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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/30/2026 has been entered.
1. Claims 1, 2, 4, 6, 8, 9, 11, 15 – 17, 20, 22, 23, 25, 27, 29, and 31 are pending and under consideration.
Withdrawn Claim Rejections
2. The rejection of claim 44 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancelation of the claim.
Maintained Claim Rejections
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.
3. Claim(s) 1, 2, 4, 6, 8, 9, 11, 15 – 17, 20, 22, 23, 25, 27, 29, and 31 remain rejected under 35 U.S.C. 103 as being unpatentable over Purcell (Purcell, Anthony W. HPLC of Peptides and Proteins: Methods and Protocols. Totowa, NJ: Springer New York, 2004. 291-306; previously cited), hereinafter Purcell as evidenced by Sigma (Octyl-Sepharose™ CL-4B. https://www.sigmaaldrich.com/US/en/product/sigma/o6001; Retrieved 08/04/2025) in view of Fahmy (US20100284965A1; Filed 01/14/2009, Published 11/11/2010; previously cited) hereinafter Fahmy which is cited on the IDS filed 02/10/2022, in view of Nguyen (Nguyen, Thelinh, et al. " International journal of cancer 81.4 (1999): 607-615; previously cited), hereinafter Nguyen.
Regarding claim 1, 6, 8, and claim 15, Purcell teaches a composition comprising protein A beads (“substrate particles” of claim 1 and 31) linked to an antibody that only recognizes class I or class II MHC (“via a polypeptide capable of specifically binding MHC” of claim 1 and 31) bound to endogenous MHC-peptide complexes obtained from a cell lysate (claim 6) (page 293, section 2.1 – 2.3; page 294, section 2.4 – 2.5 and section 3.1; page 295 – 296; page 297, section 3.5; Figure1). Purcell teaches protein A -sepharose beads (Pharmacia CL-4B) (page 296, section 3.4.1), which are cross-linked agarose (“polymer material” of claim 15) as evidenced by Sigma (page 2; matrix).
Regarding claim 2, Purcell teaches the endogenous MHC-peptide complexes comprise a plurality of different MHC-peptide complexes as shown in Figures 1 – 3. Purcell does not teach the MHC-peptide complexes are from cancer cells.
Purcell does not teach “contacting CD8+ T cells” with the composition of that the lysate is prepared from cancer cells of claim 1, 2, or 8 or the “endogenous MHC I-peptide complexes comprise peptides from one or more tumor-specific antigens” of claim 4 or the substrate particles are additionally bound to a co-stimulatory molecule of claim 9 or a T cell activating cytokine of claim 11 or the size of the particles of claim 16 or the particles are biodegradable of claim 17 or contacting occurs in vivo of claim 20 or further comprising administering the composition to a patient of claim 22 or contacting occurs ex vivo of claim 23 or administering the CD8+ T cells to a patient after contacting of claim 25 or the cancer cells are from a patient of claim 27 or from a tumor biopsy of claim 29. However, Purcell teaches MHC class I peptide loaded complexes are scrutinized by CD8+ cytotoxic T lymphocytes (CTLs) and should the peptide be foreign, the cell is killed via the CTLs (page 291). Purcell teaches CD8+ T cells recognize MHC class I molecules (page 292, para. 1). Purcell teaches immunoaffinity purification of the MHC-peptide complexes provides the best chance of epitope identification owing to the simplification of the range of cellular peptides isolated (page 292, para. 2; page 293, para. 2). Purcell teaches the use of appropriate monoclonal antibodies can select single MHC allele (page 293, para. 2). Purcell teaches technologies that allow the direct isolation and identification of peptide antigens associated with class I or II molecules have highlighted the ligand specificity of different MHC molecules and allowed direct identification of naturally processed and presented antigens associated with cancers (page 292, para. 1).
Regarding “contacting CD8+ T cells” of claim 1, 2, and 8 and claims 16, and 17, Fahmy teaches activation of T cells by contacting OT-I CD8+ T cells with aAPCs (page 20, 0259 – 0264). Fahmy teaches the fabrication of aAPCs comprises formation of PLGA (claim 17) microparticles with 8 µm diameter (claim 16) (page 5, 0071 – 0072; page 15, 0203; page 19, 0242, 0248, and 0251 – 0254). Fahmy teaches contacting CD8+ T cells with aAPCs to cause activation of T cells where the aAPCs comprise particles that contain MHC class I molecules bound to peptide antigens (page 17, 0225, 0226, 0227; page 5, 0068; page 7, 0104; page 9, 0124). Fahmy teaches the method produces cytotoxic T cells (page 18, 0239).
Regarding the lysate is prepared from cancer cells of claim 1, 2, and 8, Fahmy teaches the antigen of the aAPCs can be derived from cancer cells or tumors (page 9, 0126).
Regarding claim 4, Fahmy teaches the antigen can be a tumor-specific antigen (page 10, 0138).
Regarding claim 9, Fahmy teaches the aAPCs comprise at least one co-stimulatory molecule including CD80, CD86, OX40L, 4-1BBL, CD70, ICOS-L or antibodies that specifically bind these molecules (page 11, 0149 – 0150).
Regarding claim 11, Fahmy teaches the aAPCs contain a T cell activating cytokine such as GM-CSF (page 11, 0153).
Regarding claim 20 and 22, Fahmy teaches treating tumor-bearing mice with aAPCs (claim 20 and 22) (page 22, 0287 – 0291). Famy teaches administration of aAPCs caused a delay in tumor development which correlates with an expansion of cytotoxic T lymphocytes in the vicinity of tumor growth (page 22 – 23, 0291).
Regarding claims 23 and 25, Fahmy teaches ex vivo contacting of T cells with aAPCs to generate cytotoxic T cells (claim 23) that are then administered to a subject (claim 25) (page 18, 0239).
Fahmy does not teach the cancer cells are from a patient of claim 27 or from a tumor biopsy of claim 29. Fahmy teaches HLA class I molecules bind to peptides derived from proteins expressed by a tumor cell and are presented and recognized by T-cell receptors which engage T-lymphocytes in an immune response to induce antigen-specific cellular immunity (page 8, 0105). Fahmy teaches there are currently no aAPC technologies that exist that incorporate all of the necessary signals for T cell activation in a safe, ready-to-use system that could be rapidly modified for antigen-specific T cell activation and expansion (page 1, 0008). Fahmy teaches the ability of the aAPCs to elicit T-cell mediated immune responses by activation and expansion of T cells makes them especially useful for eliciting a cell-mediated response to a disease-related antigen in order to attack the disease (page 16, 0207). Fahmy teaches the aAPCs can be used to treat breast cancer (page 16, 0214). One would have been motivated to combine the teachings of Purcell regarding a composition comprising substrate particles bound via an MHC I antibody to endogenous MHC I-peptide complexes from a cell lysate with the teachings of Fahmy regarding contacting CD8+ T cells with aAPCs in a method of producing activated antigen-specific CTLs to treat breast cancer as Fahmy teaches there are currently no aAPC technologies that exist that incorporate all of the necessary signals for T cell activation in a safe, ready-to-use system that could be rapidly modified for antigen-specific T cell activation and expansion and Purcell teaches immunoaffinity purification of the MHC-peptide complexes provides the best chance of epitope identification owing to the simplification of the range of cellular peptides isolated.
