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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Status of Claims
Claims 3, 6-11, 15-17 and 21-23 are currently pending. Claims 6-11 and 15-17 have been amended by Applicants’ amendment filed 02-20-2026. Claims 1, 2, 4, 5 and 12-14 have been canceled by Applicant’s amendment filed 02-20-2026. Claims 21-23 have been added by Applicants’ amendment filed 02-20-2026.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 3, 6-11, 15-17 and 21-23 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed October 17, 2022 is a 35 U.S.C. 371 national stage filing of
International Application No. PCT/US21/27778, filed April 16, 2021; which claims the benefit of
US Provisional Patent Application 63011026, filed April 16, 2020.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed February 20, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or
objection not specifically addressed below are herein withdrawn.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 3, 6-11 and 15-17 are maintained, and claims 21-23 are newly rejected, under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 3, 6-8, 11, 15-17 and 21 are indefinite for the recitation of the terms “the nanoparticles” and “individual nanoparticles” such as recited in claim 3, lines 3, 5 and 6. There is insufficient antecedent basis for the terms “the nanoparticles” and “individual nanoparticles” in the claim because claim 3, lines 2-3 recites the term “an effective amount of nanoparticles.” The Examiner suggests that Applicant amend claim 3 to recite, for example, “an effective amount of a plurality of nanoparticles…wherein the surface of comprising of each of the plurality of nanoparticles comprises a plurality of specific binding agents to CD3…”
Claims 3 and 11 are indefinite for the recitation of the term “comprise less than 5 specific binding agents to CD19” such as recited in claim 3, line 6 because claim 3, line 4 recites that the nanoparticles surface comprises “a specific binding agent to CD19” (e.g., one specific binding agent to CD19). Because claim 3 does not recite that each nanoparticle comprises ‘a plurality of specific binding agents to CD19’, it is unclear whether the surface of each individual nanoparticle comprises one specific binding agent to CD19, or whether the surface of each individual nanoparticle comprises less than 5 specific binding agents to CD19 and, thus, the metes and bounds of the claim cannot be determined.
Claims 6 and 15 are indefinite for the recitation of the term “comprise 20 to 70 specific binding agents to CD3 on the surface of the individual nanoparticles” such as recited in claim 6, lines 2-3 because claim 3, line 4 recites that the nanoparticles surface comprises “a specific binding agent to CD19” (e.g., a single specific binding agent to CD19). Because claim 3 does not recite that each nanoparticle comprises ‘a plurality of specific binding agents to CD3’, such that it is unclear whether each individual nanoparticle comprises one specific binding agent to CD3, or whether it comprises less than 20 to 70 specific binding agents to CD3 and, thus, the metes and bounds of the claim cannot be determined.
Claims 7 and 16 are indefinite for the recitation of the term “a 10-fold excess of specific binding agents to CD3 as compared to specific binding agents to CD19” such as recited in claim 7, lines 2-3 because claim 7 depends from claims 3 and 6, where claim 3, line 4 recites the presence of one specific binding agent to CD3, and that each nanoparticle comprises either one or less than 5 specific binding agents to CD19. Thus, the number of specific binding agents to CD3 recited in claim 7 does not allow for a 10-fold excess because each nanoparticle either comprises CD3 and CD19 in equal amounts (e.g., 1:1), or the specific binding agents to CD3 are at a deficit of up to 20% as compared to specific binding agents to CD19 (e.g., 1:2, 1:3, 1:4 or 1:5) and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the term “25 to 60 specific binding agents to CD3, 2 to 4 specific binding agents to CD19, and 1 to 12 interleukin-12 sequences on the surface of the individual nanoparticles” such as recited in claim 8, lines 2-4 because claim 8 depends from instant claim 3, where claim 3 recites that an individual nanoparticle comprises one specific binding agent to CD3; either one or less than 5 specific binding agents to CD19; and interleukin-12. Moreover, claim 3 does not recite the presence of IL-12 sequences and, thus, the metes and bounds of the claim cannot be determined.
Claims 8 and 21 are indefinite for the recitation of the term “interleukin-12 sequences” such as recited in claim 8, line 3 because claim 8 depends from instant claim 3, and claim 21 depends from instant claim 11, wherein claims 3 and 11 do not recite the presence of interleukin-12 sequences and, thus, the metes and bounds of the claim cannot be determined.
