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 .
Status of Application
In view of further search and consideration, the previous non-final office action is withdrawn. The following rejections are applicable, although not necessitated by Applicants arguments. It should be noted that the instant action is a non-final office action.
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Rejections not reiterated here are withdrawn in light of Applicant’s amendments and/or arguments.
Priority
This application was filed 20th of May 2020, and is a 371 application of PCT/US2018/062354 filed on 21st of Nov. 2018, which claims benefit to the provisional application PRO 62/589,562 filed on the 22nd of Nov. 2017. The effective filing date for claims is Nov. 22nd, 2017.
Status of Claims
In the response filed on the 24th of July 2026, Applicant has canceled claims 1-20, 24-28, 31-34, 36-77, 79-89, 91-92, 94-99, and 111-113 and currently, claims 90 and 93 are withdrawn.
In the reply filed on the 15th of November 2022, Applicant elected with traverse of Group II, directed to an immune cell having a chimeric antigen receptor (CAR) (claims 20-23, 29, 30, 35 and 98-101), is acknowledged. The traversal is on the grounds that there is no serious search burden to the examiner. This is not found persuasive because the search burden is not a consideration under lack of unity practice.
Currently, claims 21-23, 29-30, 35, 78, 100-110 and 114-116 are under consideration.
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed by Dr. Anjana Rao on the 24th of July 2026, is sufficient to overcome the rejection of instant claims based upon 35 U.S.C 103 as being unpatentable over Wang et al. (US 2019/0262399 A1, Application US16/331,410, priority date 09/07/2017, prior art of record) in view of Pereira, Renata M., et al. (Journal of leukocyte biology 102.3: 601-615, published Sept. 2017, hereinafter as “Pereira”), Sekiya, et al. (Nature immunology 14.3: 230-237, published 2013, prior art of record), Golz et al., (WO2005/075983A2, published 2005, hereinafter as “Golz”), Nowyhed, et al. (The Journal of Immunology 195.8: 3515-3519, published 2015, prior art of record), and Cheng et al. (The EMBO journal, published 1997, prior art of record), as set forth in the last Office action for the following reasons: The declaration filed by Dr. Rao disqualifies the disclosure of Pereira et al., as prior art because it was made by the inventor and a joint inventor, and the subject matter disclosed was obtained directly or indirectly from the inventor and joint inventor.
Claim Rejections - 35 USC § 112(a)
Written Description
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 21-23, 29-30, 35, 78, 100-110 and 114-116 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.
Independent claims 21 and 109 recite: A CD8+ T cell engineered to reduce or eliminate expression and/or function of NR4A3 (NOR1), and comprising a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain; (b) a transmembrane domain; and (c) an intracellular domain.
As written the claim, encompasses a large genus of any CD8+ T cell engineered to reduce or eliminate expression and/or function of NR4A3 (NOR1), and comprising any CAR that can reduce or eliminate expression and/or function of a gene or genes wherein the gene is Nr4a3, and given its broadest reasonable interpretation in light of the specification any CAR T cell that has the function of reduce or eliminate expression and/or function of NR4A3 (NOR1)(i.e. RNA interference (RNAi), CRISPR, TALEN, ZFN or other methods that target specific sequences to reduce or eliminate expression and/or function of NR4A or TOX transcription factors), corresponding to any type of CAR T cell with the structure of any kind of chimeric antigen receptor (CAR) immune cell that reduces or eliminates of expression and/or function of Nr4a3 would be encompassed by the claims as instantly presented.
However, the specification does not have adequate support in the disclosure for any CD8+ T cells that encompasses any chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain; (b) a transmembrane domain; and (c) an intracellular domain that is engineered to reduce or eliminate expression and/or function of NR4A3 (NOR1). As written in the claim a CD8 T cell comprising a chimeric antigen receptor (CAR) encompasses a broad genus of CARs that includes multiple types of immune cells, comprising a genus of modifications comprising an insertion, deletion, or mutation for reducing or eliminating expression and/or function of NR4A3 (NOR1), while the specification describes only a limited genus of modifications, in a limited genus of immune cells, in a limited genus of cancers, in an animal model (see e.g. Specification page 84).
Under the written description guidelines (see MPEP 2163), the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail so that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
In analyzing whether the written description requirement is met for genus, any CAR that reduces or eliminates expression of NR4a3, the specification is first assessed to determine whether a representative number of species have been described by their complete structure of the genus.
Dependent claims 22-23, 29-30, 35, 78, 100-108, 110 and 114-116 encompass a genus of wherein the antigen binding domain comprises: an anti-ROR1 binding domain; the transmembrane domain comprises a CD28 transmembrane domain or a CD8 transmembrane domain; and the intracellular domain comprises a CD28 co-stimulatory signaling region, a 4-lBB costimulatory signaling region, an ICOS costimulatory signaling region, or an OX40 costimulatory region, wherein the anti-ROR1 binding domain of the CAR comprises a single-chain variable fragment (scFv), and wherein the CD8+ T cell further comprises a poly nucleotide encoding the CAR, and wherein the CD8+ T cell is further engineered to reduce or eliminate expression and/or function of Nr4a2 (Nurr1).