Nguyen teaches generating alloreactive CTLs against a breast cancer cell line where a HLA-class I peptide identified by immunoprecipitating HLA-class I peptide complex reconstituted the tumor antigenic epitope recognized by the CTLs (page 607, right col. para. 2). Nguyen teaches isolating tumor tissue (claim 29) from HBL-100 breast cancer cell line grown in mice (claim 27) for peptide isolation (page 608, left col. para. 3). Nguyen teaches HLA class I bound peptides were isolated by affinity purification from detergent extracts of HLB-100 tumor tissues harvested from mice using HLA class I antibodies W6/32 and PA2.6 (page 608, left col. last para. and right col. para. 1). Nguyen teaches purification of the peptides followed by addition of purified peptide fractions to B-LCL cells (page 608, right col. para. 1 – 2). Nguyen teaches generating CD8+ CTLs by contacting T cells with HBL-100 (page 607, right col. para. 3; page 609, left col. para. 2). Nguyen teaches removal of HLA bound peptides in HBL-100 and there was not recognition of these HBL-100 cells by the tumor specific CTSs (Figure 6; page 611, left col. para. 2). Nguyen teaches the isolated peptides in the HLA class I-peptide complex are recognized by the tumor specific CTLs (page 611, right col. para. 1; Figure 9).
Nguyen teaches breast cancer represents the most common malignancy in women, carrying a high morbidity and mortality where about 1 in 9 women will develop breast cancer in her life time (page 607, left col. para. 1). Nguyen teaches despite advances in chemo/radiation therapy, advanced breast cancer still carries a high mortality rate and there is a need for more effective therapies and immunotherapy is a promising treatment option (page 607, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Purcell regarding a composition comprising substrate particles bound via an MHC I antibody to endogenous MHC I-peptide complexes from a cell lysate with the teachings of Fahmy regarding contacting CD8+ T cells with aAPCs with the teachings of Nguyen regarding immunoaffinity isolation of HLA-class I peptides identify peptides that generate CTLs to arrive at the claimed method for producing activated antigen-specific CTLs where CD8+ T cells are contacted with a composition comprising PLGA particles coupled to MHC class I W6/32 antibody bound to endogenous MHC I peptide complexes obtained from breast cancer cells. One would have been motivated to combine the teachings of Purcell, Fahmy and Nguyen in a method of producing cytotoxic T cells to treat breast cancer as Nguyen teaches breast cancer represents the most common malignancy in women, carrying a high morbidity and mortality and despite advances in chemo/radiation therapy, advanced breast cancer still carries a high mortality rate and there is a need for more effective therapies and immunotherapy is a promising treatment option and Fahmy teaches aAPCs can be used to treat breast cancer. One would have a reasonable expectation of success in combining the teachings as Fahmy teaches the ability of the aAPCs to elicit T-cell mediated immune responses by activation and expansion of T cells makes them especially useful for eliciting a cell-mediated response to a disease-related antigen in order to attack the disease and Nguyen teaches the identified peptides by immunoaffinity from the breast cancer cell line are recognized by the CTLs generated against the breast cancer cell line.
Regarding claim 31, Purcell teaches a composition comprising protein A beads (“substrate particles”) linked to an antibody that only recognizes class I or class II MHC (“via a polypeptide capable of specifically binding MHC”) bound to endogenous MHC-peptide complexes obtained from a cell lysate (page 293, section 2.1 – 2.3; page 294, section 2.4 – 2.5 and section 3.1; page 295 – 296; page 297, section 3.5; Figure1). Purcell does not teach “contacting CD8+ T cells” of step (a) or “contacting the target cell with the activated, target antigen-specific CD8+ T cells of step (b).
Regarding “contacting CD8+ T cells” of step (a) and step (b), Fahmy teaches activation of T cells by contacting OT-I CD8+ T cells with aAPCs (page 20, 0259 – 0264). Fahmy teaches contacting CD8+ T cells with aAPCs to cause activation of T cells where the aAPCs comprise particles that contain MHC class I molecules bound to peptide antigens (page 17, 0225, 0226, 0227; page 5, 0068; page 7, 0104; page 9, 0124). Fahmy teaches ex vivo contacting of T cells with aAPCs to generate cytotoxic T cells that are then administered to a subject (page 18, 0239). Fahmy teaches administration of aAPCs caused a delay in tumor development which correlates with an expansion of cytotoxic T lymphocytes in the vicinity of tumor growth (page 22 – 23, 0291). Fahmy teaches the ability of the aAPCs to elicit T-cell mediated immune responses by activation and expansion of T cells makes them especially useful for eliciting a cell-mediated response to a disease-related antigen in order to attack the disease (page 16, 0207). Fahmy teaches following activation and expansion of the T cells they are administered to the subject where they may be administered separately from, or in combination with the aAPCs and the immune response mediated by CD8+ T cells are capable of killing tumor or infected cells (page 17, 0228). Fahmy teaches the aAPCs can be used in vivo for active immunotherapy and ex vivo for adoptive immunotherapy (page 2, 0018). Fahmy teaches the aAPCs can be used to treat breast cancer (page 16, 0214).
Nguyen teaches generating alloreactive CTLs against a breast cancer cell line where a HLA-class I peptide identified by immunoprecipitating HLA-class I peptide complex reconstituted the tumor antigenic epitope recognized by the CTLs (page 607, right col. para. 2). Nguyen teaches isolating tumor tissue from HBL-100 breast cancer cell line grown in mice for peptide isolation (page 608, left col. para. 3). Nguyen teaches HLA class I bound peptides were isolated by affinity purification from detergent extracts of HLB-100 tumor tissues harvested from mice using HLA class I antibodies W6/32 and PA2.6 (page 608, left col. last para. and right col. para. 1). Nguyen teaches purification of the peptides followed by addition of purified peptide fractions to B-LCL cells (page 608, right col. para. 1 – 2). Nguyen teaches generating CD8+ CTLs by contacting T cells with HBL-100 (page 607, right col. para. 3; page 609, left col. para. 2). Nguyen teaches the isolated peptides in the HLA class I-peptide complex are recognized by the tumor specific CTLs and cause cell lysis (page 611, right col. para. 1; Figure 9).
Nguyen teaches breast cancer represents the most common malignancy in women, carrying a high morbidity and mortality where about 1 in 9 women will develop breast cancer in her life time (page 607, left col. para. 1). Nguyen teaches despite advances in chemo/radiation therapy, advanced breast cancer still carries a high mortality rate and there is a need for more effective therapies and immunotherapy is a promising treatment option (page 607, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Purcell regarding a composition comprising substrate particles bound via an MHC I antibody to endogenous MHC I-peptide complexes from a cell lysate with the teachings of Fahmy regarding a method of killing a tumor cells aAPCs with the teachings of Nguyen regarding immunoaffinity isolation of HLA-class I peptides identify peptides that generate CTLs to arrive at the claimed method CD8+ T cells are contacted with a composition comprising protein A beads bound via an MHC I antibody to endogenous MHC-1 peptide complexes from breast cancer cells creating activated, target antigen-specific CD8+ T cells and contacting the breast cancer cells with the activated, target antigen-specific CD8+ T cells to kill the breast cancer cells. One would have been motivated to combine the teachings of Purcell, Fahmy and Nguyen in a method of killing breast cancer cells as Nguyen teaches breast cancer represents the most common malignancy in women, carrying a high morbidity and mortality and despite advances in chemo/radiation therapy, advanced breast cancer still carries a high mortality rate and there is a need for more effective therapies and immunotherapy is a promising treatment option and Fahmy teaches aAPCs can be used to treat breast cancer. One would have a reasonable expectation of success in combining the teachings as Fahmy teaches the ability of the aAPCs to elicit T-cell mediated immune responses by activation and expansion of T cells makes them especially useful for eliciting a cell-mediated response to a disease-related antigen in order to attack the disease and Nguyen teaches the identified peptides by immunoaffinity from the breast cancer cell line are recognized by the CTLs generated against the breast cancer cell line that lyse the breast cancer cells.
Claim Interpretation
4. Recitation of “contacting” in claims 1, 8, 20, 23, 25, and 31 is interpreted as an active step by whoever is performing the method rather than naturally occurring passive contact, and is interpreted to include “administering” because Applicant’s specification states “the contacting may occur as a result of administering the composition” at para. 0010.
5. Recitation of “substrate particles” in claims 1, 6, 8, 9, 11, 15, 16, 17, and 31 is interpreted to include cells because Applicant’s specification at para. 0011 states “substrate particles comprising a lipid bilayer may also be cell-based”.
6. Recitation of “tumor” in claims 4 and 29 is given the broadest reasonable interpretation to include cancer cells.
New Claim Rejections
Claim Rejections - 35 USC § 112
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.
7. Claim 22 is 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.
8. Because “contacting” of claim 20 is interpreted to include “administering”, it is unclear how claim 22 further limits claim 20 because claim 20 requires in vivo contact and claim 22 requires administering the composition to a patient. Therefore, claim 22 is interpreted as a duplicate of claim 20. Should Applicant amend claim 20 to narrow the breadth of “contacting” and/or amend 22 to narrow the breadth of “administering”, the rejection may be overcome.
Duplicate Claims Warning
9. Applicant is advised that should claim 20 be found allowable, claim 22 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). The breadth of “contacting” of claim 20 is interpreted to include “administering” in light of Applicant’s specification at para. 0010. Therefore, claim 22 is a substantial duplicate of claim 20.
Claim Rejections - 35 USC § 112
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.
10. Claim 22 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. The breadth of “contacting” of claim 20 is interpreted to include “administering” because claim 20 requires the contacting occur in vivo. Therefore, claim 22 fails to further limit claim 20. 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.
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.
11. Claim(s) 1, 2, 4, 6, 8, 9, 11, 15, 16, 17, 23, 27, and 29 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mahdian (Mahdian R, et. al.. Med Oncol. 2006;23(2):273-82), hereinafter Mahdian as evidenced by Dumortier (Dumortier H, et. al. J Immunol. 2005 Jul 15;175(2):855-63), hereinafter Dumortier and as evidenced by Chen (Chen M, et. al. Immunol Rev. 2010 Jul;236:11-27), hereinafter Chen and as evidenced by ATCC (ATCC. A-375 Product Information Sheet. 12/03/2025).
Claim 1 is drawn to a method of producing activated antigen-specific cytotoxic T cells, the method comprising contacting CD8+ T cells with a composition comprising substrate particles bound, via a polypeptide capable of specifically binding MHC, to endogenous MHC I-peptide complexes obtained from a lysate prepared from one or more cancer cells.
Regarding claim 1, Mahdian teaches coculturing T cells with tumor lysate-pulsed dendritic cells (“substrate particles”) (page 275, left col. para. 3 and right col. last para.; page 276, left col. para. 1). Mahdian teaches the tumor-lysate pulsed dendritic cells were bound to MHC I-peptide complexes endogenous to the tumor lysate because MHC class I antibody inhibited T cell proliferation (page 276, left col. para. 1; page 277, right col. para. 1; Figure 3). Mahdian teaches the T cells are CD8+ T cells and that stimulation of these cells with tumor lysate-pulsed dendritic cells produced activated CD8+ cytotoxic T cells that recognized specific antigens in melanoma cells, lysed melanoma cells, and produced IFN-γ (page 277, right col. last para.; Figure 4 and 6; page 278, right col.; page 279; page 280, right col. para. 1; page 281, left col. para. 2 – 3).
Regarding claim 2, Mahdian teaches the melanoma lysate-stimulated T cells react to a plurality of melanoma antigens (Figure 6; page 278, right col. para. 2) and therefore Mahdian teaches the MHC I-peptide complexes comprise a plurality of different MHC I-peptide complexes.
Regarding claim 4, Mahdian teaches the peptides that the melanoma-lysate stimulated T cells react to are known melanoma associated antigens (page 278, right col. last para.).
Regarding claim 6, Mahdian teaches the dendritic cells are bound to endogenous MHC complexes from tumor cell lysate (page 275, left col. para. 3).
Regarding claim 8, Mahdian teaches generating tumor lysate-pulsed dendritic cells by contacting dendritic cells with tumor lysate (page 275, left col. para. 3).
Regarding claim 9, Mahdian teaches CD80 and CD86 are bound to the tumor lysate-pulsed dendritic cells (page 276, right col. para. 2).
Regarding claim 11, Mahdian teaches the tumor lysate-pulsed dendritic cells were treated with TNF-α (page 275, left col. para. 3).
Regarding “a lipid bilayer” of claim 15, Mahdian teaches dendritic cells are eukaryotic cells which contain a lipid bilayer (page 274, right col. para. 2; page 275, left col. para. 1 – 3).
Regarding claim 16, Mahdian teaches dendritic cells (page 275, left col. para. 3) which are 10 – 15 µm as evidenced by Dumortier (page 860, left col. para. 1; Figure 6).
Regarding claim 17, Mahdian teaches dendritic cells (page 275, left col. para. 3) which undergo programmed cell death as evidenced by Chin (Abstract; page 1; page 2, para. 1 – 3; page 3, para. 3; page 5, last para.; page 6, last para.; page 7, para. 1).
Regarding claim 23, Mahdian teaches coculturing of isolated T cells and tumor-lysate pulsed dendritic cells (page 275, right col. last para.).
Regarding claim 27 and claim 29, Mahdian teaches the tumor lysate is from A375 cells (page 275, left col. para. 3), which was isolated from the skin (claim 29) of a patient (claim 27) with malignant melanoma as evidenced by ATCC (page 1, para. 1).
Therefore, Mahdian anticipates claims 1, 2, 4, 6, 8, 9, 11, 15, 16, 17, 23, 27, and 29.
12. Claim(s) 31 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mahdian (Mahdian R, et. al.. Med Oncol. 2006;23(2):273-82), hereinafter Mahdian as evidenced by Dumortier (Dumortier H, et. al. J Immunol. 2005 Jul 15;175(2):855-63), hereinafter Dumortier and as evidenced by Chen (Chen M, et. al. Immunol Rev. 2010 Jul;236:11-27), hereinafter Chen and as evidenced by ATCC (ATCC. A-375 Product Information Sheet. 12/03/2025).
Claim 31 is drawn to A method of killing a target cell, the method comprising: (a) contacting CD8+ T cells with a composition comprising substrate particles bound, via a polypeptide capable of specifically binding MHC, to endogenous MHC I-peptide complexes obtained from one or more cells of the same type as the target cell, thereby creating activated, target antigen-specific CD8+ T cells; and (b) contacting the target cell with the activated, target antigen-specific CD8+ T cells, thereby killing the target cell.
Regarding step (a), Mahdian teaches coculturing T cells with melanoma (“target cell”) lysate-pulsed dendritic cells (“substrate particles”) (page 275, left col. para. 3 and right col. last para.; page 276, left col. para. 1). Mahdian teaches the tumor-lysate pulsed dendritic cells were bound to MHC I-peptide complexes endogenous to the tumor lysate because MHC class I antibody inhibited T cell proliferation (page 276, left col. para. 1; page 277, right col. para. 1; Figure 3).
Regarding step (b), Mahdian teaches the T cells are CD8+ T cells and that stimulation of these cells with tumor lysate-pulsed dendritic cells produced activated CD8+ cytotoxic T cells that when contacted with melanoma cells recognized specific antigens in melanoma cells and lysed the melanoma cells (page 277, right col. last para.; Figure 4 and 6; page 278, right col.; page 279; page 280, right col. para. 1; page 281, left col. para. 2 – 3).
Therefore, Mahdian anticipates claim 31.
Claim Rejections - 35 USC § 103
13. Claim(s) 1, 2, 4, 6, 8, 9, 11, 15, 16, 17, 20, 22, 23, 27, and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mahdian (Mahdian R, et. al.. Med Oncol. 2006;23(2):273-82), hereinafter Mahdian as evidenced by Dumortier (Dumortier H, et. al. J Immunol. 2005 Jul 15;175(2):855-63), hereinafter Dumortier and as evidenced by Chen (Chen M, et. al. Immunol Rev. 2010 Jul;236:11-27), hereinafter Chen and as evidenced by ATCC (ATCC. A-375 Product Information Sheet. 12/03/2025) in view of Nestle (Nestle, Frank O., et al. Nature medicine 4.3 (1998): 328-332.), hereinafter Nestle.
Mahdian anticipates claim 1 as set forth above. Mahdian does not teach administering the tumor lysate-pulsed dendritic cells to a patient of claims 20 and 22. However, Mahdian teaches the T cells that were cocultured with the tumor lysate-pulsed dendritic cells secreted IFN-γ, reacted with multiple known melanoma antigens and lysed melanoma cells (Figure 4 – 6; page 278, right col.; page 279). Mahdian teaches several tumor-associated antigen delivery methods to dendritic cells have been utilized with all methods showing induction of T-cell responses and clinical antitumor effects, but each method has potential limitations including the use of a single epitope (page 274, left col. para. 1). Mahdian teaches the use of tumor lysate may allow for the sensitization of T cells to a variety of antigens that may be heterogeneously expressed on growing tumors (page 274, left col. para. 1). Mahdian teaches although antigen-specific cytotoxic CD8 T cells have been considered responsible for tumor cell lysis, CD4+ T cells provide necessary help for the induction of cytotoxic CD8 T cells and might also directly lyse MHC class II+ target cells (page 280, left col. last para. and right col. para. 1). Mahdian teaches inhibition of antigen-specific T cell proliferation by anti-MHC class I and anti-MHC class II antibodies indicates induction of both MHC class I and class II restricted T cells, which is in keeping with a previous clinical report demonstrating the generation of both CD4+ and CD+ T cell responses in patients immunized with tumor lysate-pulsed dendritic cells (page 280, right col. para. 1). Mahdian teaches their results provide preliminary evidence that a humanized melanoma cell line may serve as a standardized and validated polyclonal antigen source for stimulating antitumor T cells for clinical immunotherapy of melanoma patients (page 281, left col. para. 2).
Regarding claims 20 and 22, Nestle teaches administering dendritic cells pulsed with autologous tumor lysate to melanoma patients (page 328, right col. para. 2; page 332, left col. para. 3 – 4 and 6). Nestle teaches vaccination was well tolerated (page 328, left col. last para.; page 331, left col. last para.). Nestle teaches patient 4 had a complete response, patient 7 had a partial response and patients 2 and 3 had progressive disease following vaccination (Table 1; page 331, right col. para. 1). Nestle teaches cytotoxic T lymphocytes attack melanoma cells in an HLA-restricted and tumor antigen-specific manner, and these antigens are suitable candidates for a vaccination therapy of melanoma (Abstract). Nestle teaches dendritic cells are antigen presenting cells specialized for the induction of a primary T cell response (Abstract). Nestle teaches current vaccination strategies do not induce a sufficient antigen-specific immune response for tumor eradication in patients with advanced melanoma (page 328, left col.). Nestle teaches dendritic cells have been proposed to be the ideal candidate for the generation and amplification of a primary immune response in a vaccination setting (page 328, left col. and right col. para. 1). Nestle teaches that even though only a small number of selected patients were treated, the clinical responses observed are encouraging and demand future studies of dendritic cell vaccination (page 331, right col. para. 1 – 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Mahdian regarding a method of producing activated melanoma antigen-specific T cells by contacting T cells with tumor lysate-pulsed dendritic cells with the teachings of Nestle regarding administering tumor lysate-pulsed dendritic cells to arrive at the claimed method wherein contacting the CD8+ T cells with the composition occurs in vivo by administering the composition to a patient. One would have been motivated to combine the teachings of Mahdian and Nestle in a method of evaluating the therapeutic effect of a vaccine comprising allogeneic dendritic cells pulsed with tumor lysate from a standardized and validated polyclonal antigen melanoma cell line as Mahdian teaches their results provide preliminary evidence that a humanized melanoma cell line may serve as a standardized and validated polyclonal antigen source for stimulating antitumor T cells for clinical immunotherapy of melanoma patients and Nestle teaches variable responses including progressive disease by administering dendritic cells pulsed with autologous tumor lysate and Nestle teaches current vaccination strategies do not induce a sufficient antigen-specific immune response for tumor eradication in patients with advanced melanoma. One would have a reasonable expectation of success in combining the teachings as Mahdian teaches the T cells that were cocultured with the tumor lysate-pulsed dendritic cells secreted IFN-γ, reacted with multiple known melanoma antigens and lysed melanoma cells and Nestle teaches vaccination was well tolerated with patient 4 had a complete response and patient 7 had a partial response.
14. Claim(s) 1, 2, 4, 6, 8, 9, 11, 15, 16, 17, 23, 25, 27, and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mahdian (Mahdian R, et. al.. Med Oncol. 2006;23(2):273-82), hereinafter Mahdian as evidenced by Dumortier (Dumortier H, et. al. J Immunol. 2005 Jul 15;175(2):855-63), hereinafter Dumortier and as evidenced by Chen (Chen M, et. al. Immunol Rev. 2010 Jul;236:11-27), hereinafter Chen and as evidenced by ATCC (ATCC. A-375 Product Information Sheet. 12/03/2025) in view of Yee (Yee C, et. al. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73), hereinafter Yee.
Mahdian anticipates claim 1 and 23 as set forth above. Mahdian does not teach administering the CD8+ T cells to a patient after the contacting of claim 25. However, Mahdian teaches the T cells that were cocultured with the tumor lysate-pulsed dendritic cells secreted IFN-γ, reacted with the known melanoma antigens gp100 and MART-1 in two different melanoma cell lines, and lysed melanoma cells (Figure 4 – 6; page 278, right col.; page 279). Mahdian teaches several tumor-associated antigen delivery methods to dendritic cells have been utilized with all methods showing induction of T-cell responses and clinical antitumor effects, but each method has potential limitations including the use of a single epitope (page 274, left col. para. 1). Mahdian teaches the use of tumor lysate may allow for the sensitization of T cells to a variety of antigens that may be heterogeneously expressed on growing tumors (page 274, left col. para. 1). Mahdian teaches although antigen-specific cytotoxic CD8 T cells have been considered responsible for tumor cell lysis, CD4+ T cells provide necessary help for the induction of cytotoxic CD8 T cells and might also directly lyse MHC class II+ target cells (page 280, left col. last para. and right col. para. 1). Mahdian teaches inhibition of antigen-specific T cell proliferation by anti-MHC class I and anti-MHC class II antibodies indicates induction of both MHC class I and class II restricted T cells, which is in keeping with a previous clinical report demonstrating the generation of both CD4+ and CD+ T cell responses in patients immunized with tumor lysate-pulsed dendritic cells (page 280, right col. para. 1). Mahdian teaches their results provide preliminary evidence that a humanized melanoma cell line may serve as a standardized and validated polyclonal antigen source for stimulating antitumor T cells for clinical immunotherapy of melanoma patients (page 281, left col. para. 2).
Regarding claim 25, Yee teaches a method of preparing melanoma antigen-specific cytotoxic CD8+ T cells by using dendritic cells pulsed with a peptide epitope of MART-1 or gp100, followed by administering the CD8+ T cells to patients with metastatic melanoma (page 16168, left col. last para. and right col. para. 1 – 4; page 16169, right col. para. 2 – 3; page 16172, left col. last para. and right col. last para.). Yee teaches no grade III or IV toxicity was observed in the patients (page 16169, right col. para. 3). Yee teaches the administered T cells were observed in tumors (page 16171, left col. para. 2 and right col. para. 1). Yee teaches some patients showed stable disease (Table 1; page 16171, right col. para. 2). Yee teaches adoptive therapy using ex vivo expanded T cells provides a means of treating patients with cancer by augmenting the antigen-specific immune response (page 16172, left col. last para.). Yee teaches in contrast to vaccination strategies, adoptive therapy strategies can overcome the in vivo constraints that influence the magnitude and avidity of the targeted response (page 16168, left col. para. 2). Yee teaches T cells of a given specificity, function, and avidity for tumor can be selected in vitro and then expanded to achieve in vivo frequencies in the peripheral blood that are higher than generally attained by current immunization regimens and are consistent with levels predicted by murine tumor therapy models to be required to mediate tumor elimination (page 16168, left col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Mahdian regarding a method of producing activated melanoma antigen-specific T cells by contacting T cells with tumor lysate-pulsed dendritic cells with the teachings of Yee regarding administering activated melanoma antigen-specific cytotoxic CD8+ T cells to patients with melanoma to arrive at the claimed method further comprising administering the CD8+ T cells to a patient after the contacting. One would have been motivated to combine the teachings of Mahdian and Yee in a method of evaluating the therapeutic effect of a plurality of antigen-specific cytotoxic CD8+ T cells prepared by contacting T cells with dendritic cells pulsed with tumor lysate instead of a single peptide antigen as Mahdian teaches tumor-associated antigen delivery methods have potential limitations including the use of a single epitope and Mahdian teaches the use of tumor lysate may allow for the sensitization of T cells to a variety of antigens that may be heterogeneously expressed on growing tumors and Yee teaches in contrast to vaccination strategies, adoptive therapy strategies can overcome the in vivo constraints that influence the magnitude and avidity of the targeted response. One would have a reasonable expectation of success in combining the teachings as Mahdian teaches the T cells that were cocultured with the tumor lysate-pulsed dendritic cells secreted IFN-γ, reacted with multiple known melanoma antigens and lysed melanoma cells and Yee teaches no grade III or IV toxicity was observed in the patients and Yee teaches the administered T cells were observed in tumors and Yee teaches some patients showed stable disease.
15. Claim(s) 1, 2, 4, 6, 8, 9, 11, 15, 16, 23, 27, and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mahr (US10576132B2; Filed 05/17/2018; Published 03/03/2020), hereinafter Mahr in view of Mahdian (Mahdian R, et. al.. Med Oncol. 2006;23(2):273-82), hereinafter Mahdian.
