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 .
Election/Restrictions
Applicant’s election without traverse of the below-listed species in the reply filed on 06/01/2026 is acknowledged.
Elected Species:
A human population comprising subjects having liver metastases who have received an immune checkpoint inhibitor therapy;
A secondary condition of an absolute neutrophil count of no less than 1500/mm3; and
A linker having formula -Aa-Ww-Yy- wherein -A- is a stretcher unit, a is 0 or 1, -W- is an amino acid unit, w is an integer from 0 to 1, -Y- is a spacer unit, and y is 0, 1, or 2.
Claim Status
Claims 2-13, 15, 20-21, 23, 25, 29-44, 49, 51-52, 56, 65-66, 69, 73-75, 78-81, 83-85, 87-90, 92-93, and 96-98 have been cancelled and claims 24, 26-28, and 91 have been amended, as requested in the amendment filed on 06/01/2026. Following the amendment, claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are pending in the instant application.
Claims 17-18, 24, 27-28, and 48 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of invention in the Response filed 06/01/2026, there being no allowable generic or linking claim.
Claims 1, 14, 16, 19, 22, 26, 45-47, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1, 14, 16, 19, 22, 26, 45-47, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 have an effective filing date of September 17, 2020 corresponding to PRO 63/080,013.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/10/2023 and 06/01/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because Figures 5 and 12 comprise text that is blurry and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because it is less than 50 words in length. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is further objected to because it contains an embedded hyperlink and/or other form of browser-executable code at Pages 1-3. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the use of the terms Tecentriq, Opdivo, Imfinzi, Bavencio, Keytruda (see, for example, Paragraph 0010), and TWEEN (see, for example, Pages 13-14), which are trade names and/or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 14, 16, 19, 22, 26, 45-46, 50, 53-55, 57-62, 64, 67-68, 70-72, 76-77, 82, 86, and 94-95 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”) as evidenced by PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as "PADCEV") and US 8,637,642 (US patent document citation A01 on 10/10/2023 IDS; herein after referred to as “Satpayev”).
Rosenberg discloses a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy; the primary end point was objective response rate per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability (Abstract, Methods; emphasis added). Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies (Abstract: Conclusion). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added). Table A1 of the Appendix section provides a summary of demographics and disease characteristics at baseline for patients in the study, wherein it is specifically noted that patients included in the study having previously been treated with anti-PD-1/L1 therapies include treatment with nivolumab, pembrolizumab, atezolizumab, avelumab, and/or durvalumab (emphasis added).
It is noted that Rosenberg discloses the administration of the ADC enfortumab vedotin, however Rosenburg does not disclose the structure nor antibody sequences thereof. However, these features are inherent to the ADC, as evidenced by PADCEV and Satpayev. Moreover, it is noted that enfortumab vedotin goes by the additional identifiers: EV, PADCEV, AGS-22M6E (comprising antibody identified as Ha22-2(2,4)6.1), AGS-22C3E, and ASG-22C3E (see Paragraph 00376 of the instant specification).
PADCEV discloses prescribing information for enfortumab vedotin-ejfv (i.e., PADCEV, enfortumab vedotin) for injection, for intravenous use. More specifically, Section 11 of PDACEV discloses that enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006), wherein conjugation takes place on cysteine residues that comprise the interchain disulfide
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bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1 (i.e., approximately 4 MMAE molecules per antibody) (Page 11). Notably, the structure of enfortumab vedotin-ejfv is reproduced below (Id.):
Satpayev teaches an anti-191P4D12 antibody designated as Ha22-2(2,4)6.1, wherein said antibody comprises (i) the heavy chain variable region consisting of the amino acid sequence ranging from 20th E residue to the 136th S residue of SEQ ID NO:7, and (ii) the light chain variable region consisting of the amino acid sequence ranging from 23rd D residue to the 130th R residue of SEQ ID NO:8 (Column 26, Lines 52-66). The heavy chain of Ha22-2(2,4)6.1 consists of the amino acid sequence ranging from 20th E residue to the 466th K residue of SEQ ID NO:7 and the light chain of Ha22-2(2,4)6.1 consists of amino acid sequence ranging from 23rd D residue to the 236th C residue of SEQ ID NO: 8 sequence (Column 28, Lines 56-63). It is specifically noted that residues 20-136 and 20-466 of Satpayev SEQ ID NO: 7 are an exact match to instant SEQ ID NO: 22 and residues 20-466 of instant SEQ ID NO: 7, respectively. It is specifically noted that residues 23-130 and 23-236 of Satpayev SEQ ID NO: 8 are an exact match to instant SEQ ID NO: 23 and residues 23-236 of instant SEQ ID NO: 8, respectively. Furthermore, Satpayev SEQ ID NOs: 7 and 8 comprise exact matches to (i) CDRs H1-3 of instant SEQ ID NOs: 9-11 (Kabat numbering) and 16-18 (IMGT numbering) and (ii) CDRs L1-3 of instant SEQ ID NOs: 12-14 (Kabat numbering) and 19-21 (IMGT numbering).
Thus, as evidenced by PADCEV and Satpayev, Rosenberg anticipates a method of treating urothelial cancer (e.g., metastatic or locally advanced urothelial carcinoma) in a human subject comprising administering to the subject an effective amount of an ADC wherein: (i) the ADC comprises an antibody or antigen binding fragment thereof binds 191P4D12 and comprises the instantly claimed sequences, said antibody or antigen binding fragment thereof being conjugated to one or more units of MMAE (e.g., via the instantly claimed linker, the ADC being enfortumab vedotin), and said ADC being administered at the claimed doses and according to the claimed dosing schedule; (ii) the subject has liver metastases, has been previously treated with an immune checkpoint inhibitor therapy and/or platinum-based chemotherapy, has an ANC of no less than 1500/mm3, has no more than Grade 2 sensory or motor neuropathy, has no active CNS metastases, and/or has no uncontrolled diabetes; and (iii) the subject, or a population of subjects, who receive the treatment experience the claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response.
Claims 1, 46-47, 50, 53-55, 59-62, 64, 67-68, 70-72, 76-77, and 86 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107") as evidenced by PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as “PADCEV” and US 8,637,642 (US patent document citation A01 on 10/10/2023 IDS; herein after referred to as “Satpayev”).
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
It is noted that NCT03474107 discloses the administration of the ADC enfortumab vedotin, however NCT03474107 does not disclose the structure nor antibody sequences thereof. However, these features are inherent to the ADC, as evidenced by PADCEV and Satpayev. Moreover, it is noted that enfortumab vedotin goes by the additional identifiers: EV, PADCEV, AGS-22M6E (comprising antibody identified as Ha22-2(2,4)6.1), AGS-22C3E, and ASG-22C3E (see Paragraph 00376 of the instant specification).
PADCEV discloses prescribing information for enfortumab vedotin-ejfv (i.e., PADCEV, enfortumab vedotin) for injection, for intravenous use. More specifically, Section 11 of PDACEV discloses that enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006), wherein conjugation takes place on cysteine residues that comprise the interchain disulfide
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bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1 (i.e., approximately 4 MMAE molecules per antibody) (Page 11). Notably, the structure of enfortumab vedotin-ejfv is reproduced below (Id.):
Satpayev teaches an anti-191P4D12 antibody designated as Ha22-2(2,4)6.1, wherein said antibody comprises (i) the heavy chain variable region consisting of the amino acid sequence ranging from 20th E residue to the 136th S residue of SEQ ID NO:7, and (ii) the light chain variable region consisting of the amino acid sequence ranging from 23rd D residue to the 130th R residue of SEQ ID NO:8 (Column 26, Lines 52-66). The heavy chain of Ha22-2(2,4)6.1 consists of the amino acid sequence ranging from 20th E residue to the 466th K residue of SEQ ID NO:7 and the light chain of Ha22-2(2,4)6.1 consists of amino acid sequence ranging from 23rd D residue to the 236th C residue of SEQ ID NO: 8 sequence (Column 28, Lines 56-63). It is specifically noted that residues 20-136 and 20-466 of Satpayev SEQ ID NO: 7 are an exact match to instant SEQ ID NO: 22 and residues 20-466 of instant SEQ ID NO: 7, respectively. It is specifically noted that residues 23-130 and 23-236 of Satpayev SEQ ID NO: 8 are an exact match to instant SEQ ID NO: 23 and residues 23-236 of instant SEQ ID NO: 8, respectively. Furthermore, Satpayev SEQ ID NOs: 7 and 8 comprise exact matches to (i) CDRs H1-3 of instant SEQ ID NOs: 9-11 (Kabat numbering) and 16-18 (IMGT numbering) and (ii) CDRs L1-3 of instant SEQ ID NOs: 12-14 (Kabat numbering) and 19-21 (IMGT numbering).
