DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election of Group I in the reply filed on 09/15/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The restriction is made final.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
The incorporation by reference is defective because the size of the text file is required to be in bytes instead of KB or kilobytes (see 37 CFR 1.52(e)(5)).
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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 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 30-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 10-13, 21-24 of U.S. Patent No. 9,068,011 B2 (‘011) in view of US Patent 8,911,726 B2 (Takahashi).
Instant claims 30-35 and 38 of the instant application are drawn to a monoclonal antibody that binds c-Met and has variable heavy chain region (VH) of SEQ ID NO:97 and variable light chain region (VL) of SEQ ID NO:101 ( see claim 2(f) of ‘011, which inherently have the heavy chain CDR1-3 (HCRD1-3) of SEQ ID NO:97 (i.e., SEQ ID NO:98-101) and light chain CDR1-3 (LCRD1-3) of SEQ ID NO:101 (i.e., SEQ ID NO:102-104). Claims 33-35 specify the antibody is, respectively, bivalent, a full-length antibody and a human IgG1 antibody. Claim 36 recites the antibody is a “stabilized” human IgG4 antibody. Claim 37 is drawn to the IgG4 antibody having amino acid Arg409 substituted with Lys, Thr, Met or Leu. Claim 38 limits the antibody of claim 30 to a monovalent antibody. Instant claims 39-40 are drawn to a bispecific antibody comprising the c-Met binding site of claims 30 and 32. Claims 41-42 are respectively drawn to a pharmaceutical comprising the monoclonal antibody of claim 30 or comprising bispecific antibody of claim 39.
US Patent ‘011 claim 1 is drawn to a c-Met human monoclonal antibody, wherein the CDRs are defined by consensus sequences. HCDR1-3 of SEQ ID NO:194-196 encompassing instant SEQ ID NO:98-101, and LCDR1-3 of SEQ ID NO:209-211 encompassing instant SEQ ID NO:102-104. Claim 24(c) recites the instant H - and L-CDR1-3 sequences. Claim 2 (which does not depend from claim 1), section (f), recites a human c-Met monoclonal antibody having the same VH and VL of the instant claims (SEQ IDNO:97 and 101, respectively). Claims 5, 10 and 13 depend from claim 1 and respectively recite a bivalent antibody, a full-length antibody and a monovalent antibody. Claim 17 is drawn to the antibody of claim 1 comprising a hinge region comprising CPPC. Claim 21 recites a bispecific antibody comprising the human c-Met antibody of claim 1 and claim 22 recites a pharmaceutical composition comprising the antibody of claim 1. Patent ‘011 does not claim wherein the antibody isotype is an IgG1 or a stabilized human IgG4, including IgG4 which comprises amino acid R409 substituted with K, T, M or L according to the EU index of Kabat.
Takahashi (US 8,911,726) teaches stabilized human IgG4 antibodies (col. 2, lines 46-47), including wherein R at position 409 of human IgG4 is substituted with K, T, M or L to improve stability (col. 2, lines 60-65). IgG4-derived products have lower complement activation and antibody-dependent cellular cytotoxicity (ADCC) and, therefore, are appropriate as pharmaceuticals (col. 1, lines 43-47). Claim 8 is drawn to a method of inhibiting antibody aggregation by introducing the substitution at position R409. However, Takahashi also teaches “In recent years, many monoclonal antibodies have been placed on the market. However, most of the monoclonal antibodies used as pharmaceutical agents that have been on the market or clinically developed are derived from IgG1.”
It would have been obvious wherein the instant c-Met antibody was a full-length human IgG4 antibody because Takahashi taught that IgG4 antibodies are appropriate for pharmaceuticals and introducing substitution R409 into the IgG4 region inhibits antibody aggregation and stabilizes the antibody. Alternatively, it would have been obvious wherein the human c-Met antibody was of the IgG1 isotype since that is the type of most monoclonal antibodies clinically developed or on the market. It further would have been obvious wherein the human c-Met antibody of IgG1 or stabilized IgG4 was in a pharmaceutical composition comprising either the monoclonal or bispecific antibody since ‘011 claimed a pharmaceutical composition comprising the c-Met-binding antibody.
