DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 2/25/2026.
Claims 1, 2, 7-10, 12, 13, 17-21, 23, 24, 26,30, 35 and 37-41 are pending. Claims 12, 13, 17-21, 23, 24, 26, 30, 35 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Hence, claims 1, 2, 7-10, and 38-41 are under examination.
This application is a divisional of U.S. Application No. 14/968,853, filed December 14, 2015, now abandoned, which claims the benefit of priority to U.S. Provisional Patent Application No. 62/148, 386, filed April 16, 2015 and to U.S. Provisional Patent Application No. 62/092,149, filed December 15, 2014.
Information Disclosure Statement
An information disclosure statement 2/17/2026 has been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action.
Response to Amendments
The amendments were sufficient to overcome the objection to the claims as well as the rejections under 35 USC 112, second and first. The following objection is newly identified.
Claim Objections
Claim 8 is objected to because of the following informalities: Applicants have provided the article “the” prior to the first occurrence of FRB. However, it should be either “a FRB or a FRB variant domain” or “’ one of the one or more FRB or FRB variant domains” to reflect the recitation as provided throughout the claims. Upon reconsideration, claim 38 should recite “an antigen recognition moiety, the antigen selected from the group”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1, 2, 7-10, and 38-41 are rejected under 35 U.S.C. 103(a) as being unpatentable over Green et al (US 20160160189) in view of Brogdon (US 20170274014) and Narayanan et al (J Clinical Investigation). This rejection is maintained.
The instant claims are drawn to at least two polynucleotides wherein in both there is a chimeric peptide comprising a multimerizing peptide and MyD88 with or without TIR and CD40 cytoplasmic protein with or without the extracellular domain, a second comprising Caspase-9 and a multimerizing peptide and a third comprising a chimeric T receptor or CAR to i.e. Her2/Neu wherein the multimerizing peptides are different i.e. FRB and FKBP12v36.
Green teaches means of regulating dimerization of caspase-8 to lead to apoptotic pathways by use of multiple FKBP on one chimeric polypeptide and FRB on the other (see figure 6 and abstract). These methods include use of two FKBP molecules (see Figure 6), The molecules form complexes based upon addition of rapamycin or AP-1903 which binds to Phe36Val (Fv).
[0153] In some embodiments, the present invention contemplates the use of dimerizing agents such as rapamycin or derivatives thereof. AP21967 is a chemically modified derivative of rapamycin that can be used to induce heterodimerization of FKBP and FRB T2098L-containing fusion proteins.
[0256] Consequently, two Fv domains were attached to the C-terminus of RIPK3, creating a RIPK3-2xFv construct, with the goal of promoting AP1-induced crosslinking and oligomerization independent of the RHIM domain. See, FIG. 12A. Notably, a faster and more robust necroptotic response was observed in cells expressing RIPK3-2xFv, to a degree comparable to that observed upon dimerization of RIPK3-1xFv following caspase-8 inhibition or knockdown.
The constructs are on vectors with promoters (see ¶0279).
Applying this to the Cas9 dimerization model would end up with a system for dimerization as taught by Brogdon wherein one would use the system of Green as set forth below.
[0256] Consequently, two Fv domains were attached to the C-terminus of RIPK3, creating a RIPK3-2xFv construct, with the goal of promoting AP1-induced crosslinking and oligomerization independent of the RHIM domain. See, FIG. 12A. Notably, a faster and more robust necroptotic response was observed in cells expressing RIPK3-2xFv,
Brogdon teaches,
In another example, CAR-expressing cells can also express an inducible Caspase-9 (iCaspase-9) molecule that, upon administration of a dimerizer drug (e.g., rimiducid (also called AP1903 (Bellicum Pharmaceuticals) or AP20187 (Ariad)) leads to activation of the Caspase-9 and apoptosis of the cells. The iCaspase-9 molecule contains a chemical inducer of dimerization (CID) binding domain that mediates dimerization in the presence of a CID.
The only missing aspect is that the combination comprises MyD88 with or without CD40. In a similar system, Narayanan teach use of MyD88 and CD40 to make more potent immune activation by activating both Myd88 and CD40 pathways. This is used as well with two FKBP12 domains.
