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 .
Application Status
This action is written in response to applicant’s correspondence received on 6/12/2026. Claims 38-39 and 56-57 are pending. Claims 38-39 have been amended. Claims 1-37 and 40-55 have been cancelled. All pending claims are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment. 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. This Office Action is Final.
Claim Rejections - 35 USC § 112
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 38-39 and 56-57 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.
Regarding claim 38, claim 38 recites “(ii) a regulatory sequence operably linked to (b),” (line 12). However, item “(b)” in claim 38 is recited as “(b) the helper cell comprises.” It is unclear how a regulatory sequence is operably linked to item (b) of claim 38. Furthermore, claim 38 recites two instances of items “ii” in element (b) of the claim. It is recommended that line 12 be rephrased to state “a regulatory sequence operably linked to (ii),” and furthermore to change one of the existing “ii” items to a “iii” to clarify the components of the claims as well as their relationship with one another.
Claims 39 and 56-57 depend from claim 38 and do not resolve this issue and are therefore also rejected.
Claim Rejections - 35 USC § 103 – New Rejection Necessitated by Amendment
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 38-39 and 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Roybal (Roybal KT et al. Cell. 2016 Oct 6;167(2):419-432.e16) in view of Sockolosky (Sockolosky JT et al. Science. 2018 Mar 2;359(6379):1037-1042) and Tang (Tang H et al. Cancer Lett. 2016 Jan 1;370(1):85-90).
Regarding claim 38, Roybal teaches a cell (a helper cell), comprising a nucleic acid sequence encoding a binding triggered transcriptional activator that binds to an antigen, a nucleic acid sequence encoding a cvtokine, wherein the cvtokine binds to a cvtokine receptor; and a regulatory sequence operably linked to the sequence encoding the cytokine that is responsive to the binding triggered transcriptional activator, wherein binding of the binding triggered transcriptional activator to the antigen activates expression of the cvtokine (SynNotch cells programmed to control the expression of a cytokine, Abstract, page 5 paragraphs 3-4 to page 6 first two paragraphs). Roybal teaches administering such cells to a mouse (an “individual” as defined by the specification at paragraph 41, Figure 6 of Roybal and page 9 final paragraphs to page 10 first paragraph). Roybal teaches that they treated solid tumors in mice (page 3, third paragraph, bottom of page 9 to page 10). Roybal teaches using synNotch cells which produce cytokines in order to improve the outcomes of cellular therapeutics by priming the tumor environment for an improved immune response (page 11, final paragraph). . Roybal teaches cytotoxic T cells as effector cells which are known to be critical to targeting solid tumors (page 6, final paragraph) and therefore teaches effector cytotoxic immune cells.
Furthermore, Roybal also teaches that:
“[a]n immediate application of synNotch circuits could be to improve existing T cell therapies. synNotch receptors can act as an additional environmental sensing system for TCR and CAR T cell therapies and help to modulate the activity of the cells to improve their effectiveness and safety profile. We have demonstrated that synNotch receptors can be used to control expression of directly cytotoxic factors (CARs, BiTEs). But, in addition, an important use of synNotch receptors could be the control the local production of immune stimulatory factors, such as IL-12 or other innate immune adjuvants, in TIL or engineered T cell therapies. This type of local delivery and enhancement may be particularly important, given that factors like IL-12 are potent at driving anti-tumor immunity, but are too toxic for systemic administration. The inability of many of the current T cell therapies to infiltrate and eliminate solid tumors could be greatly improved by utilizing synNotch receptors to help the T cells to prime the local disease environment to make it more susceptible to both the cellular therapeutic and the endogenous immune response,” (page 11, final paragraph)
Thus, Roybal also teaches applying their methodological designs to improve the effects of cellular immune therapies, to include tumor infiltrating lymphocytes (“TIL,” above). Furthermore, Roybal supplies a direct motivation to do so because they teach that applying their synNotch circuits to produce cytokines such as IL-12 would improve cellular therapeutic approaches (page 11, final paragraph). Furthermore, Roybal has reduced to practice the introduction of their synNotch cells which express a cytokine, in vivo, and shown that the cell circuits and their cytokine proliferation are functional and therefore predictable (Figure 6, and throughout).
Roybal, while teaching helper cells programmed to secrete cytokines to elicit and effect changes in effector cells, does not teach that the cytokines and cytokine receptors of the helper cells/effector cells are modified so that the cytokine/receptor pair have increased affinity compared with wildtype, or that the effector cell is a cytotoxic CAR T cell.
Roybal references Tang with regards to immune cell therapeutics (page 11, final paragraph). Roybal and Tang therefore directly overlap in subject matter and field of endeavor because Roybal directly references Tang, and furthermore both are directed to engineered immune cell therapies. Tang teaches CAR T cells as exogenous immune cells (e..g, see page 4). Thus, Tang teaches exogenous immune cells which are effector cells that are genetically modified and introduced into an individual, to include an exogenous CAR (page 4). Tang teaches that CAR T cells can be engineered with enhanced infiltration an antitumor activity (page 4, 3rd paragraph, final three lines).
Sockolosky is a research article focused on engineering T cell therapies to improve cell therapeutic outcomes, specifically in diseases such as cancer (Title, Abstract, and throughout, e.g., Introduction, first paragraph). Roybal and Sockolosky therefore directly overlap in subject matter and field of endeavor because both relate to engineered immune cells to program therapeutic responses. Sockolosky teaches the inventive strategy of modifying cytokines and cytokine receptor pairings:
“Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal (ortho) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of orthoIL-2Rβ into T cells enabled the selective cellular targeting of orthoIL-2 to engineered CD4+ and CD8+ T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. OrthoIL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells,” (Abstract).
Thus, Sockolosky directly teaches modifying cytokines and their receptors, so that such pairs of modified cytokines and cytokine receptors only bind with/interact with one another (i.e., the modified cytokines bind with the modified receptor with a higher affinity than with respect to wildtype receptors, as presently claimed). Sockolosky teaches that such modified cytokine circuits are known to have advantages because they reduce off target effects and offer selective targeting (Abstract). Furthermore, Sockolosky teaches that they have reduced to practice their modified cytokine circuits in vivo, where such modified cytokines are efficacious in mouse cancer models (Abstract).
Additionally, Sockolosky teaches that:
“Orthogonal IL-2/IL-2R pairs may be useful not only as a research tool but in the clinic to specifically enrich transduced T cells that express a target gene of interest, such as a CAR or engineered TCR, when coupled with expression of the orthoIL-2R-beta” (page 7, first paragraph).
Thus, Sockolosky directly teaches that such modified cytokine circuits should be applied and used to enrich T cells (effector cells) that express CARs and engineered TCRs/CAR T cells (page 7, first paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the helper/effector tumor treatment strategy taught by Roybal to further include modified cytokine/cytokine receptors as taught by Sockolosky and effector CAR T cells as taught by Tang, as such as combination is the simple combination of known prior art elements with predictable success. Furthermore, the combination is not simply the combination of known elements; the practitioner would be motivated to use modified cytokine/cytokine receptors with the methods of Roybal because Sockolosky teaches known advantages to using such modified pairings, where such modified cytokines/receptors are useful for expanding localized effector cell populations, reduce off-target effects, and creative selective targeting by creating niche cytokine-induced cell expansion (Sockolosky, Abstract). Furthermore, Tang teaches that CAR T cells are known engineered effector cells useful in antitumor targeting. The results are predictable because the methods of Roybal have already been reduced to practice and shown to be efficacious in in vivo mouse cancer treatment models to treat solid tumors (page 3, third paragraph, bottom of page 9 to page 10). Thus, the CAR T cells of Tang can predictably be applied to the known solid tumor treatment methods of Roybal.
Regarding claim 39, Roybal teaches effector cytotoxic T cells which are useful for solid tumor targeting and invasion (page 6, final paragraph). Furthermore Sockolosky also teaches that cytotoxic T cells are known effectors which are responsive to the IL-2 cytokines which they have engineered (page 6, second paragraph).
