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 .
1. Claims 1-20 are pending and being examined.
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.
2. Claims 3, 5, 6, 9, and 12-20 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.
Claim 3 depends on itself, therefore there is insufficient antecedent basis for the limitations in the claim.
Claim 5 depends on itself, therefore there is insufficient antecedent basis for the limitations in the claim.
Claim 6 recites the limitation "The method of claim 4, wherein the second CAR polypeptide". There is insufficient antecedent basis for this limitation in the claim because no second CAR polypeptide is mentioned claims 4 or 1.
Claim 9 recites the limitation "The method of claim 10, wherein the checkpoint inhibitor". There is insufficient antecedent basis for this limitation in the claim because no checkpoint inhibitor is mentioned in claim 10 or 1.
Claim 12 recites the limitation “and ejrtrom”. It is unclear what this means.
Claim 13 depends on itself, therefore there is insufficient antecedent basis for the limitations in the claim. Claims 12, 14, 15, 16 all depend from claim 13.
Claim 18 depends on itself, therefore there is insufficient antecedent basis for the limitations in the claim. Claims 17, 19, and 20 all ultimately depend from claim 18.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
3. Claim 10 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 10 depends from claim 1. Claim 1 is limited to treating ALL. Claim 10 recites treating a cancer that comprises DLBCL, MZL, CLL, MM, and many others that are outside the scope of ALL. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Examiner suggests correcting the same issue in claim 20 that may arise when claim dependency is corrected.
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.
NOTE: The rejection below presumes claim 12 is supposed to depend from claim 11.
4. Claims 1-3, 5-11, and 13-20 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method of providing an anti-cancer immunity in a subject with a CD83-expressing and/or T cell acute lymphoblastic leukemia (ALL), the method comprising administering to the subject an effective amount of an immune effector cell genetically modified to express a first chimeric antigen receptor (CAR) polypeptide that selectively binds CD83. Thus, the claims identify the CD83 CAR polypeptide by function only:
Selectively binds CD83; and
Provides anti-cancer immunity to a subject having ALL.
No CAR binding domain sequence structure is recited.
The instant specification discloses three structurally distinct anti-CD83 antibodies used to construct a CAR, each comprising a different set of six CDR sequences:
SEQ ID NOs:1-6;
SEQ ID NOs:7-12; and
SEQ ID NOs:13-18 (p. 14-25).
The specification demonstrates CD83 CAR T cells and bispecific CD83/CD19 CAR T cells kill cancer cells in vitro that express CD83 (Figures 6-10).
A search of relevant art does not indicate CD83-binding CARs were well established and readily available in the prior art at the time of effective filing.
Thus, the instant specification describes three structurally distinct anti-CD83 antibodies used to construct a CAR that can kill CD83-expressing cancer cells. The specification fails to disclose any structural sequence required of any other anti-ErbB3 antibody CAR to possess the function of binding to CD83 and providing anti-cancer immunity in a subject.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative anti-CD83 antibodies or CARs that function to bind CD83 and provide anti-cancer immunity in a subject, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the CAR functions as listed above. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only three exemplary structurally distinct anti-CD83 monoclonal antibodies used in CARs that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the three monoclonal anti-CD83 antibodies disclosed, the specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequences used in the claimed CARs for the genus of CARs that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
In the instant case, the specification discloses three structurally distinct anti-CD83 monoclonal antibodies used in CAR construction that function as claimed. The claims broadly encompass any anti-CD83 CAR of unknown sequence structure. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain CD83 binding function and provide anti-cancer immunity in a subject. The instant claims attempt to claim a method using every CD83-binding CAR, wherein the instant specification does not describe representative examples to support the full scope of the claims because the instant specification discloses only three structurally distinct anti-CD83 monoclonal antibodies used in CAR construction that function as claimed. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies/CARs encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of three structurally distinct anti-CD83 CARs that function as claimed to the structure of any and all anti-CD83 CARs as broadly claimed in the methods. Therefore, one could not readily envision members of the broadly claimed genus required to practice the claimed method.
