DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's reply filed on 1/2/2026 is acknowledged. Claims 61-76 and 79-82 are pending. Claims 1-60 and 77-78 are canceled. Claims 75-76 are withdrawn. Claims 61, 79 and 81 are amended.
3. Claims 61-74 and 79-82 are under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 11/20/2025 has been considered by the examiner.
Objections Withdrawn
5. The objection of claim 79 because applicant inadvertently deleted “specific human T cells” in line 2 is withdraw in view of applicant’s amendment.
Rejections Maintained
Double Patenting
6. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
7. Claims 61-74 and 79-82 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,999,967, in view of Weber et al. (Clin Cancer Res., 2013, 19(18):5079-5091).
Claim 1 of the patent discloses a process for producing an HPV antigen-specific T cell comprising: (a) dividing a sample of mononuclear cells from a subject naïve to HPV antigens into several portions; (b) stimulating a first portion of said sample with PHA or another mitogen and with IL-2 to produce ATCs activated T cells (“ATCs”) that serve antigen presenting functions during subsequent stimulations and optionally treating the ATCs with radiation or another agent to inhibit their outgrowth; (c) separating T cells and T-cell precursor cells from dendritic cells and dendritic precursor cells in a second portion of the sample to form a T cell portion and a dendritic cell portion; (d) cryopreserving or otherwise reserving the T cells and T-cell precursor cells in the T cell portion; (e) differentiating the dendritic cells and dendritic precursor cells in the dendritic cell portion of the sample with cytokine(s) or other agent(s) that generate and mature dendritic cells and with at least one HPV peptide antigen or HPV antigen mix to produce antigen-presenting dendritic cells that present at least one HPV peptide antigen, and optionally treating said antigen-presenting dendritic cells with radiation or another agent sufficient to inhibit their outgrowth; (f) stimulating the cryopreserved or otherwise reserved T cells and T-cell precursor cells from the T cell portion in (d) with the dendritic antigen-presenting cells produced from the dendritic cell portion in (e) in the presence of IL-7 and IL-15 to produce antigen-specific T cells that recognize the at least one HPV peptide antigen; (g) stimulating antigen-specific T cells produced by (f) with the ATCs of (b) in the presence of the at least one HPV peptide antigen, optionally, in the presence of K562 cells or other accessory cells in the presence of IL-2 and/or IL-15; optionally, repeating (g) one or more times; and (h) recovering HPV antigen-specific T cells that recognize at least one peptide antigen.
Dependent claims further limit claim 1,
wherein the process further comprising separating naïve T cells from the mononuclear cells from a subject naïve to HPV antigens prior to (a),
wherein the mononuclear cells are obtained from cord blood,
wherein (b) comprises stimulating a first portion of said sample with PHA and with IL-2 to produce activated T cells (“ATCs”),
wherein in (e) the dendritic cells and dendritic precursor cells are allowed to undergo maturation with a dendritic cell-maturing cytokine or agent selected from the group consisting of one or more of LPS, TNF-alpha, IL-1 beta, IL-6, PGE-1, PGE-2, and other immune adjuvants, along with IL-4 and GM-CSF,
wherein in (f) the cytokines consist essentially of IL-7 and IL-15, wherein said at least one antigen comprises a series of overlapping peptides spanning an entire HPV protein or antigen.
wherein said at least one peptide antigen comprises a HPV antigen or peptide library.
The claims of patent do not teach making PRAME antigen-specific T cells.
The teachings of Weber et al. have been set forth previously (see art rejections).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of the patent to make PRAME antigen-specific T cells. One of ordinary skill in the art would have been motivated to do so because Weber et al. teaches that PRAME is a tumor associated antigen and teaches making PRAME antigen-specific T cells. Moreover, the substitution of one known element (PRAME antigen) for another (HPV antigen) would have yielded predictable results to one of ordinary skill in the art at the time of invention. One would have had a reasonable expectation of success because the method of the patent can be used for making any antigen-specific T cells.
All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
8. Claims 61-74 and 79-82 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 9,885,021, in view of Weber et al. (Clin Cancer Res., 2013, 19(18):5079-5091).
