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 .
Election/Restriction
Applicant’s election without traverse of Invention III, in the reply filed on 16DEC2025 is acknowledged.
Claims 1-5 and 11-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Election was made without traverse in the reply filed on 16DEC2025.
Claim Status
Claims 4-5 and 10-11 have been amended.
Claims 1-14 are pending in the instant application (i.e., Claim(s) 1 and 6 is/are independent).
Claims 1-5 and 11-14 are withdrawn.
Claims 6-10 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2021/035184, filed 01JUN2021, which claims the benefit of US Provisional Patent Application No. 63/033392, filed 02JUN2020. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 30NOV2022 and 30JAN2023 is/are acknowledged and the references cited therein have been considered.
Drawings
The drawings filed 30NOV2022 are objected to because in in Fig 2 the text is difficult to read, in Fig 3A-D and 5 the lines used to differentiate the data lack contrast and/or resolution and in Fig 4 the y-axis title is cropped. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
The Brief Description of Figures section should include a brief description for each individual subset, for example on p 7 including “ cell lines (Fig 3A: H23, Fig 3B: H460, Fig 3C: H520, and Fig 3D: PC9)” after “NSCLC” in line 9. Similar correction is required for Fig 4A-4C, 6A-6D, and 7A-7D.
Appropriate correction is required.
The use of the terms “XCELLigence” (p 7), “Sleeping Beauty” (p106), PiggyBac (p106), etc., which is a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The lengthy specification has not been checked to the extent necessary to determine the presence of and to catalog all possible minor errors. Applicant’s assistance and cooperation in finding and correcting any errors of which the applicant may become aware of in the specification is appreciated.
Claim Objections
Claim 6 and 8-9 are objected to because of the following informalities:
Claim 6 contains a typographical error, “…comprising a EGFR…” should be updated to “…comprising an EGFR…” in line 1 of the claim.
Claim 6 is also missing a period at the end of the claim.
Claims 8 and 9 contain a typographical error, “…represents and optional hinge…” should be updated to “…represents an optional hinge….”
Claim 9 is missing an “or” between the last two formulas.
Appropriate correction is required.
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 8-9 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.
Claims 8-9, recite the phrase "optional," which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(h)(II).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claims 6-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Scope of the claim:
In the instance of claim 6, the nature of the invention drawn to a CAR polypeptide comprising essentially any EGFR antigen binding domain, essentially any MUC1 antigen binding domain, essentially any transmembrane domain, essentially any co-stimulatory signaling region, and essentially any intracellular signaling domain in essentially any conformation (i.e., AND-gate or OR-gate formats) is not fully enabled. The broadest claim is not fully enabled because:
The breadth of the CAR construct variables (i.e., binding domains, transmembrane domains, and co-stimulatory/intracellular signaling domains);
The breadth of the CAR polypeptide format (i.e., AND-gate or OR-gate CARs);
The lack of support for the antigen binding domains being anything other than an scFv;
More specifically the lack of support for the EGFR scFv being anything other than an amino acid sequence selected from SEQ ID NOs: 11 and 12 and the MUC1 scFv being anything other than an amino acid sequences selected from SEQ ID NOs: 32 and 33;
The prior art which supports that there are significant design differences between AND-gate or OR-gate CARs; and therefore
The undue experimentation necessary for one of ordinary skill in the art to make the currently claimed invention. Claims 7-10 are also rejected since they depend from claim 6, but do not remedy this deficiency.
Furthermore, in claims 8-9, the prior art supports that there are challenges in identifying the ideal Tandem or Loop CAR bivalent formats inclusive of selecting appropriate target antigens and improving transduction efficiency. Additionally, there are only working examples which support a dual CAR construct, wherein the EGFR scFv is located in the first position and the MUC1 scFv is located in the second position (Fig 2-7) and there is no support for either sequential or loop tandem bispecific CARs as shown in Fig 8.
