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 .
Priority
This application is the National Stage application under 35 U.S.C. § 371 of International
Patent Application No. PCT/EP2021/075145, filed September 13, 2021, which claims the benefit
of U.S. Application No. 63/078, 193, filed September 14, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on dates 11/30/2023 and 09/08/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of claims
Claims 1-2, 4-9, 11, 13, 15-25, 27-29, 31-33, and 35-37 are currently pending and under examination. Claims 1, 4, 6, 8, 19-20, 24-25 and 33 have been amended. Claims 3, 10, 12, 14, 26, 30, 34, and 38-160 have been cancelled by applicant without prejudice or disclaimer.
Applicant’s arguments, filed 02/18/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 11/25/2025 Office Action and modified in order to address the most recent amendments.
Claim Rejections - 35 USC § 103
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim 1-2, 4, 6-9, 11, 13, 15, 18-19, 21-22, 24-25, 27-29, 31, 33, and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein (U.S. 2019/0256924 Al) in view of Haura (Erdafitinib Overcomes FGFR3-TACC3-Mediated Resistance to Osimertinib) sourced from IDS and further in view of Chiu (U.S. 2014/0141000 Al) sourced from IDS.
The instant claims are directed to a method of treating cancer by administering a fibroblast growth factor receptor (FGFR) inhibitor and an epidermal growth factor receptor (EGFR) inhibitor and a CCND1 inhibitor to a patient in need of cancer treatment, wherein the cancer harbors at least one FGFR2 genetic alteration or at least one FGFR3 genetic alteration,. and at least one EGFR genetic alteration wherein the EGFR/c-Met antibody comprises a first heavy chain (HC1 ), a first light chain (LC1), a second heavy chain (HC2) and a second light chain (LC2), wherein the HCl, the LC1, the HC2 and the LC2 comprise the amino acid sequences of SEQ ID NOs: 41, 42, 43, and 44, respectively.
Vogelstein et al teach Vogelstein et al. teach methods for detecting and treating a subject with cancer in which the presence of members of two or more classes of biomarkers are detected (Abstract). Vogelstein teaches a cancer can have genetic biomarkers to include EGFR and FGFR2 [0885]. Vogelstein discloses the identified treatment is any of the variety of therapeutic interventions disclosed herein including without limitation, chemotherapy, neoadjuvant chemotherapy, radiation therapy, hormone therapy, cytotoxic therapy, immunotherapy, adoptive T cell therapy and targeted therapy such as administration of kinase inhibitors (e.g., kinase inhibitors that target a particular genetic lesion, such as a translocation or mutation), (e.g. a kinase inhibitor, an antibody, a bispecific antibody), and In some embodiments in which the disease is cancer, an identified therapeutic intervention reduces the severity of the cancer, reduces a symptom of the cancer, and/or reduces the number of cancer cells present within the subject [0167]. Vogelstein also teaches embodiments in which a urothelial carcinoma has mutations in FGFR3 [0917]. Vogelstein also teaches an embodiment in which a FGFR2 inhibitor is JNJ-42756493 ( erdafitinib) [0792]. Vogelstein teaches an embodiment in which a covalent or non-covalent FGFR3 inhibitor is used and the compound of JNJ-42756493 ( erdafitinib) [0804]. Vogelstein discloses examples of cancer treatment using platinum containing compounds including carboplatin and cisplatin [0747]. Vogelstein teaches that detection of a genetic biomarker can include methods, compositions, and kits for detecting gene dysregulations such as those arising from gene fusions [0564]. Vogelstein discloses detection of genetic biomarkers FGFR2, BRAF1, EGFR [0234]. Vogelstein teaches administration of a BRAF inhibitor [0783]. Vogelstein also discloses an effective amount of a composition containing one or more therapeutic interventions can be any amount that reduces the number of cancer cells present within the subject without producing significant toxicity to the subject. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and severity of the condition (e.g., cancer) may require an increase or decrease in the actual effective amount administered [0821]. Vogelstein teaches “In some embodiments of identifying a subject as having cancer, the methods further include administering to the subject one or more therapeutic interventions. In some embodiments, the one or more therapeutic interventions are one or more of: surgery, chemotherapy, hormone therapy, targeted therapy, or radiation therapy.” [0839]. Vogelstein also discloses embodiments in which the cancer is bladder cancer or an upper-tract urothelial cancer (UTUC). [0870].
