DETAILED ACTION
Applicant’s amendment and response received on 11/26/25 has been entered. Claims 23-28 have been canceled. Claims 2-13, 15, 18-20, and 22 are now pending and currently under examination. An action on the merits follows. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 11/19/25 and 1/2/26 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner and initialed and signed copies of the 1449s are attached to this action.
Claim Rejections - 35 USC § 112
The rejection of claims 2-13, 15, 18-20, and 22-28 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn over canceled claims 23-28 and maintained over amended claims 2-13, 16, 18-20, and 22. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that the claims as amended, by limiting the target antigen to tyrosine kinase growth factor receptor overexpressed on tumor cells, are now commensurate in scope with the data in Examples 1-6. According to applicant, the examples show examples of a conditionally pH active CAR specific for a target antigen which is Axl- referred to in the specification as X1, and ROR2, referred to as X2 in the specification, and that both of these are tyrosine kinase growth factor receptors overexpressed by tumors. The applicant states that they have provided a poster presentation and press release from F1 Oncology/Exuma Biotechnology showing that CAR-T cells made by the method of present invention can address off tumor toxicity of CAR-T therapy. The applicant also argues that despite a lack of description for the structure/sequence or any anti-tyrosine kinase growth factor receptor antibody which has the claimed increased activity at the pH of the tumor microenvironment and less activity as physiological pH, that such antibodies can be easily made using known antibodies to tyrosine kinase growth factor receptors overexpressed on the surface of cancer cells following the procedures disclosed in the specification. The applicant has also provided an attached poster regarding CAR comprising conditionally active antibodies -CAB-CAR, and a presentation related to logic-gating HER2 CAR-T cells. The applicant argues that these post-filing posters and presentations should be considered as they confirm the Examples and statement made in the as filed application.
In response, it is noted the statement made by applicant’s counsel regarding the identify of X1 and X2 in the specification as Axl and ROR are not supported by any evidence of record. Further, it is noted that the working examples refer to “X3” not “X2”. In addition, the submitted poster presentations and press releases appear to be post-filing evidence related to what appear to be specific conditionally pH active antibodies whose structures are not disclosed in the as filed application. It is also noted that none of the poster presentations, or the press release actually provides guidance as to the mutations present in any of these antibodies which render them more active at the pH of the tumor environment and less active as physiological pH.
As amended, the claims are directed to a cytotoxic cell comprising a nucleic acid encoding a chimeric antigen receptor (CAR) for binding with a tyrosine kinase receptor which is overexpressed on a cancer cell, which comprises an antigen specific targeting region having a decreased binding activity in an assay at a normal physiological pH compared to the same activity at an aberrant pH, and a method of administering said cytotoxic cell to a subject for the treatment of cancer. Dependent claims further recite that the extracellular spacer domain of the CAR has an enhanced ubiquitylation-resistance level at the aberrant pH, and/or the linker present in the bispecific CAR undergoes a conformational change, i.e. higher antigen-binding at an aberrant pH than at a normal physiological condition. Given the broadest reasonable interpretation, all of the pending claims embrace a genus of CARs, whose structures are defined by their function, i.e. decreased binding activity of the at least one antigen specific targeting region present in the CAR at a normal pH versus binding of the antigen specific targeting region at a pH above or below the normal pH. The claims further embrace a genus of transmembrane domains and extracellular spacer domains whose structures are also defined by their functions.
It is maintained that the specification fails to provide an adequate disclosure for the genus of CAR encompassed by the claims, including the genus of antigen specific targeting regions that are conditionally pH active, the genus of extracellular spacer domains, and the genus of linkers with the specific functional properties recited in the instant claims. The specification fails provide sufficient description for the broad genus of CAR and any of the subgenuses of antigen specific targeting regions, extracellular spacer domains, and linkers in terms of distinguishing characteristics of the genus or the structure and functional relationship for each of the functional properties claimed.
