To MDETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-13 are pending in the instant application.
Applicant’s election without traverse of a CAR with an antigen binding domain that binds to CD19 in the reply filed on January 29, 2026 is acknowledged.
Claims 1-13 are under examination as they read on anti-CD19 CAR constructs.
Information Disclosure Statement
The IDS forms received 5/2/2023 and 1/8/2025 are acknowledged and the references cited therein have been considered.
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.
Claim 13 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.
In dependent claim 13, applicant has called a pharmaceutical composition comprising a cell, wherein said cell comprises a chimeric antigen receptor for the purpose of treating, preventing, or improving the symptoms of a cancer patient. Chimeric antigen receptors typically comprise an antigen binding domain derived from an antibody with intracellular signaling domains of a T cell, such that a cell bearing a CAR binds its intended target like an antibody while killing the target like a T cell (see for example the entirety of Srivastava et al., particularly Figure 1). Claim 13 ultimately dependent from independent claim 1, which requires the CAR to a) have a spacer domain between the antigen binding domain (typically a scFv) and the transmembrane domain of 100 amino acid resides or less, b) bind an antigen that is NOT CD19, or satisfy both a and b. CAR T cells targeting CD19 are very well known in the art including their successful administration to treat many B cell malignancies (see for example WO 2013/126712) and indeed the CAR constructs disclosed in the working examples of the instant application employ a scFv that binds to CD19 (as is most graphically shown in Figure 1 of the instant specification). However, the CAR constructs of claim 1 are not required to have any particular antigen specificity. While many different antigens can be bound by a CAR and thus used to treat cancer (see for example Kahn et al., most particularly Table 1) there is always a nexus between the antigen targeted and its expression on the cancer that is to be treated. For example, while CARs that target CD19 are well known for treating B cell tumors, such a CAR is not useful for treating breast cancer as the CD19 antigen is not expressed on breast cancer cells. In the instant claim, applicant has recited an intended use for a product without informing practitioners what exactly the claimed product is as there is no required antigen specificity in the chain of dependency. Thus it would require artisans to engage in unpredictable basic science research and experimentation to know what cancers can be treated with the claimed cells given that no antigen specificity is required.
Leaving aside questions concerning the formation of a nexus between the antigen specificity of the CAR and the cancer being treated, claim 13 recites the three intended uses of “treatment, prevention, or improvement of cancer”. Given that all three terms appear in the same claim, it is reasonable to assume that the terms differ in their meaning. Inspection of the instant specification does not appear to provide any specific guidance or direction concerning how these terms are to be interpreted. As discussed above, the art indicates that administration of CAR T cells that target CD19 to treat B cell cancers is widely known in the art. “Improvement” reasonably means that the clinical status of the patient has gotten better (as compared to worse) which reasonably is the goal of “treatment” performed by artisans. Thus, does “improvement” mean the patient must get better while “treatment” encompasses the administration not working and the patient getting worse from a clinical standpoint? In any event, the term “prevention” is the most problematic as it could be refereeing to timing (i.e. administration has to occur prior to clinical signs and symptoms (as you can’t “prevent” something that has already occurred)) efficacy (the treatment is so good it is totally effective working 100% of the time) or a combination of timing and efficacy. No in vivo clinical data appears to be presented in the instant application, but both concepts in “prevention” are problematic. Given that CD19 is expressed on substantially all B cells, administering a CD19 CAR typically depletes the entire B cell pool (i.e. cancerous and non-cancerous cells) which can leave a patient at risk for infection so administration to a healthy patient in the hope that they will not develop a B cell tumor reasonably will have so many side effects that it is clinically unwise, and again there is no data in the instant specification indicating that anti-CD19 CARs are safe to use in such a manner as reasonably every person on the planet is in the patient pool as having a B cell tumor reasonably is undesirable for everyone. With regard to efficacy, while the data of the instant specification do appear to demonstrate superior results as compared to constructs comprising costimulatory domains lacking CD79A/CD40, no clinical data has been presented and given that while CD19 CAR have been quite successful in the clinic, their success is far from 100% for all symptoms in all patients due to numerous issues including toxicity, exhaustion, and downregulation of the target antigen in the tumor (i.e. escape mutants, see for example Srivastava et al. and Kahn et al.). All of such issues do not appear to be completely eliminated by using a CAR comprising a costimulatory domain that comprises CD79A and CD40 based upon the data of record. As such artisans would need to engage in additional unpredictable trial and error research in order to achieve the full extend to the recited intended uses including “prevention”.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Julamanee ’21 (Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival - Mol Ther. 2021 Sep 1;29(9):2677-2690. doi:10.1016/j.ymthe.2021.04.038. Epub 2021 May 1.)