US Patent 9,068,011 B2 was filed as application 13/583,743 and issued as a patent on 30 June 2015. It issued to the same inventive entity and the same assignee as the instant application. Although a restriction requirement between the product claims and the methods of use claims was issued in 13/583,743, the instant application was not “filed as a result” of that restriction requirement. It was filed as a continuation instead of a divisional application. Further, 13/583,743 was not copending at the time the instant application was filed. Accordingly, the protections of 35 U.S.C. 121 do not apply.
Claims 30-37 and 39-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 10-13, 21-24 of U.S. Patent No. 9,593,164 B2 (‘164) in view of US Patent 8,911,726 B2 (Takahashi).
Instant claims 30-35 of the instant application are drawn to a human monoclonal antibody that binds human c-Met and has variable heavy chain region (VH) of SEQ ID NO:97 and variable light chain region (VL) of SEQ ID NO:101, which are identical to SEQ ID NO:201 and 202, respectively, of ‘164, and which inherently have the heavy chain CDR1-3 (HCRD1-3) of SEQ ID NO:98-101 and light chain CDR1-3 (LCRD1-3) of SEQ ID NO:102-104. Claims 33-35 specify the antibody is, respectively, bivalent, a full-length antibody and a human IgG1 antibody. Claim 36 recites the antibody is a “stabilized” human IgG4 antibody. Claim 37 is drawn to the IgG4 antibody having amino acid Arg409 substituted with Lys, Thr, Met or Leu. Claims 41 and 42 are dawn respectively to a pharmaceutical comprising the monoclonal antibody of claim 30 and comprising the bispecific antibody of claim 39.
US Patent ‘164 claim 1 is a bispecific antibody that binds c-Met and comprises a heavy chain comprising SEQ ID NO:201 and light chain comprising SEQ ID NO:202. Claim 2 is drawn to a pharmaceutical composition comprising the antibody of claim 1. Patent ‘164 does not claim wherein the antibody isotype is an IgG1 or a stabilized human IgG4, including IgG4 which comprises amino acid R409 substituted with K, T, M or L according to the EU index of Kabat.
Takahashi (US 8,911,726) teaches stabilized human IgG4 antibodies (col. 2, lines 46-47), including wherein R at position 409 of human IgG4 is substituted with K, T, M or L to improve stability (col. 2, lines 60-65). IgG4-derived products have lower complement activation and antibody-dependent cellular cytotoxicity (ADCC) and, therefore, are appropriate as pharmaceuticals (col. 1, lines 43-47). Claim 8 is drawn to a method of inhibiting antibody aggregation by introducing the substitution at position R409. However, Takahashi also teaches “In recent years, many monoclonal antibodies have been placed on the market. However, most of the monoclonal antibodies used as pharmaceutical agents that have been on the market or clinically developed are derived from IgG1.” The invention is focused on a CD40 antibody, which includes a monoclonal full-length antibody as well as a partial-length antibody (col. 7, lines 41-52).
It would have been obvious wherein the c-Met antibody was a full-length human IgG4 antibody because Takahashi taught that IgG4 antibodies are appropriate for pharmaceuticals and introducing substitution R409 into the IgG4 region inhibits antibody aggregation and stabilizes the antibody. Alternatively, it would have been obvious wherein the human c-Met antibody was of the IgG1 isotype since that is the type of most monoclonal antibodies clinically developed or on the market. It further would have been obvious wherein the human c-Met antibody of IgG1 or stabilized IgG4 was in a pharmaceutical composition comprising either the monoclonal or bispecific antibody since ‘164 claimed a pharmaceutical composition comprising the c-Met-binding antibody.
Claims 30-37 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15 of U.S. Patent No. 9,580,508 B2 (‘508) in view of US Patent 8,911,726 B2 (Takahashi).
Instant claims 30-35 of the instant application are drawn to a human monoclonal antibody that binds human c-Met and has variable heavy chain region (VH) of SEQ ID NO:97 and variable light chain region (VL) of SEQ ID NO:101, which are identical to SEQ ID NO:201 and 202, respectively of ‘164, and which inherently have the heavy chain CDR1-3 (HCRD1-3) of SEQ ID NO:98-101 and light chain CDR1-3 (LCRD1-3) of SEQ ID NO:102-104. Claims 33-35 specify the antibody is, respectively, bivalent, a full-length antibody and a human IgG1 antibody. Claim 36 recites the antibody is a “stabilized” human IgG4 antibody. Claim 37 is drawn to the IgG4 antibody having amino acid Arg409 substituted with Lys, Thr, Met or Leu. Claim 41 is dawn to a pharmaceutical comprising the monoclonal antibody of claim 30.
