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 .
Election/Restrictions
Applicant's election without traverse of invention Group I, claims 1-3, and of the elected species ‘linker separating the polypeptide and the nucleic acid binding domain’ as additional sequence comprised by a fusion protein, in the reply filed on 11/11/2025, is acknowledged. Claims 4-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Claim Status
The amendment of 11/11/2025 has been entered. Claims 1-20 are pending (claim set as filed on 11/11/2025). Claims 4-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-3 are currently under examination and were examined on their merits.
Priority
This application filed on 06/30/2025 claims priority to PCT application PCT/US2024/056236, filed on 11/15/2024, and claims priority to provisional application no. PRO 63/599,141, filed on 11/15/2023. PRO 63/599,141 cites the sequence of instant SEQ ID NO: 2 (specification of provisional application; see first row in table on page 38), however, it is noted that PRO 63/599,141 is not accompanied by a ‘Sequence Listing XML’ as required under 37 CFR 1.53 (see MPEP 2415.02).
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 11/11/2025 has been received and considered.
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 1-3 are rejected under 35 U.S.C. 101 because the claimed
invention is directed to a combination of judicial exceptions without significantly more. The statutory categories of invention under 35 U.S.C. 101 are processes, machines, manufactures, and compositions of matter. However, certain members of these categories constitute judicial exceptions, i.e., the courts have determined that these entities are not patentable subject matter. These judicial exceptions include abstract ideas, laws of nature, and natural phenomena. The Office released guidance on January 7, 2019 for the examination of claims reciting natural products under 35 U.S.C. 101 in light of the recent Supreme Court decisions in Association for Molecular
Pathology v. Myriad Genetics, Inc. (569 U.S., 133 S. Ct. 2107, 2116, 106 USPQ2d 1972
(2013)) and Mayo Collaborative Services v. Prometheus Laboratories (566 U.S.,132 S.
Ct. 1289, 101 USPQ2d 1961 (2012)). This guidance indicates that claims must pass an
eligibility test to avoid rejection under 35 U.S.C. 101. Under this test, the product must
(a) not be directed to a judicial exception or must (b) contain additional elements that
amount to significantly more than the judicial exception itself.
'Directed to a judicial exception' analysis:
Prong One: Does the claim recite an abstract idea, law of nature, or natural
phenomenon?
Claims 1 recites “a polypeptide comprising an adenosine deaminase” which is considered a natural phenomenon. Adenosine deaminase exists in nature, and it is further noted that the instant specification states that “[t]he polypeptide can be natural, synthetic, or a modification or combination of natural and synthetic” (paragraph [37]). As such, ‘polypeptide comprising an adenosine deaminase’ reads on natural adenosine deaminase.
Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No additional elements are cited that would integrate the judicial exception into a practical application.
'Significantly more' analysis:
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions because the claims do not include any additional elements other than the judicial exceptions.
Therefore, claims 1-3 are directed to subject matter that is not patent-eligible and are rejected under 35 U.S.C. 101.
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.
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 1-3 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 1-2 are directed to a genus of adenosine deaminase variants of the polypeptides of SEQ ID NO: 2 that have at least 75% identity or 90% identity to the polypeptide of SEQ ID NO: 2.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is either (a) no structural limitation, or (b) a significant amount of structural variability with respect to the members of the genus of adenosine deaminase proteins required by the claims. While the specification in the instant application discloses the structure of the adenosine deaminase of SEQ ID NO: 2, it provides no clue as to the structural elements required in any adenosine deaminase protein, nor does it teach which structural elements within SEQ ID NO: 2 are required in any adenosine deaminase protein. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of the polypeptide of SEQ ID NO: 2 have the recited % sequence identity and have adenosine deaminase activity.
