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 .
Applicants’ amendment to the claims filed on 7/6/2023 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 1, 3-5, 13-14, 22, 25-27, 31, 35-36, 42, 46, 50, 53, 58-59, 71 are pending.
Claims 2, 6-12, 15-21, 23-24, 28-30, 32-34, 37-41, 43-45, 47-49, 51-52, 54-57, 60-70, 72 are cancelled.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1, 3-5, 13-14, 22) in the reply filed on 11/18/2025 is acknowledged.
Claims 1, 3-5, 13-14, 22, 25-27, 31, 35-36, 42, 46, 50, 53, 58-59, 71 are pending.
Claims 2, 6-12, 15-21, 23-24, 28-30, 32-34, 37-41, 43-45, 47-49, 51-52, 54-57, 60-70, 72 are cancelled.
Claims 25-27, 31, 35-36, 42, 46, 50, 53, 58-59, 71 stands withdrawn pursuant to 37 CFR 1.142(b).
Claims 1, 3-5, 13-14, 22 are pending and examined on the merits.
Priority
Acknowledgement is made of applicants’ claimed domestic priority to U.S. provisional application 63/298,822 filed on 1/12/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/18/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The Drawings filed on 1/11/2023 are acknowledged and accepted by the examiner.
Claim Rejections - 35 USC § 112
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, 3-5, 13-14, 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claims 1, 3-5, 13-14 are drawn to a Cas9 protein comprising a cavity domain that comprises a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified ("amino acid modification") compared to a corresponding wild-type Cas9 protein, and wherein the amino acid modification is capable of increasing the specificity of the Cas9 protein. The structure of a Cas9 protein comprising a cavity domain with a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified is unlimited.
Claim 22 is drawn to a composition comprising the Cas9 protein of claim 1. The structure of a Cas9 protein comprising a cavity domain with a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified is unlimited.
In this case, the specification discloses the following representative Cas9 protein comprising modifications of a plurality of positively charged amino acids within a cavity domain as encompassed by the claims (i.e. Cas9 protein comprising the amino acid sequence of SEQ ID NO: 1 wherein the at least one amino acid modification is at residue K405, R455, K546, K561, K562, K564, K566, K578, K579, R618, R622, K664, R721, R785, K786, K788, K789, R807, K808, R849, R856, K914, K917, R919, R920, K921, K922, R926, K934, K936, R939, K941, K945, R1047, R1131, R1137, K1142, K1152, K1155, R1178, K1189, K1198, K1206, K1213, K1223, R1226, K1227, K1228, R1241, or a combination thereof). Other than the above disclosed species, there is no prior-art or disclosed teaching as to the infinite modifications within a cavity domain comprising positively charged amino acids of Cas9 for increasing the specificity of the Cas9 protein. The breadth of the claims encompass any modification within the cavity domain of Cas9 comprising a plurality of positively-charged amino acids through modifications such as site-directed mutagenesis, etc. for increasing the specificity of the Cas9 protein.
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004). Here, the disclosure fails to teach which combination of modifications out of the numerous possibilities for increasing the specificity of the Cas9 protein.
Accordingly, one of skill in the art would not accept the disclosure a cavity domain comprising a plurality of positively- charged amino acids of Cas9 protein (SEQ ID NO: 1), wherein at least one of the plurality of positively charged amino acids is modified to: K405, R455, K546, K561, K562, K564, K566, K578, K579, R618, R622, K664, R721, R785, K786, K788, K789, R807, K808, R849, R856, K914, K917, R919, R920, K921, K922, R926, K934, K936, R939, K941, K945, R1047, R1131, R1137, K1142, K1152, K1155, R1178, K1189, K1198, K1206, K1213, K1223, R1226, K1227, K1228, R1241, or a combination thereof as being representative of all Cas9 protein modifications as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of the Cas9 protein, fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph.
Scope of Enablement
Claims 1, 3-5, 13-14, 22 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 Cas9 protein (SEQ ID NO: 1) comprising a cavity domain with a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified to: K405, R455, K546, K561, K562, K564, K566, K578, K579, R618, R622, K664, R721, R785, K786, K788, K789, R807, K808, R849, R856, K914, K917, R919, R920, K921, K922, R926, K934, K936, R939, K941, K945, R1047, R1131, R1137, K1142, K1152, K1155, R1178, K1189, K1198, K1206, K1213, K1223, R1226, K1227, K1228, R1241, it does not reasonably provide enablement for all possible modifications within a cavity domain of Cas9 as encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A)The breadth of the claims:
Claims 1, 3-5, 13-14 are drawn to a Cas9 protein comprising a cavity domain with a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified ("amino acid modification") compared to a corresponding wild-type Cas9 protein, and wherein the amino acid modification is capable of increasing the specificity of the Cas9 protein. The structure of a Cas9 protein comprising a cavity domain with a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified is unlimited.
Claim 22 is drawn to a composition comprising the Cas9 protein of claim 1. The structure of a Cas9 protein comprising a cavity domain with a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified is unlimited.
