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 .
Application Status
Claims 66, 72, 76-83, and 91 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
Previous objection to the specification is withdrawn in view of amendment.
All previous rejections and objections 67-71, 73-75, and 84-90 are rendered moot in view of claim cancellations.
Previous rejection of claims 66, 72, 76-83, and 91 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Previous rejection of claims 66, 72, 76-83, and 91 under non-statutory double patenting over U.S. Patent No. US 12,139,548 B2 are withdrawn in view of claim amendments.
Previous rejection of claims 66, 72, 76-83, and 91 under non-statutory double patenting over U.S. Patent No. US 11,780,925 B2 are withdrawn in view of claim amendments.
Previous rejection of claims 81, 83, and 91 under non-statutory double patenting over copending application 18/419,527 are withdrawn in view of claim amendments.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 66, 72, 76-83, and 91 are rejected under 35 U.S.C. 103 as being unpatentable over Geuijen (WO 2015/130173 A1; IDS entered 07/31/2020) and Stravodimou (ISRN Oncol. 2014 Mar 30;2014:289836; PTO-892).
Regarding claims 66, 80-81, 83, Geuijen teaches a bispecific antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3, wherein said first antigen-binding site binds domain I of ErbB-2 and said second antigen-binding site binds domain III of ErbB-3 (claim 7), wherein said antibody comprises at least the CDR3 sequence of an ErbB-2 specific heavy chain variable region selected from the group consisting of MF3958 (claim 21), wherein said antibody comprises at least the CDR3 sequence of an ErbB-3 specific heavy chain variable region selected from the group consisting of MF3178 (claim 22), wherein the immunoglobulin light chain in the variable domain preferably comprises the amino acid sequence of figure 16C (page ), a method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB- 2/ErbB-3 positive tumor or at risk of having said tumor comprising administering to the subject an antibody or pharmaceutical composition according to any one of claims 1-35 (claim 36), wherein said tumor cell is a breast cancer, … brain cancer, … (claim 51). Geuijen further teaches combination treatment with PB4188 and chemotherapeutic drugs and cyclin inhibitors were tested in vitro (page 108, line 13-14) and synergy was seen with paclitaxel (page 109, lines 1-3) and bispecific antibodies according to the invention comprising a first antigen-binding site that binds domain I of ErbB-2 are particularly suitable for use in combination with existing anti-ErbB-2 therapies like trastuzumab and pertuzumab, because trastuzumab and pertuzumab bind different domains of ErbB-2 (page 16, lines 18-22).
Regarding claims 72 and 91, Geuijen teaches in one preferred embodiment, said antibody is antibody PB4188 (page 23, lines 26-27) and that the bispecific HER2xHER3 combination MF3958xMF3178 resulted in PB4188 (page 94, lines 4-5).
Regarding claim 77, Geuijen teaches trastuzumab and pertuzumab are only prescribed to ErbB-2 [+++] patients because patients with lower ErbB-2 concentrations typically do not exhibit a sufficient clinical response when treated with trastuzumab and pertuzumab (page 12, lines 6-9).
Regarding claim 78, Geuijen teaches in patients with HER2+ metastatic breast cancer, resistance to trastuzumab either as single-agent or in combination with chemotherapy, commonly occurs within months of starting therapy (page 2, lines 29-31). Mechanisms of resistance include signaling from other HER family of receptors and compensatory signaling from RTKs outside of the HER family such as overexpression of HER3 or its ligands (page 3, lines 1-5) and upregulation of NRGl-βΙ is a key resistance mechanism against HER2 targeted therapies. Other strategies to treat ErbB-2 positive tumors are directed towards ErbB-3 (page 3, lines 14-15). PB4188 can completely revert the hereregulin (HRG) induced phenotype (Fig 10b), PB4188 was far more effective compared to all anti-HER3 antibodies tested (Fig 10c), adding trastuzumab to PB4188 in the presence of HRG reduced the proliferation and branching/ invasion of SK-BR-3 cells compared to PB4188 alone (Fig 10e).
Regarding 79, Geuijen teaches a pharmaceutical composition comprising a bispecific antibody according to any one of claims 1-34 (claim 35).