Regarding claim 56, Roybal teaches that their SynNotch cells comprise an extracellular domain that comprises a binding domain that recognizes the antigen, a transmembrane domain; one or more protease cleavage domains; and a transcriptional activator domain, wherein binding of the extracellular domain to the antigen results in cleavage of the binding triggered transcriptional activator at the one or more protease cleavage domains to release the transcriptional activator domain, and wherein the released transcriptional activator domain binds to the regulatory sequence and activates expression of the cytokine (e.g., page 3, final paragraph to page 4 first paragraph, page 5 third paragraph, drawing at the top of page 2).
Regarding claim 57, Sockolosky teaches that the modified cytokine is an ortho IL-2 variant and that the IL-2 modified receptor is a modified IL-2Rbeta modified receptor (e.g., Abstract, and throughout).
Response to Arguments
The Applicant’s arguments filed 6/12/2026 have been considered but are not persuasive. The Applicant argues that the previous 102 and 103 rejections did not address the limitations that the cytokine is a modified cytokine and that the receptor is a modified receptor, and that the cytokine/receptor pair have higher affinity for each other relative to the modified cytokine’s binding to a wild-type receptor. This argument is persuasive. However, the amendments to the claims introduced previously unexamined limitations. Upon searching the newly recited limitations, the Office has uncovered the teachings of Sockolosky, who teaches that such modified cytokine/modified receptor pairings are already a known strategy used in in vivo T cell therapies, where such modified cytokine/receptor pairings offer known advantages to cell therapies (see new 103 rejection, above). Thus, the Applicant’s amendments are not sufficient to place the claims in condition for allowance for the reasons outlined in the 103 rejection above.
Double Patenting – Maintained/Updated in Response to Amendments
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 38-39 and 56-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,590,182 B2 (‘182) in view of Roybal (Roybal KT et al. Cell. 2016 Oct 6;167(2):419-432.e16) and Sockolosky (Sockolosky JT et al. Science. 2018 Mar 2;359(6379):1037-1042) and Tang (Tang H et al. Cancer Lett. 2016 Jan 1;370(1):85-90).
Regarding claims 38-39, claims 1-2 of ‘182 recite:
1. A method of locally modulating an activity of a cell, the method comprising: expressing in the cell a synthetic Notch receptor comprising, in N-terminal to C-terminal order: an extracellular domain comprising a first member of a specific binding pair that is heterologous to the Notch receptor; a Notch receptor regulatory region comprising Lin-12 Notch repeats A-C, heterodimerization domains HD-N and HD-C, a binding-induced proteolytic cleavage site, and a transmembrane domain; and an intracellular domain heterologous to the Notch receptor; and contacting the cell with a second member of the specific binding pair, wherein binding of the first member of the specific binding pair to the second member of the specific binding pair induces cleavage of the binding-induced proteolytic cleavage site to activate the intracellular domain, thereby producing an activated intracellular domain, wherein the activated intracellular domain modulates an activity of the cell selected from the group consisting of: expression of a gene product of the cell, proliferation of the cell, apoptosis of the cell, non-apoptotic death of the cell, differentiation of the cell, dedifferentiation of the cell, migration of the cell, secretion of a molecule from the cell and cellular adhesion of the cell.
2. The method of claim 1, wherein the gene product of the cell is an endogenous gene product selected from the group consisting of: a chemokine, a chemokine receptor, a cytokine, a cytokine receptor, a differentiation factor, a growth factor, a growth factor receptor, a hormone, a metabolic enzyme, a proliferation inducer, a receptor, a small molecule 2.sup.nd messenger synthesis enzyme, a T cell receptor, a transcription activator, a transcription repressor, a transcriptional activator, a transcriptional repressor, a translation regulator, a translational activator, a translational repressor, an activating immunoreceptor, an apoptosis inhibitor, an apoptosis inducer, an immunoactivator, an immunoinhibitor and an inhibiting immunoreceptor.
Thus, claims 1-2 of ‘182 recite the cell of claim 1 and a method of modulating activity of a cell where the gene product can be a cytokine. Thus, ‘182 recites the same cell presently recited, where the prior art teaches the administration of said cell to an individual for various beneficial effects (see below)
‘182 does not recite that the cell is administered to an individual to treat a solid tumor (claim 38), and that the target cell is a cytotoxic T cell (claim 39). ‘182 does not recite that the treatment method further comprises an effector CAR cell, where the helper and effector cells encode modified cytokines/cytokine receptors, respectively, where the modified cytokine has a higher affinity for the modified cytokine receptor relative to the wildtype receptor.
