DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a U.S. national phase of International Application No. PCT/US2021/050341, filed on 09/14/2021, which claims domestic benefit to US provision application 63/078,134, filed 09/14/2020.
Claim Status
The amendment, filed on 11/08/2023, in which claims 1, 3, 6, 11-12, 14, 16, 18, 20, 24, 26, 29-31, and 33 are amended; claims 2, 4-5, 7-10, 13, 15, 17, 21-23, and 27-28 are canceled; and claims 34-35 are new, is acknowledged.
Claims 1, 3, 6, 11-12, 14, 16, 18-20, 24-26, and 29-35 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/08/2023 has been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
¶ [0085], line 1 - missing space between “theCAR”
¶ [0085], line 6 - “emboidments” should read “embodiments”
¶ [0092], line 2 - “limintation” should read “limitation”
¶ [0114], line 4 - “syalylated” should read "sialylated"
¶ [0133], second to last line - “ABiraterone” should read “Abiraterone”
¶ [0179], line 14 - “mTanerine” should read “mTangerine”
¶ [0199], line 2 - “m-Dish” should read “μ-Dish”
¶ [0203], line 6 - space missing between “1min”
Appropriate correction is required.
The use of the terms: “BIACORE” (¶ [0126], line 2), “lipofectin” (¶ [0153], line 11), “lipofectamine” (¶ [0190], line 4), “Dynabeads” (¶ [0190], line 10), “AIM-V” (¶ [0190], lines 11, 13, and 17), “IncuCyte” (¶ [0193], lines 4 and 7), “IVIS” (¶ [0203], line 4), “Living Image” (¶ [0203], line 6, and “(GraphPad) Prism” (¶ [0205], line 1), which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 14 and 26 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.
The phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. While the use of the term “optionally” is not pro se indefinite, as used in the instant claims the term reads as exemplary claim language and introduces ambiguity to the claims as the intended scope of the claims becomes unclear. See MPEP § 2173.05(d) and MPEP § 2173.05(h)(II).
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.
Claims 1, 6, 11-12, 14, 16, 18-20, 24-26, and 29-35 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.
Instant claim 1 is drawn to an anti-CD33 antibody, or antigen-binding fragment thereof, comprising an amino acid sequence selected from a group consisting of SEQ ID NOs: 1-88 or a complementarity determining region (CDR) sequence encompassed within any one of SEQ ID NOs: 1-88. Similarly, instant claim 6 is drawn to an anti-CD33 antibody or antigen-binding fragment thereof, comprising a VHH comprising an amino acid sequence selected from a group consisting of SEQ ID NOs: 1-88 or a CDR encompassed within any one of SEQ ID NO: 1-88. These claims encompass a genus of antibody formulations which suggests interchangeability of CDRs from any one of the sequences provided.
MPEP 2163.II.A.3.a.ii. states that the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.
The instant specification discloses 11 species of single domain anti-CD33 antibodies (pages 67-72) with sufficient written description summarized in the table below. However, guidance for arriving at additional variations encompassed by the genus of anti-CD33 antibodies as currently claimed is not sufficient to allow one of ordinary skill in the art to envision all potential CDR combinations within sequences claimed (SEQ ID NO: 1-88) that would predictably retain CD33 binding.
SEQ ID NO:
#
Clone
VDJ
CDR1
CDR2
CDR3
1
Hu195
1
3
5
7
2
348
9
11
13
15
3
353
17
19
21
23
4
389
25
27
29
31
5
413
33
35
37
39
6
416
41
43
45
47
7
420
49
51
53
55
8
424
57
59
61
63
9
426
65
67
69
71
10
429
73
75
77
79
11
430
81
83
85
87
The state of the art near the effective filing date of the claimed invention demonstrates that antibody functionality is dependent on amino acid structure, particularly regarding complementarity of the CDRs. It is understood by one of ordinary skill in the art that mutations to CDRs is unpredictable and that each construct requires function testing.
Rabia (Biochem Eng J. 2018 Sep 15;137:365-374.) teaches that antibody-antigen binding specificity is primarily mediated by their CDRs within the sequences of variable regions (Introduction, ¶ 1). Given the chemical diversity possible within combined CDRs alone (~20 different amino acids at ~60 sites), not all combinations can result in viable antibodies suitable for therapeutic applications. Rabia et al. teaches that natural antibody maturation relies on random somatic mutations followed by clonal selection for antibodies with improved affinity and/or with mutations that compensate for destabilizing affinity enhancing mutations (page 366, column 2, ¶ 2). However, it is expected that most somatic mutations that increase affinity, such as those that increase hydrophobicity or charge, can also reduce specificity. For instance arginine in CDRs was identified as the greatest risk factor for non-specific interactions (page 368, column 1, ¶ 5). In a study involving optimization of a camelid single domain antibody alanine mutations were used to identify 14 permissive sites within CDR2 and CDR3, though most single reversion affinity-enhancing mutations acquired by the first antibody variant reduced specificity (Figure 3A; page 368, column 2, ¶ 2). Furthermore, affinity/specificity trade-offs of individual mutations were highly context dependent as an identical mutation (S96) in a closely related variant antibody lead to opposite impacts on antibody specificity (Figure 3; page 368, column 2, ¶ 2) Based on these teachings, introducing mutations in antibody structure, particularly in the CDR regions, requires thorough testing to ensure suitable binding specificity and antibody stability.
