DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 July 2026 has been entered.
Status of Application
The amendments and response filed 16 July 2026 are acknowledged and have been considered in their entireties. Claim 101 is cancelled and the limitations incorporated into independent claim 93; claim 276 is new. Thus, claims 93-96, 98-100, 102, 108-109, 111-115, 117, 124, 126-127 and 273-275 are pending. Thus, claims 93-96, 98-102, 108-109, 111-115, 117, 124, 126-127 and 273-276 are subject to examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 16 July 2026 has been considered by the examiner. See initialed and signed PTO/SB/08.
Withdrawal of Previous Rejections
The rejection of claims 93-98, 99-100, 111-115, 117, and 273-275 on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12133884, is withdrawn in view of the amendments to incorporate the limitations of claim 101 into claim 93.
The rejection of claims 93-97, 99-100, 110-115, 117 and 273-275 on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11142760, is withdrawn in view of the amendments to incorporate the limitations of claim 101 into claim 93.
The rejection of claim 93-100, 110-115, 117 and claims 273-275, provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-6, 9, 11-12, 14, 16-17, 22-23, 27, 32, 47-48, 55, 65, 71, 76, 95 and 114 of copending Application No. 17799159 (reference application), is withdrawn in view of the amendments to incorporate the limitations of claim 101 into claim 93.
The rejection of claim 93-102, 108-115, 117, 124-127, and 273-275 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 7, 18-19, 24, 44, 60-63, 88-89, 92, 115-116, 121, 172-173, 176-178, 180-181, 184-186 and 194-195 of copending Application No. 17430298 (reference application), is upon further consideration, withdrawn in view of the amendments to incorporate the limitations of claim 101 into claim 93.
Maintained - Modified Rejections
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Non-Provisional NSDP Rejections:
Claims 276 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12133884 in view of Hirsch et al. (Antioxidants & Redox Signaling, May 2017 – cited herein).
The instant claims in their broadest are drawn to a method for deaminating an adenosine (A) nucleobase in a sense or antisense strand of an HBB gene, the method comprising contacting the HBB gene with a base editor and a guide RNA (gRNA) bound to the base editor, wherein the gRNA comprises a guide sequence that is complementary to a target nucleic acid sequence in the HBB gene, wherein the base editor comprises a fusion protein comprising (i) a nucleic acid programmable DNA binding protein (napDNAbp) domain, and (ii) an adenosine deaminase, wherein the adenosine deaminase comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of a wild-type adenosine deaminase, with the exception of substitution(s) at one or more of W23, H36, N37, P48, 149, R51, N72, L84, S97, A106, D108, H123, G125, A142, S146, D147, R152, E155, I156, K157, and K161 of the amino acid sequence of SEQ ID NO: 1, or corresponding substitution(s) in another wild-type adenosine deaminase, and wherein the step of contacting the HBB gene results in a T-A base pair in the HBB gene being mutated to a C-G base pair in the HBB gene; and the deamination corrects said mutation (Dependent claim 94-95) and the method is for treating sickle cell (Dependent claims 111-112, 117, 273-275).
The claim to the ‘884 patent in its broadest is drawn to: A method of editing a β-globin (HBB) polynucleotide comprising a single nucleotide polymorphism (SNP) associated with sickle cell disease, wherein the SNP associated with sickle cell disease results in expression of an HBB polypeptide having a valine at amino acid position 7 of SEO ID NO: 37, the method comprising contacting the HBB polynucleotide with a base editor in complex with one or more single guide RNAs (sgRNAs), wherein the base editor comprises a Streptococcus pyogenes Cas9 polynucleotide programmable DNA binding domain having specificity for a protospacer-adjacent motif comprising the nucleic acid sequence 5′-NGC-3′ and an adenosine deaminase domain, wherein the one or more guide polynucleotides target the base editor to effect an A•T to G•C alteration of the SNP associated with sickle cell disease, thereby substituting an alanine for the valine at amino acid position 7 referenced to SEO ID NO: 37, wherein the first and the last three bases of the one or more sgRNAs are phosphorothioate and 2′-O-methyl modified, and wherein the one or more sgRNAs comprise a spacer complementary to an HBB nucleic acid sequence corresponding to the target sequence ACTTCTCCACAGGAGTCAGA (positions 1-20 of SEO ID NO: 251) and adjacent to a protospacer-adjacent motif comprising the nucleic acid sequence 5′-NGC-3′. Dependent claim 4 recites the adensine deaminase has at least 85% sequence identity to amino acids 2-167 of SEQ ID NO: 151.
