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 a deaminase or base editor of SEQ ID NO:386, an endonuclease of SEQ ID NO:597, and a UGI of SEQ ID NO:52 in the reply filed on 11/11/2025 is acknowledged. However, the species election requirement for a sequence of UGI (Group C) has been withdrawn.
Claim 143 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species of endonuclease sequences, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/11/2025.
Claims Status
Claims 1-133 is/are cancelled. Claims 134-160 is/are currently pending with claim 143 withdrawn. Claims 134-142 and 144-160 is/are under examination.
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.
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.
Figs. 3, 5, and 14 show plasmid maps with annotated sequences. However, Figs. 3, 5, and 14 (and the descriptions of Fig. 3, paragraph [0063], and Fig. 5, paragraph [0065], and Fig. 14, paragraph [0074]) do not provide corresponding SEQ ID NOs for the plasmid maps or annotated sequences within the plasmid maps.
Fig. 4 shows multiple amino acid sequences longer than 4 consecutive amino acids, with no corresponding SEQ ID NOs in the drawings or specification (paragraph [0064]).
Figs. 6A, 6B, 8A, 8B, 8C, 10A, 10B, 11A, 11B, 13A, 13B, 14 show multiple nucleotide sequences longer than 10 consecutive nucleotides with no corresponding SEQ ID NOs in the drawings or specification.
Claim Objections
Claim 139 is objected to because of the following informalities: line 3 should be amended to add the word “and” between “an uncultivated microorganism,” and “wherein said endonuclease is a class 2, type II Cas endonuclease.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
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.
Claim 148 is 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 148 recites a PAM sequence of SEQ ID NO:598. However, the sequence listing does not provide a nucleotide sequence for SEQ ID NO:598 (see screenshot of SEQ ID NO:598 in the provided sequence listing). The required limitation of SEQ ID NO:598 cannot be examined, as the sequence has not been provided. As the sequence required by claim 148 has not been provided, the limitations of claim 148 are unclear, and claim 148 is rendered indefinite.
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112(d):
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 136 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 136 recites that the base editor of claim 134, which “comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:386”, “comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 50-51, 385-443, or 448-475.” However, neither claims 135 nor 136 recite that the base editor further comprises an adenosine deaminase at least 85% identical to SEQ ID NOs:50-51, 385-443, or 448-475. SEQ ID NOs:50-51, 385-443, and 448-475 are not all at least 80% identical to SEQ ID NO:386. SEQ ID NO:386 of claim 134 is a deaminase sequence and is encompassed by the deaminase sequences of claim 136. As claim 136 recites that the base editor of claim 134 comprises (and not that it further comprises) an adenosine deaminase comprising a sequence at least 85% identical to SEQ ID NOs:50-51, 385-443, or 448-475, claim 136 does not require all of the limitations of claim 134 (that the base editor comprises a sequence at least 80% identical to SEQ ID NO:386), and thus is in improper dependent form. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 134-137, 139-142, 144-160 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the 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 (see i)(A) above), reduction to drawings (see i)(B) above), 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 i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claim 139 recites the term “uncultivated microorganism” (line 3), and recites an endonuclease “derived from an uncultivated microorganism”. The term “uncultivated” indicates that said microorganism, in some fashion, has not been cultivated, but not necessarily that said microorganism is impossible to cultivate. This creates an enormous and poorly-defined genus of microorganism species. The claims and disclosure leave unclear what genera or species of microorganisms are encompassed by “uncultivated microorganisms”. Additionally, the disclosure leaves unclear whether the successful cultivation after the effective filing date of the instant application of a microorganism species which previously had never been cultivated (i.e., uncultivated) would exclude a microorganism species which before had been encompassed by the claim. As the specification does not disclose the microorganism species from which the described endonuclease sequences (SEQ ID NOs:70-78, 597) are derived, an artisan would not be able to determine whether the described endonuclease species were derived from a microorganism which at the time of filing or after the time of filing was uncultivated. As such, the disclosure does not provide sufficient written description of “uncultivated microorganisms” and of endonucleases derived from uncultivated microorganisms, and an artisan would not be able to determine whether the applicants were in possession of endonucleases derived from “uncultivated microorganisms”. The disclosure has only provided sufficient description of endonucleases of SEQ ID NOs:70-78 and 597.
