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 .
Claim 193 and 205 have been amended. Claims 193-195,197 and 199-212 are pending and under consideration.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 205 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 205 requires the multifunctional polypeptide of claim 193, wherein the first antibody molecule that binds to NKp30 or NKp46 is a Fab and (a) a second polypeptide comprising in the N to C-orientation the VH-CH1 of the Fab connected to the first immunoglobulin chain constant region. It is unclear if the second polypetide comprising he Fasb molecule is in addition to the first Fab that binds to NKp30 or NKp46 because it is qualified as “further comprises” rather than “comprises”
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.
The rejection of claims 193-195, 197, 199-202, and 209-212 under 35 U.S.C. 103 as being unpatentable over Romagne et al (WO2004/056392) in view of Kiefer and Neri (Immunological Reviews, first published February 10, 2016, Vol. 270, pp. 178-192, see publication data, downloaded from the web on 9/13/2025) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562) is maintained for reasons of record.
Romagne et al teach a method of treating cancers susceptible to NK cell lysis comprising administering a pharmaceutical composition comprising an anti-NKp30 or an anti-NKp46 antibody or an immunoreactive fragment thereof in combination with Il-2, wherein the cancer include melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma (claims 1 and 15 of ‘392).
Romagne et al do not teach the delivery of the IL-2 by means of fusion of the cytokine to the Fc region of the anti-NKp30 or anti-NKp46 antibody. Romagne et al do not teach bispecific antibodies comprising anti-NKp30 or NKp46 coupled with an antibody which binds to a tumor antigen or antigen binding fragment thereof of, wherein the cytokine is fused to the Fc region of the anti-NKp30 or anti-NKp46 antibody or antigen-binding fragment. Romagne et al do not teach the replacement of one or more residues that make up the CH3-CH3 interface with a charged amino acid such that the interaction between like chains becomes electrostatically unfavorable in order to discourage the homodimer formation to provide the bispecific antibody.
Kiefer and Neri teach immunocytokines, wherein cytokine payloads which can be efficiently delivered to the tumor site include Il-2 (page 180, second column, number 1). Kiefer and Neri teach common formats for immunocytokines include IgG format with the cytokine fused to the heavy chain (page 180. Figure 1B). Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass which may be responsible for the therapeutic activity of the products (page 182, first column, lines 182, lines 1-6 of the second full paragraph).
Kiefer and Neri teach common formats for bispecific antibodies including “knobs-into-hole” bispecific antibodies (page 184, Figure 2) comprising point mutations in the CH3 domain allowing for the matching of two asymmetric chains, each bearing a different antigen specificity (page 184, second column, lines 6-12 of the first full paragraph) which meets the same limitation of claim 195. Kiefer and Neri teach that in most applications of bispecific antibodies, one antibody moiety was specific for a tumor specific antigen and the other antibody moiety was specific for a leukocyte antigen (page 185, lines 1-5 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that in most of the applications CD3 was used to recruit T cells, but other molecular targets such as CD16 on NK cells have been contemplated (page 185, lines 6-8 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action (page 188, first column, lines 8-11 of the first full paragraph).
It would have been prima facie obvious at the time prior to the effective filing date to construct a bispecific antibody in knobs-in-hole format (Figure 2A of Kiefer and Neri), wherein the antibody comprised a binding specificity for tumor antigen and NKp30 or NKp46 and wherein Il-2 was fused to each carboxyl terminus of the heavy chain in the N-C direction (Figure 1B of Kiefer and Neri). It is noted that Kiefer and Neri teach that the N terminus of the cytokine is attached to the C-terminus of the Fc region. This configuration fulfills the limitation of “the first polypeptide comprising in the N to C-orientation, the first cytokine connected to the second immunoglobulin chain constant region”. It is noted that the claim does not specify that the first antibody molecule that binds to NKp30 or NKp46 is part of a first immunoglobulin chain or alternatively, a second immunoglobulin chain and thus the identity of the second immunoglobulin chain comprising the “first cytokine” is not established. One of skill in the art would have been motivated to combine the resulting bispecific immunocytokine with a pharmaceutically acceptable carrier for the admisntration to a subject with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma. One of skill in the art would have been motivated to do so by the teachings of Romagne et al on the administration of anti-NKp30 or anti-NKp46 in combination with Il-2 for the treatment of melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma. Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action. One of skill in the art would understand that providing the Il-2 with the anti-NKp30 or NKp46 bispecific antibody would provide NK cells at the site of action in the tumor mass because Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass. Thus, one of skill in the art would understand that the massive infiltration of NK cells were the accessory lymphocytes needed at the site of action for the bispecific antibodies targeting tumor antigen and NKp30 or NKp46.
The administration of the bispecific immuocytokine to patients taught by Romagne et al to be treatable with anti-NKp30 or anti-NKp46 are patients with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma which meets the limitations of claim 210 and a solid tumor and a hematological cancer in claim 211, lung cancer, skin cancer and liver cancer in claim 212(i) and chronic myeloid leukemia and multiple myeloma in claims 212ii). The resulting bispecific immuocytokine based on the bispecific format of A in figure 2 of Kiefer and Neri and the common immunocytokine format of B of Kiefer and Neri, wherein the cytokine was Il-2 and the antigen binding specificity for a leukocyte was either anti-NKp30 or anti-NKp46 meets the limitations of claim 193 wherein the multifunctional polypeptide further comprises a dimerization module comprising a first Ig constant region and a second Ig constant region, wherein the anti-NKp30 or the anti-NKp46 and the Il-2 is linked to the Ig constant region as in immunocytokine format B of Kiefer and Neri. The resulting bispecific immunocytokine meets the limitation of claim 194 for having a first and second Fc region. The knobs -in-hole format A for the bispecific antibody meets the limitation of claim 195. Il-2 attached to the C-terminus of both heavy chains in format B for immunocytokines meets the limitation of claims 197 and 202 as evidenced by Boger and Goldberg who teach that cytokine receptors are activated by ligand-induced homodimerization (page 557, second column, lines 4-9). Because Il-2 is a ligand of the Il-2 receptor, it therefore comprises a receptor dimerizing domain. The resulting bispecific immunocytokine meets the limitation of claim 199 because figure 1B of Kiefer and Neri shows that the cytokine is attached to the carboxyl terminus of the heavy chain by means of a linker; and claim 200(c) wherein the tumor-targeting moiety is linked to the first antibody molecule through heavy chain-heavy chain disulfide bonds. The resulting bispecific immunocytokine meets the limitation of claim 201 wherein the first and second cytokine molecules are Il-2. The resulting bispecific immunocytokine meets the limitation of claim 205 wherein the anti-NKp30 or anti-NKp46 is a full -length antibody.
The rejection of claim 193-195, 197, 199-202, 206, 207, 209-212 under 35 U.S.C. 103 as being unpatentable over Romagne et al, Kiefer and Neri, and Boger and Goldberg as applied to claims 193-195, 197, 199-202, and 209-212 above, and further in view of Gauthier et al (WO2015/197598, cited in the previous action) and Scheuermann and Racila (Leukemia & Lymphoma, 1995, Vol. 18, pp. 385-397) is maintained for reasons of record.
Claim 206 requires that the cancer antigen to which the tumor-targeting moiety binds is present on a hematological cancer. Claim 207 specifies, in part, (iii) that the cancer antigen of claim 206 is a hematological antigen, selected from a group including CD19.
The combined teachings of Romagne et al, Kiefer and Neri and Boger and Goldberg render obvious claims 193-195, 197, 200-202, 205, 209-212 for the reasons set forth above for the administration of a bispecific immunocytokine for the treatment of Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, or Multiple Myeloma. None of Romagne et al, Kiefer and Neri nor Boger and Goldberg teach a specific anti-tumor antigen of the bispecific immunocytokine that binds to a hematological antigen.
Gauthier et al teach a multimeric proteins that bind to monovalently to an activating receptor on a NK cell and to a cancer antigen (claim 7 of ‘598). Gauthier et al exemplify the anti-NKp46 as the binding specificity which binds to the activating receptor on NK cells and anti-CD19 as the binding specificity that binds to lymphoma cells (page 58, lines 28-32).
Scheuermann and Racila teach that CD19 is broadly expressed in non-Hodgkin’s lymphomas.
It would have been prima facie obvious at the time prior to the effective filing date to construct a bispecific immunocytokine comprising anti-NKP46 and Il-2 rendered obvious by the combined teachings of Romagne et al, Kiefer and Neri and Boger and Goldberg, wherein the anti-cancer binding specificity was anti-CD19 for binding to lymphoma. One of skill in the art would have been motivated to do so by the teachings of Romagne et al that lymphomas were treatable by the combination of an anti-NKp46 antibody and Il-2; the teachings of Scheuermann and Racila that CD19 is broadly expressed in non-Hodgkin's lymphomas, thus meeting that specific limitation in claim 212(ii); the teachings of Kiefer and Neri that Il-2 can be efficiently delivered to the tumor site by antibodies and the further teachings of Kiefer and Neri that bispecific antibodies commonly comprise a cancer antigen binding specificity and a leukocyte antigen (page 185, paragraph under the heading “Antigen-binding specificities for bispecific antibody products”).
Claim 193-195, 197, 199-202, 205, 206, 207, 209-212 are rejected under 35 U.S.C. 103 as being unpatentable over Romagne et al, Kiefer and Neri, and Boger and Goldberg as applied to claims 193-195, 197, 199-202, and 209-212 above, and in further view of Desjarlais et al (U.S. 2014/0294833) and Koide (U.S.2003/0027319).
Claim 205 requires that the multifunctional polypeptide of claim 193 comprises (a) a second polypeptide in the N to C-orientation comprising (a) a VH-CH1 of a Fab molecule which binds to NKp30 or NKp46, wherein the second polypeptide is connected to the first immunoglobulin constant region; and (b) a third polypeptide comprising in the N to C- orientation, a VL-CL of the Fab.
The combined teachigns of Romagne et al, Kiefer and Neri, and Boger and Goldberg render obvious a bispecific antibody in knobs-in-hole format, wherein the antibody comprised a binding specificity for tumor antigen and a binding specificity for NKp30 or NKp46 and wherein Il-2 was fused to each carboxyl terminus of the heavy chain in the N-C direction. The combined teachings do not provide for the strcutrue of the multifunctional polypeptide wherein the antibody that binds to NKp30 or NKp46 is a FAB comprising, in the N to C-orientation a second polypeptide comprising VH-CH1 of the Fab and a a third polypeptide comprising in the N to C- orientation, a VL-CL of the FAB.
Desjariais et al teach a novel immunoglobulin that co-engages a first and second antigen, wherein one heavy chain comprises a scFv and the other heacy chain is in a FAB format comprising a variable chain and a light chain, and that the two chains are broguth together by the dimeric Fc region, termed “triple F” format (paragraph [0299]). Figure 2 (B) of ‘833 indeicates that the Fab comprises VL-CL complexed to the VH-CH1 (figure 1B). Desjariais et al teach that Fc substitutions can be made in the triple F format to skew formation of the desired product over that of underisred dimeric scFv and Fab-Fc dimers (paragraph [0301]). Desjariais et al also teach that the “triple F” format allows for separation of the desired scFv-Fab by size (paragraphs [0060] and [0064] and Figure 1. Thus, the triplet F format allows for the elimination of underisred dimeric scFv and Fab-Fc dimers, first by enrichment of the desired format and second by isolation of the desired format. Desjariais et al teach that the resulting isolated triple F format bispecific antibodies exhibited poetne bioactivity (paragraphs [0307] and [0309]). Desjariais et al o not specifically teach that a cytokine was fused to the the first or second Fc chains at the C-terminus, but Desjariais et al do teach that that an additional binding specificiaty can be fused to the C-terminus (Figure 2 of ‘833).
Koide teaches that a scFv reactive against a wide variety of tumor antigens are known in the art (paragraph [0007]).
It would have been prima facie obvous to construct the bispecific antibody in the triple F format wherein the antibody comprised a binding specificity for tumor antigen was a scFv and a antibody comprising a binding specificity for NKp30 or NKp46 was a FAB and wherein Il-2 was fused to each or either carboxyl terminus of the heavy chain in the N-C direction. One of skill in the art would have been motivated to do so by the teachings of Desjariais et al on the triple F format for bispecific antibodies allowing for enrichment and isolation of the desired bispecific without the underired mono-specifics, and the teaching of Koide that scFv to a large variaety of tumor antigens are known in the art, thus relgating the anti-tumor specifity of the triple F format to scFv for the tumor antgen and FAB for the anti-NKp30 or NKp46. One of skill n the art would have been motivated to fuse the cytokine at the C-teminus of the Fc because Kiefer and Neri teach fusion of a cytokine to bispecific antibody, wherein the N-terminus of the cytokine was fused to the C-terminus of the constant region (Figure 1) and Desjariais et al teach the fusion of a third binding specificity to the C terminus of the Fc.
Applicant argues that none of Romagne, Kiefer or Boger teach the requirement of a polypeptide in the N to C-orientation the first cytpkine connected to the immunoglobulin chain constant region because Kiefer merely teaches a bispecific antibody wherein Il-2 was fused at the carboxyl terminus of the heavy chain. This has been considered but not found persuasive. A closer look at figures 1A and 1B of Kiefer will reveal that in addition to being attached to the carboxyl terminus of the immnogloulin chain which is running in the N to C oprientation, the cytokine is also attached in the N to C direction since the “tail” of the cytokine is labeled “C”. Thus, the N terminus of the cytokine is attached to C terminus of the Fc. Applicant’s argument is moot.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 193, 194, 197-204, 206-212 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 and 21-23 of U.S. Patent No.12,384,842, (formerly 17/402,320) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims are obvious over the ‘842 claims.
Claim 9 of the ‘842 patent teaches a multispecific molecule comprising the antigen or antigen-binding portion thereof of claim 2. Claim 2 specifies that the antibody or antigen-binding portion binds to NKp30. Claim 10 teaches that the multispecific molecule of claim 9 further comprises a tumor targeting moiety, a cytokine molecule, a T-cell engager, a stromal modifying moiety or a combination thereof which meets the limitations of instant claim 193, part (ii). Claim 13 teaches that the antibody or antigen-binding portion thereof of claim 47 comprises an immunoglobulin chain constant region, which meets the limitation of “the first antibody molecule binds to NKp30 or antigen binding fragment thereof is linked to dimerization module which is an immunoglobulin constant region in claim 193 and the first FC in claim 194. Claim 12(a) teaches that the multispecific molecule comprises a linker between the targeting moiety and the cytokine or stromal modifying moiety(a) which meets the limitation of instant claims 200 and 204 requiring, in part, a linker between the cytokine moiety, the stromal modifying moiety and the tumor targeting moiety. Claim 12 also teaches a linker between (e) the targeting moiety and the immunoglobulin chain constant region which meets the limitation of a linker between the first antibody molecule that binds NKp30 or antigen-binding fragment thereof and the first immunoglobulin constant region in claim 199. Claim 21 teaches the pharmaceutical composition comprising the antibody of claim 2; claim 22 and 23 are drawn in part to a method of treating a disease or condition which is cancer by administering the antibody of claim 2, all of which render obvious a pharmaceutical composition comprising the multispecific molecule comprising the antibody of claim 2; and a method of treating a disease or condition which is cancer by administering the comprising the multispecific molecule comprising antibody of claim 2 comprising a tumor targeting antibody which fulfils the limitations of claim 209 and 210,
The claims of the application do not teach that the multispecific molecule includes an antibody of claim 2 which is a scFv; the particular cytokines of claims 193 and 201; the particular stromal modifying moieties of claim 198 and 203; the particular tumor-targeted antigens or the particular cancers treated by administration of the multispecific molecule of claim 2 comprising a tumor targeting moiety.
Section 804 IIb of the M.P.E.P. teaches:
The specification can be used as a dictionary to learn the meaning of a term in the claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)
In the instant case, the specification of the ‘842 patent teaches that cytokines of the inventive multispecific molecule include:
IL-2, IL-7, IL-10, IL-12, IL-15, IFN-α, and IFN-γ.
the stromal modifying moieties of the inventive multispecific molecule include:
hyaluronidase, a collagenase, a chondroitinase, a matrix metalloproteinase
the cancer antigens of the tumor targeting moieties of the of the inventive multispecific molecule include:
PDL1, CD47, mesothelin, ganglioside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Her2/neu, Telomerase, SAP-1, Survivin, NY-ESO-1/LAGE-1, PRAME, SSX-2, Melan-A/MART-1, Gp100/pmel17, Tyrosinase, TRP-1/-2, MC1R, β-catenin, BRCA1/2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, MUC-1, CA-125, BAGE, GAGE, NY-ESO-1, β-catenin, CDK4, CDC27, CD47, a actinin-4, TRP1/gp75, TRP2, gp100, Melan-A/MART1, gangliosides, WT1, EphA3, Epidermal growth factor receptor (EGFR), CD20, MART-2, MART-1, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TRP1, TSTA, Folate receptor alpha, L1-CAM, CAIX, EGFRvIII, gpA33, GD3, GM2, VEGFR, Intergrins (Integrin alphaVbeta3, Integrin alpha5Beta1), Carbohydrates (Le), IGF1R, EPHA3, TRAILR1, TRAILR2, or RANKL;
the T cell engagers of the of the inventive multispecific molecule include:
CD3, TCRα, TCRβ, TCRγ, TCRζ, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIMI, SLAM, CD2, or CD226;
The cancers of claims 71 and 72 of the ‘842 patent include:
solid tumor cancer, or a metastatic lesion, wherein the solid tumor cancer is one or more of pancreatic (e.g., pancreatic adenocarcinoma), breast, colorectal, lung (e.g., small or non-small cell lung cancer), skin, ovarian, or liver cancer; and the antibody of the multispecific molecule includes:
a single chain antibody…. The single chain antibody can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target protein.
Regarding claims 197 and 202, Boger and Goldberg provide evidence that cytokine receptors are activated by ligand-induced homodimerization (page 557, second column, lines 4-9). Because Il-2 is a ligand of the Il-2 receptor, it therefore comprises a receptor dimerizing domain.
Thus, instant claims 193, 197, 198, 201, 202, 203, 206-212 are obvious over claims 2 and 10 of the ‘842 patent based on the definitions of antibody, tumor targeting moiety, a cytokine moiety, a T cell engager and a stromal modifying moiety in the ‘842 specification.
.
Claims 193-195, 197, 199-204, 206-212 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 and 21-23 of U.S. Patent No.12,384,842, (formerly 17/402,320) as evidenced by Boger and Goldberg in view of Carter et al (U.S. 5,731,168).
Claim 14 of the ‘842 patent teaches that the immunoglobulin constant region is an IgG1 constant region that comprises, in part, an amino acid substitution at position 366, 394, 405, 407 and combinations thereof. The claims of the patent do not teach that the enhancement of dimerization between the first and second Fc region by providing an Fc interface of the first Fc and the second Fc with a paired cavity protuberance to provide a greater ratio of hetero-multimers to homomultimers as required in claim 195.
Carter et al teach the engineering of the CH3 interface between two immunoglobulin constant domains of an antibody and an immunoadhesin, by different mutations of the two constant domains to create a protuberance into cavity allowing for maximization of heteromultimer formation (column 36, lines 55-62). Carter et al teach the paired mutations of CH3 to form the protuberance into cavity including mutations at 366, 394, 405, and 407(column 37, Table 4).
It would have been prima facie obvious at the time prior to the effective filing date to engineer the mutation pairs into the dimerized structures of claim 14 of the ‘842 patent. One of skill in the art would have been motivated to do so in order to decrease the amount of homodimers and increase the amount of desired heterodimers.
Claims 193-195, 197, 200, 201, 202, 204, 208-212 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-69 of copending Application No. 18/172,928 in view of Kiefer and Neri (Immunological Reviews, first published February 10, 2016, Vol. 270, pp. 178-192) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562).
Claim 51 of ‘928 teaches a composition comprising an anti-NKp30 antibody, wherein the antibody is a full antibody. Claim 53 teaches that the antibody of claim 52 comprises an immunoglobulin constant region, which meets that limitation of instant claims 193 and 194 requiring a dimerization module comprising a first immunoglobulin chain constant region and a second immunoglobulin constant region. Claim 55 teaches that the dimerization of the first and second heavy chain constant regions is enhanced by providing a paired cavity protuberance, an electrostatic interaction or a strand exchange such than a greater ratio of heteromultimer to homomultimer is formed relative to a non-engineered Fc region which meets the limitations of instant claim 195. Claim 60 teaches that the antibody of claim 52 further comprise a tumor targeting moiety, an autoreactive T cell targeting moiety, or an infected cell targeting moiety, which meets the limitation of a tumor targeting moiety linked to the first antibody molecule in claim 200 wherein the tumor targeting moiety is a monovalent portion of a bispecific antibody. The T cell targeting moiety in claims 60-62 meets the limitation of the T cell engager in claim 208 . Claims 57 of the ‘928 application teaches that the antibody of claim 52 further comprises a cytokine. Claim 58 specifies that the cytokine is Il-2, Il-7, Il-15, Il-18, Il-21 or functional variants thereof.
The claims of the application do not teach that the first cytokine molecule is linked to the first immunoglobulin constant region, the second immunoglobulin constant region or both of the first and second immunoglobulin constant regions as required in instant claim 193.
Kiefer and Neri teach common formats for immunocytokines include IgG format with the cytokine linked to the heavy chain (page 180. Figure 1B). Kiefer and Neri teach common formats for bispecific antibodies including “knobs-into-hole” bispecific antibodies (page 184, Figure 2) comprising point mutations in the CH3 domain allowing for the matching of two asymmetric chains, each bearing a different antigen specificity (page 184, second column, lines 6-12 of the first full paragraph) which is consistent with claim 55 of the ‘928 application.
