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 .
Status of Claims
Claims 15-26 are pending and under examination.
Sequence Requirements
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § § 1.821-1.825 for the reason(s) set forth below. The specification is replete with sequences that are not followed by a sequence identifier. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Information Disclosure Statement
The information disclosure statements have been considered. Initialed copies are enclosed.
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.
Claims 15-26 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.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. All factors have been considered, but the most relevant are discussed in detail below.
The breadth of the claims: With respect to claim breadth, the standard under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. The claims are drawn to methods of treating all types of cancer which includes all types of cancer in all subjects, including humans by administering immune cells comprising a chimeric antigen receptor that binds the thyroid specific hormone receptor (TSHR). The cancer may be broadly any type of cancer and does not have to express the antigen that the chimeric antigen receptor binds (see claims 15 and 20-26). Immune cells by its broadest reasonable interpretation comprise cells of the immune system including for example: B cells, T cells, NK cells, monocytes, macrophages, basophils, neutrophils, eosinophils, mast cells and dendritic cells. The chimeric antigen receptor has specific scFv complementarity determining regions that bind TSHR.
The amount of direction provided by the inventor: The specification teaches in vitro killing of two human thyroid cancer cell lines with anti-TSHR CAR T cells. No other immune cells were made or tested in vitro. The specification does not teach any in vivo data. Importantly, the in vitro killing assay is not reflective of the ability of the CAR T cell to target cancer in the in vivo tumor environment. It was well known in the art at the time of filing, that barriers within the tumor environment including failure of T cell trafficking, lack of chemokines for migration and dominant suppression through immune inhibitory mechanisms (see Gajewski et al, Current Opinion in Immunology 25:268-267, 2013, at column 1, Abstract) contributed to the difficulties of solid tumor immunotherapy. Additionally, the level of expression of the cell surface marker and any tumor heterogeneity thereof is known to provide for variable killing in vivo and lack of a clinical response of solid tumors in vivo (see Li et al, The Journal of Clinical Endocrinology & Metabolism, 107(4):1110-1126, 2021) at page 1111, column 2). With respect to CAR T cells, it was still recognized in 2021, that while chimeric antigen receptor T cells demonstrate remarkable efficacy in hematological cancers, they had not yet translated into treating solid tumors (see Li et al, The Journal of Clinical Endocrinology & Metabolism, 107(4):1110-1126, 2021) at page 1110, Background). The art at the time of filing that both the tumor microenvironment and the ability of CAR T cells to treat solid tumors had not been accomplished. Shah et al (Shah et al Nat Rev Clin Oncol. 16(6): 372–385, 2019) also teach that in 2019 that “Going beyond haematological tumours, solid tumours present a new set of unique challenges to the development effective CAR T cell therapies, as reviewed elsewhere150–153. One key issue with solid tumours is that the inherent tumour heterogeneity is likely to be a substantial barrier to identifying an optimal target, and relatedly, antigen loss will probably be a key factor precluding curative remissions. Indeed, antigen density (as mentioned above regarding ALK in neuroblastoma cells118) and inherent tumour heterogeneity in antigen expression in solid tumours (for example, mesothelin154, HER2 (REF.155) or MUC1 (REF.156) expression in non-small cell lung cancers) can limit the therapeutic potential of agents that target a single antigen and raise concerns over differing on-target, off-tumour toxicities.” at page 16, third full paragraph. Shah et al teach earlier reviews that describe the difficulties in treatment of solid tumors. As such, the in vitro evidence of killing thyroid cancer cells expressing TSHR is not found to be reasonably predictive of therapeutic efficacy in vivo at the time of filing.
The level of ordinary skill: The level of ordinary skill at the time of filing is illustrated by the references cited above. The references collectively make clear that although one of ordinary skill is capable of using techniques known to the art, such as cell culturing or administering chimeric antigen receptor T cells (e.g. a subset of immune cells) as a potential therapy, the outcomes from using those techniques cannot necessarily be predicted especially as it relates to solid tumors and cancer in general.
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. The art establishes that multiple hurdles exist for the treatment of solid tumors, thyroid cancer being on thereof. Li et al (The Journal of Clinical Endocrinology & Metabolism 107(4):1110-1126, 2022) teach that the state of the art for chimeric antigen receptor T cells while efficacy in hematological cancers, have not yet translated in treating solid tumors (see page 1110, abstract). Given that the nature of the invention is treatment of cancer, a person having ordinary skill in the art would have to perform multiple further in vivo experiments in human clinical trials or in animal models that are predictive of treatment in a representative number of cancers, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully recognizing and treating cancer.
Conclusion: The claims are considered non-enabled for at least the following reasons: First, there is nothing in the claims that requires the cancer cells to express TSHR and it is known that TSHR expression is variable. Second, the specification manufactures a single immune cell, a CAR T cell and demonstrates in vitro cell killing of TSHR expressing thyroid cancer cells. No other TSHR expressing cancer cells were tested. No other immune cells were manufactured or tested and the activity if any of the other cell types is unknown both on the thyroid cancer cells and any other cancer cell expressing TSHR. Anti-TSHR CAR T cells are a system of treating cancer in a human, that must selectively destroy TSHR cancer cells in a subject or human. This has not been effectively demonstrated. Finally, one skilled in the art at the time the invention was made would not accept in vitro data in the specification as efficacy of therapeutic efficacy in vivo with solid tumors or efficacy with any other immune cell type. For at least these reasons, successfully implementing the claimed method would require an unreasonable burden of in vivo testing for one of ordinary skill in the art before they could use the claimed method with a reasonable expectation of success. Therefore, the claims are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, for failing to meet the enablement requirement.
Double Patenting
Applicant is advised that should claim 20 be found allowable, claim 21 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k).
Conclusion
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/Patricia Duffy/Primary Examiner, Art Unit 1645