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 .
Response After Final
Applicant’s arguments filed in the after final submitted 09/02/2025 have been fully considered and are persuasive. Therefore, the finality of the office action issued 08/04/2025 is withdrawn. PROSECUTION IS HEREBY REOPENED. The amendment after final has been entered. New grounds of rejection are set forth below.
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US20/43505, filing date 07/24/2020, which claims the benefit of the prior-filed United States Provisional Patent Application No. 62/879,220, filing date 07/26/2019.
Status of Application/Claims
The amended claims, filed 09/02/2025, is acknowledged. Claims 10, 17, 19-21, and 30 are original. Claims 4-7 and 31-37 were previously canceled. Claims 1-3, 8-9, 12-13, 15-16, 18, and 22-29 were previously presented. Claim 14 is newly canceled. Claim 11 is currently amended. Claims 1-3, 8-13, and 15-30 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 01/25/2022, 08/21/2023, and 10/25/2023 have been fully considered by the examiner.
Withdrawn Rejections
Claims 1-3, 8-13, and 15-30 were rejected under 35 USC 103. In view of applicant’s arguments in the after final dated 09/02/2025, the rejections are withdrawn. New grounds of rejection are set forth below.
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.
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.
Claims 1, 8-9, 11, 15-16, 23, 25, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Velica et al. Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation. Cancer Research (2015), 75:13, p.2641-2652 (herein referred to as Velica), and in further view of Singh, et al. Alkaline cytosolic pH and high sodium hydrogen exchanger 1 (NHE1) activity in Th9 cells. JBC (2016), 291:45, p.23662-23671 (herein referred to as Singh).
Velica teaches that the tumor microenvironment limits the efficacy of T-cell therapies (p.2641, col.2, para.2). Velica teaches overexpression of a protein (i.e., RHEB) to enhance protective function in T cells and prevent disease progression in a murine model of adoptive immunotherapy for cancer (p.2641, col.2, para.3 – p.2642, col.1, para.1). Velica teaches genetic modification of T cells via transduction with a vector (p.2642, col.1, paras.6 and 9; Fig.1) and assessed the effect of overexpression on cytokine production and cytotoxicity which was enhanced (Figs.2-3). Velica teaches intravenous administration of a composition comprising genetically modified immune cells/T cells to treat solid tumors (i.e., subcutaneously administered tumor cells following 5 days of growth; Fig.5 and legend). Thus, Velica teaches administration of an intravenously delivered composition comprising a modified immune cell/T cell to mouse subjects (i.e., mammals) harboring solid tumors to enhance antitumor cytotoxicity by introducing to the immune cell/T cell a genetic modification using a vector for the purpose of treating the solid tumors (instant claims 1, 8, 9, 11, 15-16, 23, 25, and 28).
Velica does not teach a method for enhancing antitumor cytotoxicity by overexpressing NHE1 (instant claim 1); the method wherein the immune cell is a natural killer cell (NK cell) or T cell (instant claim 8); that the vector encodes NHE1 (instant claim 9); or, that the modified immune cell overexpresses NHE1 in an NK cell or T cell (instant claim 11).