Regarding claim 1, Mahr teaches contacting CD8+ T cells with streptavidin (“via a polypeptide capable of specifically binding MHC”) beads (“substrate particles”) coated with peptide-MHC-biotin complexes (col. 175, lines 24 – 64). Mahr does not teach “endogenous MHC I-complexes obtained from a lysate prepared from one or more cancer cells”. However, Mahr teaches isolating peptides from shock-frozen tumor tissue (“lysate prepared from one or more cancer cells”) using immune precipitation using antibodies that bind MHC I peptide complexes where the antibodies are bound to Sepharose beads (col. 109, lines 60 – 67; col. 110, lines 34 – 42).
Regarding claim 9, Mahr teaches the beads are additionally bound to anti-CD28 (col. 175, lines 24 – 64).
Regarding claim 11, Mahr teaches supplementing with IL-12 and IL-2 (col. 175, lines 50 – 59).
Regarding claim 15, Mahr teaches the beads are polystyrene particles (col. 175, lines 42 – 43).
Regarding claim 16, Mahr teaches the beads are 5.6 µm in diameter (col. 175, lines 42 – 43).
Regarding claim 23, Mahr teaches the contacting occurs ex vivo with isolated CD8+ T cells (col. 175, lines 24 – 64).
Regarding claims 27 and 29, Mahr teaches isolating peptides from shock-frozen tumor tissue (claim 29) from patients (claim 27) using immune precipitation using antibodies that bind MHC I peptide complexes where the antibodies are bound to Sepharose beads (col. 109, lines 60 – 67; col. 110, lines 34 – 42).
Mahr does not teach “endogenous MHC I-complexes obtained from a lysate prepared from one or more cancer cells” of claim 1 or “the endogenous MHC I-peptide complexes comprise a plurality of different MHC I-peptide complexes” of claim 2 or “the endogenous MHC I-peptide complexes comprise peptides from one or more tumor-specific antigens” of claim 4 or “the substrate particles are not bound to recombinantly expressed MHC complexes” of claim 6 or “contacting the lysate prepared from the one or more cancer cells with substrate particles” of claim 8. However, Mahr teaches isolating peptides from shock-frozen tumor tissue (“lysate prepared from one or more cancer cells”) using immune precipitation using antibodies that bind MHC I peptide complexes where the antibodies are bound to Sepharose beads (col. 109, lines 60 – 67; col. 110, lines 34 – 42). Mahr teaches the bead-bound peptide-loaded complex is an artificial antigen presenting cell (col. 175, lines 5 – 10). Mahr teaches dendritic cells have been used as antigen presenting cells to elicit an anti-tumor response where dendritic cells have been loaded ex vivo with tumor associated peptides or tumor cell lysate (col. 3, lines 9 – 12). Mahr teaches dendritic cells loaded with tumor cell lysate increased tumor-specific CD8+ T cell responses (col. 3, lines 15 – 20). Mahr teaches the stimulation method demonstrates that the peptides identified by immune precipitation and mass spectrometry are T cell epitopes against which CD8+ precursor T cells exist in humans (col. 110, lines 43 – 67; col. 111, lines 1 – 3; col. 175, lines 10 – 15). Mahr teaches the peptides loaded into the MHC complexes include a peptide from MART-1 (col. 175, lines 45 – 49). Mahr teaches active immunotherapy includes dendritic cell-based vaccines and tumor associated antigen (TAA)-derived peptide vaccines (col. 2, lines 64 – 67). Mahr teaches enhancing the anti-tumor immune response appears to be a promising strategy for the treatment of advanced melanoma but vaccination strategies need to be improved (col. 6, lines 5 – 7 and 24 – 27). Mahr teaches adoptive T cell transfer shows great promise for the treatment of advanced stage melanoma (col. 6, lines 31 – 36). Mahr teaches in vitro expanded T cells with a high affinity for the antigen NY-ESO-1 had significant beneficial and low toxic effects upon transfer into melanoma patients (col. 6, lines 31 – 36). Mahr teaches unfortunately T cells with high affinity for MART1 and gp100 and MAGEA3 induced considerable toxic effects in clinical trials (col. 6, lines 36 – 40). Mahr teaches adoptive T cell transfer has high therapeutic potential, but safety and tolerability of these treatments needs to be further increased (col. 6, lines 40 – 43).
Regarding “endogenous MHC I-complexes obtained from a lysate prepared from one or more cancer cells” of claim 1 and “the substrate particles are not bound to recombinantly expressed MHC complexes” of claim 6 and “contacting the lysate prepared from the one or more cancer cells with substrate particles” of claim 8, Mahdian teaches coculturing T cells with tumor lysate-pulsed dendritic cells (page 275, left col. para. 3 and right col. last para.; page 276, left col. para. 1). Mahdian teaches the tumor-lysate pulsed dendritic cells were bound to MHC I-peptide complexes endogenous to the tumor lysate because MHC class I antibody inhibited T cell proliferation (page 276, left col. para. 1; page 277, right col. para. 1; Figure 3). Mahdian teaches the T cells are CD8+ T cells and that stimulation of these cells with tumor lysate-pulsed dendritic cells produced activated CD8+ cytotoxic T cells that recognized specific antigens in melanoma cells, lysed melanoma cells, and produced IFN-γ (page 277, right col. last para.; Figure 4 and 6; page 278, right col.; page 279; page 280, right col. para. 1; page 281, left col. para. 2 – 3).
Regarding “the endogenous MHC I-peptide complexes comprise a plurality of different MHC I-peptide complexes” of claim 2 and “the endogenous MHC I-peptide complexes comprise peptides from one or more tumor-specific antigens” of claim 4, Mahdian teaches the melanoma lysate-stimulated T cells react to a plurality of known melanoma associated antigens (Figure 6; page 278, right col. para. 2) and therefore Mahdian teaches the MHC I-peptide complexes comprise a plurality of different MHC I-peptide complexes.