However Vogelstein does not teach a patient resistant to treatment with erdafitinib or a solid oral dose of 8-9 mg erdafitinib daily or an EGFR/c-Met antibody comprises a first heavy chain (HC1 ), a first light chain (LC1 ), a second heavy chain (HC2) and a second light chain (LC2), wherein the HCl, the LC1, the HC2 and the LC2 comprise the amino acid sequences of SEQ ID NOs: 41, 42, 43, and 44, respectively.
Haura et al. teach “[t]he FGFR pathway cooperates with the EGFR pathway in oncogenesis, and the combined EGFR and FGFR inhibition has synergistic effects/ EGFR plus FGFR inhibitors suppress the development of resistance to EGFR tyrosine kinase inhibitors” and “The patient received first-line therapy with osimertinib (80 mg orally [PO] daily)” (pg. e154, to the editor). Haura teaches a method of treating a patient with lung cancer and discloses “Erdafitinib is approved by the US Food and Drug Administration for urothelial carcinomas that harbor FGFR2 or FGFR3 fusions and activating mutations on the basis of the BLC2001 study that enrolled patients with unresectable or metastatic urothelial carcinomas harboring FGFR3 alterations or FGFR2 or FGFR3 fusions” (pg. e155, col 1) Haura teaches to orally administer 8 mg erdafitinib daily while continuing 80 mg Osimertinib oral daily dose and that within days, the patient reported less left sided pleuritic chest pain as well as a repeat computed tomography scan on day 36 revealed obvious partial response. (pg. e155, col 1 and 2) See MPEP2144.05(II)
However, Haura et al. fail to disclose treatment for a patient resistant to erdafitinib or a CCND1 or BRAF genetic alteration or an EGFR/c-Met antibody comprises a first heavy chain (HC1 ), a first light chain (LC1 ), a second heavy chain (HC2) and a second light chain (LC2), wherein the HCl, the LC1, the HC2 and the LC2 comprise the amino acid sequences of SEQ ID NOs: 41, 42, 43, and 44, respectively..
Chiu et al. teach bispecific EGFR/c-Met antibodies and methods of making and using the molecules (Abstract). Chiu discloses c-Met is frequently amplified, mutated or over-expressed in many types of cancer including bladder cancer [0007]. Chiu teaches an embodiment of the invention is method of treating a subject having cancer, comprising administering a therapeutically effective amount of the bispecific EGFR/cMet antibody of the invention to a patient in need thereof for a time sufficient to treat the cancer [0034]. Chiu discloses findings that the bispecific agents specifically binding EGFR and c-Met provide a significantly improved synergistic inhibitory effect when compared to a mixture of EGFR-binding and c-Met binding monospecific agents [0209]. Chiu also discloses an embodiment in which a bispecific epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody, comprises a) a first heavy chain (HCl), b) a second heavy chain (HC2), c) a first light chain (LC1) and a second light chain (LC2) [0362-0366]. Chiu et al. teach In some methods described herein, the antibodies of the invention may be used to treat a subject having cancer that is resistant or has acquired resistance to treatment with one or more EGFR inhibitors [0511]. Chiu also teaches "In some embodiments described herein, the bispecific EGFR/cMet antibody comprises the HCl, the LC1, the HC2 and the LC2 amino acid sequences of SEQ ID NOs: 199, 200, 201 and 202, respectively, optionally having a C-terminal lysine removed from the HCl, the HC2, or both the HCl and the HC2" [0456]. Chiu also discloses VH, VL, HC and LC antibody sequences of 199 (EM1-mAb Hl (anti-EGFR, 405L)), Sequence 200 (EM-1-mAb L1), sequence 201 (EM-1 mAb H2 (K409R, anti-cMet)) and sequence 202 (EM-1 mAb L2) [0637].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer a method of treating a patient with a urothelial carcinoma with an FGFR2 or FGFR3 genetic alteration and at least one EGFR genetic alteration by following the teachings of the pan-FGFR inhibitor erdafitinib along with other FGFR inhibitors and FGFR2, FGFR3, BRAF, CCND1, and EGFR biomarkers taught by Vogelstein with Haura’s disclosures of erdafitinib 8 mg daily oral dose and its FDA approval as a treatment for urothelial carcinoma. A skilled artisan seeking to improve a patient’s health, following Haura’s teachings of administering an EGFR and FGFR inhibitor simultaneously after prior treatment with an EGFR inhibitor. Furthermore, a person of ordinary skill would have adjusted the 8 mg erdafitinib dose to a higher or lower dose range based on patient response to treatment. See MPEP2144.05(II) It would have also been obvious to a person of ordinary skill to administer a EGFR/c-Met antibody comprising a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2) and a second light chain (LC2), wherein the HC1, LC1, HC2 and LC2 comprise the amino acid sequences of SEQ ID NOs: 41, 42, 43, and 44 because of Chiu disclosure of unexpected results in the prior art of bispecific agents specifically binding EGFR and c-Met provide a significantly improved synergistic inhibitory effect when compared to a mixture of EGFR-binding and c-Met binding monospecific agents. disclosed treating cancer in a patient with a bispecific EGFR/c-Met antibody comprising the HCl, LCI, HC2 and LC2 sequences of 199-202 which are equivalent to the sequences of 41-44 of the instant claims respectively. See MPEP 2144.
Examiner notes that administering a solid form of an oral dose of a pharmaceutical compound is well known to a person of ordinary skill in the art such as, pills, tablets, and powdered dosage forms. See MPEP 2144.03.
A person of ordinary skill in the art would have been motivated to administer a method of treating a urothelial carcinoma in a patient by administering an oral daily pharmaceutical composition comprising an EGFR and FGFR inhibitor. A skilled artisan would have had a reasonable expectation of success in treating a cancer patient with a bi specific EGFR/c-Met antibody as taught by Chiu because of the significantly improved synergistic inhibitory effects of administering bispecific agents over administering a mixture of EGFR antibody and a c-Met antibody monospecific agents and would have also combined Vogelstein and Haura’s disclosures of EGFR and FGFR inhibitors with FGFR2, FGFR3, BRAF, CCND1 biomarkers because Vogelstein, Haura and Chiu all disclose treatments for bladder cancer or urothelial carcinoma (a type of bladder cancer) and EGFR in a subject. See MPEP 2144.06.
Claim Rejections - 35 USC § 103
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein (U.S. 2019/0256924 Al) in view of Ruiz-Llorent (Abstract 5288: Mechanisms of resistance to FGFR inhibitors in urothelial cancer cell lines and patients harboring FGFR3 alterations and strategies to overcome it) sourced from IDS.
The instant claims are directed to a method of treating cancer by administering a fibroblast growth factor receptor (FGFR) inhibitor and an epidermal growth factor receptor (EGFR) inhibitor to a patient in need of cancer treatment, wherein the cancer harbors at least one FGFR2 genetic alteration or at least one FGFR3 genetic alteration wherein the patient is resistant to treatment with erdafitinib or has acquired resistance to treatment with erdafitinib.
