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 .
Status of the Claims
Claims 1-2 and 4-5 are pending. Claim 1 is amended. Claims 3 and 6-12 are canceled. Accordingly, claims 1-2 and 4-5 are examined herein.
Priority
The present application, filed 09/07/2023, is a 371 of PCT/EP2022/056463, filed 03/14/2022, which claims foreign priority of EP21163172.6, filed 03/17/2021. The priority is acknowledged and the claims examined herein are treated as having an effective filing date of 03/17/2021.
Maintained 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
The rejection of claims 1, 2, 4, and 5 under 35 U.S.C. § 103 is maintained, but has been updated in view of Applicant’s amendment to claim 1 requiring that the effector molecule is IFNγ.
Claims 1-2 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Oelke et al. (WO2017161092A1) in view of Hauskins et al. (WO2018023100A2).
Regarding claim 1, Oelke et al. teaches methods for activating and expanding engineered T cells, including CAR-expressing T cells, using paramagnetic artificial antigen-presenting nanoparticles. In particular, Oelke et al. states that “the invention provides methods for expanding antigen-specific T cell populations for adoptive immunotherapy, including engineered T cells that express a heterologous T cell receptor or a chimeric antigen receptor (CAR)” (paragraph 4, page 3). Oelke et al. further teaches the use of surface-presented ligands on nanoparticles, stating that “the method comprises magnetically enriching and/or magnetically expanding a heterogeneous T cell population with paramagnetic nanoparticles having an MHC-peptide antigen presenting complex on the surface” (paragraph 5, page 8). Furthermore, Oelke et al. discloses incubation in which “in various embodiments, the process of enrichment and expansion includes magnetic activation, in which paramagnetic nano-aAPCs harboring signal 1 and signal 2 (either on the same of different populations of nanoparticles) are incubated in the presence of a magnetic field. The incubation in the presence of a magnetic field generally takes place for at least 5 minutes, or at least 10 minutes, or at least 15 minutes, or at least 30 minutes, or at least one hour, or at least 2 hours” (paragraph 1, page 7). Also, Oelke et al. teaches magnetic clustering during incubation, stating that “incubation of paramagnetic nano-aAPCs in the presence of a magnetic field, either during enrichment and/or expansion steps, activates T cells through magnetic clustering of paramagnetic particles on the T cell surface” (paragraph 3, page 3). Lastly, Oelke et al. teaches costimulatory molecules, stating that “in certain embodiments, signal 2 is a T cell costimulatory molecule. T cell costimulatory molecules contribute to the activation of antigen-specific T cells. Such molecules include, but are not limited to, molecules that specifically bind to CD28 (including antibodies)” (paragraph 2, page 21).
Additionally, Oelke et al. teaches that CD8+ lymphocytes stimulated with artificial antigen-presenting cells produce IFNγ, stating that “CD8+ lymphocytes enriched and expanded in accordance with embodiments of the invention produce proinflammatory markers such IFNγ, TNFa, IL-2, MIP-1B, GrzB, and/or perforin when stimulated with aAPCs loaded with cognate antigen” (paragraph 4, page 8).
Although Oelke et al. teaches a substrate (paramagnetic nanoparticle) having a surface-presented activating ligand and a costimulatory molecule such as anti-CD28, and further teaches that CD8+ lymphocytes stimulated with artificial antigen-presenting cells produce IFNγ - Oelke et al. does not disclose the specific use of anti-CAR idiotype antibodies as the activating surface ligand, nor does Oelke et al. expressly disclose activating the CAR-T cells to express effector molecules, wherein the effector molecule is IFNγ.
On the other hand, Hauskins et al. teaches anti-idiotype antibodies that specifically bind chimeric antigen receptors (CARs). In particular, Hauskins et al. discloses that “the present disclosure relates in some aspects to anti-idiotype antibodies that specifically recognize anti-CD19 antibody moieties, in particular, anti-CD19 antibody moieties present in recombinant receptors, including chimeric antigen receptors (CARs)” (paragraph [0003], page 3). Hauskins et al. further teaches stimulation of CAR-expressing cells, stating that “also among the provided methods are methods for stimulating cells using the agents, such as stimulating cells containing a molecule such as a CAR that is or contains the target antibody recognized by the anti-idiotype antibody” (paragraph [0053], page 16). Additionally, Hauskins et al. teaches immobilization of such antibodies on a solid substrate, stating that “in some embodiments, the anti-idiotype antibody or antigen-binding fragment thereof is immobilized to a solid support” (paragraph [0467], page 142).