Claims 9 and 22 are indefinite for the recitation of the term “the specific binding agents to CD3” such as recited in claim 9, line 1. There is insufficient antecedent basis for the term “the specific binding agents to CD3” in the claim because claim 9 depends from instant claims 3 and 8, wherein claim 3, line 4 recites the term “a specific binding agent to CD3”; while claim 8 recites ”25 to 60 specific binding agents to CD3.”
Claims 10 and 23 are indefinite for the recitation of the term “the specific binding agents to CD19” such as recited in claim 10, line 1. There is insufficient antecedent basis for the term “the specific binding agents to CD19” in the claim because claim 10 depends from instant claims 3 and 8, wherein claim 3, lines 3-4 and 6 recites the terms “a specific binding agent to CD19” and “less than 5 specific binding agents to CD19”; while claim 8, line 3 recites the term “2 to 4 specific binding agents to CD19.”
Claim 10 is indefinite for the recitation of the term “anti-CD3 antibodies” such as recited in claim 10, line 2 because anti-CD3 antibodies are not specific binding agents to CD19 and, thus, the metes and bounds of the claim cannot be determined.
Claim 17 is indefinite for the recitation of the term “a 20-fold excess of specific binding agents to CD3 as compared to specific binding agents to CD19” such as recited in claim 17, lines 2-3 because claim 17 depends from claims 11 and 15, where claim 11, lines 2-3 recites the presence of one specific binding agent to CD3, and that each nanoparticle comprises either one or less than 5 specific binding agents to CD19. Thus, the number of specific binding agents to CD3 recited in claim 17 cannot correspond to a 20-fold excess because each nanoparticle either comprises CD3 and CD19 in a 1:1 ratio, or each nanoparticle either comprises the specific binding agents to CD3 at up to a 5-fold deficiency as compared to specific binding agents to CD19 (e.g., CD3:CD19 is present in a ratio of 1:1, 1:2, 1:3, 1:4 or 1:5) and, thus, the metes and bounds of the claim cannot be determined.
Claim 21 is indefinite for the recitation of the term “25 to 60 specific binding agents to CD3; 2 to 4 specific binding agents to CD19; and 1 to 12 interleukin-12 sequences on the surface of the individual nanoparticles” such as recited in claim 21, lines 2-4 because claim 21 depends from instant claim 11, where claim 11 recites that an individual nanoparticle comprises one specific binding agent to CD3; either one or less than 5 specific binding agents to CD19; and interleukin-12. Moreover, claims 3 and 11 do not recite the presence of interleukin-12 sequences and, thus, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 6-8 and 15-17 is maintained, and claims 10 and 21 are newly rejected, under 35 U.S.C. 112(d) 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.
Claims 6-8, 15-17 and 21 recite (in part): “comprises between 20 and 70 specific binding agents”; “the nanoparticle has a 10-fold excess of specific binding agents to CD3” and/or “have 25 to 60 specific binding agents to CD3, 2 to 4 specific binding agents to CD19, and 1-12 interleukin-12 sequences”, such as recited in claim 6, lines 2-3 because claims 6-8 depend from instant claim 3; and claims 15-17 and 21 depend from instant claim 11, where claim 3, line 4 recites that the nanoparticles surface comprises “a specific binding agent to CD19” (e.g., a single specific binding agent to CD19); less than 5 specific binding agents to CD19; one specific binding agent to CD3, and interleukin-12, such that claims 3 and 11 do not recite more than 5 specific binding agents to CD19; interleukin-12 sequences; and/or an excess of specific binding agents to CD3 as compared to specific binding agents to CD19. Thus, claims 6-8, 15-17 and 21 are improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 recites (in part): “wherein the specific binding agents to CD19 are anti-CD3 antibodies” in lines 1-2 because anti-CD3 antibodies are not specific binding agents to CD19. Thus, claim 10 is an improper dependent claim 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.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The rejection of claims 3, 6-11 and 15-17 is maintained, and claims 21-23 are newly rejected under 35 U.S.C. 103 as being unpatentable over Chang et al. (hereinafter “Chang”) (International Application WO2014163684, published October 9, 2014) in view of Kadiyala et. al. (hereinafter “Kadiyala”) (US Patent Application Publication 20180221503, published August 9, 2018).
