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 .
DETAILED ACTION
The preliminary amendment filed 09/28/2023 is acknowledged. Claims 12, 20, 22-26 and 28-34 are canceled. Claims 1-11, 13-19, 21, and 27 are pending and under consideration in this action.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The instant claims are entitled to an effective filing date of 01/26/2023, which is the filing date of PCT/JP2023/002475.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In paragraph [0045], the specification recites the browser-executable code: http://www.ncbi.nlm.nih.gov/.
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 1-11, 13-19, 21, and 27 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 recites “amino acid sequence B”, which is indefinite because it is unclear whether B is used as a generic identifier or not. The specification describes the amino acid sequence B as preferably an amino acid sequence B1 represented by SEQ ID NO: 2 or SEQ ID NO: 3, or an amino acid sequence B2 having 80% or more identity to amino acid sequence B1. See [0077]. Therefore, it is unclear whether the “amino acid sequence B” recited in claim 1 refers to a specific sequence not recited in the claim, or any amino acid sequence, rendering the structural limitation vague and indefinite.
Claims 2-11, 13-19, 21, and 27 require the limitations of claim 1 and are rejected for the reason set forth above.
Claims 2, 13 and 16 recite an amino acid sequence that is obtained by performing deletion, insertion, substitution, and/or addition of 1 to 126 amino acids, which is indefinite because there are multiple reasonable interpretations for this limitation. See part (a2) of claim 2, part (b2) of claim 13 and part (c2) of claim 16. In the first interpretation, the claims require a mutation of 1 to 126 amino acid residues in addition to the K169 and D529 substitutions; such that the structure of the sequence has a minimum of three mutations. In the second interpretation, the claims require an amino acid sequence that is obtained by performing deletion, insertion, substitution and/or addition of 1 to 126 amino acids as to arrive at an amino acid sequence that comprises that the K169 and D529 substitutions; such that the structure of the sequence has a minimum of two mutations. In other words, it is unclear whether the claims intend to limit the structure of the amino acid sequence product, or limit the process by which the product is obtained.
Claims 14-15, and 17-18 depend from either claim 13 or claim 16 and are rejected for the reason set forth above.
Claim 27 recites the limitation "the guide RNA targeted on a target site" in the last two lines. There is insufficient antecedent basis for this limitation in the claim. It is unclear which guide RNA is being referenced in claim 27 because there is no earlier recitation of a guide RNA. As such, it is unclear whether claim 27 intends to reference any guide RNA or a specific guide RNA that is not recited in the claim.
Claim Rejections - 35 USC § 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 2 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 2 (a1) does not clearly limit claim 1 from which it depends. Claim 1 requires the amino acid sequence B to comprise K169 and D529 mutations in the amino acid sequence A represented by SEQ ID NO: 1. Claim 2 requires the amino acid sequence B to comprise an amino acid sequence of (a1), (a2) or (a3) where (a1) is an amino acid sequence that comprises amino-acid substitution mutations of K169 and D529 in the amino acid sequence represented by SEQ ID NO: 1. Thus, claim 2 does not further limit the structure of amino acid sequence B, because claim 2 option (a1) merely reiterates the mutations of claim 1.
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.
Claim Interpretation
Claim 1 is a MAD7 protein comprising an amino acid sequence of SEQ ID NO: 1 with K169 and D529 mutations. To clarify, claim 1 requires the MAD7 protein to comprise amino acid sequence B; amino acid sequence B comprises K169 and D529 mutations in amino acid sequence A; and amino acid sequence A is represented by SEQ ID NO: 1, such that amino acid sequence A is interpreted as being synonymous with SEQ ID NO: 1.
Claim 9 requires K970 to be substituted with a hydrophilic neutral amino acid, or E1227 to be substituted with a basic residue. According to the instant specification, examples of the hydrophilic neutral amino acids include asparagine, glutamine, serine, threonine, tyrosine, and cysteine. See [0062]. Examples of basic amino acids include lysine, arginine, and histidine. See [0063].