Direction provided by the inventor and existence of working examples:
The specification discloses that MUC1 and EGFR are overexpressed on the surface of NSCLC cells (Fig 1), a set of four dual EGFR x MUC1 CAR constructs (i.e., Fig 2) expressed in T cells, and their efficacy in treating NSCLC in vitro (Figs 3-7), wherein the dual CART cell activation requires co-expression of both targets (p 9). The specification teaches that the four dual CAR constructs are expressed in a single vector and comprise a 2A peptide, which results in two constructs: the EGFR scFv-TM-CD3ζ signaling construct and the MUC1 scFv-TM-41BB costimulatory signaling domain construct (i.e., Fig 2) in the same T cell. Of the four dual constructs, only CARs1-3 effectively treat four target NSCLC cell lines in vitro (i.e., Fig 3 and 5). CAR4 comprising the C10KV3 scFv-TM-CD3ζ-2A-MUC1* scFv-TM-41BB did not elicit a significant response against NSCLC cell lines in comparison to a mock-transduced T cell (i.e., UT, Fig 3), which supports that dual bispecific CAR structures given comparable TM and CSR/IDS regions are unpredictable and would require significant screening to determine the efficacy. Additionally, given the vast number of scFv combinations, which is compounded by the exponential combinations of CSR/IDS for dual CARs (i.e., Tables 4-6, p 90-96) and the infinite combinations of CSR/IDS for tandem CARs (i.e., Tables 2 and 3, p 12-90), screening all combinations would require significant undue experimentation for one of ordinary skill in the art.
State of prior art and level of predictability in the art:
Furthermore, the literature teaches that the CAR structural design can significantly influence the toxicity and efficacy of CAR T cells; that there are a variety of multiple antigen CAR construct formats (i.e., two antigens split across a signaling and co-stimulatory domain in one cell (i.e., AND-gate CARs), two full CARs expressed in one cell (i.e., OR-gate CARs), multiple single CARs expressed in multiple cells (i.e., pooled CARs, OR-gate CARs), or two antigens in one CAR comprising both signaling and co-stimulatory domains expressed in one cell (i.e., OR-gate CARs)) which impact the safety of the CAR upon expression in a CAR T cell; and in the instance of utilizing a single CAR polypeptide there are typically two strategies used for expression of the CAR in the T cell.
Specifically, Alsaieedi, et al., and Gomez-Melero, et al., teach that the choice of targets (i.e., antigen), antigen-binding domain(s), co-stimulatory domain(s), transmembrane domain(s), hinge region(s), and the length of the endodomain all affect the toxicity and efficacy of the CAR expressed in a CAR T cell (Alsaieedi, et al., Front Immunol, 2025, 16, 1-21, see section 5.1, Gomez-Melero, et al., Front Immunol, 2025, 16, 1-20, see abstract). Attlnanese teach a variety of multi-antigen CAR constructs, and by carefully selecting the construct/format results in favoring CAR T cell activation directly and minimizing toxicity in patients (i.e., split or AND-gate CAR) or guarding against tumor antigen loss (i.e., tandem, two full CARs, or OR-gate CARs) (Attlnanese, et al., Immuno Rev, 2023, 320, 166-198, see Logic gated CARs section, Fig 5). Furthermore, in the instance of using a single vector, which expresses multiple antigen binding domains in a single CAR polypeptide, there are typically two strategies: i) expression of two constructs utilizing a 2A peptide between the different constructs, which mediates the “cleavage” of the two constructs during translation (i.e., split or AND-gate CAR or two full CARs or OR-gate CAR) or ii) two scFv antigen binding domains in tandem or loop, which results in a single CAR construct during translation (i.e., tandem or OR-gate CARs) (Brillembourg, et al., Br J Haem, 2024, 204, 1649-1659, see graphical abstract). Therefore, the literature supports the lack of predictability in making a CAR polypeptide comprising any two antigen binding domains, transmembrane domains, intracellular signaling domain, and co-stimulatory domain.
Quantity of experimentation needed to make or use the invention based on the disclosure:
Thus, one skilled in the art would be unable to make a CAR polypeptide comprising essentially any EGFR antigen binding domain, essentially any MUC1 antigen binding domain, essentially any transmembrane domain, essentially any co-stimulatory signaling region, and essentially any intracellular signaling domain in essentially any conformation. Therefore, the implementation of the invention in view of the breadth of variables (i.e., EGFR binding domain, MUC1 binding domain, TM/CSR/IDS, and combinations of formats), level of predictability in the art, and lack of direction provided in the specification and working examples, would require undue experimentation for one of ordinary skill in the art to make the instantly claimed invention.
Written Description
Claims 6-10 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure). Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of a reagent (such as the epitope to which the reagent binds or the fact that it does or does not inhibit some process) does not provide evidence of possession of the reagent itself.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted. To show invention, a patentee must convey in its disclosure that they “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Further, an adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Indeed, the courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69. It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”. Further, the courts have indicated that the enablement and written description requirements of 35 USC 112 are separable as can be seen in for example Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111.