It is noted, the correction of valine at position 7 of SEQ ID NO: 37, is the same position as position 6 of instant SEQ ID NO: 340 (e.g. correcting a Glu to Ala substitution at position 6, e.g. a corresponding posistion), given that the two sequences are identical with the exception of an N-terminal Met for SEQ ID NO: 37 – See below (Qy = instant SEQ ID NO: 340; Db = SEQ ID NO: 37).
GenCore version 6.5.2
Copyright (c) 1993 - 2025 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: February 6, 2025, 09:14:28 ; Search time 1 Seconds
(without alignments)
0.021 Million cell updates/sec
Title: US-18-460-178-340
Perfect score: 775
Sequence: 1 VHLTPEEKSAVTALWGKVNV..........QAAYQKVVAGVANALAHKYH 146
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 147 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : AASEQ2_02062025_091426.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 775 100.0 147 1 AASEQ2_02062025_091426
ALIGNMENTS
RESULT 1
AASEQ2_02062025_091426
Query Match 100.0%; Score 775; DB 1; Length 147;
Best Local Similarity 100.0%;
Matches 146; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 VHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 VHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKV 61
Qy 61 KAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 KAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGK 121
Qy 121 EFTPPVQAAYQKVVAGVANALAHKYH 146
||||||||||||||||||||||||||
Db 122 EFTPPVQAAYQKVVAGVANALAHKYH 147
It is further noted, instant SEQ ID NO: 1 and SEQ ID NO: 151 of the ‘884 patent have 100% sequence identity to one another.
While the claims to the ‘884 patent do not recite the specific adenosine deaminase substitutions which result in an adenosine deaminase having the ability to act upon DNA, in construing the scope of the claims consistent and defined by specification of the ‘884, it clear the adenosine deaminase are defined as encompassing the same percent sequence identity and substitutions at the specific positions (See Col. 153, line 62 to Col. 154, line 1-10; Col. 155, line 65 to Col. 165, line 49) – See MPEP 804(II)(B)(1)).
The claims to the ‘884 patent, however, does not stipulate which HBB gene abnormality is specifically targeted, i.e. a gene encoding an HBB protein comprising SEQ ID NO: 340 (human hemoglobin) having a Glu 26 Lys mutation.
Hirsch et al. teach that hemoglobin E, which is a human hemoglobin having a substitution of Glu 26 Lys on the beta-strands of human hemoglobin, is very prevalent with somewhat minor outcomes (See Abstract, Critical Issues). However, if this is combined with other abnormal human hemoglobins (HBB) the outcome can be devastating and results in severe hemoglobinopathies (See Abstract, Critical Issues). It is noted, the instant specification recognizes HbE as an HBB having the Glu 26 Lys mutation (See paragraph 0189 of PG-Pub). The cause of HbE is a Glu to Lys substitution at amino acid/codon 26 caused by a GAGGlu [Wingdings font/0xE0] AAGLys substitution – See Figure 2.
Therefore it would have been obvious to one of ordinary skill in the art to specifically utilize the methods as claimed but to specifically target the HbE abnormality of Glu26Lys caused by a single point mutation of GAGGlu [Wingdings font/0xE0] AAGLys in order to revert the point mutation of Lys at position 26 back to a Glu because it would overcome and essentially cure any subject from having the potential mild or devastating effects of such a mutation as taught by Hirsch et al. This would be motivation in and of itself. One skilled in the art would have a reasonable expectation of success in doing so given the method specifically is for introducing a point mutation which at an A-T nucleotide and reverts it back to a C-G base pair, which would necessarily remove the devastating Lys at position 26 and make it the wild-type and normal Glu, thereby treating if not curing the disease as taught by Hirsch et al.
Claims 276 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11142760 in view of Hirsch et al. (Antioxidants & Redox Signaling, May 2017 – cited herein).
The instant claims in their broadest are drawn to a method for deaminating an adenosine (A) nucleobase in a sense or antisense strand of an HBB gene, the method comprising contacting the HBB gene with a base editor and a guide RNA (gRNA) bound to the base editor, wherein the gRNA comprises a guide sequence that is complementary to a target nucleic acid sequence in the HBB gene, wherein the base editor comprises a fusion protein comprising (i) a nucleic acid programmable DNA binding protein (napDNAbp) domain, and (ii) an adenosine deaminase, wherein the adenosine deaminase comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of a wild-type adenosine deaminase, with the exception of substitution(s) at one or more of W23, H36, N37, P48, 149, R51, N72, L84, S97, A106, D108, H123, G125, A142, S146, D147, R152, E155, I156, K157, and K161 of the amino acid sequence of SEQ ID NO: 1, or corresponding substitution(s) in another wild-type adenosine deaminase, and wherein the step of contacting the HBB gene results in a T-A base pair in the HBB gene being mutated to a C-G base pair in the HBB gene; and the deamination corrects said mutation (Dependent claim 94-95) and the method is for treating sickle cell (Dependent claims 111-112, 117, 273-275).