B) The nature of the invention; C)The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: As noted above, the scope of the claimed Cas9 protein comprising a cavity domain with a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified is unlimited. The structure of the claimed cas9 protein with amino acid modifications of a plurality of positively charged amino acids within a cavity domain are unlimited.
It is well-known in the prior art that the amino acid sequence of a polypeptide determines the polypeptide’s functional properties. The positions within a protein's sequence where modifications can be made with a reasonable expectation of success in obtaining a polypeptide having the desired activity/utility are limited in any protein and the result of such modifications is highly unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g., multiple substitutions. The reference of Singh et al. (Current Protein and Peptide Science, 2017; examiner cited) reviews various protein engineering methods and discloses 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 [see p. 7, column 1, top]. The reference of Zhang et al. (Structure, 2018; examiner cited) discloses that a mutation of a residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide [p. 1475, column 1].
It is well-known in the art that even a single amino acid alteration can alter the folding of a polypeptide. See, e.g., MPEP 2144.08.II.A.4.(c), which states, “[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (“the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.” Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990).”
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of Cas9 protein (SEQ ID NO: 1) with modifications within a cavity domain that comprises a plurality of positively- charged amino acids (i.e. Cas9 (SEQ ID NO:1) comprising the amino acid sequence of K405, R455, K546, K561, K562, K564, K566, K578, K579, R618, R622, K664, R721, R785, K786, K788, K789, R807, K808, R849, R856, K914, K917, R919, R920, K921, K922, R926, K934, K936, R939, K941, K945, R1047, R1131, R1137, K1142, K1152, K1155, R1178, K1189, K1198, K1206, K1213, K1223, R1226, K1227, K1228, R1241). Other than the above disclosed species, there is no prior-art or disclosed teaching as to the infinite amino acid modifications within a cavity domain comprising a plurality of positively charged amino acids of the Cas9 protein. Other than the above disclosed species, there is no prior-art or disclosed teaching as to the infinite modifications within a cavity domain comprising a plurality of positively charged amino acids of the Cas9 protein through any modification technique such as: site-directed mutagenesis, etc. for increasing the specificity of Cas9. Other than these working examples, the specification fails to disclose any other working examples of modifications of the positivity charged amino acids within a cavity domain of Cas9.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
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.
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, 3-5, 13-14, 22 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.
Regarding claim 1 (claims 3-5, 13-14, 22 dependent thereof), the phrase ‘wherein at least one of the plurality of positively charged amino acids is modified ("amino acid modification")’ renders the claim indefinite because it is unclear whether the limitation(s) in brackets following the terms are part of the claimed invention. See MPEP § 2173.05(d). It is unclear whether the items inside of the brackets are examples or generic terms.
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.
Claims 1, 13, 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al (Date Published: 25 November 2021, Nucleic Acids Research) {herein Zhang}.
Claims 1, 13, 22 are drawn to a Cas9 protein comprising a cavity domain that comprises a plurality of positively- charged amino acids, wherein at least one of the plurality of positively charged amino acids is modified ("amino acid modification") compared to a corresponding wild-type Cas9 protein, and wherein the amino acid modification is capable of increasing the specificity of the Cas9 protein; a composition comprising the Cas9 protein of claim 1.
With respect to claims 1, 13, 22, Zhang teaches a composition comprising Cas9 protein that comprises a plurality of positively charged lysine amino acids in the PI domain (page 12436, column 2, para 1). At least one of the positively charged amino acids was mutated to alanine or arginine (page 1246, column 2, para 1). The endonucleolytic activity and specificity of the mutant was slightly enhanced compared with wild-type Cas9 (page 12436, column 2, para 2).
For the reasons stated herein, the teachings of Zhang anticipate claims 1, 13, 22.
Claim Rejections - 35 USC § 103
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.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Date Published: 25 November 2025, Nucleic Acids Research) {herein Zhang} as applied to claims 1, 13, 22 in view of Vyas et al (US2017/0166928A1, Date Published: Jun. 15, 2017, Examiner cited) {herein Vyas}.
Claim 14 is drawn to the Cas9 protein of claim 1, which comprises, consists of, or consists essentially of: (a) the amino acid sequence set forth in SEQ ID NO: 2; (b) the amino acid sequence set forth in SEQ ID NO: 3; (c) the amino acid sequence set forth in SEQ ID NO: 4; (d) the amino acid sequence set forth in SEQ ID NO: 5; (e) the amino acid sequence set forth in SEQ ID NO: 6; (f) the amino acid sequence set forth in SEQ ID NO: 7; (g) the amino acid sequence set forth in SEQ ID NO: 8; (h) the amino acid sequence set forth in SEQ ID NO: 9.
The teachings of Zhang as applied to claims 1, 13, 22 are set forth in the 103 rejection above.
