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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 22, 2026 has been entered.
Application Status
The amended claims filed September 22, 2026 are acknowledged. Claims 24-30, 36-37, 39-40, 45, and 47 have been canceled. Claims 22, 41-44, and 46 have been amended.
Claims 22-23, 31-35, 38, 41-44, and 46 are pending and under examination herein.
WITHDRAWN OBJECTIONS AND REJECTIONS
All prior objections and/or rejections of claims 24-30, 36-37, 39-40, 45, and 47 are rendered moot by the cancelation of the claims.
The prior grounds of rejection over claim 46 under 35 U.S.C. § 112(b) are withdrawn in view of Applicant's amendments to the preamble of the claim.
The rejection of claims 22-23 and 31-35 under 35 U.S.C. § 102 as being anticipated by Young (US 2018/0118808 A1; cited in IDS) is withdrawn in view of Applicant's amendments to claim 22.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Objections
Claims 43-44 are objected to for the following informalities: The claims appear to contain a misspelling of “biotinidase” as “bitoinidase” in line 2.
Appropriate correction is required.
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.
Claim 46 is 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 46 recites the method of claim 22, wherein “a surface-attached polypeptide comprising a small molecule acceptor peptide further comprises a binding domain specific for a target”. There is insufficient antecedent basis for this limitation in the claim. Independent claim 22 also recites “a surface-attached polypeptide comprising a small molecule acceptor peptide”. Based on the construction of the claim, it is unclear whether the “a surface-attached polypeptide” recited in claim 46 is intended to refer to the earlier-recited surface-attached polypeptide in claim 22 or to a separate surface-attached polypeptide. Accordingly, the intended metes and bounds of the claim are unclear.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 43 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 43 recites that the small molecule is biotin, biotinidase-resistant biotin, a biotinylamide, or a “bitotinidase”-resistant biotinylamide, and that the antibody reagent comprises the six CDRs of SEQ ID NOs: 4-9. These limitations fail to further limit the claimed subject matter of claim 22, because (1) the independent claim earlier recites that the small molecule is biotin, biotinidase-resistant biotin, a biotinylamide, or a biotinidase-resistant biotinylamide, and (2) by virtue of the antibody reagent comprising the sequences of amino acids 1-119 of SEQ ID NO: 1 and amino acids 1-117 of SEQ ID NO: 2, the respective CDRs corresponding to SEQ ID NOs: 4-9 are contained within those sequences.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 22-23, 31-35, 38, 41-44, and 461 are rejected under 35 U.S.C. 103 as unpatentable over Lohmueller (Oncoimmunology (2018) 7(1): e1368604; cited in PTO-892) in view of Irvine (US 2020/0230221 A1; cited in PTO-892) and Dengl (FASEB Journal (2015) 29(5): 1763-1779; cited in IDS), as evidenced by RCSB Protein Data Bank (PDB) (Entry for “4S1D” released March 4, 2015; see Office Action Appendix).
Lohmueller teaches that the creation of CARs that bind to common tag molecules (e.g., FITC or biotin, conjugated to TAA-specific antibodies) seeks to address known challenges with the application of CAR therapy, namely, antigen loss by tumors and tumor heterogeneity (e.g., Introduction). Lohmueller describes anti-tag CARs (“AT-CARs”) that bind to tags on tumor-targeting antibodies (e.g., Abstract). Lohmueller discloses, “So-called anti-tag CAR (AT-CAR) therapy would be designed so that patients are infused with a tagged, TAA-specific antibody that binds to tumor cells, followed by T cells expressing AT-CARs that react with the tagged antibodies on tumor cells (Fig. 1A). This approach has the potential to allow for sequential or simultaneous targeting of multiple tumor antigens with different antibodies. Additionally, the activity of AT-CARs can be regulated by altering the concentration of tagged antibodies or halting antibody administration for better control over potential toxicities” (Introduction, page 1).
Lohmueller generated CAR-T cells expressing an affinity-enhanced monomeric streptavidin (mAS2) protein engineered to have high affinity for biotin (i.e., a domain that binds to the small molecule biotin), a CD28 transmembrane/cytoplasmic domain, and a CD3ζ stimulatory domain2 (e.g., pages 1-2; Figure 1), which was co-administered with a biotinylated anti-CD20 antibody (rituximab) or a biotinylated anti-CD19 antibody (FMC63) in vitro to activate the CAR-T cells, inducing cytokine release and tumor lysis (e.g., pages 2-4; Figures 3-4), relevant to claims 22-23, 31-35, and 46. The affinity-enhanced mAS2 protein reads on the instantly claimed synthetic signaling system, while the biotinylated antibodies read on a surface-attached polypeptide comprising a (soluble) small molecule as presently claimed.