Claim 1 of the patent discloses a composition comprising HIV-antigen specific CD4+ and CD8+ T-cells produced by a method comprising:
(a) separating T-cells or T-cell precursors from dendritic cells or dendritic cell precursors in a hematopoietic cell sample, (b) producing blasts by contacting a portion of a hematopoietic cell sample, or a portion of said separated T-cells or T-cell precursors, with PHA or another mitogen, or by CD3/CD28 stimulation, and, optionally, treating the blasts with radiation or another agent to inhibit their outgrowth; (c) contacting the dendritic cells or dendritic precursor cells separated in (a) with cytokine(s) or other agent(s) that generate and mature dendritic cells and with at least one HIV peptide antigen to produce HIV-antigen-presenting dendritic cells that present at least one HIV-peptide antigen, and, optionally, treating said HIV-antigen-presenting dendritic cells with radiation or another agent sufficient to inhibit their outgrowth; (d) contacting the T-cells or T-cell precursors from (a) with the dendritic antigen-presenting cells produced in (c) in the presence of IL-7, IL-12 and/or IL-15 to produce CD4.sup.+ and CD8.sup.+ HIV-antigen-specific T-cells that recognize the at least one HIV-peptide antigen; (e) contacting HIV-antigen-specific CD4.sup.+ and CD8.sup.+ T-cells produced by (d) with the blasts of (b) in the presence of the at least one HIV-peptide antigen, optionally, in the presence of K562 cells or other accessory cells in the presence of IL-2 and/or IL-15; (f) optionally, repeating (e) one or more times to restimulate and/or expand the HIV-antigen specific CD4.sup.+ and CD8.sup.+ T-cells; and (g) recovering HIV-antigen-specific T-cells that recognize the at least one HIV-peptide antigen;
Dependent claims further limit claim 1,
wherein the hematopoietic cell sample is a cord blood sample or other sample containing naive immune cells, the hematopoietic cell sample is obtained from a peripheral blood sample from a donor who is HIV-negative,
wherein in (b) the blasts are produced using PHA, concanavalin A, pokeweed mitogen, or another mitogen, the blasts are irradiated or chemically treated to prevent their outgrowth,
wherein in (c) the separated dendritic cells or dendritic cell precursors are cultured in a dendritic cell medium containing IL-4 and GM-CSF, and then subsequently matured in a dendritic cell medium containing a mixture of IL-4, GM-CSF, IL-1B, IL-4, IL-6, PGE2, and/or TNF-α,
wherein in (c) the dendritic cells are further contacted with HIV Gag, Pol, Nef and/or Env peptides or HIV Gag. Pol, Nef and/or Env peptide libraries,
wherein in (d) the T-cells or T-cell precursors from (a) are contacted with the dendritic antigen-presenting cells produced in (c) in the presence of IL-7, IL-12 and IL-15 to produce HIV-antigen-specific T-cells that recognize the at least one HIV-peptide antigen,
wherein in (e) the HIV-antigen-specific CD4.sup.+ and CD8.sup.+ T-cells from (d) are maintained in a medium containing IL-15,
wherein in (e) the HIV-antigen-specific CD4.sup.+ and CD8.sup.+ T-cells from (d) are contacted with blasts that have been pulsed with HIV Gag, Pol, Nef and/or Env peptides or HIV Gag, Pol, Nef and/or Env peptide libraries,
wherein in (e) the HIV-antigen-specific CD4.sup.+ and CD8.sup.+ T-cells from (d) are contacted and restimulated with blasts that have been pulsed with HIV Gag, Pol, Nef and/or Env peptides or HIV Gag, Pol, Nef and/or Env peptide libraries at least three times every 5-8 days.
The claims of the patent do not teach making PRAME antigen-specific T cells.
The teachings of Weber et al. have been set forth previously (see art rejections).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of the patent to make PRAME antigen-specific T cells. One of ordinary skill in the art would have been motivated to do so because Weber et al. teaches that PRAME is a tumor associated antigen and teaches making PRAME antigen-specific T cells. Moreover, the substitution of one known element (PRAME antigen) for another (HIV antigen) would have yielded predictable results to one of ordinary skill in the art at the time of invention. One would have had a reasonable expectation of success because the method of the patent can be used for making any antigen-specific T cells.