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a composite activation receptor for DCs (DC-CAR) that unifies 2 separate signaling pathways with the use of a single drug. CID mediated DC licensing represents what we believe is a novel strategy for exploiting the natural synergy between CD40 and TLR signaling that can markedly improve on MCs in augmenting the therapeutic efficacy of antitumor DC-based vaccines /
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to incorporate the iMC of Narayanan with the RCAR system of Brogdon using the improvement taught by Green et al and to do so would have arrived at the compositions of the claims. As noted above: 1) Green et al teach that using two or more FKBPv12 improves the switch system wherein 2) Brogdon teaches use of a related heterodimerization switch to regulate caspase 9 3) Narayanan teaches that this system is improved by
Thus, the iMyDSS CD40 unified "switch" effectively and safely replaced exogenous adjuvant cocktails, allowing remote and sustained DC activation in vivo. DC "licensing" through iMyD88/CD40 may represent a mechanism by which to exploit the natural synergy between the TLR and CD40 signaling pathways in DCs using a single small molecule drug and could augment the efficacy of antitumor DC-based vaccines..
Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow improved treatment.
Brogdon et al teach CAR with antigen recognition for Her2 is taught (see e.g. ¶0426) as are T-cell receptors (see e.g. ¶0003 and 0442). FRB can be FRBL (¶0638). Narayanan et al teaches use of two FKBP12v36 (see figure 1), DTIR and a CD40 cytoplasmic molecule (see page 1525, col 2).
Response to Arguments
Applicants arguments which reiterate the stance of the affidavit are not persuasive for the following reasons. The affidavit states that it would not be obvious to combine Green with Brogdon and Narayanan or use them interchangeably without further experiments. The affidavit asserts that basically that the claimed behavior - a CAR containing cell that can achieve activation via an iMyD88/CD40 switch while remaining simultaneously and reliably abortive via a distinct caspase-9 module - required substantial, application-specific experimentation and could not have been predicted. However, the rejection establishes that 1) use of FK506 and FRB to allow titratable regulation is known. Green teaches that at the time of filing the use of heterodimers and homodimers as recited in the instant claims was very well known.
[0109] Inducible protein interaction systems have provided fundamental insight into many cellular processes, including cell death. For example, versions of an FKBP-rapamycin interaction system has been used to create caspase proteases that could be induced to undergo homo- or heterodimerization by addition of specific drug ligands (27a-31a).
Furthermore, Green demonstrates how to use CID to regulate homodimerization vs heterodimerization with impact on linked molecules wherein in addition to the details below, extensive guidance is provided on how to use these constructs. Steps to deliver as well as use are provided in extensive detail (see e.g. ¶0145-0154 and 0277).
[0145] Commercially available dimerization kits can be used to control any signaling process that involves regulated protein-protein interactions, in particular, for creating specific interactions between two different proteins, especially where the directionality of dimerization is desired to be controlled. One dimerizer, AP21967, is suitable for in vivo use and has been used successfully in mice. Other reagents are based on the human protein FKBP12 (FKBP, for FK506 binding protein) and its small molecule ligands. FKBP is an abundant cytoplasmic protein that serves as the initial intracellular target for the natural product immunosuppressive drugs FK506 and rapamycin. Both these drugs naturally act as heterodimerizers, and both have been used as the basis for heterodimerization systems, as has FK-CsA, a cyclosporin-FK506 hybrid molecule. Rapamycin functions by binding with high affinity to FKBP, and then to the large PI3K homolog FRAP, thereby acting as a heterodimerizer to join the two proteins together. To use rapamycin to induce heterodimers between proteins of interest, one of the proteins is fused to FKBP domains, and the other to a 93 amino acid portion of FRAP, termed FRB, that is sufficient for binding the FKBP-rapamycin complex.
Hence, the arguments of applicants (“The references are only about simplified systems and by reading them, it would not be obvious to me or my colleagues that two independent FKBP/FRB-based switches could be co-expressed and independently drug-tuned in a single CAR cell without unacceptable cross-talk, toxicity, or loss of function. Success of such a system could not be reasonably predicted by these references without specific guidance. It seems that the Examiner ignores pharmacodynamics issues and off target biology of dual ligand dosing regimens in a single CAR cell that ensure mutually exclusive engagement in vivo without cross effects.”) are unclear. Green demonstrates this functionality and the progress with use of the compounds in vivo.
[0154] Rapamycin is available commercially from Sigma (cat #R0395) or Affinity BioReagents (cat # IR-022). Similarly, AP20187 is a synthetic dimerizer that can be used to induce homodimerization of Fv domain-containing fusion proteins. AP20187 has no immunosuppressive activity and is non-toxic to cells. AP20187 cannot be used to dimerize wild type FKBP domains. AP20187 has been successfully used in mice with maximal effects seen at doses in the range of 0.5-10 mg/kg delivered intravenously. The AP20187-based system has the advantages of working at lower concentrations, and AP20187 has better pharmacokinetic properties than AP1510, allowing it to be used in vivo.