Regarding claim 82, Geuijen teaches the bispecific for use in the treatment or prevention of the formation of metastases of breast cancer (page 62, lines 12-13).
Gueijen does not teach combination treatment with vinorelbine.
Stravodimou teaches that one of the cytotoxins that are commonly used in metastatic breast cancer is vinorelbine particularly because of its good tolerance profile (page 5, col 1, para 1) and that responses observed with the combination of vinorelbine and trastuzumab in HER2 positive patients are in general higher than with monotherapy (page 5, col 2, para 2). Stravodimou further teaches the activity of trastuzumab combined with chemotherapy in HER2 overexpressing breast cancer has been documented and we have observed in the current cohort that the combination is highly effective in terms of TTP and OS (page 6, col 1, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use vinorelbine as the chemotherapeutic as taught by Stravodimou to the method of treating cancer as with the Erbb2/ErbB3 bispecific PB4188, chemotherapeutic, and trastuzumab. The ordinary artisan would have been motivated to do so because Gueijen teaches in patients with HER2+ metastatic breast cancer, resistance to trastuzumab either as single-agent or in combination with chemotherapy, commonly occurs within months of starting therapy through overexpression of HER3 and upregulation of NRGl-βΙ. Gueijen further teaches that PB4188 can completely revert the hereregulin (HRG) induced phenotype and adding trastuzumab to PB4188 in the presence of HRG reduced the proliferation and branching/ invasion. Stravodimou teaches that vinorelbine is well tolerated and that responses observed with the combination of vinorelbine and trastuzumab in HER2 positive patients are in general higher than with monotherapy. The ordinary artisan has a reasonable expectation of success to combine PB4188, trastuzumab and vinorelbine for the treatment of trastuzumab resistant breast cancer and metastases from that breast cancer.
Response to Arguments
Applicant’s arguments with respect to claim(s) 66, 72, 76-83, and 91 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
In the effort of thoroughness, in partial response to the concept of non-obviousness based on the failure of MM-111. The results of the clinical trial NCT01774851 (PTO-892) were not posted prior to the effective filing date of the instant application as seen in the results posted section with the first result post on 06/22/2017. Denlinger (Exhibit A) confirms that MM-111 failed to meet efficacy goals and the study was closed early before the effective filing date. Karachaliou (BioDrugs. 2017 Feb;31(1):63-73; PTO-892) teaches the efficacy of MM-111 was correlated with HER2 expression in xenograft models, and in vitro studies indicated that MM-111 is more efficient when combined with lapatinib or trastuzumab. However, the clinical development of the drug was interrupted after the interim analysis results of a phase II trial comparing the combination of MM-111, trastuzumab and paclitaxel with trastuzumab and paclitaxel in HER2-positive gastric cancer. The expression of NRG in gastric cancer is lower than expected, probably explaining the low efficacy of MM-111 (page 69, col 2, para 1).
As taught by Geuijen (WO 2015/130173 A1; IDS entered 07/31/2020) above, upregulation of NRGl-βΙ is a key resistance mechanism against HER2 targeted therapies in metastatic breast cancer and strategies to treat ErbB-2 positive tumors are directed towards ErbB-3. Pederson (Mol Cancer Ther. 2015 Mar;14(3):669-80; IDS entered 03/31/2021) also teaches that strategies that target three distinct HER2 domains (I, II, and IV) with recombinant antibody mixtures overcome trastuzumab resistance synergistically (abstract). Therefore the approach to use MCLA-128, vinorelbine and trastuzumab would still be considered obvious in view of this art and mechanism of MM-111 failure.
Double Patenting
New Rejection Necessitated by Amendment
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.
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Claims 66, 72, 76-83, and 91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 5 of U.S. Patent No. US 11,780,925 B2 in view of Geuijen (WO 2015/130173 A1; IDS entered 07/31/2020) and Stravodimou (ISRN Oncol. 2014 Mar 30;2014:289836; PTO-892).