All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
9. Claims 61-74 and 79-80 remain/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of US Patent No. 12,478,670 (previous claims 1-20 of copending Application No. 17/404,105), in view of Weber et al. (Clin Cancer Res., 2013, 19(18):5079-5091).
Claim 1 of the copending application discloses a process for producing an HPV antigen-specific T cell comprising:
(a) dividing mononuclear cells from a sample from any cell source containing naive immune cells, wherein the cells in the sample are naive to HPV antigens, into several portions;
(b) stimulating a first portion of said sample with PHA or another mitogen and with IL-2 to produce ATCs activated T cells (°ATCs”) that serve antigen presenting functions during subsequent simulations and optionally treating the ATCs with radiation or another agent to inhibit their outgrowth;
(c) separating T cells and T-cell precursor cells from dendritic cells and dendritic precursor cells in a second portion of the sample;
(d) cryopreserving or otherwise reserving the T cells and T-cell precursor cells from (c);
(e) differentiating the separated dendritic cells and dendritic precursor cells from (c) with cytokine(s) or other agent(s) that generate and mature dendritic cells and with at least one HPV peptide antigen or HPV antigen mix to produce antigen-presenting dendritic cells that present at least one HPV peptide antigen, and optionally treating said antigen-presenting dendritic cells with radiation or another agent sufficient to inhibit their outgrowth;
(f) stimulating the cryopreserved or otherwise reserved T cells and T-cell precursor cells from (d) with the dendritic antigen-presenting cells produced in (e) in the presence of TL-7 and IL-15 to produce antigen-specific T cells that recognize the at least one HPV peptide antigen;
(g) stimulating antigen-specific T cells produced by (g) with the ATCs of (b) in the presence of the at least one HPV peptide antigen, optionally, in the presence of K562 cells or other accessory cells in the presence of IL-2 and/or IL-15; optionally, repeating (g) one or more times; and
(h) recovering antigen-specific T cells that recognize the at least one HPV peptide antigen.
Dependent claims further limit claim 1,
wherein the process further comprising separating mononuclear cells containing naive T cells prior to (a);
wherein the mononuclear cells are obtained from hematopoietic stem cells naive to the at least one HPV peptide antigen, wherein the mononuclear cells are obtained from a subject whose immune system is naive to the at least one HPV peptide antigen;
wherein (b) comprises stimulating a first portion of said sample with PHA and with and EL-2 to produce activated T cells (“ATCs”),
wherein in (e) the dendritic cells and dendritic precursor cells are grown in the presence of one or more of LPS, TNF-alpha, IL-1 beta, IL-6, PGE-1, PGE-2, and other immune adjuvants, along with IL-4 and GM-CSF;
wherein said at least one antigen comprises a series of overlapping peptides spanning an entire HPV protein or antigen.
The claims of copending application do not teach making PRAME specific T cells.
The teachings of Weber et al. have been set forth previously (see art rejections).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of copending application to make PRAME antigen-specific T cells. One of ordinary skill in the art would have been motivated to do so because Weber et al. teaches PRAME is a tumor associated antigen and teaches making PRAME antigen-specific T cells. Moreover, the substitution of one known element (PRAME antigen) for another (HPV antigen) would have yielded predictable results to one of ordinary skill in the art at the time of invention. One would have had a reasonable expectation of success because the method of the copending application can be used for making any antigen-specific T cells.
All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
Applicant’s Arguments
The response states that the prior issued claims of US Patent Nos. 11,999,967, 9,885,021 and the claims of US Application No. 17/204,105 do not refer to methods or compositions requiring production of antigen-specific T cells to PRAME. Page 3 of the election species requirement of April 23, 2024 indicates that T cells to different antigens (e.g., PRAME, Survivin or WT-1) are "independent and distinct" and "not obvious variants of each other". PRAME (human) and HPV (viral) antigens are different antigens. Accordingly, this rejection cannot be sustained. Moreover, tumor antigens such as PRAME differ in their interaction with the immune system because they are derived from self-proteins unlike viral antigens. Thus, PRAME is more likely to be resistant to inducing PRAME-specific T cells due to likely tolerance of a patient's immune system to PRAME-like antigens. None of the prior art cited in the following rejections addresses this point and thus the cited references cannot provide a reasonable expectation of success for the claimed process that uses PRAME antigen in distinction to any antigen of potential interest. However, upon an indication of allowable subject matter, the Applicant will revisit these issues if necessary to distinguish allowable claims from the claims of these prior patents.
