DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/17/2025 has been entered.
Claims 2-3, 5-24, and 26-27, of record 11/17/2025, are pending and subject to prosecution. Claims 2 and 26 are amended. Claims 25 and 29 are cancelled.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 2-3, 5-8, 10-13, 17-20, 23-27, and 29 under 35 U.S.C. 103 over Berenson et al. (US 20060121005 A1), evidenced by Altman et al. (Science, 1996):
RE: Rejection of claims 2-3, 5-13, 17-21, 23-27, and 29 under 35 U.S.C. 103 over Berenson et al. (US 20060121005 A1), evidenced by Altman et al. (Science, 1996), in view of Li et al. (Journal of Immunology, 2005):
RE: Rejection of claims 2-3, 5-8, 10-20, 23-27, and 29 under 35 U.S.C. 103 over Berenson et al. (US 20060121005 A1), evidenced by Altman et al. (Science, 1996), in view of Santamaria (US 20170095544 A1):
RE: Rejection of claims 2-3, 5-8, 10-13, 17-20, 22-27, and 29 under 35 U.S.C. 103 over Berenson et al. (US 20060121005 A1), evidenced by Altman et al. (Science, 1996), in view of Chain et al. (Journal of Immunological Methods, 1987):
The cancellation of claims 25 and 29 renders the rejection thereto moot.
The applicant asserts that one of ordinary skill in the art would not have been able to unambiguously derive the claimed liganded surface area from the disclosure of Berenson et al., which teaches bead-cell ratios in embodiments (Applicant Remarks, page 9-11). Upon further consideration, the rejections are withdrawn.
The applicant further asserts that Berenson et al. do not suggest limiting the area of an antigen-presenting covalently functionalized region (or a benefit therein) (Applicant Remarks, page 10), which is not convincing of error. The applicant’s assertion is not altogether accurate, as Berenson et al. teach that a first or second or more surfaces can be utilized with or without ligands or agents bound thereto (See ¶0081). As applied to a plate or tissue culture dish (See ¶0150 and 0153), this teaching suggests that the entire planar substrate exposed to the cells need not be covered with activating ligand and is thus limited. The teachings of Berenson et al. remain relevant over the pending claims.
New 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2-3, 5-8, 10-13, 17-20, 23-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson et al. (US 20060121005 A1), of record, evidenced by Corning (Product data sheet, 2023) and Altman et al. (Science, 1996), of record, in view of Stone et al. (Proceedings of the National Academy of Sciences, 2005) and Deviren et al. (Journal of Molecular Recognition, 2007).
Regarding claims 2-3, 5, 10-13, and 26-27: Berenson et al. teach the activation and expansion of a cell population (which reads on “converting at least a portion… to activated T cells”) such as CD8+ T cells (which read on “plurality of T cells” and “a lymphocyte”) using agents attached to a surface (which reads on “a first region”) (See ¶0011 and 0084). The cell population can also comprise B cells or NK cells (See ¶0018 and 0084). The agents can be coupled to the surface by covalent attachment (which reads on “covalently functionalized” and “linked to the surface”) (See ¶0152). The surface can be a plate (which reads on “well plate”) or tissue culture dish (See ¶0150 and 0153). The agents can be first, second, and third agents, wherein the first agent is an anti-CD2 antibody or fragment thereof (which reads on “co-activating molecular ligands” and “an adjunct TCR activating molecule”), the second agent is an anti-CD28 antibody or fragment thereof (which reads on “co-activating molecular ligands” and “a TCR co-activating molecule”), and the third agent is an MHC dimer or a peptide-MHC tetramer (which read on “primary activating molecular ligands” and “MHC molecule configured to bind to a TCR of a T cell”) (See ¶0015). Berenson et al. teach that a first, second, or more surfaces can be used without any ligands or agents bound thereto (See ¶0081). The cells can be concentrated or aggregated at a surface to promote ligation and binding-mediated cellular signaling events or activation (See ¶0069, 0080, and 0090). Means to bring the cells and ligands together in a concentrated fashion are available in the art (See ¶0090). Berenson et al. do not expressly teach the dimensions occupied by the T cell activating agents on a plate surface.