Claim 13 requires the amino acid sequence B to comprise (b1), (b2) or (b3). Part (b1) recites “an amino acid sequence represented by SEQ ID No. 2”, which encompasses any amino acid sequence that comprises the full-length SEQ ID NO: 2 or any portion of SEQ ID NO: 2. SEQ ID NO: 2 differs from SEQ ID NO: 1 in that SEQ ID NO: 2 has arginine at positions 169 and 529 (i.e. K169R, D529R mutations), asparagine at position 970 (i.e. K970N mutation) and phenylalanine at position 1086 (i.e. Y1086F mutation). Part (b2) recites an active method step of “performing deletion, insertion, substitution, and/or addition of 1 to 126 amino acids”. However, the claim is drawn to product, so part (b2) requires an amino acid sequence structure in which arginine (R) is conserved at positions 169 and 529 relative to SEQ ID NO: 2. Part (b3) is an amino acid sequence that is 90% identical to SEQ ID NO: 2 and has arginine at positions 169 and 529.
In claim 14, the required conserved amino acid residue is phenylalanine (F) at position 1086 relative to SEQ ID NO: 2.
Claim 15 requires residue 970 or 1227 in SEQ ID NO: 2 to be conserved. SEQ ID NOs: 1 and 2 both have glutamic acid (E) at position 1227. In other words, SEQ ID NO: 2 does not include a substitution at position 1227. However, at position 970, SEQ ID NO: 2 has a K970N mutation relative to SEQ ID NO: 1, such that SEQ ID NO: 2 has asparagine (N) at that position.
Claim 16 requires the amino acid sequence B to comprise (c1), (c2) or (c3). SEQ ID NO: 3 differs from SEQ ID NO: 1 in that SEQ ID NO:3 has arginine at positions 169 and 529 (i.e. K169R, D529R mutations), phenylalanine at position 1086 (i.e. the Y1086F mutation), and lysine at position 1227 (i.e. E1227K).
Claim 18 requires residue 970 or 1227 in SEQ ID NO: 3 to be conserved. Instant SEQ ID NOs: 1 and 3 have lysine K at position 970. At position 1227, SEQ ID NO: 3 has a lysine residue.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 8, 11, 13, 15-16, 18-19 and 21 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Jones (WO 2021/257716, in the IDS filed 09/28/2023).
Regarding claim 1, Jones teaches a modified MAD7 enzyme comprising a mutation. See claims 1 and 17-19 of Jones. The mutation comprises a substitution selected from a group that includes K169R and D529R. See claim 24 of Jones. Jones indicates that the mutations are relative to MAD 7 (SEQ ID NO: 1). The MAD7 sequence (SEQ ID NO: 1) of Jones is a 100% identity match to instant SEQ ID NO: 1. See figures 5A-5B for the MAD7 sequence of Jones, and see the alignment provided in the office action appendix.
Regarding claim 2, Jones teaches a MAD7 (SEQ ID NO: 1) amino acid sequence that is 100% identical to instant SEQ ID NO: 1. See the alignment in the office action appendix and figures 5A-5B of Jones. Furthermore, Jones teaches a substitution selected from a group that includes K169R and D529R. See claim 24 of Jones. Thus, Jones teaches a sequence that is over 90% identical to instant SEQ ID NO: 1 and comprises K169 and D529 substitutions.
Regarding claim 3, Jones teaches K169R and D529R substitutions. See claim 24 of Jones. Jones teaches that arginine is a basic residue. See [0039].
Regarding claim 4, Jones teaches K169R and D529R substitutions. See claim 24 of Jones.
Regarding claim 5, Jones teaches a modified MAD7 enzyme wherein the mutation comprises a substitution at one or more amino acid positions selected from a group that includes 1086 relative to SEQ ID NO: 1, wherein the mutation comprises Y1086A or Y1086Q. See claims 13-15 of Jones and [0007]-[0009]. SEQ ID NO: 1 of Jones is a 100% identity match to instant SEQ ID NO: 1. See the office action appendix. Thus, Jones teaches a Y1086 substitution.
Regarding claim 8, Jones teaches a modified MAD7 enzyme, wherein the enzyme comprises a substitution mutation selected from a group that includes K970R relative to SEQ ID NO: 1. See claims 20-23 of Jones and [0010]-[0012], and [0079]-[0082].
Regarding claim 11, Jones teaches a modified MAD7 enzyme comprising a substitution mutation relative to SEQ ID NO: 1 selected from a group that includes C892K, Y907T, and I922K (see claim 21 of Jones); a group that includes Y966K, K1247R and N1250H (see claim 23 of Jones); a group that includes T1014A, K1040A, D1200A, and I1231A (see claim 14 of Jones); a group that includes K1098A, and F1198A (see claim 4 of Jones); and a group that includes F1241K, and S1242K (see claim 20 of Jones).