Brogdon et al teaches that these safety switch systems can be used with Cas9.
[0616] There are many ways CAR activities can be regulated. In some embodiments, a regulatable CAR (RCAR) where the CAR activity can be controlled is desirable to optimize the safety and efficacy of a CAR therapy. For example, inducing apoptosis using, e.g., a caspase fused to a dimerization domain (see, e.g., Di et al., N Engl. J. Med. 2011 Nov. 3; 365(18):1673-1683), can be used as a safety switch in the CAR therapy of the instant invention. In another example, CAR-expressing cells can also express an inducible Caspase-9 (iCaspase-9) molecule that, upon administration of a dimerizer drug (e.g., rimiducid (also called AP1903 (Bellicum Pharmaceuticals) or AP20187 (Ariad)) leads to activation of the Caspase-9 and apoptosis of the cells. The iCaspase-9 molecule contains a chemical inducer of dimerization (CID) binding domain that mediates dimerization in the presence of a CID. This results in inducible and selective depletion of CAR-expressing cells. In some cases, the iCaspase-9 molecule is encoded by a nucleic acid molecule separate from the CAR-encoding vector(s). In some cases, the iCaspase-9 molecule is encoded by the same nucleic acid molecule as the CAR-encoding vector. The iCaspase-9 can provide a safety switch to avoid any toxicity of CAR-expressing cells. See, e.g., Song et al. Cancer Gene Ther. 2008; 15(10):667-75; Clinical Trial Id. No. NCT02107963; and Di Stasi et al. N. Engl. J. Med. 2011; 365:1673-83.
[0621] In embodiments, an RCAR can comprise a “multi switch.” A multi switch can comprise heterodimerization switch domains or homodimerization switch domains. A multi switch comprises a plurality of, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, switch domains, independently, on a first member, e.g., an antigen binding member, and a second member, e.g., an intracellular signaling member. In an embodiment, the first member can comprise a plurality of first switch domains, e.g., FKBP-based switch domains, and the second member can comprise a plurality of second switch domains, e.g., FRB-based switch domains. In an embodiment, the first member can comprise a first and a second switch domain, e.g., a FKBP-based switch domain and a FRB-based switch domain, and the second member can comprise a first and a second switch domain, e.g., a FKBP-based switch domain and a FRB-based switch domain.
[0627] In any of the RCAR configurations described here, the first and second switch domains comprise a FKBP-FRB based switch as described herein.
The affidavit continues “The pharmacology in this context is not a trivial superposition of Narayanan's single-switch DC system and Brogdon's single iCasp9 safety switch. In a live CAR T cell, each small molecule (AP1903-like CID versus rapalog/mTOR inhibitor) has its own absorption, distribution, clearance, and tissue penetration kinetics, and each may engage distinct and overlapping FKBP12-containing complexes, for example engineered fusion proteins and endogenous targets. Achieving the claimed behavior - a CAR containing cell that can achieve activation via an iMyD88/CD40 switch while remaining simultaneously and reliably abortive via a distinct caspase-9 module-required substantial, application-specific experimentation and could not have been predicted based on the references cited by the examiner.” However, Narayanan teaches how one could combine CID with iMC successfully (page 1524, col 1).
We show that iMyD88 induces higher NF-KB activation and requires several logs lower CID concentrations in vitro for NF-KB induction relative to iCD40-expressing cells.
Hence, consistent with the principles of KSR, the references demonstrate that all of the instant steps are available in the art and applicable together.
If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. Id. at ,82 USPQ2d at 1396.
When considering obviousness of a combination of known elements, the operative question is thus "whether the improvement is more than the predictable use of prior art elements according to their established functions.” 82 USPQ2d at 1396. In this case, lower CID, increased DC survival, regulation for a safe manner of using caspase warrant combining the references.
(Brogdon, ¶0616) The iCaspase-9 can provide a safety switch to avoid any toxicity of CAR-expressing cells. See, e.g., Song et al. Cancer Gene Ther. 2008; 15(10):667-75; Clinical Trial Id. No. NCT02107963; and Di Stasi et al. N. Engl. J. Med. 2011; 365:1673-83.