The teachings of the specification and the claimed invention:
Applicant has broadly claimed a CAR polypeptide comprising essentially any EGFR antigen binding domain, essentially any MUC1 antigen binding domain, essentially any transmembrane domain, essentially any co-stimulatory signaling region, and essentially any intracellular signaling domain in essentially any format. The broadest claims do not require the CAR polypeptide to have any function apart from functioning as a CAR and binding two antigens (i.e., EGFR and MUC1) in a T cell, with dependent limitations adding additional functional limitations. No claims recite any specific or particular structure of the dual CAR that gives rise to the specific efficacy for NSCLC treatment functions.
To support such broad claims, the specification teaches a set of four dual EGFR x MUC1 CAR constructs (i.e., Fig 2) expressed in T cells, and their efficacy in treating NSCLC in vitro (Figs 3-7), wherein the dual CART cell activation requires co-expression of both targets (p 9). Although the claims are drawn to any EGFR x MUC1 CAR polypeptide of which there are a seemingly endless number of binding domains, combinations of T cell activation domains, and formats, the experimental data teach that of the four dual constructs considered in the specification, only CARs1-3 effectively treat four target NSCLC cell lines in vitro (i.e., Fig 3 and 5). Furthermore, there are no examples wherein the sequential tandem or loop tandem constructs (i.e., Fig 8) function to effectively treat four target NSCLC cell lines.
The state of the prior art:
With regard to CAR constructs, the literature teaches that the CAR structural design can significantly influence the toxicity and efficacy of CAR T cells; that there are a variety of multiple antigen CAR construct formats (i.e., two antigens split across a signaling and co-stimulatory domain in one cell (i.e., AND-gate CARs), two full CARs expressed in one cell (i.e., OR-gate CARs), multiple single CARs expressed in multiple cells (i.e., pooled CARs, OR-gate CARs), or two antigens in one CAR comprising both signaling and co-stimulatory domains expressed in one cell (i.e., tandem, OR-gate CARs)) which impact the safety of the CAR upon expression in a CAR T cell; and in the instance of utilizing a single CAR polypeptide there are typically two strategies used for expression of the CAR in the T cell. Specifically, Alsaieedi, et al., teach that the choice of antigen-binding domain(s), co-stimulatory domain(s), transmembrane domain(s), hinge region(s), and the length of the endodomain all affect the toxicity and efficacy of the CAR expressed in a CAR T cell (Alsaieedi, et al., Front Immunol, 2025, 16, 1-21, see section 5.1). Attlnanese teach a variety of multi-antigen CAR constructs, and by carefully selecting the construct/format results in favoring CAR T cell activation directly and minimizing toxicity in patients (i.e., split or AND-gate CAR) or guarding against tumor antigen loss (i.e., tandem, two full CARs, or OR-gate CARs) (Attlnanese, et al., Immuno Rev, 2023, 320, 166-198, see Logic gated CARs section, Fig 5). Furthermore, in the instance of using a single vector, which expresses multiple antigen binding domains in a single CAR polypeptide, there are typically two strategies: i) expression of two constructs utilizing a 2A peptide between the different constructs, which mediates the “cleavage” of the two constructs during translation (i.e., split or AND-gate CAR or two full CARs or OR-gate CAR) or ii) two scFv antigen binding domains in tandem or loop, which results in a single CAR construct during translation (i.e., tandem or OR-gate CARs) (Brillembourg, et al., Br J Haem, 2024, 204, 1649-1659, see graphical abstract). To further support Alsaieedi, et al., Qin, et al., teach the systematic development and comparison (i.e., screening) of the structure and therapeutic function of dual CARs (i.e., (i) sequential tandem CAR, (ii) loop tandem CAR, and (iii) two full CARs expressed in a single vector targeting the same antigens) and that the order of the scFv, size of the linker, type of leader sequence, and co-stimulatory domain in the CAR constructs all impact the efficacy of the dual targeting CARs (Qin, et al., Blood, 2017, 130, 810, specifically see abstract).
