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 .
DETAILED ACTION
The Amendment filed 4/28/2026 in response to Office Action of 1/28/2026, is acknowledged and has been entered. Claims 1-13 are now pending. Claims 1, 3, 5 and 13 are amended. The 112(a) enablement rejection is hereby withdrawn in view of amendments. Claims 1-13 are currently being examined.
Maintained Rejection
(Amendments and Arguments Addressed)
Claim Rejections - 35 USC § 112
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.
Claims 1-13 remain 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.
The claims are drawn to:
A chimeric antigen receptor comprising a co-stimulatory receptor, wherein said chimeric antigen receptor has a structure of scFv(X)-(Y)CD3zeta-2A-(Z);
wherein X comprises a tumor-targeting antibody or a ligand or receptor capable of specifically binding to a tumor;
Y is an intracellular domain of a co-stimulatory receptor, and said co-stimulatory receptor is 4-1BB; and
Z is a co-stimulating receptor, and said co-stimulatory receptor is OX40.
The written description rejection is directed towards “X” which comprises a tumor-targeting antibody. Dependent claim 2, recites that the antibody may selected from a group consisting of: anti-CD19 antibody, anti-CD20 antibody, anti-EGFR antibody, anti-HER2 antibody, anti-EGFRVIII antibody, anti-PSMA antibody, anti-BCMA antibody, anti-CD22 antibody, and anti-CD30 antibody.
With regards to these antibodies, the instant specification does not disclose any sequences of any of the tumor-targeting antibodies.
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
To provide adequate written description and evidence of possession of the claimed composition antibody genus, the instant specification can structurally describe representative antibodies or antigen binding proteins that function as listed above (1)-(4), 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.
Although Applicants may argue that it is possible to screen for antibodies that 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 yet to be discovered that may function as claimed.
Response to Arguments
Applicants argue that the present disclosure is related to a structure of a chimeric antigen receptor. Applicant argues that the specification provides three antibodies (the sequence of said anti-CD20 scFv is as set forth in SEQ ID No: 1; the sequence of said anti-CD19 scFv is as set forth in SEQ ID No: 11; and/or the sequence of said anti-EGFR scFv is as set forth in SEQ ID No: 12.). Applicant argues that the specification provides adequate written description and evidence of possession of the claimed composition antibody genus
Applicant’s arguments have been considered but are not persuasive. The claims are drawn to a chimeric antigen receptor with the following structure: scFv(X)-(Y)CD3zeta-2A-(Z). The written description is drawn to “X”, wherein X is drawn to the broad genus of wherein X comprises a tumor-targeting antibody or a ligand or receptor capable of specifically binding to a tumor. Thus, the “X” is drawn to the broad genus of tumor-targeting antibodies, or ligands or receptors that bind to a tumor. The specification defines an antibody as “an immunoglobulin that specifically binds to an antigen and contains at least two heavy (H) chains and two light (L) chains..” [see paragraph 0102 of the published specification] Three examples of scFv antibodies do not represent the whole scope of genus of “Tumor-targeting antibodies” and does not provide enough guidance in the art or possession of the claimed product.
Maintained Rejection
(Arguments and Amendments Addressed)
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(s) 1, 2, 3, 7, and 12-13 remain rejected under 35 U.S.C. 103 as being unpatentable over Sadelain et al (Cancer Discov (2013) 3 (4): 388–398), in view of Ma et al (WO2017112877 A1; Published 6/29/2017; cited in IDS 1/26/2023).
Sadelain teaches the use of chimeric antigen receptors (CARs) and the different generations and structures of CARS. Sadelain teaches that second and third generation CARS have dual signaling, and that a key attribute of dual signaling is to confer greater strength of signaling and persistence of the T cells, resulting in their overall greater potency. Sadelain teaches the structure of third generation CARS, that encompass 2 costimulatory domains to confer yet a greater potency. [pg 392]
Sadelain teaches the following structure of a chimeric antigen receptor, that is the “third – generation” CAR [see figure 1]
scFv comprising an antibody, such as a CD19 antibody [see pg 289, 1st column, 2nd paragraph, pg 393, 2nd column “CD19 Paradigm”]
costimulatory domains and co-stimulating receptors, such as 4-1BB and OX40.
