DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 March 2026 has been entered.
Claims 32, 33, 35, and 37-41, submitted on 16 March 2026, represent all claims currently under consideration.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Arguments
The 35 U.S.C. § 103 rejection of Claims 32, 33, 35, and 37-41 over Doebelle, Heymach, and Jones is withdrawn. Applicant argues that Doebelle only generically discloses the use of a second agent in combination with a TKI, with no particular suggestion of a combined treatment of a TKI with a HER2/HER3 targeting antibody. Applicant further provides evidence via Tables 1 and 2 which demonstrate a surprisingly synergistic effect in cancers which comprise an NRG1 fusion event. These tables contain the IC50 values of the claimed TKI compounds, as well as the IC50- values of anti-HER2/HER3 antibodies alone or in combination with a TKI compound. The data demonstrate that when the TKI inhibitor is used at doses more than an order of magnitude lower than its IC50 with an anti-HER2 antibody, there is a significant reduction in the IC50 of the anti-HER2 antibody against this cell which harbors an NRG1 fusion. The Examiner finds this argument persuasive. This synergistic effect is unexpected, and when combined with the lack of specific guidance from Doebelle to combine a TKI with an anti-HER2/HER3 antibody, this method is non-obvious.
The 35 U.S.C. § 103 rejections of Claims 32, 33, 35, and 37-41 over Doebelle, Lee and Jones and Doebelle, Byun, and Jones are each withdrawn as Lee, Jones, and Byun fail to resolve the failures of Doebelle, as described above.
The provisional non-statutory patenting rejection of Claims 32, 33, 35, and 37-41 over Claims 1, 3, 4, 5, and 7-9 over co-pending application US. 17/759,713 is maintained. Applicant has not provided any arguments as to why this rejection should be withdrawn. Moreover, this application has the same effective filing date (29 January 2020) as the examined application.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 32, 33, 35, and 37-41 are rejected under 35 U.S.C. 103 as being unpatentable over Carpten (US Patent No. 11,186,875; Patent Date: 30 November 2021; International Publication Date: 15 December 2016) in view of Doebelle (WO 2019/051155; Publication Date: 14 March 2019), Lee (WO 2008/1501181A1; Publication Date: 11 December 2008), and Jones (Annals of Oncology, 28: 3092-3097, 2017).
Carpten teaches a method of treating cholangiocarcinoma comprising identifying an NRG1 fusion event in a patient sample and administering to the patient having the fusion event a therapeutic agent comprising an ERBB2 (HER2) inhibitor (Claim 1). This inhibitor further comprises at least one agent selected from a group including afatinib (covalent EGFR/HER2 TKI) (Claim 2) or a combination of trastuzumab and pertuzumab (Claim 3; Figures 3 and 4). This method also comprises at least one treatment with an ERBB2 inhibitor selected from the group consisting of afatinib, trastuzumab, and pertuzumab, and can further comprise an EGFR inhibitor such as afatinib (Claims 7, 8 and 11). The ERBB2 inhibitor can include a covalent TKI (such as afatinib) or an antibody (trastuzumab or pertuzumab) (Claim 8), and the EGFR inhibitor is selected from a group which includes afatinib. These agents may be administered prior to, concurrently with, or after administration of a second composition that may or may not include the therapeutic agent (Column 9, Lines 26-29) (i.e. in combination and/or may further comprise other active agents that can potentially treat the cancer (Column 4, Lines 55-58)).
Carpten fails to teach the treatment of the claimed NRG1 fusion events, claimed cancers, and the use of the claimed compounds.
Doebelle (See IDS, 29 October 2024) teaches methods of treating or preventing HER-driven drug resistant cancer. The method of treatment involves identifying if the cancer has an NRG1 fusion, and administering a therapeutically effective amount of a compound of the invention to the subject (Page 63, Lines 7-17). The compounds of the invention are quinazoline derivatives which are small molecule EGFR inhibitors, with EGFR being a tyrosine kinase (Compound A and B, Page 10). The invention further comprises at least one additional agent that treats or prevents a HER-derive drug resistant cancers, with additional anti-proliferative agents including other molecular targeted agents that modulate parallel pathways such as Herceptin (also referred to as trastuzumab) (Page 65, Lines 10-30). Doebelle states that this method can be used to treat several NRG1 fusions, including DOC4-NRG1, CD74-NRG1, SCL3A2-NRG1, RMPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, ATP1B1-NRG1, CDH6-NRG1, APP-NRG1, AKAP13-NRG1, THBS1-NRG1, PDE7A-NRG1, THAP7-NRG1, SMAD4-NRG1, RAB3IL1-NRG1, NRG1-PMEPA1, and NRG1-STMN2 (Page 5, Lines 15-19). The specific types of cancers to be treated include lung cancer, gastric cancer, breast cancer, esophageal cancer, ovarian cancer, pancreatic cancer, colon cancer, glioblastoma, and adenocarcinoma (Page 41, Line 30- Page 42 Line 2). The method further treats a subject with cancer wherein the treatment is part of a maintenance therapy for subjects with recurring or refractory cancer, contemplating a method of treating a resistant or refractory cancer in a subject using the compounds disclosed herein (Page 59, Lines 18-22).
Lee (See IDS, 29 October 2024) teaches novel compounds for the inhibition of cancer cells induced by the overexpression of an EGFR, and the prevention of drug resistance caused by mutation to the EGFR tyrosine kinase (Abstract). Compounds of the invention include Example 24 (IACS-015293) (Page 88), Example 36 (IACS-070709) (Page 89) and Example 61 (IACS-070982) (Page 93).