Regarding claim 13, Jones teaches a modified MAD7 enzyme comprising a substitution selected from a group that includes K169R and D529R. See claims 1, 17-19 and 24 of Jones. Jones indicates that the mutations are relative to SEQ ID NO: 1. See figures 5A-5B. The MAD7 enzyme with K169R and D529R substitutions taught by Jones is a 99.9% identity match to instant SEQ ID NO: 2. See the office action appendix for the alignment.
Regarding claim 15, Jones teaches a MAD7 enzyme (SEQ ID NO: 1) that includes an E at position 1227. See figures 5A-5B. Instant SEQ ID NO: 2 also has an E residue at position 1227. See the alignment in the office action appendix. Therefore, Jones teaches the instantly required conserved residue.
Regarding claim 16, Jones teaches a modified MAD7 enzyme comprising a substitution selected from a group that includes K169R and D529R. See claims 1, 17-19 and 24 of Jones. Jones indicates that the mutations are relative to SEQ ID NO: 1. See figures 5A-5B. The MAD7 enzyme with K169R and D529R substitutions taught by Jones is a 99.9% identity match to instant SEQ ID NO: 3. See the office action appendix for the alignment.
Regarding claim 18, Jones teaches a MAD7 enzyme (SEQ ID NO: 1) that includes an K at position 970. See figures 5A-5B. Instant SEQ ID NO: 3 also has an K residue at position 970. See the alignment in the office action appendix. Therefore, Jones teaches the instantly required conserved residue.
Regarding claim 19, Jones teaches a fusion protein comprising the modified MAD7 enzyme and further comprising one or more moieties selected from a group that includes nuclear colocalization signal protein (i.e. a nuclear localization signal sequence). See claims 25-26 of Jones.
Regarding claim 21, Jones teaches a vector comprising a nucleic acid sequence encoding the modified MAD7 enzyme. Jones teaches a modified MAD7 enzyme comprising a substitution selected from a group that includes K169R, and D529. See claims 31 and 24 of Jones.
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.
Claims 6-7, 9-10, 14, 17 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Jones (WO 2021/257716, in the IDS filed 09/28/2023).
Regarding claim 6, Jones teaches a MAD7 (SEQ ID NO: 1), which is 100% identical to instant SEQ ID NO: 1. See figures 5A-5B and the office action appendix. Jones teaches K169R, and D529R substitutions. See claim 24 of Jones. Furthermore, Jones teaches a substitution at position 1086 (i.e. Y1086) relative to SEQ ID NO: 1. See claim 13 of Jones and paragraph [0007]. Jones discloses that tyrosine (Y), phenylalanine (F) and tryptophan (W) are conservative substitutions for one another. See [0038]. Jones discloses that F, Y and W are non-polar aromatic residues. See [0039].
Jones does not explicitly teach an amino acid substitution of Y1086 with an aromatic amino acid other than tyrosine.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute F or W for the Y at position 1086 relative to SEQ ID NO: 1 of Jones. One would be motivated to do so because Jones suggests that it would be a conservative substitution amongst non-polar aromatic residues. There would be a reasonable expectation of success because Jones explicitly teaches a substitution at position 1086 relative to SEQ ID NO: 1, which is identical to instant SEQ ID NO: 1.
Regarding claim 7, Jones teaches a MAD7 (SEQ ID NO: 1), which is 100% identical to instant SEQ ID NO: 1. See figures 5A-5B and the office action appendix. Jones teaches K169R, and D529R substitutions. See claim 24 of Jones. Furthermore, Jones teaches a substitution at position 1086 (i.e. Y1086) relative to SEQ ID NO: 1. See claim 13 of Jones and paragraph [0007]. Jones discloses that tyrosine (Y) and phenylalanine (F) are conservative substitutions for one another. See [0038].
Jones does not explicitly teach a Y1086F substitution.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute F for Y at position 1086 relative to SEQ ID NO: 1 of Jones. One would be motivated to do so because Jones suggests that such substitution would be conservative. There would be a reasonable expectation of success because Jones explicitly teaches substitutions at position 1086.
Regarding claim 9, Jones teaches a MAD7 (SEQ ID NO: 1), which is 100% identical to instant SEQ ID NO: 1. See figures 5A-5B and the office action appendix. Jones teaches K169R, and D529R substitutions. See claim 24 of Jones. Furthermore, Jones teaches a K970R substitution relative to SEQ ID NO: 1. See claims 20-23 of Jones and [0010]-[0012], and [0079]-[0082]. Jones teaches dead mutations which include replacing amino acids near the catalytic residue 962E with a neutral residue, e.g. asparagine, cysteine, glutamine, serine, and threonine. See [0071].