Furthermore, Hauskins et al. expressly teaches that stimulation of CAR-expressing T-cells with anti-idiotype antibody-coated beads induces IFNγ expression, stating that “as shown in FIG. 10A, intracellular cytokine levels of TNFα, IFNγ and IL2 cytokines were induced in CAR+ T cells (EGFRt+), but not in CAR-T cells (EGFR-), when the cells were cultured in the presence of the anti-ID B-1 conjugated beads” (paragraph [0587], page 208). Hauskins et al. additionally concludes that “these results demonstrated that anti-ID conjugated to beads are agonistic and specifically stimulate T cells expressing a CAR having an antigen-binding domain recognized by the anti-ID antibody” (paragraph [0587], page 208). Thus, Hauskins et al. teaches anti-CAR idiotype antibodies immobilized on a solid support that specifically stimulate CAR-expressing T cells and induce IFNγ expression in the CAR+ T cells following stimulation.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Oelke et al. by replacing the MHC-peptide antigen presenting complex on the surface of the paramagnetic nanoparticles with an anti-CAR idiotype antibody as taught by Hauskins et al. in order to directly activate CAR-expressing T cells through engagement of their chimeric antigen receptor. Oelke et al. teaches a nanoparticle-based artificial antigen-presenting cell (aAPC) system designed to activate T cells by presenting a surface ligand (signal 1) together with a costimulatory molecule (signal 2, e.g., anti-CD28). The mechanism described in Oelke et al. relies on receptor engagement and clustering on the T cell surface to trigger activation and expansion. Hauskins et al. teaches that anti-idiotype antibodies specifically bind CAR molecules and can stimulate CAR-expressing T cells, including inducing intracellular IFNγ expression in CAR+ T cells following stimulation with anti-ID B-1-conjugated beads, resulting in activation and functional responses. Both references operate within the same field of CAR-T cell activation and expansion and address methods of stimulating engineered T cells through receptor engagement. Substituting one known receptor-binding ligand (MHC-peptide) with another known receptor-binding ligand (anti-CAR idiotype antibody) for the purpose of activating engineered CAR T cells constitutes a predictable design choice within a known activation platform. Oelke et al. explicitly contemplates modular presentation of activation signals on nanoparticles, and Hauskins et al. provides a known ligand capable of specifically engaging CAR receptors. The modification does not change the fundamental operating principle of Oelke et al.’s nanoparticle system; it merely substitutes the identity of the receptor-binding ligand presented on the nanoparticle surface in order to target CAR receptors specifically. Such substitution would have been an obvious variation motivated by the desire to selectively activate CAR-expressing T cells rather than relying on endogenous T cell receptor (TCR) recognition.
Lastly, a person having ordinary skills in the art (PHOSITA) would have had a reasonable expectation of success in making this modification. First, Oelke et al. demonstrates that nanoparticle-based artificial APC systems activate T cells through surface ligand engagement and magnetic clustering. The activation mechanism depends on receptor binding and costimulation, not on the specific identity of the MHC-peptide ligand itself. Second, Hauskins et al. demonstrates that anti-CAR idiotype antibodies bind CAR receptors and stimulate CAR-expressing cells, with experimental evidence that intracellular IFNγ is induced in CAR+ T cells, but not CAR- T cells, following stimulation with anti-ID B-1-conjugated beads, confirming that CAR receptors can be directly stimulated via anti-idiotype antibodies. Third, both references describe well-understood immunological principles: receptor engagement combined with costimulatory signaling leads to T cell activation. Receptor clustering is known to enhance activation signaling. Since Oelke et al. already uses magnetic clustering to enhance activation and Hauskins et al. confirms that anti-idiotype antibodies can stimulate CAR receptors and induce IFNγ expression in stimulated CAR+ T cells, combining these teachings would have predictably resulted in activation of CAR T cells expressing IFNγ and other activation markers. The modification requires no change in the nanoparticle architecture, magnetic field application, or costimulatory signaling disclosed by Oelke et al. It simply substitutes a known CAR-binding ligand in place of an MHC-peptide ligand. Given the routine and predictable nature of receptor-ligand mediated T cell activation in the art at the time of filing, a skilled artisan would reasonably expect successful activation of CAR T cells using anti-CAR idiotype antibody-coated nanoparticles with CD28 costimulation.