Lohmueller discloses that future experiments will include in vivo testing of mSA2 CAR-T cells with differing biotinylated antibody doses and schedules in mice bearing human tumor xenografts, thereby reading on a treatment method that comprises administering cells comprising a small molecule-controlled signaling peptide (mSA2 CAR, pertinent to claims 22-23) and a polypeptide comprising a small molecule (biotin) conjugated to an antibody against a cancer cell-specific antigen (CD19 or CD20) to a subject in need of an immunotherapy, wherein said antibody would be a surface-attached polypeptide upon binding to the surface of a cancer cell expressing the target antigen.
However, Lohmueller does not teach that the binding domain that binds specifically to biotin is an antibody or antibody reagent comprising amino acids 1-119 of instant SEQ ID NO: 1 and amino acids 1-117 of instant SEQ ID NO: 2.
Irvine teaches amphiphilic ligand conjugates comprising a CAR ligand (e.g., a tag such as biotin), which activate and induce proliferation of T cells expressing a CAR comprising an antigen-binding domain against said tag (i.e., AT-CAR) and increase their anti-tumor activity (e.g., Abstract; ¶ 0004-0012, 0149-0178). Irvine teaches that the CARs of the invention comprise an antigen-binding domain that is selected from scFv, scFab, and others, containing three heavy chain CDRs and three light chain CDRs (e.g., ¶ 0190-0196), relevant to claims 41-42.
Dengl describes the design of hapten-binding IgGs with an accessible cysteine close to their binding pockets, including a novel anti-biotin antibody corresponding to PDB code: 4S1B, which comprises an engineered Cys at residue 52b/53 (Kabat numbering) (e.g., Abstract; Results). As evidenced by RCSB PDB, the antibody corresponding to 4S1D comprises a heavy chain comprising an amino acid sequence having 100% sequence identity to instant SEQ ID NO: 1 and a light chain comprising an amino acid sequence having 100% sequence identity to instant SEQ ID NO: 2, relevant to claims 22 and 43-44. Dengl teaches that the cysteine modification allows for covalent coupling of a payload to the antibody, wherein the payloads do not dissociate in vitro or in vivo and are more stable (i.e., cleared from serum less quickly) than non-covalently bound payloads (e.g., Abstract; Results). Dengl discloses, “The coupling technology is applicable to many haptens and hapten binding antibodies (confirmed by automated analyses of the structures of 140 additional hapten binding antibodies) and can be applied to modulate the pharmacokinetics of small compounds or peptides. It is also suitable to link payloads in a reduction-releasable manner to tumor- or tissue-targeting delivery vehicles” (Abstract), including cytotoxic payloads that can be directed to tumor cells to achieve antibody-drug conjugate-like functionalities (e.g., Discussion).
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the treatment method described by Lohmueller, which comprises administering a cell comprising a small molecule-controlled signaling polypeptide (i.e., a biotin-targeting CAR-T cell) in combination with a surface-attaching polypeptide (i.e., a tumor-targeting antibody) that comprises a soluble small molecule (i.e., wherein the tumor-targeting antibody is biotinylated), such that the mSA2 targeting peptide is substituted with the 4S1D biotin-targeting antibody, based on the further teachings of Irvine and Dengl. The skilled artisan would have been motivated to do so because Irvine teaches that AT-CAR constructs activate and induce proliferation of AT-CAR-expressing T cells and enhance their anti-tumor activity. The specific anti-biotin antibody construct described by Dengl would be recognized by the skilled artisan as being advantageous because the antibody comprises a modification that permits the conjugation of a payload to the antibody, which Dengl teaches can be used to modulate the pharmacokinetic properties of small molecules/peptides or to link a cytotoxic payload that can be directed to tumor cells in the tumor microenvironment, achieving an ADC-like effect. There would have been a reasonable expectation of success because it was within the skill of one of ordinary skill in the art at the time of filing to generate and to administer antibodies (with or without a synthetic tag) having specificity for a tumor-associated antigen as well as CAR constructs having specificity for a variety of antigens, including synthetic antigens such as a common tag (e.g., FITC or biotin). Further, it was routine and conventional in the art to use antibody-based reagents (e.g., scFv or scFab) as the antigen-binding domain in CAR constructs.