Thus, as evidenced by PADCEV and Satpayev, NCT03474107 anticipates a method of treating urothelial cancer in a human subject comprising administering to the subject an effective amount of an ADC wherein: (i) the ADC comprises an antibody or antigen binding fragment thereof binds 191P4D12 and comprises the instantly claimed sequences, said antibody or antigen binding fragment thereof being conjugated to one or more units of MMAE (e.g., via the instantly claimed linker, the ADC being enfortumab vedotin); and (ii) the subject has liver metastases, has been previously treated with an immune checkpoint inhibitor therapy and/or platinum-based chemotherapy, has an ANC of no less than 1500/mm3, has no more than Grade 2 sensory or motor neuropathy, has no active CNS metastases, and/or has no uncontrolled diabetes.
Claims 1, 14, 16, 19, 22, 26, 45-46, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, and 94-95 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2023/0025600 A1 (US patent document citation A17 on 10/10/2023 IDS; herein after referred to as "Gartner") as evidenced by non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”).
Gartner teaches methods for the treatment of cancers with antibody drug conjugates (ADC) that bind to 191P4D12 proteins; also provided are methods for the treatment of urothelial cancer using an antibody drug conjugate (ADC) that binds 191P4D12 (Abstract). In a first embodiment, Gartner teaches a method of treating cancer in a human subject, comprising (a) administering to the subject a first regimen comprising an effective amount of an antibody drug conjugate (ADC), wherein the ADC comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE),
wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; wherein the subject has urothelial cancer; and wherein the subject has received an immune checkpoint inhibitor therapy and received a chemotherapy (Paragraphs 0008-0011; emphasis added). It is specifically noted that Gartner SEQ ID NOs: 22 and 23 are exact matches for instant SEQ ID NOs: 22 and 23, respectively. An additional embodiment further limits the method of the first embodiment wherein the ADC is administered on days 1, 8, and 15 of a 28 day cycle (Paragraph 0013; emphasis added). Any of the above-listed embodiments may be further drawn to urothelial cancer that is locally advanced or metastatic (Paragraphs 0014-0015; emphasis added). In any of the above-listed embodiments, the immune checkpoint inhibitor therapy is a PD-1 inhibitor or a PD-L1 inhibitor (Paragraphs 0016-0017; emphasis added). In any of the above-listed embodiments, the chemotherapy is a platinum-based chemotherapy (Paragraph 0018; emphasis added). For any of the above-listed embodiments, the first regimen comprises an ADC dose of about 1.25 mg/kg of the subject’s body weight (Paragraph 0023; emphasis added). The method of the above-listed embodiments may further comprise determining peripheral neuropathy in the subject, and if the peripheral neuropathy is no less than Grade 2, withholding the administration of the antibody drug conjugate (i.e., the subject does not receive treatment if peripheral neuropathy is Grade ≥2) (Paragraphs 0045-0046; emphasis added) wherein the peripheral neuropathy is predominantly sensory neuropathy (Paragraph 0053; emphasis added). In the method of any one of the above-listed embodiments, the antibody or antigen binding fragment thereof comprises: (i) CDR Hl comprising the amino acid sequence of SEQ ID NO:9, CDR H2 comprising the amino acid sequence of SEQ ID NO:10, CDR H3 comprising the amino acid sequence of SEQ ID NO: 11 and CDR L1 comprising the amino acid sequence of SEQ ID NO: 12, CDR L2 comprising the amino acid sequence of SEQ ID NO: 13, and CDR L3 comprising the amino acid sequence of SEQ ID NO:14; (ii) CDR Hl comprising the amino acid sequence of SEQ ID NO: 16, CDR H2 comprising the amino acid sequence of SEQ ID NO:17, CDR H3 comprising the amino acid sequence of SEQ ID NO:18 and CDR L1 comprising the amino acid sequence of SEQ ID NO: 19, CDR L2 comprising the amino acid sequence of SEQ ID NO:20, and CDR L3 comprising the amino acid sequence of SEQ ID NO:21; (iii) CDR Hl consisting of the amino acid sequence of SEQ ID NO:9, CDR H2 consisting of the amino acid sequence of SEQ ID NO: 10, CDR H3 consisting of the amino acid sequence of SEQ ID NO: 11 and CDR L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:14; or (iv) CDR Hl consisting of the amino acid sequence of SEQ ID NO:16, CDR H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR H3 consisting of the amino acid sequence of SEQ ID NO: 18 and CDR L1 consisting of the amino acid sequence of SEQ ID NO:19, CDR L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:21 (Paragraphs 0234-0237). It is specifically noted that Gartner SEQ ID NOs: 9-14 and 16-21 are exact matches to instant SEQ ID NOs: 9-14 and 16-21, respectively. In the method of any one of the above-listed embodiments, the antibody or antigen binding fragment thereof comprises: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID
NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23; and (ii) a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising
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the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8 (Paragraphs 0238-0239). It is specifically noted that Gartner residues 20-466 of SEQ ID NO: 7 and residues 23-236 of SEQ ID NO: 8 are exact matches to residues 20-466 of instant SEQ ID NO: 7 and residues 23-236 of instant SEQ ID NO: 8, respectively, and Gartner SEQ ID NOs: 22 and 23 are exact matches to instant SEQ ID NOs: 22 and 23, respectively. In any of the above-listed embodiments, the antigen binding fragment is: (i) a Fab, F(ab')2, Fv or scFv fragment; (ii) a fully human antibody; and/or (iii) recombinantly produced (Paragraphs 0240-0242; emphasis added). Paragraphs 0243-0253 disclose the above-listed embodiments, wherein structural details of the ADC are provided; it is noted that any one of the above-listed embodiments has an ADC of the below-listed structure:
wherein L- represents the antibody or antigen binding fragment thereof and wherein p is: (i) from 1 to 10; (ii) from 2 to 8; (iii) from 3 to 5; (iv) from 3 to 4; (v) about 4; or (vi) about 3.8 (Paragraphs 0254-0259). For any one of the above-listed embodiments, the ADC is formulated in a pharmaceutical composition comprising: (i) about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and hydrochloride, and wherein the pH of the pharmaceutical composition is about 6.0 at 25°C; or (ii) about 9 mM histidine, about 11 mM histidine hydrochloride monohydrate, about 0.02% (w/v) TWEEN-20, and about 5.5% (w/v) trehalose dihydrate, and wherein the pH of the pharmaceutical composition is about 6.0 at 25° C (Paragraphs 0260-0261; emphasis added). It is specifically noted that TWEEN-20 is also commonly known as polysorbate-20. In any one of the above-listed embodiments, the ADC is administered by an intravenous (IV) injection or infusion and/or the ADC or the ADC formulated in the pharmaceutical composition is administered by an intravenous (IV) injection or infusion over about 30 minutes (Paragraphs 0265-0266; emphasis added). Gartner further discloses that in some embodiments, the one or more other treatments for cancer, which the subjects have received or from which the cancers of the subjects have progressed or relapsed, are a PD-1 inhibitor or a PD-Ll inhibitor wherein (i) the PD-1 inhibitor is pembrolizumab or nivolumab; and (ii) the PD-Ll inhibitor is atezolizumab, avelumab, or durvalumab (Paragraph 0426; emphasis added). In some the antibody drug conjugate is administered to (i) patients with metastatic urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with an immune checkpoint inhibitor or (ii) patients with locally advanced urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with an immune checkpoint inhibitor (Paragraph 0838). Gartner further teaches an example in section 6.3.2.1 (see Page 89), wherein PADCEV (i.e., enfortumab vedotin) was evaluated in EV-201 (NCT03219333), a single-arm, multicenter trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-Ll inhibitor and platinum-based chemotherapy; patients were excluded if they had active CNS metastases, ongoing sensory or motor neuropathy >Grade 2, or uncontrolled diabetes defined as hemoglobin AlC (HbAlc) ≥8% or HbAlc ≥7% with associated diabetes symptoms (Paragraph 0870; emphasis added). Ninety percent of patients had visceral metastases, including 40% with liver metastases; Nectin-4 expression was detected in all patients tested (n=120); the median number of prior systemic therapies was 3 (range: 1 to 6) wherein forty-six percent of
patients received prior PD-1 inhibitor, 42% received prior PD-Ll inhibitor, and an additional 13% received both PD-1 and PD-Ll inhibitors and sixty-six percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin- based regimens, and an additional 8% received both cisplatin and carboplatin-based regimens (Paragraph 0871; emphasis added). Efficacy results are presented in Table 21 (see Page 89) wherein the confirmed ORR was 44%, CR was 12%, PR was 32%, and the median duration of response was 7.6 months.