Regarding claim 38, Roybal teaches a cell (a helper cell), comprising a nucleic acid sequence encoding a binding triggered transcriptional activator that binds to an antigen, a nucleic acid sequence encoding a cvtokine, wherein the cvtokine binds to a cvtokine receptor; and a regulatory sequence operably linked to the sequence encoding the cytokine that is responsive to the binding triggered transcriptional activator, wherein binding of the binding triggered transcriptional activator to the antigen activates expression of the cvtokine (SynNotch cells programmed to control the expression of a cytokine, Abstract, page 5 paragraphs 3-4 to page 6 first two paragraphs). Roybal teaches administering such cells to a mouse (an “individual” as defined by the specification at paragraph 41, Figure 6 of Roybal and page 9 final paragraphs to page 10 first paragraph). Roybal teaches that they treated solid tumors in mice (page 3, third paragraph, bottom of page 9 to page 10). Roybal teaches using synNotch cells which produce cytokines in order to improve the outcomes of cellular therapeutics by priming the tumor environment for an improved immune response (page 11, final paragraph). Roybal teaches cytotoxic T cells as effector cells which are known to be critical to targeting solid tumors (page 6, final paragraph) and therefore teaches effector cytotoxic immune cells.
Furthermore, Roybal also teaches that:
“[a]n immediate application of synNotch circuits could be to improve existing T cell therapies. synNotch receptors can act as an additional environmental sensing system for TCR and CAR T cell therapies and help to modulate the activity of the cells to improve their effectiveness and safety profile. We have demonstrated that synNotch receptors can be used to control expression of directly cytotoxic factors (CARs, BiTEs). But, in addition, an important use of synNotch receptors could be the control the local production of immune stimulatory factors, such as IL-12 or other innate immune adjuvants, in TIL or engineered T cell therapies. This type of local delivery and enhancement may be particularly important, given, that factors like IL-12 are potent at driving anti-tumor immunity, but are too toxic for systemic administration. The inability of many of the current T cell therapies to infiltrate and eliminate solid tumors could be greatly improved by utilizing synNotch receptors to help the T cells to prime the local disease environment to make it more susceptible to both the cellular therapeutic and the endogenous immune response,” (page 11, final paragraph)
Thus, Roybal also teaches applying their methodological designs to improve the effects of cellular immune therapies, to include tumor infiltrating lymphocytes (“TIL,” above). Furthermore, Roybal supplies a direct motivation to do so because they teach that applying their synNotch circuits to produce cytokines such as IL-12 would improve cellular therapeutic approaches (page 11, final paragraph). Furthermore, Roybal has reduced to practice the introduction of their synNotch cells which express a cytokine, in vivo, and shown that the cell circuits and their cytokine proliferation are functional and therefore predictable (Figure 6, and throughout).
Roybal, while teaching helper cells programmed to secrete cytokines to elicit and effect changes in effector cells, does not teach that the cytokines and cytokine receptors of the helper cells/effector cells are modified so that the cytokine/receptor pair have increased affinity compared with wildtype, or the effector CAR T cell.
Roybal references Tang with regards to immune cell therapeutics. Roybal and Tang therefore directly overlap in subject matter and field of endeavor because Roybal directly references Tang, and furthermore both are directed to engineered immune cell therapies. Tang teaches CAR T cells as exogenous immune cells (e..g, see page 4). Thus, Tang teaches exogenous immune cells which are effector cells that are genetically modified and introduced into an individual, to include an exogenous CAR (page 4). Tang teaches that CAR T cells can be engineered with enhanced infiltration an antitumor activity (page 4, 3rd paragraph, final three lines).
Sockolosky is a research article focused on engineering T cell therapies to improve cell therapeutic outcomes, specifically in diseases such as cancer (Title, Abstract, and throughout, e.g., Introduction, first paragraph). Roybal and Sockolosky therefore directly overlap in subject matter and field of endeavor because both relate to engineered immune cells to program therapeutic responses. Sockolosky teaches the inventive strategy of modifying cytokines and cytokine receptor pairings:
“Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal (ortho) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of orthoIL-2Rβ into T cells enabled the selective cellular targeting of orthoIL-2 to engineered CD4+ and CD8+ T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. OrthoIL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells,” (Abstract).
