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
Applicant’s election without traverse of (1) an anti-CD3 first antigen binding moiety comprising HCDR1-3 of SEQ ID NOs: 2, 4, 10, and LCDR1-3 of SEQ ID NOs: 20-22; (2) an anti-FolR1 second antigen binding moiety comprising HCDR1-3 of SEQ ID NOs: 54-56, and LCDR1-3 of SEQ ID NOs: 20-22; (3) a masking moiety comprising HCDR1-3 of SEQ ID NOs: 58-60, and LCDR1-3 of SEQ ID NOs: 62-64; and (4) a protease cleavable linker comprising SEQ ID NO: 114 in the reply filed on 29Jan2026 is acknowledged.
Claim(s) 22-24, 29, 33-43, and 50-51 is/are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 29Jan2026.
Claim(s) 1-21, 25-28, 30-32, and 44-49 is/are currently pending and presented for examination on the merits.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in EP on 06/19/2020. It is noted, however, that applicant has not filed a certified copy of the EP20181072.8 application as required by 37 CFR 1.55.
Specification
The use of trade name(s) or mark(s) used in commerce (e.g., Thermo Scientific, GE Healthcare, Gibco, Tecan, Bio-Rad, BioLegend), 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 Objections
Claim 1 is objected to because of the following informalities:
“binding moiety comprises” in line 3 should be “binding moiety comprises:”.
Appropriate correction is required.
Claim 2 is objected to because of the following informalities:
“wherein the VH comprises” in lines 1-2 should be “wherein the VH of the first antigen binding domain comprises”.
“wherein the VL comprises” in line 3 should be “wherein the VL of the first antigen binding domain comprises”.
Appropriate correction is required.
Claim 47 is objected to because of the following informalities:
“The vector or claim 46, which is an expression vector” should be “The vector [[or]]of claim 46, wherein the vector.
Appropriate correction is required.
Claim(s) 48-49 is/are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
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.
Claim(s) 1-19, 25-28, and 44-47 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) 1-19, 25-28, and 44-47, are drawn to a multispecific molecule, wherein the masking moiety binds the idiotype of the first antigen binding moiety.
Breadth of Claims
The invention as disclosed in claim(s) 1 (and dependent claim(s) 2-19, 25-28, 44-47) recite(s) “…wherein the masking moiety is capable of binding to the idiotype of the first antigen binding moiety thereby reversibly concealing the first antigen binding moiety”. The claims are readable to encompass a genus of molecules comprising a heavy chain variable region comprising 3 HCDRs and a light chain variable region comprising 3 HCDRs. 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, recognition, and binding affinity. The claim(s) do/does not disclose the structure associated with the claimed function(s). 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.
Scope of Disclosed Species
The multispecific molecule masking moiety comprising HCDR1-3 and LCDR1-3 (SEQ ID NOs: 58-60, and 62-64, respectively) in the Applicant disclosure with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the masking moieties that the applicant was in possession of at the time of filing.
State of the Prior Art
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 that mutation to CDRs 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, Kohler et al. (Front. Immuno., Apr 2019, Col 10, Article 808; hereinafter “Kohler”) taught anti-idiotype (anti-Id) antibodies were recognized in the art [e.g., title; abstract]. Kohler taught various separate species of anti-Id antibodies were known in the art at the time of filing [e.g., introduction; pgs. 2-4]. Therefore, the prior art demonstrates that the binding of idiotype antibodies is possible by various anti-Id antibodies. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in anti-Id antibody that would allow prediction of all of the possible combinations of CDR residues that specifically bind to Idiotype antigen.
Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in an antibody that binds to the idiotype of the first antigen binding moiety, with the claimed function(s). 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 an 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-and LCDR1-3) of the masking moiety that bind binds to the idiotype of the first antigen binding moiety, without variability in the sequences thereof. Dependent claim(s) 2-19, 25-28, and 44-47 can overcome this rejection by amending claim 1 as recited above.
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, and 7-10 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-3, 45-48, and 51 of copending Application No. 17/350,457 (reference application; hereinafter “A457”), in view of WO 2017/162587 A1 (hereinafter “WO587”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim(s) 1, 8, A457 claims 1, 46 teaches an antibody comprising a first anti-CD3 antibody comprising the same instant HCDRs and LCDRs as the instant invention (see alignment below), and a second antigen binding domain that specifically binds a second antigen.
Alignment of instant anti-CD3 HCDR1-3 and LCDR1-3 (SEQ ID NOs:2, 4, 10 and 20-22, respectively) with A457 anti-CD3 HCDR1-3 and LCDR1-3 (SEQ ID NOs:2, 4, 10 and 20-22, respectively):
CLUSTAL O(1.2.4) multiple sequence alignment
529_SeqID_2x4x10xxx20x21x22 SYAMNxRIRSKYNNYATYYADSVKGxASNFPASYVSYFAYxxxGSSTGAVTTSNYANxGT 60
A457_SeqID_2x4x10xxx20x21x22 SYAMNxRIRSKYNNYATYYADSVKGxASNFPASYVSYFAYxxxGSSTGAVTTSNYANxGT 60
************************************************************
529_SeqID_2x4x10xxx20x21x22 NKRAPxALWYSNLWV 75
A457_SeqID_2x4x10xxx20x21x22 NKRAPxALWYSNLWV 75
***************
Regarding instant claim(s) 2, A457 claims 2-3 teaches the VH and VL (SEQ ID NOs: 16 and 23; see alignment below).