Regarding claims 3, 11 and 21-23, Chang teaches that the invention concerns combinations of two or more agents for inducing an immune response to cancer or infectious disease, wherein agents can include leukocyte redirecting complexes, antibody-drug conjugates, interferons, and/or checkpoint inhibitor antibodies, such that the leukocyte redirecting complexes have at least one binding site for a leukocyte antigen and at least one binding site for an antigen on a diseased cell or pathogen, wherein the complex is preferably a DNL complex and/or the complex comprises a bispecific antibody (bsAb) including an anti-CD3 x anti-CD19 bispecific antibody, although antibodies against other leukocyte antigens and/or disease-associated antigens can be used, such that the complex is capable of targeting effector T cells, NK cells, monocytes or neutrophils to induce leukocyte-mediated cytotoxicity of cells associated with cancer or infectious disease, wherein the cytotoxic immune response is enhanced by co-administration of interferon, checkpoint inhibitor antibody and/or ADC (interpreted as a bispecific antibodies; specific binding agents anti-CD3 and anti-CD19; which are binding agents against CD3 and CD19; and encompassing immune regulated diseases including chronic viral infection and cancer, claims 3 and 9-11) (Abstract). Chang teaches that the therapeutic effectiveness of IFNs has been validated to date by the approval of IFN-a2 for treating diseases including hairy cell leukemia and chronic myelogenous leukemia (interpreted as treating leukemia, claims 3, 11, 22 and 23) (paragraph [015]). Chang teaches that the subject combination therapy can be used to treat subjects infected with pathogenic organisms such as bacteria, viruses or fungi, wherein viruses include feline leukemia virus, human T-cell leukemia viruses, and murine leukemia virus (interpreted as treating leukemia, claims 3 and 11) 9paragraph [032]). Chang teaches that the subject combination therapy can be of use for treating cancer, wherein any type of tumor and any type of tumor antigen can be targeted including acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, and chronic myelogenous leukemia (interpreted as treating leukemia, claims 3 and 11) (paragraph [027]). Chang teaches that the subject agents can be administered in combination with one or more other immunomodulators to enhance the immune response, where the immunomodulators can include, but are not limited to, a cytokine, a chemokine, and IL-12 (interpreted as administering to a subject; treatment of an immune regulated disease; and an additional agent IL-12, claims 1, 3 and 11) (paragraph [034]). Chang teaches that combinations of therapeutic agents can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the bsAb, ADC, interferon and/or checkpoint inhibitor antibody is combined in a mixture with a pharmaceutically suitable excipient (interpreted as a pharmaceutical composition, claim 11) (paragraph [0255], lines 1-4). Chang teaches that because the molecular size of DNL bsAbs is above the threshold typically associated with renal clearance, it should exhibit slower clearance from circulation, wherein biphasic clearance was observed with a t½ a and t½ b of 1.1 and 5.1 h, respectively, resulting in an area under the curve of 1880 pmol*h/mL (data not shown), which was nearly 6-fold greater than that reported for MT103 (anti-CD19 x anti-CD3 BITE) administered at the same molar concentration (US Patent US2010/0303827Al) (interpreting MT103 as comprising anti-CD19 antibodies and anti-CD3 antibodies; and administering an effective amount of specific binding agents, claims 1, 3 and 9-11) (paragraph [0307]). Chang teaches that blinatumomab is an anti-CD19 x anti-CD3 BITE, where it is a bispecific single-chain antibody targeting CD3 and CD19 antigen with efficacy in hematologic cancers (interpreting blinatumomab to comprise a 1:1 ratio of specific binding agents; and interpreting hematologic cancers to include leukemia, claims 3, 11, 22 and 23) (paragraph [0205]). Chang teaches that the leukocyte-redirecting bsAb is selected from the group consisting of blinatumomab, MT110, catumaxomab, ertumaxomab, FBTA05 and TRBS07 (interpreted as pharmaceutical compositions; and anti-CD19 and anti-CD3 antibodies, claims 1, 3, 9-11, 22 and 23) (pg. 129, claim 7). Chang teaches that additional pharmaceutical methods can be employed to control the duration of action of the therapeutic combinations, wherein control release preparations can be prepared through the use of polymers to complex or adsorb