It is noted that Gartner does not specifically teach median progression free survival of patients treated according to the disclosed methods, notably by the method of NCT03219333; Rosenburg is a publication corresponding to NCT03219333 which provides more detailed results/outcomes which result from treating the cohort of patients according to the methods of section 6.3.2.1 of Gartner.
Rosenberg discloses that enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added).
Thus, as evidenced by Rosenberg, Gartner anticipates a method of treating urothelial cancer (e.g., metastatic or locally advanced urothelial carcinoma) in a human subject comprising administering to the subject an effective amount of an ADC wherein: (i) the ADC comprises an antibody or antigen binding fragment thereof binds 191P4D12 and comprises the instantly claimed sequences, said antibody or antigen binding fragment thereof being conjugated to one or more units of MMAE (e.g., via the instantly claimed linker, the ADC being enfortumab vedotin), and said ADC being administered in the claimed formulation, at the claimed doses, and according to the claimed dosing schedule; (ii) the subject has liver metastases, has been previously treated with an immune checkpoint inhibitor therapy and/or platinum-based chemotherapy, has an ANC of no less than 1500/mm3, has no more than Grade 2 sensory or motor neuropathy, has no active CNS metastases, and/or has no uncontrolled diabetes; and (iii) the subject, or a population of subjects, who receive the treatment experience the claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response.
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, 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 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”) in view of non-patent literature PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as “PADCEV”, US 8,637,642 (US patent document citation A01 on 10/10/2023 IDS; herein after referred to as “Satpayev”), and non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107").
Rosenberg discloses a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy; the primary end point was objective response rate per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability (Abstract, Methods; emphasis added). Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies (Abstract: Conclusion). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added). Table A1 of the Appendix section provides a summary of demographics and disease characteristics at baseline for patients in the study, wherein it is specifically noted that patients included in the study having previously been treated with anti-PD-1/L1 therapies include treatment with nivolumab, pembrolizumab, atezolizumab, avelumab, and/or durvalumab (emphasis added).
However, Rosenburg does not disclose the structure nor antibody sequences corresponding to enfortumab vedotin, nor does Rosenberg teach or suggest that patients receiving treatment have an absolute neutrophil count (ANC) of ≥1500/mm3. These deficiencies are remedied by PADCEV, Satpayev, and NCT03474107. Furthermore, it is noted that enfortumab vedotin goes by the additional identifiers: EV, PADCEV, AGS-22M6E (comprising antibody identified as Ha22-2(2,4)6.1), AGS-22C3E, and ASG-22C3E (see Paragraph 00376 of the instant specification).
PADCEV discloses prescribing information for enfortumab vedotin-ejfv (i.e., PADCEV, enfortumab vedotin) for injection, for intravenous use. More specifically, Section 11 of PDACEV discloses that enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006), wherein conjugation takes place on cysteine residues that comprise the interchain disulfide
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bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1 (i.e., approximately 4 MMAE molecules per antibody) (Page 11). Notably, the structure of enfortumab vedotin-ejfv is reproduced below (Id.):
PADCEV further teaches a formulation of enfortumab vedotin, wherein PADCEV for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL; each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0. Thus, the formulation of PADCEV comprises approximately 20 mM histidine (total), 0.02% w/v polysorbate 20, and 5.5% w/v trehalose dihydrate.
Satpayev teaches an anti-191P4D12 antibody designated as Ha22-2(2,4)6.1, wherein said antibody comprises (i) the heavy chain variable region consisting of the amino acid sequence ranging from 20th E residue to the 136th S residue of SEQ ID NO:7, and (ii) the light chain variable region consisting of the amino acid sequence ranging from 23rd D residue to the 130th R residue of SEQ ID NO:8 (Column 26, Lines 52-66). The heavy chain of Ha22-2(2,4)6.1 consists of the amino acid sequence ranging from 20th E residue to the 466th K residue of SEQ ID NO:7 and the light chain of Ha22-2(2,4)6.1 consists of amino acid sequence ranging from 23rd D residue to the 236th C residue of SEQ ID NO: 8 sequence (Column 28, Lines 56-63). It is specifically noted that residues 20-136 and 20-466 of Satpayev SEQ ID NO: 7 are an exact match to instant SEQ ID NO: 22 and residues 20-466 of instant SEQ ID NO: 7, respectively. It is specifically noted that residues 23-130 and 23-236 of Satpayev SEQ ID NO: 8 are an exact match to instant SEQ ID NO: 23 and residues 23-236 of instant SEQ ID NO: 8, respectively. Furthermore, Satpayev SEQ ID NOs: 7 and 8 comprise exact matches to (i) CDRs H1-3 of instant SEQ ID NOs: 9-11 (Kabat numbering) and 16-18 (IMGT numbering) and (ii) CDRs L1-3 of instant SEQ ID NOs: 12-14 (Kabat numbering) and 19-21 (IMGT numbering).
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the invention of Rosenberg to arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because Rosenberg teaches a method of treating urothelial cancer (e.g., metastatic or locally advanced urothelial carcinoma) in a human subject comprising administering to the subject an effective amount of an ADC wherein: (i) the ADC comprises an antibody or antigen binding fragment thereof binds 191P4D12 and comprises the instantly claimed sequences, said antibody or antigen binding fragment thereof being conjugated to one or more units of MMAE (e.g., via the instantly claimed linker, the ADC being enfortumab vedotin), and said ADC being administered at the claimed doses and according to the claimed dosing schedule; (ii) the subject has liver metastases, has been previously treated with an immune checkpoint inhibitor therapy and/or platinum-based chemotherapy, has an ANC of no less than 1500/mm3, has no more than Grade 2 sensory or motor neuropathy, has no active CNS metastases, and/or has no uncontrolled diabetes; and (iii) the subject, or a population of subjects, who receive the treatment experience the claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response, and the prior art recognizes that patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see PADCEV and Satpayev). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, and the prior art further indicates treatment in populations of patients with the claimed inclusion/exclusion criteria, wherein it would reasonably be expected that a treated population of patients would have (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and/or (iv) estimated median overall survival was 11.7 months.
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0025600 A1 (US patent document citation A17 on 10/10/2023 IDS; herein after referred to as "Gartner") in view of non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”), and non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107").