The specification teaches that antigen specific targeting regions, such as scFV, may be obtained through the evolution of a wild-type antibody, where resulting “evolved” receptor binding regions are then screened for a desired activity. For example, agents are evaluated for potential activity as conditionally active biologic therapeutic enzymes by inclusion in screening assays (parag. 0037); a protein or antibody, or a portion of an antibody, maybe expressed and displayed on a mammalian host cell surface for screening purposes, followed by screening for specific antigen binding by a combination of magnetic beads and fluorescence-activated cell sorting (parag. 0087). The specification refers to the general knowledge in the art for design and optimizing strategies for generating high-affinity antibodies (e.g. parag. 228) and for selection process (e.g. parag. 0299, 0360). However, while the specification discloses evolving scFV specific for a target antigen which is a tyrosine kinase growth factor receptor, such as EGFR, FGFR, or erbb2, or even Her2/Neu, the specification does not actually describe any such antibody, or scFV which binds to any tyrosine kinase growth factor receptor which can be used as a starting material for mutation to generate an scFV with pH conditional binding. The specification also fails to disclose any structural features or specific mutations present in CDR or framework regions of any antibody that correlate with pH sensitivity and specifically to decreased binding to a target antigen at a normal pH. The specification also fails to disclose any structural features or specific mutations present in CDR or framework regions of any antibody that correlates with increased binding to the target antigen at the lower pH present in a tumor microenvironment. In addition, the specification, while broadly disclosing extracellular spacers and linkers, fails to provide any specific description for the structure or sequence of extracellular spacer with enhanced ubiquitylation-resistance level at the aberrant pH, and/or the structure or sequence of a linker which can undergo a conformational change, i.e. higher antigen-binding at an aberrant pH than at a normal physiological condition.
Turning to the working examples, in example 2, the specification teaches obtaining conditionally active antibodies for the drug target antigen X1 by simultaneously screening for selectivity and affinity, as well as expression level at both pH 6.0 and pH 7.4. The working example also teaches making a conditionally active CAR using an antibody binding domain selected for pH sensitivity. However, the specification does not actually identify what drug target antigen X1 is, i.e. is it a protein, a carbohydrate etc., and further does not identify any specific epitope which is bound by any of the disclosed anti-X1 antibodies. As noted above, while the response by counsel identifies X1 as Axl, there is no evidence of record supporting this assertion. The specification also does not provide any sequence information of V, (D), J usage for the parent antibodies or any sequence information for the evolved antibodies, such as specific mutations. In example 3 of the specification, CAR-T cells comprising a conditionally active scFv antibody against target antigen X1 induced cytotoxicity in model CHO cells expressing target antigen X1. In example 6, the specification reported that five conditionally active scFv antibodies against target antigen X3 were also selected. As with antigen X1, antigen X3 is not identified and no information, structural or sequence related, is provided for any antibody that binds to X3 or for any mutant based on such an antibody with pH conditional binding activity. Ultimately, the specification fail to provide any teaching on how the structure of the selected conditionally active scFv antibodies targeting X1 of X3 antigen relate to the structural requirement for the genus. It is further noted that the specification does not identify which part of the extracellular domain change of the antibody caused the altered binding activity, the hinge domain or the antigen-targeting domain. The specification does not provide any data or any specific description of residues which can be modified in any antibody sequence, such CDR sequences, framework sequences, or hinge sequence, in one or both of heavy or light chain without substantially affecting antibody structure and function, including antigen specificity, affinity, and function.
The applicant argues that parent antibodies to tyrosine kinase growth factor receptors overexpressed on cancer cells were known in the prior art. However, as discussed in the rejection of record, the prior art at the time of filing is replete with teachings that while the overall structure between antibodies is shared, the structure of the antigen binding region of an antibody and the residues involved in binding to its cognate antigen are unique to each antibody and can involve residues both within any one or all of the heavy and light chain CDRs and framework regions (see for example, Vajdos et al. (2002) J. Mol. Biol., Vol. 320, 415-428, Chen et al. (1992) J. Exp. Med., Vol. 176, 855-866, and Sela-Culang et al. (2013) Frontiers in Immunology, Vol. 4, pages 1-13). Vajdos et al. teaches that residues in both the CDRs and framework regions of antibodies can be important for antigen recognition and binding, and discloses attempts to identify key residues in the antigen binding site of the Fab2C4 antibody for its peptide epitope derived from the extracellular domain of the human oncogene ErbB2 (Vajdos et al., pages 416-418). Vajdos et al. teaches that two different mutagenesis strategies were used to identify key residues in peptide binding- shotgun alanine scanning mutagenesis and shotgun homolog-scanning mutagenesis- and report that the results of the