Claim 144 recites an endonuclease “configured to be deficient in nuclease activity” (line 2). For an endonuclease to be so “configured”, the endonuclease must comprise some structural alteration which decreases or eliminates nuclease activity. Claim 149 recites that the endonuclease is catalytically dead. The disclosure only provides the sequence of a D10A Cas9 nickase (see claim 142). The disclosure does not provide any other endonuclease sequence or structural alteration which would configure the endonuclease to be deficient in nuclease activity. An artisan would not be able to determine that the applicants were in possession of any endonuclease deficient in nuclease activity (including catalytically dead endonucleases) except a Cas9 nickase endonuclease comprising a D10A mutation. As such, claims 144 and 149 are not sufficiently described.
Claim 148 recites an endonuclease “configured to bind a protospacer adjacent motif (PAM) sequence comprising SEQ ID NO: 598.” However, the disclosure does not describe which endonuclease sequences are capable of binding the PAM sequence SEQ ID NO:598. An artisan would not be able to determine, based on the disclosure, which endonucleases of SEQ ID NOs:70-78 or 597, or of another, undisclosed sequence, were “configured to bind” SEQ ID NO:598. As such, an artisan would not be able to determine whether the applicants were in possession of endonucleases configured to bind SEQ ID NO:598, or in possession of a representative number of endonucleases configured to bind SEQ ID NO:598.
Claim 150 recites endonucleases having “less than 80% sequence identity to a full length amino acid sequence of an S. pyogenes Cas9 endonuclease.” The disclosure does not provide a sequence of S. pyogenes Cas9 endonuclease, nor does the disclosure provide specific S. pyogenes strains from which the Cas9 endonuclease is derived. A search of the NCBI protein database of S. pyogenes Cas9 endonuclease sequences produces hundreds of amino acid sequences, including Ref. Seq. WP_228650283.1. A BLAST search of Ref. Seq. WP_228650283.1 excluding the species S. pyogenes or any Streptococcus organism produces a large number of Cas9 species which have not been described by the present disclosure, but which are encompassed by claim 150 (BLAST search results have been provided with this office action). Endonucleases of SEQ ID NOs:70-78 and 597 are not representative of the full scope of the genus of endonucleases less than 80% identical to any S. pyogenes Cas9 endonuclease sequence. Therefore, the disclosure does not provide sufficient written description of the genus of all endonuclease sequences less than 80% identical to any S. pyogenes Cas9 endonuclease sequence.
Claim 152 requires that a guide RNA be “configured to bind to said endonuclease and said nucleic acid molecule”. Based on the common understanding of Cas9 function, the tracrRNA sequence determines the binding of a guide RNA to a Cas9, and the crRNA sequence determines the binding of a guide RNA to a target nucleic acid molecule. The disclosure has not provided specific gRNA or tracrRNA sequences which are ”configured to bind” to the disclosed endonuclease sequences (SEQ ID NOs:70-78, 597); an artisan would not be able to determine, based on the present disclosure, what tracrRNA or gRNA sequences would be capable of binding the disclosed endonuclease sequences (SEQ ID NOs:70-78, 597).
