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
Status of the Claims
1. Claims 1-159 are the original claims filed 3/2/2023. In the Preliminary Amendment of 6/14/2023, claims 3-17, 21-22, 136, and 158 are amended and Claims 23-77, 79-135, 137-157, and 159 are cancelled. In the Response of 3/5/2026, Claims 1-20, 78, 136, and 158 are amended and claims 21-22 are canceled.
Claims 1-20, 78, 136, and 158 are pending.
The amendments to the claims raise new grounds for rejection. This Office Action is final.
Priority
2. USAN 18/177,571, filed 03/02/2023, Claims Priority from Provisional Application 63/316,338, filed 03/03/2022.
Information Disclosure Statement
3. As of 4/9/2026, a total of one (1) IDS is filed: 10/27/2023. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objection to the disclosure because of informalities is withdrawn.
a) The specification is amended to rectify the improper use of the term ATCC, GenBank, Alexa, Octet, PROTAC, lucanix, which is a trade name or a mark used in commerce. Applicants’ explanation of the term TALEN is acknowledged and the objection withdrawn therewith.
5. The objection to the abstract of the disclosure is withdrawn for the deletion of the term “3E10”.
Claim Objections
6. The objection to Claims 1-22, 78, 136 and 158 because of informalities is moot for the canceled claims and withdrawn of the pending claims.
a) Claims 1-22, 78, 136 and 158 are amended to delete the term “3E10.”
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(a)
Written Description
7. The rejection of Claims 1-17, 78, 136 and 158 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn for the claims.
Claims 1-17, 78, 136 and 158 are amended in claim 1 to recite the VHCDR1-3 and VLCDR1-3 that are common to the species of VH and VL domains, respectively, in claim 1. The amendment establishes that any percent variation within any given VH and/or VL domain does not occur in and falls outside of the corresponding CDRs.
Claims 4-16 are amended to recite 100% identity to the SEQ ID No to which they pertain.
Rejections Maintained
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
8. The rejection of Claim 136 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained because the specification does not reasonably provide enablement for prevention of the newly recited cancers.
a) Applicants allege Claim 136 is amended to recite the claimed method is for "minimizing or partially or completely inhibiting the development of a cancer" "wherein the cancer is melanoma, pancreatic ductal adenocarcinoma, or breast cancer." The amendment to claim 136 is supported by the originally filed specification, for example at paragraph [0055].
Response to Arguments
Applicants amendment to claim 136 does not remove the claim from the original grounds for rejection. The premise of the rejection is that specification does not provide an enabling disclosure for the prevention of the cancers recited in the amended claim. For example, [0055] is dispositive to Applicants implied rationale that the claim reads on a therapeutic instead of a prophylactic; [0055] stating in part “In addition, this term [treat] includes preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder;.” Applicants have not supplemented the record with declaration evidence to substantiate a prophylactic effect.
b) Applicants allege Example 9 illustrates tumor targeting in a KPC syngeneic mouse model (paragraph [0474], FIG. 20B) and Example 11 shows an anti-tumor effect of V66 or chimeric D31N complexed with 3p-hpRNA in a B 16 melanoma mouse model (paragraph [0480].
Response to Arguments
The KPC tumor is an established tumor in the model for [0474]. See [00473] The first comparability study analyzed systemic targeted functional delivery of GFP mRNA payload to subcutaneous tumors in mice. Previous studies showed targeted functional delivery using 3E10 D31N in an MDA-MB-231 model (FIG. 20A). The current study used a subcutaneous KPC tumors. Each murine cohort was single dosed at a 10:1 weight:weight ratio (400:40ug). Tumor / normal tissue was analyzed for GFP expression by IVIS after 24 hours. The experiment measures delivery of an mRNA payload to the extant KPC tumor and that is not established as prevention.
The B16 melanoma is an established tumor in the model for [0480]. See [00478] Example 11: Comparability of chimeric 3E10 D31N and the humanized 3E10 antibodies (V66) in B16 tumor model.