Claim analysis:
In this instance, the prior art supports that specific scFv antigen binding domains and specific TM, CSRs, and IDS in a specific format are necessary for dual or bivalent CARs to function. As presently written, the claims recite that any combination of a single CAR polypeptide functions to bind the antigen targets and is effective in a T cell. However, the specification and working examples fail to disclose any data indicating that the breadth of structures (i.e., dual CARs, tandem CARs, etc.) encompassed by the language of the instant claims will have the same function (i.e., bind both targets and/or function effectively upon expression in a T cell). Therefore, as presently written, the claimed broad genus of a dual or bivalent CAR polypeptide lacks adequate written description because there does not appear to be any correlation between the very broad structure of the CAR polypeptide and the ability to bind EGFR/MUC1 and function effectively upon expression in a T cell. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of a bivalent or dual CAR polypeptide, at the time the instant application was filed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 6-7 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9447194, herein referred to as “’194.” Although the claims at issue are not identical, they are not patentably distinct from each other because the CAR and the engineered cell of the ‘194 patent is an obvious variation of the CAR and engineered cell of the instant application. Specifically, the CAR of claims 1 and 15-16 and the engineered cell comprising a CAR of claim 28 of the ‘194 patent comprises at least two antigen-specific targeting regions, a transmembrane domain, at least one co-stimulatory domain, and an intracellular signaling domain, wherein each antigen-specific targeting region comprises an antigen-specific scFv and binds a different antigen of EGFR and MUC1.
The ’194 patent claims recite:
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In this instance, because the CAR and the engineered cell comprising the CAR comprise two scFv antigen binding domains of EGFR and MUC1, a transmembrane domain, intracellular signaling domain and co-stimulatory signaling region, there is no clear difference in the scope between the products of the instant application and the ’194 patent.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,639,387, herein referred to as “’387.” Although the claims at issue are not identical, they are not patentably distinct from each other because the CAR of the ‘387 patent is an obvious variation of the CAR of the instant application. Specifically, the CAR of claims 1-4 of the ‘387 patent comprise two antigen-specific targeting regions (i.e., EGFR and MUC1), a specific transmembrane domain, a specific co-stimulatory domain, and a specific intracellular signaling domain.
The ’387 patent claims recite:
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In this instance, because the CAR comprises two antigen binding domains of EGFR and MUC1, a transmembrane domain, intracellular signaling domain and co-stimulatory signaling region, there is no clear difference in the scope between the products of the instant application and the ’387 patent.
Claims 6-7 and 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 22 of co-pending Application No. 18/573670; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the CAR polypeptide and immune effector cell comprising an EGFR scFv binding domain, MUC1 scFv binding domain, transmembrane domain, intracellular signaling domain, and co-stimulatory signaling region of claims 13, and 1 and 4, respectively of the reference application anticipates the CAR polypeptide and immune effector cell of the instant application.
The co-pending claims of the reference application recite: A chimeric antigen receptor (CAR) polypeptide, comprising an EGFR antigen binding domain, a MUC1 binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region, wherein the MUC1 binding domain is a single-chain variable fragment (scFv) of an antibody that specifically binds MUC1 comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSNYWMN (SEQ ID NO:34); the CDR2 sequence of the VH domain comprises the amino acid sequence RLKSNNYATHYAES (SEQ ID NO:35); the CDR3 sequence of the VH domain comprises the amino acid sequence VGQFAY (SEQ ID NO:36); the CDR1 sequence of the VL comprises the amino acid sequence STGAVTTSNYAN (SEQ ID NO:37); the CDR2 sequence of the VL domain comprises the amino acid sequence GTNNRAP (SEQ ID NO:38); and the CDR3 sequence of the VL domain comprises the amino acid sequence ALWYSNHWV (SEQ ID NO:39) (i.e., claim 13). An immune effector cell engineered to express a first chimeric antigen receptor (CAR) polypeptide comprising an EGFR binding domain and a second chimeric antigen receptor comprising a MUC1 binding domain, wherein the MUC1 binding domain is a single-chain variable fragment (scFv) of an antibody that specifically binds MUC1 comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSNYWMN (SEQ ID NO:34); the CDR2 sequence of the VH domain comprises the amino acid sequence RLKSNNYATHYAES (SEQ ID NO:35); the CDR3 sequence of the VH domain comprises the amino acid sequence VGQFAY (SEQ ID NO:36); the CDR1 sequence of the VL comprises the amino acid sequence STGAVTTSNYAN (SEQ ID NO:37); the CDR2 sequence of the VL domain comprises the amino acid sequence GTNNRAP (SEQ ID NO:38); and the CDR3 sequence of the VL domain comprises the amino acid sequence ALWYSNHWV (SEQ ID NO:39) (i.e., claim 1). The immune effector cell of claim 1, wherein the EGFR binding domain is a single-chain variable fragment (scFv) of an antibody that specifically binds EGFR comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence KASGGTFSSYAIS (SEQ ID NO:1); wherein the CDR2 sequence of the VH domain comprises the amino acid sequence GIIPIFGTANYAQKFQG (SEQ ID NO:2); wherein the CDR3 sequence of the VH domain comprises the amino acid sequence AREEGPYCSSTSCYGAFDI (SEQ ID NO:3); wherein the CDR1 sequence of the VL domain comprises the amino acid sequence QGDSLRSYFAS (SEQ ID NO:4); wherein the CDR2 sequence of the VL domain comprises the amino acid sequence YARNDRPA (SEQ ID NO:5); and wherein the CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGYL (SEQ ID NO:6) (i.e., claim 4).
