 6 as interpreted are directed in part to a glutaminase protein comprising a substitution at the position corresponding to position 38 of the polypeptide of SEQ ID NO:1 with an alanine residue, a phenylalanine residue, an isoleucine residue, a leucine residue, a methionine residue, an arginine residue, a valine residue, a tyrosine residue, a cysteine residue, a lysine residue, a serine residue, or a threonine residue, and a composition comprising said glutaminase protein.
Mah teaches a glutaminase domain-containing protein comprising a substitution at the position corresponding to position 38 of the polypeptide of SEQ ID NO:1 with an alanine residue. See alignment below. Mah teaches that this protein is endogenously produced by C. gambrini. Since the intracellular content of C. gambrini would comprise the glutaminase protein, Mah teaches a composition (intracellular content) that comprises the glutaminase protein. Therefore, the teachings of Mah anticipate the instant claims as written/interpreted.
RESULT 24
A0A1N7P918_9FLAO
ID A0A1N7P918_9FLAO Unreviewed; 319 AA.
AC A0A1N7P918;
DT 15-MAR-2017, integrated into UniProtKB/TrEMBL.
DT 15-MAR-2017, sequence version 1.
DT 02-APR-2025, entry version 20.
DE RecName: Full=Protein glutaminase domain-containing protein {ECO:0000259|Pfam:PF18626};
GN ORFNames=SAMN05421785_10661 {ECO:0000313|EMBL:SIT06949.1};
OS Chryseobacterium gambrini.
OC Bacteria; Pseudomonadati; Bacteroidota; Flavobacteriia; Flavobacteriales;
OC Weeksellaceae; Chryseobacterium group; Chryseobacterium.
OX NCBI_TaxID=373672 {ECO:0000313|EMBL:SIT06949.1, ECO:0000313|Proteomes:UP000185781};
RN [1] {ECO:0000313|EMBL:SIT06949.1, ECO:0000313|Proteomes:UP000185781}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=DSM 18014 {ECO:0000313|EMBL:SIT06949.1,
RC ECO:0000313|Proteomes:UP000185781};
RA Mah S.A., Swanson W.J., Moy G.W., Vacquier V.D.;
RL Submitted (JAN-2017) to the EMBL/GenBank/DDBJ databases.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; FTOV01000006; SIT06949.1; -; Genomic_DNA.
DR RefSeq; WP_076393259.1; NZ_FTOV01000006.1.
DR AlphaFoldDB; A0A1N7P918; -.
DR OrthoDB; 8417456at2; -.
DR Proteomes; UP000185781; Unassembled WGS sequence.
DR Gene3D; 2.40.50.340; -; 1.
DR Gene3D; 3.10.620.30; -; 1.
DR InterPro; IPR041325; Gln_deamidase_2.
DR NCBIfam; NF040782; PG_glutam_Chrys; 1.
DR Pfam; PF18626; Gln_deamidase_2; 1.
PE 4: Predicted;
KW Signal {ECO:0000256|SAM:SignalP}.
FT SIGNAL 1..21
FT /evidence="ECO:0000256|SAM:SignalP"
FT CHAIN 22..319
FT /note="Protein glutaminase domain-containing protein"
FT /evidence="ECO:0000256|SAM:SignalP"
FT /id="PRO_5012862626"
FT DOMAIN 145..254
FT /note="Protein glutaminase"
FT /evidence="ECO:0000259|Pfam:PF18626"
SQ SEQUENCE 319 AA; 34562 MW; F0F035866C25ADA4 CRC64;
Query Match 88.4%; Score 876; Length 319;
Best Local Similarity 88.5%;
Matches 162; Conservative 8; Mismatches 13; Indels 0; Gaps 0;
Qy 3 SVIPDVATLNSLFNQIKNQSCGTSTASSPCITFRYPVDGCYARAHKMRQILMNNGYDCEK 62
||||::||||:|| ||||||||||||||||||||| |||||||||||||||:| ||||||
Db 137 SVIPNLATLNNLFIQIKNQSCGTSTASSPCITFRYAVDGCYARAHKMRQILLNAGYDCEK 196
Qy 63 QFVYGNLKASTGTCCVAWSYHVAILVSYKNASGVTEKRIIDPSLFSSGPVTDTAWRNACV 122
||||||||||||||||:| ||||||||:|||||| ||||||||||:||||||||||||||
Db 197 QFVYGNLKASTGTCCVSWGYHVAILVSFKNASGVVEKRIIDPSLFTSGPVTDTAWRNACV 256
Qy 123 NTSCGSASVSSYANTAGNVYYRSPSNSYLYDNNLINTNCVLTKFSLLSGCSPSPAPDVSS 182
|||||||| |||||||||||||||| | ||||| |||||||| || |||||| ||| |:|
Db 257 NTSCGSASASSYANTAGNVYYRSPSGSLLYDNNYINTNCVLTTFSTLSGCSPVPAPSVAS 316
Qy 183 CGF 185
|||
Db 317 CGF 319
Conclusion
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SYNPHANE SHELTON whose telephone number is (571)272-6318. The examiner can normally be reached 9:00am-7pm.
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, Robert Mondesi can be reached at (408) 918-7584. 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.
/S.L.S./Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
Prosecution Insights