The claims to the ‘760 patent in their broadest are drawn to: A method for editing a beta globin (HBB) polynucleotide associated with sickle cell disease, the method comprising contacting a cell comprising a single nucleotide polymorphism (SNP) in the beta globin (HBB) polynucleotide with a guide RNA and a fusion protein comprising a polynucleotide programmable DNA binding domain and an adenosine deaminase domain comprising a serine (S) at amino acid position 82 of the following amino acid sequence and having at least 85% sequence identity to the following amino acid sequence
(SEQ ID NO: 2) MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNR AIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAM IHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADEC AALLCYFFRMPRQVFNAQKKAQSSTD,
wherein said guide RNA targets said polynucleotide programmable DNA binding domain to the SNP in the beta globin (HBB) polynucleotide. Dependent claim 4 recites substitutions of Y147R, Q154S, Y123H and Q154R. These positions are corresponding positions as compared to instant SEQ ID NO: 1 (in SEQ ID NO: 1, it is D147).
It is noted, instant SEQ ID NO: 1 and SEQ ID NO: 2 of the ‘760 patent have about 89% sequence identity to one another.
GenCore version 6.5.2
Copyright (c) 1993 - 2025 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: July 31, 2025, 11:21:57 ; Search time 1 Seconds
(without alignments)
0.028 Million cell updates/sec
Title: US-18-460-178-1
Perfect score: 877
Sequence: 1 MSEVEFSHEYWMRHALTLAK..........FFRMRRQEIKAQKKAQSSTD 167
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 167 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : AASEQ2_07312025_112153.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 781 89.1 167 1 AASEQ2_07312025_112153
ALIGNMENTS
RESULT 1
AASEQ2_07312025_112153
Query Match 89.1%; Score 781; DB 1; Length 167;
Best Local Similarity 91.6%;
Matches 153; Conservative 2; Mismatches 12; Indels 0; Gaps 0;
Qy 1 MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAEI 60
|||||||||||||||||||||| |||||||||||| ||||||||||| || |||||||||
Db 1 MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEI 60
Qy 61 MALRQGGLVMQNYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDV 120
||||||||||||||||||||||| ||||||||||||||||||||| |:||||||||||||
Db 61 MALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDV 120
Qy 121 LHHPGMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD 167
||:|||||||||||||||||||||| |||| || ||||||||||
Db 121 LHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD 167
Thus, the claims of the ‘760 patent render obvious the instant claims because the claims of the ‘760 patent to methods of editing HBB with a base editor or an adenosine deaminase fused to a programmable DNA binding domain and targeting said HBB gene for deamination of adenosine thereby editing the gene, having for example an A∙T to G∙C alteration (See combined claims 1, 19-22 of the ‘760 patent) render obvious the instant claims when further considering the substitutions of the specific amino acids in each set of claims directly overlap (e.g. Dependent claim 4 of the ‘760 patent recites substitutions of Y147R, Q154S, Y123H and Q154R. These positions are corresponding positions as compared to instant SEQ ID NO: 1 (in SEQ ID NO: 1, it is D147).
The claims to the ‘760 patent, however, does not stipulate which HBB gene abnormality is specifically targeted, i.e. a gene encoding an HBB protein comprising SEQ ID NO: 340 (human hemoglobin) having a Glu 26 Lys mutation.
Hirsch et al. teach that hemoglobin E, which is a human hemoglobin having a substitution of Glu 26 Lys on the beta-strands of human hemoglobin, is very prevalent with somewhat minor outcomes (See Abstract, Critical Issues). However, if this is combined with other abnormal human hemoglobins (HBB) the outcome can be devastating and results in severe hemoglobinopathies (See Abstract, Critical Issues). It is noted, the instant specification recognizes HbE as an HBB having the Glu 26 Lys mutation (See paragraph 0189 of PG-Pub). The cause of HbE is a Glu to Lys substitution at amino acid/codon 26 caused by a GAGGlu [Wingdings font/0xE0] AAGLys substitution – See Figure 2.