two methods in combination three dimensional crystal structure of the Fab2C4 antibody provided distinct yet complementary view of key residues in binding between the antibody and antigen (Vajdos et al., page 417, Figure 1 and Table 2). As can be seen in Figure 1, each method identified different key residues, with some overlap. Vajdos et al. states that key residues for binding are present in both the heavy and light chain and include both solvent exposed and buried residues, where the buried residues may act as essential scaffolding residues that maintain the structural integrity of the antigen binding site (Vajdos et al, page 423). Thus, Vajdos demonstrates that identification of key residues in an antibody that affect antigen binding and are not tolerant of modification, or which may only tolerate certain modifications, is a labor intensive process which cannot be predicted a priori. Chen et al. provides the results of random point mutation mutagenesis of the heavy chain CDR2 in the PC-specific T15 antibody and demonstrates that mutations in this CDR alone can abrogate binding and further that increasing the number of mutations within this one CDR results in a significant increase in non-binding mutants, from approximately 7% nonbinding mutants with 1 mutation to 58% nonbinding mutants with 2 mutations in HCDR2 (Chen et al., pages 855-859, Table 2).Chen et al. also demonstrated that mutations in at least 5 residues in this CDR2 were important in antigen binding (Chen et al., page 855). Thus, Chen et al., like Vajdos et al. demonstrates that mutations affecting antigen binding in antibody chains cannot be determined a priori, and further teaches that increasing the number of mutations within a CDR substantially increases the chances of generating a non-binding mutant. Sela-Culang et al., in a recent review of the structural basis of antibody-antigen recognition teaches that some off-CDR residues can contribute critically to the interaction of the antibody with antigen (Sela-Culang et al. (2013) Frontiers in Immunology, Vol. 4, pages 1-13, page 1). Sela-Culang et al. teaches that in some antibodies framework residues contribute to the antigen binding site, and in other antibodies, the frame work residues affect the antigen binding site indirectly by shaping the antigen binding site (Sela-Culang et al., page 7). In fact, Sela-Culang et al. teaches that constructing an antibody using only the CDRs from an known antigen-specific antibody usually results in a significant drop or a complete loss of binding of the antibody to its antigen (Sela-Culang et al., page 7). Sela-Culang et al. further teaches that different CDR identification methods may often identify radically different stretches as “CDRs”, indicating that CDRs are not well defined and thus are not necessarily a good proxy for the binding site (Sela-Culang et al., page 8). Thus, Sela-Culang et al. provides additional evidence that the effects of mutations of a known antibody with known heavy and light chain sequences cannot be predicted a priori, including mutations within the framework regions of the antibody. Therefore, the prior art at time of filing clearly teaches that the effects of the introduction of any one or more mutations into any one of the six CDR or the framework region of an antibody, including a known antibody, cannot be predicted from the sequence of the antibody alone.
Turning to the state of the art with regard to the influence of pH and binding activities of a monoclonal antibody, Raso et al. taught the development of an antibody that could release the binding partner/antigen-Diphtheria toxin in response to low pH (Raso et al. (1997) J Biol Chem Vol. 272:27618-22). Raso et al. taught the antibodies bind DT at neutral pH but spontaneously release DT when critical epitopes denature or unfold at low pH (see the abstract). The observation was consistent with the studies of Gandhi (Master’s Theses, U. Rhode Island, 2002, IDS), who reported that antibody binding to ANS-tagged proteins (=model antigen) were appreciably greater at pH 3.0 than that at pH 8.0 in the temperature range studied. But such binding activity variation was attributed to at least two different factors, the hydrophobic residues as well as electrostatic interactions of the antibody at different pH; and conformational changes of proteins, i.e. protein unfolded at low pH, so that the hydrophobic residues exposed to the aqueous solution allowing greater antibody binding (see Section 4.2.2.2, pages 35-36). As such, the binding activity of antigen-targeting region of a CAR at different pH environment would have been determined by the conformational changes of both antibodies and antigens. Liao et al. (2006) J Virol Vol. 80:9599-9607 further echoes such consensus. Liao taught that low pH triggers viral membrane fusion through conformational change during Semliki Forest virus infection, and the E1 envelop protein of the SFV mediates low pH-triggered membrane fusion, particularly the E1 stem region. Liao reported that the E1 stem was hidden on neutral pH, became accessible after low pH-triggered dissociation of the E2/E1 heterodimer, and then packed onto the trimer core in the postfusion conformation and became inaccessible to antibody binding (see e.g. the abstract). As such, not only the conformational changes of the antibody but also that of the corresponding antigen contribute to the increased or decreased binding activities of a CAR antigen targeting region at various pH environment, and such conformational alteration may bring about constantly changing binding activities. In view of the complex nature for the basis of the antibody-antigen binding activity, it was unclear whether the activity change at low pH for the disclosed CARs was attributed to antigen-targeting domain, the hinge domain or the X antigen conformational changes.