Although Applicants may argue that it is possible to screen for antibodies and CARs that bind CD83 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies/CARs yet to be discovered that may function as claimed. The CD83 antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed antibodies used in the claimed method, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs that provide CD83-binding function and anti-cancer immunity, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of CARs that bind CD83 and provide anti-cancer immunity that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
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.
5. Claims 1-5, 7-10, 12, and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of copending Application No. 18/856,207 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application claims methods of treating CD83-expressing acute lymphoblastic leukemia (ALL) in a subject by administering to the subject an effective amount of the dual-CAR-T cell that binds to CD83 and comprises the same CDR and variable domain sequences, rendering obvious the instantly claimed methods.
The copending application claims:
1. A dual-chimeric antigen receptor (CAR)-T cell, comprising an immune effector cell genetically modified to express a first CAR polypeptide that selectively binds CD83 and a second CAR polypeptide that selectively binds a second antigen selected from the group consisting of CD33, CLEC12A, CD123, CD38, and FLT3.
2. The dual-CAR-T cell of claim 1, wherein the first CAR polypeptide is defined by the formula:SP-CD83-HG-TM-CSR, and
wherein the second CAR polypeptide is defined by the formula:SP-TA-HG-TM-SD; or
wherein the first CAR polypeptide is defined by the formula:SP-CD83-HG-TM-SD, and
wherein the second CAR polypeptide is defined by the formula:SP-TA-HG-TM-CSR;
wherein “SP” represents an optional signal peptide,
wherein “CD83” represents a CD83-binding region,
wherein “TA” represents an CD33-binding region, CLEC12A-binding region, CD123-binding region, CD83-binding region, or FLT3-binding region,
wherein “HG” represents an optional hinge domain,
wherein “TM” represents a transmembrane domain,
wherein “CSR” represents one or more co-stimulatory signaling regions,
wherein “SD” represents a signaling domain, and
wherein “-” represents a peptide bond or linker.
3. The dual-CAR-T cell of claim 1, wherein the CD83 antigen binding domain is a single-chain variable fragment (scFv) of an antibody comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, and wherein
the CDR1 sequence of the VH domain comprises the amino acid sequence GFSITTGGYWWT (SEQ ID NO:1), the CDR2 sequence of the VH domain comprises the amino acid sequence GYIFSSGNTNYNPSIKS (SEQ ID NO:2), the CDR3 sequence of the VH domain comprises the amino acid sequence CARAYGKLGFDY (SEQ ID NO:3), the CDR1 sequence of the VL comprises the amino acid sequence TLSSQHSTYTIG (SEQ ID NO:4), the CDR2 sequence of the VL domain comprises the amino acid sequence VNSDGSHSKGD (SEQ ID NO:5), and the CDR3 sequence of the VL domain comprises the amino acid sequence GSSDSSGYV (SEQ ID NO:6);
the CDR1 sequence of the VH domain comprises the amino acid sequence SDGIS (SEQ ID NO:7), the CDR2 sequence of the VH domain comprises the amino acid sequence IISSGGNTYYASWAKG (SEQ ID NO:8), the CDR3 sequence of the VH domain comprises the amino acid sequence VVGGTYSI (SEQ ID NO:9), the CDR1 sequence of the VL comprises the amino acid sequence QSSQS VYNNDFLS (SEQ ID NO:10), the CDR2 sequence of the VL domain comprises the amino acid sequence YASTLAS (SEQ ID NO:11), and the CDR3 sequence of the VL domain comprises the amino acid sequence TGTYGNSAWYEDA (SEQ ID NO:12); or
the CDR1 sequence of the VH domain comprises the amino acid sequence SNAMI (SEQ ID NO:13), the CDR2 sequence of the VH domain comprises the amino acid sequence AMDSNSRTYYATWAKG (SEQ ID NO:14), the CDR3 sequence of the VH domain comprises the amino acid sequence GDGGSSDYTEM (SEQ ID NO:15), the CDR1 sequence of the VL comprises the amino acid sequence QSSQSVYGNNELS (SEQ ID NO:16), the CDR2 sequence of the VL domain comprises the amino acid sequence QASSLAS (SEQ ID NO:17), and the CDR3 sequence of the VL domain comprises the amino acid sequence LGEYSISADNH (SEQ ID NO:18).
