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 .
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 255, 256, 260, 261, 265, and 266 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 255, 260, and 265 recites the limitation " the population of CD4+ cells". There is insufficient antecedent basis for this limitation in the claims. Claims 255, 260, and 265 depend from claims 135, 137, and 174, respectively, and no independent claim recites a population of CD4+ cells. For the purpose of compact prosecution, claims 255, 260, and 265 are interpreted as referring to the therapeutically effective amount of genetically modified CD4+ cells of claims 135, 137, and 174.
Claims 256, 261, and 266 depend from claims 255, 260, and 265 and fail to remedy the indefiniteness.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 135, 137, 257-259, 262-264, and 270 are rejected under 35 U.S.C. 103 as being unpatentable over McCauley et al. (WO 2019/245817 A1; Published: December 26, 2019).
Regarding claims 135 and 137, McCauley et al. teaches T cells expressing both a CAR and hIL-10 wherein the nucleic acid sequence encoding hIL-10 is downstream from that which encodes the CAR; see Example 11. McCauley et al. teaches a method of modulating a T-cell-mediated response to a target cell population in a subject comprising administering a therapeutically effect amount of cell genetically modified to express a CAR capable of binding the target cell population and an IL-10 agent; see claim 39. McCauley et al. teaches that the CAR and IL-10 can be expressed by the same genetically modified cells, including being expressed by the same or different vectors and comprise a secretion leader sequence; see pages 6-7 and 88, and Example 11. Regarding the human IL-10 of claim 270, McCauley et al. teaches a CAR T cell expressing a CAR and human IL-10 (“hIL-10”); see Example 11. McCauley et al. teaches that CD4+ T cells are appropriate source cells for the CAR T cells; see pages 90-91. Regarding hematological cancer or malignancy and that anti-CD19 CAR of claims 257 and 262, McCauley et al. teaches treating mice inoculated with a CD19+ Raji human Burkitt's lymphoma cell line and treating with anti-CD19 CAR T cells; see Examples 13 and 17. Regarding allo-HSCT in claim 137, McCauley et al. teaches that the CAR T cell and IL-10 therapy can be used in combination with bone marrow transplantation, peripheral blood stem cell transplantation, or other types of transplantation therapy; see page 107. Regarding cytotoxicity in claims 258, 259, 263, and 264, McCauley et al. demonstrates that anti-CD19 CAR T cells generated from expanded PBMCs, which comprises a population of CD4+ cells, have cytotoxicity against the CAR target; see Examples 13, 14, and 15.
While McCauley et al. teaches producing T cells expressing IL-10 and a CAR from PMBCs which include CD4+ T cells and teaches the method of treating cancer comprising administering a CAR T cell and IL-10, the reference does not reduce to practice the method of treating with the T cells expressing IL-10 and a CAR. The reference does not teach that CD4+ T cells expressing IL-10 and a CAR in the method of treating cancer result in the reduction of NLRP3 inflammasome hyperactivity nor the inhibition of proinflammatory cytokine production.
Given that McCauley et al. teaches treating hematological cancer or malignancy with a combination of a CAR T cell and IL-10 which can be used in combination with bone marrow or stem cell transplant and wherein the polynucleotide sequence encoding the secreted IL-10 and the CAR is expressed by the same cells, and demonstrating cytotoxicity of IL-10 treated CD19-targeting CAR T cells generated from PBMCs, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat hematological cancer or malignancy with CD4+ T cells expressing a CD19-targeting CAR and secreting IL-10, which McCauley et al. teaches enhances T cell function, including in combination with allo-HSCT.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 174, 176, 267, 268, and 269 are rejected under 35 U.S.C. 103 as being unpatentable over Sentman et al. (WO 2017/058752 A1; Published: April 6, 2017) in view of Imura et al. (JCI Insight. 5(14): e136185; Published: July 23, 2020).
Regarding instant claim 174, Sentman et al. teaches a method of treating inflammation or immune-mediated autoimmunity comprising administering to a subject the engineered immune cell, including CD4+ T cells, comprising nucleic acids encoding a CAR and encoding at least one exogenous anti-inflammatory or immunosuppressant protein, including viral IL-10; see Example 1, claims 1, 7, and 19 and paragraph 0075 for dose. Regarding instant claim 176, Sentman et al. teaches treating several of the inflammatory or autoimmune diseases claimed; see Table 1. Regarding claim 268, Sentman et al. teaches that the CAR comprises CD28 and CD3ζ signaling domains; see paragraph 0042.
While Sentman et al. teaches that the CAR comprises CD28 and CD3ζ domains, the reference does not state that the CAR T cells are cytotoxic. Nor does Sentman et al. teach targeting CD19.
Regarding claims 267-269, Imura et al. that CD19-targeting CAR T cells can be used to treat autoantibody-mediated autoimmune diseases; see Abstract. Imura et al. teaches generating CD19-targeting CAR T cells from CD4+ T cells (“Tconvs”) in which the CAR comprises CD28 and CD3ζ signaling domains; see Figure 1. Imura et al. teaches that CD19-targeting CAR T cells from CD4+ T cells (“Tconvs”) in which the CAR comprises CD28 and CD3ζ signaling domains resulted in cytotoxicity against CD19+ K562 cells; see Figure 2.