Stone et al. teach a microarray for screening specific antigen recognition and functional activity in T cells (See Abstract and page 3745, col. 2, 1). Solutions comprising peptide-MHC tetramers and an anti-CD28 antibody for co-stimulatory or an anti-CD11a or anti-CD2 antibody for adhesion were spotted onto a substrate (See page 3744, col. 2, full ¶4 and page 3745, col. 1, ¶1). Each spot had an approximate area of 0.44 mm2 (See page 3747, col. 1, ¶1).
Deviren et al. teach an approach for optimizing the reproducibility of T cell binding and activation assays, like those taught by Stone et al. (See page 32, col. 2, ¶1 and page 33, col. 1, ¶1-3). Deviren et al. teach a surface comprising circular regions approximately 100 µm or 1-1.5 mm in diameter (which reads on spotted with peptide-MHC complexes that can be used for assays (See page 37, col. 1, full ¶1 and fig. 1-2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al. to comprise the use of plates having T cell stimulating agent-bound areas of 0.44 mm2 or 0.79-1.77 mm2 (corresponding to the areas of 1-1.5 mm-diameter circles), such as are taught by Stone et al. and Deviren et al. One would be motivated to make this modification because Stone et al. (See fig. 2-3) and Deviren et al. (fig. 1-2) demonstrate that these areas of these particular sizes bearing T cell-stimulating ligands are effective for capturing and/or activating T cells. There would be a reasonable expectation of success in making this modification because the Berenson et al. teach that the immobilized ligands can be used for concentration or aggregation of the cells and that aspects of the surface can be used without any ligands bound thereto (See ¶0069, 0081-0082, 0084, and 0090).
While “an area of 2 mm2 to not more than 35 mm2” is not expressly taught, a prima facie case of obviousness exists where the claimed ranges do not overlap but are merely close. See MPEP 2144.05(I). Berenson et al. also do not expressly teach the type of plate that can be used, however, the use of standard well plates ranging from 6 well (well diameter 34.8 mm, well area 951 mm2) to 96 well (well diameter 4.26 mm, well area 14.25 mm2) (See Corning product sheet, page 2) would read on “wherein an area of the antigen-presenting functionalized region is less than about 25% of an area of a bottom surface of a well of the well plate”.
Regarding claims 6 and 17: Following the discussion of claims 2-3, 5, 10-13, and 26-27, Berenson et al. teach that the anti-CD3 antibody and the anti-CD28 antibody can be present at a ratio of about 1:1 to about 1:100 (which reads on “the ratio… is 3:1 to 1:3”) (See ¶0014). Where the claimed ranges overlap or lie inside ranges disclosed by the prior art, a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claim 7: Following the discussion of claims 2-3, 5, 10-13, and 26-27, Berenson et al. teach the use of peptide (which reads on “an antigenic peptide”)-MHC tetramers and reference Altman et al. (See ¶0092). Altman et al. is cited solely as evidence to show that peptide-MHC tetramers can be made of monomers comprising a HLA-A2 heavy chain (which reads on “MHC class I protein sequence”), β-2-microglobulin (which reads on “beta microglobulin”), and a peptide antigen (See page 94, col. 2, ¶1).
Regarding claim 8: Following the discussion of claims 2-3, 5, 10-13, and 26-27, Berenson et al. do not expressly teach peptide-MHC tetramers as comprising a peptide of tumoral or microbial origin. However, Berenson et al. teach that the T cell responsiveness can be induced or enhanced toward infectious organisms such as viruses, bacteria, fungi, and protozoan pathogens (See ¶0192).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al. to comprise the use of a microbial antigenic peptide in MHC tetramers. One would be motivated to make this modification because Berenson et al. teach that the T cells activated and expanded by this method can be used for treating microbial infections (See ¶0192). There would be a reasonable expectation of success in doing so because peptides of viral, bacterial, fungal, or protozoal origin could be readily used in the method of Berenson et al.