In this instance, because the CAR polypeptide of the reference application comprises an EGFR binding domain, a specific MUC1 antigen binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory domain and because the immune effector cell engineered to express a first and second CAR polypeptide comprising a specific EGFR scFv and MUC1 scFv, respectively, there is no clear difference in the scope between the products of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 6 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/126724 (Bluebird Bio, Inc., et al., 27JUN2019), herein referred to as “’724.”
‘724 teaches a multivalent CAR comprising a scFv that binds a first antigen of EGFR or MUC1, a sdAb that binds a second antigen of EGFR or MUC1, a transmembrane domain, one or more intracellular costimulatory signaling domains and a primary signaling domain (see entire document, specifically see abstract, claims 1 and 6-7).
Therefore, the prior art anticipates the invention as presently claimed.
Claims 6-8 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020/050993 (Bioatla, LLC, et al., 12MAR2020, included in IDS), herein referred to as “’993.”
‘993 teaches a first and second antigen specific targeting region (i.e., ASTR), wherein the ASTR comprises a first EGFR scFv and a second MUC1 scFv, transmembrane domain (i.e., TM), co-stimulatory domain (i.e., CSD), and intracellular signaling domain (i.e., ISD), wherein the first and second ASTRs are in tandem (see Fig 1, ¶00010, 000158-000159, and 000164). ‘993 further teaches engineered cytotoxic cells comprising the CARs (¶0028), wherein the CARs comprise a signal sequence-ASTR1 (i.e., scFv comprising a VH and VL)-linker-ASTR2 (i.e., scFv comprising a VH and VL)-TM-CSD-ISD (¶000158-000159, 000164, and 000327). Additionally, ‘993 teaches that connection of the C-terminus of the VL or VH of one scFv to the N-terminus of the VL or VH of the other scFv have been developed without significantly disrupting antigen binding or specificity of binding (¶000159).
Therefore, the prior art anticipates the invention as presently claimed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/050993 (Bioatla, LLC, et al., 12MAR2020), herein referred to as “’993” as applied to claims 6-8 and 10 and in further view of Qin, et al., (Mol Ther Oncolytics, 2018, 11, 127-137), herein referred to as “Qin.”
The teachings of ‘993 are summarized above.
However, they do not teach: wherein the CAR polypeptide is defined by the formula signaling peptide-EGFR VH-MUC1 VL-MUC1 VH-EGFR VL-optional hinge domain-transmembrane domain-costimulatory/intracellular signaling domain (i.e., loop CAR), etc..
Nevertheless, Qin teaches the development of bivalent CARs, having a loop configuration which were active both in vitro and in vivo against both antigen targets; while the tandem configuration was only active in vitro (see entire document, specifically see discussion section). Furthermore, Qin teach that CAR design and antigens targeted may have a substantial impact on the potency of the bivalent CAR construct (see discussion section).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the tandem CAR disclosed by ‘993 by utilizing the loop CAR disclosed by Qin because the loop CAR was more effective both in vitro and in vivo. One would have been motivated to do so, given the teachings of ‘993 that tandem constructs in general did not impact binding or specificity of binding and given the teachings of Qin that it was important to evaluate both sequential tandem and loop tandem constructs because it could be antigen dependent. There would have been a reasonable expectation of success, given the knowledge that modification from the sequential tandem to the loop tandem bivalent construct lead to an effective therapeutic targeting both antigens in vitro and in vivo, as taught by Qin.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641