Given that Sentman et al. teaches treating autoimmune or inflammatory diseases with CD4+ T cell expressing a CAR, comprising CD28 and CD3ζ signaling domains, and expressing IL-10 and Imura et al. teaches treating autoantibody-mediated autoimmune disease with CD4+ T cell expressing a CD19-targeting CAR, comprising CD28 and CD3ζ signaling domains, and having cytotoxicity against CD19+ cells, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat autoimmune or inflammatory diseases with CD4+ T cells comprising a CAR targeting CD19 or an autoantigen resulting in cytotoxicity against a cell expressing the CAR target antigen.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Double Patenting
Claims 135, 137, 257, 258, 259, 262, 263, 264, and 270 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-38 of copending Application No. 19/062,832 in view of McCauley et al. (WO 2019/245817 A1; Published: December 26, 2019).
The copending claims of 19/062,832 teach treating a hematological cancer or malignancy comprising administering allo-HSCT and genetically modified CD4+ T cells modified to comprise the coding sequence or polynucleotide sequence encoding human IL-10.
The copending claims do not teach that the CD4+ T cell comprises a CAR nor a CAR targeting CD19.
Regarding claims 135 and 137, McCauley et al. teaches T cells expressing both a CAR and hIL-10 wherein the nucleic acid sequence encoding hIL-10 is downstream from that which encodes the CAR; see Example 11. McCauley et al. teaches a method of modulating a T-cell-mediated response to a target cell population in a subject comprising administering a therapeutically effect amount of cell genetically modified to express a CAR capable of binding the target cell population and an IL-10 agent; see claim 39. McCauley et al. teaches that the CAR and IL-10 can be expressed by the same genetically modified cells, including being expressed by the same or different vectors and comprise a secretion leader sequence; see pages 6-7 and 88, and Example 11. Regarding the human IL-10 of claim 270, McCauley et al. teaches a CAR T cell expressing a CAR and human IL-10 (“hIL-10”); see Example 11. McCauley et al. teaches that CD4+ T cells are appropriate source cells for the CAR T cells; see pages 90-91. Regarding hematological cancer or malignancy and that anti-CD19 CAR of claims 257 and 262, McCauley et al. teaches treating mice inoculated with a CD19+ Raji human Burkitt's lymphoma cell line and treating with anti-CD19 CAR T cells; see Examples 13 and 17. Regarding allo-HSCT in claim 137, McCauley et al. teaches that the CAR T cell and IL-10 therapy can be used in combination with bone marrow transplantation, peripheral blood stem cell transplantation, or other types of transplantation therapy; see page 107. Regarding cytotoxicity in claims 258, 259, 263, and 264, McCauley et al. demonstrates that anti-CD19 CAR T cells generated from expanded PBMCs, which comprises a population of CD4+ cells, have cytotoxicity against the CAR target; see Examples 13, 14, and 15.
Given that both the copending claims and McCauley et al. teaches treating hematological cancer or malignancy with a genetically modified CD4+ cell expressing IL-10 and McCauley et al. teaches that IL-10 enhance T cell function and that the polynucleotide sequence encoding the secreted IL-10 and the CAR can be expressed by the same cells, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat hematological cancer or malignancy with CD4+ T cells expressing a CD19-targeting CAR and secreting IL-10, which McCauley et al. teaches enhances T cell function, including in combination with allo-HSCT.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Potentially Allowable Subject Matter
Regarding claims 255, 256, 260, 261, 265, and 266, IL-10 is known to be a negative regulator of the NLRP3 inflammasome and resulting proinflammatory cytokines; see Greenhill et al. (Arthritis Research & Therapy. 16: 419; Published: August 30, 2014) and Gao et al. (International Journal of Molecular Sciences. 21: 465; Published: January 11, 2020). However, Brockmann et al. (Nature Communications 9(1): 5457; Published: December 21, 2018) teaches that IL-10 producing CD4+ T cells are phenotypically and functionally heterogenous and identifies an IL-10-producing subpopulation of CD4+ T cells which are proinflammatory and potentially pathogenic in inflammatory bowel disease. Additionally, Caielli et al. (Nature Medicine. 25: 75-81; Published: November 26, 2018) teaches that an IL-10-producing CD4+ T cell subtype with elevated IFN-gamma and IL-3 expression supports inflammatory autoreactive B cell response in lupus. More specific to the NLRP3 inflammasome, Yao et al. (The Journal of Immunology. 195(2): 488-497; Published: July 15, 2015) teaches that CD4+ FOXP3 negative cells suppress NLRP3 inflammasome activation and the subsequent production of proinflammatory cytokines via an IL-10 dependent mechanism. And while the instantly claimed CD4 IL-10/CAR cells express IL-10, Yao et al. acknowledges that the role of IL-10 in CD4+ FOXP3 positive Treg-mediated suppression is controversial and that since as little as 6 ng/ml rIL-10 efficiently suppressed the inflammasome and CD4+ FOXP3 positive Tregs produced an average of 26.1 mg/ml IL-10, the inability of FOXP3 positive cells to reduce NLRP3 inflammasome activation is likely not due to a lack of sufficient IL-10 production; see paragraph bridging pages 495-496. Moreover, regarding the CAR, Liu et al. (Science Immunology. 5(43): eaax7969; Published: January 3, 2020) demonstrates that pyroptosis of target cells by CAR T cells leads to the activation of caspase 1, the activator of proinflammatory IL-1beta and IL-18.
Thus, simply expressing IL-10 does not inherently result in the inhibition of the NLRP3 inflammasome or subsequent production of proinflammatory cytokines and one of ordinary skill in the art would not have a reasonable expectation of success that a CD4+ T cell expressing IL-10 and a CAR administered in the method of treating a hematological cancer, malignancy, or a patient in need of immune tolerization would also reduce NLRP3 inflammasome or inhibit the production of proinflammatory cytokine.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571)272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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