The claims encompass a large genus of proteins which are structurally unrelated or substantially unrelated in structure. A polypeptide having 75% sequence identity with the polypeptide of SEQ ID NO: 2 allows for any combination of 37.25 amino acid modifications within SEQ ID NO: 2 (37.25 = 0.25x149; SEQ ID NO: 2 has 149 amino acids). The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula N!x19A/(N-A)!/A!, where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. Thus, the total number of variants of the polypeptide of SEQ ID NO: 2 having 75% sequence identity to the polypeptide of SEQ ID NO: 2 that result from amino acid substitutions is 149!x1937.25/(149-37.25)!/37.25! (SEQ ID NO: 2 has 149 amino acids) or 7.92x1082 variants. A similar calculation for variants of the polypeptide of SEQ ID NO: 2 having 90% sequence identity to the polypeptide of SEQ ID NO: 2 yields 1.33x1039 variants. A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or 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 either no recited structural feature which is representative of all the members of the genus of proteins recited, or the recited structural feature, i.e., 75% sequence identity to SEQ ID NO: 2, is not representative of all the members of the genus of adenosine deaminases recited since there is no information as to which are the structural elements within the polypeptide of SEQ ID NO: 2 that are essential for the recited activity, which are the remaining structural elements required in the recited polypeptides in addition to those recited in the claims such that the desired adenosine deaminase activity is displayed, or a correlation between structure and function which would provide those unknown structural features. Furthermore, while one could argue that the species disclosed are representative of the structure of all the members of the genus, it is noted that the art teaches how even highly structurally homologous polypeptides can have different enzymatic activities. For example, Valerio et al. (“One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity”, published in 1986, The EMBO Journal , Vol. 5, No. 1, pages 113-119) teaches that one amino acid substitution renders the human adenosine deaminase ADA inactive (see entire document, including abstract). Wolf et al. (“tadA, an essential tRNA-specific adenosine deaminase from Escherichia coli”, published in 2002, The Embo Journal, Vol. 21, No. 14, pages 3841-3851) discloses wherein a single amino acid substitution in the adenosine deaminase tadA from E. coli results in inactivation of the adenosine deaminase in vitro (see entire document, including page 3848, right column, paragraph 4 -page 3849, left column, paragraph 1; see Fig. 1). 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 are representative of the structure of all the adenosine deaminase proteins required by the claims.
Due to the lack of description of any species by any relevant, identifying characteristics or properties that indicate a structure function relationship, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Closest prior art
Regarding claims 1-3, the closest prior art to the claimed invention is provided by the teachings of Lin et al. (US 2022/0364067 A1, published on 11/17/2022), hereinafter ‘Lin’, and by the teachings of Uniprot (“A0A931VZP0_UNCAI”, published on 02/22/2023, downloaded from https://www.uniprot.org/uniparc/UPI001DA0F361/entry/A0A931VZP0#sequence, 4 pages), hereinafter ‘Uniprot’.
Lin teaches a polypeptide comprising an adenosine deaminase (SEQ ID NO: 392; 143 amino acids; paragraph [0004] on page 2, left column, lines 12-15), wherein the polypeptide has 66.6 % sequence identity with instant SEQ ID NO: 2.
GenCore version 6.5.2
Copyright (c) 1993 - 2025 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: August 11, 2025, 14:03:58 ; Search time 29 Seconds
(without alignments)
9305.568 Million cell updates/sec
Title: US-19-255-359-2
Perfect score: 763
Sequence: 1 MDPEDVAFMRKALDEARKAR..........TGGVLAEECGALLRGFFRAR 149
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 15708631 unique seqs, 1811150770 residues
Total number of hits satisfying chosen parameters: 15708631
Minimum DB seq length: 0
Maximum DB seq length: 2000000000
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 150 summaries
Database : Published_Applications_AA_Main:*
ALIGNMENTS
RESULT 1
US-17-841-082-392
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
Sequence 392, US/17841082
Publication No. US20220364067A1
GENERAL INFORMATION
APPLICANT: METAGENOMI IP TECHNOLOGIES, LLC
TITLE OF INVENTION: BASE EDITING ENZYMES
FILE REFERENCE: 55921-715.301
CURRENT APPLICATION NUMBER: US/17/841,082
CURRENT FILING DATE: 2022-06-15
PRIOR APPLICATION NUMBER: PCT/US2021/049962
PRIOR FILING DATE: 2021-09-10
PRIOR APPLICATION NUMBER: 63/222,351
PRIOR FILING DATE: 2021-07-15
PRIOR APPLICATION NUMBER: 63/077,057
PRIOR FILING DATE: 2020-09-11
NUMBER OF SEQ ID NOS: 593
SEQ ID NO 392
LENGTH: 143
TYPE: PRT
ORGANISM: Unknown
FEATURE:
OTHER INFORMATION: Description of Unknown:
uncultivated organism
FEATURE:
OTHER INFORMATION: Category: MG68 putative adenosine deaminase (TadA-like)
FEATURE:
OTHER INFORMATION: Description: MG68-10 deaminase
Query Match 66.6%; Score 508.5; Length 143;
Best Local Similarity 67.6%;
Matches 96; Conservative 21; Mismatches 24; Indels 1; Gaps 1;
Qy 9 MRKALDEARKAREAGEVPVGAVVVK-DGEIVARAHNRTIQKSDPTAHAEILALRKAARAL 67
| |:::|| | ||||||||||:: :||:||| || :: ||||||||::||| | | |
Db 1 MLLAMEQARAAEEAGEVPVGAVILSPEGEVVARGENRVLRDSDPTAHAEMVALRAAGRVL 60
Qy 68 GNYRLTGCTLYATLEPCAMCAGAILHARIERLVYGVPNPKAGATGSVLNVLNHPRLNHRV 127
||||| |||||:|||||:||:|||||||: |||: :||||| |||| |:|||||||:|
Db 61 GNYRLPGCTLYSTLEPCSMCSGAILHARVARLVFAASDPKAGACGSVLEVMNHPRLNHQV 120
Qy 128 EVTGGVLAEECGALLRGFFRAR 149
|: ||||| ||| :| |||||
Db 121 ELVGGVLALECGQMLTEFFRAR 142
Uniprot teaches the putative tRNA-specific adenosine deaminase with the accession number A0A931VZP0_UNCAI (174 amino acids) which has 72.1% identity with instant SEQ ID NO: 2.
