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 .
Claims Status
Claim(s) 1-12 is/are currently pending and presented for examination on the merits.
Response to Amendment
The objection(s) to claim(s) 2, 9, and/or the specification, as well as the 112(f) claim interpretation of claims1-2, 5-12 have been withdrawn in view of the Amendment filed on 21Jul2026.
The rejection(s) of claim(s) 1-2, 5-12 under 35 U.S.C. § 112(a)-enablement, of claim(s) 3-4 under 35 U.S.C. § 112(a)-written description, and of claim(s) 1, 5-12; 1-2 under 35 U.S.C. § 102 have been withdrawn in view of the recent claim amendment filed on 21Jul2026, which added new limitations to the claims, that were not considered in the previous rejections.
All other previously presented rejection(s) and objection(s) are maintained for reasons given in the "Response to Arguments" below. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(a) -written description
Claim(s) 1-12 is/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.
Claimed Invention
Claim(s) 1-12, are drawn to an antibody that binds CD38 antigen.
Breadth of Claims
Further the invention as disclosed in claim(s) 1-12 recite(s) “…an antigen binding domain binding the extracellular domain of CD38, wherein the binding of said antibody to the extracellular domain of CD38 does not affect the number and activity of populations of T, B and NK cell in vitro…” in claim 1. The specification identifies a one monoclonal antibody, 1 bispecific antibody, and 2 CAR constructs comprising a single set of 6 CDRs (e.g., HCDR1-3 are the same across all the examples; see summary table below for details). One of ordinary skill in the art would understand that the 6 CDRs of an antibody are responsible for antigen binding characteristics, including antigen specificity, binding affinity, and affects thereof (e.g., on populations of T, B and NK cells). The claim does not disclose the structure associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision light and heavy chain sequences, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Further, the invention as disclosed in claim(s) 3-4 are readable to 3CDRs, which is effectively half of an antibody binding site of a classical antibody, as being sufficient for a functional antibody binding region. Specifically, the claim limitations as written require only either (1) HCDR1-3 (e.g., claim 2), or (2) one VH domain comprising 3 CDRs (e.g., HCDR1-3), which is effectively half an antibody binding site missing either (1) the LCDR1-3 complement, or (2) the VL complement comprising LCDR1-3, to create a full antibody binding site (e.g., 6 CDRs). One of ordinary skill in the art would understand that one cannot use half of an antibody binding domain (e.g., HCDR1-3 only; VH only) and reasonably expect to maintain CD38 antigen binding function.
Scope of Disclosed Species
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The anti-CD38 antibody and/or antigen binding domains in the Applicant disclosure (see summary tables above) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the anti-CD38 antibody and/or antigen binding domains that the applicant was in possession of at the time of filing. The disclosure defines the term “antibody” as comprising any of a list of antigen binding fragments and/or types of antibodies including single domain antibodies [e.g., pg. 3, lines 26-40; pg. 4, lines 1-8]; however, no anti-CD38 single domain antibodies (e.g., VHH antibodies) are specifically disclosed, nor is any evidence of testing the claimed single-domain antibody. Therefore, at the time of filing Applicant was considered to be in possession of only classical antibodies and/or antigen binding domains thereof that bind CD38 antigen.
State of the Prior Art
Classical Antibodies
At the time of filing, antibody functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that changes to the CDR region(s) is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, ¶ 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, ¶ 3].
At the time of filing, US 2019/0135937 A1 (hereinafter “US937”) taught anti-CD38 antibodies and/or antigen binding domains thereof were recognized in the art [e.g., abstract; ¶ 0005-0009; tbl. 1]. US937 taught various separate species of anti-CD38 antibodies and/or antigen binding fragments thereof [e.g., ¶ 0005-0009; tbl. 1]. Therefore, the prior art demonstrates that the binding of CD38 antigen is possible by various anti-CD38 antibodies. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in anti-CD38 antibody and/or antigen binding fragment thereof that would allow prediction of CDR residues that specifically bind to CD38 antigen.
VHH Antibodies
At the time of filing, VHH single domain antibody antigen binding domain functionality was known to depend on the entire structure, particularly a full complement of three CDRs. It is understood by one of ordinary skill in the art that that uncharacterized CDR binding is unpredictable and that each VHH construct requires function testing.
Bever et al. (Anal Bioanal Chem (2016) 408:5985–6002; hereinafter “Bever”) teaches VHH antibodies, and the production and screening thereof [e.g., title, abstract]. Bever teaches Nanobodies® are VHH domain antibodies that are heavy chain only (e.g. HcAb) that are naturally produced by camelids and sharks [e.g., pg. 5985, “Introduction”]. Bever teaches the overview of process of making VHH antibodies wherein (1) an alpaca is the camelid species, (2) mRNA is collected from the alpaca and a cDNA library is constructed therefrom, (3) VHH genes are isolated, (4) a phage-display VHH library is generated, (5) solid phase panning conducted to select the desired VHH, and (6) desired VHH is obtained [e.g., fig. 2].