Regarding claim 4, Oelke et al. teaches detection and identification of antigen-specific T cells by flow cytometry following expansion with artificial antigen-presenting nanoparticles. Specifically, Oelke et al. states that “the expanded T cells are then sorted (e.g., by flow cytometry) with the MHC-peptide ligand, to obtain a T cell population that is highly enriched for antigen-specific TCRs” (paragraph 1, page 9). Oelke et al. further discloses that “antigen-specific T cells which are bound to the aAPCs can be separated from cells which are not bound using magnetic enrichment, or other cell sorting or capture technique. Other processes that can be used for this purpose include flow cytometry and other chromatographic means” (paragraph 4, page 30).
Regarding claim 5, Oelke et al. teaches that signal 1 and signal 2 may be provided on separate nanoparticles, stating that “FIGURE 5 shows that signal 1 and signal 2 can support T cell expansion even when present on separate nanoparticles (A, left panel), and that the resultant CD8 T cells are equivalent to those activated by aAPC presenting both signals (A, right panel)” (Figure 5, page 5). Oelke et al. further states that co-stimulatory ligands may be placed on the same or separate nanoparticles. In particular, Oelke et al. states that “combinations of co-stimulatory ligands that may be employed (on the same or separate nanoparticles) include anti-CD28/anti-CD27 and anti-CD28/anti-41BB. The ratios of these co-stimulatory ligands can be varied to effect expansion” (paragraph 3, page 21). Lastly, Oelke et al. discloses that more than one nano-aAPC may be used during incubation, stating that “optionally, a cell population comprising antigen-specific T cells can continue to be incubated with either the same nano-aAPC or a second nano-aAPC for a period of time sufficient to form a second cell population comprising an increased number of antigen-specific T cells relative to the number of antigen-specific T cells in the first cell population” (paragraph 5, page 32).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Oelke et al. and Hauskins et al., as applied to claim 1 above, and further in view of Shen et al. (Frequency and Reactivity of Antigen-Specific T Cells Were Concurrently Measured through the Combination of Artificial Antigen-Presenting Cell, MACS and ELISPOT. Scientific Reports. Vol. 7, No. 1, November 2017).
With respect to the teachings of Oelke et al. and Hauskins et al., see the discussion above, which applies equally here. These references differ from the instant claim in failing to teach or specify that the particles have a mean diameter of at least 0.4 µm.
However, Shen et al. teaches cell-sized magnetic beads having a diameter well above 0.4 µm. In particular, Shen et al. discloses that “the magnetic Dynabead M-450 Epoxy with a diameter of 4.5 μm is hydrophobic and covered with surface epoxy groups” (Results, paragraph 1, page 2). Shen et al. further teaches using such beads as artificial antigen-presenting cell beads by coupling activation and costimulatory ligands onto the bead surface, stating that “we developed an artificial antigen-presenting cell microplate (termed AAPC-microplate) by co-coupling pMHC multimers and anti-CD28 mAbs onto magnetic beads” (paragraph 2, page 2). Lastly, Shen et al. teaches incubation of the beads with cells under conditions consistent with a bead/cell suspension, stating that “AAPC-beads were seeded into the microplate containing CD8+ T cells and co-incubated for 2 hrs on a mild shaker at RT” (Materials and Methods, paragraph 4, page 11).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Oelke et al., as combined with Hauskins et al., to provide the claimed substrate as particles having a mean diameter of at least 0.4 µm as taught by Shen et al. As discussed above, Oelke et al. teaches nanoparticle-based artificial antigen-presenting systems that present activation and costimulatory ligands on particle surfaces to stimulate immune cells. Hauskins et al. teaches the use of anti-CAR idiotype antibodies to activate CAR-expressing cells. Shen et al. likewise teaches artificial antigen-presenting particles that present activation and costimulatory ligands on magnetic beads to stimulate T cells. Since both Oelke et al. and Shen et al. operate within the same field of particle-based immune activation systems, a PHOSITA would recognize that particle size represents a known and routinely adjustable design parameter that can be selected based on desired cell-particle characteristics. Shen et al. teaches that magnetic beads having a diameter of approximately 4.5 µm can be used as artificial antigen-presenting cell particles that present activation and costimulatory ligands to immune cells. These particles are substantially larger than the minimum size recited in claims 2 and 7. A PHOSITA would have understood that larger particle sizes can improve the physical interaction between particle substrate and immune cells by increasing available ligand presentation surface area and facilitating multivalent receptor engagement. Since receptor clustering and signal strength in immune activation systems depend on ligand density and spatial organization, selecting particle sizes within the micrometer range would have been recognized as a practical approach to improving or maintaining effective receptor engagement. Furthermore, particle size selection in nanoparticle-based immune activation systems is a routine engineering consideration that can be modified without altering the underlying chemistry or biological mechanism of activation. The same ligands, surface chemistries, and coupling methods taught by Oelke et al. can be applied to particles of varying sizes. Shen et al. demonstrates that micrometer scale beads can successfully function as artificial antigen-presenting cells. Thus, a skilled artisan would have been motivated to implement particles sizes equal to or greater than 0.4 µm in the Oelke et al. system as a predictable variation within the same particle-based immune activation platform. Accordingly, modifying the particle substrates of Oelke et al. to have a mean diameter of at least 0.4 µm as taught by Shen et al. would have been a routine and predictable design choice motivated by the desire to provide effective immune cell engagement in artificial antigen-presenting particle systems.