Therefore it would have been obvious to one of ordinary skill in the art to specifically utilize the methods as claimed but to specifically target the HbE abnormality of Glu26Lys caused by a single point mutation of GAGGlu [Wingdings font/0xE0] AAGLys in order to revert the point mutation of Lys at position 26 back to a Glu because it would overcome and essentially cure any subject from having the potential mild or devastating effects of such a mutation as taught by Hirsch et al. This would be motivation in and of itself. One skilled in the art would have a reasonable expectation of success in doing so given the method specifically is for introducing a point mutation which at an A-T nucleotide and reverts it back to a C-G base pair, which would necessarily remove the devastating Lys at position 26 and make it the wild-type and normal Glu, thereby treating if not curing the disease as taught by Hirsch et al.
Provisional NSDP Rejections:
Claim 276 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 5, 12, 14, 17, 22-23, 27, 32, 47-48, 55, 65, 71, 76, 95 and 115 of copending Application No. 17799159 (reference application) in view of Hirsch et al. (Antioxidants & Redox Signaling, May 2017 – cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims to the ‘159 anticipate the instant claims.
The instant claims in their broadest are drawn to a method for deaminating an adenosine (A) nucleobase in a sense or antisense strand of an HBB gene, the method comprising contacting the HBB gene with a base editor and a guide RNA (gRNA) bound to the base editor, wherein the gRNA comprises a guide sequence that is complementary to a target nucleic acid sequence in the HBB gene, wherein the base editor comprises a fusion protein comprising (i) a nucleic acid programmable DNA binding protein (napDNAbp) domain, and (ii) an adenosine deaminase, wherein the adenosine deaminase comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of a wild-type adenosine deaminase, with the exception of substitution(s) at one or more of W23, H36, N37, P48, 149, R51, N72, L84, S97, A106, D108, H123, G125, A142, S146, D147, R152, E155, I156, K157, and K161 of the amino acid sequence of SEQ ID NO: 1, or corresponding substitution(s) in another wild-type adenosine deaminase, and wherein the step of contacting the HBB gene results in a T-A base pair in the HBB gene being mutated to a C-G base pair in the HBB gene; and the deamination corrects said mutation (Dependent claim 94-95) and the method is for treating sickle cell (Dependent claims 111-112, 117, 273-275).
A method of engrafting nucleobase-edited hematopoietic stem cells or progenitors thereof in a subject having a hemoglobinopathy, the method comprising: (a) contacting hematopoietic stem cells or progenitors thereof in vitro with a guide RNA and a base editor comprising a polynucleotide programmable DNA binding domain and a deaminase domain, or a polynucleotide encoding the base editor, wherein the guide RNA targets the polynucleotide programmable DNA binding domain to induce a nucleobase change in a target hemoglobin (HBB) gene or in the promoter region of HBG1/ 2, thereby obtaining nucleobase-edited hematopoietic stem cells or progenitors thereof; and wherein the nucleobase-edited hematopoietic stem cells or progenitors thereof are contacted with the gRNA and the base editor within 48 hours following collection from a donor; and (b) administering the nucleobase-edited hematopoietic stem cells or progenitors thereof to a subject in an effective amount to obtain engraftment of the nucleobase-edited hematopoietic stem cells or progenitors thereof in tissues of the subject after administration.
Dependent claim 5 recites the nucleobase change is an A to G change; (See also independents claim 14, 32); wherein the cells have a single nucleotide polymorphism causing sickle cell, and as a result of an E6V substitution (claims 47-48); wherein the guide sequences in dependent claim 95 encompass those in instant claim 108 (for example SEQ ID NO: 126 comprises instant SEQ ID NO: 281) ; wherein the base editing has sickle cell or a thalassemia (claim 76). Dependent claim 6 recites the deaminase comprises a sequence having at least 85% sequence identity to SEQ ID NO: 3 and Dependent claim 9 recites substitutions at positions including Y147R, Q154R, Y123H.
It is noted, instant SEQ ID NO: 1 and SEQ ID NO: 3 of the ‘159 application have about 89% sequence identity to one another.