[00479] Tumor stasis was previously shown using a 4:1 molar ratio of chimeric 3E10 D31N:3p- hpRNA, using the antibody at a concentration of 20 mg/kg, and administering 4 doses on a 3 to 4-day interval. The current study used the same conditions for chimeric 3E10 D31N and the humanized 3E10 antibodies (V66), and a treatment control (PBS). Dose 1 was administered at day 10,dose 2 was administered on day 13, and dose 3 was administered on day 18. The study lasted for 30-35 days. The experiment measures delivery of an mRNA payload to the extant B16 tumor and that is not established as prevention.
In the absence of a clear and defined antigen to which the claimed antibodies bind, the POSA can not reasonably practice the method invention without undue experimentation.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19, 24 (CCPA 1970). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)).
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
SEQ ID NO
18/177,571
18/841,356
18/841,043
19/150,521
19/167,684
85 VL
85
125
120
85
85
86 VL
86
126
121
86
86
87 VL
87
127
122
87
87
88 VL
88
128
123
88
88
89 VL
89
129
124
89
89
90 VL
90
130
125
90
90
64 VH
64
104
99
64
64
65 VH
65
105
100
65
65
66 VH
66
106
101
66
66
67 VH
67
107
102
67
67
68 VH
68
108
103
68
68
69 VH
69
109
104
69
69
70 VH
70
110
105
70
70
SEQ ID NO
18/177,571
18/841,356
18/841,043
19/150,521
19/167,684
91 LC
91
131
126
91
91
92 LC
92
132
127
92
92
93 LC
93
133
128
93
93
94 LC
94
134
129
94
94
95 LC
95
135
130
95
95
96 LC
96
136
131
96
96
97 LC
97
137
132
97
97
98 LC
98
138
133
98
98
99 LC
99
139
134
99
1045
100 LC
100
140
135
100
100
101 LC
101
141
136
101
101
102 LC
102
142
137
102
102
71 HC
71
111
106
71
71
72 HC
72
112
107
72
72
73 HC
73
113
108
73
73
74 HC
74
114
109
74
74
75 HC
75
115
110
75
(82)
76 HC
76
116
111
76
(83)
77 HC
77
117
112
77
77
78 HC
78
118
113
78
78
79 HC
79
119
114
79
79
80 HC
80
120
115
80
80
81 HC
81
121
116
81
82 HC
82
122
117
82
82
83 HC
83
123
118
83
83
84 HC
84
124
119
84
84
9. The provisional rejection of Claims 1-22, 78, 136 and 158 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 15, 17, 20, 24, 26, and 59 of copending Application No. 18/841,356 (reference application US 20250170259) is moot for the canceled claims and maintained for the pending claims.
Applicants invocation of M.P.E.P. 804(I)(B)(1) is not ripe in view of the outstanding and new grounds for rejection.
10. The provisional rejection of Claims 1-22, 78, 136 and 158 on the ground of nonstatutory double patenting as being unpatentable over claims 55-56, 80-86 of copending Application No. 18/841,043 (reference application US 20250161484) is moot for the canceled claims and maintained for the pending claims.
Applicants invocation of M.P.E.P. 804(I)(B)(1) is not ripe in view of the outstanding and new grounds for rejection.
11. The provisional rejection of Claims 1-22, 78, 136 and 158 on the ground of nonstatutory double patenting as being unpatentable over claims 85-89 of copending Application No. 19/150,521 (reference application) is moot for the canceled claims and maintained for the pending claims.
Applicants invocation of M.P.E.P. 804(I)(B)(1) is not ripe in view of the outstanding and new grounds for rejection.
12. The provisional rejection of Claims 1-22, 78, 136 and 158 on the ground of nonstatutory double patenting as being unpatentable over claims 79-85 of copending Application No. 19/167,684 (reference application) is moot for the canceled claims and maintained for the pending claims.
Applicants invocation of M.P.E.P. 804(I)(B)(1) is not ripe in view of the outstanding and new grounds for rejection.
New Grounds for Rejection
Claim Rejections - 35 USC § 112
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.