Regarding claims 66, the patented claims teach a method of treating cancer in a subject, wherein the cancer comprises an ErbB-2 and ErbB-3 positive tumor, the method comprising administering a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2 and a second antigen-binding site that can bind an extracellular part of ErbB-3 to the subject, wherein one or more cells of the cancer express an NRG1 fusion gene comprising at least the 3′ end of the NRG1 gene fused to a 5′ sequence from a different chromosomal location; wherein
the first antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:40, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:41, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:42; the second antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:54, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:55, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:56; and wherein the first antigen binding site and the second antigen binding site comprise a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:75, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:76, and a light chain CDR3 comprising the amino acid sequence SEQ ID NO:77.
(claim 4), wherein SEQ ID NOs: 40-42, and 54-56 are identical to the instant claimed sequences of the same number that correspond to MF3958 and MF3178 and SEQ ID NOs:75-77 are 100% identical to the instant claimed SEQ ID NO: 74.
Regarding claim 76, the patented claims teach wherein the tumor is a breast tumor, an ovarian tumor, a lung tumor, a non-small cell lung tumor, or a metastasis thereof (claim 5). A metastasis thereof would include a brain tumor that had metastasized from breast cancer.
The patented claims do not teach combination treatment with trastuzumab and vinorelbine.
Regarding claims 66, 80-81, 83, Geuijen teaches a bispecific antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3, wherein said first antigen-binding site binds domain I of ErbB-2 and said second antigen-binding site binds domain III of ErbB-3 (claim 7), wherein said antibody comprises at least the CDR3 sequence of an ErbB-2 specific heavy chain variable region selected from the group consisting of MF3958 (claim 21), wherein said antibody comprises at least the CDR3 sequence of an ErbB-3 specific heavy chain variable region selected from the group consisting of MF3178 (claim 22), wherein the immunoglobulin light chain in the variable domain preferably comprises the amino acid sequence of figure 16C (page ), a method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB- 2/ErbB-3 positive tumor or at risk of having said tumor comprising administering to the subject an antibody or pharmaceutical composition according to any one of claims 1-35 (claim 36), wherein said tumor cell is a breast cancer, … brain cancer, … (claim 51). Geuijen further teaches combination treatment with PB4188 and chemotherapeutic drugs and cyclin inhibitors were tested in vitro (page 108, line 13-14) and synergy was seen with paclitaxel (page 109, lines 1-3) and bispecific antibodies according to the invention comprising a first antigen-binding site that binds domain I of ErbB-2 are particularly suitable for use in combination with existing anti-ErbB-2 therapies like trastuzumab and pertuzumab, because trastuzumab and pertuzumab bind different domains of ErbB-2 (page 16, lines 18-22).
Regarding claims 72 and 91, Geuijen teaches in one preferred embodiment, said antibody is antibody PB4188 (page 23, lines 26-27) and that the bispecific HER2xHER3 combination MF3958xMF3178 resulted in PB4188 (page 94, lines 4-5).
Regarding claim 77, Geuijen teaches trastuzumab and pertuzumab are only prescribed to ErbB-2 [+++] patients because patients with lower ErbB-2 concentrations typically do not exhibit a sufficient clinical response when treated with trastuzumab and pertuzumab (page 12, lines 6-9).
Regarding claim 78, Geuijen teaches in patients with HER2+ metastatic breast cancer, resistance to trastuzumab either as single-agent or in combination with chemotherapy, commonly occurs within months of starting therapy (page 2, lines 29-31). Mechanisms of resistance include signaling from other HER family of receptors and compensatory signaling from RTKs outside of the HER family such as overexpression of HER3 or its ligands (page 3, lines 1-5) and upregulation of NRGl-βΙ is a key resistance mechanism against HER2 targeted therapies. Other strategies to treat ErbB-2 positive tumors are directed towards ErbB-3 (page 3, lines 14-15). PB4188 can completely revert the HRG induced phenotype (Fig 10b), PB4188 was far more effective compared to all anti-HER3 antibodies tested (Fig 10c), Adding trastuzumab to PB4188 in the presence of HRG reduced the proliferation and branching/ invasion of SK-BR-3 cells compared to PB4188 alone (Fig 10e).
Regarding 79, Geuijen teaches a pharmaceutical composition comprising a bispecific antibody according to any one of claims 1-34 (claim 35).
Regarding claim 82, Geuijen teaches the bispecific for use in the treatment or prevention of the formation of metastases of breast cancer (page 62, lines 12-13).