Singh teaches that all major intracellular processes such as glycolysis-dependent ATP production or protein synthesis require tight regulation of intracellular pH (pHi); and, that maintenance of glycolysis and OXPHOS processing enzymes are highly dependent on pHi. Thus, Singh teaches that pHi can modify cellular metabolism (p.23662, col.2, para.3 – p.23663, col.1, para.1). Singh teaches the importance of NHE1 in regulating pHi in T helper 9 cell (Th9 cell) development and function with could “open up new avenues to treat autoimmune disorders, allergic inflammation, or cancer by immunotherapeutic manipulation of Th9 cells” (p.23663, col.1, para.1-3). Singh further teaches that NHE1 mRNA levels, protein levels, and exchanger activity, as well as T cell pHi, varied depending on the T cell subtype (p.23663, col.2). Singh teaches that there is a relationship between NHE1 and metabolism, and that NHE1 activation can lead to enhanced glycolysis (p.23664, col.2). Singh further teaches that NHE1 knockdown in Th9 cells reduced intracellular cytokine production (p.23664, Fig.5). Singh teaches that Akt positively regulates NHE1 activity and Th9 cytokine production, and discusses the relationship between Akt and mTOR expression levels (p.23665, col.2, para.1 – p.23667, col.1, para.1). Singh teaches that, following NHE1 inhibition, Th9 cells lose glycolytic potential, cytokine production, and convert into Tregs (p.23667, col.1, para.4, Fig.5). Singh further teaches that the Th9/Treg balance is critical in cancer patients because tumor cells generate lactate which leads to a highly acidic environment and an adequate tumor response against tumor cells requires survival of immune cells in the acidic environment; and that NHE1 activity may confer protection against the acidic environment (p.23667, col.2, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Velica and Singh to produce a genetically modified immune cells/T cells by overexpressing a protein that enhances the protective function of immune cells/T cells in a vector that could be intravenously administered as a composition to a mammalian subject, as taught by Velica, by using NHE1 as the immune cell/T cell function enhancing protein, as taught by Singh, to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Singh, that expression of NHE1 in immune cells/T cells promotes survival and cytokine production function thereby conferring protection of the immune cell/T cell against the acidic tumor environment. One of ordinary skill in the art would have a reasonable expectation of success because Velica teaches expression of protective proteins using vectors and Velica and Singh teach the importance of immune cell/T cell survival and antitumor protein expression.
Claims 2-3 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Velica and Singh as applied to claims 1 and 11 above, and in further in view of Galapagos Genomics N.V. – WO2005103716A2 (herein referred to as Galapagos).
The combination of Velica and Singh teaches a modified immune cell comprising overexpression of NHE1 in an immune cell/T cell and a method of enhancing antitumor cytotoxicity thereof, as applied to instant claims 1 and 11 above.
Velica and Singh do not teach that NHE1 has an amino acid sequence at least 85% identity to applicant SEQ ID NO: 5 (instant claims 2 and 12); or, that NHE1 has an amino acid sequence of applicant SEQ ID NOs: 5 or 6 (instant claims 3 and 13).
Galapagos teaches NHE1 amino acid SEQ ID NO: 236, which shares 100% identity to instant SEQ ID NO: 5 (p.61, NHE1 = SLC9A1; claim 10; see sequence alignment below; instant claims 2-3 and 12-13).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Velica and Singh with Galapagos to produce and use a genetically modified immune cells/T cells by overexpressing NHE1 to enhance the antitumor cytotoxicity of immune cells/T cells, as taught by Velica and Singh, by using the NHE1 sequence SEQ ID NO: 236, as taught by Galapagos, to arrive at the instantly claimed invention, because Galapagos teaches that SEQ ID NO: 236 encodes NHE1. One of ordinary skill in the art would have a reasonable expectation of success because Galapagos teaches that amino acid SEQ ID NO: 236 encodes for NHE1 and the combination of Velica and Singh teach that NHE1 can be expressed in immune cells/T cells.
[AltContent: textbox (Sequence Alignment: Galapagos NHE1 SEQ ID NO: 236 vs. instant SEQ ID NO: 5 NHE1
[img-media_image1.png])]
Claims 10, 17-19, 22, 24, 26-27, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Velica and Singh as applied to instant claims 1, 9, 11, and 16 above, and in further view of CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy. ClinicalTrials.gov Identifier: NCT01029366. Sponsor: University of Pennsylvania. Study Completion Date: 05/2016 herein referred to as U. Penn.
The combination of Velica and Singh teaches a modified immune cell/T cell comprising overexpression of NHE1 in an immune cell/T cell using a vector and a method of enhancing antitumor cytotoxicity thereof, by administering the modified immune cell/Tcell to a subject to treat a tumor as applied to instant claims 1, 9, 11, and 16 above.
Velica and Singh do not teach the vector is a lentiviral vector (instant claim 10); that the genetically modified immune cell is autologous to the subject (instant claim 17); that the method, before the step of administering the immune cell, comprises obtaining from the subject a sample comprising the immune cell and transfecting that immune cell with a vector (instant claim 18); culturing the immune cell in a medium before or after transfection (instant claim 19); that the vector is a lentiviral vector (instant claim 22); that the subject is human (instant claim 24); that the cancer/tumor is hematologic (instant claim 26); that the cancer can be leukemia or lymphoma (instant claim 27); that the method further comprises administration of a second therapeutic agent (instant claim 29); or, that the second therapeutic agent is an antitumor agent (instant claim 30).