13. Claims 1-20, 78, 136, and 158 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 the limitation "the humanized 3E10 antibody or antigen binding fragment thereof" in the final “wherein” clause. There is insufficient antecedent basis for this limitation in claim and the dependent claims thereof. In the Response of 3/5/2026, the term was deleted throughout the claim set yet however the term is re-instated in claim 1.
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.
Written Description
14. Claims 1-20, 78, 136, and 158 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.
The POSA cannot reasonably ascertain the antigen to which the antibodies of the instant claims bind. The specification teaches the following about the antigen(s):
[0008] Advantageously, the present disclosure provides humanized 3E10 antibodies and antigen binding fragments thereof that retain core 3E10 properties, such as ENT2-based cell penetrating activity and nucleic acid binding activity. Accordingly, as described herein, the present disclosure provides humanized 3E10 antibodies and antigen binding fragments thereof, pharmaceutical compositions, and methods for treating various medical disorders using the same.
[0014] In some embodiments, a humanized 3E10 antibody or antigen binding fragment thereof described herein comprises a lysine at position 72 in the 3E10-VL, numbered according to Kabat numbering, which supports nucleic acid binding affinity.
[0015] In some embodiments, the compositions include (i) a humanized 3E10 antibody or antigen binding fragment thereof with nucleic acid binding activity.
[0045] The humanized 3E10 antibodies and antigen binding fragments thereof described herein can penetrate cells, …retain key 3E10 properties, such as sequence non-specific nucleic acid binding and antigen mediated cellular penetration. Moreover, as reported in the Examples, various combinations of the humanized 3E10 variable heavy and variable light domains have different nucleic acid binding affinities, allowing for better control of nucleic acid binding and release in vivo.
[0079] With respect to 3E10 antibodies and antigen binding fragments thereof, the cell-penetrating antibody or antigen binding fragment thereof can penetrate a cell expressing an ENT2 receptor on its cell surface in the presence of nucleic acids, e.g., non-covalently bound and/or conjugated to the 3E10 antibody or antigen binding fragment thereof, resulting in internalization of the 3E10 antibodies and antigen binding fragments thereof. In some embodiments, the cell-penetrating 3E10 antibody or antigen binding fragment thereof is conjugated to a functional molecule, e.g., a chemical agent, polynucleotide, or polypeptide.
[0099] In some embodiments, the present disclosure relates to the use of antigen binding domains (ABDs) that bind to nucleic acids, and specifically that bind to therapeutic polynucleotides used to a disease, e.g., cancer, derived from a 3E10 antibody.
[0102] In some embodiments, a humanized 3E10 antibody or antigen binding fragment thereof binds and/or inhibits Rad51. See, e.g., Turchick, et al., Nucleic Acids Res., 45(20): 11782-11799 (2017), WO 2020/047344, and WO 2020/047353, each of which is specifically incorporated by reference herein, in its entirety.
[0103] Humanized 3E10 antibodies and antigen binding fragments thereof that can be used in the compositions and methods include whole immunoglobulin (e.g., an intact antibody) of any class, fragments thereof, and synthetic proteins containing at least nucleic acid binding and ENT2 mediated cell internalization that are the hallmark of a 3E10 antibody.
[0199] In some embodiments, a humanized 3E10 antibody or antigen binding fragment thereof, of the present disclosure has a nucleic acid binding affinity for a polynucleotide, e.g., a DNA, RNA, PNA, morpholino, etc., that is less than the affinity of a reference 3E10 antibody or antigen binding fragment thereof, for example, the 3E10 monoclonal antibody produced by ATCC No. PTA 2439 hybridoma or a D31N variant thereof, has for the same polynucleotide. Accordingly, in some embodiments, the humanized 3E10 antibody or antigen binding fragment thereof, has an affinity for a polynucleotide that is from 0.00001-fold to less than 1-fold as strong as the affinity the reference 3E10 antibody has for the same polynucleotide. In some embodiments, the humanized 3E10 antibody or antigen binding fragment thereof, has an affinity for a polynucleotide that is from 0.00001-fold to 0.001-fold as strong as the affinity the reference 3E10 antibody has for the same polynucleotide. In some embodiments, the humanized 3E10 antibody or antigen binding fragment thereof, has an affinity for a polynucleotide that is from 0.0001-fold to 0.01-fold as strong as the affinity the reference 3E10 antibody has for the same polynucleotide. In some embodiments, the humanized 3E10 antibody or antigen binding fragment thereof, has an affinity for a polynucleotide that is from 0.001-fold to 0.1-fold as strong as the affinity the reference 3E10 antibody has for the same polynucleotide. In some embodiments, the humanized 3E10 antibody or antigen binding fragment thereof, has an affinity for a polynucleotide that is from 0.01-fold to less than 1-fold as strong as the affinity the reference 3E10 antibody has for the same polynucleotide.