Further in regard to the design of antigen targeting region of CARs, around the time of instant filing, Jensen et al. taught, in the context of structural issues in CAR design using scFvs as antigen targeting domain, “the design of CARs for individual target molecules has largely been empiric” and “It is uncertain whether the design of CARs for other tumor-associated molecules that are not as abundantly expressed as CD19 on target cells will be as amenable to empiric design, or might benefit from structural modeling of T-cell/tumor cell interactions to promote effective T-cell signaling and tumor cell death.” (Jensen et al. (2014) Immunol Rev 2014 Jan; 25:127-44, IDS, See page 6).
Applicant’s response does not address any of the cited references and simply maintains that one could make such conditional pH active antibodies from any known parental antibodies using their mutational methods and screening. However, given such under-developed, complex, and unpredictable state of the art for mutating antibodies for desired functionality, the breadth of tyrosine kinase growth factor receptors antigens, the breadth of antibody scFV, and the breadth of aberrant pH encompassed by the claims, the limited antibodies with pH sensitivity for binding to unknown antigens X1 and X3 are not considered representative for the breadth of the genus claimed and are further not described in terms of specific mutations or sequences. Therefore, the specification fails to provide an adequate description for the sequences, structures, identifying characteristics, and structure-function relationship of genus of scFV, extracellular spacers, and linkers with specific functional properties, and CAR molecules comprising these elements encompassed by the claims. Accordingly, the specification does not provide sufficient description for what is now broadly claimed. In addition, the applicant has not addressed the lack of written description for extracellular spacers, and linkers which have particular claimed functional properties.
The applicant is also reminded that an adequate written description for an active agent, such as a CAR, an antigen specific targeting region, an extracellular spacer or a linker with specific functional properties requires more than a mere statement that it is part of the invention; what is required is a description of the chemical structures and physical properties itself. It is not sufficient to define the CARs solely by its principal biological property, i.e. “a target region having a decreased activity in an assay at a normal physiological pH compared to the same activity at an aberrant pH” because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any CAR with that biological property. Also, naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, claiming all CARs that achieve a result without further definition is not in compliance with the description requirement. Rather, it is an attempt to preempt the future before it has arrived. (See Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)). The court has made it very clear “Conception of chemical compound requires that inventor be able to define compound so as to distinguish it from other materials, and to describe how to obtain it, rather than simply defining it solely by its principal biological activity”. Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
The court also stated (see MPEP 2163) “The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347,1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of these considerations, it is maintained that a skilled artisan would not have viewed the teachings of the specification as sufficient to show that the applicant was in possession of the claimed invention commensurate to its scope because it does not provide adequate written description for the broad classes or representative species of CAR having the recited changing activity at various pH environment.
Claim Rejections - 35 USC § 103
The rejection of claims 2-5, 9, 11-13, 15, 18-20, 22, 24-25, and 27-28 under 35 U.S.C. 103 as being unpatentable over US Patent Application 2014/0255363, hereafter referred to as Metalitsa et al., in view of US Patent Application Publication 2013/0266579, hereafter referred to as Wei et al., is withdrawn over canceled claims 24-25 and 27-28, and further withdrawn over amended claims 2-5, 9, 11-13, 15, 18-20, and 22 in view of applicant’s amendments to independent claim 18 which now limits the target antigen toa tyrosine growth factor receptor that is overexpressed on a surface of a cancer cell.
Amended claims 6-7 and 10 remain and amended claims 2-5, 9, 11-13, 15, 18-20, and 22 are newly rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application 2014/0255363, hereafter referred to as Metalitsa et al., in view of US Patent Application Publication 2013/0266579, hereafter referred to as Wei et al., and U.S. Patent 9,447,194 (2016), hereafter referred to as Jensen. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed below.
As noted in the previous office action, claim 3, which depends on claim 18, recites the wherein clause, “wherein the chimeric antigen receptor further comprises an extracellular spacer domain or at least one co-stimulatory domain” (emphasis added by examiner). Claims 5 and 22 depend on claim 3 and further recite additional limitations for the alternative which is an extracellular spacer domain. However, none of claims 5, or 22 recites that the chimeric antigen receptor is a chimeric antigen receptor which has an extracellular spacer domain. Thus, claims 5, and 22 continue to encompass both of the alternatives recited in claim 3 such that a teaching for the embodiment which is a chimeric antigen receptor comprising at least one co-stimulatory domain will meet the claim limitations of all of claims 3, 5 and 22.