Lastly, a PHOSITA would have had a reasonable expectation of success in making this modification because both systems (Oelke et al. and Shen et al.) rely on the same fundamental biological mechanism: immune cell activation through receptor engagement with ligands presented on particle surfaces. The modification does not involve introducing new ligands, new coupling chemistries, or new biological pathways. Rather, it merely involves adjusting the physical size of the particle substrate used to present the activation and costimulatory ligands. The ligands themselves, the surface attachment methods, and the receptor-mediated signaling mechanisms remain unchanged. Since the activation mechanism depends on ligand-receptor interaction rather than on a specific particle size, changing the particle diameter within the range taught by Shen et al. would not disrupt the function of the system. Shen et al. further demonstrates that beads with diameters of approximately 4.5 µm successfully present activation and costimulatory ligands, and stimulate T cells when incubated together in suspension. A PHOSITA would therefore reasonably expect that particles meeting the claimed minimum size requirement would function effectively within the Oelke et al. system. Moreover, particle fabrication methods capable of producing particles within defined size ranges were well known in the art at the time of the invention. Thus, modifying the particle size of the Oelke et al. substrates to meet the size parameter taught by Shen et al. would have represented a straightforward and predictable implementation of known particle design principles without requiring undue experimentation. Therefore, a skilled artisan would have had a reasonable expectation of success in implementing particles having a mean diameter of at least 0.4 µm in the Oelke et al. activation system.
Response to Arguments
Applicant’s arguments filed 06/04/2026 have been fully considered. Applicant’s amendments have been entered. The objection to claim 1 is withdrawn because claim 1 has been amended to recite “the at least one substrate,” thereby correcting the informality identified in the prior Office action. The objection to claim 6 is moot because claim 6 has been canceled. The rejection of claims 10 and 11 under 35 U.S.C. 112(b) is likewise moot because claims 10 and 11 have been canceled.
The rejection of claims 1, 2, 4, and 5 under 35 U.S.C. 103 is maintained. The rejection has been updated in view of Applicant’s amendment to claim 1 expressly identifying IFNγ as the effector molecule. The updated rejection continues to rely on Oelke et al. in view of Hauskins et al. The additional discussion of Hauskins clarifies that Hauskins expressly demonstrates intracellular IFNγ induction in CAR-positive T cells following stimulation with anti-CAR idiotype antibody-conjugated beads.
Applicant principally argues that Hauskins is limited to an embodiment in which IFNγ is expressed by an engineered artificial antigen-presenting cell and is therefore supplied exogenously to the CAR T cells. Applicant relies on paragraph [0446] of Hauskins and contends that the CAR T cells are not the cells producing IFNγ. Applicant further argues that the claimed method requires the CAR T cells to produce and secrete IFNγ and requires detection of the secreted, cell-derived IFNγ as a direct readout or confirmatory marker of activation. These arguments are not persuasive.
The Examiner acknowledges that paragraph [0446] describes an embodiment in which an engineered artificial antigen-presenting cell may be generated to express a cytokine, including IFNγ. Applicant’s characterization of that particular embodiment, however, does not account for the separate experimental disclosure in Hauskins concerning stimulation of CAR-expressing T cells with anti-idiotype-antibody-conjugated beads.