(Green, [0140]) The affinity and specificity of these molecules was further improved by eliminating their ability to bind to endogenous FKBP. These homodimerizers, AP1903 and AP20187, bind with subnanomolar affinity to FKBPs with a single amino acid substitution, Phe36Val (Fv), while binding with 1000-fold lower affinity to the wild type protein. The new system invariably provides more potent activation of homodimerization, and have pharmacologic properties suitable for in vivo use. AP20187 and Fv form the basis of the reagents provided in the ARGENT Regulated Homodimerization Kit (herein incorporated by reference).
Applicants arguments mirror thee affidavit. However, the arguments also extend that the art does not teach a single cell with independent, drug tunable control of activation versus apoptosis but rather single-switch systems not co-expressed operating in one therapeutic cell without cross-talk. However, both Green and Brogdon teach that the dual regulation of heterodimers or homodimers lead to opposing activity of the linked molecule i.e. caspase (Brogdon) and RIPK3 (Green). Narayanan teaches that the FKBP12 system and the iMC function with predictability for dual regulation wherein dimer formation leads to activation of DC for enhanced anti-tumor ability and no dimer formation does not. Each of these systems require dual controlled effects that are independent wherein the combination would inherently lead to activation vs apoptosis.
It is noted that if applicants can demonstrate unexpected success of the scope of the claimed invention compared to the art this would be sufficient to overcome the rejection.
Double Patenting
A rejection based on double patenting of the "same invention" type finds its support in the language of 35 U.S.C. 101 which states that "whoever invents or discovers any new and useful process ... may obtain a patent therefor ..." (Emphasis added). Thus, the term "same invention," in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957); and In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
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. See 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);and, 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) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1, 2, 7-10, and 38-41 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 2, 4-8, 10 and 11 of (copending Application No. 17/053,275) U.S. Patent 1,241,0231. This rejection is maintained. Applicants request for abeyance until allowable claim matter is identified is acknowledged.
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claims because the examined claim is either anticipated by, or would have been obvious over, the reference claims. Although the conflicting claims are not identical, they are not patentably distinct from each other because the cited claims of the instant invention are generic to all that is recited in claims 38, 41, 44, 45-46, 50, 53, 54 and 73 of copending Application No. 17/053,275. Both claims are drawn ultimately to cells comprising at least two polynucleotides wherein in both there is a chimeric peptide comprising a multimerizing peptide and MyD88 with or without TIR and CD40 cytoplasmic protein with or without the extracellular domain (i.e. claim 38), a second comprising Caspase-9 and a multimerizing peptide (i.e. claim 44) and a third comprising a chimeric T receptor or CAR to i.e. Her2/Neu (copending claim 41) wherein the multimerizing peptides are different i.e. FRB and FKBP12v36 (claim 45). The dependency of method claims if amended to the listed claims would lead to their inclusion in the rejection.
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding the of copending Application No. 17/053,275, then two different assignees would hold a patent to the claimed invention of copending Application No. 17/053,275, and thus improperly there would be possible harassment by multiple assignees.
Claims 1, 2, 7-10, and 38-41 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-5, 7, 8, 11-18, 23, 26 and 28-30 of copending Application No. 18/471,761 (parents 17/219, 116 and 15/377,776 are abandoned). This rejection is maintained. Applicants request for abeyance until allowable claim matter is identified is acknowledged.
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claims because the examined claim is either anticipated by, or would have been obvious over, the reference claims. Although the conflicting claims are not identical, they are not patentably distinct from each other because the cited claims of the instant invention are generic to all that is recited in claims of copending Application No. 18/471,761. Both claims are drawn ultimately to cells comprising at least two polynucleotides wherein in both there is a chimeric peptide comprising a multimerizing peptide and MyD88 with or without TIR and CD40 cytoplasmic protein with or without the extracellular domain (i.e. claim 1), a second comprising Caspase-9 and a multimerizing peptide (i.e. claim 7) and a third comprising a chimeric T receptor or CAR to i.e. Her2/Neu (i.e. claim 3) wherein the multimerizing peptides are different i.e. FRB and FKBP12v36 (claim 1). Regarding claims 13-15, 26 and 28-30, the safe harbor for non-statutory double patenting only applies for applications filed as divisional applications. Because all sets of claims are drawn to the same cells and the methods of use are the only disclosed use of these cells, the claims are related under the non-statutory double patenting statute. Copending Application No. 18/471,761 have been filed as divisional applications.
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding the copending Application No. 18/471,761, then two different assignees would hold a patent to the claimed invention copending Application No. 18/471,761, and thus improperly there would be possible harassment by multiple assignees.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached on 8 am - 5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARIA MARVICH/Primary Examiner, Art Unit 1633
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