Mahdian teaches the T cells that were cocultured with the tumor lysate-pulsed dendritic cells secreted IFN-γ, reacted with multiple known melanoma antigens, including MART-1 of Mahr, and lysed melanoma cells (Figure 4 – 6; page 278, right col.; page 279). Mahdian teaches several tumor-associated antigen delivery methods to dendritic cells have been utilized with all methods showing induction of T-cell responses and clinical antitumor effects, but each method has potential limitations including the use of a single epitope (page 274, left col. para. 1). Mahdian teaches the use of tumor lysate may allow for the sensitization of T cells to a variety of antigens that may be heterogeneously expressed on growing tumors (page 274, left col. para. 1). Mahdian teaches their results provide preliminary evidence that a humanized melanoma cell line may serve as a standardized and validated polyclonal antigen source for stimulating antitumor T cells for clinical immunotherapy of melanoma patients (page 281, left col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Mahr regarding isolating endogenous MHC-peptide complexes from melanoma tumor lysate using immune precipitation with beads containing antibodies to MHC I and preparing artificial antigen presenting cells comprising beads with peptide-loaded MHC complexes and stimulating CD8+ T cells with the artificial antigen presenting cells with the teachings of Mahdian regarding a method of preparing tumor lysate-pulsed antigen presenting cells and activating T cells with the tumor lysate-pulsed antigen presenting cells to arrive at the claimed method of producing activated antigen-specific cytotoxic T cells, the method comprising contacting CD8+ T cells with a composition comprising substrate particles bound, via a polypeptide capable of specifically binding MHC, to endogenous MHC I-peptide complexes obtained from a lysate prepared from one or more cancer cells. One would have been motivated to combine the teachings of Mahr and Mahdian in a method of evaluating the therapeutic effect of a plurality of antigen-specific cytotoxic CD8+ T cells prepared by contacting T cells with artificial antigen presenting cells loaded with MHC I-peptide complexes from tumor lysate instead of a single peptide antigen as Mahr teaches enhancing the anti-tumor immune response appears to be a promising strategy for the treatment of advanced melanoma but vaccination strategies need to be improved and Mahr teaches adoptive T cell transfer shows great promise for the treatment of advanced stage melanoma and Mahdian teaches tumor-associated antigen delivery methods have potential limitations including the use of a single epitope and Mahdian teaches the use of tumor lysate may allow for the sensitization of T cells to a variety of antigens that may be heterogeneously expressed on growing tumors. One would have a reasonable expectation of success in combining the teachings as Mahr teaches the bead-bound peptide-loaded complex is an artificial antigen presenting cell and Mahr teaches dendritic cells loaded ex vivo with tumor cell lysate have been used as antigen presenting cells to elicit an anti-tumor response and Mahdian teaches the T cells that were cocultured with the tumor lysate-pulsed antigen presenting cells secreted IFN-γ, reacted with multiple known melanoma antigens, including MART-1 of Mahr, and lysed melanoma cells.
16. Claim(s) 17, 20, 21, and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mahr (US10576132B2; Filed 05/17/2018; Published 03/03/2020), hereinafter Mahr in view of Mahdian (Mahdian R, et. al.. Med Oncol. 2006;23(2):273-82), hereinafter Mahdian as applied to claims 1, 2, 4, 6, 8, 9, 11, 15, 16, 23, 27, and 29 above, and further in view of Steenblock (Steenblock, Erin R., et. al. Molecular Therapy 16.4 (2008): 765-772.), hereinafter Steenblock which is cited on the IDS filed 02/10/2022 in view of Meyer (Meyer RA, et. al. Small. 2015 Apr;11(13):1519-25), hereinafter Meyer.
Mahr in view of Mahdian make obvious the limitations of claim 1 and 23 as set forth above. Mahr does not teach the polystyrene beads are biodegradable of claim 17 or contacting the CD8+ T cells with the composition in vivo by administering the composition to a patient of claims 20 and 21 or administering the CD8+ T cells to a patient after the contacting of claim 25.
Regarding claim 17, Steenblock teaches an artificial antigen presenting cell (aAPC) that is biodegradable comprising bound peptide-MHC complexes and anti-CD28 via biotin-avidin interactions (Figure 1; page 771, left col. para. 2 – 4). Steenblock teaches the particle of the aAPC comprises a biodegradable polymer, PLGA (page 766, left col. para. 2 – 3 and right col. para. 1 – 2; page 771, left col. para. 2). Steenblock teaches contacting the aAPC with CD8+ T cells activated the CD8+ T cells (page 766, right col. para. 1; page 767, left col. and right col. para. 1; Figure 3 and 4; page 771, left col. last para. and right col. para. 1).
Steenblock teaches biodegradable polymer particulates are well suited for the design of an aAPC that is both easily generalized and highly optimized, possessing the essential features of professional cellular aAPCs with additional attractive properties including reproducible biodegradability without the addition of enzymes or cofactors and well-understood fabrication methodologies offering flexibility (page 770, left col. para. 2). Steenblock teaches a practical advantage of the acellular aAPC is its potential for long-term storage and transportation without loss of integrity (page 770, right col. last para.). Steenblock teaches these aAPCs represent a true “off-the-shelf” flexible technology that is amenable to both long-term storage and immediate use where aAPCs retain their stimulatory capacity for at least 1 week when stored at 4 °C (page 766, left col. para. 1; page 770, right col. para. 2). Steenblock does not teach contacting the CD8+ T cells with the composition in vivo by administering the composition to a patient of claims 20 and 21 or administering the CD8+ T cells to a patient after the contacting of claim 25. One would have been motivated to combine the teachings of Mahr and Steenblock because both teach aAPCs comprising beads made of polymers for activation of CD8+ T cells and because Steenblock teaches the biodegradable aAPCs retain their stimulatory capacity for at least 1 week when stored at 4 °C.
Regarding claims 20 and 22, Meyer teaches biodegradable nanoellipsoidal aAPCs (naAPCs) comprising PLGA particles with bound melanoma peptide-loaded MHC complexes and anti-CD28 that stimulate CD8+ T cells upon contacting in vitro and in vivo by injecting naAPCs in an adoptive immunotherapy murine model (page 3, para. 2 and 4; page 4, para. 1 – 2; Figure 1 and 2; page 6, para. 2 – 3; Figure 5; Supplementary Information page 3, last para. and page 6). Meyer teaches the naAPCs are more effective at antigen specific induction of cytotoxic T lymphocytes than spherical naAPCs and demonstrated stronger in vivo stimulation of immune cells and enhanced pharmacokinetic properties (page 6, last para.). Meyer teaches naAPCs achieved T cell activation and proliferation at a reduced overall protein dose offering an efficiency advantage (page 6, last para.; page 7, para. 1). Meyer teaches naAPCs resist hepatic and splenic elimination in vivo (page 7, para. 1). Meyer teaches the enhanced immune stimulatory capabilities and systemic biodistribution of ellipsoidal naAPCs make them a promising platform for “off the shelf” immunotherapy and nanomedicine (page 7, para. 1). Meyer teaches biodegradable aAPCs are more amenable for in vivo therapeutic use (page 3, para. 1).