CD3zeta [pg 289, 2nd column’ “CAR signaling”]
Sadelain teaches costimulatory ligands, including OX40L and 4-1BBL – have been shown to enhance T-cell proliferation and cytokine secretion upon antigen engagement. [pg 392, 2nd column “Costimulatory ligands”]
However, Sadelain does not teach that that the CAR does not comprise a self-cleaving peptide, 2A.
Ma teaches construction and use of CARs. Ma teaches that CARs comprise two costimulatory domains, including 4-1BB and OX-40, a signaling domain, an antigen recognition domain, and an self-cleaving peptide, 2A. [pg 15-20, pg 54] Ma teaches that the antigen recognition domain may be an antibody, or an scFv that binds specifically to a target antigen, such as CD19 scFv. [pg 16, lines 18-30, pg 18, lines 11-15] Ma teaches that the signaling domain may be CD3zeta. [pg 20, lines 18-25] Ma teaches that the co-stimulatory domains is an intracellular domain. [ pg 21, lines 6-10] Ma teaches that the formulation comprising the CAR-T cell can be used to treat cancer, including solid tumors and leukemia. [pg 16, 25, 31] Ma teaches a method of preparing said CAR-T cells, comprising construction of a lentiviral vector and production of a virus [pg 22, lines 16-19]
It would have been prima facie obvious to construct a CAR comprising the structure scFv(tumor targeting antibody)-(intracellular domain of a co-stimulatory receptor)CD3zeta-2a-(co-stimulating receptor). One would have been motivated to, and have a reasonable expectation of success, because: (1) Sadelain and Ma teach constructs of CARs that include two costimulatory domains, a tumor targeting domain, and a signaling domain, CD3zeta, (2) Sadelain teaches that two costimulatory domains to confer yet a greater potency, (3) Ma teaches that that the CAR comprises self-cleaving peptides, 2A. Given the known structure of CARS that include two costimulatory domains, targeting domain, signaling domain, and a self-cleaving peptide, one of skilled in the art could have pursued constructing a CAR comprising the instantly claimed structure.
Response to Arguments
Applicants argue that that Sadelain does not disclose combination of 4-1BB and OX40 and Ma only discloses that the CAR polypeptide further includes one or more costimulatory domains and lists over 20 kinds of domains and does not teach 4-1BB and OX40. Applicants argue that the CAR T-cells containing 4-1BB-OX40, that OX40 had good amplification on CAR-T cells with 4-1BB but not with CD28. Applicant argues that this specific combination described in claim 1 can enhance the proliferative and tumor-killing activities of CAR T-cells.
Applicant’s arguments have been considered but are not persuasive. Examiner acknowledges typographical error, however, Sadelain does teach “OX40” on page 392, 2nd column. The section refers to the co-stimulatory ligands of the domains that have been shown to enhance T-cell proliferation and cytokine secretion upon antigen engagement. [pg 392, 2nd column “Costimulatory ligands”] The prior art does not need to provide a working example for obviousness or to provide a reasonable expectation of success. MPEP 2164.02 states that: The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In reBorkowski, 422 F.2d 904, 164 USPQ 642, 645 (CCPA 1970). However, Sadelain and Ma teach constructs of CARs that include two costimulatory domains, a tumor targeting domain, and a signaling domain, CD3zeta. Sadelain teaches that the costimulatory domains and co-stimulating receptors, such as 4-1BB and OX40, and .Ma teaches that CARs comprise two costimulatory domains, including 4-1BB and OX-40, a signaling domain, an antigen recognition domain, and a self-cleaving peptide, 2A.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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