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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 18 December 2025 has been entered.
Status of Application
The amendments and response filed 18 December 2025 are acknowledged and have been considered in their entireties. Withdrawn claims 62 and 265 are cancelled; and claims 97 and 125 are also canceled, their limitations inserted into claims 96 and 124, respectively; Thus, claims 93-96, 98-102, 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 273-275 are subject to examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 18 December 2025 has been considered by the examiner. See initialed and signed PTO/SB/08.
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 93-98, 99-100, 111-115, 117, and new claims 273-275 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12133884.
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 ‘884 patent in their broadest are 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)).
Thus, the claims of the ‘884 patent render obvious the instant claims.
Claims 93-97, 99-100, 110-115, 117 and new claims 273-275 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11142760.
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).
Applicant’s Response and Examiner’s Rebuttal:
Applicant’s traverse the two non-provisional non-statutory double patenting (NSDP) rejections over US Patents 12133884 and 11142760. Applicant’s have not argued against the merits that the two patents are indistinct from the instant applications claims. Rather, they have argued that the rejections are improper given the recent Federal court decision of Allergen USA, Inc. v MSN Labs, Private Ltd., I111 F. 4th 1358 (Fed. Circ. 2024) and the Patent Trial Appeal Board (PTAB) decision in Ex parte Baurin, Appeal 2024-002920, Appl. No. 17135529 (PTAB Nov. 6, 2024). Essentially Applicant’s arguments can be distilled down to the following: because the present Application is earlier-filed and earlier expiring relative to each of the cited patents, the cited patents are later-filed, later-expiring, and unrelated (at least by continuity) patent documents that cannot serve as proper references in a non-provisional NSDP rejection (See Remarks, p. 11).
The examiner acknowledges Applicant’s arguments but does not find them convincing. It is noted, Applicant’s are not arguing the merits of the rejection that the patent and claims and the instant claims are not indistinct.
First, In re Allergen, as acknowledged by Applicant’s differs from the instant situation because the references/patents in question here do not share the same priority date.
Second, regarding the merits of Ex parte Baurin, this decision is a non-precedential decision and as such, the merits of the decision will not be discussed in depth herein. However, there is a distinction in both the decisions of In re Allergen and Ex parte Baurin, that should be made regarding this instant application and that is, this application can never be considered as the “first patent ever” in the family or even in a series of unrelated patents.
Third, Applicant’s seemingly are overlooking the fact there are two separate justifications for making a double patenting rejection. See In re Hubbell, 709 F. 3d 1140 (Fed. Cir. 2013) (“There are two justifications for obviousness-type double patenting. The first is ‘to prevent unjustified timewise extension of the right to exclude granted by a patent no matter how the extension is brought about.’ … The second rationale is to prevent multiple infringement suits by different assignees asserting essentially the same patented invention … this court reaffirmed the multiple assignee harassment rationale and applied it to a situation where, as here, the patents were related to the application only by way of a common inventor … ."). See also MPEP 804(II)(B) (“A rejection based on nonstatutory double patenting is based on a judicially created doctrine grounded in public policy so as to prevent the unjustified or improper timewise extension of the right to exclude granted by a patent … A double patenting rejection also serves public policy interests by preventing the possibility of multiple suits against an accused infringer by different assignees of patents claiming patentably indistinct variations of the same invention. In re Van Ornum, 686 F.2d 937, 944-48, 214 USPQ 761, 767-70 (CCPA 1982).”).
As such, and for these reasons, the instant rejections of record are maintained.
Provisional NSDP Rejections:
Claim 93-100, 110-115, 117 and new claims 273-275 are 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). 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
Thus, the claims of the ‘159 application render obvious the instant claims because the claims of the ‘159 application ultimately recite 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, resulting for example in a G6V substitution, resulting in sickle cell or thalassemia, wherein said reference claims are further obvious to the instant claims when also considering the substitutions of the specific amino acids in each set of claims directly overlap (e.g. Dependent claims 9, 11, 12) of the ‘159 application 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).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 93-102, 108-115, 117, 124-127 and new claims 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). 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
Thus, the claims of the ‘298 application render obvious the instant claims because the claims of the ‘298 application ultimately recite 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, resulting for example in a G6V substitution, resulting in sickle cell or thalassemia, wherein said reference claims are further obvious to the instant claims when also considering the substitutions of the specific amino acids in each set of claims directly overlap (e.g. Dependent claims 9, 11, 12) of the ‘298 application 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).
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
No claim is allowed.
It is noted, the amendments to the claims did not in any way change the scope of the previously examined claims. Canceled claim 97 was previously dependent upon claim 96; the limitations from claim 97 have been introduced into claim 96, thus there is no difference in scope. Canceled claim 125 was previously dependent upon claim 124, the limitations from claim 125 have been introduced into claim 124, thus there is no difference in scope. The remaining amendments do not alter the scope of the previously examined claims in any way.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 14 January 2026