the agents to be administered, such as for example, biocompatible polymers include matrices of poly(ethylene-co-vinyl acetate) and matrices of a polyanhydride copolymer of a stearic acid dimer and sebacic acid; Sherwood et al., Bio/Technology 10: 1446 (1992), where the rate of release from such a matrix depends upon the molecular weight of the therapeutic agent, the amount of agent within the matrix, and the size of dispersed particles. Saltzman et al., Biophys. J 55: 163 (1989); Sherwood et al., supra. Other solid dosage forms are described in Ansel et al., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 5th Edition (Lea & Febiger 1990), and Gennaro (ed.); REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition (Mack Publishing Company 1990), and revised editions thereof (interpreted as pharmaceutical composition comprising a nanoparticle, claims 3 and 11) (paragraph [0257]). Chang teaches that exemplary leukocyte redirecting bispecific antibodies were made an DNL complexes, wherein the complexes were effective to induce an immune response against appropriate target cells (interpreted as an effective amount, claim 3) (paragraph [0276]). Chang teaches that the (E1)-3s bsAb was effective to reduce tumor growth and increase survival in gastric cancer (interpreted as an effective amount, claims 1 and 3) (paragraph [0325], lines 2-3). Chang teaches that the invention concerns combinations of two or more agents for inducing an immune response to cancer or infectious disease (interpreted as cancer; and encompassing chronic viral infection, claims 3 and 11) (Abstract, lines 1-2). Chang teaches that because checkpoint activation can be associated with chronic infections, such combinations therapies can be used to treat infectious disease (interpreted as encompassing chronic infection, claims 3 and 11) (paragraph [0121], lines 14-16). Chang teaches the leukocyte redirecting complexes have at least one binding site for a leukocyte antigen and at least one binding site for an antigen on a diseased cell or pathogen, wherein the complex is preferably a DNL complex and/or the complex comprises a bispecific antibody (bsAb) (Abstract). Chang teaches that the subject agents can be administered in combination with one or more other immuno-modulators to enhance the immune response, where the immunomodulators can include, but are not limited to, a cytokine, a chemokine, and IL-12 (interpreted as interpreted as a nanoparticle comprising a surface binding agent to IL-12; and specifically binding the antigen, claims 12 and 13) (paragraph [034]). Chang teaches a second antibody or antigen-binding fragment thereof the binds to a target antigen or pathogen selected from the group including CD19 and IL-12 (interpreted as a nanoparticle comprising a surface binding agent to IL-12; and specifically binding the antigen, claims 12 and 13) (pg. 127, claim 2).
Regarding claims 9 and 10, Chang teaches utilizing leukocyte-redirecting complexes including bispecific antibodies (bsAbs), with one binding site against a leukocyte expressed antigen and a second binding site that binds to a target antigen on a tumor cell or pathogen (i.e., micro-organism), wherein exemplary T-cell antigens are selected from the group including CD3; and target antigens for the second antibody can be selected from the group including CD19 (interpreted as a CD3 antibody and a CD19 antibody, claims 9 and 10) (paragraph [020]). Chang teaches that because checkpoint inhibitor antibodies act primarily by regulating the immune response to diseased cells, tissues or pathogens, they can be used in combination with other therapeutic modalities, such as the subject leukocyte redirecting bispecific antibodies, ADCs and/or interferons to enhance the anti-tumor effect of such agents (interpreted as a CD3 antibody and a CD19 antibody, claims 9 and 10) (paragraph [0121], lines 10-14).
Chang does not specifically exemplify a hydrodynamic diameter, and less than 5 specific binding agents to CD19 on the surface of the particle (claims 5 and 14); a hydrodynamic diameter, and 20 to 70 specific binding agents to CD3 on the surface of the particle (claims 6 and 15); a ratio of specific binding agents to CD3 compared to CD19 that is in excess of 10-fold (claims 7 and 16); a hydrodynamic diameter, and 25-60 specific binding agents to CD3, 2-4 specific binding agents to CD19, and 1-12 IL-12 sequences on the surface of the particle (claim 8); and the nanoparticle has a ratio of specific binding agents to CD3 compared to CD19 that is in excess of 20-fold (claim 17).