Claim 134 recites base editors comprising amino acid sequences at least 80% identical to SEQ ID NO:386; claim 136 recites base editors comprising amino acid sequences at least 85% identical to SEQ ID NOs:50-51, 385-443, or 448-475. This creates an enormous genus of base editors which is not sufficiently described by the disclosure. Claim 141 recites endonucleases comprising sequences at least 80% identical to SEQ ID NO:597, creating an enormous genus of endonuclease species which is not sufficiently described by the disclosure. Claim 153 recites guide RNA sequences at least 80% identical to SEQ ID NO:489, creating an enormous genus of guide RNA sequences which is not sufficiently described by the disclosure. Claim 158 recites UGI sequences at least 70% identical to SEQ ID NOs:52-56 or 67, creating an enormous genus of UGI sequences which is not sufficiently described by the disclosure.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, SEQ ID NOs:50-51, 385-443, and 448-475 are the only base editor or adenosine deaminase species whose complete structures are disclosed; SEQ ID NOs:70-78 and 597 are the only endonuclease species whose complete structures are disclosed; SEQ ID NO:489 is the only gRNA species whose complete structure is disclosed; SEQ ID NOs:52-56 and 67 are the only UGI species whose complete structures are disclosed. While these genera encompass large numbers of variants and molecules that have the same activity of adenosine deaminases (SEQ ID NOs:50-51, 385-443, 448-475, capable of deaminating adenosine in a nucleic acid), endonucleases (SEQ ID NOs:70-78, 597), UGIs (SEQ ID NOs:52-56, 67), and guide RNAs (SEQ ID NO:489, capable of binding an endonuclease and a target nucleic acid molecule, see claim 152) in kind and the genera encompass large numbers of variants and molecules that have a different structure, the specification does not describe the complete structure of a representative number of species of the large genera of adenosine deaminases, endonucleases, UGIs, and guide RNAs or functional equivalents thereof. Additionally, the specification does not describe the complete structure of a representative number of species of the large genera of modified adenosine deaminases, endonucleases, UGIs, and guide RNAs.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only other identifying characteristics are: the capacity of the adenosine deaminases to convert an adenine to a guanine in a nucleic acid molecule (claim 137); and the capacity of the endonucleases to bind a PAM sequence (claim 148), to bind a guide RNA (claim 152), to cleave at least one strand of a nucleic acid molecule (claim 145). Such functional limitation cannot be identifying characteristics for the claimed diverse genus of molecules since all members of the claimed genera will have that characteristic. The claims require that the endonuclease comprises a RuvC and an HNH domain (claim 139); however, this structural requirement cannot be an identifying characteristic for the claimed diverse genus of endonucleases because all members of the claimed genus will have this structural characteristic. Further, no identifying characteristics of the modified adenosine deaminases, endonucleases, guide RNAs, or UGIs are disclosed. The disclosure has not described which sequence elements, including nucleotides or amino acid residues, and domains, can be altered or should be preserved in order to fulfill the functional requirements of the claimed diverse genera of adenosine deaminases, endonucleases, gRNAs, or UGIs.
The inventions of Claims 135, 137, 139-140, 142, 144-152, 154-157, and 159-160 require the use of the inventions of Claims 134, 136, 141, 153, or 158 and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Claim Rejections - 35 USC § 103
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 134-137, 139-140, 142, 144-147, 149-152, 154-160 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2018027078 A1) in view of NCBI Reference Sequence: WP_062484216.1 (2017) and NCBI Reference Sequence: NC_015683.1 (2017).
Regarding claims 134-136, Liu teaches an adenosine deaminase (a base editor), wherein the adenosine deaminase is a TadA deaminase (claims 1-2, 4). Liu also teaches a method for editing (modifying) a nucleic acid sequence, the method comprising contacting the nucleic acid sequence with a complex comprising the base editor (claim 226). Liu teaches that any known TadA ortholog may be used (paragraph [00201]).
Regarding claim 137, Liu teaches that the adenosine deaminase converts an adenine to a guanine (paragraph [0002]).
Regarding claim 139, Liu teaches a base editor comprising a TadA deaminase and a Cas9 (claims 114-115). Liu teaches that the Cas9 domain comprises a RuvC domain and an HNH domain (paragraph [00213]). Liu teaches that the Cas9 can be any known Cas9, including Cas9 from Corynebacterium ulcerans (paragraph [00217]). A search of the art for cultivation of C. ulcerans did not produce results indicative of successful cultivation of C. ulcerans, thus rendering C. ulcerans an “uncultivated microorganism”.
Regarding claim 140, Liu teaches that the Cas9 domain and adenosine deaminase domain are fused with or without a linker (paragraph [0006]; claims 114, 126, 133).