Regarding claim 18: Following the discussion of claims 2-3, 5, 10-13, and 26-27, Berenson et al. teach an embodiment wherein T cell activation can be enhanced by stimulation of other T cell integral membrane proteins such as the interaction of T cell integrin LFA-1 with its natural ligand ICAM-1 (which reads on “contacting the plurality of T cells with a plurality of adhesion-stimulating molecular ligands” and “an ICAM molecule”) (See ¶0097).
Regarding claims 19-20: Following the discussion of claims 2-3, 5, 10-13, and 26-27, Berenson et al. teach that additional molecules for T cell stimulation can include cytokines, soluble receptors, and growth factors (which read on “growth stimulatory molecular ligands” and “growth factor receptor ligand”) (See ¶0092, 0096, and 0121).
Regarding claim 23: Following the discussion of claims 2-3, 5, 10-13, and 26-27, Berenson et al. teach that stimulation and expansion can be carried out for 6 days or less or for 4 days or less (which read on “a period from about four days to about seven days”) (See ¶0132).
Regarding claim 24: Following the discussion of claims 2-3, 5, 10-13, and 26-27, Berenson et al. teach that the T cell population can be enriched for markers such as CD45RO (which reads on “the activated T cell is CD45RO+”) (See ¶0175).
Claims 2-3, 5-13, 17-21, 23-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson et al. (US 20060121005 A1), of record, evidenced by Corning (Product data sheet, 2023) and Altman et al. (Science, 1996), of record, in view of Stone et al. (Proceedings of the National Academy of Sciences, 2005) and Deviren et al. (Journal of Molecular Recognition, 2007), further in view of Li et al. (Journal of Immunology, 2005), of record.
The teachings of Berenson et al., Corning, Altman et al., Stone et al., and Deviren et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 9: Following the discussion of claims 2-3, 5-8, 10-13, 17-20, 23-4, and 26-27, Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., teach the activation and expansion of T cells using peptide-MHC tetramers but do not teach the peptide as derived from SLC45A2, TCL1, VCX3A, MART-1, or NY-ESO-1.
Li et al. teach MHC tetramers comprising a MART-1 peptide or NY-ESO-1 peptide for identifying antigen-specific T cells (See Abstract and fig. 1-4 and 10).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., to comprise MART-1 or NY-ESO-1 peptide-MHC tetramers, such as are taught by Li et al., for expanding T cells. One would be motivated to make this modification because Berenson et al. teach that the T cells can be directed against tumors (See ¶0182, 0194, and 0199) and because Li et al. demonstrate that the complex is recognized by tumor antigen-specific T cell receptors (See page 2265, col. 1, full ¶2). There would be a reasonable expectation of success in doing so because the peptide-MHC tetramers of Berenson et al. could be readily loaded with a MART-1 or NY-ESO-1 peptide.
Regarding claim 21: Following the discussion of claims 2-3, 5-8, 10-13, 17-20, 23-24, and 26-27, Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., do not teach the culture of T cells in the presence of IL-21.
Li et al. teach that the addition of IL-21 to T cell cultures increased the numbers of antigen-specific T cells (See Abstract and fig. 3-4, 6, and 8).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., to comprise the addition of IL-21 to T cell cultures. One would be motivated to make this modification because Li et al. teach increased T cell expansion in the presence of IL-21 (See Abstract and fig. 3-4, 6, and 8). There would be a reasonable expectation of success in doing so because IL-21 could be readily added to the T cell cultures of Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al.
Claims 2-3, 5-8, 10-20, 23-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson et al. (US 20060121005 A1), of record, evidenced by Corning (Product data sheet, 2023) and Altman et al. (Science, 1996), of record, in view of Stone et al. (Proceedings of the National Academy of Sciences, 2005) and Deviren et al. (Journal of Molecular Recognition, 2007), further in view of Santamaria (US 20170095544 A1), of record.
The teachings of Berenson et al., Corning, Altman et al., Stone et al., and Deviren et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 14: Following the discussion of claims 2-3, 5-8, 10-13, 17-20, 23-24, and 26-27, Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., teach the use of immobilized peptide-MHC tetramers for activating and expanding T cells but do not teach the density of MHC molecules attached to the substrate.