Regarding claims 5-8 and 14-17, Kadiyala teaches conjugates and nanoparticles comprising active agents that can elicit a cancer specific immune response are provided, wherein the conjugates comprise one or more targeting moieties that are connected to the active agents, such that the nanoparticles comprising the conjugates of the present invention are also provided to increase the delivery of the conjugates, and increase immunogenicity and lower toxicity (interpreted as nanoparticles, claims 3-17) (Abstract). Kadiyala teaches that conjugates provide platforms for cancer immunotherapy modalities, such that the conjugate comprise three moieties: an active agent, a targeting moiety, and a linker that connects the active agent and the targeting moiety, wherein the active agent can be an agent that can stimulate/increase a cancer specific immune response including antibodies specific to a tumor antigen; tumor antigenic peptides (i.e., epitopes) that can increase the antigen presentation to T cells; agents that can stimulate proliferation (e.g., cytokines), expansion, maturation and migration of antigen presenting cells (e.g., dendritic cells), and/or increase antigen capture and processing in antigen presenting cells; agents that enhance cancer specific T cells expansion, proliferation and migration, and/or increase antigen recognition; cytokines and chemokines that positively regulate immune responses; or agents that can inhibit immunosuppressive signals in the tumor tissues (interpreted as including anti-CD19 and anti-CD3 antibodies; and the cytokine IL-12, claims 5-8 and 14-17) (paragraph [0012]). Kadiyala teaches that the targeting moiety of the conjugate can function to deliver an active agent of the conjugate to a targeted area such as a tumor tissue or lymph node, or a type of cell of interest such as T cells, dendritic cells and/or NK cells, wherein the targeting moiety itself can have an immune stimulating activity, the same or different from the active agent in the same conjugate (interpreted as including anti-CD19 and anti-CD3 antibodies; and the cytokine IL-12, claims 5-8 and 14-17) (paragraph [0013]). Kadiyala teaches that more than one targeting moiety can be linked to active agents of the conjugate for targeting different tissues, cells or even different intracellular components such as those of the cell surface and cytoplasm (interpreted as a nanoparticle comprising three agents, claims 5-8 and 14-17) (paragraph [0016]). Kadiyala teaches that the term "administration" means the actual physical introduction of the composition into or onto (as appropriate) the host, wherein any and all methods of introducing the composition into the host are contemplated according to the invention; the method is not dependent on any particular means of introduction and is not to be so construed (interpreted as administering, claims 1, 3 and 11) (paragraph [0020]). Kadiyala teaches that antibodies can exist as full length intact antibodies or as a number of well-characterized fragments produced by digestion with various peptidases or chemicals, such as F(ab')2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond; an Fab' monomer, a Fab fragment with the hinge region; and a Fc fragment, a portion of the constant region of an immunoglobulin (interpreted as encompassing anti-CD19 and anti-CD3 antibodies, claims 5-8 and 14-17) (paragraph [0027]). Kadiyala teaches that the term "cytokine" refers to a substance secreted by certain cells of the immune system and has a biological effect on other cells, wherein cytokines can be a number of different substances such as interferons, interleukins and growth factors (interpreted as encompassing IL-12, claims 3, 8 and 11) (paragraph [0039]). Kadiyala teaches that the term "mean particle size" generally refers to the statistical mean particle size (diameter) of the particles in the composition, wherein the diameter of an essentially spherical particle can be referred to as the physical or hydrodynamic diameter, such that the particles can be nanoparticles or microparticles, wherein the particle can have a diameter of about
10 nm to about 10 microns (interpreted as a hydrodynamic diameter; and encompassing a diameter of less than 200 nm, claims 5-8 and 14-17) (paragraph [0050], lines 1-5; and [0233], lines 2-4). Kadiyala teaches that one active payload can be linked to two or more targeting ligands wherein the conjugate has the formula: (X- Y)n- Z, or one or more targeting ligands can be connected to one or more active payloads wherein the conjugate formula can be (X- Y-Z)n; X- Y- Z- Y- X; (X- Y- Z)n-Y- Z; or X- Y- (X- Y- Z)n, wherein X is a targeting moiety; Y is a linker; Z is an active agent, such that the number of each moiety in the conjugate can vary dependent on types of agents, sizes of the conjugate, delivery targets, particles used to packaging the conjugate, other active agents (e.g., immunologic adjuvants) and routes of administration, such that at