Koenig (PNAS USA. 2017;114(4):E486-E495) teaches that single amino acid mutations across both VL and VH can alter stability and antibody-antigen binding. In generating a single mutation library in VL and VH chains (Figure 1), Koenig et al. identified mutations distal to CDRs can improve anti-VEGF antibody G6.31 stability (anti-gD tag; enriched in red) and affinity (VEGF; enriched in red), but conserved framework positions including the hydrophobic core and interface residues in addition to a few CDR positions, particularly in HCDR3, exhibited low tolerance to mutation (depleted in blue/ strongly depleted in black). Furthermore, single cysteine mutations or single residue deletions in nearly all residues across VL and VH chains resulted in reduced stability and binding. Therefore, a single mutation, let alone full swapping of CDRs (variability in CDRs) as encompassed by the instant claim could therefore potentially result in loss of antibody stability and/or binding.
Regarding single domain antibodies (sdAbs) recombinantly-produced from heavy chain variable regions specifically (i.e. VHH with 3 CDRs instead of 6 CDRs), Zabetakis (PLoS One. 2013;8(10):e77678) teaches the highly-variable CDRs embody the specific binding interaction of the antigen-antibody complex (introduction ¶ 2). Through CDR swapping experiments in sdAbs, Zabetakis observed that while swapping framework regions and CDRs will work in some cases to increase thermal stability this can cause unpredictable variability in affinity (i.e. swapping CDRs within sdAbs can change target specificity) (Abstract; Table 1; page 5, column 2, last ¶ ).
Overall, neither the disclosure nor the prior art recognize a fully mapped structure- function relationship that would allow a priori determination of antibody sequence within the breadth of the claimed genus that fulfills claimed function of GPC3 binding with reasonable expectation of success. As such, an ordinarily skilled artisan would not have recognized that applicant was in possession of the entire scope of the claimed genus at the time of the effective filing date of the claimed invention and; therefore, instant claims 1 and 6, and additional dependent claims 11-12, 14, 16, 18-20, 24, 26, and 29-35, which do not rectify the issues presented within said claim as stated above, were found to not meet the written description requirement of 35 USC 112(a).
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.
US 18/026,092
Claims 1, 3, 6, 16, 18-20, 24-26, and 34-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 12, 15-16, 19, 27 and 37 of copending Application No. 18/026,092 (herein US092). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1, 3, 16, 18, and 24, claim 1 of US092 claims an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the comprises a CD33 binding domain, wherein the encoded CD33 binding domain comprises a heavy chain variable region and/or a light chain variable region. Subsequent dependent claim 10 of US092 further specifies the CAR of claim 1 further comprises any one of sequences that are identical to instant anti-CD33 VDJ sequences within instant claims 1, 3, and 6 (see table below). Therefore a skilled artisan would recognize that an antigen binding fragment as disclosed in the CAR recited in US092 would be within scope of the antigen binding fragments and chimeric antigen receptor comprising said antigen binding fragment with identical antigen-binding sequences as recited in the instant claims.
SEQ ID NOs:
Instant VDJ
US092 binding domain
9
69
17
61
25
60
73
83
Regarding claims 19-20 and 25-26 (dependent on claim 1), claim 12 of US092 claims an expression vector comprising the nucleic acid molecule of US092 claim 1. Claim 15 of US092 claims an immune effector cell comprising the nucleic acid molecule (i.e. an expression construct) of US902 claim 1 discussed above as within scope of instant anti-CD33 antigen-binding fragment in view of US902 claim 10. Moreover, claim 16 of US092 claims the immune effector cell of US902 claim 15, wherein the cell is selected from cell types within scope of species listed in instant claim 20 (lymphocyte, T-cell or an NK cell).
Regarding claims 34-35 (dependent on claim 19), claim 19 of US092 claims a method of treating a hematopoietic malignancy, comprising administering an immune cell expressing anti-CD33 chimeric antigen receptor. In view of sequences claimed in subsequent dependent claim 37 of US092 (same overlapping identical species as disclosed in the table above), a skilled artisan would recognize these immune cells expressing anti-CD33 CAR would be within scope of the anti-CD33 CAR expressing immune cells of the instant invention. Claim 27 of US092 further claims the malignancy of US092 claim 19 as characterized by the expression of CD33 (i.e. CD33-associated disease).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
Antibody/antigen-binding fragment species with sufficient written description as discussed above (11 sdAb with specific CDR sets) are free from prior art.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647