Hauskins expressly reports that “as shown in FIG. 10A, intracellular cytokine levels of TNFα, IFNγ and IL2 cytokines were induced in CAR+ T cells (EGFRt+), but not in CAR− T cells (EGFRt−), when the cells were cultured in the presence of the anti-ID B-1 conjugated beads” (paragraph [0587], page 208). Hauskins further states that “these results demonstrated that anti-ID conjugated to beads are agonistic and specifically stimulate T cells expressing a CAR having an antigen-binding domain recognized by the anti-ID antibody” (paragraph [0587], page 208). Thus, the IFNγ relied upon in the rejection is not merely IFNγ expressed by an engineered artificial antigen-presenting cell under paragraph [0446]. Paragraph [0587] separately demonstrates that intracellular IFNγ was induced in the CAR-positive T-cell population after culture in the presence of anti-ID B-1-conjugated beads. The anti-ID-conjugated beads are the stimulating substrate; they are not cytokine-producing cells.
The comparison between the CAR-positive and CAR-negative T-cell populations further establishes the CAR-specific nature of the response. Hauskins reports IFNγ induction in CAR-positive T cells, but not CAR-negative T cells, under the anti-ID bead-stimulation conditions. Hauskins therefore directly attributes the intracellular cytokine response to stimulation of CAR-expressing T cells by anti-CAR idiotype antibody-conjugated beads. Applicant contends that Hauskins does not demonstrate that the CAR T cells themselves produce IFNγ. That contention is inconsistent with the intracellular cytokine-staining results reported in paragraph [0587]. Intracellular cytokine staining measures cytokine present within the stained cellular population. Hauskins identifies the tested populations as CAR-positive T cells and CAR-negative T cells and reports that intracellular IFNγ was induced in the CAR-positive T cells but not the CAR-negative T cells. Consequently, Hauskins directly demonstrates IFNγ expression or production by the stimulated CAR-positive T cells. This disclosure is distinct from the paragraph [0446] embodiment upon which Applicant relies. The presence of one embodiment in which an engineered artificial antigen-presenting cell may express a cytokine does not negate a separate embodiment expressly showing intracellular IFNγ induction within anti-ID-bead-stimulated CAR-positive T cells.
Applicant repeatedly characterizes amended claim 1 as requiring secretion of IFNγ from the CAR T cells into the culture medium, detection of the secreted IFNγ, use of secreted IFNγ as a direct readout of activation, and use of IFNγ as a confirmatory activation marker. Amended claim 1, however, requires incubation that activates the CAR T cells to express effector molecules, wherein the effector molecule is IFNγ. Claim 1 does not expressly require extracellular secretion, supernatant collection, ELISA analysis, detection of secreted IFNγ, or use of IFNγ as a confirmatory marker. In response to applicant’s argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., secretion of IFNγ into the culture medium, detection of secreted IFNγ, and use of the secreted IFNγ as a direct readout or confirmatory marker of activation) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Hauskins’ intracellular IFNγ disclosure therefore addresses the actual amended claim language. Because claim 1 requires expression rather than extracellular secretion, the intracellular cytokine staining reported in paragraph [0587] directly demonstrates the claimed cellular expression of IFNγ. Applicant’s distinction between “exogenous” and “endogenous” IFNγ likewise does not overcome the rejection. The paragraph [0587] disclosure relied upon by the Examiner concerns intracellular IFNγ induced within CAR-positive T cells following stimulation with anti-ID B-1-conjugated beads. The relied-upon IFNγ is therefore not merely IFNγ externally added to the culture under the separate paragraph [0446] embodiment. The combined teachings of Oelke and Hauskins address amended claim 1. Oelke supplies the nanoparticle-based activation platform. Oelke teaches activation and expansion of engineered T cells, including CAR-expressing T cells; paramagnetic artificial antigen-presenting nanoparticle substrates; surface presentation of an activating ligand as signal 1; presentation of a costimulatory molecule as signal 2; costimulatory molecules that specifically bind CD28, including antibodies; incubation of the particles and T cells; magnetic clustering of particles on the T-cell surface; and activation resulting from receptor engagement and clustering. Oelke also teaches that stimulated CD8-positive lymphocytes produce IFNγ, stating that “CD8+ lymphocytes enriched and expanded in accordance with embodiments of the invention produce proinflammatory markers such IFNγ, TNFα, IL-2, MIP-1β, GrzB, and/or perforin when stimulated with aAPCs loaded with cognate antigen” (paragraph 4, page 8).