Stravodimou teaches that one of the cytotoxics that are commonly used in metastatic breast cancer is vinorelbine particularly because of its good tolerance profile (page 5, col 1, para 1) and that responses observed with the combination of vinorelbine and trastuzumab in HER2 positive patients are in general higher than with monotherapy (page 5, col 2, para 2). Stravodimou further teaches the activity of trastuzumab combined with chemotherapy in HER2 overexpressing breast cancer has been documented and we have observed in the current cohort that the combination is highly effective in terms of TTP and OS (page 6, col 1, para 2).
It would have been obvious to one of ordinary skill in the art to use the bispecific molecule of patented claims targeting HER2/HER3 in in combination with vinorelbine and trastuzumab as taught by Gueijen and Stravidomou. The ordinary artisan would have been motivated to do so because Gueijen and the patented claims teach the same bispecific molecule PB4188. Gueijen further teaches in patients with HER2+ metastatic breast cancer, resistance to trastuzumab either as single-agent or in combination with chemotherapy, commonly occurs within months of starting therapy through overexpression of HER3 and upregulation of NRGl-βΙ. Gueijen further teaches that PB4188 can completely revert the hereregulin (HRG) induced phenotype and adding trastuzumab to PB4188 in the presence of HRG reduced the proliferation and branching/ invasion. Stravodimou teaches that vinorelbine is well tolerated and that responses observed with the combination of vinorelbine and trastuzumab in HER2 positive patients are in general higher than with monotherapy. The ordinary artisan has a reasonable expectation of success to combine PB4188, trastuzumab and vinorelbine for the treatment of patient with HER2+/HER3+ MBC that expresses NRG1 to overcome the resistance to trastuzumab caused by NRG1 expression.
Claims 66, 72, 76-83, and 91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9 and 16 of U.S. Patent No. US 12,139,548 B2 in view of Geuijen (WO 2015/130173 A1; IDS entered 07/31/2020) and Stravodimou (ISRN Oncol. 2014 Mar 30;2014:289836; PTO-892).
Regarding claim 66 and 72, the patented claims teach a method of treating a human subject having an ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor comprising administering to the subject a bispecific antibody comprising: a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences of AYYIN (SEQ ID NO:49), RIYPGSGYTSYAQKFQG (SEQ ID NO:50), and PPVYYDSAWFAY (SEQ ID NO:51), respectively, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87; and a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences GYYMH (SEQ ID NO:64), WINPNSGGTNY AQKFQG (SEQ ID NO:65), and DHGSRHFWSYWGFDY (SEQ ID NO:66), respectively, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87 (claim 1), wherein SEQ ID NOs: 49-51 have 100% sequence identity to the instant claimed SEQ ID NOs: 40-42 (comprising MF3958), SEQ ID NOs:64-66 share 100% sequence identity with the instant claimed SEQ ID NOs: 54-56 (comprising MF3178), SEQ ID NO: 87 shares 100% sequence identity to the instant claimed SEQ ID NO: 74. The patented claims further teach further comprising administering to the subject at least one additional therapeutic agent, selected from BYL719, MK-2206, everolimus, saracatinib, paclitaxel, and vorinostat (claim 8), wherein the tumor is an ErbB-2/ErbB-3 positive tumor (claim 9).
Regarding claim 77, the patented claims teach wherein the subject has an ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor having less than 1,000,000 ErbB-2 cell-surface receptors per tumor cell (claim 16) (which by definition of the instant specification constitutes an ErbB-2 ++ tumor).
Regarding claim 79, the patented claims teach wherein the subject is administered a pharmaceutical composition comprising the bispecific antibody (claim 7).
The patented claims do not teach combination treatment with trastuzumab and vinorelbine.