US Patent ‘508 claim 1 is drawn to a method of treating a subject having a c-Met and/or EGFR expressing cancer comprising administering a bispecific antibody binding EGFR and c-Met, wherein the c-Met-binding site comprises a heavy chain comprising SEQ ID NO:201 and light chain comprising SEQ ID NO:202. Claim 15 is drawn to a method of inhibiting growth or proliferation of cells that express EGFR and/or c-MET by contacting the cells with the bispecific antibody. Patent ‘508 does not claim wherein the antibody isotype is an IgG1 or a stabilized human IgG4, including IgG4 which comprises amino acid R409 substituted with K, T, M or L according to the EU index of Kabat.
Takahashi (US 8,911,726) teaches stabilized human IgG4 antibodies (col. 2, lines 46-47), including wherein R at position 409 of human IgG4 is substituted with K, T, M or L to improve stability (col. 2, lines 60-65). IgG4-derived products have lower complement activation and antibody-dependent cellular cytotoxicity (ADCC) and, therefore, are appropriate as pharmaceuticals (col. 1, lines 43-47). Claim 8 is drawn to a method of inhibiting antibody aggregation by introducing the substitution at position R409. However, Takahashi also teaches “In recent years, many monoclonal antibodies have been placed on the market. However, most of the monoclonal antibodies used as pharmaceutical agents that have been on the market or clinically developed are derived from IgG1.” The invention is focused on an CD40 antibody, which includes a monoclonal full-length antibody as well as a partial-length antibody (col. 7, lines 41-52).
The bispecific antibody used in the methods of ‘508 renders a c-Met monoclonal antibody having the same VH and VL obvious since the methods include treatment of a c-Met expressing cancer. It would have been obvious wherein the c-Met antibody was a full-length human IgG4 antibody because Takahashi taught that IgG4 antibodies are appropriate for pharmaceuticals and introducing substitution R409 into the IgG4 region inhibits antibody aggregation and stabilizes the antibody. Alternatively, it would have been obvious wherein the human c-Met antibody was of the IgG1 isotype since that is the type of most monoclonal antibodies clinically developed or on the market. It further would have been obvious wherein the human c-Met antibody of IgG1 or stabilized IgG4 was in a pharmaceutical composition comprising either the monoclonal or bispecific antibody since ‘164 claimed a pharmaceutical composition comprising the c-Met-binding antibody.
Claims 30-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 9,695,242 B2 (‘242) in view of US Patent 8,911,726 B2 (Takahashi).
Instant claims 30-35 are drawn to a human monoclonal antibody that binds human c-Met and has variable heavy chain region (VH) of SEQ ID NO:97 and variable light chain region (VL) of SEQ ID NO:101, which are identical to SEQ ID NO:201 and 202, respectively, of ‘164, and which inherently have the heavy chain CDR1-3 (HCRD1-3) of SEQ ID NO:98-101 and light chain CDR1-3 (LCRD1-3) of SEQ ID NO:102-104. Claims 33-35 specify the antibody is, respectively, bivalent, a full-length antibody and a human IgG1 antibody. Claim 36 recites the antibody is a “stabilized” human IgG4 antibody. Claim 37 is drawn to the IgG4 antibody having amino acid Arg409 substituted with Lys, Thr, Met or Leu. Claim 38 limits the antibody of claim 30 to a monovalent antibody. Instant claims 39-40 are drawn to a bispecific antibody comprising the c-met binding site of claims 30 and 32. Claims 41 and 42 are dawn respectively to a pharmaceutical comprising the monoclonal antibody of claim 30 and comprising the bispecific antibody of claim 39.
US Patent ‘242 claim 1 is drawn to a polynucleotide encoding a bispecific antibody that binds c-Met and comprises a heavy chain comprising SEQ ID NO:201 and light chain comprising SEQ ID NO:202. Claim 5 is drawn to a method of producing a bispecific anti-EGFR x anti-c-Met antibody by combining bivalent anti-EGFR and bivalent anti-c-Met antibodies, each comprising two heavy and two light chains, i.e., were full-length antibodies, under reducing conditions. Patent ‘164 does not claim wherein the antibody isotype is an IgG1 or a stabilized human IgG4, including IgG4 which comprises amino acid R409 substituted with K, T, M or L according to the EU index of Kabat.