Jones does not specifically teach a substitution of K970 with a hydrophilic neutral amino acid or a substitution of E1227 with a basic amino acid.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to replace the arginine (R) in the K970R mutation of Jones with a neutral residue including asparagine, cysteine, glutamine, serine, and threonine (i.e. hydrophilic neutral residues). One would be motivated to do so because Jones suggests replacing residues near the catalytic residue at position 962 with neutral residues. There would be a reasonable expectation of success because Jones explicitly teaches a substitution at the K970 residue.
Regarding claim 10, Jones teaches a MAD7 (SEQ ID NO: 1), which is 100% identical to instant SEQ ID NO: 1. See figures 5A-5B and the office action appendix. Jones teaches K169R, and D529R substitutions. See claim 24 of Jones. Furthermore, Jones teaches a K970R substitution relative to SEQ ID NO: 1. See claims 20-23 of Jones and [0010]-[0012], and [0079]-[0082]. Jones teaches dead mutations which include replacement of amino acids near the catalytic residue 962E with a neutral residue, e.g. asparagine. See [0071].
Jones does not specifically teach a substitution of K970 with asparagine or a substitution of E1227 with lysine.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to replace the arginine (R) in the K970R mutation of Jones with a neutral residue including asparagine. One would be motivated to do so because Jones suggests replacing residues near the catalytic residue at position 962 with neutral residues including asparagine. There would be a reasonable expectation of success because Jones explicitly teaches a substitution at the K970 residue; and Jones further teaches asparagine amongst a finite list of neutral residues to choose from.
Regarding claim 14, Jones teaches a modified MAD7 enzyme comprising a substitution selected from a group that includes K169R, and D529R. See claim 24 of Jones. With the K169R and D529R substitutions, the modified MAD7 enzyme of Jones is a 99.9% identity match to instant SEQ ID NO: 2. See the office action appendix for the alignment. Furthermore, Jones teaches a MAD7 substitution at position 1086 (i.e. Y1086) relative to SEQ ID NO: 1. See claim 13 of Jones. Jones discloses that tyrosine (Y) and phenylalanine (F) are conservative substitutions for one another. See [0038].
Jones does not explicitly teach an amino acid at position 1086 in instant SEQ ID NO: 2 that is further conserved (i.e. a F residue).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to replace the Y with F at position 1086 relative to the modified MAD7 enzyme of Jones. One would be motivated to do so because Jones suggests that such substitution would be conservative. There would be a reasonable expectation of success because Jones explicitly teaches substitutions at position 1086.
Regarding claim 17, Jones teaches a modified MAD7 enzyme comprising a substitution selected from a group that includes K169R, and D529R. See claim 24 of Jones. With the K169R and D529R substitutions, the modified MAD7 enzyme of Jones is a 99.9% identity match to instant SEQ ID NO: 3.
Jones does not specifically teach an amino acid at position 1086 in instant SEQ ID NO: 3 that is further conserved (i.e. a F residue).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to replace the Y with F at position 1086 relative to the modified MAD7 enzyme of Jones. One would be motivated to do so because Jones suggests that such substitution would be conservative. There would be a reasonable expectation of success because Jones explicitly teaches substitutions at position 1086.
Regarding claim 27, in example 2, Jones teaches transfecting a MAD7 variant enzyme and/or a gRNA1 and/or a gRNA2 into a cell line containing a target gene. The target gene may be any desired target gene. See example 2 paragraph [00129]. Jones teaches a modified MAD7 enzyme comprising a substitution selected from K169R, D529R and K535R. See claims 1, 17-19 and 24 of Jones.
Jones does not teach introducing into a cell or non-human organism, the mutant MAD7 protein comprising instant SEQ ID NO: 1 with K169 and D529 substitutions, because the MAD7 variant used in example 2 of Jones is not specifically disclosed as having the instantly required K169 and D529 substitutions.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to use the modified MAD7 enzyme comprising substitutions K169R and D529R as the MAD7 variant enzyme in example 2 of Jones. One would be motivated to use the K169R and D529R MAD7 mutant of Jones (see [0078]), because Jones suggests that the mutations are practical for use in CRISPR-based applications (see [0004]). There would be a reasonable expectation of success because Jones demonstrates transfecting a variant enzyme and gRNA into a cell line containing a target gene.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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, LOUISE HUMPHREY can be reached at (571)272-5543. 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.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657