Regarding claims 66, 80-81, 83, Geuijen teaches a bispecific antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3, wherein said first antigen-binding site binds domain I of ErbB-2 and said second antigen-binding site binds domain III of ErbB-3 (claim 7), wherein said antibody comprises at least the CDR3 sequence of an ErbB-2 specific heavy chain variable region selected from the group consisting of MF3958 (claim 21), wherein said antibody comprises at least the CDR3 sequence of an ErbB-3 specific heavy chain variable region selected from the group consisting of MF3178 (claim 22), wherein the immunoglobulin light chain in the variable domain preferably comprises the amino acid sequence of figure 16C (page ), a method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB- 2/ErbB-3 positive tumor or at risk of having said tumor comprising administering to the subject an antibody or pharmaceutical composition according to any one of claims 1-35 (claim 36), wherein said tumor cell is a breast cancer, … brain cancer, … (claim 51). Geuijen further teaches combination treatment with PB4188 and chemotherapeutic drugs and cyclin inhibitors were tested in vitro (page 108, line 13-14) and synergy was seen with paclitaxel (page 109, lines 1-3) and bispecific antibodies according to the invention comprising a first antigen-binding site that binds domain I of ErbB-2 are particularly suitable for use in combination with existing anti-ErbB-2 therapies like trastuzumab and pertuzumab, because trastuzumab and pertuzumab bind different domains of ErbB-2 (page 16, lines 18-22).
Regarding claims 72 and 91, Geuijen teaches in one preferred embodiment, said antibody is antibody PB4188 (page 23, lines 26-27) and that the bispecific HER2xHER3 combination MF3958xMF3178 resulted in PB4188 (page 94, lines 4-5).
Regarding claim 78, Geuijen teaches in patients with HER2+ metastatic breast cancer, resistance to trastuzumab either as single-agent or in combination with chemotherapy, commonly occurs within months of starting therapy (page 2, lines 29-31). Mechanisms of resistance include signaling from other HER family of receptors and compensatory signaling from RTKs outside of the HER family such as overexpression of HER3 or its ligands (page 3, lines 1-5) and upregulation of NRGl-βΙ is a key resistance mechanism against HER2 targeted therapies. Other strategies to treat ErbB-2 positive tumors are directed towards ErbB-3 (page 3, lines 14-15). PB4188 can completely revert the HRG induced phenotype (Fig 10b), PB4188 was far more effective compared to all anti-HER3 antibodies tested (Fig 10c), Adding trastuzumab to PB4188 in the presence of HRG reduced the proliferation and branching/ invasion of SK-BR-3 cells compared to PB4188 alone (Fig 10e).
Regarding claim 82, Geuijen teaches the bispecific for use in the treatment or prevention of the formation of metastases of breast cancer (page 62, lines 12-13).
Stravodimou teaches that one of the cytotoxics that are commonly used in metastatic breast cancer is vinorelbine particularly because of its good tolerance profile (page 5, col 1, para 1) and that responses observed with the combination of vinorelbine and trastuzumab in HER2 positive patients are in general higher than with monotherapy (page 5, col 2, para 2). Stravodimou further teaches the activity of trastuzumab combined with chemotherapy in HER2 overexpressing breast cancer has been documented and we have observed in the current cohort that the combination is highly effective in terms of TTP and OS (page 6, col 1, para 2).
It would have been obvious to one of ordinary skill in the art to use the bispecific molecule of patented claims targeting HER2/HER3 in combination with vinorelbine and trastuzumab as taught by Gueijen and Stravidomou. The ordinary artisan would have been motivated to do so because Gueijen and the patented claims teach the same bispecific molecule PB4188. Gueijen further teaches in patients with HER2+ metastatic breast cancer, resistance to trastuzumab either as single-agent or in combination with chemotherapy, commonly occurs within months of starting therapy through overexpression of HER3 and upregulation of NRGl-βΙ. Gueijen further teaches that PB4188 can completely revert the hereregulin (HRG) induced phenotype and adding trastuzumab to PB4188 in the presence of HRG reduced the proliferation and branching/ invasion. Stravodimou teaches that vinorelbine is well tolerated and that responses observed with the combination of vinorelbine and trastuzumab in HER2 positive patients are in general higher than with monotherapy. The ordinary artisan has a reasonable expectation of success to combine PB4188, trastuzumab and vinorelbine for the treatment of patient with HER2+/HER3+ MBC that expresses NRG1 to overcome the resistance to trastuzumab caused by NRG1 expression.
Response to Arguments
Applicant’s arguments with respect to claim(s) 66, 72, 76-83, and 91 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643