U.Penn teaches that, in a clinical trial directed at treating cancer patients with a modified immune cell, autologous (instant claim 17) T cells were purified from the peripheral blood mononuclear cells of human subjects, transduced with TCR-ζ/4-1BB lentiviral (instant claims 10 and 22) vector (instant claim 18), expanded in vitro (instant claims 19) and then frozen for future administration. U.Penn teaches that the human subjects harbored hematologic tumors including leukemia and lymphoma (Researcher View tab: Title; Brief Summary, paragraph 1; Condition; Study Arms; instant claims 24, 26 and 27). Further, U. Penn teaches that, during the screening phase of this study, subjects with adequate T cells were leukapheresed to obtain large numbers of peripheral blood mononuclear cells (instant claims 17 and 18) for CART19/CTL019 genetic manufacturing (Researcher View tab: Brief Summary, paragraph 4). Further, U. Penn teaches second therapeutic agents including antitumor agents (Researcher View tab: Brief Summary, paragraph 5); instant claims 29 and 30). Further, the study highlights that, “Unless contraindicated and medically not advisable based on previous chemotherapy, subjects were given conditioning chemotherapy prior to CTL019 infusion. The chemotherapy was completed 1 to 4 days before (instant claim 30) the planned infusion of the first dose of CTL019.”
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Velica and Singh with U.Penn to enhance antitumor activity of immune cells/T cells and to treat cancer (i.e., a hematologic tumor, leukemia, or lymphoma) by administering to a human subject autologous immune cells that were obtained from that human subject and genetically modified by overexpressing NHE1 using lentiviral vector and cultured in a medium, along with administering a second antitumor therapeutic agent, to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Velica teaches overexpression of antitumor proteins in immune cells/T cells, Singh teaches that NHE1 expression is critical for immune cell/T cell function in the context of cancer, and U.Penn teaches that immune cells can be autologously obtained (from humans), genetically modified, and cultured prior to administration for treatment of cancers such as hematologic tumors, leukemia, and lymphoma; and, that autologous cells can be administered with a second antitumor agent.
(Claim Interpretation: Claim 19 is drawn to “medium.” The specification recites both “culture medium” and “dispersion medium.” Claims 19 and 20 provide that the purpose of “medium” is to culture the immune cell. The disclosure further recites “The term “culturing” or “expanding” refers to maintaining or cultivating cells under conditions in which they can proliferate and avoid senescence.” Thus, “medium” in claims 19 and 20 is interpreted to mean “culture medium” or “expansion medium” for maintaining or cultivating cells to promote proliferation and avoid senescence.)
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Velica, Singh, and U.Penn as applied to instant claims 11, 16, and 18-19 above, and further in view of Besser et al. Modifying interleukin-2 concentrations during culture improves function of T cells for adoptive immunotherapy. Cytotherapy (2009), 11:2, p.206-217 herein referred to as Besser.
The combination of Velica, Singh, and U.Penn teaches a modified immune cell comprising overexpression of NHE1 in a T cell for a method of treating cancer; wherein, the immune cell is obtained from a subject, transfected with a vector encoding NHE1, and cultured in a medium as applied to claims 11, 16, and 18-19 above.
Velica, Singh, and U. Penn do not teach that expansion in the medium comprises a cytokine (instant claim 20) to promote the growth of the immune cell nor that the cytokine is interleukin-2 (IL-2; instant claim 21).
Besser teaches that adoptive immunotherapy with T cells has shown promising clinical results in patients with metastatic melanoma and that transfer therapies often require the ex vivo expansion of large numbers of reactive lymphocytes (p. 206, column 1, paragraph 1). Besser also teaches that interleukin-2 (IL-2; instant claim 21) is a potent T-cell mitogenic cytokine (instant claim 20) that critically affects the features and effectiveness of T cells and is frequently added to cell culture media (claim 19).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Velica, Singh, and U.Penn with the teachings of Besser by using the IL-2 cytokine in the medium for culturing the modified immune cell/T cell, to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Velica and U.Penn teach treating cancer with genetically modified immune cells/T cells, Singh teaches the importance of NHE1 expression in the context of T cells in cancer, U.Penn teaches expansion of T cells in a medium, and Besser teaches the IL-2 cytokine is frequently added to culture media for immune cell/T cell expansion.
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647