Thus, Sockolosky directly teaches modifying cytokines and their receptors, so that such pairs of modified cytokines and cytokine receptors only bind with/interact with one another (i.e., the modified cytokines bind with the modified receptor with a higher affinity than with respect to wildtype receptors, as presently claimed). Sockolosky teaches that such modified cytokine circuits are known to have advantages because they reduce off target effects and offer selective targeting (Abstract). Furthermore, Sockolosky teaches that they have reduced to practice their modified cytokine circuits in vivo, where such modified cytokines are efficacious in mouse cancer models (Abstract).
Additionally, Sockolosky teaches that:
“Orthogonal IL-2/IL-2R pairs may be useful not only as a research tool but in the clinic to specifically enrich transduced T cells that express a target gene of interest, such as a CAR or engineered TCR, when coupled with expression of the orthoIL-2R-beta” (page 7, first paragraph).
Thus, Sockolosky directly teaches that such modified cytokine circuits should be applied and used to enrich T cells (effector cells) that express CARs and engineered TCRs/CAR T cells (page 7, first paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modifying cellular activity using the cells recited in ‘182 with the helper/effector tumor treatment strategy taught by Roybal to further include modified cytokine/cytokine receptors as taught by Sockolosky, as such as combination is the simple combination of known prior art elements with predictable success. Furthermore, the combination is not simply the combination of known elements; the practitioner would be motivated to use modified cytokine/cytokine receptors with the methods of Roybal because Sockolosky teaches known advantages to using such modified pairings, where such modified cytokines/receptors are useful for expanding localized effector cell populations, reduce off-target effects, and creative selective targeting by creating niche cytokine-induced cell expansion (Sockolosky, Abstract). The results are predictable because such methods have already been reduced to practice and shown to be efficacious in in vivo mouse cancer treatment models (above).
Regarding claim 39, Roybal teaches effector cytotoxic T cells which are useful for solid tumor targeting and invasion (page 6, final paragraph). Furthermore Sockolosky also teaches that cytotoxic T cells are known effectors which are responsive to the IL-2 cytokines which they have engineered (page 6, second paragraph).
Regarding claim 56, Roybal teaches that their SynNotch cells comprise an extracellular domain that comprises a binding domain that recognizes the antigen, a transmembrane domain; one or more protease cleavage domains; and a transcriptional activator domain, wherein binding of the extracellular domain to the antigen results in cleavage of the binding triggered transcriptional activator at the one or more protease cleavage domains to release the transcriptional activator domain, and wherein the released transcriptional activator domain binds to the regulatory sequence and activates expression of the cytokine (e.g., page 3, final paragraph to page 4 first paragraph, page 5 third paragraph, drawing at the top of page 2).
Regarding claim 57, Sockolosky teaches that the modified cytokine is an ortho IL-2 variant and that the IL-2 modified receptor is a modified IL-2Rbeta modified receptor (e.g., Abstract, and throughout).
Claims 38-39 and 56-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 10,822,387 B2 (‘387) in view of Roybal (Roybal KT et al. Cell. 2016 Oct 6;167(2):419-432.e16) in view of Sockolosky (Sockolosky JT et al. Science. 2018 Mar 2;359(6379):1037-1042) and Tang (Tang H et al. Cancer Lett. 2016 Jan 1;370(1):85-90).
Regarding claim 38, claims 1 and 4 of ‘387 recite:
A method of treating a subject for a cancer, the method comprising: administering to the subject: i) a nucleic acid encoding a chimeric Notch receptor polypeptide comprising: (a) an extracellular domain that comprises an antigen binding region of an antibody, (b) a Notch core regulatory region, and (c) an intracellular domain that comprises a DNA binding domain, wherein the intracellular domain does not comprise an immunoreceptor activation domain or a co-stimulatory domain and wherein binding of the antigen binding region of the antibody to an antigen on a cancer cell induces proteolytic cleavage of the Notch core regulatory region to release the intracellular domain; and ii) a transcriptional control element that is bound by the released intracellular domain and is operably linked to a nucleic acid sequence encoding one or more cancer immunotherapy agents, wherein the released intracellular domain induces expression of the one or more cancer immunotherapy agents, thereby treating the subject for the cancer.