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.
Claims 22-23, 31-35, 38, 41-44, and 46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,672,828 in view of Lohmueller (Oncoimmunology (2018) 7(1): e1368604; supra), Irvine (US 2020/0230221 A1; supra), and Dengl (FASEB Journal (2015) 29(5): 1763-1779; supra), as evidenced by RCSB PDB (Entry for “4S1D” released March 4, 2015; see Office Action Appendix).
The reference patent claims a combination comprising (I) a cell or set of cells comprising one or more nucleic acids encoding a small molecule-controlled polypeptide comprising at least a first signaling domain and a polypeptide comprising a domain that binds specifically to a small molecule, and (II) a surface-attached molecule comprising a binding domain specific for a target, and a small molecule acceptor peptide (e.g., patented claims 15-18), relevant to claims 22 and 32. Patented claims 16-18 further recite that the domain that specifically binds to a small molecule binds to biotin and is extracellular, relevant to claims 22, 38, and 43.
The reference patent also claims a synthetic signaling system comprising (1) a small molecule-controlled signaling polypeptide comprising a small molecule acceptor peptide, a transmembrane domain, and a CAR stimulatory domain; (2) a polypeptide comprising a domain that binds specifically to the small molecule (e.g., biotin); and (3) a surface-attached molecule comprising a binding domain specific for a target and a small molecule acceptor peptide; and further comprising a soluble molecule comprising a small molecule (e.g., patented claims 1-14), further relevant to claims 22 and 25. Patented claims 21-23 recite a method of treating a subject in need of immunotherapy by administering an immune cell (T cell) comprising a synthetic signaling system, said system comprising (1) a small molecule-controlled signaling polypeptide comprising a small molecule acceptor peptide and at least a first signaling domain and (2) a polypeptide comprising a domain that binds specifically to a small molecule, pertinent to claims 22-23 and 31.
The reference patent does not teach a small molecule-controlled polypeptide comprising all three of a small molecule-binding domain, a transmembrane domain, and a CAR stimulatory domain, which is administered in a treatment method for a subject in need of immunotherapy, nor that the binding domain that binds specifically to biotin is an antibody or antibody reagent comprising amino acids 1-119 of instant SEQ ID NO: 1 and amino acids 1-117 of instant SEQ ID NO: 2. However, these deficiencies are remedied by the teachings of Lohmueller, Irvine, and Dengl as set forth in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the treatment method claimed in the reference patent, which comprises administering a cell comprising a small molecule-controlled signaling peptide comprising a polypeptide having a domain that binds to a small molecule (e.g., biotin), a transmembrane domain, and an intracellular signaling domain, such that the binding domain comprises an antibody comprising amino acids 1-119 of SEQ ID NO: 1 and amino acids 1-117 of SEQ ID NO: 2, and such that said small molecule-controlled signaling peptide is co-administered with a surface-attaching molecule comprising a tumor-targeting antibody and the small molecule to which the signaling peptide binds, based on the further teachings of Lohmueller, Irvine, and Dengl. The skilled artisan would have been motivated to do so because Lohmueller and Irvine that AT-CAR-based systems allow for administration of a disease-treating therapeutic cell (e.g., a CAR-T cell) with enhanced anti-tumor functionality, the activity of which can be modulated in vivo to minimize toxic effects. The specific anti-biotin antibody construct described by Dengl would be recognized by the skilled artisan as being advantageous because the antibody comprises a modification that permits the conjugation of a payload to the antibody, which Dengl teaches can be used to modulate the pharmacokinetic properties of small molecules/peptides or to link a cytotoxic payload that can be directed to tumor cells in the tumor microenvironment, achieving an ADC-like effect. There would have been a reasonable expectation of success because it was within the skill of one of ordinary skill in the art at the time of filing to generate and to administer antibodies (with or without a synthetic tag) having specificity for a tumor-associated antigen as well as CAR constructs having specificity for a variety of antigens, including synthetic antigens such as a common tag (e.g., FITC or biotin). Further, it was routine and conventional in the art to use antibody-based reagents (e.g., scFv or scFab) as the antigen-binding domain in CAR constructs.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 The final Office Action mailed on July 13, 2026 previously indicated that claims 44-45 would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. This position has been reconsidered in the present Office Action.
2 As evidenced by the instant specification at page 25, CD3ζ is an exemplary CAR stimulatory domain.