Gartner teaches methods for the treatment of cancers with antibody drug conjugates (ADC) that bind to 191P4D12 proteins; also provided are methods for the treatment of urothelial cancer using an antibody drug conjugate (ADC) that binds 191P4D12 (Abstract). In a first embodiment, Gartner teaches a method of treating cancer in a human subject, comprising (a) administering to the subject a first regimen comprising an effective amount of an antibody drug conjugate (ADC), wherein the ADC comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE),
wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; wherein the subject has urothelial cancer; and wherein the subject has received an immune checkpoint inhibitor therapy and received a chemotherapy (Paragraphs 0008-0011; emphasis added). It is specifically noted that Gartner SEQ ID NOs: 22 and 23 are exact matches for instant SEQ ID NOs: 22 and 23, respectively. An additional embodiment further limits the method of the first embodiment wherein the ADC is administered on days 1, 8, and 15 of a 28 day cycle (Paragraph 0013; emphasis added). Any of the above-listed embodiments may be further drawn to urothelial cancer that is locally advanced or metastatic (Paragraphs 0014-0015; emphasis added). In any of the above-listed embodiments, the immune checkpoint inhibitor therapy is a PD-1 inhibitor or a PD-L1 inhibitor (Paragraphs 0016-0017; emphasis added). In any of the above-listed embodiments, the chemotherapy is a platinum-based chemotherapy (Paragraph 0018; emphasis added). For any of the above-listed embodiments, the first regimen comprises an ADC dose of about 1.25 mg/kg of the subject’s body weight (Paragraph 0023; emphasis added). The method of the above-listed embodiments may further comprise determining peripheral neuropathy in the subject, and if the peripheral neuropathy is no less than Grade 2, withholding the administration of the antibody drug conjugate (i.e., the subject does not receive treatment if peripheral neuropathy is Grade ≥2) (Paragraphs 0045-0046; emphasis added) wherein the peripheral neuropathy is predominantly sensory neuropathy (Paragraph 0053; emphasis added). In the method of any one of the above-listed embodiments, the antibody or antigen binding fragment thereof comprises: (i) CDR Hl comprising the amino acid sequence of SEQ ID NO:9, CDR H2 comprising the amino acid sequence of SEQ ID NO:10, CDR H3 comprising the amino acid sequence of SEQ ID NO: 11 and CDR L1 comprising the amino acid sequence of SEQ ID NO: 12, CDR L2 comprising the amino acid sequence of SEQ ID NO: 13, and CDR L3 comprising the amino acid sequence of SEQ ID NO:14; (ii) CDR Hl comprising the amino acid sequence of SEQ ID NO: 16, CDR H2 comprising the amino acid sequence of SEQ ID NO:17, CDR H3 comprising the amino acid sequence of SEQ ID NO:18 and CDR L1 comprising the amino acid sequence of SEQ ID NO: 19, CDR L2 comprising the amino acid sequence of SEQ ID NO:20, and CDR L3 comprising the amino acid sequence of SEQ ID NO:21; (iii) CDR Hl consisting of the amino acid sequence of SEQ ID NO:9, CDR H2 consisting of the amino acid sequence of SEQ ID NO: 10, CDR H3 consisting of the amino acid sequence of SEQ ID NO: 11 and CDR L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:14; or (iv) CDR Hl consisting of the amino acid sequence of SEQ ID NO:16, CDR H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR H3 consisting of the amino acid sequence of SEQ ID NO: 18 and CDR L1 consisting of the amino acid sequence of SEQ ID NO:19, CDR L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:21 (Paragraphs 0234-0237). It is specifically noted that Gartner SEQ ID NOs: 9-14 and 16-21 are exact matches to instant SEQ ID NOs: 9-14 and 16-21, respectively. In the method of any one of the above-listed embodiments, the antibody or antigen binding fragment thereof comprises: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID
NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23; and (ii) a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising
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the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8 (Paragraphs 0238-0239). It is specifically noted that Gartner residues 20-466 of SEQ ID NO: 7 and residues 23-236 of SEQ ID NO: 8 are exact matches to residues 20-466 of instant SEQ ID NO: 7 and residues 23-236 of instant SEQ ID NO: 8, respectively, and Gartner SEQ ID NOs: 2 and 23 are exact matches to instant SEQ ID NOs: 22 and 23, respectively. In any of the above-listed embodiments, the antigen binding fragment is: (i) a Fab, F(ab')2, Fv or scFv fragment; (ii) a fully human antibody; and/or (iii) recombinantly produced (Paragraphs 0240-0242; emphasis added). Paragraphs 0243-0253 disclose the above-listed embodiments, wherein structural details of the ADC are provided; it is noted that any one of the above-listed embodiments has an ADC of the below-listed structure:
wherein L- represents the antibody or antigen binding fragment thereof and wherein p is: (i) from 1 to 10; (ii) from 2 to 8; (iii) from 3 to 5; (iv) from 3 to 4; (v) about 4; or (vi) about 3.8 (Paragraphs 0254-0259). For any one of the above-listed embodiments, the ADC is formulated in a pharmaceutical composition comprising: (i) about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and hydrochloride, and wherein the pH of the pharmaceutical composition is about 6.0 at 25°C; or (ii) about 9 mM histidine, about 11 mM histidine hydrochloride monohydrate, about 0.02% (w/v) TWEEN-20, and about 5.5% (w/v) trehalose dihydrate, and wherein the pH of the pharmaceutical composition is about 6.0 at 25° C (Paragraphs 0260-0261; emphasis added). It is specifically noted that TWEEN-20 is also commonly known as polysorbate-20. In any one of the above-listed embodiments, the ADC is administered by an intravenous (IV) injection or infusion and/or the ADC or the ADC formulated in the pharmaceutical composition is administered by an intravenous (IV) injection or infusion over about 30 minutes (Paragraphs 0265-0266; emphasis added). Gartner further discloses that in some embodiments, the one or more other treatments for cancer, which the subjects have received or from which the cancers of the subjects have progressed or relapsed, are a PD-1 inhibitor or a PD-Ll inhibitor wherein (i) the PD-1 inhibitor is pembrolizumab or nivolumab; and (ii) the PD-Ll inhibitor is atezolizumab, avelumab, or durvalumab (Paragraph 0426; emphasis added). In some the antibody drug conjugate is administered to (i) patients with metastatic urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with an immune checkpoint inhibitor or (ii) patients with locally advanced urothelial or bladder cancer who have shown disease progression or relapse during or after treatment with an immune checkpoint inhibitor (Paragraph 0838). Gartner further teaches an example in section 6.3.2.1 (see Page 89), wherein PADCEV (i.e., enfortumab vedotin) was evaluated in EV-201 (NCT03219333), a single-arm, multicenter trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-Ll inhibitor and platinum-based chemotherapy; patients were excluded if they had active CNS metastases, ongoing sensory or motor neuropathy >Grade 2, or uncontrolled diabetes defined as hemoglobin AlC (HbAlc) ≥8% or HbAlc ≥7% with associated diabetes symptoms (Paragraph 0870; emphasis added). Ninety percent of patients had visceral metastases, including 40% with liver metastases; Nectin-4 expression was detected in all patients tested (n=120); the median number of prior systemic therapies was 3 (range: 1 to 6) wherein forty-six percent of
patients received prior PD-1 inhibitor, 42% received prior PD-Ll inhibitor, and an additional 13% received both PD-1 and PD-Ll inhibitors and sixty-six percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin- based regimens, and an additional 8% received both cisplatin and carboplatin-based regimens (Paragraph 0871; emphasis added). Efficacy results are presented in Table 21 (see Page 89) wherein the confirmed ORR was 44%, CR was 12%, PR was 32%, and the median duration of response was 7.6 months.
However, Gartner does not specifically teach median progression free survival of patients treated according to the disclosed methods, notably by the method of NCT03219333, nor does Gartner teach or suggest treating patients having an ANC of ≥1500/mm3. These deficiencies are remedied by Rosenburg (publication corresponding to NCT03219333) and NCT03474107.
Rosenberg discloses that enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added).
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the invention of Gartner to arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because Gartner teaches methods of treating cancer with an ADC that specifically binds 191P4D12, and comprises MMAE (reading on enfortumab vedotin), at the instantly claimed dosages, formulations, and schedule, and the prior art recognizes (i) the use of enfortumab vedotin (e.g., 1.25 mg/kg body weight via IV injection/infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle) in the treatment of patients with metastatic or locally advanced urothelial carcinoma, including patients with liver metastases, who have previously been treated with immune checkpoint inhibitors and platinum-based chemotherapy is taught by Rosenberg, patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see Gartner, PADCEV). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, wherein (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and (iv) estimated median overall survival was 11.7 months.
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over:
US 8,637,642 (US patent document citation A01 on 10/10/2023 IDS; herein after referred to as "Satpayev");
US 9,078,931 (US patent document citation A02 on 10/10/2023 IDS);
US 9,314,538 (US patent document citation A03 on 10/10/2023 IDS);
US 9,962,454 (US patent document citation A04 on 10/10/2023 IDS);
US 10,894,090 (US patent document citation A06 on 10/10/2023 IDS);
US 11,559,582 (US patent document citation A07 on 10/10/2023 IDS);
US RE48,389 (US patent document citation A05 on 10/10/2023 IDS); or
US 2026/0034234 A1 (US patent document citation A138 on 06/01/2026 IDS)
each in view of non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”), non-patent literature PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as “PADCEV”, and non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107"). It is specifically noted that the above-listed patents and Pre-Grant Publication all belong to the same patent family; Satpayev is the parent patent and all of the other above-listed patents and PG Publication are, in order, continuations of each other and therefore all have the same disclosure. Satpayev is being used for the citations in the rejection presented below.