Response to Arguments
Applicant’s arguments have been carefully considered but are not found persuasive. Although viral antigens are different from tumor specific antigens, in vitro methods of making viral antigen specific T cells were often used in the art to generate tumor specific T cells, as evidenced by Weber et al. Weber’s method of making PRAME specific T cells is substantially similar to the methods of the patents (see art rejection). One would have had a reasonable expectation of success because Weber et al. has successfully generated PRAME specific T cells.
Claim Rejections - 35 USC § 103
10. 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.
11. Claims 79-80 and 82 remain rejected under 35 U.S.C. 103 as being unpatentable over Weber et al. (Clin Cancer Res., 2013, 19(18):5079-5091), in view of Stuhler (WO 2013/104804A2, pub. date 7/18/2013), Leen et al. (US 2011/0182870A1, pub date: 7/28/2011), and Gerdemann et al. (Molecular Therapy, 2012, 20(8): 1622-1632).
Claims 61-69 and 72-74 are withdrawn from the rejection in view of applicant’s amendment to the claims.
Regarding claims 79-80 and 82, Weber et al. (page 5082, column 1, para 1 and pages 5080-5081) teaches a method comprising:
(a) obtaining peripheral blood from 50 pediatric patients with ALL (step (a) of instant claim 79 obtaining from a human donor a sample comprising T cells and immature dendritic cell, step (a) of instant claim 82 obtaining from peripheral blood of a human donor a sample comprising T cells and dendritic cells or immature dendritic cells);
(b) generation of PHA-blast by the following steps:
(i) stimulating PBMC with the mitogen PHA-P in presence of IL-2 to promote blast formation (PHA-blasts),
(ii) culturing PHA-blasts (the instant ATCs) in the presence of IL-2 (instant step (c) contacting the first portion (PBMC) with phytohemagglutinin (PHA) and/or with human interleukin 2 ( IL-2) thereby producing activated T cells ("ATCs"))
(c) generation of antigen-presenting cells (APC) by the following steps:
(i) generating monocyte-derived dendritic cells by plate adherence of PBMC, incubating PBMC in dendritic cell media supplemented with 2 mmol/L GlutaMax (Invitrogen) (instant step (d) separating T cells from immature dendritic cells),
(ii) collecting and washing nonadherent cells,
(iii) culturing adherent cells in dendritic cell media in the presence of
IL-4 and GM-CSF (instant step (e) contacting immature dendritic cells with human IL-4, human GM-CSF, but missing lipopolysaccharide (LPS)).
(iii) further culturing immature dendritic cells in dendritic cell media with a cytokine cocktail consisting of IL-4, GM-CSF, IL-6, TNF-α, IL-1β, and PGE2
(iv) harvest mature dendritic cells after 48 hours of maturation for use as APC (antigen presenting cells)
(d) Generation of TAA-specific T-cell lines by the following steps:
(i) pulsing the mature dendritic cells with a mix of four peptide libraries WT1, Survivin, MAGE-A3, and PRAME spanning the entire amino acid sequence of the TAAs WT1, Survivin, MAGE-3 and PRAME,
(ii) Mixing the peptide pulsed dendritic cells at a stimulator-to-effector
ratio of 1:10 with T cells (initial stimulation),
(iii) culturing the cells in the presence IL-7, IL-12, IL-15 and IL-6 (instant step (f) and (g))
(iv) restimulating T cells with peptide-pulsed autologous irradiated (30 Gy) PHAblasts (instant step (c) irradiating the ATCs to inhibit their outgrowth and step (h)).
Regarding instant step (b), Weber teaches one PBMC sample is for making DC and the other PBMC is for making PHAblasts, which implies or render obvious that the PBMC sample was divided into to two portions.
