DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment and Arguments
2. The amendment to the claims renders the former non-elected claims, 7 and 13 available to be examined on the merits.
3. Claims 1-7, 13 and 27 are pending.
Claims 31, 37 and 51 have been cancelled.
Claims 1-7, 13 and 27 have been amended.
Claims 1-7, 13 and 27 are examined on the merits with species, SEQ ID NO: 1 and SEQ ID NO: 4.
4. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Objections
Claim Objections
5. Claims 4 and 6 are no longer objected to under 37 CFR 1.75(c) as they have been amended and are no longer in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim, see Amendments to the Claims submitted March 23, 2026. Claim 27 has been cancelled.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 102
6. The rejection of claim(s) 1-3 under 35 U.S.C. 102(a)(1) as being anticipated by Champion et al., US 2006/0204508 A1 (published September 14, 2006/ IDS reference, U.S. Patent Application Publications #1 on sheet 1 submitted January 11, 2022) is withdrawn in light of the amendment to independent claims 1-3, see Amendments to the Claims submitted March 23, 2026.
Claim Rejections - 35 USC § 103
7. The rejection of claim(s) 1-3 and 5 under 35 U.S.C. 103 as being unpatentable over Champion et al., US 2006/0204508 A1 (published September 14, 2006/ IDS reference, U.S. Patent Application Publications #1 on sheet 1 submitted January 11, 2022), and further in view of Kelliher et al. (Frontiers in Non-Patent Literature Documents #2 on sheet 2 submitted January 11, 2022) is withdrawn in light of the amendment to independent claims 1-3 and 5, see Amendments to the Claims submitted March 23, 2026.
New Grounds of Rejection
Claim Rejections - 35 USC § 102
8. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
9. Claim(s) 1-7, 13 and 27 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Luca, Vincent. WO 2020/223610 A1 (effectively filed 01 May 2019). “Notch antagonists can be used as treatments for cancer and the disclosed DLL4 proteins operate as Notch signaling antagonists in soluble form. Accordingly, disclosed herein are methods of treating a cancer in a subject comprising administering to the subject any of the engineered DLL4 proteins disclosed herein. Furthermore, it is understood and herein contemplated that when anchored to a surface or substrate the disclosed DLL4 proteins become Notch agonists and can thus, activate Notch signaling in cells with which they come into contact. This can be useful in the activation of Notch on cells undergoing adoptive transfer such as, for example, stem cells, chimeric antigen receptor (CAR) T cells, tumor infiltrating lymphocytes (TILs) and TCR T cells. Thus, in one aspect disclosed herein are methods of activating Notch signaling in cell used in an adoptive transfer cell comprising contacting the cell any of the engineered DLL4 proteins, [comprising a conservative amino acid substitution at a residue corresponding to residues 28, 107, 143, 194, and 206 as set forth in SEQ ID NO: 1 and further comprising at least one conservative amino acid substitution at residues 256, 257, 271, 280, 301, and 305 as set forth in SEQ ID NO: 1.]; wherein the adoptively transferred cell comprises a stem cell, chimeric antigen (CAR) T cell, tumor infiltrating lymphocyte (TIL), or TCR T; and wherein the engineered DLL4 protein is anchored to a solid surface or substrate.”, see segments 59 and 60 bridging pages 9 and 10; page 11, segment 61. The T cell population including a CAR-T cell is useful for adoptive cell therapy for an individual with cancer and/or other conditions that may impair T cell development or function., see page 11, segment 61.
“The disclosed engineered DLL4 proteins can comprise several substitutions at the disclosed residues including “the substitution of the engineered DLL4 protein can comprise a [glycine] to serine substitution at residue 28 (G28S), a phenylalanine to leucine substitution at residue 107 (F107L), an isoleucine to phenylalanine substitution at residue 143 (I143F), a histidine to tyrosine substitution at residue 194 (H194Y), and a leucine to proline substitution at residue 206 (L206P).”, see page 10, segment 59.