Satpayev teaches antibody drug conjugates (ADC's) that bind to 191P4D12 protein and variants thereof are described herein; 191P4D12 exhibits tissue specific expression in normal adult tissue, and is aberrantly expressed in the cancers listed in Table I and, consequently, the ADCs of the invention provide a therapeutic composition for the treatment of cancer (Abstract). 191P4D12 monoclonal antibodies can be produced by various means including (i) immortalized cell lines using hybridoma technology (Column 25, Lines 46-51) and (ii) recombinant methods (Column 25, Lines 57-67; emphasis added); in a preferred embodiment, the antibodies of the present invention comprise fully human 191P4D12 antibodies (191P4D12 MAbs) which may be produced by various methods in the art for producing fully human 191P4D12 Mabs (e.g., transgenic mice) (Column 26, Lines 5-12; emphasis added). Human monoclonal antibodies of the invention can also be prepared using phage display methods (i.e., recombinant methods) for screening libraries of human immunoglobulin genes (Column 26, Lines 36-38). Satpayev teaches an anti-191P4D12 antibody designated as Ha22-2(2,4)6.1, wherein said antibody comprises (i) the heavy chain variable region consisting of the amino acid sequence ranging from 20th E residue to the 136th S residue of SEQ ID NO:7, and (ii) the light chain variable region consisting of the amino acid sequence ranging from 23rd D residue to the 130th R residue of SEQ ID NO:8 (Column 26, Lines 52-66). The heavy chain of Ha22-2(2,4)6.1 consists of the amino acid sequence ranging from 20th E residue to the 466th K residue of SEQ ID NO:7 and the light chain of Ha22-2(2,4)6.1 consists of amino acid sequence ranging from 23rd D residue to the 236th C residue of SEQ ID NO: 8 sequence (Column 28, Lines 56-63). It is specifically noted that residues 20-136 and 20-466 of Satpayev SEQ ID NO: 7 are an exact match to instant SEQ ID NO: 22 and residues 20-466 of instant SEQ ID NO: 7, respectively. It is specifically noted that residues 23-130 and 23-236 of Satpayev SEQ ID NO: 8 are an exact match to instant SEQ ID NO: 23 and residues 23-236 of instant SEQ ID NO: 8, respectively. Furthermore, Satpayev SEQ ID NOs: 7 and 8 comprise exact matches to (i) CDRs H1-3 of SEQ ID NOs: 9-11 (Kabat numbering) and 16-18 (IMGT numbering) and (ii) CDRs L1-3 of instant SEQ ID NOs: 12-14 (Kabat numbering) and 19-21 (IMGT numbering). In one embodiment, human IgG1 constant region as the heavy chain constant region and human Ig kappa constant region as the light chain constant region can be used (Column 27, Lines 1-4; emphasis added). Satpayev teaches exemplary ADC embodiments, including one wherein MMAE is linked to the Ab via a sulfur atom of said antibody via various linker components, wherein an exemplary ADC structure is
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shown below:
wherein p is about 1 to 8 (Columns 32-34). A further object of the invention is to provide methods to inhibit angiogenesis and other biological functions and thereby reduce tumor growth in mammals, preferably humans, using such 191P4D12 ADCs, and in particular using such 191P4D12 ADCs combined with other drugs or immunologically active treatments (Column 71, Lines 19-24; emphasis added). Treatment generally involves repeated administration of the 191P4D12 ADC preparation, via an acceptable route of administration such as intravenous injection (IV), typically at a dose in the range, including but not limited to, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 mg/kg body weight (Column 70, Lines 48-53; emphasis added). Satpayev further teaches Example 7, wherein the therapeutic efficacy of Ha22-2(2,4)6.1 vcMMAE in human bladder, lung, breast, and pancreatic cancer xenograft mouse models is evaluated; Ha22-2(2,4)6.1 ADC inhibits formation lung, bladder, breast, and pancreatic cancer xenografts, and these results indicate the utility of Ha22-2(2,4)6.1 ADC in the treatment of local and advanced stages of cancer and preferably those cancers set forth in Table I (Columns 78-79; emphasis).
However, Satpayev does not disclose that the ADCs of the invention are enfortumab vedotin, inclusion and/or exclusion criteria for the method of treatment, the treatment of urothelial cancer, cancer patients with liver metastases, cancer patients previously treated with immune checkpoint inhibitors and/or chemotherapy, ADC structures, doses, dosing schedules, or formulations, nor therapeutic outcomes. These deficiencies are remedied by Rosenberg, PADCEV, and NCT03474107. Furthermore, it is noted that enfortumab vedotin goes by the additional identifiers: EV, PADCEV, AGS-22M6E (comprising antibody identified as Ha22-2(2,4)6.1), AGS-22C3E, and ASG-22C3E (see Paragraph 00376 of the instant specification).
Rosenberg discloses a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy; the primary end point was objective response rate per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability (Abstract, Methods; emphasis added). Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies (Abstract: Conclusion). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added). Table A1 of the Appendix section provides a summary of demographics and disease characteristics at baseline for patients in the study, wherein it is specifically noted that patients included in the study having previously been treated with anti-PD-1/L1 therapies include treatment with nivolumab, pembrolizumab, atezolizumab, avelumab, and/or durvalumab (emphasis added).
PADCEV discloses prescribing information for enfortumab vedotin-ejfv (i.e., PADCEV, enfortumab vedotin) for injection, for intravenous use. More specifically, Section 11 of PDACEV discloses that enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006), wherein conjugation takes place on cysteine residues that comprise the interchain disulfide
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bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1 (i.e., approximately 4 MMAE molecules per antibody) (Page 11). Notably, the structure of enfortumab vedotin-ejfv is reproduced below (Id.):
PADCEV further teaches a formulation of enfortumab vedotin, wherein PADCEV for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL; each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0. Thus, the formulation of PADCEV comprises approximately 20 mM histidine (total), 0.02% w/v polysorbate 20, and 5.5% w/v trehalose dihydrate.
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the invention of Satpayev to arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because Satpayev teaches methods of treating cancer with an ADC that specifically binds 191P4D12, and comprises MMAE (reading on enfortumab vedotin) and the prior art recognizes (i) the use of enfortumab vedotin (e.g., 1.25 mg/kg body weight via IV injection/infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle) in the treatment of patients with metastatic or locally advanced urothelial carcinoma, including patients with liver metastases, who have previously been treated with immune checkpoint inhibitors and platinum-based chemotherapy is taught by Rosenberg, patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see PADCEV and Satpayev). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, wherein (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and (iv) estimated median overall survival was 11.7 months.
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over:
US 12,257,340 (US patent document citation A83 on 06/01/2026 IDS; herein after referred to as “McGarvey”) or
US 2026/0000604 A1 (US patent document citation A137 on 06/01/2026 IDS)
each in view of non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”), non-patent literature PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as “PADCEV”, and non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107"). It is specifically noted that US 2026/0000604 A1 is a continuation of McGarvey, and as such both have the same disclosure. McGarvey is being used for the citations in the rejection presented below.