Jones describes two patients with advanced cancers refractory to standard therapy, and both patients were found to be positive for NRG1 gene fusions. Patient 1 was an SDC4-NRG1 gene fusion and Patient 2 had an ATP1B1-NRG1 gene fusion. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment (Abstract). The observations of this study lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1-fusion positive in both cancers of lung and hepatocellular origin, and indicate more broadly that cancers found to be NRG1-fusion positive may benefit from such a clinical approach regardless of their origin site (Conclusion).
Carpten, Doebelle, Lee, and Jones are considered analogous to the claimed invention as all are involved in the treatment of cancers with dysregulated HER2 signaling using quinazoline-based tyrosine kinase inhibitors. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to substitute the TKIs used by Lee (IACS-015293, IACS-070709, or IACS-070982) for the treatment of the claimed cancers comprising an NRG1 fusion as Carpten states that the combination of an anti-HER2/HER3 antibody in combination with a TKI is useful for the treatment of cholangiocarcinoma with an NRG1 fusion, with Doebelle further expanding on the types of cancers and fusion events which can be treated with these TKIs and antibodies. The artisan would have a reasonable expectation of success in performing this substitution as Jones states that their study supports the use of pan HER-tyrosine kinase inhibitors for the treatment of cancers with NRG1 fusions. The use of IACS-015293, IACS-070709, or IACS-070982 in place of the compounds of the TKI of Carpten is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)), wherein the known element is the TKI IACS-015293, IACS-070709, or IACS-070982, substituted for the tyrosine kinase inhibitors of Carpten, predictably resulting in an effective cancer treatment. This substitution is also prima facie obvious substitution of a known equivalent known for the same purpose (See MPEP § 2144.06 II); the artisan would recognize that IACS-015293, IACS-070709, or IACS-070982 are each pan HER-tyrosine kinase inhibitor, which serves the same purpose as afatinib in the method of Carpten, and as Jones demonstrates, there would be a reasonable expectation that this substitution would be successful.
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 32, 33, 35, and 37-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, and 7-9 of copending Application No. 17/759,713 (Amended Claims of 18 December 2025) (‘713) (reference application) in view of Lee (WO 2008/150118A1; Publication Date: 11 December 2008) and Jones (Annals of Oncology, 28: 3092-3097, 2017).
Claim 1 of ‘713 claims the use of poziotinib in the treatment of a patient having a cancer having an NRG1 fusion, the method comprising administering to the patient a therapeutically effective amount of poziotinib and a HER2/HER3 targeting antibody. Poziotinib is also referred to as IACS-070709, which is claimed in the examined application. Claim 3 of ‘713 claims the method of Claim 1 wherein the NRG1 fusions are identical to those claimed in the examined application. Claim 5 of ‘731 claims the method of Claim 1 wherein the HER2/HER3 targeting antibody is trastuzumab, pertuzumab, or T-DM1. Claim 7 of ‘731 claims the method of Claim 1 further comprising administering an anti-cancer therapy to the patient. Claim 8 of ‘731 claims the method of Claim 7 wherein the further anti-cancer therapy is a surgical therapy, chemotherapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, or a cytokine therapy. Claim 9 of ‘731 claims the method of Claim 1 wherein the cancer is selected from several cancers which overlaps with those claimed in the examined application.
‘713 fails to teach the use of all compounds claimed in the examined application.
Lee (See IDS, 29 October 2024) teaches novel compounds for the inhibition of cancer cells induced by the overexpression of an EGFR, and the prevention of drug resistance caused by mutation to the EGFR tyrosine kinase (Abstract). Compounds of the invention include Example 24 (IACS-015293) (Page 88), Example 36 (IACS-070709) (Page 89), and Example 61 (IACS-070982) (Page 93).
Jones demonstrates the effectiveness of treating NRG1 fusion cancers with afatinib, a pan HER-tyrosine kinase inhibitor, and states that their results more broadly support the use of pan HER-tyrosine kinase inhibitors for the treatment of these cancers.
‘713, Lee, and Jones are considered analogous to the claimed invention as all are involved in the treatment of cancers which involve aberrant EGFR signaling using quinazoline-based tyrosine kinase inhibitors. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to substitute the inhibitors of Lee for poziotinib as claimed in ‘731 as Jones states that their study supports the use of pan HER-tyrosine kinase inhibitors for the treatment of cancers with NRG1 fusions, providing a reasonable expectation of success for the artisan to perform this substitution. The use of the compounds of Lee in place of poziotinib is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)), wherein the known elements are the TKI of Lee, substituted for the known TKI of ‘731, predictably resulting in an effective cancer treatment. This substitution is also prima facie obvious substitution of a known equivalent known for the same purpose (See MPEP § 2144.06 II); the artisan would recognize that the compounds of Lee are pan HER-TKIs, which serves the same purpose as poziotinib, and as Jones demonstrates, there would be a reasonable expectation that this substitution would be successful.
Regarding Claim 41, there is nothing which precludes the use of this treatment method in a patient who has undergone at least one round of anti-cancer therapy. The artisan would be motivated to apply this this treatment method to treat a patient who has undergone at least one round of anti-cancer therapy because that would indicate that the cancer was not responsive to the treatment, and thus would require a new treatment strategy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 32, 33, 35, and 37-41 are rejected.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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