Furthermore, “disclosed herein are engineered DLL4 proteins wherein the amino acid at residue 256 comprises a histidine, tyrosine, phenylalanine, leucine, asparagine, isoleucine, valine, or aspartic acid. For example, the amino acid at residue 256 can comprise a histidine or a substitution from histidine in wild-type (WT) human DLL4 (as set forth in SEQ ID NO: 3) to a tyrosine (a H256Y substitution) to a phenylalanine (a H256F substitution), a leucine (a H256L substitution), an asparagine (a H256N substitution), a isoleucine (a H256I substitution), a valine (a H256V substitution), or aspartic acid (a H256D substitution). Similarly, the engineered DLL4 proteins can comprise a proline, histidine, leucine, isoleucine, threonine, asparagine, tyrosine, serine, or phenylalanine at residue 257. Thus, in one aspect, the engineered DLL4 protein can comprise an asparagine at residue 257 or substitution from the asparagine in wild-type (WT) human DLL4 (as set forth in SEQ ID NO: 3) to a tyrosine (a H257Y substitution), a proline (a N257P substitution), a histidine (a N257H substitution), a leucine (a N257L substitution), an isoleucine (a N257I substitution), a threonine (a N257T substitution), a serine (a N257S substitution), or a phenylalanine (a N257F substitution). In one aspect, disclosed herein are engineered DLL4 proteins wherein the amino acid at residue 271 comprises a leucine, proline, histidine, asparagine, threonine, or isoleucine (such as, for example, a wild-type residue as set forth in SEQ ID NO: 1 (i.e., the threonine) or a substitution of the threonine for a leucine (a T271L substitution), a threonine to proline substitution (a T271P substitution), a threonine to histidine substitution (a T271H substitution), a threonine to arginine substitution (a T271N substitution), or a threonine to isoleucine substitution (a T271I substitution). Also disclosed herein are engineered DLL4 proteins, wherein the amino acid at residue 280 comprises a phenylalanine or a substitution of the phenylalanine with a leucine (a F280L substitution), a tyrosine (a F280Y substitution), or histidine (a F280H substitution). Additionally, in one aspect, the disclosed engineered DLL4 proteins can comprise the native serine amino acid at residue 301 as set forth in SEQ ID NO: 1 or comprise a substitution of the serine for an asparagine (a S301N substitution), arginine (a S301R substitution), or a histidine (a S301H substitution). Also disclosed herein are engineered DLL4 proteins, wherein the amino acid at residue 305 comprises a glutamine, proline, arginine, or leucine and thus can comprise the wild-type amino acid as set forth in SEQ ID NO: 1 (i.e., a glutamine) or a substitution of the glutamine for a proline (a Q305P substitution), a substitution of the glutamine for an arginine (a Q305R substitution), or a substitution of the glutamine for a leucine (a Q305L substitution). In one aspect, disclosed herein are engineered DLL4 proteins of any preceding aspect, wherein DLL4 protein comprises SEQ ID NO: 3 or SEQ ID NO: 4.”, see segment 60 bridging pages 10 and 11.
Given the interaction between the said agents and the T-cells, intrinsically, the efficacy of adoptive T cell immunotherapy is enhanced, as well as the T-cell is made resistant to tumor suppression, thereby rendering anti-tumor T-cells refractory to the tumor microenvironment.
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim Rejections - 35 USC § 103
10. 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.
11. Claims 1-7, 13 and 27 is/are rejected under 35 U.S.C. 103 as being obvious over Champion et al., US 2006/0204508 A1 (published September 14, 2006/ IDS reference, U.S. Patent Application Publications #1 on sheet 1 submitted January 11, 2022) and further in view of Luca, Vincent. WO 2020/223610 A1 (effectively filed 01 May 2019) and Kelliher et al. (Frontiers in Non-Patent Literature Documents #2 on sheet 2 submitted January 11, 2022). The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). Champion teaches “…manipulation of the Notch signalling pathway can be used in immunotherapy and in the…treatment of T-cell mediated diseases.”, see page 1, section 0005. “A T cell [may be] obtained from a human or animal patient.”, see page 73, section 1009. T cells are contacted by a Notch signalling pathway modulator, an agent directly activates a Notch receptor in T-cells, see sections 0223 and 0224 spanning pages 14 and 15. The said agent may be administered directly to patients in vivo, see page 62, section 0826.
The agent that modulates the Notch signalling pathway may comprise “…a Notch ligand or a fragment, derivative, homologue, analogue or allelic variant thereof…”, “…an amino acid sequence or a chemical derivative thereof”, as well as “…synthetic compounds…”, see page 15, section 0230-0232; page 41, sections 0548 and 0555. These taught agents are regarded by the Examiner as chemically designed Notch ligands.
Given the interaction between the said agents and the T-cells, intrinsically, the efficacy of adoptive T cell immunotherapy is enhanced, as well as the T-cell is made resistant to tumor suppression, thereby rendering anti-tumor T-cells refractory to the tumor microenvironment.
Champion does not teach the disease treated in a subject comprising administering a T cell contacted with an agent, a chemically designed Notch ligand is cancer, wherein the engineered DLL4 protein comprises conservative amino acid substitutions.
However, Luca teaches “…engineered DLL4 proteins, [comprising a conservative amino acid substitution at a residue corresponding to residues 28, 107, 143, 194, and 206 as set forth in SEQ ID NO: 1 and further comprising at least one conservative amino acid substitution at residues 256, 257, 271, 280, 301, and 305 as set forth in SEQ ID NO: 1.]; wherein the adoptively transferred cell comprises a stem cell, chimeric antigen (CAR) T cell, tumor infiltrating lymphocyte (TIL), or TCR T; and wherein the engineered DLL4 protein is anchored to a solid surface or substrate.”, see segments 59 and 60 bridging pages 9 and 10; page 11, segment 61. The T cell population including a CAR-T cell is useful for adoptive cell therapy for an individual with cancer and/or other conditions that may impair T cell development or function., see page 11, segment 61.