McGarvey provides a pharmaceutical composition comprising (a) an antibody drug conjugate comprising an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:7 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:8; and (b) a pharmaceutically acceptable excipient comprising L-histidine, polysorbate-20 (TWEEN-20), and at least one of trehalose dihydrate and sucrose (Columns 1-2; emphasis added). In some embodiments, the antibody or antigen binding
fragment thereof comprises CDR H1 comprising an amino acid sequence of SEQ ID NO:9, CDR H2 comprising an amino acid sequence of SEQ ID NO: 10, CDR H3 comprising an amino acid sequence of SEQ ID NO: 11; CDR L1 comprising an amino acid sequence of SEQ ID NO:12, CDR L2 comprising an amino acid sequence of SEQ ID NO:13, and CDR L3 comprising an amino acid sequence of SEQ ID NO:14 (Column 2, Lines 14-22). In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 136th amino acid (serine) of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine) of SEQ ID NO:8 (Column 2, Lines 23-30). In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8 (Column 2, Lines 31-37). It is specifically noted that McGarvey SEQ ID NOs: 9-14 are exact matches to instant SEQ ID NOs: 9-14; McGarvey residues 20-466 of SEQ ID NO: 7 and residues 23-236 of SEQ ID NO: 8 are exact matches to residues 20-466 of instant SEQ ID NO: 7 and residues 23-236 of instant SEQ ID NO: 8; and McGarvey residues 20-136 of SEQ ID NO: 7 and residues 23-130 of SEQ ID NO: 8 are an exact match to instant SEQ ID NOs: 22 and 23, respectively. Furthermore, it is noted that SEQ ID NOs: 7 and 8 of McGarvey also comprise exact matches to instant SEQ ID NOs: 16-18 and 19-21 (CDRs according to IMGT numbering). In some embodiments, the antigen binding fragment is: (i) a Fab, F(ab')2, Fv or scFv fragment; (ii) fully human antibody; and/or (iii) recombinantly produced (Column 2, Lines 38-43; emphasis added). In some embodiments, the pharmaceutical composition comprises about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, and at least one of about 5.5% (w/v) trehalose dihydrate or about 5% (w/v) sucrose; in some embodiments, the pharmaceutical composition provided herein further comprises HCI or succinic acid, the pH is about 6.0 at room temperature, and/or the pH is about 6.0 at 25° C (Column 4, Lines 60-67; emphasis added). McGarvey further provides a method of treating a disease or disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition provided herein; in some embodiments, the subject is a human subject, the cancer is a solid tumor, and/or the cancer is colon cancer, pancreatic cancer, ovarian cancer, lung cancer, bladder cancer, breast cancer, esophageal cancer, head cancer, or neck cancer (Column 7, Lines 56-64; emphasis added). In some embodiments, the antibody drug conjugate formulated in the pharmaceutical composition is administered at a dose of 1 to 10 mg/kg of the subject's body weight; doses include 1-5 mg/kg, 1-2.5 mg/kg, 1-1.25 mg/kg, about 1 mg/kg, or about 1.25 mg/kg of the subject’s body weight (Column 8, Lines 47-64; emphasis added). In some embodiments, the ADC formulated in the pharmaceutical composition is administered by an intravenous (IV) injection or infusion over about 30 minutes on days 1, 8, and 15 of every four week cycle (Column 9, Lines 22-26; emphasis added). An exemplary ADC is AGS-22M6E, which comprises the structure shown below:
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wherein L is the antibody designated as Ha22-2(2,4)6.1 (i.e., an antibody comprising the sequences provided above) and p is from 1 to 20 (Column 75, Lines 50-67). McGarvey further discloses that, in some embodiments, the cancer is: advanced bladder cancer, metastatic bladder cancer, or advanced urothelial cancer (Column 77, Lines 21-25; emphasis added). In some embodiments, treatment with the pharmaceutical composition provided herein is indicated for subjects who have received one or more rounds of chemotherapy (Column 77, Lines 31-33; emphasis added) and in some embodiments the pharmaceutical composition is administered to patients with metastatic urothelial cancer who have shown disease progression or relapse during or after treatment with an immune checkpoint inhibitor (Column 77, Lines 41-45).
However, McGarvey does not disclose inclusion and/or exclusion criteria for the method of treatment, cancer patients with liver metastases, the types of immune checkpoint inhibitors used in patients previously treated, cancer patients previously treated with platinum-based chemotherapy, nor therapeutic outcomes. These deficiencies are remedied by Rosenberg, PADCEV, and NCT03474107. Furthermore, it is noted that enfortumab vedotin goes by the additional identifiers: EV, PADCEV, AGS-22M6E (comprising antibody identified as Ha22-2(2,4)6.1), AGS-22C3E, and ASG-22C3E (see Paragraph 00376 of the instant specification).
Rosenberg discloses a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy; the primary end point was objective response rate per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability (Abstract, Methods; emphasis added). Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies (Abstract: Conclusion). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added). Table A1 of the Appendix section provides a summary of demographics and disease characteristics at baseline for patients in the study, wherein it is specifically noted that patients included in the study having previously been treated with anti-PD-1/L1 therapies include treatment with nivolumab, pembrolizumab, atezolizumab, avelumab, and/or durvalumab (emphasis added).
PADCEV discloses prescribing information for enfortumab vedotin-ejfv (i.e., PADCEV, enfortumab vedotin) for injection, for intravenous use. More specifically, Section 11 of PDACEV discloses that enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006), wherein conjugation takes place on cysteine residues that comprise the interchain disulfide
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bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1 (i.e., approximately 4 MMAE molecules per antibody) (Page 11). Notably, the structure of enfortumab vedotin-ejfv is reproduced below (Id.):
PADCEV further teaches a formulation of enfortumab vedotin, wherein PADCEV for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL; each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0. Thus, the formulation of PADCEV comprises approximately 20 mM histidine (total), 0.02% w/v polysorbate 20, and 5.5% w/v trehalose dihydrate.
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the invention of McGarvey to arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because McGarvey teaches methods of treating cancer with an ADC that specifically binds 191P4D12, and comprises MMAE (reading on enfortumab vedotin), at the instantly claimed dosages, formulations, and schedule, and the prior art recognizes (i) the use of enfortumab vedotin (e.g., 1.25 mg/kg body weight via IV injection/infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle) in the treatment of patients with metastatic or locally advanced urothelial carcinoma, including patients with liver metastases, who have previously been treated with immune checkpoint inhibitors and platinum-based chemotherapy is taught by Rosenberg, patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see McGarvey, PADCEV). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, wherein (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and (iv) estimated median overall survival was 11.7 months.
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0001005 A1 (US patent document citation A16 on 10/10/2023 IDS; herein after referred to as “Abidoye”) in view of non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”), non-patent literature PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as “PADCEV”, and non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107").
Abidoye teaches a method of treating cancer in a subject, comprising administering to the subject an effective amount of an antibody drug conjugate, wherein the antibody drug conjugate comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CD Rs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; and wherein the subject has (i) NSCLC, locally advanced or metastatic head and neck cancer, gastric or esophageal cancer (Paragraphs 0199-0201; emphasis added). In some specific embodiments, subjects treated with the methods provided have histologically- or
cytologically-confirmed squamous NSCLC, non-squamous NSCLC, or head and neck cancer; have a locally advanced or metastatic disease; have progressed or relapsed following platinum-based therapy; and/or have received prior therapy with an anti-programmed cell death protein-1 (PD-1) or anti-programmed cell death-ligand 1 (PD-L1) if eligible based on subject's tumor PD-1 or PD-Ll expression and local treatment guidelines (Paragraphs 0210-0211 and 0213-0214; emphasis added). In some embodiments, the antibody or antigen binding fragment thereof comprises CDR Hl comprising an amino acid sequence of SEQ ID NO:9, CDR H2 comprising an amino acid sequence of SEQ ID NO:10, CDR H3 comprising an amino acid sequence of SEQ ID NO: 11, CDR L1 comprising an amino acid sequence of SEQ ID NO: 12, CDR L2 comprising an amino acid sequence of SEQ ID NO:13, and CDR L3 comprising an amino acid
sequence of SEQ ID NO:14 (Paragraph 0273). In some embodiments, the antibody or antigen binding fragment thereof comprises CDR Hl comprising an amino acid sequence of SEQ ID NO: 16, CDR H2 comprising an amino acid sequence of SEQ ID NO:17, CDR H3 comprising an amino acid sequence of SEQ ID NO: 18, CDR L1 comprising an amino acid sequence of SEQ ID NO: 19, CDR L2 comprising an amino acid sequence of SEQ ID NO:20, and CDR L3 comprising an amino acid sequence of SEQ ID NO:21 (Paragraph 0274). In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable
region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23 (Paragraph 0275). In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8 (Paragraph 0276). It is specifically noted that Abidoye SEQ ID NOs: 9-14 and 16-21 are exact matches to instant SEQ ID NOs: 9-14 and 16-21; Abidoye residues 20-466 of SEQ ID NO: 7 and residues 23-236 of SEQ ID NO: 8 are exact matches to residues 20-466 of instant SEQ ID NO: 7 and residues 23-236 of instant SEQ ID NO: 8; and Abidoye SEQ ID NOs: 22 and 23 are an exact match to instant SEQ ID NOs: 22 and 23, respectively. In some embodiments the antibody drug conjugate of the methods provided is AGS-22M6E, the structure of which is shown below:
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wherein L is Ha22-2(2,4)6.1 and p is from 1 to 20, with more specific ranges/values for p further provided. (Paragraphs 0399-0401). In some specific embodiments, the pharmaceutical composition of the invention comprises: (i) about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, and at least one of about 5.5% (w/v) trehalose dihydrate or about 5% (w/v) sucrose, and may further comprise HCl or succinic acid, wherein the pH is about 6.0 at 25° C; or about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate and HCl. wherein the pH is about 6.0 at 25° C (Paragraphs 0426-0427; emphasis added). In some more specific embodiments, the antibody drug conjugate formulated in the pharmaceutical composition provided is administered at a dose of about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, or about 1.5 mg/kg of the subject's body weight by an intravenous (IV) injection or infusion over about 30 minutes on Days 1, 8, and 15 of every four-week cycle (Paragraph 0507; emphasis added). In some embodiments, the antibody drug conjugate is administered to patients with urothelial cancer (including metastatic urothelial cancer) who have shown disease progression or relapse during or after treatment with an immune checkpoint inhibitor (Id.).