Weber does not teach culturing DC with IL-4, GM-CSF and LPS. Weber does not teach irradiating peptide pulsed mature DC. Weber does not teach that the restimulating T cells with peptide-pulsed PHAblasts in the presence of IL-15. Weber does not teach that T cells stimulated by peptide-pulsed mature DC are T cells which are separated from DC.
Regarding claim 82, Weber et al does not teach that step (g) is performed without the addition of IL-12.
However, these deficiencies are made up for in the teachings of Stuhler, Leen and Gerdemann.
Stuhler teaches that DC were matured in medium containing IL-4, GM-CSF, and LPS; peptide loaded mature DC were irradiated, and naïve CD8+ T cells were stimulated with irradiated DC and cultured in the medium containing IL-7 and IL-15 (without IL-12) (page 89, last para).
Leen teaches isolating PBMC, separating T cells from immature DC, preparing peptide-pulsed mature DC and stimulating the T cells retained from the non-adherent PBMC fraction with the peptide-pulsed mature DC ([0020]).
Gerdemann et al. teaches that for expansion, CTLs were restimulated with irradiated (30Gy) pepmix-pulsed autologous PHA blasts in CTL media with IL4+7 and IL15 (5 ng/ml) on the day of restimulation and fed with IL15 twice weekly. Seven days later CTLs were harvested (page 1630, column 2, para 6).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Weber to add LPS to the medium containing IL-4 and GM-CSF for preparation of mature DC, irradiate peptide pulsed DC, stimulate naïve T cells with the irradiated DC, and culture stimulated and restimulated T cells in the presence of IL-7 and IL-15 without IL-12 in view of Stuhler. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Stuhler teaches that LPS, IL-4 and GM-CSF can be used for making mature DC cells, the peptide pulsed DC was irradiated before used as APC, and naïve T cells can be stimulated with APC and cultured in the presence of IL-7 and IL-15 (without IL-12). All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the T cells separated from immature DC to prepare PRAME antigen-specific T cells in view of Leen et al. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Leen teaches isolating PBMC, separating T cells from immature DC, preparing peptide-pulsed mature DC and stimulating the T cells retained from the non-adherent PBMC fraction with the peptide-pulsed mature DC ([0020]). Using naïve T cells for making PRAME antigen-specific T cells would suggest one to obtain T cells from a donor who is naïve to PRAME.
Regarding claim 82, Weber et al. teaches that T cells were stimulated with PHA-blasts on day 10 to 12 and restimulated every 7 days (page 5080, column 2). If the T cells is restimulated 1 or 2 times, the process would be completed within 30 days.
Gerdemann et al. teaches that for expansion, CTLs were restimulated with irradiated (30Gy) pepmix-pulsed autologous PHA blasts in CTL media with IL-4+7 and IL-15 (5 ng/ml) on the day of restimulation and fed with IL-15 twice weekly. Seven days later CTLs were harvested (page 1630, column 2, para 6).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Weber to performed step (h) in the presence of IL-15 for not more than 30 days without freezing the T cells in view of Gerdemann. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Gerdemann et al. teaches that for expansion, CTLs can be restimulated with irradiated (30Gy) pepmix-pulsed autologous PHA blasts in CTL media with IL4+7 and IL15 (5 ng/ml) on the day of restimulation, fed with IL15 twice weekly and harvested seven days later (page 1630, column 2, para 6).