4. The dual-CAR-T cell of claim 3, wherein the anti-CD83 scFv VL domain comprises the amino acid sequence SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, or SEQ ID NO:43.
32. A method of providing an anti-cancer immunity in a subject with a CD83-expressing B and/or T cell acute lymphoblastic leukemia (ALL), the method comprising administering to the subject an effective amount of the dual-CAR-T cell of claim 1, thereby providing an anti-tumor immunity in the mammal.
33. The method of claim 32, further comprising administering to the subject a checkpoint inhibitor.
34. The method of claim 33, wherein the checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, or a combination thereof.
35. The method of claim 32, wherein the cancer comprises an acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
6. Conclusion: No claim is allowed. The closest prior art made of record but not relied upon are WO2016061617, Casey et al; WO 2019/165156, Davila et al; US Patent Application Publication 2023/0051885, Davila, claiming priority to December 2019; US Patent 12,492,254, Davila et al, claiming priority to 2019; Shrestha et al (Blood, 2019, 134 (Supplement_1): 196); and Shrestha et al (J. Clinical Invest., 2020, 130:4652-4662).
WO 2019/165156, Davila, teaches treating graft-versus-host-disease (GVHD) in a subject receiving transplant donor cells by administering an anti-CD83 CAR T cell to the subject, in order to suppress alloreactive donor cells, wherein the CAR comprises the same CDR and variable region sequences instantly claimed (p. 1-14). Davila also exemplifies the anti-CD83 CAR T cells exert cytotoxicity on K562 cells in vitro which are chronic myelogenous leukemia (CML) cells (Figure 10; Examples). Davila only mentions acute lymphoblastic leukemia (ALL) once (p. 125):
Currently, these cell products remain largely investigational, though Tregs and NK cells have been widely studied in the clinical setting. More recently, CAR T cells have demonstrated unparalleled activity in refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma (Neelapu S.S., et al., N Engl J Med 2017 377:2531-2544; Schuster S.J., et al., N Engl J Med 2019 380:45-56; Maude S.L., et al., N Engl J Med 2018 378:439-448). Thus, FDA indications were awarded to CD19 CAR T cells in these high risk hematologic malignancies. While these CAR T cells are indeed cytolytic and by no means immune suppressive, they do highlight the potential role for CAR T cells in targeting mediators of GVHD pathogenesis.
Davila does not teach or suggest treating CD83-expressing ALL by administering the immune effector cell expressing the anti-CD83 CAR.
US Patent Application Publication 2023/0051885, Davila, teaches treating GVHD or various cancers including leukemia by administering an immune effector cell expressing anti-CD83 CAR comprising the same CDR and variable region sequences instantly claimed ([6-68]; [172]). Davila does not teach or suggest treating CD83-expressing ALL by administering the immune effector cell expressing the anti-CD83 CAR immune cells.
US Patent 12,492,254, Davila teaches and claims a CD83 CAR comprising the same sequences instantly claimed, and a method of suppressing alloreactive donor cells in a subject receiving transplant donor cells, the method comprising administering to the subject an effective amount of an immune effector cell genetically modified to express the CD83 CAR. Davila does not teach or suggest treating CD83-expressing ALL by administering the immune effector cell expressing the anti-CD83 CAR immune cells.
Shrestha (Blood, 2019, 134 (Supplement_1): 196) teaches treating GVHD prevention by administering CD83 CAR T cells, and suggests CD83 appears to be a promising candidate to target myeloid malignancies, based on the expression of CD83 on malignant myeloid cell lines. Shrestha does not teach or suggest treating CD83-expressing ALL by administering the immune effector cell expressing the CD83 CAR T cells.
Shrestha (J. Clinical Invest., 2020, 130:4652-4662) taches treating GVHD by administering CD83 CAR T cells, demonstrates that acute myeloid leukemia (AML) expresses CD83 and can be killed by CD83 CAR T cells, and suggests treating CD83+ AML by administering CD83 CAR T cells. Shrestha does not teach or suggest treating CD83-expressing ALL by administering the immune effector cell expressing the CD83 CAR T cells.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642