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
Election response
The Election filed 10/20/2025, in response to the Office Action of 8/20/2025, is acknowledged and has been entered. Applicants elected without traverse the following species: (1) X = CD19, (2) Y= 4-1BB, (3), Z = OX40. Claims 1-15 are pending and are currently under prosecution.
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 1-15 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.
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 selected from a group consisting of ICOS, CD28, CD27, HVEM, LIGHT, CD40L, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, and CD226; and
Z is a co-stimulating receptor, and said co-stimulatory receptor is selected from a group consisting of ICOS, CD28, CD27, HVEM, LIGHT, CD40L, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, and CD226.
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.
Claims 13-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating tumors does not reasonably provide enablement for preventing tumors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The claims recite a method of treating or preventing tumors, comprising administering said chimeric antigen receptor to any one of claims 1-6 or said CAR T-cell according to claim 7 to the subject in need of.
STATE OF THE ART: A search of relevant art, does not reveal any demonstration any chimeric antigen receptor or CAR T-cells prevents cancer. Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman MA et al. The Oncologist 2017; 22(5); 542–548). Even though cancer is featured by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan D et al. Cell 2011 144(5) p646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph). Szabo et al (Selecting targets for cancer prevention: where do we go from here? Nat Rev Cancer 6, 867–874; 2006) teaches the intricacies and complications of cancer prevention. Szabo teaches that in addition to efficacy and toxicity concerns of cancer drugs targeting functions, there are a number of practical issues that should be considered, including drug formulation and dosing schedule to ensure adherence, as well as the cost. Szabo also teaches that in some cases the targets selected for drug therapy may even cause harm. [Whole document]
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee KW et al. Nature Reviews Cancer 2011 11 211-218, page 211, left column last paragraph)
PRESENCE OR ABSENCE OF EXAMPLES: The specification does not provide any examples of preventing tumors. Examples 12 and 13 discloses the use of the claimed agents for the treatment of cancer. The examples in the specification does not disclose the use of any CAR for the prevention of tumors as claimed.
PREDICTIABILITY: The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent tumors with the instantly claimed combination. There is no evidence in the instant application or the art that as noted in the prior that demonstrate that a drug that treats cancer would prevent the onset of cancer in subjects as claimed. The amount of experimentation required to formulate such guidance would be enormous; one would have to demonstrate the efficacy of the combination in several models across several different types of cancers and determine the appropriate regimen (doses and frequency) for use of the combination or composition in a preventative setting. Further, one would have to conduct population analysis to identify definitive characteristics which indicate that a subject is at risk of developing any cancer to a degree that would outweigh potential adverse effects of treatment with the claimed combination or composition. Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation required to enable the full scope of the claimed invention would not be reasonable.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine which chimeric antigen receptor/CAR-T cell is administered to which population of subjects could predictably prevent tumors as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether the claimed CAR prevents tumors. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 12-15 are 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, CD28 and OX40.
CD3zeta [pg 289, 2nd column’ “CAR signaling”]
Sadelain teaches costimulatory receptors, 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, CD28 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.
Conclusion
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600