The method according to claim 1, wherein the one or more cancer immunotherapy agents comprises one or more surface expressed gene products, one or more secreted gene products or a combination thereof.
The method according to claim 2, wherein the one or more secreted gene products are selected from the group consisting of: an antibody, a cytokine, a chemokine, a hormone and combinations thereof.
‘387 does not recite that the cell is administered to an individual to treat a solid tumor (claim 38), and that the target cell is a cytotoxic T cell (claim 39). ‘387 does not recite that the treatment method further comprises an effector CAR cell, where the helper and effector cells encode modified cytokines/cytokine receptors, respectively, where the modified cytokine has a higher affinity for the modified cytokine receptor relative to the wildtype receptor.
Regarding claims 38-39 and 56-57, the teachings of Roybal/Tang and Sockolosky are incorporated herein from the rejection of ‘182, and for the sake of brevity are not included in their entirety.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of ‘387 with the helper/effector tumor treatment strategy taught by Roybal to further include modified cytokine/cytokine receptors as taught by Sockolosky, as such as combination is the simple combination of known prior art elements with predictable success. Furthermore, the combination is not simply the combination of known elements; the practitioner would be motivated to use modified cytokine/cytokine receptors with the methods of Roybal because Sockolosky teaches known advantages to using such modified pairings, where such modified cytokines/receptors are useful for expanding localized effector cell populations, reduce off-target effects, and creative selective targeting by creating niche cytokine-induced cell expansion (Sockolosky, Abstract). The results are predictable because such methods have already been reduced to practice and shown to be efficacious in in vivo mouse cancer treatment models (above).
Claims 38-39 and 56-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,836,808 B2 (‘808) in view of Roybal (Roybal KT et al. Cell. 2016 Oct 6;167(2):419-432.e16) and Sockolosky (Sockolosky JT et al. Science. 2018 Mar 2;359(6379):1037-1042) and Tang (Tang H et al. Cancer Lett. 2016 Jan 1;370(1):85-90).
Regarding claim 38, claims 1 and 10 of ‘808 recite:
1 A molecular circuit comprising: (a) a nucleic acid encoding a chimeric Notch receptor polypeptide comprising: (i) an extracellular binding domain that comprises an antigen binding region of an antibody; (ii) a Notch receptor regulatory domain; and (iii) an intracellular domain that comprises a DNA binding domain, wherein the intracellular domain does not comprise an immunoreceptor activation domain or a co-stimulatory domain; wherein binding of the antigen binding region of (a)(i) to an antigen induces proteolytic cleavage of the Notch receptor regulatory domain of (a)(ii) and releases the DNA binding domain-of (a)(iii); and (b) an expression cassette comprising a transcriptional control element operably linked to a nucleic acid encoding a therapeutic agent, wherein the released DNA binding domain binds to the transcriptional control element and induces expression of the nucleic acid encoding the therapeutic agent.
10 The molecular circuit according to claim 1, wherein the therapeutic agent is selected from the group consisting of: an antibody, a chemokine, a chemokine receptor, a cytokine, a cytokine receptor, a chimeric antigen receptor (CAR), a T cell receptor (TCR), an activating immunoreceptor, an inhibiting immunoreceptor, an immunoactivator, an immunoinhibitor, an apoptosis inducer, an apoptosis inhibitor, a toxin derived protein and a site-specific nuclease.
‘808 does not recite that the cell is administered to an individual to treat a solid tumor (claim 38), and that the target cell is a cytotoxic T cell (claim 39). ‘808 does not recite that the treatment method further comprises an effector CAR cell, where the helper and effector cells encode modified cytokines/cytokine receptors, respectively, where the modified cytokine has a higher affinity for the modified cytokine receptor relative to the wildtype receptor.