each occurrence of X, Y, and Z can be the same or different, e.g. the conjugate can contain more than one type of targeting moiety, more than one type of linker, and/or more than one type of active agent, wherein n is an integer equal to or greater than 1; n is an integer between 1 and 50, or between 2 and 20, or between 5 and 40; or n can be an integer of 2 to 50 (interpreted as encompassing the different combinations of specific binding groups, claims 5-8 and 14-17) (paragraphs [0064]). Kadiyala teaches that payloads of the conjugates of the present invention can comprise between 1 to 20 antigen peptides, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 different antigen peptide, or more than 20 antigen peptides can be included in the conjugates as payloads (interpreted as encompassing 2 to 4, 20 to 70, or 25 to 60 conjugates, claims 6-8, 15-17 and 21) (paragraph [0103]). Kadiyala teaches that the active agent of the conjugate can be a cytokine or other immunoregulatory agent, wherein cytokines can be secreted by activated APCs after T cell encounters and impact expansion, survival, effector function, and memory of stimulated T cells, such that preferred cytokines include, but are not limited to, granulocyte macrophage colony stimulating factor (GMCSF), tumor necrosis factor alpha (TNFa), tumor necrosis factor beta (TNFB), macrophage colony stimulating factor (M-CSF), interleukin-I (IL-1), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-IO (IL-10), interleukin-12 (IL-12) (interpreted as IL-12, claims 5-8 and 14-17) (paragraph [0131]). Kadiyala teaches that CARs specific for a wide range of TAAs have been developed, for example, CD19 specific CAR for leukemia (Kochenderfer et al., adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells; and that antibodies can recognize tumor antigens that are overexpressed in tumor cells, or tumor antigens associated with leukemias and lymphomas such as cell differentiation (CD) antigens include: CD19, CD20, CD21, CD25 and CD37 in non-Hodgkin lymphoma (interpreted as CD19, claims 5-8 and 14-17) (paragraph [0140]; and [0158]). Kadiyala teaches that non-limiting examples of CD19 binding agents that can be used as a tumor cell binding moiety in the conjugates include any CD19 binding agent disclosed in Dreier et al. (J Immunol. , vol.170:4397 (2003)), in Klinger et al. (Blood, vol.119:6226 (2012)), or blinatumomab, a bispecific single-chain antibody targeting CD3 and CD19 antigen disclosed in Topp et al. (J Clin Oneal., vol.29:2493 (2011)). Non-limiting examples of CD20 binding agents include anti-CD20/CD3 T cell-dependent bispecific antibody disclosed in Sun et al. (Sci Transl Med., vol.7:287 (2015)) or anti-CD3 x anti-CD20 bispecific antibody disclosed in Gall et al. (Exp Hematol. , vol.33( 4): 452 (2005)). Non-limiting examples of CEA binding agents include CEA/CD3-bispecific T cell-engaging (BiTE) antibody disclosed in Osada et al. (Cancer Immunol Immunother., vol.64(6):677 (2015)). Non-limiting examples of EpCAM binding agents include EpCAM/CD3-bispecific T-cell engaging antibody MTl110 disclosed in Cioffi et al. (Clin. Cancer Res., vol.18(2):465 (2012)) (interpreted as CD19 and CD3, claims 6-8, 15-17 and 21) (paragraph [0190]). Kadiyala teaches that PLGA nanoparticles with melanoma antigens to elicit effective anti-tumor activity by CTLs in vivo (Zhang, Z., et al., Biomaterials. 2011, 32(14): 3666-78; Ma, W., et al., Int. J. Nanomedicine. 2012, 7:1475-87; the contents of each of which are incorporated herein by reference in their entirety), wherein chitosan nanoparticles targeting dendritic cells carrying IL-12 were administered in an animal model that resulted in suppression of tumor growth and increased induction of apoptosis (Kim, T H., et al., Mo! Cancer Ther. 2006, 5(7): 1723-32; the contents of which are incorporated herein by reference in their entirety (interpreted as IL-12 binding agents, claims 5-8 and 14-17) (paragraph [0400]). Kadiyala teaches that the amount of targeting moieties of the conjugate can also be expressed in terms of proportion to the active agent(s), for example, in a ratio of ligand to active agent of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4; 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10 (interpreted as a ratio of 1:1, 20:70, 25:60, 10-fold excess, and 20-fold excess, claims 3, 11, 6-8, 15-17 and 21) (paragraph [0223]). Kadiyala teaches that conjugates, particles and formulations comprising conjugates and vaccines can be used to treat any cancer including, but not limited to, any of acute lymphocytic cancer, acute myeloid leukemia and chronic lymphocytic leukemia (interpreted as treating leukemia, claims 3 and 11) (paragraph [0450]).