GenCore version 6.5.2
Copyright (c) 1993 - 2025 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: August 11, 2025, 14:00:46 ; Search time 211 Seconds
(without alignments)
59310.173 Million cell updates/sec
Title: US-19-255-359-2
Perfect score: 763
Sequence: 1 MDPEDVAFMRKALDEARKAR..........TGGVLAEECGALLRGFFRAR 149
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 230465795 unique seqs, 83989573198 residues
Total number of hits satisfying chosen parameters: 230465795
Minimum DB seq length: 0
Maximum DB seq length: 2000000000
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 150 summaries
Database : UniProt_202503:*
ALIGNMENTS
RESULT 1
A0A931VZP0_UNCAI
ID A0A931VZP0_UNCAI Unreviewed; 174 AA.
AC A0A931VZP0;
DT 22-FEB-2023, integrated into UniProtKB/TrEMBL.
DT 22-FEB-2023, sequence version 1.
DT 18-JUN-2025, entry version 13.
DE RecName: Full=tRNA-specific adenosine deaminase {ECO:0000256|HAMAP-Rule:MF_00972};
DE EC=3.5.4.33 {ECO:0000256|HAMAP-Rule:MF_00972};
GN Name=tadA {ECO:0000256|HAMAP-Rule:MF_00972,
GN ECO:0000313|EMBL:MBI1983126.1};
GN ORFNames=HYS61_02895 {ECO:0000313|EMBL:MBI1983126.1};
OS Acidobacteriota bacterium.
OC Bacteria; Pseudomonadati; Acidobacteriota.
OX NCBI_TaxID=1978231 {ECO:0000313|EMBL:MBI1983126.1, ECO:0000313|Proteomes:UP000752455};
RN [1] {ECO:0000313|EMBL:MBI1983126.1}
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=NC_groundwater_114_Ag_S-0.65um_61_48
RC {ECO:0000313|EMBL:MBI1983126.1};
RA He C.Y., Keren R., Whittaker M., Farag I.F., Doudna J., Cate J.H.D.,
RA Banfield J.F.;
RT "Huge and variable diversity of episymbiotic CPR bacteria and DPANN archaea
RT in groundwater ecosystems.";
RL Submitted (JUL-2020) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Catalyzes the deamination of adenosine to inosine at the
CC wobble position 34 of tRNA(Arg2). {ECO:0000256|HAMAP-Rule:MF_00972}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine(34) in tRNA + H2O + H(+) = inosine(34) in tRNA +
CC NH4(+); Xref=Rhea:RHEA:43168, Rhea:RHEA-COMP:10373, Rhea:RHEA-
CC COMP:10374, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:74411, ChEBI:CHEBI:82852; EC=3.5.4.33;
CC Evidence={ECO:0000256|ARBA:ARBA00048045, ECO:0000256|HAMAP-
CC Rule:MF_00972};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000256|HAMAP-Rule:MF_00972};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000256|HAMAP-Rule:MF_00972};
CC -!- SUBUNIT: Homodimer. {ECO:0000256|ARBA:ARBA00011738, ECO:0000256|HAMAP-
CC Rule:MF_00972}.
CC -!- SIMILARITY: Belongs to the cytidine and deoxycytidylate deaminase
CC family. ADAT2 subfamily. {ECO:0000256|ARBA:ARBA00010669}.