Takahashi (US 8,911,726) teaches stabilized human IgG4 antibodies (col. 2, lines 46-47), including wherein R at position 409 of human IgG4 is substituted with K, T, M or L to improve stability (col. 2, lines 60-65). IgG4-derived products have lower complement activation and antibody-dependent cellular cytotoxicity (ADCC) and, therefore, are appropriate as pharmaceuticals (col. 1, lines 43-47). Claim 8 is drawn to a method of inhibiting antibody aggregation by introducing the substitution at position R409. However, Takahashi also teaches “In recent years, many monoclonal antibodies have been placed on the market. However, most of the monoclonal antibodies used as pharmaceutical agents that have been on the market or clinically developed are derived from IgG1. The invention is focused on an CD40 antibody, which includes a monoclonal full-length antibody as well as a partial-length antibody (col. 7, lines 41-52).
The claimed encoding polynucleotide of ‘242 renders obvious the anti-cMet antibody is encodes. Under reducing conditions, that artisan of ordinary skill would have reasonably expected the presence of single arm, i.e., monovalent, form of human c-Met binding antibody because it has a functional Fab fragment. It would have been obvious wherein the encoded bivalent c-Met antibody was a full-length human IgG4 antibody because Takahashi taught that IgG4 antibodies are appropriate for pharmaceuticals and introducing substitution R409 into the IgG4 region inhibits antibody aggregation and stabilizes the antibody. Alternatively, it would have been obvious wherein the human c-Met antibody was of the IgG1 isotype since that is the type of most monoclonal antibodies clinically developed or on the market. It further would have been obvious wherein the human c-Met antibody of IgG1 or stabilized IgG4 was in a pharmaceutical composition comprising either the monoclonal or bispecific antibody since Takahashi taught that antibodies for therapeutic use are generally IgG or IgG4 isotypes.
Claims 30-37 and 39-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-11 and 21-22 of U.S. Patent No. 12,247,077 B2 (‘077) in view of US 8,911,726 B2 (Takahashi).
Claims 30-35 of the instant application are drawn to a human monoclonal antibody that binds human c-Met and has particular heavy and light chain variable region sequences. These sequences are identical to those of ‘077 as follows: instant variable heavy chain region (VH) of SEQ ID NO:97 is identical to instant SEQ ID NO:193 of ‘077 and instant variable light chain region (VL) of SEQ ID NO:101 is identical to instant SEQ ID NO:194 of ‘077. In agreement with this, instant heavy chain CDR1-3 (HCRD1-3) of SEQ ID NO:97 (i.e., SEQ ID NO:98-101) are the same as SEQ ID NO:216-218 of ‘077, and instant light chain CDR1-3 (LCRD1-3) of SEQ ID NO:101 (i.e., SEQ ID NO:102-104) are the same as SEQ ID NO:219-221 of ‘77. Claims 33-35 specify the antibody is, respectively, bivalent, a full-length antibody and a human IgG1 antibody. Claim 36 recites the antibody is a “stabilized” human IgG4 antibody. Claim 37 is drawn to the IgG4 antibody having amino acid Arg409 substituted with Lys, Thr, Met or Leu. Instant claims 39-40 are drawn to a bispecific antibody comprising the c-met binding site of claims 30 and 32. Claims 41-42 are respectively drawn to a pharmaceutical comprising the monoclonal antibody of claim 30 or bispecific antibody of claim 39.
Copending application ‘077 claims (claims 1 and 4) a bispecific antibody that binds c-Met and EGFR. The c-Met portion has a VH and VL and CDRs thereof of ‘077 are identical to the instantly claimed antibody (see above). The bispecific antibody renders the instant monoclonal antibody obvious and anticipates the instant bispecific antibody. Claim 5 specifies the heavy chains are an IgG1 isotype. Claim 6-8 specify the IgG1 bispecific antibody comprises a heavy chain substitution of K409R. Claim 11 is drawn to a method of treating cancer with the bispecific antibody. Similarly, claim 22 is drawn to a method of inhibiting growth or metastasis of EGFR and/or c-Met expressing tumor or cancer cells. US ‘077 does not claim wherein the antibody isotype is a stabilized human IgG4.