Santamaria teaches nanoparticles for expanding and differentiating T cell populations have a peptide-MHC density of about 0.025-100 per 100 nm2 (See ¶0006 and 0008-0009), which corresponds to about 250-1,000,000 peptide-MHC molecules per µm2.
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., to comprise using a density of about 250-1,000,000 peptide-MHC monomers per µm2, such as is taught by Santamaria, or about 60-250,000 peptide-MHC tetramers per µm2 attached to a substrate for culturing T cells. One would be motivated to make this modification because Santamaria suggests that such a density is appropriate for expanding T cells (See ¶0006 and 0008-0009). There would be a reasonable expectation of success in doing so because the method of Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., could be readily modified to comprise a substrate having this peptide-MHC density.
Regarding claim 15: Following the discussion of claims 2-3, 5-8, 10-14, 17-20, 23-27, and 29, Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., do not teach a density for co-activating ligands on the substrate for T cell activation and expansion.
Santamaria teaches nanoparticles wherein the density of co-stimulatory molecules on the surface is about 0.0022-13.26 molecules per 100 nm2 (See ¶0225), which corresponds to about 22-132,600 molecules per µm2.
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al. to comprise using a density of about 22-132,600 co-stimulatory molecules per µm2, such as is taught by Santamaria, attached to a substrate for culturing T cells. One would be motivated to make this modification because Santamaria suggests that such a density is appropriate for expanding T cells (See ¶0225). There would be a reasonable expectation of success in doing so because the method of Berenson et al. could be readily modified to comprise a substrate having this co-stimulatory molecule density.
Regarding claim 16: Following the discussion of claims 2-3, 5-8, 10-14, 17-20, 23-27, and 29, Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., do not teach a ratio of primary activating molecular ligands to co-activating molecular ligands.
Santamaria teaches nanoparticles wherein the ratio of co-stimulatory molecules to peptide-MHC complexes (which reads on “primary activating molecular ligands”) can range from about 0.1:1 to 100:1 (See ¶0225).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al. to comprise using a ratio of 0.1:1 to 100:1 co-stimulatory molecules to peptide-MHC complexes, such as is taught by Santamaria, for activating and expanding T cells. One would be motivated to make this modification because Santamaria suggests that such a ratio is appropriate for expanding T cells (See ¶0225). There would be a reasonable expectation of success in doing so because the method of Berenson et al. could be readily modified to comprise a substrate having such ratios of co-stimulatory molecules to peptide-MHC complexes.
Claims 2-3, 5-8, 10-13, 17-20, 22-24, and 27-27 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson et al. (US 20060121005 A1), of record, evidenced by Corning (Product data sheet, 2023) and Altman et al. (Science, 1996), of record, in view of Stone et al. (Proceedings of the National Academy of Sciences, 2005) and Deviren et al. (Journal of Molecular Recognition, 2007), further in view of Chain et al. (Journal of Immunological Methods, 1987), of record.
The teachings of Berenson et al., Corning, Altman et al., Stone et al., and Deviren et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 22: Following the discussion of claims 2-3, 5-8, 10-13, 17-20, 23-24, and 26-27, Berenson et al. teach that additional stimulatory molecules such as IL-2 can be added to the culture but do not express teach their addition following at least one day of culturing (See ¶0012, 0121, and 0262).
Chain et al. teach that antigen-specific T cell proliferation is increased by culturing T cells in the presence of antigen for three days prior to expansion in the presence of IL-2 (See Abstract; page 225, col. 1-2 and page 226, col. 1, ¶1; and fig. 3-4).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Berenson et al., evidenced by Corning and Altman et al., and modified by Stone et al. and Deviren et al., to comprise the addition of IL-2 approximately three days (which reads on “at least one day”) after first contacting the T cells with peptide-MHC tetramers. One would be motivated to make this modification because Chain et al. teach that adding IL-2 several days after first contacting cells with antigen increases the proliferation of antigen-specific cells over non-specific cells (See Abstract; page 225, col. 1-2 and page 226, col. 1, ¶1; and fig. 3-4). There would be a reasonable expectation of success in making this modification because the addition of molecules such as IL-2 could readily be performed in this manner.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633