Regarding claims 38-39 and 56-57, the teachings of Roybal/Tang and Sockolosky are incorporated herein from the rejection of ‘182, and for the sake of brevity are not included in their entirety.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of ‘808 with the helper/effector tumor treatment strategy taught by Roybal to further include modified cytokine/cytokine receptors as taught by Sockolosky, as such as combination is the simple combination of known prior art elements with predictable success. Furthermore, the combination is not simply the combination of known elements; the practitioner would be motivated to use modified cytokine/cytokine receptors with the methods of Roybal because Sockolosky teaches known advantages to using such modified pairings, where such modified cytokines/receptors are useful for expanding localized effector cell populations, reduce off-target effects, and creative selective targeting by creating niche cytokine-induced cell expansion (Sockolosky, Abstract). The results are predictable because such methods have already been reduced to practice and shown to be efficacious in in vivo mouse cancer treatment models (above).
Claims 38-39 and 56-57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/708,921(‘921) in view of Roybal (Roybal KT et al. Cell. 2016 Oct 6;167(2):419-432.e16) and Sockolosky (Sockolosky JT et al. Science. 2018 Mar 2;359(6379):1037-1042) and Tang (Tang H et al. Cancer Lett. 2016 Jan 1;370(1):85-90).
Regarding claim 38, claims 1 and 5-6 of ‘921 recite:
1. An engineered immune cell comprising the following components: (a) a nucleic acid encoding an immune receptor that is activated by binding to a cancer-associated antigen in a solid tumor; (b) a binding triggered transcriptional switch (BTTS) that is independently activated by either a tissue- or a cancer-associated antigen in the solid tumor; and (c) a nucleic acid encoding a pro-inflammatory protein, wherein: binding of the immune receptor to the cancer-associated antigen activates the immune cell; and binding of the BTTS to its antigen activates expression of the pro-inflammatory protein and, optionally, the immune receptor if the immune receptor is not constitutively expressed in the cell.
5. The engineered immune cell of claim 1, wherein the pro-inflammatory protein is a pro-inflammatory cytokine.
6. The engineered immune cell of claim 1, wherein the pro-inflammatory protein is a cytokine selected from IL-2, IL-12, IL-15, IL-7, CD40L, or a non-natural variant of IL-2, an orthogonal cytokine, IL-12, IL-15, IL-7, CD40L that has pro-inflammatory activity, an immune checkpoint inhibitor, a decoy resistant IL-18, a dominant negative TGF-β, a dominant negative TGFb receptor, or a TGFb inhibitor/agonist.
Claim 18 recites administering the cell of claim 1 to an individual.
‘921 does not recite that the cell is administered to an individual to treat a solid tumor (claim 38), and that the target cell is a cytotoxic T cell (claim 39). ‘921 does not recite that the treatment method further comprises an effector CAR cell, where the helper and effector cells encode modified cytokines/cytokine receptors, respectively, where the modified cytokine has a higher affinity for the modified cytokine receptor relative to the wildtype receptor.
Regarding claims 38-39 and 56-57, the teachings of Roybal/Tang and Sockolosky are incorporated herein from the rejection of ‘182, and for the sake of brevity are not included in their entirety.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of ‘921 with the helper/effector tumor treatment strategy taught by Roybal to further include modified cytokine/cytokine receptors as taught by Sockolosky, as such as combination is the simple combination of known prior art elements with predictable success. Furthermore, the combination is not simply the combination of known elements; the practitioner would be motivated to use modified cytokine/cytokine receptors with the methods of Roybal because Sockolosky teaches known advantages to using such modified pairings, where such modified cytokines/receptors are useful for expanding localized effector cell populations, reduce off-target effects, and creative selective targeting by creating niche cytokine-induced cell expansion (Sockolosky, Abstract). The results are predictable because such methods have already been reduced to practice and shown to be efficacious in in vivo mouse cancer treatment models (above).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
The Applicant’s arguments filed 6/12/2026 have been considered but are not persuasive. The Applicant argues that the amendments to the claims address the double patenting rejections. However, as discussed above in the 103 rejection, a new prior art search was performed and incorporated into the previous double patenting rejections. Thus, the Applicant’s amendments have not rendered claims which are patent eligible, as addressed in the 103 discussion in view of Roybal/Tang and Socklosoky, and as applied to each of the patents and/or patent applications in the double patenting rejection, above.
Conclusion
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.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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