However, the specification does not have adequate support in the disclosure for any CD8+ T cell engineered with any chimeric antigen receptor (CAR) to reduce or eliminate expression and/or function of NR4A3. The specification discloses “To identify changes in gene expression and associated regulatory elements in CAR T cells infiltrating solid tumors, and compared the properties of three distinct classes of cos+ tumor-infiltrating lymphocytes (TILs): CAR TILs that recognize human C019 (huC019), OT-IT cell receptor (TCR)-transgenic TILs (OT-I TILs) that recognize the SIINFEKL(SEQ ID NO. 33) peptide from chicken ovalbumin (OVA) presented by H-2Kh, and endogenous TILs from the recipient congenic mice (FIG. 7). As targets for the CAR T cells, the B16-0VA mouse melanoma cell line, the EL4 mouse thymoma cell line, and the MC38 colon adenocarcinoma cell line to express human CD19 (huCD19) were engineered (FIG. 1A, left panels); the resulting Bl6-0VA-huC019 cells are recognized by OVA-reactive OT-I as well as by huCD19-reactive CAR-expressing CD8+ T cells. (see p. 68, para. 308, fig. 1a and 7). Further, the specification discloses “CD8 T cells were isolated and activated with 1 ug/ml anti-CD3 and 1ug/m anti-CD28 for 1 d, then removed from activation and transduced with retrovirus expressing CAR, non-targeting shRNA, TOX targeting shRNA or combination of the above” (para. 367). Further, the specification discloses “On Day 12, 3 million CAR- and non-targeting shRNA vector transduced TOX2+/+ T cells or CAR- and TOX targeting shRNA vector transduced TOX2-/- T cells were adoptively transferred into tumor size-matched tumor-bearing mice” (para. 368).
Therefore, the specification fails to identify any CD8+ T cell engineered to reduce or eliminate expression and/or function of NR4A3, comprising any chimeric antigen receptor (CAR).
Although the method of making a chimeric antigen receptor (CAR) with the claimed invention is well established at the time of filling. However, one of skill in the art would neither expect nor predict the appropriate method of exhibiting any CD8+ T cell comprising any CAR that reduces or eliminates expression of NR4a3 as claimed.
The teachings of Mullican et al., (US20030220288A1) discloses that “that deletion of both nor-1 and nur77 would result in a defect in the later stages of t-lymphocyte development, specifically negative selection. Unexpectedly, as shown herein, upon deletion of both of these nuclear receptors, mice do not survive past 4 weeks of age. Also unexpectedly, in addition to a defect during the stage of negative selection, lymphocyte development is also altered during the earlier stages. This early defect in lymphocyte development is secondary to a severe overproduction of myeloid cells in the bone marrow leading to myeloid leukemia with differentiation in the mice lacking both nor-1 and nur77 (nor-1KO/nur77KO).”(p. 4, para. 51). Additionally, the prior art of Sekiya, et al. (Nature immunology 14.3 (2013): 230-237; published 2013, prior art of record), teaches that “recently reported that loss of NR4A1, NR4A2 and NR4A3 in T-cells blocked development of Treg-cells (CD4+ T cells) and resulted autoimmune diseases in multiple organs”(see e.g. page 49, section 2). Therefore, Mullican et al., and Sekiya et al., provide robust evidence that only specific immune cells can be engineered to reduce or eliminate the expression and/or function of NR4A3. Further, Sekiya provides additional evidence that eliminating expression of NR4a3 in any immune cells are complex and not having a specific target may result in autoimmune diseases in multiple organs. Therefore, with the additional evidence, the ordinary artisan cannot predictably identify that a CD8+ T cell with any CAR will be engineered to reduce or eliminate the expression and/or function of NR4A3.
Furthermore, functionally defined genus claims can be inherently vulnerable for lack of adequate written description, especially in highly unpredictable technology fields, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
The Applicant has recited that the “CD8+ T cell engineered to reduce or eliminate expression and/or function of NR4a3 (NOR1), and comprising a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain; (b) a transmembrane domain; and (c) an intracellular domain” for the purpose of this disclosure includes all types of immune cells comprising any CD8+ T cell expressing any chimeric antigen receptor. Given the breadth of any CD8+ T cell comprising any CAR that the claims embrace, a description of one species (e.g. a CAR T cell against solid tumors, i.e. tumor huCD19-reactive CAR-expressing CD8+ T cells), fails to provide a representative number of species that teaches the complete structure of the genus (i.e. any CD8+ T cell comprising any CAR that reduces and/or elimination function of NR4a3). Consequently, any CD8+ T cell comprising any chimeric antigen receptor (CAR) is not apparent to one of ordinary skill in the art from the description present in the specification. Therefore, an artisan of ordinary skill could not envision all the embodiments encompassed by the breadth of the claims.
Accordingly, the specification doesn't have adequate support in the disclosure for the generic CD8+ T cell comprising any CAR that will be engineered to reduce or eliminate the expression and/or function of NR4A3. Similarly, disclosure doesn't identify a generic CD8+ T cell comprising any CAR that characterizes any CD8+ T cell comprising any CAR engineered with the reduction or elimination of the expression of NR4A3. Therefore, the claimed recitation of any CD8+ T cell comprising any CAR doesn't have an adequate written description. Furthermore, neither the specification nor the art indicates the ability to identify generic CD8+ T cell comprising any CAR that characterize any CD8+ T cell comprising any CAR engineered with the function to reduce or elimination of the expression and/or function of NR4A3.
Therefore, the Examiner concludes that the claimed recitation of any CD8+ T cell comprising any CAR engineered to reduce or eliminate the expression and/or function of NR4A3 doesn't have an adequate written description. Specifically, the specification does not identify the generic CD8+ T cell comprising a generic CAR to characterize any CD8+ T cell comprising any CAR that can be engineered to reduce or eliminate the expression and/or function of NR4A3. It concludes that a skilled artisan would find the specification inadequately described. Therefore, the Applicant did not sufficiently possess the broader invention as claimed.
Allowable Subject Matter
SEQ ID NO: 1 and 2 are free of prior art, therefore Claims 35 and 101 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in the independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 10AM - 5:00PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josephine Gonzales PhD
Examiner
Art Unit 1638
/JOSEPHINE GONZALES/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights