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 .
Claims 165-179 are pending and being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/346,414 filed 06/06/2016 and claims benefit of 62/276,796 filed 01/08/2016 and claims benefit of 62/276,801 filed 01/08/2016 and claims benefit of 62/265,887 filed 12/10/2015 and claims benefit of 62/202,772 filed 08/07/2015 and claims benefit of 62/202,775 filed 08/07/2015 and claims benefit of 62/202,779 filed 08/07/2015, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 29, 2025 and July 29, 2024 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on December 14, 2023 are acceptable.
Specification
Applicants should amend the first line of the specification to update the relationship between the instant application and U.S. Application No. 18/185,255, filed March 16, 2023, now abandoned.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 165-179 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
Claim 165 encompasses a method of treating any individual having non-Hodgkin lymphoma, the method comprising administering to the individual:(a) a therapeutically effective amount of a polypeptide that comprises:(i) a signal-regulatory protein a (SIRP-a) D1 variant comprising SEQ ID NO: 85; and (ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, and wherein the C-terminus of the SIRP-aD1 variant is linked to the N-terminus of the human IgG1 Fc region; and(b) any anti-CD20 antibody.
Claim 166 encompasses the method of claim 165, wherein the Fc region comprises the amino acid sequence of SEQ ID NO: 91.
Claim 167 encompasses the method of claim 165, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 136.
Claim 168 encompasses the method of claim 165, wherein the polypeptide forms a dimer.
Claim 169 encompasses the method of claim 167, wherein the polypeptide forms a dimer.
Claim 170 encompasses the method of claim 165, wherein the polypeptide is part of a pharmaceutical composition that comprises the polypeptide and a pharmaceutically acceptable excipient.
Claim 171 encompasses the method of claim 167, wherein the polypeptide is part of a pharmaceutical composition that comprises the polypeptide and a pharmaceutically acceptable excipient.
Claim 172 encompasses the method of claim 165, wherein the anti-CD20 antibody is rituximab.
Claim 173 encompasses the method of claim 167, wherein the anti-CD20 antibody is rituximab.
Claim 174 encompasses the method of claim 165, wherein the anti-CD20 antibody is ofatumumab.
Claim 175 encompasses the method of claim 167, wherein the anti-CD20 antibody is ofatumumab.
Claim 176 encompasses the method of claim 165, wherein the anti-CD20 antibody is obinutuzumab.
Claim 177 encompasses the method of claim 167, wherein the anti-CD20 antibody is obinutuzumab.
Claim 178 encompasses the method of claim 165, wherein the polypeptide and/or the anti-CD20 antibody is/are administered intravenously to the individual.
Claim 179 encompasses the method of claim 165, wherein the individual is a human.
Regarding antibody, the specification discloses:
[0278] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), antibody fragments, and antibody-like proteins so long as they exhibit the desired activity. “Antibody fragments” include a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab′, F(ab′)2, and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules, and multi-specific antibodies. Monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., individual antibodies in the population have the same primary sequence except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies can be highly specific and directed against a single antigenic site (e.g., an epitope on a cancer antigen). In contrast to polyclonal antibody preparations which typically include different antibodies directed against different epitopes, each monoclonal antibody is generally directed against a single epitope on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogenous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. In some embodiments, an antibody in a composition of the present disclosure causes antibody-dependent cellular phagocytosis (ADCP) or antibody-dependent cellular cytotoxicity (ADCC). Non-limiting examples of diseases that are treated using such strategies include cancers such hematological cancers, for example leukemias (e.g., acute myeloid leukemia); immune disorders (e.g., to enhance a subject's impaired or diminished immune response, or alternately to limit a subject's over-active immune response); and pathogenic infections.
[0282] In some embodiments, an antibody targets cancer cells, for example, by binding to proteins expressed by cancer cells. Some proteins are expressed at higher levels in cancer cells than in non-cancer cells. For example, a cancer antigen is a protein that is expressed preferentially by cancer cells (e.g., it is expressed at higher levels in cancer cells than on non-cancer cells) and in some instances it is expressed solely by cancer cells. Non-limiting examples of proteins, e.g., proteins expressed by cancer cells, that are be targeted by an antibody in a composition of the disclosure include: 4-1BB, 5T4, AGS-16, ALK1, ANG-2, B7-H3, B7-H4, c-fms, c-Met, CA6, CCR4, CD123, CD19, CD20, CD22, CD27, EpCAM, CD30, CD32b, CD33, CD37, CD38, CD40, CD52, CD70, CD74, CD79b, CD98, CEA, CEACAM5, CLDN18.2, CLDN6, CS1, CTLA-4, CXCR4, DLL-4, EGFR, EGP-1, ENPP3, EphA3, ETBR, FGFR2, fibronectin, FR-alpha, Frizzled receptor, GCC, GD2, glypican-3, GPNMB, HER-2, HER3, HLA-DR, ICAM-1, IGF-1 R, IL-3R, LAG-3, LIV-1, mesothelin, MUC16, MUC1, NaPi2b, Nectin-4, Notch 2, Notch 1, OX40, PD-1, PD-L1, PD-L2, PDGFR-a, PS, PSMA, SLTRK6, STEAP1, TEM1, VEGFR, CD25, CD27L, DKK-1, CSF-1 R, or any combinations thereof.
[0285] In some embodiments, the methods disclosed herein comprise administering a polypeptide described herein (e.g., a SIRP-α D1 variant) and an immuno-oncology antibody. In some embodiments, antibodies that are used in compositions of the disclosure include, but are not limited to: cetuximab, necitumumab, pembrolizumab, nivolumab, pidilizumab, MEDI0680, MED16469, atezolizumab, avelumab, durvalumab, MEDI6383, RG7888, ipilimumab, tremelimumab, urelumab, PF-05082566, enoblituzumab, vantictumab, varlilumab, mogamalizumab, SAR650984, daratumumab, trastuzumab, trastuzumab emtansine, pertuzumab, elotuzumab, rituximab, ofatumumab, obinutuzumab, RG7155, FPA008, panitumumab, brentuximab vedotin, MSB0010718C, belimumab, bevacizumab, denosumab, panitumumab, ramucirumab, necitumumab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, MEDI0680, pidilizumab, or BMS-93659, anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-EGFR antibody, anti-PD1 antibody, anti-RANKL antibody, anti-OX40 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-CD274 antibody, anti-CTLA-4 antibody, anti-CD137 antibody, anti-4-1BB antibody, anti-B7-113 antibody, anti-FZD7 antibody, anti-CD27 antibody, anti-CCR4 antibody, anti-CD38 antibody, anti-CSF1R antibody, anti-CSF antibody, anti-CD30 antibody, anti-BAFF antibody, anti-VEGF antibody, or anti-VEGFR2 antibody. In some embodiments, the methods disclosed herein comprise administering a polypeptide comprising a SIRP-α D1 variant comprising a SIRP-α D1 domain, or a fragment thereof, having an amino acid mutation at residue 80 relative to a wild-type SIRP-α D1 domain; and at least one additional amino acid mutation relative to a wild-type SIRP-α D1 domain at a residue selected from the group consisting of: residue 6, residue 27, residue 31, residue 47, residue 53, residue 54, residue 56, residue 66, and residue 92; and an antibody, wherein the antibody is, an anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-EGFR antibody, anti-PD1 antibody, anti-RANKL antibody, anti-OX40 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-CD274 antibody, anti-CTLA-4 antibody, anti-CD137 antibody, anti-4-1BB antibody, anti-B7-H3 antibody, anti-FZD7 antibody, anti-CD27 antibody, anti-CCR4 antibody, anti-CD38 antibody, anti-CSF1R antibody, anti-CSF antibody, anti-CD30 antibody, anti-BAFF antibody, anti-VEGF antibody, or anti-VEGFR2 antibody. In some embodiments, the methods disclosed herein comprise administering a polypeptide comprising a SIRP-α D1 variant comprising a SIRP-α D1 domain, or a fragment thereof, having an amino acid mutation at residue 80 relative to a wild-type SIRP-α D1 domain; and at least one additional amino acid mutation relative to a wild-type SIRP-α D1 domain at a residue selected from the group consisting of residue 6, residue 27, residue 31, residue 47, residue 53, residue 54, residue 56, residue 66, and residue 92; and an antibody, wherein the antibody is cetuximab, necitumumab, pembrolizumab, nivolumab, pidilizumab, MEDI0680, MED16469, atezolizumab, avelumab, durvalumab, MEDI6383, RG7888, ipilimumab, tremelimumab, urelumab, PF-05082566, enoblituzumab, vantictumab, varlilumab, mogamalizumab, SAR650984, daratumumab, trastuzumab, trastuzumab emtansine, pertuzumab, elotuzumab, rituximab, ofatumumab, obinutuzumab, RG7155, FPA008, panitumumab, brentuximab vedotin, MSB0010718C, belimumab, bevacizumab, denosumab, panitumumab, ramucirumab, necitumumab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, MEDI0680, pidilizumab, or BMS-93659.
The specification exemplifies Anti-Tumor Activity of High Affinity SIRP-α Constructs in a Mouse Xenograft Tumor Model
[0393] Immunodeficient NOD scid gamma (NSG) mice (NOD.Cg-Prkdc.sup.scid Il2rg.sup.tm1Wjl/SzJ; 50 females, plus spares) were purchased as 6- to 10-week-old animals. Human lymphoma cell line GFP-Luc-Raji cells were grown in RPMI 1640 containing 10% fetal bovine serum, penicillin, streptomycin, and L-glutamine. Cells then were spun down and re-suspended at a concentration of 1.0×10.sup.7 cells/mL in serum-free medium without additives and combined 1:1 with Matrigel™ (Trevigen, Gaithersburg, MD). On Day −11 (i.e., 11 days before the projected staging day), the mice were implanted by subcutaneous injection into the left flank with 200 μl (1.0×10.sup.6 cells) per mouse of the freshly prepared GFP-Luc-Raji:Matrigel mixture. When the tumors reached a mean volume of approximately 55 mm.sup.3, fifty animals with established tumors and moderate body weights were randomized into 5 treatment groups (Group 1-5, n=10 mice each). Starting on Day 1, Groups 1 to 5 were treated with (1) SEQ ID NO: 215 [10 mg/kg (mpk), 3×/week]; (2) SEQ ID NO: 104 (10 mpk, 3×/week); (3) rituximab (5 mpk, 2×/week)+SEQ ID NO: 100 (10 mpk, 3×/week); (4) rituximab (5 mpk, 2×/week)+SEQ ID NO: 104 (10 mpk, 3×/week); or (5) rituximab (5 mpk, 2×/week)+SEQ ID NO: 215 (10 mpk, 3×/week), respectively. Doses were administered by intraperitoneal (IP) injection at 0.05 mL/mouse. For all animals, doses were administered starting on the staging day and continuing for a total of 31 days (Days 1-31).
[0394] Clinical observations were recorded twice per day (morning and evening). Additional findings were recorded as observed. Body weights were measured three times per week using an electronic balance (Ohaus SCOUT® PRO). Tumor sizes were measured three times per week, and at study completion, using microcalipers (Mitutoyo, Aurora, Illinois) to measure the perpendicular minor (width, W, and height, H) and major (length, L) dimensions. Tumor volume (mm.sup.3) was calculated using the formula for the volume of an ellipsoid sphere (L×W.sup.xH/2). Blood samples were drawn from 20 animals on Day 1 (baseline; prior to group assignment) and from all animals on Day 8 (Week 1) and Day 31 (at termination). Blood specimens were submitted for complete blood counts (CBCs) on the respective day of draw.
[0395] The SIRP-α construct of SEQ ID NO: 215 does not exhibit measurable binding to CD47 (see Table 28). Tumors in the SEQ ID NO: 215-dosed group (Group 1) grew linearly through Day 31 (FIG. 19A), similar to tumors observed in the PBS vehicle group of the same model (data not shown). This observation demonstrates ongoing tumor growth in the absence of effective treatment.
[0396] Comparisons between Groups 1 and 5 (SEQ ID NO: 215 with or without rituximab) and between Groups 2 and 4 (SEQ ID NO: 104 with or without rituximab) reveal that the combination treatments yielded significant attenuation of tumor volume, both as raw values (from Day 9) and normalized values (from Day 7). By Day 16, the majority of mice in Group 3 (SEQ ID NO: 100+rituximab) and Group 4 (SEQ ID NO: 104+rituximab) no longer harbored detectable tumors; these two combination treatments showed similar efficacy. In contrast, tumor growth appeared to recover in animals of Group 5 (SEQ ID NO: 215+rituximab) from Day 18 on. Tumor volumes of all five groups over the study period (mean+/−SEM and individual scatter plots) are presented in FIG. 19A and FIG. 19B respectively.
[0397] Complete blood count (CBC) values (red blood cells, hemoglobin, hematocrit, platelets, etc.) measured pre-dose (Day 1), 1 week after dosing (Day 9), and 4 weeks after dosing (Day 31). Parameters did not differ significantly at Week 1 or Week 4 among the five groups. Hemoglobin (HGB) values are shown in FIG. 19C. These results demonstrate that high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with rituximab in an in vivo mouse model of cancer. Furthermore, in contrast to anti-CD47 based antibody treatments, no acute episodes of anemia were observed in any of the test groups treated with the high affinity SIRP-α constructs.
Example 19: SIRP-α Fc Variant Constructs Exhibit Decreased Red Blood Cell Toxicity
[0398] Red blood cell loss is a concern when targeting CD47. To examine the effects of a SIRP-α Fc variant construct on red blood cell toxicity, mice were treated with a high affinity SIRP-α variant construct containing either a wildtype IgG1 Fc construct (SEQ ID NO: 216) or a IgG1 Fc variant construct (SEQ ID NO:96) with IgG1 mutations L234A, L235A, G237A, and N297A (IgG1_AAA_N297A). Mice were assigned to five groups of six and were treated on day 1 and 7 (see solid arrows in FIG. 20) with either: (1) PBS; (2) 10 mg/kg SEQ ID NO: 216 (wildtype IgG1 Fc); (3) 30 mg/kg SEQ ID NO: 216; (4) 10 mg/kg SEQ ID NO: 96 (IgG1_AAA_N297A); or (5) 30 mg/kg SEQ ID NO: 96. Baseline complete blood count (CBC) measurements were taken from all animals on day −7 and for three of six animals on day 1. The blood draws (see FIG. 20) rotated between three mice from each group to not exceed the amount of blood withdrawal allowed per week. As demonstrated in FIG. 20, treatment with a wildtype IgG1 containing SIRP-α D1 variant construct resulted in a dose-dependent decrease in red blood cell counts. Conversely, treatment with an IgG1_AAA_N297A containing SIRP-α D1 variant construct resulted in red blood cell counts similar to the PBS treated control group.
However, the specification does not describe the structure, e.g., amino acid sequences of heavy and light chain variable regions of any and all possible anti-CD20 for treating any and all individual having non-Hodgkin lymphoma.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Piche-Nicholas et al., (MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only (1) a method of treating an individual having non-Hodgkin lymphoma, the method comprising administering to the individual: (a) a therapeutically effective amount of a polypeptide that comprises:(i) a signal-regulatory protein a (SIRP-a) D1 variant comprising SEQ ID NO: 85; and (ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, and wherein the C-terminus of the SIRP-aD1 variant is linked to the N-terminus of the human IgG1 Fc region; and (b) an anti-CD20 antibody selected from the group consisting of rituximab, ofatumumab and Obinutuzumab, (2) The said method, wherein the Fc region comprises the amino acid sequence of SEQ ID NO: 91, (3) The said method, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 136, (4) The said method of claim 165, wherein the polypeptide forms a dimer, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 165-179 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a method of treating an individual having non-Hodgkin lymphoma, the method comprising administering to the individual:(a) a therapeutically effective amount of a polypeptide that comprises: (i) a signal-regulatory protein a (SIRP-a) D1 variant comprising SEQ ID NO: 85; and (ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, and wherein the C-terminus of the SIRP-aD1 variant is linked to the N-terminus of the human IgG1 Fc region; and (b) an anti-CD20 antibody selected from the group consisting of rituximab, ofatumumab and Obinutuzumab, (2) The said method, wherein the Fc region comprises the amino acid sequence of SEQ ID NO: 91, (3) The said method, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 136, (4) the said method of claim 165, wherein the polypeptide forms a dimer, does not reasonably provide enablement for the method as set forth in claims 165-179. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 165 encompasses a method of treating any individual having non-Hodgkin lymphoma, the method comprising administering to the individual:(a) a therapeutically effective amount of a polypeptide that comprises:(i) a signal-regulatory protein a (SIRP-a) D1 variant comprising SEQ ID NO: 85; and (ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, and wherein the C-terminus of the SIRP-aD1 variant is linked to the N-terminus of the human IgG1 Fc region; and(b) any anti-CD20 antibody.
Claim 166 encompasses the method of claim 165, wherein the Fc region comprises the amino acid sequence of SEQ ID NO: 91.
Claim 167 encompasses the method of claim 165, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 136.
Claim 168 encompasses the method of claim 165, wherein the polypeptide forms a dimer.
Claim 169 encompasses the method of claim 167, wherein the polypeptide forms a dimer.
Claim 170 encompasses the method of claim 165, wherein the polypeptide is part of a pharmaceutical composition that comprises the polypeptide and a pharmaceutically acceptable excipient.
Claim 171 encompasses the method of claim 167, wherein the polypeptide is part of a pharmaceutical composition that comprises the polypeptide and a pharmaceutically acceptable excipient.
Claim 172 encompasses the method of claim 165, wherein the anti-CD20 antibody is rituximab.
Claim 173 encompasses the method of claim 167, wherein the anti-CD20 antibody is rituximab.
Claim 174 encompasses the method of claim 165, wherein the anti-CD20 antibody is ofatumumab.
Claim 175 encompasses the method of claim 167, wherein the anti-CD20 antibody is ofatumumab.
Claim 176 encompasses the method of claim 165, wherein the anti-CD20 antibody is obinutuzumab.
Claim 177 encompasses the method of claim 167, wherein the anti-CD20 antibody is obinutuzumab.
Claim 178 encompasses the method of claim 165, wherein the polypeptide and/or the anti-CD20 antibody is/are administered intravenously to the individual.
Claim 179 encompasses the method of claim 165, wherein the individual is a human.
Regarding antibody, the specification discloses:
[0278] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), antibody fragments, and antibody-like proteins so long as they exhibit the desired activity. “Antibody fragments” include a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab′, F(ab′)2, and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules, and multi-specific antibodies. Monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., individual antibodies in the population have the same primary sequence except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies can be highly specific and directed against a single antigenic site (e.g., an epitope on a cancer antigen). In contrast to polyclonal antibody preparations which typically include different antibodies directed against different epitopes, each monoclonal antibody is generally directed against a single epitope on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogenous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. In some embodiments, an antibody in a composition of the present disclosure causes antibody-dependent cellular phagocytosis (ADCP) or antibody-dependent cellular cytotoxicity (ADCC). Non-limiting examples of diseases that are treated using such strategies include cancers such hematological cancers, for example leukemias (e.g., acute myeloid leukemia); immune disorders (e.g., to enhance a subject's impaired or diminished immune response, or alternately to limit a subject's over-active immune response); and pathogenic infections.
[0282] In some embodiments, an antibody targets cancer cells, for example, by binding to proteins expressed by cancer cells. Some proteins are expressed at higher levels in cancer cells than in non-cancer cells. For example, a cancer antigen is a protein that is expressed preferentially by cancer cells (e.g., it is expressed at higher levels in cancer cells than on non-cancer cells) and in some instances it is expressed solely by cancer cells. Non-limiting examples of proteins, e.g., proteins expressed by cancer cells, that are be targeted by an antibody in a composition of the disclosure include: 4-1BB, 5T4, AGS-16, ALK1, ANG-2, B7-H3, B7-H4, c-fms, c-Met, CA6, CCR4, CD123, CD19, CD20, CD22, CD27, EpCAM, CD30, CD32b, CD33, CD37, CD38, CD40, CD52, CD70, CD74, CD79b, CD98, CEA, CEACAM5, CLDN18.2, CLDN6, CS1, CTLA-4, CXCR4, DLL-4, EGFR, EGP-1, ENPP3, EphA3, ETBR, FGFR2, fibronectin, FR-alpha, Frizzled receptor, GCC, GD2, glypican-3, GPNMB, HER-2, HER3, HLA-DR, ICAM-1, IGF-1 R, IL-3R, LAG-3, LIV-1, mesothelin, MUC16, MUC1, NaPi2b, Nectin-4, Notch 2, Notch 1, OX40, PD-1, PD-L1, PD-L2, PDGFR-a, PS, PSMA, SLTRK6, STEAP1, TEM1, VEGFR, CD25, CD27L, DKK-1, CSF-1 R, or any combinations thereof.
[0285] In some embodiments, the methods disclosed herein comprise administering a polypeptide described herein (e.g., a SIRP-α D1 variant) and an immuno-oncology antibody. In some embodiments, antibodies that are used in compositions of the disclosure include, but are not limited to: cetuximab, necitumumab, pembrolizumab, nivolumab, pidilizumab, MEDI0680, MED16469, atezolizumab, avelumab, durvalumab, MEDI6383, RG7888, ipilimumab, tremelimumab, urelumab, PF-05082566, enoblituzumab, vantictumab, varlilumab, mogamalizumab, SAR650984, daratumumab, trastuzumab, trastuzumab emtansine, pertuzumab, elotuzumab, rituximab, ofatumumab, obinutuzumab, RG7155, FPA008, panitumumab, brentuximab vedotin, MSB0010718C, belimumab, bevacizumab, denosumab, panitumumab, ramucirumab, necitumumab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, MEDI0680, pidilizumab, or BMS-93659, anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-EGFR antibody, anti-PD1 antibody, anti-RANKL antibody, anti-OX40 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-CD274 antibody, anti-CTLA-4 antibody, anti-CD137 antibody, anti-4-1BB antibody, anti-B7-113 antibody, anti-FZD7 antibody, anti-CD27 antibody, anti-CCR4 antibody, anti-CD38 antibody, anti-CSF1R antibody, anti-CSF antibody, anti-CD30 antibody, anti-BAFF antibody, anti-VEGF antibody, or anti-VEGFR2 antibody. In some embodiments, the methods disclosed herein comprise administering a polypeptide comprising a SIRP-α D1 variant comprising a SIRP-α D1 domain, or a fragment thereof, having an amino acid mutation at residue 80 relative to a wild-type SIRP-α D1 domain; and at least one additional amino acid mutation relative to a wild-type SIRP-α D1 domain at a residue selected from the group consisting of: residue 6, residue 27, residue 31, residue 47, residue 53, residue 54, residue 56, residue 66, and residue 92; and an antibody, wherein the antibody is, an anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-EGFR antibody, anti-PD1 antibody, anti-RANKL antibody, anti-OX40 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-CD274 antibody, anti-CTLA-4 antibody, anti-CD137 antibody, anti-4-1BB antibody, anti-B7-H3 antibody, anti-FZD7 antibody, anti-CD27 antibody, anti-CCR4 antibody, anti-CD38 antibody, anti-CSF1R antibody, anti-CSF antibody, anti-CD30 antibody, anti-BAFF antibody, anti-VEGF antibody, or anti-VEGFR2 antibody. In some embodiments, the methods disclosed herein comprise administering a polypeptide comprising a SIRP-α D1 variant comprising a SIRP-α D1 domain, or a fragment thereof, having an amino acid mutation at residue 80 relative to a wild-type SIRP-α D1 domain; and at least one additional amino acid mutation relative to a wild-type SIRP-α D1 domain at a residue selected from the group consisting of residue 6, residue 27, residue 31, residue 47, residue 53, residue 54, residue 56, residue 66, and residue 92; and an antibody, wherein the antibody is cetuximab, necitumumab, pembrolizumab, nivolumab, pidilizumab, MEDI0680, MED16469, atezolizumab, avelumab, durvalumab, MEDI6383, RG7888, ipilimumab, tremelimumab, urelumab, PF-05082566, enoblituzumab, vantictumab, varlilumab, mogamalizumab, SAR650984, daratumumab, trastuzumab, trastuzumab emtansine, pertuzumab, elotuzumab, rituximab, ofatumumab, obinutuzumab, RG7155, FPA008, panitumumab, brentuximab vedotin, MSB0010718C, belimumab, bevacizumab, denosumab, panitumumab, ramucirumab, necitumumab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, MEDI0680, pidilizumab, or BMS-93659.
The specification exemplifies Anti-Tumor Activity of High Affinity SIRP-α Constructs in a Mouse Xenograft Tumor Model
[0393] Immunodeficient NOD scid gamma (NSG) mice (NOD.Cg-Prkdc.sup.scid Il2rg.sup.tm1Wjl/SzJ; 50 females, plus spares) were purchased as 6- to 10-week-old animals. Human lymphoma cell line GFP-Luc-Raji cells were grown in RPMI 1640 containing 10% fetal bovine serum, penicillin, streptomycin, and L-glutamine. Cells then were spun down and re-suspended at a concentration of 1.0×10.sup.7 cells/mL in serum-free medium without additives and combined 1:1 with Matrigel™ (Trevigen, Gaithersburg, MD). On Day −11 (i.e., 11 days before the projected staging day), the mice were implanted by subcutaneous injection into the left flank with 200 μL (1.0×10.sup.6 cells) per mouse of the freshly prepared GFP-Luc-Raji:Matrigel mixture. When the tumors reached a mean volume of approximately 55 mm.sup.3, fifty animals with established tumors and moderate body weights were randomized into 5 treatment groups (Group 1-5, n=10 mice each). Starting on Day 1, Groups 1 to 5 were treated with (1) SEQ ID NO: 215 [10 mg/kg (mpk), 3×/week]; (2) SEQ ID NO: 104 (10 mpk, 3×/week); (3) rituximab (5 mpk, 2×/week)+SEQ ID NO: 100 (10 mpk, 3×/week); (4) rituximab (5 mpk, 2×/week)+SEQ ID NO: 104 (10 mpk, 3×/week); or (5) rituximab (5 mpk, 2×/week)+SEQ ID NO: 215 (10 mpk, 3×/week), respectively. Doses were administered by intraperitoneal (IP) injection at 0.05 mL/mouse. For all animals, doses were administered starting on the staging day and continuing for a total of 31 days (Days 1-31).
[0394] Clinical observations were recorded twice per day (morning and evening). Additional findings were recorded as observed. Body weights were measured three times per week using an electronic balance (Ohaus SCOUT® PRO). Tumor sizes were measured three times per week, and at study completion, using microcalipers (Mitutoyo, Aurora, Illinois) to measure the perpendicular minor (width, W, and height, H) and major (length, L) dimensions. Tumor volume (mm.sup.3) was calculated using the formula for the volume of an ellipsoid sphere (L×W.sup.xH/2). Blood samples were drawn from 20 animals on Day 1 (baseline; prior to group assignment) and from all animals on Day 8 (Week 1) and Day 31 (at termination). Blood specimens were submitted for complete blood counts (CBCs) on the respective day of draw.
[0395] The SIRP-α construct of SEQ ID NO: 215 does not exhibit measurable binding to CD47 (see Table 28). Tumors in the SEQ ID NO: 215-dosed group (Group 1) grew linearly through Day 31 (FIG. 19A), similar to tumors observed in the PBS vehicle group of the same model (data not shown). This observation demonstrates ongoing tumor growth in the absence of effective treatment.
[0396] Comparisons between Groups 1 and 5 (SEQ ID NO: 215 with or without rituximab) and between Groups 2 and 4 (SEQ ID NO: 104 with or without rituximab) reveal that the combination treatments yielded significant attenuation of tumor volume, both as raw values (from Day 9) and normalized values (from Day 7). By Day 16, the majority of mice in Group 3 (SEQ ID NO: 100+rituximab) and Group 4 (SEQ ID NO: 104+rituximab) no longer harbored detectable tumors; these two combination treatments showed similar efficacy. In contrast, tumor growth appeared to recover in animals of Group 5 (SEQ ID NO: 215+rituximab) from Day 18 on. Tumor volumes of all five groups over the study period (mean+/−SEM and individual scatter plots) are presented in FIG. 19A and FIG. 19B respectively.
[0397] Complete blood count (CBC) values (red blood cells, hemoglobin, hematocrit, platelets, etc.) measured pre-dose (Day 1), 1 week after dosing (Day 9), and 4 weeks after dosing (Day 31). Parameters did not differ significantly at Week 1 or Week 4 among the five groups. Hemoglobin (HGB) values are shown in FIG. 19C. These results demonstrate that high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with rituximab in an in vivo mouse model of cancer. Furthermore, in contrast to anti-CD47 based antibody treatments, no acute episodes of anemia were observed in any of the test groups treated with the high affinity SIRP-α constructs.
Example 19: SIRP-α Fc Variant Constructs Exhibit Decreased Red Blood Cell Toxicity
[0398] Red blood cell loss is a concern when targeting CD47. To examine the effects of a SIRP-α Fc variant construct on red blood cell toxicity, mice were treated with a high affinity SIRP-α variant construct containing either a wildtype IgG1 Fc construct (SEQ ID NO: 216) or a IgG1 Fc variant construct (SEQ ID NO:96) with IgG1 mutations L234A, L235A, G237A, and N297A (IgG1_AAA_N297A). Mice were assigned to five groups of six and were treated on day 1 and 7 (see solid arrows in FIG. 20) with either: (1) PBS; (2) 10 mg/kg SEQ ID NO: 216 (wildtype IgG1 Fc); (3) 30 mg/kg SEQ ID NO: 216; (4) 10 mg/kg SEQ ID NO: 96 (IgG1_AAA_N297A); or (5) 30 mg/kg SEQ ID NO: 96. Baseline complete blood count (CBC) measurements were taken from all animals on day −7 and for three of six animals on day 1. The blood draws (see FIG. 20) rotated between three mice from each group to not exceed the amount of blood withdrawal allowed per week. As demonstrated in FIG. 20, treatment with a wildtype IgG1 containing SIRP-α D1 variant construct resulted in a dose-dependent decrease in red blood cell counts. Conversely, treatment with an IgG1_AAA_N297A containing SIRP-α D1 variant construct resulted in red blood cell counts similar to the PBS treated control group.
However, the specification does not teach the structure, e.g., amino acid sequences of heavy and light chain variable regions of any and all possible anti-CD20 antibodies for treating any and all individual having non-Hodgkin lymphoma.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Piche-Nicholas et al., (MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
There are insufficient in vivo working examples. It is unpredictable which undisclosed anti-CD20 antibody in combination with a polypeptide that comprises; (a) a signal-regulatory protein alpha (SIRP-α) D1 variant comprising SEQ ID NO: 85 and (ii) a human IgG1 Fc region comprising L234A, L235A, G237A and N297A mutation wherein the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region is effective for treating all mammalian individual having non-Hodgkin lymphoma.
As such, it would require undue experimentation of one skilled in the art to practice the claimed invention commensurate in scope with the claims.
Double Patenting
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 165-179 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 63-65. 67-69, 73-78, 82-83 of U.S. Patent No. 10,259,859. Although the conflicting claims are not identical, they are not patentably distinct from each other because while the ‘859 patent issued from the application which served as the great grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 63 recites a method of treating an individual having a disease or disorder, the method comprising administering to the individual a polypeptide comprising: (a) a signal-regulatory protein α (SIRP-α) D1 variant, wherein the SIRP-α D1 variant comprises the amino acid sequence, EEX.sub.1X.sub.2QX.sub.3IQPDKX.sub.4VX.sub.5VAAGEX.sub.6X.sub.7X.sub.8LX.sub.9CTX.sub.10TSLX.sub.11PVGPIQWFRGAGPX.sub.12RX.sub.13LIY.sub.14X.sub.15GX.sub.16FPRVTTVSX.sub.17X.sub.18TX.sub.19RX.sub.20NMDFX.sub.21IX.sub.22IX.sub.23X.sub.24ITX.sub.25ADAGTYYCX.sub.26KX.sub.27RKGSPDX.sub.28X.sub.29EX.sub.30KSGAGTELSVRX.sub.31KPS (SEQ ID NO: 47), wherein X.sub.1 is E, or G; X.sub.2 is L, I, or V; X.sub.3 is V, L, or I; X.sub.4 is S, or F; X.sub.5 is L, or S; X.sub.6 is S, or T; X.sub.7 is A, or V; X.sub.8 is I, or T; X.sub.9 is H, R, or L; X.sub.10 is A, V, I, or L; X.sub.11 is I, T, S, or F; X.sub.12 is A, or G; X.sub.13 is E, V, or L; X.sub.14 is K, or R; X.sub.15 is E, or Q; X.sub.16 is H, P, or R; X.sub.17 is D, or E; X.sub.18 is S, L, T, or G; X.sub.19 is K, or R; X.sub.20 is E, or N; X.sub.21 is S, or P; X.sub.22 is S, or R; X.sub.23 is S, or G; X.sub.24 is A; X.sub.25 is any amino acid; X.sub.26 is V, or I; X.sub.27 is F, L, or V; X.sub.28 is D; X.sub.29 is T, or V; X.sub.30 is F, or V; and X.sub.31 is A, or G; and comprises at least two amino acid substitutions relative to a wild-type SIRP-α D1 domain having a sequence according to any one of SEQ ID NOs: 1 to 10; and (b) an Fc variant selected from the group consisting of: (i) a human IgG1 Fc region comprising a N297A mutation; (ii) a human IgG1 Fc region comprising L234A, L235A, and G237A mutations; (iii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations; (iv) a human IgG2 Fc region comprising a N297A mutation; (v) a human IgG2 Fc region comprising A330S and P331S mutations; (vi) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations; (vii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations; and (viii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat.
64. The method of claim 63, wherein the disease or disorder is a cancer (genus), an autoimmune disease, or an inflammatory disease, whereas instant claim 165 limits the cancer to non-Hodgkin lymphoma (species).
65. The method of claim 63, wherein the disease or disorder is a cancer, and the cancer is selected from solid tumor cancer, hematological cancer, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, bladder cancer, pancreatic cancer, cervical cancer, endometrial cancer, lung cancer, bronchus cancer, liver cancer, ovarian cancer, colon and rectal cancer, stomach cancer, gastric cancer, gallbladder cancer, gastrointestinal stromal tumor cancer, thyroid cancer, head and neck cancer, oropharyngeal cancer, esophageal cancer, melanoma, non-melanoma skin cancer, Merkel cell carcinoma, virally induced cancer, neuroblastoma, breast cancer, prostate cancer, renal cancer, renal cell cancer, renal pelvis cancer, leukemia, lymphoma, sarcoma, glioma, brain tumor, and carcinoma, which corresponds to instant claim 165.
67. The method of claim 63, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 98-104, 107-113, 116-122, and 135-137, where the reference SEQ ID NO: 136 corresponds to instant claim 167, see sequence alignment below.
ALIGNMENT:
Query Match 100.0%; Score 1844; Length 345;
Best Local Similarity 100.0%;
Matches 345; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
68. The method of claim 67, further comprising administration of at least one additional agent.
69. The method of claim 68, wherein the at least one additional agent is an antibody, tumor associated antigen, or a non-antibody therapeutic.
73. The method of claim 69, wherein the at least one additional agent is an antibody.
74. The method of claim 73, wherein the antibody is a human IgG1 isotype antibody.
75. The method of claim 73, wherein the antibody is a human IgG2 isotype antibody.
76. The method of claim 73, wherein the antibody is a human IgG4 isotype antibody.
77. The method of claim 73, wherein the antibody is selected from an anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-EGFR antibody, anti-PD1 antibody, anti-OX40 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-RANKL antibody, anti-CD274 antibody, anti-CTLA-4 antibody, anti-CD137 antibody, anti-4-1BB antibody, anti-B7-H3 antibody, anti-FZD7 antibody, anti-CD27 antibody, anti-CCR4 antibody, anti-CD38 antibody, anti-CSF1R antibody, anti-CSF antibody, anti-CD30 antibody, anti-BAFF antibody, anti-VEGF antibody, or anti-VEGFR2 antibody, which corresponds to instant claim 165.
78. The method of claim 77, wherein the antibody is selected from an anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-PD-1 antibody, anti-RANKL antibody, or anti-PD-L1 antibody.
79. The method of claim 73, wherein the at least one additional agent is at least one antibody and the antibody is cetuximab, necitumumab, pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, urelumab, daratumumab, trastuzumab, trastuzumab emtansine, pertuzumab, elotuzumab, rituximab, ofatumumab, obinutuzumab, panitumumab, brentuximab vedotin, MSB0010718C, belimumab, bevacizumab, denosumab, ramucirumab, or atezolizumab, which corresponds to instant claims 172-177.
A person of skill in the art, reading the claims of the ‘859 patent, would look to the patent and follow the ‘859 patent’s express instruction on how to combine the product within the patent, e.g., Examples 18, thereby arriving at the method of the examined claims.
Claims 165-179 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 9-13, 23-27 of U.S. Patent No. 10,696,730. Although the conflicting claims are not identical, they are not patentably distinct from each other because while the ‘730 patent issued from the application which served as the grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 63 recites a method of treating an individual having cancer (genus), the method comprising administering to the individual a pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable excipient, wherein the polypeptide comprises (a) a signal-regulatory protein α (SIRP-α) D1 variant comprising SEQ ID NO: 85; and (b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region, whereas instant claims limit the cancer to non-Hodgkin lymphoma (species).
The reference SEQ ID NO: 85 is 100% identical to instant SEQ ID NO: 85, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 620; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
10. The method of claim 9, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species. The ‘730 patent also teaches the claimed anti-CD20 antibody such as rituximab, see Example 18.
11. A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises a polypeptide that comprises: (a) a signal-regulatory protein α (SIRP-α) D1 variant comprising SEQ ID NO: 85; and (b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region, which corresponds to instant claim 165.
12. The method of claim 11, wherein each monomer in the dimer comprises a polypeptide that comprises: (a) a signal-regulatory protein α (SIRP-α) D1 variant comprising SEQ ID NO: 85; and (b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region, which corresponds to instant claim 165.
13. The method of claim 11, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
23. A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 136 and a pharmaceutically acceptable excipient, which corresponds to instant claim 167, see sequence alignment below.
ALIGNMENT:
Query Match 100.0%; Score 1844; Length 345;
Best Local Similarity 100.0%;
Matches 345; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
24. The method of claim 23, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
25. A method of treating an individual having cancer (genus), the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 136, which corresponds to instant claim 167.
26. The method of claim 25, wherein each monomer in the dimer comprises a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 136, which corresponds to instant claim 167.
27. The method of claim 25, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
A person of skill in the art, reading the claims of the ‘730 patent, would look to the patent and follow the ‘730 patent’s express instruction on how to combine the product within the patent, e.g., Examples 18, thereby arriving at the method of the examined claims.
Claims 165-179 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 5-7, 9-16 of U.S. Patent No. 11,639,376. Although the conflicting claims are not identical, they are not patentably distinct from each other because while the ‘376 patent issued from the application which served as the grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 5. A method of treating an individual having a disease or disorder, the method comprising administering to the individual a polypeptide comprising: (a) a signal-regulatory protein α (SIRP-α) polypeptide or a fragment thereof that is capable of binding CD47; and (b) an Fc variant, wherein the Fc variant a human IgG1 Fc region comprising mutations L234A, L235A, G237A, and N297A, wherein numbering is according to the EU index; wherein the polypeptide does not cause acute anemia in the individual after administration, which corresponds to instant claim 165.
6. The method of claim 5, wherein the disease or disorder is a cancer (genus), an autoimmune disease, or an inflammatory disease.
7. The method of claim 5, wherein the disease or disorder is a cancer, and the cancer is selected from solid tumor cancer, hematological cancer, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma (which corresponds to instant claim 165), Hodgkin lymphoma, multiple myeloma, bladder cancer, pancreatic cancer, cervical cancer, endometrial cancer, lung cancer, bronchus cancer, liver cancer, ovarian cancer, colon and rectal cancer, stomach cancer, gastric cancer, gallbladder cancer, gastrointestinal stromal tumor cancer, thyroid cancer, head and neck cancer, oropharyngeal cancer, esophageal cancer, melanoma, non-melanoma skin cancer, Merkel cell carcinoma, virally induced cancer, neuroblastoma, breast cancer, prostate cancer, renal cancer, renal cell cancer, renal pelvis cancer, leukemia, lymphoma, sarcoma, glioma, brain tumor, and carcinoma.