“The disclosed engineered DLL4 proteins can comprise several substitutions at the disclosed residues including “the substitution of the engineered DLL4 protein can comprise a [glycine] to serine substitution at residue 28 (G28S), a phenylalanine to leucine substitution at residue 107 (F107L), an isoleucine to phenylalanine substitution at residue 143 (I143F), a histidine to tyrosine substitution at residue 194 (H194Y), and a leucine to proline substitution at residue 206 (L206P).”, see page 10, segment 59.
Furthermore, “disclosed herein are engineered DLL4 proteins wherein the amino acid at residue 256 comprises a histidine, tyrosine, phenylalanine, leucine, asparagine, isoleucine, valine, or aspartic acid. For example, the amino acid at residue 256 can comprise a histidine or a substitution from histidine in wild-type (WT) human DLL4 (as set forth in SEQ ID NO: 3) to a tyrosine (a H256Y substitution) to a phenylalanine (a H256F substitution), a leucine (a H256L substitution), an asparagine (a H256N substitution), a isoleucine (a H256I substitution), a valine (a H256V substitution), or aspartic acid (a H256D substitution). Similarly, the engineered DLL4 proteins can comprise a proline, histidine, leucine, isoleucine, threonine, asparagine, tyrosine, serine, or phenylalanine at residue 257. Thus, in one aspect, the engineered DLL4 protein can comprise an asparagine at residue 257 or substitution from the asparagine in wild-type (WT) human DLL4 (as set forth in SEQ ID NO: 3) to a tyrosine (a H257Y substitution), a proline (a N257P substitution), a histidine (a N257H substitution), a leucine (a N257L substitution), an isoleucine (a N257I substitution), a threonine (a N257T substitution), a serine (a N257S substitution), or a phenylalanine (a N257F substitution). In one aspect, disclosed herein are engineered DLL4 proteins wherein the amino acid at residue 271 comprises a leucine, proline, histidine, asparagine, threonine, or isoleucine (such as, for example, a wild-type residue as set forth in SEQ ID NO: 1 (i.e., the threonine) or a substitution of the threonine for a leucine (a T271L substitution), a threonine to proline substitution (a T271P substitution), a threonine to histidine substitution (a T271H substitution), a threonine to arginine substitution (a T271N substitution), or a threonine to isoleucine substitution (a T271I substitution). Also taught herein are engineered DLL4 proteins, wherein the amino acid at residue 280 comprises a phenylalanine or a substitution of the phenylalanine with a leucine (a F280L substitution), a tyrosine (a F280Y substitution), or histidine (a F280H substitution). Additionally, in one aspect, the disclosed engineered DLL4 proteins can comprise the native serine amino acid at residue 301 as set forth in SEQ ID NO: 1 or comprise a substitution of the serine for an asparagine (a S301N substitution), arginine (a S301R substitution), or a histidine (a S301H substitution). Also taught herein are engineered DLL4 proteins, wherein the amino acid at residue 305 comprises a glutamine, proline, arginine, or leucine and thus can comprise the wild-type amino acid as set forth in SEQ ID NO: 1 (i.e., a glutamine) or a substitution of the glutamine for a proline (a Q305P substitution), a substitution of the glutamine for an arginine (a Q305R substitution), or a substitution of the glutamine for a leucine (a Q305L substitution). In one aspect, disclosed herein are engineered DLL4 proteins of any preceding aspect, wherein DLL4 protein comprises SEQ ID NO: 3 or SEQ ID NO: 4.”, see segment 60 bridging pages 10 and 11.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the Notch signalling pathway activated T cells of Champion and Luca to treat cancer as Kelliher teaches “[s]everal studies have shown that NOTCH is required for activation and effector function of CD4 and CD8 T-cells. Tumor cells can dampen T-cell responses by producing immunosuppressive cytokines, expressing inhibitory ligands, and recruiting immunosuppressive myeloid and lymphoid cells into the tumor microenvironment. Given that NOTCH is required for T-cell activation and effector function it is reasonable to hypothesize that NOTCH contributes to T-cell anti-tumor responses and that tumor cells may evade T-cell mediated killing by suppressing NOTCH activation. Consistent with this hypothesis, new data suggests that NOTCH activation is suppressed in tumor-infiltrating T-cells and that NOTCH re-activation induces potent anti-tumor T-cell responses in mouse cancer models. Adoptive transplants of tumor antigen-specific T-cells is one immunotherapy used to overcome the limitations of endogenous T-cells and enhance anti-tumor responses.”, see Kelliher, page 2, 1st column, 1st paragraph.
One of ordinary skill in the art would have been motivated to implement the Notch signalling pathway activated T cells of Champion to treat cancer because they have been used in immunotherapy of other T-cell mediated diseases and “[t]herapies that activate/ maintain NOTCH signaling were shown to improve T-cell mediated tumor clearance, prolonging the survival of tumor bearing mice, see Champion, page 1, section 0005; and entire Luca document.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Double Patenting
12. 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.
13. Claims 1-7, 13 and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 19 of U.S. Patent No. 12,624,072 B2 (issued May 12, 2026). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims read on the chemically designed Notch ligands comprising an engineered DLL4 protein comprising conservative amino acid substitutions utilized in the treatment of cancer.
Conclusion
14. 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.
15. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
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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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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
28 May 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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