GenCore version 6.5.2
Copyright (c) 1993 - 2025 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: July 31, 2025, 11:32:01 ; Search time 1 Seconds
(without alignments)
0.028 Million cell updates/sec
Title: US-18-460-178-1
Perfect score: 877
Sequence: 1 MSEVEFSHEYWMRHALTLAK..........FFRMRRQEIKAQKKAQSSTD 167
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 167 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : AASEQ2_07312025_113159.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 781 89.1 167 1 AASEQ2_07312025_113159
ALIGNMENTS
RESULT 1
AASEQ2_07312025_113159
Query Match 89.1%; Score 781; DB 1; Length 167;
Best Local Similarity 91.6%;
Matches 153; Conservative 2; Mismatches 12; Indels 0; Gaps 0;
Qy 1 MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAEI 60
|||||||||||||||||||||| |||||||||||| ||||||||||| || |||||||||
Db 1 MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEI 60
Qy 61 MALRQGGLVMQNYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDV 120
||||||||||||||||||||||| ||||||||||||||||||||| |:||||||||||||
Db 61 MALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDV 120
Qy 121 LHHPGMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD 167
||:|||||||||||||||||||||| |||| || ||||||||||
Db 121 LHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD 167
The claims to the ‘159 application, however, does not stipulate which HBB gene abnormality is specifically targeted, i.e. a gene encoding an HBB protein comprising SEQ ID NO: 340 (human hemoglobin) having a Glu 26 Lys mutation.
Hirsch et al. teach that hemoglobin E, which is a human hemoglobin having a substitution of Glu 26 Lys on the beta-strands of human hemoglobin, is very prevalent with somewhat minor outcomes (See Abstract, Critical Issues). However, if this is combined with other abnormal human hemoglobins (HBB) the outcome can be devastating and results in severe hemoglobinopathies (See Abstract, Critical Issues). It is noted, the instant specification recognizes HbE as an HBB having the Glu 26 Lys mutation (See paragraph 0189 of PG-Pub). The cause of HbE is a Glu to Lys substitution at amino acid/codon 26 caused by a GAGGlu [Wingdings font/0xE0] AAGLys substitution – See Figure 2.
Therefore it would have been obvious to one of ordinary skill in the art to specifically utilize the methods as claimed but to specifically target the HbE abnormality of Glu26Lys caused by a single point mutation of GAGGlu [Wingdings font/0xE0] AAGLys in order to revert the point mutation of Lys at position 26 back to a Glu because it would overcome and essentially cure any subject from having the potential mild or devastating effects of such a mutation as taught by Hirsch et al. This would be motivation in and of itself. One skilled in the art would have a reasonable expectation of success in doing so given the method specifically is for introducing a point mutation which at an A-T nucleotide and reverts it back to a C-G base pair, which would necessarily remove the devastating Lys at position 26 and make it the wild-type and normal Glu, thereby treating if not curing the disease as taught by Hirsch et al.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Response and Examiner’s Rebuttal:
Applicants assert that since the limitations of claim 124 have essentially been introduced into what was previous claim 93, now making new claim 276, that this should overcome all the previous NSDP rejections for the three rejections above.
The Examiner acknowledges this but upon further search and consideration, the newly combined limitations have been met with the secondary reference of Hirsch et al. as cited above.
Claim 276 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 7, 18-19, 24, 44, 60-63, 88-89, 92, 115-116, 121, 172-173, 178, of copending Application No. 17430298 (reference application) in view of Hirsch et al. (Antioxidants & Redox Signaling, May 2017 – cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims to the ‘298 application anticipate the instant claims.
The instant claims in their broadest are drawn to a method for deaminating an adenosine (A) nucleobase in a sense or antisense strand of an HBB gene, the method comprising contacting the HBB gene with a base editor and a guide RNA (gRNA) bound to the base editor, wherein the gRNA comprises a guide sequence that is complementary to a target nucleic acid sequence in the HBB gene, wherein the base editor comprises a fusion protein comprising (i) a nucleic acid programmable DNA binding protein (napDNAbp) domain, and (ii) an adenosine deaminase, wherein the adenosine deaminase comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of a wild-type adenosine deaminase, with the exception of substitution(s) at one or more of W23, H36, N37, P48, 149, R51, N72, L84, S97, A106, D108, H123, G125, A142, S146, D147, R152, E155, I156, K157, and K161 of the amino acid sequence of SEQ ID NO: 1, or corresponding substitution(s) in another wild-type adenosine deaminase, and wherein the step of contacting the HBB gene results in a T-A base pair in the HBB gene being mutated to a C-G base pair in the HBB gene; and the deamination corrects said mutation (Dependent claim 94-95) and the method is for treating sickle cell (Dependent claims 111-112, 117, 273-275).