CC -!- CAUTION: The sequence shown here is derived from an EMBL/GenBank/DDBJ
CC whole genome shotgun (WGS) entry which is preliminary data.
CC {ECO:0000313|EMBL:MBI1983126.1}.
CC ---------------------------------------------------------------------------
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DR EMBL; JACOWA010000155; MBI1983126.1; -; Genomic_DNA.
DR Proteomes; UP000752455; Unassembled WGS sequence.
DR GO; GO:0052717; F:tRNA-specific adenosine-34 deaminase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-UniRule.
DR GO; GO:0002100; P:tRNA wobble adenosine to inosine editing; IEA:UniProtKB-UniRule.
DR CDD; cd01285; nucleoside_deaminase; 1.
DR FunFam; 3.40.140.10:FF:000005; tRNA-specific adenosine deaminase; 1.
DR Gene3D; 3.40.140.10; Cytidine Deaminase, domain 2; 1.
DR HAMAP; MF_00972; tRNA_aden_deaminase; 1.
DR InterPro; IPR016192; APOBEC/CMP_deaminase_Zn-bd.
DR InterPro; IPR002125; CMP_dCMP_dom.
DR InterPro; IPR016193; Cytidine_deaminase-like.
DR InterPro; IPR028883; tRNA_aden_deaminase.
DR NCBIfam; NF008113; PRK10860.1; 1.
DR PANTHER; PTHR11079; CYTOSINE DEAMINASE FAMILY MEMBER; 1.
DR PANTHER; PTHR11079:SF202; TRNA-SPECIFIC ADENOSINE DEAMINASE; 1.
DR Pfam; PF14437; MafB19-deam; 1.
DR SUPFAM; SSF53927; Cytidine deaminase-like; 1.
DR PROSITE; PS00903; CYT_DCMP_DEAMINASES_1; 1.
DR PROSITE; PS51747; CYT_DCMP_DEAMINASES_2; 1.
PE 3: Inferred from homology;
KW Hydrolase {ECO:0000256|ARBA:ARBA00022801, ECO:0000256|HAMAP-Rule:MF_00972};
KW Metal-binding {ECO:0000256|ARBA:ARBA00022723, ECO:0000256|HAMAP-
KW Rule:MF_00972};
KW tRNA processing {ECO:0000256|ARBA:ARBA00022694, ECO:0000256|HAMAP-
KW Rule:MF_00972};
KW Zinc {ECO:0000256|ARBA:ARBA00022833, ECO:0000256|HAMAP-Rule:MF_00972}.
FT DOMAIN 12..127
FT /note="CMP/dCMP-type deaminase"
FT /evidence="ECO:0000259|PROSITE:PS51747"
FT ACT_SITE 65
FT /note="Proton donor"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_00972"
FT BINDING 63
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_00972"
FT BINDING 93
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_00972"
FT BINDING 96
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_00972"
SQ SEQUENCE 174 AA; 18953 MW; 7716796228FB148F CRC64;
Query Match 72.1%; Score 550; Length 174;
Best Local Similarity 70.1%;
Matches 103; Conservative 19; Mismatches 25; Indels 0; Gaps 0;
Qy 3 PEDVAFMRKALDEARKAREAGEVPVGAVVVKDGEIVARAHNRTIQKSDPTAHAEILALRK 62
|:| :||:|| ||||| | |||||||||| || ::|||||| |: ||:|||||||||
Db 12 PDDTKYMRQALREARKAVEEGEVPVGAVVVHDGRVIARAHNRPIRLKDPSAHAEILALRG 71
Qy 63 AARALGNYRLTGCTLYATLEPCAMCAGAILHARIERLVYGVPNPKAGATGSVLNVLNHPR 122
| | |||||| |||||||:||||||||||: ||: |:|:| :||||| || | |||||:
Db 72 AGRRLGNYRLMGCTLYATIEPCAMCAGAIVQARLRRVVFGASDPKAGANGSALTVLNHPK 131
Qy 123 LNHRVEVTGGVLAEECGALLRGFFRAR 149
|||:||: |||||:| |:|:||| ||
Db 132 LNHQVEIVPGVLAEDCAAVLKGFFGAR 158
Conclusion
No claims are allowed.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA ZINGARELLI whose telephone number is (703)756-1799. The examiner can normally be reached M-F 9-5.
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, Sharmila Landau can be reached at (571) 272-0614. 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.
/SANDRA ZINGARELLI/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653