Further, near the time of filing, Hacisuleyman and Erman (Journal of Biological Physics (2020) 46:189–208; hereinafter “Hacisuleyman”) teaches VHH optimization [e.g., title, abstract]. Hacisuleyman teaches VHH antibodies comprise 3 CDRs which determine target specificity, with CDR3 being the “dominating contributor in antigen recognition” [e.g., pg. 191; fig. 2]. Hacisuleyman further teaches residue numbers for the VHH CDRs may vary, and that in nature CDRs are mutated naturally to increase the binding affinity and specificity towards a target antigen [e.g., pg. 191]. Hacisuleyman teaches that computational screening methods for optimization are a first step that is then followed by experimental strategies [e.g., pg. 191]. Hacisuleyman does not support de novo generation of VHH CDRs to bind a selected antibody, but rather requires the researcher start with a VHH antibody known to bind the target antigen [e.g., 191].
At the time of filing, WO 2017/081211 A2 (hereinafter “WO211”) taught anti-CD38 single domain antibodies were recognized in the art [e.g., title, abstract; tbl. 4.3A].WO211 taught various separate species of anti-CD38 single domain antibodies [e.g., tbl. 4.3A; example 5]. Therefore, the prior art demonstrates that the binding of CD38 is possible by various anti-CD38 single domain antibodies. The prior art does not teach a known structure activity relationship for CDR1-3 in anti-CD38 single domain antibody that would allow prediction of all of the possible combinations of CDR residues that specifically bind to CD38 antigen.
Summary
Thus, (1) creating a classical antibody comprising 6 CDRs (e.g., HCDR1-3 and LCDR1-3 that would possess the recited function and/or (2) creating a VHH antibody comprising half of the CDR sequences of a classical antibody (e.g., HCDR1-3) is a highly unpredictable process and one skilled in the art could not a priori make any predications nor envisage the breadth of all of the possible (1) classical antibody 6 CDR (e.g., HCDR1-3 and LCDR1-3), and/or (2) single domain 3 CDR combinations (e.g., HCDR1-3) that would still possess the required function(s). Further, one skilled in the art would understand that the full 6 CDR complement of a classical antibody are required for antigen binding, and a skilled artisan could not a priori make any predications nor envisage the breadth of all of the possible 3 CDR combinations (e.g., HCDR1-3) of a classical antibody that would still possess the required function (e.g., maintain CD38 antigen binding) without the light chain complement (e.g., LCDR1-3).
Conclusion
Per the instant disclosure, Applicant is only in possession of anti-CD38 classical antibody binding domain(s). As indicated by the art, a full complement of 6 CDRs are required for classical antibody antigen binding and one cannot predict which, if any, 3 CDR combinations (e.g., HCDR1-3) thereof would still result in an antibody that binds CD38 antigen. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in a classical antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 1 would need to recite the 6 CDRs (e.g., HCDR1-3 and LCDR1-3) in the antibody that bind CD38 antigen with the claimed functions, without variability in the sequences thereof. Claims 2-12 can overcome this rejection by amending claim 1 as described above.
Response to Arguments
Applicant argues:
Claim 3 is amended to depend from claim 1 and therefore now also recites the structural limitations thereof, and therefore overcome written description. Further, “The specification provides examples of antibodies and antibody fragments having antigen-binding domains targeting the extracellular domain of CD38, including scFv and bispecific antibody formats, and discloses BB51-derived CD38-binding sequences, including VH SEQ ID NO:3 and H-CDR1, HCDR2, and H-CDR3 as SEQ ID NOs:5-7, together with the corresponding light chain variable region and CDRs…Therefore, the specification provides sufficient support for the claimed CD38-binding antibody, including the recited H-CDR sequences of SEQ ID NOs:5-7 and the functional property inherited from claim 1. The written description requirement is therefore met.”
In response, per Applicant’s own response regarding claim 3, the instant disclosure teaches BB51 antibody comprising heavy chain and light chain domains; however, this is not sufficient to provide written description for a single-domain antibody comprising only the heavy chain binding domain of the BB51 antibody, for the reasons discussed in detail in the rejections above. Further, new rejections are included herein for the recitation of functional limitations (e.g., “wherein the binding…does not affect the number and activity of populations of T, B and NK cells in vitro”) without the associated structure (e.g., HCDR1-3 and LCDR1-3), see rejections above for details.