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, “…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of conjugating one or more active agents to nanoparticles as exemplified by Kadiyala, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of administering combinations of two or more agents for inducing an immune response to cancer or infectious disease including antibody-drug conjugates, bispecific antibodies and/or bispecific antibody constructs or BiTE or DART, including anti-CD19 x anti-CD3 antibodies or antibody fragments thereof, and IL-12 as disclosed by Chang to include the cancer immunotherapy modalities comprising nanoparticles conjugated to active agents such as antibodies and/or cytokines including anti-CD19 x anti-CD3 antibodies or antibody fragments thereof, and IL-12 as taught by Kadiyala with a reasonable expectation of success in providing for the directed targeting, delivery, and release of active agents from the nanoparticles including within specific environments; in positively manipulating cancer-specific immune responses by increasing tumor antigen presentation, enhancing cancer specific T cell proliferation, migration and cytotoxic functions, to increase cytokine mediated defensive mechanisms, and/or to modulate the immunosuppressive tumor microenvironment; in enhancing efficacy, specificity, and lowering toxicity; and/or in producing combination therapies and/or complexes that have longer T1/2, better pharmacokinetic properties, increased in vivo stability, and/or improved treatment efficacy in vivo.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103(a) as obvious over the art.
Response to Arguments
Applicant’s arguments filed February 20, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) it is noted that bispecific antibodies of Chang are in a 1 to 1 ratio; and the combined references do not teach a lower number of CD19 binding agents compared to CD3 binding agent has a benefit when on the exterior of the nanoparticles (Applicant Remarks, pg. 8, second full paragraph); (b) the combined references do not teach treating leukemia with nanoparticles comprising specific binding agents to CD19, a specific binding agent to CD3, and interleukin-12, where there are less than 5 specific binding agents to CD19 on the surface of the nanoparticle as provided in claims 3 and 11 (Applicant Remarks, pg. 8, third full paragraph); and (c) the combined references do not teach treating leukemia with nanoparticles comprising specific binding agents to CD19, a specific binding agent to CD3, and interleukin-12, where there are less than 5 specific binding agents to CD19 on the surface of the nanoparticle as provided in claims 6, 7, 15 and 16 (Applicant Remarks, pg. 8, fourth full paragraph).
Regarding (a), 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, 26USPQ2d 1057 (Fed. Cir. 1993). Moreover, it is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. 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). Additionally, MPEP 2112.01(I) states that:
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
MPEP 2112.01(II) indicates:
“Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. “The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty”) (underline added).
Applicant’s assertion that bispecific antibodies of Chang are in a 1 to 1 ratio; and there is nothing in Change and Kadiyala does not teach a lower number of CD19 binding agents compared to CD3 binding agent has a benefit when on the exterior of the nanoparticles, is not found persuasive. Please see the discussion supra regarding claims 3 and 11, and the 35 USC 112(b) and 35 USC 112(d) rejections. As an initial matter, instant claims 3 and 11 do not recite: (i) a lower number of specific binding agents CD19 as compared to the number of specific binding agents to CD3; (ii) any specific benefit of a nanoparticle having a lower number of binding agents to CD19 as compared to binding agents to CD3; and/or (iii) that the binding agents are specifically located on the “exterior” of the nanoparticle. Thus,
No evidence supporting the unexpected results has been provided by Applicant.
Applicant’s has not provided any evidence of improved properties that are reasonably commensurate in scope with the claimed invention.
There is no nexus or co-extensiveness between Applicant’s asserted improvements and the steps as recited in claims 3 and 11.
Applicant has not pointed to where these advantages or surprising results were recognized in the as-filed Specification.
Applicants have not clearly stated the nature of the unexpectedly improved properties that Applicant asserts are not taught in the prior art.
Evidence has not been provided that the “superior results” asserted by Applicant were unknown in the prior art.
As indicated in MPEP 2112.01(II), products of identical chemical composition cannot have mutually exclusive properties, such that any nanoparticle comprising the ratio of specific binding agents as recited in claims 3 and 11 will provide the same benefits asserted by Applicant. The combined references of Chang and Kadiyala clearly teach the recited 1:1 ratio of CD19 to CD3 specific binding agents as recited in claims 3 and 11. Thus, the rejection is maintained.