Regarding claim 25, Meyer teaches administering PMEL CD8+ T cells along with the naAPC in an adoptive immunotherapy murine model (page 6, para. 2). Meyer teaches the ellipsoidal naAPCs mediated a 3-fold greater PMEL CD8+ T cell expansion in vivo compared to no aAPCs (page 6, para. 3; Figure 5; Supplementary Information page 6).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Mahr regarding isolating endogenous MHC-peptide complexes from melanoma tumor lysate using immune precipitation with beads containing antibodies to MHC I and preparing artificial antigen presenting cells comprising beads with peptide-loaded MHC complexes and stimulating CD8+ T cells with the artificial antigen presenting cells with the teachings of Mahdian regarding a method of preparing tumor lysate-pulsed antigen presenting cells and activating T cells with the tumor lysate-pulsed antigen presenting cells with the teachings of Steenblock regarding aAPCs comprising a biodegradable particle comprising a polymer that retains their stimulatory capacity for at least 1 week when stored at 4 °C with the teachings of Meyer regarding administering melanoma antigen-specific CD8+ T cells and biodegradable naAPCs in vivo result in expansion of the melanoma antigen-specific CD8+ T cells to arrive at the claimed method wherein the substrate particles are biodegradable and contacting occurs in vivo by administering the composition to a patient and administering the CD8+ T cells to a patient after the contacting. One would have been motivated to combine the teachings of Mahr, Mahdian, Steenblock, and Meyer in a method of in vivo expansion of melanoma antigen-specific CD8+ T cells for treating melanoma as Mahr teaches adoptive T cell transfer shows great promise for the treatment of advanced stage melanoma and Steenblock teaches biodegradable polymer particulates are well suited for the design of an aAPC possessing the essential features of professional cellular aAPCs and Meyer teaches biodegradable aAPCs are more amenable for in vivo therapeutic use. One would have a reasonable expectation of success in combining the teachings as Mahr teaches the polymeric bead-bound peptide-loaded complex with anti-CD28 is an artificial antigen presenting cell that activates CD8+ T cells and Steenblock teaches biodegradable aAPC comprising bound peptide-MHC complexes and anti-CD28 activates CD8+ T cells and Meyer teaches the naAPC mediated a 3-fold greater PMEL CD8+ T cell expansion in vivo compared to no aAPCs.
Oath/Declaration
17. The declaration under 37 CFR 1.132 filed 03/30/2026 is insufficient to overcome the rejection of claims 1, 2, 4, 6, 8, 9, 11, 15 – 17, 20, 22, 23, 25, 27, 29, and 31 based upon the Purcell reference applied under 35 U.S.C. 103 as set forth in the last Office action because: the declaration fails to set forth facts regarding why the immunoaffinity captured MHC class I complex with bound antigen from lysate of Purcell is not able to be contacted with T cells to produce activated antigen-specific cytotoxic T cells.
Declaration states: Dr. Igyarto states that he would not take beads meant to be discarded as being useful for other processes and nothing in Purcell would lead him to believe that the purification beads could be used as artificial antigen presenting cells as there is no indication in Purcell that the purification beads have use outside of their analytical purpose. Dr. Igyarto states that he would not be able to predict how the MHC-peptide complexes on the beads may change if placed in cell culture media. Dr. Igyarto states that he would not have taken Purcell’s beads as being interchangeable with PLGA microparticles of Fahmy.
Response to Declaration: In response, claim 1 broadly recites “substrate particles” that encompass the Protein A beads of Purcell and the PLGA beads of Fahmy both of which capture endogenous peptide-bound MHC class I complexes. Purcell teaches isolation and characterization of naturally processed MHC-bound peptides from the surface of antigen-presenting cells (title of publication). Purcell teaches the naturally occurring in vivo process for generating activated CTLs includes peptides derived from both self and foreign antigens are assembled with MHC class I molecules which are then transported to the cell surface where they are scrutinized by CD8+ cytotoxic T lymphocytes and should the peptide ligand be derived from a pathogen and be recognized as foreign in an immunocompetent host, the cell is killed via the cytotoxic armory of the CTL (page 291). Therefore, Purcell teaches that in vivo, peptide-loaded MHC class I molecules interact with CD8+ T cells and activate these cells leading to killing of the cells having the peptide. Purcell teaches obtaining these peptide-loaded MHC class I molecules by immunoaffinity. Therefore, one of ordinary skill in the art would recognize that beads containing the peptide-loaded MHC molecules are antigen presenting particles and that in addition to identifying the peptide antigen, the beads could also be used to produce CTLs in vitro. Further, Dr. Igyarto states that “affinity beads can be used to pull down peptide-MHC directly from cell lysates, and it is a viable option to generate patient-specific aAPCs in matters of days at minimal costs”. Therefore, Applicant is stating that the affinity beads of Purcell and Fahmy can be used as aAPCs. Should Applicant present evidence that peptide-loaded MHC complexes captured on immunoaffinity beads or PLGA beads cannot form CTLs in vitro, or should Applicant amend claim 1 to narrow the breadth of “substrate particles” to exclude Protein A beads or PLGA beads, the rejection may be overcome upon further consideration.
Applicant Arguments/ Response to Arguments
18. Applicant argues: Applicant argues that the Action does not provide a rational underpinning for why one skilled in the art would be motivated to use the purification beads of Purcell in protocols described in other references. Applicant asserts that one skilled in the art would not have a reasonable expectation of success when modifying or combining the references. Applicant asserts that the claimed method is a non-obvious solution to immune cell activation that does not require the identification of any MHC-bound peptides, which is in direct contrast to the teachings of the cited references.
Response to arguments: One skilled in the art would be free to use the peptide-loaded MHC complexes bound to Protein A beads for other purposes, and not be required to only use the beads to identify the peptide antigen. As stated in the previous Office Action, one would have been motivated to combine the teachings of Purcell and Fahmy as Fahmy teaches there are currently no aAPC technologies that exist that incorporate all of the necessary signals for T cell activation in a safe, ready-to-use system that could be rapidly modified for antigen-specific T cell activation and expansion and Purcell teaches immunoaffinity isolation of peptide-loaded MHC class I complexes.
Claim 1 broadly recites “substrate particles” which encompass the beads of both Purcell and Fahmy. One skilled in the art would recognize that the peptide-loaded MHC class I complexes on beads of Purcell and Fahmy are the equivalent of antigen presenting cells where the bead acts as the cell presenting the loaded MHC complex based on the previously cited teachings of Purcell regarding MHC class I peptide loaded complexes are scrutinized by CD8+ cytotoxic T lymphocytes (CTLs) and should the peptide be foreign, the cell is killed via the CTLs (page 291); and Purcell teaches CD8+ T cells recognize MHC class I molecules (page 292, para. 1). Therefore, one of ordinary skill in the art would have a reasonable expectation of success in combining the teachings to predictably form CTLs by contacting bead-bound peptide-loaded MHC class I complexes with CD8+ T cells. Applicant states that “affinity beads can be used to pull down peptide-MHC directly from cell lysates, and it is a viable option to generate patient-specific aAPCs in matters of days at minimal costs”. Should Applicant provide evidence that the peptide-loaded MHC class I complexes on beads of Purcell and Fahmy cannot form CTLs (e.g., do not maintain “biological activity for use as aAPCs generally” or “affect protein conformation and MHC-peptide binding”), or amend claim 1 to narrow the breadth of “peptide”, the rejection may be overcome upon further consideration.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
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