Applicant arguments have been thoroughly reviewed but are not persuasive. The new rejection(s) necessitated by amendment(S) of claim(s) 1-12 are maintained.
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.
Claim(s) 1-2, 6-12 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-12, 17-23, 25 of U.S. Patent No. 12,319,745 B2 (hereinafter “US745”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim(s) 1, US745 claim(s) 1-12 teach species of anti-CD38 antibody that anticipate the genus of instant claim 1.
Regarding instant claim(s) 2, US745 claim(s) 1, 5 teach a species of humanized anti-CD38 antibody that anticipates the genus of instant claim 2.
Regarding instant claim(s) 6, US745 claim(s) 17-18 teach a nucleic acid sequence encoding the anti-CD38 antibody.
Regarding instant claim(s) 7, US745 claim(s) 19 teaches a vector comprising the nucleic acid of claim 17.
Regarding instant claim(s) 8-9, US745 claim(s) 20 teaches a host cell engineered to express the anti-CD38 antibody, and US745 claim(s) 21 teaches the host cell is a CAR T cell.
Regarding instant claim(s) 10, US745 claim(s) 22 teach a method of treating or inhibiting cancer in a patient in need thereof comprising administering to the subject the anti-CD38 antibody and/or a population of CAR T cell engineered to express the anti-CD38 antibody. The
Regarding instant claim(s) 11, US745 claim(s) 25 teaches the cancer is a CD38-positive hematological malignancy.
Regarding instant claim(s) 12, US745 claim(s) 23 teaches a pharmaceutical composition comprising the anti-CD38 antibody.
For the purposes of compact prosecution, Applicant is advised that the anti-CD38 antibody of US745 claim(s) 1-3 recites identical sequences to those of the (1) instant claimed VHH HCDR1-3 and VH sequences; and/or (2) the instant disclosed anti-CD38 “BB51” antibody (e.g., anti-CD38 antibody Applicant was in possession of at time of filing, see 112a rejection above for details).
Claim 1, 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-9 of copending Application No. 18/725,312 (reference application; hereinafter “A312”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim(s) 1, 10, A312 claim(s) 1-9 teach a method for treating T cell lymphoma (e.g., cancer) in a patient in need thereof comprising administering an anti-CD38 antibody species that anticipates the genus of instant claim 1.
For the purposes of compact prosecution, Applicant is advised that the anti-CD38 antibody of A312 claim(s) 1, 4, 6 recites identical sequences to those of the (1) instant claimed VHH HCDR1-3 and VH sequences; and/or (2) the instant disclosed anti-CD38 “BB51” antibody (e.g., anti-CD38 antibody Applicant was in possession of at time of filing, see 112a rejection above for details).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues:
Concurrently filed herewith is a terminal disclaimer to obviate the double patenting issue with respect to the parent US Patent 12,319,745.
No response was provided for the provisional non-statutory double-patenting over copending Application No. 18/725,312.
In response, the terminal disclaimer filed in reference to US Patent 12,319,745 was not approved. It is noted that “The applicant cited on the TD must be cited exactly as it is cited on the ADS form, in its entirety. Please resubmit the TD.”. Additionally as no arguments and/or terminal disclaimer were filed for copending Application No. 18/725,312, the rejection is maintained.
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) are maintained.
Free From the Prior Art
During the course of examination, the anti-CD38 “BB51” antibody antigen binding domain comprising (1) HCDR1-3 and LCDR1-3 of SEQ ID NOs: 5-7 and 8-10; (2) a VH/VL of SEQ ID NOs: 3/4, and/or (3) an scFv of SEQ ID NO: 11 were found to nonobvious in view of the closest prior art. Briefly, a sequence search of the prior art returned no 100% matches to either of the instant claimed HCDR1-3, VH, or scFv and therefore cannot return a 100% identity match to the antigen binding domain of anti-CD38 “BB51” antibody (see closest prior art alignments below).
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Alignment of anti-CD38 “BB51” antibody HCDR1-3 (SEQ ID NO: 5-7) with WO2018112474-A1 (Human anti-LGALS3BP mAb VH_166 VH CDR1/CDR2/CDR3 fusion protein SEQ 1503):
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Alignment of anti-CD38 “BB51” antibody VH (SEQ ID NO: 3) with CN112142847-A (Anti-B7-H3 antibody VH region, SEQ ID 13):
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Alignment of anti-CD38 “BB51” antibody scFv (SEQ ID NO: 11) with WO2019136419-A2 (Anti-CD99 single-chain variable fragment (scFv) antibody, SEQ 88):
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Conclusion
No claims are currently allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