The applicant argues that Metalitsa et al. only teaches CAR comprising an antibody binding domain that binds to the GD2 antigen and does not teach to produce mutants of the GD2 CAR which are pH sensitive. The applicant also argues that Metalitsa et al. does not teach EGFR or any other tyrosine kinase receptor overexpressed in tumors as recited in claim 1 as a target for use with their combined therapy of CAR-NKT cells and IL-15. The applicant further argues that Wei et al. only teaches to mutagenize anti-EGFR antibody binding sequences for humoral therapy and does not teach to use the EGFR antibodies to make CARs for any cell based therapies. The applicant argues that there is no motivation to combine the methods of Wei et al. with Metalitsa et al., because there is no reasonable expectation of success in making CAR with pH sensitive antigen binding regions and that the rejection improperly relies on hindsight reasoning. The applicant also argues that Jensen does not cure the deficiencies of Metalitsa et al. and Wei et al.
In response, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In regards to the alleged use of “hindsight reasoning” it is further noted that it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant rejection, Metalitsa has been cited for teaching a CAR comprising an scFv specific for a tumor associated antigen, such as GD2, which is a cell surface antigen on cancer cells such as neuroblastoma, fused to the CD3ζ transmembrane domain, an intracellular signaling domain, such as the CD3ζ intracellular domain, and a costimulatory signaling domain, such as the costimulatory domain of CD28 (Metalitsa et al., paragraphs 28, and 60-65). Metalitsa further teaches that the expression vector includes retroviral vectors, lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, or plasmids (Metalitsa et al., paragraphs 27, 63, 65, 68, and 75-78). It was acknowledged the Metalitsa differs from instant invention by not teaching that the scFv has decreased binding activity at a normal physiological pH of 7.4 conditions compared to binding activity at a tumor microenvironment pH of 6.0-7.0, and does not teach a method of mutagenizing an scFV and selecting for increased binding at a pH of 6.0-7.0. However, as noted above, the test for obviousness is not that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Wei et al. was cited to supplement Metalitsa et al. by teaching methods of generating conditionally active anti-epidermal growth factor receptor (EGFR) antibodies and antigen binding fragments thereof that exhibit reduced activity at non-tumor microenvironments (e.g. having a neutral pH) compared to antibodies that are not conditionally active and/or compared to their activity in the tumor microenvironment (Wei et al., paragraphs 8-9). Wei et al. teaches that by virtue of the selectivity to a tumor microenvironment, they exhibit fewer or lesser undesirable side-effects and/or exhibit improved efficacy by virtue of the ability to dose higher (Wei et al., paragraphs 8-9). Further, Wei teaches a specific method for making and screening cetuximab anti-EGFR antibody mutants for pH dependent activity. (Wei et al., Example 1).Wei et al. teaches that the anti-EGFR antibody mutants are generated using mutagenesis techniques where DNA is modified by routine molecular biology techniques for inserting, deleting, adding, or replacing nucleotides (Wei et al., paragraph 735). Wei teaches identifying an Y104D mutant of cetuximab that had decreased binding affinity at pH 7.4 compared to pH 6.5 (Wei et al., Example 5 and Table 19). Wei teaches that the Yl04D mutant exhibited greater inhibition of EGF-induced phosphorylation of EGFR at pH 6.5 compared to pH 7.4 (Wei et al., Example 6, and Fig. 3). Wei et al. further teaches that the Y104D mutant antibody inhibited EGFR expressing tumor growth (Wei et al., Example 8). Wei et al. also shows that the Y104D mutant exhibits significantly less binding to skin, including primate and human skin, and exhibits a marked preference for binding to tumor tissue than skin tissue in vivo (Wei et al., Examples 9-11). Wei also teaches scFv forms of the anti-EGFR antibodies (Wei et al., paragraphs 85-86). In addition, Wei teaches that EGFR cell surface receptor is overexpressed in various cancers (Wei et al., paragraph 413). Wei et al. also provide specific motivation to use pH sensitive antibodies that are active in a lower pH tumor microenvironment. Wei et al. specifically states in paragraph 8, “Because tissues, other than tumors, such as tissues in the skin express EGFRs, the anti-EGFR antibodies inhibit activities of these receptors, thereby causing undesirable side-effects. The antibodies provided herein are conditionally active in that they exhibit reduced activity at non-tumor microenvironments (e.g. having a neutral pH) compared to antibodies that are not conditionally active and/or compared to their activity in the tumor microenvironment. By virtue of the selectivity to a tumor microenvironment, they exhibit fewer or lesser undesirable side-effects and/or exhibit improved efficacy by virtue of the ability to dose higher”. The examples provided in Wei et al. back up these statements. Wei was able at higher dosages to achieve the same anti-tumor effects with the mutated antibody as with the unmutated antibody-example 8, and further clearly demonstrated that the mutated antibodies exhibited less binding to normal tissue such as skin, examples 9-11. As taught by Wei et al. in paragraph 8 cited above, these activities are considered advantages over the unmutated antibody.