Takahashi (US 8,911,726) teaches stabilized human IgG4 antibodies (col. 2, lines 46-47), including wherein R at position 409 of human IgG4 is substituted with K, T, M or L to improve stability (col. 2, lines 60-65). IgG4-derived products have lower complement activation and antibody-dependent cellular cytotoxicity (ADCC) and, therefore, are appropriate as pharmaceuticals (col. 1, lines 43-47). Claim 8 is drawn to a method of inhibiting antibody aggregation by introducing the substitution at position R409.
The bispecific antibody of ‘077 renders obvious a c-Met monoclonal antibody having the same VH and VL, especially because it teaches treatment of a-Met expressing cancer or inhibition of c-Met expressing tumor or cancer cells. It would have been obvious wherein the c-Met antibody was a full-length human IgG4 antibody, including with a R409K substitution, because Takahashi taught that IgG4 antibodies are appropriate for pharmaceuticals and introducing substitution R409 into the IgG4 region inhibits antibody aggregation and stabilizes the antibody. It further would have been obvious wherein the antibody was in a pharmaceutical composition since ‘077 claims a method of treatment.
Claims 30-37 and 39-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5 and 11 of copending Application No. 19/027,363 (‘363) in view of US 8,911,726 B2 (Takahashi).
Claims 30-35 of the instant application are drawn to a monoclonal antibody that binds c-Met and has particular heavy and light chain variable region sequences. These sequences are identical to copending application ‘363. Instant variable heavy chain region (VH) of SEQ ID NO:97 is identical to instant SEQ ID NO:193 of ‘363. Instant variable light chain region (VL) of SEQ ID NO:101 is identical to instant SEQ ID NO:194 of ‘363. In agreement with this, instant heavy chain CDR1-3 (HCRD1-3) of SEQ ID NO:97 (i.e., SEQ ID NO:98-101) are the same as SEQ ID NO:216-218 of ‘363, and instant light chain CDR1-3 (LCRD1-3) of SEQ ID NO:101 (i.e., SEQ ID NO:102-104) are the same as SEQ ID NO:219-221 of ‘363. Claims 33-35 specify the antibody is, respectively, bivalent, a full-length antibody and a human IgG1 antibody. Claim 36 recites the antibody is a “stabilized” human IgG4 antibody. Claim 37 is drawn to the IgG4 antibody having amino acid Arg409 substituted with Lys, Thr, Met or Leu. Instant claims 39-40 are drawn to a bispecific antibody comprising the c-Met binding site of claims 30 and 32. Claims 41-42 are respectively drawn to a pharmaceutical comprising the monoclonal antibody of claim 30 or bispecific antibody of claim 39.
Copending application ‘363 claims (claims 1 and 4) a bispecific antibody that binds c-Met and EGFR. The c-Met portion has a VH and VL and CDRs identical to the instantly claimed antibody (see above). The bispecific antibody renders the instant monoclonal antibody obvious and anticipates the instant bispecific antibody. Claim 5 specifies the heavy chains are an IgG1 isotype. Claim 11 is drawn to a method of treating an EGFR or c-Met expressing tumor or cancer cells with the bispecific antibody. Application ‘363 does not claim wherein the antibody isotype is a stabilized human IgG4 or wherein amino acid R409 is substituted with K, T, M or L or wherein it comprises a hinge region comprising CPPC according to the EU index of Kabat.
Takahashi (US 8,911,726) teaches stabilized human IgG4 antibodies (col. 2, lines 46-47), including wherein R at position 409 of human IgG4 is substituted with K, T, M or L to improve stability (col. 2, lines 60-65). IgG4-derived products have lower complement activation and antibody-dependent cellular cytotoxicity (ADCC) and, therefore, are appropriate as pharmaceuticals (col. 1, lines 43-47). Claim 8 is drawn to a method of inhibiting antibody aggregation by introducing the substitution at position R409.