Alignment of instant anti-CD3 VH/VL (SEQ ID NOs: 16/23) with A457 anti-CD3 VH/VL (SEQ ID NOs: 16/23):
CLUSTAL O(1.2.4) multiple sequence alignment
529_SeqID_16xxx23 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSRIRSKYNNYAT 60
A457_SeqID_16xxx23 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSRIRSKYNNYAT 60
************************************************************
529_SeqID_16xxx23 YYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRASNFPASYVSYFAYWGQGTL 120
A457_SeqID_16xxx23 YYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRASNFPASYVSYFAYWGQGTL 120
************************************************************
529_SeqID_16xxx23 VTVSSxxxQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGG 180
A457_SeqID_16xxx23 VTVSSxxxQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGG 180
************************************************************
529_SeqID_16xxx23 TNKRAPGTPARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVL 237
A457_SeqID_16xxx23 TNKRAPGTPARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVL 237
*********************************************************
Regarding instant claim(s) 7, A457 claim 45 teaches the first antigen binding domain is a Fab.
Regarding instant claim(s) 9-10, A457 claims 47 teaches the molecule further comprises a third antigen binding domain that specifically binds the second antigen, and claims 48, 51 teaches the second and third antigen binding domains are each a Fab.
A457 does not expressly teach (1) a protease cleavable multispecific molecule comprising (a) an anti-CD3 first moiety comprising HCDR1-3 and LCDR1-3, or VH/VL(SEQ ID NOs:2, 4, 10 and 20-22, or 16/23, respectively), (b) a second antigen binding moiety capable of binding to a target cell antigen, and (c) a masking moiety covalently attached to the T cell binding molecule through a protease-cleavable linker, wherein the masking moiety is capable of binding to the idiotype of the first antigen binding moiety, thereby reversibly concealing the first antigen binding moiety; or (2) the multispecific molecule of “(1)” wherein, (a) the first antigen binding domain is a Fab, (b) a third antigen binding domain that is an identical Fab to the second antigen binding domain.
WO587 teaches protease activated T cell multispecific molecule comprising an anti-CD3 binding domain, a second antigen binding domain that recognizes a second antigen, and an anti-idiotype masking moiety [e.g., title; abstract; pg. 40, lines 27-32, pgs. 41, 86-87, 114 ; figs. 1A].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the CD3 antigen binding domain of the multispecific molecule as taught by WO587, with the CD3 antigen binding domain as taught by A457, in the context of designing and developing a protease cleavable T cell activating multispecific molecule therapy. A PHOSITA would have been motivated to substitute the CD3 binding domain as taught by A457 in place of the CD3 antigen binding domain of the multispecific molecule as taught by WO587, because WO587 teaches the base multispecific structure comprising a CD3 arm to engage T cells, and A457 teaches a CD3 arm for a multispecific antibody. Further, WO587 and A457 are disclosures from the same Applicant, and therefore all of the elements required for the substitution were readily available to make the substitution, and it is common practice in the art to try different antigen recognizing domains/combinations for lead optimization, and therefore such a substitution would be obvious to try to a skilled artisan. There would have been a reasonable expectation of success for a PHOSITA to substitute the CD3 binding domain as taught by A457 in place of the CD3 antigen binding domain of the multispecific molecule as taught by WO587, because WO587 teaches the base multispecific structure comprising a CD3 arm to engage T cells, and A457 teaches a CD3 arm for a multispecific antibody. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified protease-activatable multispecific molecule of A457 and WO587 (see above) to include that the multispecific molecule further comprises (a) the first antigen binding domain is a Fab, (b) a third antigen binding domain that is an identical Fab to the second antigen binding domain, as taught by A457, because A457 and WO587 teach the base protease-activatable T cell multispecific molecule, and A457 further teaches specific structures for the moieties thereof. There is an expectation of success for a PHOPSITA to substitute the selected moieties of the protease-activatable multispecific molecule of A457 and WO587, with the specific moieties as taught by A457, because A457 and WO587 teach the base protease-activatable T cell activating multispecific molecule, and A457 further teaches specific structures for the moieties thereof. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Allowable Subject Matter
Claim(s) 20-21 is/are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. (See reasons for the indication of allowable subject matter below).
Claim(s) 30-32 is/are allowed. (See reasons for indication of allowable subject matter below).
The following is a statement of reasons for the indication of allowable subject matter:
Specifically, claim(s) 20-21 and 30-32 require (1) an anti-CD3 bispecific antibody antigen binding domain comprising HCDR1-3 of SEQ ID NOs: 2, 4, 10 and LCDR1-3 of SEQ ID NOs: 20-22, and (2) an anti-idiotype masking domain comprising HCDR1-3 of SEQ ID NOs: 58-60 and LCDR1-3 of SEQ ID NOs: 62-64. The anti-CD3 domain and the anti-idiotype masking moiety were each found to nonobvious in view of the prior art. Briefly, a sequence search of the prior art returned no 100% matches to either of the instant claimed HCDR1-3 (SEQ ID NOs: 2, 4, 10 for anti-CD3; SEQ ID NOs: 58-60 for anti-Idiotype), and therefore cannot return a 100% match to the combined HCDR1-3 and LCDR1-3 of the instant claimed anti-CD3 antibody binding domain or the anti-idiotype masking moiety (see closest prior art alignments below).
Alignment of anti-CD3 HCDR1-3 (SEQ ID NO: 2, 4, 10) with WO2020132574-A1 (Anti-EGFR-CD3 bAb (proBiTE-1s1spg) heavy chain construct, SEQ 52):
PNG
media_image1.png
236
619
media_image1.png
Greyscale
Alignment of anti-Idiotype masking moiety HCDR1-3 (SEQ ID NO: 58-60) with WO2017162587-A1 (Anti-idiotypic CD3 IgG scFv 4.15.64, SEQ:41):
PNG
media_image2.png
232
616
media_image2.png
Greyscale
Conclusion
Claims 1-21, 25-28, and 44-49 are NOT allowed. Claims 30-32 are allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu 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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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643