Regarding (b) and (c), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments including with regard to the 35 USC 112(b) and 112(d) rejections. Applicant’s assertion that none of the references teach treating leukemia with nanoparticles comprising specific binding agents to CD19, a specific binding agent to CD3, and interleukin-12 as recited in claims 1 and 11, is not found persuasive. As an initial matter, it is noted that instant claims 3 and 11 recite that the nanoparticle surface comprises a specific binding agent to CD19, while also reciting that the nanoparticle surface comprises less than 5 specific binding agents to CD19. It is noted that the term “less than 5” encompasses zero (0) specific binding agents. The Examiner contends that the combined references teach all of the limitations of the claims. To that end -
Chang teaches:
Blinatumomab is an anti-CD19 x anti-CD3 BITE, a bispecific single-chain antibody targeting CD3 and CD19 antigen with efficacy in hematologic cancers (interpreting blinatumomab to comprise a 1:1 ratio of specific binding agents; and interpreting hematologic cancers to include leukemia, claims 3 and 11) (paragraph [0205]).
Anti-PD1 antibodies have been used for the treatment of diseases including leukemia (interpreted as treating leukemia, claims 3 and 11) (paragraph [0124], lines 1-3).
The subject combination therapy can be of use for treating cancer, wherein any type of tumor and any type of tumor antigen can be targeted including acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, and chronic myelogenous leukemia (interpreted as treating leukemia, claims 3 and 11) (paragraph [027]).
The subject combination therapy can be used to treat subjects infected with pathogenic organisms such as bacteria, viruses or fungi, wherein viruses include feline leukemia virus, human T-cell leukemia viruses, and murine leukemia virus (interpreted as treating leukemia, claims 3 and 11) 9paragraph [032]).
Kadiyala teaches:
Payloads of the conjugates of the present invention can comprise between 1 to 20 antigen peptides, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 different antigen peptide, or more than 20 antigen peptides can be included in the conjugates as payloads (interpreted as encompassing ratios of 1 to 1, 2 to 4, 20 to 70, or 25 to 60 conjugates, claims 3 and 11) (paragraph [0103]).
The amount of targeting moieties of the conjugate can also be expressed in terms of proportion to the active agent(s), for example, in a ratio of ligand to active agent of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4; 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10 (interpreted as a ratio of 1:1, 20:70, 25:60, 10-fold excess, and 20-fold excess, claims 3 and 11) (paragraph [0223]).
The conjugates, particles and formulations comprising conjugates and vaccines can be used to treat any cancer including, but not limited to, any of acute lymphocytic cancer, acute myeloid leukemia and chronic lymphocytic leukemia (interpreted as treating leukemia, claims 3 and 11) (paragraph [0450]).
The combined references teach all of the limitations of the claims. Thus, the rejection is maintained.
New Objections/Rejections
Notice of Non-Compliant Amendment (37 CFR 1.121)
The amendment to the claims filed on February 20, 2026 does not comply with the requirements of 37 CFR 1.121(c) because the status identifier and text of claim 3 is not submitted with markings to indicate the changes that have been made relative to the immediate prior version of claims filed on October 17, 2022.
Amendments to the claims filed on or after July 30, 2003 comply with 37 CFR 1.121(c), which states:
(c) Claims - Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing
of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims,
in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
Specifically, the amendments to claim 3 filed February 20, 2026 does not recite a proper status identifier. For example, claim 3 recites the status identifier “(Original),” while also displaying underlines and strike-throughs that show that claim 3 has been amended relative to the immediate prior version.
To be fully responsible, Applicant is required to comply with the Notice of Non-Compliant Amendment (37 CFR 1.121). In the interests of compact prosecution, an action on the merits has been prepared. However, future amendments must comply with 37 CFR 1.121(c) in order to avoid a notice of non-compliant amendment.
The Examiner suggests that Applicant amend claims 3 and 11 to clarify the structure of each nanoparticle and what is bound to the surface thereof. For example, amending the claims to recite whether the surface of each nanoparticle comprises a plurality of specific binding agents to CD3, a plurality of specific binding agent to CD19, and/or a plurality of IL-12 sequences bound thereto.
Conclusion
Claims 3, 6-11, 15-17 and 21-23 are rejected.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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/AMY M BUNKER/Primary Examiner, Art Unit 1684