However, Abidoye does not disclose inclusion criteria for the method of treatment, cancer patients with liver metastases, inclusion/exclusion criteria, the types of immune checkpoint inhibitors used in patients previously treated, nor therapeutic outcomes. These deficiencies are remedied by Rosenberg, PADCEV, and NCT03474107. Furthermore, it is noted that enfortumab vedotin goes by the additional identifiers: EV, PADCEV, AGS-22M6E (comprising antibody identified as Ha22-2(2,4)6.1), AGS-22C3E, and ASG-22C3E (see Paragraph 00376 of the instant specification).
Rosenberg discloses a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy; the primary end point was objective response rate per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability (Abstract, Methods; emphasis added). Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies (Abstract: Conclusion). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added). Table A1 of the Appendix section provides a summary of demographics and disease characteristics at baseline for patients in the study, wherein it is specifically noted that patients included in the study having previously been treated with anti-PD-1/L1 therapies include treatment with nivolumab, pembrolizumab, atezolizumab, avelumab, and/or durvalumab (emphasis added).
PADCEV discloses prescribing information for enfortumab vedotin-ejfv (i.e., PADCEV, enfortumab vedotin) for injection, for intravenous use. More specifically, Section 11 of PDACEV discloses that enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006), wherein conjugation takes place on cysteine residues that comprise the interchain disulfide
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bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1 (i.e., approximately 4 MMAE molecules per antibody) (Page 11). Notably, the structure of enfortumab vedotin-ejfv is reproduced below (Id.):
PADCEV further teaches a formulation of enfortumab vedotin, wherein PADCEV for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL; each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0. Thus, the formulation of PADCEV comprises approximately 20 mM histidine (total), 0.02% w/v polysorbate 20, and 5.5% w/v trehalose dihydrate.
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the invention of Abidoye to arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because Abidoye teaches methods of treating cancer with an ADC that specifically binds 191P4D12, and comprises MMAE (reading on enfortumab vedotin), at the instantly claimed dosages, formulations, and schedule, and the prior art recognizes (i) the use of enfortumab vedotin (e.g., 1.25 mg/kg body weight via IV injection/infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle) in the treatment of patients with metastatic or locally advanced urothelial carcinoma, including patients with liver metastases, who have previously been treated with immune checkpoint inhibitors and platinum-based chemotherapy is taught by Rosenberg, patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see Abidoye, PADCEV). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, wherein (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and (iv) estimated median overall survival was 11.7 months.
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0270871 A1 (US patent document citation A18 from 10/10/2023 IDS; herein after referred to as “Lewis”) in view of non-patent literature by Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors' Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as "Rosenberg") and non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107").
Lewis teaches a method for treating cancer in a subject in need thereof comprising: (1) administering to the subject a first dose of an ADC comprising an antibody or antigen binding fragment thereof conjugated to one or more units of a cytotoxic agent via a linker, (2) determining an increase of expression of one or more ADC Set I Marker genes in the subject, and (3)(a) administering a second dose of the ADC at the same or lower amount than the first dose if the expression of the one or more ADC Set I Marker genes in the subject is increased compared to the expression of the one or more ADC Set I Marker genes in the subject before the administration of the ADC, or (b) administering a second dose of the ADC at a higher amount than the first dose if the expression of the one or more ADC Set I Marker genes in the subject is not increased compared to the expression of the one or more ADC Set I Marker genes in the subject before the administration of the ADC (Paragraph 0592). In some embodiments of the methods: (i) the antibody or antigen binding fragment thereof of the ADC is an anti-nectin-4 antibody or antigen binding fragment thereof and/or (ii) the cytotoxic agent of the ADC is an auristatin, the auristatin is MMAE (Id.; emphasis added). In other embodiments of the methods, the antibody or antigen binding fragment thereof of the ADC comprises a heavy chain variable region comprising complementarity determining region 1 (CDR-H1), CDR-H2, and CDR-H3 comprising the amino acid sequences of the corresponding CDR-Hl, CDR-H2, and CDR-H3 in the heavy chain variable region sequence set forth in SEQ ID NO: 7 and a light chain variable region comprising CDR-Ll, CDR-L2, and CDR-L3 comprising the amino acid sequences of the corresponding CDR-Ll, CDR-L2, and CDR-L3 in the light chain variable region sequence set forth in SEQ ID NO: 8, and the antibody or antigen binding fragment thereof is conjugated to 1 to 20 units of MMAE via a linker (Id.). In some embodiments, the antibody or antigen binding fragment thereof comprises CDR-Hl consisting of an amino acid sequence of SEQ ID NO:9, CDR-H2 consisting of an amino acid sequence of SEQ ID NO: 10, CDR-H3 consisting of an amino acid sequence of SEQ ID NO:11, CDR-Ll consisting of an amino acid sequence of SEQ ID NO:NO:12, CDR-L2 consisting of an amino acid sequence of SEQ ID NO:NO:13, and CDR-L3 consisting of an amino acid sequence of SEQ ID NO:NO:14 (Paragraph 0751). In some embodiments, the antibody or antigen binding fragment thereof comprises CDR-Hl consisting of
an amino acid sequence of SEQ ID NO:16, CDR-H2 consisting of an amino acid sequence of SEQ ID NO:17, CDR-H3 consisting of an amino acid sequence of SEQ ID NO:18, CDR-Ll consisting of an amino acid sequence of SEQ ID NO:NO:19, CDR-L2 consisting of an amino acid sequence of SEQ ID NO:NO:20, and CDR-L3 consisting of an amino acid sequence of SEQ ID NO:NO:21 (Paragraph 0752). In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO:22 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO:23 (Paragraph 0754). In some embodiments, the antibody comprises a heavy chain consisting of the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain consisting of the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8 (Paragraph 0756). It is specifically noted that Lewis SEQ ID NOs: 9-14 and 16-21 are exact matches to instant SEQ ID NOs: 9-14 and 16-21; Lewis residues 20-466 of SEQ ID NO: 7 and residues 23-236 of SEQ ID NO: 8 are exact matches to residues 20-466 of instant SEQ ID NO: 7 and residues 23-236 of instant SEQ ID NO: 8; and Lewis SEQ ID NOs: 22 and 23 are an exact match to instant SEQ ID NOs: 22 and 23, respectively. In some embodiments, the anti-nectin-4 antibody provided by the invention comprises heavy and light chain variable regions of an antibody designated Ha22-2(2,4)6.1; as the constant region of the antibody of the invention, any subclass of constant region can be chosen and, in one embodiment, human IgG1 constant region as the heavy chain constant region and human Ig kappa constant region as the light chain constant region can be used (Paragraph 0777; emphasis added). In one embodiment, the ADC is enfortumab vedotin, also known as EV, PADCEV, AGS- 22M6E, AGS-22C3E, ASG-22C3E; the enfortumab vedotin includes an anti-191P4D12 antibody, wherein the antibody or antigen binding fragment thereof comprises a heavy chain comprising amino acid residue 20 to amino acid residue 466 of SEQ ID NO: 7 and a light chain comprising amino acid residue 23 to amino acid residue 236 of SEQ ID NO:8 (Paragraph 0885; emphasis added). Enfortumab
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vedotin has the structure shown below (see Page 144):
Enfortumab vedotin is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL; each mL of reconstituted solution contains 10 mg of enfortumab vedotin, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0 (Paragraph 0889; emphasis added). It is noted that the reconstituted solution of enfortumab vedotin above comprises approximately 20 mM histidine (total), 0.02% w/v polysorbate 20, and 5.5% w/v trehalose dihydrate. In more specific embodiments, the antibody drug conjugate formulated in the pharmaceutical composition provided is administered at a dose of about 0.5 mg/kg, about 0.75 mg/kg, 1 mg/kg, about 1.25 mg/kg, or about 1.5 mg/kg of the subject's body weight by an intravenous (IV) injection or infusion over about 30 minutes three times every four-week cycle; in some embodiments, the antibody drug conjugate formulated in the pharmaceutical composition is administered on Days 1, 8 and 15 of every 28-day (four-week) cycle (Paragraph 0978; emphasis added).
However, Lewis does not disclose inclusion and/or exclusion criteria for the method of treatment, cancer patients with liver metastases, cancer patients previously treated with immune checkpoint inhibitors and/or platinum-based chemotherapy, nor therapeutic outcomes. These deficiencies are remedied by Rosenberg and NCT03474107.