Applicant’s Arguments
The response states that Stuhler was relied upon for maturing dendritic cells (DCs) in a medium containing IL- 4, GM-CSF, and LPS, peptide pulsing the DCs and subsequent T cell stimulation with the peptide-pulsed DCs in the presence of IL-7 and IL-15 and with no IL-12. However, as apparent from a word search, Stuhler does not even mention IL-12, much less provide a specific teaching, suggestion or motivation for specifically exclude IL-12 from the other process steps of claim 61. The inventors recognized that IL-12 can be omitted without impairing the efficacy of the claimed method. Omission of a non-essential cytokine such as IL-12 avoids the risk of severe off-target IL-12 toxicity or loss of antigen specificity triggered by IL-12. The Examiner considers that for T cell stimulation, that the cytokine medium of Weber (IL-7, IL-12, IL-15 and IL-6) and Stuhler (IL-7 and IL-15) are equivalents, and thus that it would have been obvious to substitute the IL-7 an IL-15 medium of Stuhler for the more complex medium of Weber to obtain step (g) of the invention. The rejection, which asserts that Stuhler teaches the combination of IL-7 and IL-15, overlooks the full teachings of Stuhler on pages 89-90. These teachings indicate that Stuhler coincubated the antigen-pulsed dendritic cells and naive CD8+ T cells in a medium containing 5% AB serum and IL-21 followed by addition of fresh medium also containing IL7 and IL-15. According to MPEP 2141.02: Ascertaining the differences between the prior art and the claims at issue requires interpreting the claim language and considering both the invention and the teachings of the prior art as a whole. This means that a rejection cannot be based on selective portions of isolated elements, instead the entire disclosure and context of each prior art reference must be evaluated for what it reasonable teaches a person skilled in the art.
Furthermore, there must also be a reasonable expectation of success in achieving the claimed invention through the proposed. Those skilled in the immunological arts would have recognized that the biological effects of cytokines are not simply additive and that certain cytokine combinations can create synergistic, antagonistic, or entirely novel cellular responses that cannot be predicted from studying each cytokine individually. For example, exposing dendritic cells (DCs) or T cells to multiple cytokines can lead to changes in gene expression and functional states that are distinct from those induced by any single cytokine or by a different combination of cytokines. Some combinations might enhance maturation and activation of naive T cells or dendritic cells, while others could inhibit these processes or promote unexpected phenotypes. This unpredictability preclude routine optimization.
Response to Arguments
Applicant’s arguments regarding claims 79-80 and 82 have been carefully considered but are not persuasive. For T cell stimulation, Weber teaches culturing the peptide pulsed dendritic cells with T cells in the presence IL-7, IL-12, IL-15 and IL-6. Stuhler teaches that naïve CD8+ T cells were stimulated with irradiated DC and cultured in the medium containing IL-7 and IL-15 (without IL-12 and IL-6) (page 89, last para). Both IL-7/IL-15/IL-12/IL-6 and IL-7/IL-15 have been used together with peptide pulsed DC in the art for T cell stimulation. The substitution of one known element (IL-7/IL-15) for another (IL-7/IL-15/IL-12/IL-6) would have yielded predictable results to one of ordinary skill in the art at the time of invention. Furthermore, part (g) of claim 82 recites “in the presence of human IL-7 and human IL-15 but in the presence of IL-12”, which does not preclude other components such as 5% AB serum and IL-21. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success to use IL-7 and IL-15 without IL-21 because Stuhler teaches that naïve T cells can be stimulated with APC and cultured in the presence of IL-7 and IL-15 (without IL-12). All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
New Grounds of Objection and Rejection
Claim Objections
12. To avoid any ambiguity, the following claim amendments are suggested:
In claims 61, 79 and 82,
step (c), the term “(“ATC”)” should be changed to “(ATC)” (i.e. deleting the double quotation marks),
step (g), line 2, the term “from step (d) should be added after “T cells”, and
step (h), the phrase “contacting the ATCs” should be changed to “contacting the pulsed ATCs”.
In claims 79 and 82, step (h), line 1, the comma “,” after “PRAME” is extra and should be deleted.
In claim 79, line 2, the term “antigen” should be added before “specific” to be consistent with the last line of the claim.
In claim 81, lines 2-3, the phrase “contacting the ATCs” should be changed to “contacting the pulsed ATCs”.
In claim 82, steps (a), (d), the phrase “comprising T cells and dendritic cells or immature dendritic cells” should be changed to ““comprising T cells and dendritic cells and immature dendritic cells” to be consistent with step (d) and (e).
Claim Rejections - 35 USC § 112
13. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
14. Claim 69 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 69 depends from claim 61. Claim 61 has been amended to recite “wherein said process is performed without the addition of IL-12. Claim 69, which recites “wherein step (g) is performed without the addition of IL-12”, does not further limit claim 61.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
15. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet Epps-Smith can be reached at 5712720757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HONG SANG/Primary Examiner, Art Unit 1646
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