Regarding claims 142, 144-147, and 149, Liu teaches that the Cas9 domain comprises a D10A mutation and/or an H840A mutation, wherein a D10A mutation inactivates a RuvC domain and resulting in a nickase Cas9, and wherein the combination of a D10A and an H840A mutation renders the Cas9 catalytically dead (paragraph [00218]). Regarding claim 145, both the wild-type and nickase Cas9 nucleases taught by Liu are capable of cleaving at least one strand of a nucleic acid molecule (paragraphs [00202], [00212]).
Regarding claim 150, Liu teaches that the Cas9 can be from C. ulcerans (Ref. Seq. NC_017317.1) (paragraph [00217]). A tBLASTn alignment between WP_228650283.1 (S. pyogenes Cas9) and NC_017317.1 (C. ulcerans genome) produces no significant similarity (see alignment results below). As such, Liu is considered to teach Cas9 endonucleases less than 80% identical to an S. pyogenes Cas9 endonuclease.
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Regarding claim 151, Liu teaches that the base editor further comprises one or more NLS sequences (claim 130).
Regarding claims 152 and 154-155, Liu teaches that the complex further comprises a single guide RNA molecule capable of binding to the Cas9 domain of the fusion protein through a tracrRNA sequence (claim 174; paragraph [0001] pages 47-48) and capable of hybridizing to a target nucleic acid sequence through a crRNA sequence (claims 175-176; paragraph [0001] pages 47-48).
Regarding claim 156, Liu teaches that the portion of the guide RNA complementary to the target sequence (the guide portion) comprises 15-40 contiguous nucleotides in length (claims 176-177).
Regarding claim 157, Liu teaches that the fusion protein further comprises a uracil DNA glycosylase inhibitor (UGI) domain (paragraph [00237]).
Regarding claim 158, Liu teaches that the UGI domain comprises the sequence of SEQ ID NO:3 (SEQ ID NO:3 of Liu is 100% identical to instant SEQ ID NO:54, see alignment below).
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Regarding claim 159, Liu teaches that the target nucleic acid molecule is a eukaryotic, plant, fungal, mammalian, rodent, or human nucleic acid molecule (claims 179-186).
Regarding claim 160, Liu teaches that sequence alignments can be performed using NCBI BLAST (paragraph [00430]). The search parameters recited in instant claim 160 are default options available on the widely-available NCBI BLAST search interface (see screenshot below of default BLAST interface). An artisan would recognize that NCBI BLAST could be used not only to align two sequences, but to search for adenosine deaminase sequences with any degree of homology to a known adenosine deaminase sequence (for example, to find sequences at least 80% identical to SEQ ID NO:1, claim 6).
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However, Liu does not teach an adenosine deaminase at least 80% or 85% identical to SEQ ID NO:386 (required by claims 134 and 136, respectively).
NCBI Reference Sequence: WP_062484216.1 is a tRNA adenosine(34) deaminase TadA from Lacimicrobium alkaliphilum, known at the time of filing (see provided GenPept page). This L. alkaliphilum TadA is at least 85% identical to instant SEQ ID NO:386 (see alignment below).
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As Liu teaches that any TadA sequence known to an artisan could be used in the fusion protein of Liu, an artisan would recognize that TadA sequences such as the TadA from L. alkaliphilum above could be used in the fusion protein of Liu, rendering obvious a base editor comprising a sequence at least 80% identical to SEQ ID NO:386 (as required by claim 134) and at least 85% identical to SEQ ID NO:386 (as required by claim 136).
Allowable Subject Matter
Claim 138 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: searches of SEQ ID NO:386 with ABSS and with NCBI BLAST did not produce any sequences 100% identical to SEQ ID NO:386. Therefore, it is determined that a base editor comprising an adenosine deaminase comprising the sequence SEQ ID NO:386 was not known in or rendered obvious by the art at the time of filing.
Conclusion
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/AFRICA M MCLEOD/Examiner, Art Unit 1635
/KIMBERLY CHONG/Primary Examiner, Art Unit 1636