Hauskins supplies the CAR-specific activating ligand and the specific CAR-T-cell IFNγ result. Hauskins teaches anti-idiotype antibodies that recognize anti-CD19 antibody moieties present in CARs; stimulation of cells containing a CAR recognized by the anti-idiotype antibody; immobilization of the anti-idiotype antibody on a solid support; anti-ID B-1-conjugated beads; agonistic and CAR-specific stimulation by those beads; and induction of intracellular IFNγ in CAR-positive T cells following that stimulation. Thus, the rejection does not depend on paragraph [0446] as teaching CAR-T-cell IFNγ expression. Rather, paragraph [0587] directly supplies that teaching.
The proposed modification remains the substitution of Hauskins’ known CAR-binding anti-idiotype antibody for Oelke’s MHC-peptide activating ligand on the particle-based activation platform, while retaining Oelke’s costimulatory signaling, including CD28 costimulation. This modification would selectively engage and stimulate CAR-expressing T cells. Hauskins’ experimental evidence establishes that anti-CAR idiotype-antibody-conjugated beads specifically stimulate CAR-positive T cells and induce intracellular IFNγ in those cells. Accordingly, a person of ordinary skill in the art would have had a reasonable expectation that CAR T cells stimulated through Hauskins’ anti-CAR idiotype antibody in Oelke’s particle-based activation platform would express IFNγ.
Applicant further argues that Hauskins does not remedy the asserted deficiency because paragraph [0446] concerns IFNγ associated with an engineered artificial antigen-presenting cell. That argument does not address the complete disclosure of Hauskins or the combined teachings applied in the rejection. In response to applicant’s arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Oelke is relied upon for the particle-based activation and costimulation platform. Hauskins is relied upon for the anti-CAR idiotype antibody and its demonstrated ability, when conjugated to beads, to specifically stimulate CAR-positive T cells and induce intracellular IFNγ. The issue is therefore what the combined teachings would have suggested to a person of ordinary skill in the art, not whether paragraph [0446] of Hauskins alone discloses the complete claimed method. Applicant states that the rejection is traversed with respect to claims 4 and 5 but does not present a separate substantive argument identifying a limitation of claims 4 or 5 that is absent from the applied references. Applicant’s arguments instead depend on the asserted deficiency concerning claim 1. Because the asserted deficiency concerning claim 1 is not persuasive, and because the teachings previously applied to the additional limitations of claims 4 and 5 remain applicable, the rejection of claims 4 and 5 is maintained.
Applicant also argues that claim 2 is patentable because it depends from claim 1 and because Shen does not remedy the alleged deficiency in the Oelke-Hauskins combination. The argument is not persuasive because Hauskins itself remedies the alleged deficiency. As explained above, Hauskins expressly demonstrates intracellular IFNγ induction in CAR-positive T cells following stimulation with anti-ID B-1-conjugated beads. Therefore, the underlying rejection of claim 1 is maintained. Shen is relied upon for the additional particle-size limitation of claim 2, not for the IFNγ-expression limitation inherited from claim 1. Applicant does not separately dispute Shen’s teaching of magnetic artificial antigen-presenting beads having a diameter meeting the claimed minimum. Accordingly, the rejection of claim 2 over Oelke and Hauskins, further in view of Shen, is maintained. Claim 7 has been canceled, and the rejection as to claim 7 is moot.
In conclusion, Applicant’s request for withdrawal of the objection to claim 1 is granted. The objection to canceled claim 6 and the rejection of canceled claims 10 and 11 under 35 U.S.C. 112(b) are moot.
Applicant’s arguments concerning the rejection under 35 U.S.C. 103 are not persuasive. Applicant’s reliance on Hauskins paragraph [0446] does not account for Hauskins’ separate experimental disclosure in paragraph [0587], which expressly demonstrates that intracellular IFNγ is induced in CAR-positive T cells following stimulation with anti-ID B-1-conjugated beads. Applicant’s further arguments concerning secretion and detection of secreted IFNγ rely on limitations not recited in claim 1. Accordingly, the rejections of claims 1, 2, 4, and 5 under 35 U.S.C. 103 are maintained.
Conclusion
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.
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 13, 2026
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