The bispecific antibody of ‘363 renders obvious a c-Met monoclonal antibody having the same VH and VL, especially because it teaches treatment of a c-Met expressing cancer or inhibition of c-Met expressing tumor or cancer cells. It would have been obvious wherein the c-Met antibody was a full-length human IgG4 antibody, including with a R409K substitution, because Takahashi taught that IgG4 antibodies are appropriate for pharmaceuticals and introducing substitution R409 into the IgG4 region inhibits antibody aggregation and stabilizes the antibody. It further would have been obvious wherein the antibody was in a pharmaceutical composition since ‘363 said in a bispecific form it was useful for the treatment of cancer.
‘363 shares three inventors with the instant application.
This is a provisional nonstatutory double patenting rejection.
Claim Rejections - 35 USC § 112, First Paragraph
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Claim 36 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 36 is drawn to an isolated human monoclonal antibody which binds human c-Met and comprises designated variable heavy and light chain CDR1-3 and which is “a stabilized IgG4 antibody.” The specification provides only two embodiments of a stabilized IgG4 anti-c-Met antibody: i) comprising a substitution at position R409 with an amino acid which is K, A, T, M or L, and/or ii) comprising a substitution at position 405 with an amino acid which is A, V, G, I or L, and which does or does not comprise a Cys-Pro-Pro-Cys (SEQ ID NO:213) sequence in the hinge region (p. 30, third paragraph, through paragraph bridging pp. 31-32). These two IgG4 heavy chain substitutions meet the written description provision of 35 USC 112, first paragraph. The first has been shown to increase stability by inhibiting aggregation (see US 8,911,726, col. 22, lines 60-67). The second can lead to monovalent antibody arm formation that may facilitate pairing with a monovalent antibody having a different arm (e.g., one with a heavy chain having R405K and the other having F409L), since in vivo native IgG4 antibodies may have the undesirable ability to exchange Fab arms with therapeutic antibodies, though one could argue that does not create a “stabilized” IgG4 antibody (see, for example, post-filing reference Steinhardt et al., Pharmaceutics, 12(1):3, 13 pages, 2019, e.g. p. 3/13, second paragraph, and p. 5/13; and Labrijn et al., Nat. Biotechnol. 27(8):767-771 with online methods (2 pages), 2009, p. 770, col. 1, last paragraph). However, the claims are directed to or encompass any IgG4-derived sequences that have the property of stabilization.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states 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).
The Written Description Guidelines for Examination of Patent Applications (MPEP § 2163) indicates, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus…." [See MPEP § 2163(II)(A)(3)(a)(ii)] The claims are drawn to a human monoclonal antibody that binds human c-Met and is a stabilized human IgG4 antibody. The specification does not have a limiting definition of a “stabilized human IgG4 antibody” and provides only two embodiments (see above). The recitation of the function of the IgG4 antibody being “stabilized” does not convey a common structure. It is not sufficient for a specification to define the "stabilized human IgG4 antibody” solely by its principal biological property, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. Per the Enzo court's example, (Enzo Biochem, Inc. v. Gen-Probe Inc., 63 USPQ2d 1609 (CA FC 2002) at 1616) of a description of an anti-inflammatory steroid, i.e., a steroid (a. generic structural term) couched "in terms of its function of lessening inflammation of tissues" which, the court stated, "fails to distinguish any steroid from others having the same activity or function" and the expression "an antibiotic penicillin" fails to distinguish a particular penicillin molecule from others possessing the same activity and which therefore, fails to satisfy the written description requirement. Simply reciting the function of stabilization does not allow the skilled artisan to readily envision those IgG4 antibodies that meet the functional limitation aside from those disclosed or known in the prior art and, as such, does not satisfy the written-description requirement. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the genus claimed by function. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
With the exception of the two IgG4 Fc position substitutions referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The antibody itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, only an IgG4 antibody comprising a substitution or R at position 409 with an amino acid which is K, A, T, M or L, and/or ii) comprising a substitution of F at position 405 with an amino acid which is A, V, G, I or L, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). 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).
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US 8,802,089 B2 teaches anti-CD32B antibodies, including single-chain Fv (scFv) monovalent antibodies and those with stabilized human IgG4 heavy chain constant domains comprising a substitution at R409 with K, T, M or L (col. 24, lines 11-20 and 35-42). This application has the same assignee as and shares inventors with the instant application. It does not teach a human c-Met antibody. It has an earlier effective filing date than the instant application is cumulative with Takahashi above for teaching a stabilized human IgG4 antibodies and in general for teaching a monovalent (e.g., scFv) antibody.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
November 10, 2025