Furthermore, Jensen was cited to supplement Metalitsa et al. and Wei et al. by teaching a bispecific chimeric antigen receptor, comprising: (a) at least two antigen-specific targeting regions; (b) an extracellular spacer domain; (c) a transmembrane domain; (d) at least one co-stimulatory domain; and (e) an intracellular signaling domain, wherein each antigen-specific targeting region comprises an antigen-specific single chain Fv (scFv) fragment, and binds a different antigen, (Jensen et al., abstract). Jensen further teaches that the antigen targeting region may comprise a hinge region of an antibody, e.g. lgG4 (e.g. figs. 3, 8), a transmembrane domain of CD28 or any known to the skilled (e.g. fig. 7 or column 5, lines 55-58), a costimulatory domain CD137/4-1 BB and an intracellular signaling domain CD3zeta (e.g. figure 7) or CD3epsilon (column 5, line 22); wherein one of the two target antigen may be EGFR (see e.g. columns 13-14). Thus, Jensen et al. provides specific motivation to not only generate an CAR comprising an antibody to EGFR, but further provides motivation to include in the extracellular domain of the CAR a hinge region of an antibody such as IgG4. Further in regards to applicant’s argument that not all costimulatory domains would be expected to work in a CAR, it is noted that Jensen et al. in fact teaches that making a CAR was considered routine at the time of filing, where the majority of CARs that have been constructed appear to function effectively in vitro and in vivo (Jensen et al., page 31).
Therefore, it is maintained that based on the motivation provided by Jensen to use a bispecific CAR instead of a monospecific CAR for cancer therapy in order to overcome issues with antigen loss escape variants, the specific teaching and motivation provided by Jensen et al. to generate CAR comprising an scFv specific for EGFR, the motivation provided by Jensen to include an extracellular domain which is a hinge domain in a CAR, the advantages specifically taught by Wei et al., who represents a skilled artisan at the time of filing, for making pH sensitive antibodies and scFV which are more active under the pH conditions of the tumor microenvironment and the specific teachings for an anti-EGFR scFv that had decreased binding affinity at pH 7.4 compared to pH 6.5 and the pH of a tumor microenvironment, it would have been prima facie obvious to the skilled artisan at the time of filing to generate either a bispecific CAR according to Jensen et al. or a monospecific CAR according to Metalitsa et al. using the conditionally pH active anti-EGFR CAR taught by Wei et al. and to practice the methods of using cytotoxic T cells expressing a CAR to treat cancer as taught by Metalitsa et al. where the CAR is the monospecific or bispecific conditionally pH active anti-EGFR CAR with a reasonable expectation of success.
Double Patenting
The rejection of claims 2-13, 15, 18-20, and 22-28 on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,111,288, hereafter referred to as the ‘288 patent, is withdrawn over canceled claims 23-28 and further withdrawn over the pending claims in view of applicant’s submission of a terminal disclaimer on 11/26/25. The terminal disclaimer filed on 11/26/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,111,288 has been reviewed and is accepted. The terminal disclaimer has been recorded.
The provisional rejection of claims 2-13, 15, 18-20, and 22-28 on the ground of nonstatutory double patenting as being unpatentable over claim 1-6 and 14-15 of copending Application No. 17/389,337 hereafter referred to as the ‘377 application, is withdrawn over canceled claims 23-28 and further withdrawn over the pending claims in view of applicant’s submission of a terminal disclaimer on 11/26/25. The terminal disclaimer filed on 11/26/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application Number 17/389,337 has been reviewed and is accepted. The terminal disclaimer has been recorded.
No claims are allowed.
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.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634