However, Zhang does not teach the product of claim 14, which comprises, consists of, or consists essentially of: (a) the amino acid sequence set forth in SEQ ID NO: 2; (b) the amino acid sequence set forth in SEQ ID NO: 3; (c) the amino acid sequence set forth in SEQ ID NO: 4; (d) the amino acid sequence set forth in SEQ ID NO: 5; (e) the amino acid sequence set forth in SEQ ID NO: 6; (f) the amino acid sequence set forth in SEQ ID NO: 7; (g) the amino acid sequence set forth in SEQ ID NO: 8; (h) the amino acid sequence set forth in SEQ ID NO: 9 (claim 14).
With respect to claim 14, Vyas teaches a Candida compatible nucleic acid (SEQ ID NO: 5) comprising a clustered regularly interspaced short palindromic repeat (CRISPR)-associated nuclease 9 (CaCas9) nucleotide sequence (Appendix A).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to apply the teachings of Zhang of a composition comprising Cas9 protein that comprises a plurality of positively charged lysine amino acids in the PI domain (page 12436, column 2, para 1) or combine the teachings of Vyas because Vyas teaches a Candida Cas9 compatible nucleic acid (SEQ ID NO: 5) comprising a clustered regularly interspaced short palindromic repeat (CRISPR)-associated nuclease 9 (CaCas9) nucleotide sequence (Appendix A).
One of ordinary skill in the art would be motivated to either use the teachings of Zhang et al. by itself or combine the teachings of Vyas because Vyas provides the motivation for Zhang to use SEQ ID NO: 5 (Canadia Cas9), which is 100% identical to the instant application SEQ ID NO: 2 (appendix A), for mutating positively charged amino acids within a cavity domain of Cas9 protein to increase CRISPR-Cas9 specificity to a target strain because Vyas teaches said strain has improved industrial applications and would allow for the exploration of new opportunities to study Eukaryotic pathogenic pathways (Vyas: para 0010). One of ordinary skill in the art would have a reasonable expectation of success that substituting Streptococcus pyogenes Cas9 (bacteria) with Candida Cas9 (yeast) would result in a Cas9 system with more scalability for bioproduction as said Cas9 serves as a better system for more complex cells, such as eukaryotic cells, where bacterial systems are not ideal. Furthermore, yeast are simple eukaryotes, making them ideal for studying complex eukaryotic processes, offering easier genetic manipulation for pathway engineering and precise gene editing/repair.
One of skill in the art would have a reasonable expectation of success to make and use the claimed Cas9 protein because Zhang provides the basic Cas9 protein comprising a cavity domain that comprises a plurality of positively-charged amino acids and its uses and methods of making it. Reference of Vygas provides the teachings for a Candida compatible nucleic acid (SEQ ID NO: 5) comprising a clustered regularly interspaced short palindromic repeat (CRISPR)-associated nuclease 9 (CaCas9) nucleotide sequence (Appendix A). Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
Status of the claims
Claims 1, 3-5, 13-14, 22 are pending and examined on the merits.
Claims 2, 6-12, 15-21, 23-24, 28-30, 32-34, 37-41, 43-45, 47-49, 51-52, 54-57, 60-70, 72 are cancelled.
Claims 25-27, 31, 35-36, 42, 46, 50, 53, 58-59, 71 stands withdrawn pursuant to 37 CFR 1.142(b).
Claims 1, 3-5, 13-14, 22 are rejected.
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERICA NICOLE JONES-FOSTER whose telephone number is (571)270-0360. The examiner can normally be reached mf 7:30a - 4:30p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERICA NICOLE JONES-FOSTER/ Examiner, Art Unit 1656
/PAUL J HOLLAND/ Primary Examiner, Art Unit 1656
Appendix A
Vyas et al (SEQ ID NO: 5; claim 1) vs Instant Application SEQ ID NO: 2
Query Match 100.0%; Score 7005; Length 1371;
Best Local Similarity 100.0%;
Matches 1368; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAE 60
Qy 61 ATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFG 120
Qy 121 NIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSD 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSD 180
Qy 181 VDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGN 240
Qy 241 LIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI 300
Qy 301 LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYA 360
Qy 361 GYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELH 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELH 420
Qy 421 AILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEE 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 AILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEE 480
Qy 481 VVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFL 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 VVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFL 540
Qy 541 SGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 SGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI 600
Qy 601 IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWG 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWG 660
Qy 661 RLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSL 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 RLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSL 720
Qy 721 HEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRER 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 HEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRER 780
Qy 781 MKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDH 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 MKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDH 840
Qy 841 IVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNL 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 IVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNL 900
Qy 901 TKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKS 960
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Db 901 TKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKS 960
Qy 961 KLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK 1020
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Db 961 KLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK 1020
Qy 1021 MIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF 1080
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Db 1021 MIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF 1080
Qy 1081 ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVA 1140
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Db 1081 ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVA 1140
Qy 1141 YSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPK 1200
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Db 1141 YSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPK 1200
Qy 1201 YSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVE 1260
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Db 1201 YSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVE 1260
Qy 1261 QHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGA 1320
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Db 1261 QHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGA 1320
Qy 1321 PAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD 1368
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Db 1321 PAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD 1368