Julamanee 21 discloses anti-CD19 CAR which comprise a composite CD79A/CD40 co-stimulatory endodomain that enhanced CART-T cell proliferation and survival (see entire document, particularly the title and abstract). Notably, such constructs comprise an anti-CD19 scFv, the hinge of an IgG and an intracellular CD3zeta activation domain C terminal to the CD79A/CD40 domain(see most particularly Figures 1A and 3A). Additionally constructs are disclosed which comprise an IgG hinge of 12 amino acid residues in the absence of CH2 and CH3 domains (see most particularly Figure 3A as well as the paragraph spanning the left and right columns of page 2679). Polynucleotides encoding such chimeric receptors were transfected into lymphocytes and tested for anti-tumor efficacy in vitro and in vivo (see Figures 1-7).
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Hudecek et al. in view of Julamanee ’17 (The Synergistic T-Cell Signal By CD79A/CD40 Costimulatory Endodomain Enhances CD19 Chimeric Antigen Receptor T-Cell Proliferation and Survival – Blood. Volume 130, Supplement 1, 8 December 2017, Page 2061, doi.org/10.1182/blood.V130.Suppl_1.2061.2061).
Hudecek et al. disclose making a panel of anti-ROR1 CAR T cells which varied in the length of the spacer region between the anti-ROR1 scFv and the transmembrane domain (see entire document, particularly the abstract). ROR1 is the receptor tyrosine kinase-like orphan receptor 1 which is a tumor associated molecule expressed on B-cell and epithelial cancers but is not expressed on normal mature B cells or tissues which makes it an attractive target for therapy. They found that the “hinge-only” spacer constructs which comprises just 12 residues between the anti-ROR1 scFv and the transmembrane domain provides the best tumor cell lysis and induction of T cell effector functions in vitro and in vivo (see particularly the abstract, the right column of page 3155, and Figures 1-5). Notably, the costimulatory domain used in the CAR constructs of Hudecek et al. is from CD28 (see particularly the right column of page 3155). These teachings differ from what has been presently claimed in that the intracellular signaling domain in the constructs of Hudecek et al. are not disclosed as comprising CD79A and CD40.
Julamanee ’17 discloses that persistence of CAR T cells is important for therapy, that various costimulatory domains have been used in CARs in an attempt to improve signaling, function, and persistence, and that their construct comprises a CD79A/CD40 costimulatory domain that provided enhanced CAR T cell proliferation and survival as compared to the same construct apart from the use of a conventions CD28 costimulatory domain (see entire document, particularly the introduction and conclusions sections).
Therefore, artisans would have been motivated to replace the costimulatory domains used in the CAR constructs of Hudecek et al with the CD79A/CD40 costimulatory domains found in the CAR constructs of Julamanee ’17. Artisans would be motivated to do so in order to gain the advantages of increased CAR T cell proliferation and persistence that are present in CARs that use CD79A/CD40 costimulatory domains as compared to CD28 costimulatory domains as taught by Julamanee ‘17.
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Julamanee ’17 (The Synergistic T-Cell Signal By CD79A/CD40 Costimulatory Endodomain Enhances CD19 Chimeric Antigen Receptor T-Cell Proliferation and Survival – Blood. Volume 130, Supplement 1, 8 December 2017, Page 2061, doi.org/10.1182/blood.V130.Suppl_1.2061.2061) in view of Hudecek et al.
Julamanee ’17 discloses CD19 CAR constructs wherein the convention CD28 costimulatory domain was replaced with a CD79A/CD40 costimulatory domain in an effort to improve the signaling, function and persistence of CAR T cells (see entire document, particularly the introduction). It is disclosed that constructs comprising the CD79A/CD40 costimulatory domain demonstrated enhanced CAR T cell proliferation and survival as compared to control constructs comprising the CD28 costimulatory domain. These teachings differ from what is presently claimed in that the constructs of Julamanee ’17 have more than 100 amino acid residues between the anti-CD19 scFv and the transmembrane domain as the spacer comprises an immunoglobulin hinge, CH2, and CH3 domain.
Hudecek et al. disclose making a panel of CAR T cells which varied in the length of the spacer region between the scFv of the antigen binding domain and the transmembrane domain of the CAR construct (see entire document, particularly the abstract). They found that the “hinge-only” spacer constructs which comprises just 12 residues between the scFv and the transmembrane domain demonstrated the best tumor cell lysis and induction of T cell effector functions in vitro and in vivo (see particularly the abstract, the right column of page 3155, and Figures 1-5).
Therefore it would have been obvious to ordinary artisans to shorten the spacer region in the anti-CD19 CAR constructs of Julamanee ’17 to comprise just 12 amino acid residues. Artisans would be motivated to do so based upon the data a Hudecek et al. demonstrating that CAR constructs wherein the spacer was only 12 amino acid residues from the hinge of an immunoglobulin provided the best level of tumor cell lysis and effector cell function as compared to longer spacers.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641