[0248] In some embodiments, the disclosed compositions and methods utilize humanized 3E10 antibodies and antigen binding fragments thereof that maintain the ability to bind nucleic acids such as DNA, RNA, or a combination thereof.
See in particular the use of poly-dT oligonucleotide as a nucleic acid substrate for testing the affinity of the humanized 3E10 clones:
[00201] In some embodiments, binding affinity is evaluated by determining a solution concentration of the humanized 3E10 antibody or antigen binding fragment thereof needed to achieve half maximum binding (EC50) of a polynucleotide coated on a solid surface. In some embodiments, the nucleic acid is a poly-dT oligonucleotide. In some embodiments, binding of the oligonucleotide, e.g., a poly-dT oligonucleotide, is detected using an ELISA assay with a secondary anti-human immunoglobulin antibody. [00203] In some embodiments, a humanized 3E10 antibody or antigen binding fragment thereof described herein has a weak binding affinity for a poly-dT oligonucleotide.
[00446] the teaches the substrate poly-dT for measuring nucleic acid affinities for the instant claims humanized 3E10 antibodies:
The nucleic acid affinities of the 22 humanized 3E10 antibodies were investigated using a solid-phase ELISA poly-dT binding assay. Briefly, microtiter plates were coated by incubating 100 pl of pg/ml streptavidin in PBS per well overnight at 4 °C. After removing the coating solution, the wells were washed with 0.05% PBST twice. The wells were then blocked by incubating with 1% bovine serum albumin (BSA) in PBS for 1 hour at 37 °C. After removing the blocking solution the wells were washed once with 0.05% PBST. The wells were then coated with poly-dT by incubating 100 pl of 0.1 pM biotin-labeled poly-dT in ELISA buffer for 40 minutes at room temperature. After removing the coating solution, the wells were washed three times with 0.05% PBST. A 3-fold dilution series of antibody concentrations of from 100 pg/ml down to 1.69 ng/ml was established for each of the 22 humanized antibodies described above. 100 pl of each dilution were incubated in separate wells for four hours at 4 °C. After removing the dilution solutions, the wells were again washed three times with 0.05% PBST. Antibody bound to the poly-dT was detected by incubating 100 pl of a 1:10,000 dilution of a horseradish peroxidase (HRP)-conjugated secondary mouse anti-human IgG Fc antibody in each well at room temperature for 1.5 hours. After removing the secondary antibody solution, the wells were again washed three times with 0.05% PBST. The secondary antibody was detected by incubating 3,3',5,5'-Tetramethylbenzidine (TMB) in each well for 10 minutes. [00447] Binding curves for the various binding assays are illustrated in Figures 12A, 12B, 12C, 12D, and 12E. EC50 values, representing the concentration of antibody at which half maximum binding of the poly-dT was achieved, were calculated from the curves and then normalized against EC50 values determined for each experiment using a chimeric 3E10 D31N variant having the murine VH and VL sequences.
Adequate written description for an antibody appears to hinge upon whether the specification provides adequate written description for the antigen. While a specification may enable making a genus of antibodies, this does not necessarily place applicant in possession of the resultant antibodies (See In re Kenneth Alonso October (Fed. Cir. 2008) sustaining a lack of adequate written description rejection where “the specification teaches nothing about the structure, epitope characterization, binding affinity, specificity, or pharmacological properties common to the large family of antibodies” where the specification does not characterize the antigens to which the monoclonal antibodies must bind).
Conclusion
15. No claims are allowed.
16. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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