It would have been prima facie obvious at the time prior to the effective filing date to link the cytokines required in claims 57 and 58 of the ‘928 application to the carboxyl terminus of both heavy chains, thus rendering obvious the limitation in instant claim 193 wherein the first antibody molecule that binds to NKp30 is linked to the first immunoglobulin chain constant region and the tumor targeting moiety is also linked to a cytokine molecule as in Figure 1B of Kiefer and Neri. One of skill in the art would have been motivated to do so because Kiefer and Neri teach that the format is a common format for immunocytokines.
Regarding instant claims 197 and 202, Boger and Goldberg provide evidence that cytokine receptors are activated by ligand-induced homodimerization (page 557, second column, lines 4-9). Because interleukins and interferon gamma are cognate ligand of the corresponding receptors, they therefore comprises a receptor dimerizing domain, rendering obvious the limitations of instant claims 197 and 202.
Claims 193-195, 197, 200, 201, 202, 205, 208-212 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-69 of copending Application No. 18/172,928 in view of Kiefer and Neri (Immunological Reviews, first published February 10, 2016, Vol. 270, pp. 178-192) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562) in further view of in view of Desjarlais et al (U.S. 2014/0294833) and Koide U.S. (2003/0027319).
The teachings of Kiefer and Neri as evidenced by Boger and Goldberg render obvious the instant claims 193-195, 197, 200, 201, 202, 208-212 for the reasons set forth above.
Claims 51 of ‘928 teaches, in part, that the bispecific antibody molecule of claim 46 a FAB or a scFV, wheein the antibody of claim 46 bind to NKp30. The claim does not specifically teach that the bispecific antibody is an anti-tumor scFv and anti-NP30 FAB antibody both fused in the N to C-orientation to an antibody Fc.
Desjariais et al teach a novel immunoglobulin that co-engages a first and second antigen, wherein one heavy chain comprises a scFv and the other heacy chain is in a FAB format comprising a variable chain and a light chain, and that the two chains are broguth together by the dimeric Fc region, termed “triple F” format (paragraph [0299]). Figure 2 (B) of ‘833 indeicates that the Fab comprises VL-CL complexed to the VH-CH1 (figure 1B). Desjariais et al teach that Fc substitutions can be made in the triple F format to skew formation of the desired product over that of underisred dimeric scFv and Fab-Fc dimers (paragraph [0301]). Desjariais et al also teach that the “triple F” format allows for separation of the desired scFv-Fab by size (paragraphs [0060] and [0064] and Figure 1. Thus, the triplet F format allows for the elimination of underisred dimeric scFv and Fab-Fc dimers, first by enrichment of the desired format and second by isolation of the desired format. Desjariais et al teach that the resulting isolated triple F format bispecific antibodies exhibited poetne bioactivity (paragraphs [0307] and [0309]). Desjariais et al o not specifically teach that a cytokine was fused to the the first or second Fc chains at the C-terminus, but Desjariais et al do teach that that an additional binding specificiaty can be fused to the C-terminus (Figure 2 of ‘833).
Koide teaches that a scFv reactive against a wide variety of tumor antigens are known in the art (paragraph [0007]).
It would have been prima facie obvous to construct the bispecific antibody in the triple F format wherein the antibody comprised a binding specificity for tumor antigen was a scFv and a antibody comprising a binding specificity for NKp30 or NKp46 was a FAB and wherein Il-2 was fused to each or either carboxyl terminus of the heavy chain in the N-C direction. One of skill in the art would have been motivated to do so by the teachings of Desjariais et al on the triple F format for bispecific antibodies allowing for enrichment and isolation of the desired bispecific without the underired mono-specifics, and the teaching of Koide that scFv to a large variaety of tumor antigens are known in the art, thus relgating the anti-tumor specifity of the triple F format to scFv for the tumor antgen and FAB for the anti-NKp30 or NKp46. One of skill n the art would have been motivated to fuse the cytokine at the C-teminus of the Fc because Kiefer and Neri teach fusion of a cytokine to bispecific antibody, wherein the N-terminus of the cytokine was fused to the C-terminus of the constant region (Figure 1) and Desjariais et al teach the fusion of a third binding specificity to the C terminus of the Fc. .
This is a provisional nonstatutory double patenting rejection.
All claims are rejected.
All other rejections and/or objections as set forth in the prior Office action are withdrawn.
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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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643