9. The method of claim 5, wherein the signal-regulatory protein α (SIRP-α) polypeptide or fragment thereof that is capable of binding CD47 comprises a sequence set forth in any one of SEQ ID NOs: 78-85, wherein the reference SEQ ID NO: 85 corresponds to SEQ ID NO: 85 in instant claim 165.
The reference SEQ ID NO: 85 is 100% identical to instant SEQ ID NO: 85, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 620; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
10. The method of claim 9, further comprising administration of at least one additional agent.
11. The method of claim 10, wherein the at least one additional agent is an antibody (genus), tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
12. The method of claim 11, wherein at least two additional agents are administered.
13. The method of claim 12, wherein the at least two additional agents comprise two antibodies.
14. The method of claim 12, wherein the at least two additional agents comprise an antibody and a tumor associated antigen.
15. The method of claim 11, wherein the antibody is a human IgG1 isotype antibody, a human IgG2 isotype antibody, or a human IgG4 isotype antibody. The reference human IgG1 isotype antibody corresponds to instant claims 172-173, wherein the anti-CD20 antibody rituximab (human IgG1 isotype).
16. The method of claim 11, wherein the antibody is selected from an anti-HER2 antibody, anti-CD20 antibody, anti-CD19 antibody, anti-CS1 antibody, anti-CD38 antibody, anti-EGFR antibody, anti-OX40 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-RANKL antibody, anti-CD274 antibody, anti-CTLA-4 antibody, anti-CD137 antibody, anti-4-1BB antibody, anti-B7-H3 antibody, anti-FZD7 antibody, anti-CD27 antibody, anti-CCR4 antibody, anti-CSF1R antibody, anti-CSF antibody, anti-CD30 antibody, anti-BAFF antibody, anti-VEGF antibody, or anti-VEGFR2 antibody, which corresponds to instant claim 165.
A person of skill in the art, reading the claims of the ‘376 patent, would look to the patent and follow the ‘376 patent’s express instruction on how to combine the product within the patent, e.g., Examples 18, thereby arriving at the method of the examined claims.
Claims 165-179 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 9-13, 23-27, 36-40, 50-54 of U.S. Patent No. 11,208,459. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of ‘459 patent recite:
Issued claim 9. A method of treating an individual having cancer (genus), the method comprising administering to the individual a pharmaceutical composition comprising polypeptide, comprising: (a) a signal-regulatory protein α (SIRP-α) D1 variant comprising SEQ ID NO: 80; and (b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, wherein the C-terminus of the SIRP-αD1 variant is linked to the N-terminus of the human IgG1 Fc region, whereas instant claims limit the method to non-Hodgkin lymphoma (species).
The reference SEQ ID NO: 80 is identical to the SEQ ID NO: 80 of instant application.
ALIGNMENT:
Query Match 100.0%; Score 619; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS 119
The specification can be used as dictionary for claim terminology, see MPEP 804 II(b)(1). “The specification may be used to learn the meaning of terms and in interpreting the coverage of a claim.” In re Basell Polliolefine Italia S.P.A. 89 USPQ2d 1030 (Fed. Cir. 2008).
The patent defines “cancer” to include non-Hodgkin lymphoma, see col. 109, line 43, in particular.
The patent defines “antibody” to include anti-CD20 antibody, see col. 100, lines 5-16, col. 102, line 10. Examples of anti-CD20 antibody include rituximab, ofatumumab, or Obinutuzumab, see col. 101, line 52, in particular.
10. The method of claim 9, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
11. A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises polypeptide, comprising: (a) a signal-regulatory protein α (SIRP-α) D1 variant comprising SEQ ID NO: 80; and (b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, wherein the C-terminus of the SIRP-αD1 variant is linked to the N-terminus of the human IgG1 Fc region.
12. The method of claim 11, wherein the dimer is a homodimer.
13. The method of claim 11, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
23. A method of treating an individual having cancer, the method comprising administering to the individual the pharmaceutical composition of claim 20.
24. The method of claim 23, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
25. A method of treating an individual having cancer (genus), the method comprising administering to the individual the pharmaceutical composition of claim 21.
26. A method of treating an individual having cancer (genus), the method comprising administering to the individual the pharmaceutical composition of claim 22.
27. The method of claim 25, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
36. A method of treating an individual having cancer (genus), the method comprising administering to the individual the pharmaceutical composition of claim 33.
37. The method of claim 36, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.
38. A method of treating an individual having cancer (genus), the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises the polypeptide of claim 28.
39. The method of claim 38, wherein the dimer is a homodimer.
40. The method of claim 38, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody (genus), a tumor associated antigen, or a non-antibody therapeutic, whereas instant method limits the antibody to anti-CD20 antibody (claim 165) such as rituximab (claims 172-173), ofatumumab (claims 174-175) or Obinutuzumab (claims 176-177) species.
50. A method of treating an individual having cancer (genus), the method comprising administering to the individual a pharmaceutical composition comprising a polypeptide that comprises the amino acid sequence of SEQ ID NO: 113 and a pharmaceutically acceptable excipient.
51. The method of claim 50, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.
52. A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising the dimer of claim 41 and a pharmaceutically acceptable excipient.
53. The method of claim 52, wherein the dimer is a homodimer.
54. The method of claim 52, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.
A person of skill in the art, reading the claims of the ‘459 patent, would look to the patent and follow the ‘459 patent’s express instruction on how to combine the product within the patent, e.g., Examples 18, thereby arriving at the method of the examined claims.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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