Vogelstein et al teach Vogelstein et al. teach methods for detecting and treating a subject with cancer in which the presence of members of two or more classes of biomarkers are detected (Abstract). Vogelstein teaches a cancer can have genetic biomarkers to include EGFR and FGFR2 [0885]. Vogelstein discloses the identified treatment is any of the variety of therapeutic interventions disclosed herein including without limitation, chemotherapy, neoadjuvant chemotherapy, radiation therapy, hormone therapy, cytotoxic therapy, immunotherapy, adoptive T cell therapy and targeted therapy such as administration of kinase inhibitors (e.g., kinase inhibitors that target a particular genetic lesion, such as a translocation or mutation), (e.g. a kinase inhibitor, an antibody, a bispecific antibody), and In some embodiments in which the disease is cancer, an identified therapeutic intervention reduces the severity of the cancer, reduces a symptom of the cancer, and/or reduces the number of cancer cells present within the subject [0167]. Vogelstein also teaches embodiments in which a urothelial carcinoma has mutations in FGFR3 [0917]. Vogelstein also teaches an embodiment in which a FGFR2 inhibitor is JNJ-42756493 ( erdafitinib) [0792]. Vogelstein teaches an embodiment in which a covalent or non-covalent FGFR3 inhibitor is used and the compound of JNJ-42756493 ( erdafitinib) [0804]. Vogelstein discloses examples of cancer treatment using platinum containing compounds including carboplatin and cisplatin [0747]. Vogelstein teaches that detection of a genetic biomarker can include methods, compositions, and kits for detecting gene dysregulations such as those arising from gene fusions [0564]. Vogelstein discloses detection of genetic biomarkers FGFR2, BRAF1, EGFR [0234]. Vogelstein teaches administration of a BRAF inhibitor [0783]. Vogelstein also discloses an effective amount of a composition containing one or more therapeutic interventions can be any amount that reduces the number of cancer cells present within the subject without producing significant toxicity to the subject. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and severity of the condition (e.g., cancer) may require an increase or decrease in the actual effective amount administered [0821]. Vogelstein also discloses embodiments in which the cancer is bladder cancer or an upper-tract urothelial cancer (UTUC). [0870].
However Vogelstein does not teach a patient resistant to treatment with erdafitinib.
Ruiz-Llorent et al. teach “[d]rug sensitivity to FGFRi (Erdafitinib and AZD4547) was evaluated in bladder cancer cell lines harboring FGFR3 point mutations (pS249C) or rearrangements (FGFR3/BAIA P2L1 or TACC3). After performing 7-days proliferation assays, cell lines showing nM-range sensitivity were long-term treated with high concentrations of both compounds to induce therapeutic resistance.” and “Combination of FGFRi with additional TKIs could improve the efficacy of these drugs. Further studies and validation in clinical trials are required.”
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer a cancer therapy to a patient in need thereof by administering an EGFR and FGFR inhibitor as disclosed by Vogelstein because Ruiz-Llorent disclosed resistance to erdafitinib in urothelial cancer cells with an FGFR3 mutation or rearrangement can be mediated by genetic alterations of EGFR.
A person of ordinary skill in the art would have been motivated to administer erdafitinib and an EGFR inhibitor in a combination therapy to a patient with a urothelial cancer because Ruiz-Llorent disclosed treatment for an erdafitinib resistant cancer can be achieved in a combination therapy which would give a person of ordinary skill a reasonable expectation of success in treating urothelial cancer with an EGFR and FGFR inhibitor as disclosed by the methods of Vogelstein.
Allowable Subject Matter
Claims 16-17, 20, and 23 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Response to Arguments
Applicant's arguments filed 02/18/2026 have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Claim 1 requires, for example, administering an FGFR inhibitor and an EGFR inhibitor.) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Vogelstein discloses In some embodiments of identifying a subject as having cancer, the methods further include administering to the subject one or more therapeutic interventions. In some embodiments, the one or more therapeutic interventions are one or more of: surgery, chemotherapy, hormone therapy, targeted therapy, or radiation therapy [0839]. Vogelstein also teaches the EGFR inhibitor [0878] and an FGFR inhibitor (erdafitinib) [0792]. A skilled artisan administering a therapy for urothelial cancer would have found it prima facie obvious to select erdafitinib as a medicament for patients with Metastatic Urothelial Cancer because it was FDA approved for that purpose in 2019. Vogelstein also discloses ERBB receptor inhibitor ( e.g., an EGFR inhibitor)” [0802] and “[i]n muscle invasive bladder cancers, mutations in TP53 CDKN2A MLL and ERBB2 are also frequently found” Therefore, a person of ordinary skill would have also been motivated to select an EGFR inhibitor a administer in a combination therapy to a patient with a urothelial cancer. See MPEP 2144.05(II).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
Claims 16-17, 20 and 23 are objected to, Claims 1-2, 4-9, 11, 13, 15, 18-19, 21-22, 24-25, 27-29, 31, 33, and 35-37 are rejected.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
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