The claims to the ‘298 application in their broadest are drawn to: A method of editing a beta globin (HBB) polynucleotide comprising a single nucleotide polymorphism (SNP) associated with sickle cell disease, the method comprising contacting a beta globin polynucleotide with one or more guide RNAs and a fusion protein comprising a polynucleotide programmable DNA binding domain and at least one base editor domain that is an adenosine deaminase variant comprising a T166R alteration in the following amino acid sequence and having at least 85% sequence identity to the following amino acid sequence MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNY RLIDATLYVT FEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVE ITEGILADECAALLC YFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 2), wherein said guide RNA targets said base editor domain to effect an alteration of the SNP associated with sickle cell disease.
With dependent claims reciting the base editor effects an A∙T to G∙C alteration (claim 63, 92, 115, 116) and the HBB resulting in sickle cell disease has a Valine at position 6 of said HBB polypeptide (claim 44); and encompassing overlapping gRNA’s as in claim 60-62; and dependent claim 6 reciting substitutions at positions including Y147T/R, Q154, V82, I76, Y123.
It is noted instant SEQ ID NO: 1 and SEQ ID NO: 2 of the reference claims have about 89% sequence identity to one another.
GenCore version 6.5.2
Copyright (c) 1993 - 2025 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: July 31, 2025, 11:42:39 ; Search time 1 Seconds
(without alignments)
0.028 Million cell updates/sec
Title: US-18-460-178-1
Perfect score: 877
Sequence: 1 MSEVEFSHEYWMRHALTLAK..........FFRMRRQEIKAQKKAQSSTD 167
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 167 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : AASEQ2_07312025_114237.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 781 89.1 167 1 AASEQ2_07312025_114237
ALIGNMENTS
RESULT 1
AASEQ2_07312025_114237
Query Match 89.1%; Score 781; DB 1; Length 167;
Best Local Similarity 91.6%;
Matches 153; Conservative 2; Mismatches 12; Indels 0; Gaps 0;
Qy 1 MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAEI 60
|||||||||||||||||||||| |||||||||||| ||||||||||| || |||||||||
Db 1 MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEI 60
Qy 61 MALRQGGLVMQNYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDV 120
||||||||||||||||||||||| ||||||||||||||||||||| |:||||||||||||
Db 61 MALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDV 120
Qy 121 LHHPGMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD 167
||:|||||||||||||||||||||| |||| || ||||||||||
Db 121 LHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD 167
The claims to the ‘298 application, however, does not stipulate which HBB gene abnormality is specifically targeted, i.e. a gene encoding an HBB protein comprising SEQ ID NO: 340 (human hemoglobin) having a Glu 26 Lys mutation.
Hirsch et al. teach that hemoglobin E, which is a human hemoglobin having a substitution of Glu 26 Lys on the beta-strands of human hemoglobin, is very prevalent with somewhat minor outcomes (See Abstract, Critical Issues). However, if this is combined with other abnormal human hemoglobins (HBB) the outcome can be devastating and results in severe hemoglobinopathies (See Abstract, Critical Issues). It is noted, the instant specification recognizes HbE as an HBB having the Glu 26 Lys mutation (See paragraph 0189 of PG-Pub). The cause of HbE is a Glu to Lys substitution at amino acid/codon 26 caused by a GAGGlu [Wingdings font/0xE0] AAGLys substitution – See Figure 2.
Therefore it would have been obvious to one of ordinary skill in the art to specifically utilize the methods as claimed but to specifically target the HbE abnormality of Glu26Lys caused by a single point mutation of GAGGlu [Wingdings font/0xE0] AAGLys in order to revert the point mutation of Lys at position 26 back to a Glu because it would overcome and essentially cure any subject from having the potential mild or devastating effects of such a mutation as taught by Hirsch et al. This would be motivation in and of itself. One skilled in the art would have a reasonable expectation of success in doing so given the method specifically is for introducing a point mutation which at an A-T nucleotide and reverts it back to a C-G base pair, which would necessarily remove the devastating Lys at position 26 and make it the wild-type and normal Glu, thereby treating if not curing the disease as taught by Hirsch et al.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Response and Examiner’s Rebuttal:
Applicant’s arguments are exclusively drawn to non-provisional non-statutory double patenting. As noted in MPEP 804(I)(B)(1)(b)(i): “If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent…” However, given that these provisional rejections are not the only rejections of record remaining, they are both maintained.
Conclusion
Claims 93-96, 98-102, 108-109, 111-115, 117, 124, 126-127 and 273-275 are allowed. Claim 276 is rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUZANNE M NOAKES whose telephone number is (571)272-2924. The examiner can normally be reached M-F (7-4).
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 14 August 2026
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