Rosenberg discloses a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy; the primary end point was objective response rate per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability (Abstract, Methods; emphasis added). Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma and the median follow-up was 10.2 months (range, 0.5 to 16.5 months); confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy, and the median duration of response was 7.6 months (range, 0.95 to 11.301 months) (Abstract, Results; emphasis added). Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies (Abstract: Conclusion). Patients with ongoing sensory or motor neuropathy grade 2 or greater, active CNS metastases, or uncontrolled diabetes were excluded, and more specifically uncontrolled diabetes was defined as hemoglobin A1C of 8% or greater or hemoglobin A1C of 7% to less than 8% with associated diabetes symptoms (i.e., polyuria or polydipsia) that were not otherwise explained (Page 2593, Column 2, First Full Paragraph). Target lesions were reduced in a majority of evaluable patients (84%; Fig 2B); estimated median progression-free survival was 5.8 months (95% CI, 4.9 to 7.5 months; Appendix Fig A5, online only), and estimated median overall survival was 11.7 months (95% CI, 9.1 months to not reached; Appendix Fig A6) (Page 2595, Column 2, Third Full Paragraph; emphasis added). Table A1 of the Appendix section provides a summary of demographics and disease characteristics at baseline for patients in the study, wherein it is specifically noted that patients included in the study having previously been treated with anti-PD-1/L1 therapies include treatment with nivolumab, pembrolizumab, atezolizumab, avelumab, and/or durvalumab (emphasis added).
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the invention of Lewis arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because Lewis teaches methods of treating cancer with an ADC that specifically binds 191P4D12, and comprises MMAE (reading on enfortumab vedotin), at the instantly claimed dosages, formulations, and schedule, and the prior art recognizes (i) the use of enfortumab vedotin (e.g., 1.25 mg/kg body weight via IV injection/infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle) in the treatment of patients with metastatic or locally advanced urothelial carcinoma, including patients with liver metastases, who have previously been treated with immune checkpoint inhibitors and platinum-based chemotherapy is taught by Rosenberg, patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see Lewis). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, wherein (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and (iv) estimated median overall survival was 11.7 months.
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 1, 14, 16, 19, 22, 26, 45-46, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 11, 16, 19, 22, 24, 26, 30, 35-36, 39-40, 42-44, 48, 54, 58, 63, 66-67, 77, 88, and 100 of copending Application No. 18/030,225 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of the reference application is drawn to a method of preventing or treating cancer in a human subject, comprising administering to the subject an effective amount of an antibody drug conjugate (ADC), wherein the antibody drug conjugate (ADC) comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; wherein the subject: (i) has urothelial or bladder cancer, has received an immune checkpoint inhibitor (CPI) therapy, is ineligible to receive cisplatin treatment (cisplatin ineligible), and has a primary site of tumor in the lower urinary tract; (ii) has urothelial or bladder cancer, has received an immune checkpoint inhibitor (CPI) therapy, is ineligible to receive cisplatin treatment (cisplatin ineligible), and has a primary site of tumor in the upper urinary tract; (iii) has urothelial or bladder cancer, has received an immune checkpoint inhibitor (CPI) therapy, is ineligible to receive cisplatin treatment (cisplatin ineligible), and has visceral metastases; (iv) has urothelial or bladder cancer, has received an immune checkpoint inhibitor (CPI) therapy, is ineligible to receive cisplatin treatment (cisplatin ineligible), has a primary site of tumor in the lower urinary tract, and is a platinum-naive subject; U.S. Application No. 18/030,225 (v) has urothelial or bladder cancer, has received an immune checkpoint inhibitor (CPI) therapy, is ineligible to receive cisplatin treatment (cisplatin ineligible), has a primary site of tumor in the upper urinary tract, and is a platinum-naive subject; or (vi) has urothelial or bladder cancer, has received an immune checkpoint inhibitor (CPI) therapy, is ineligible to receive cisplatin treatment (cisplatin ineligible), has visceral metastases, and is a platinum-naive subject. It is specifically noted that reference application SEQ ID NOs: 22 and 23 are exact matches to instant SEQ ID NOs: 22 and 23, respectively. Claim 3 of the reference application further limits the method of claim 1 wherein the platinum-naïve subject is: (i) a subject that received platinum in the adjuvant or neoadjuvant setting and did not progress within 12 months of completion of the platinum treatment; or (ii) a subject that has not received prior platinum-containing or other chemotherapy in the locally advanced or metastatic setting. Reference application claim 11 further limits the method of claim 1 wherein the subject has visceral metastases, and wherein the subject has: (i) liver metastases; and/or (ii) at least 1 Bellmunt risk factor. Reference application claim 16 further limits the method of claim 1 wherein the subject has, for example, an absolute neutrophil count no less than 1.0x109/L. Claim 19 of the reference application further limits the method of claim 1 wherein (i) the subject has no more than Grade 2 sensory or motor neuropathy; (ii) the subject has no active central nervous system metastases; and/or (iii) the subject has no uncontrolled diabetes. Claim 22 of the reference application further limits claim 19 wherein (i) the uncontrolled diabetes is determined by hemoglobin A1c (HbAlc) no less than 8% or HbAlc between 7 and 8% with associated diabetes symptoms that are not otherwise explained; or (ii) the uncontrolled diabetes is determined by hemoglobin A1c (HbAlc) no less than 8% or HbAlc between 7 and 8% with associated diabetes symptoms that are not otherwise explained, and wherein the associated diabetes symptoms comprise or consist of polyuria, polydipsia, or both polyuria and polydipsia. Reference application claim 24 further limits the method of claim 1 wherein the subject has local advanced or metastatic urothelial cancer or the subject has locally advanced or metastatic bladder cancer. Claim 26 of the reference application further limits the method of claim 1 wherein (i) the CPI therapy is a therapy of programmed death receptor-1(PD-1) inhibitor; (ii) the CPI therapy is a therapy of programmed death-ligand 1 (PD-L 1) inhibitor; (iii) the CPI therapy is a therapy of PD-1 inhibitor, wherein the PD-1 inhibitor is nivolumab or pembrolizumab; or (iv) the CPI therapy is a therapy of PD-L1 inhibitor, wherein the PD-L1 inhibitor is selected from a group consisting of atezolizumab, avelumab, and durvalumab. Reference application claim 30 further limits the method of claim 1 wherein (i) the antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO:9, CDR-H2 comprising the amino acid sequence of SEQ ID NO:10, CDR-H3 comprising the amino acid sequence of SEQ ID NO:11; CDR-L1 comprising the amino acid sequence of SEQ ID NO:12, CDR-L2 comprising the amino acid sequence of SEQ ID NO:13, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:14; (ii) the antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO:16, CDR-H2 comprising the amino acid sequence of SEQ ID NO:17, CDR-H3 comprising the amino acid sequence of SEQ ID NO:18; CDR-L1 comprising the amino acid sequence of SEQ ID NO:19, CDR-L2 comprising the amino acid NAI-5013010678 6 U.S. Application No. 18/030,225 sequence of SEQ ID NO:20, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:21;(iii) the antibody or antigen binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO:9, CDR-H2 consisting of the amino acid sequence of SEQ ID NO:10, CDR-H3 consisting of the amino acid sequence of SEQ ID NO:11; CDR-L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR-L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO:14; (iv) the antibody or antigen binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO:16, CDR-H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR-H3 consisting of the amino acid sequence of SEQ ID NO:18; CDR-L1 consisting of the amino acid sequence of SEQ ID NO:19, CDR-L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO:21;(v) the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23; or (vi) the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8. It is specifically noted that reference application SEQ ID NOs: 9-14 and 16-21 are exact matches to instant SEQ ID NOs: 9-14 and 16-21, respectively. Furthermore, residues 20-466 of reference application SEQ ID NO: 7 and residues 23-236 of reference application SEQ ID NO: 8 are an exact match to residues 20-466 of instant SEQ ID NO: 7 and residues 23-236 of instant SEQ ID NO: 8, respectively. Reference application claims 35 and 36 each further limit the method of claim 1 wherein, respectively: (i) the antigen binding fragment is a Fab, F(ab)2, Fv, or scFv; and/or the antigen binding fragment is recombinantly produced; and (ii) the antibody is a fully human antibody, the antibody is an IgG1 and light chain is a kappa light chain, and/or the antibody is recombinantly produced. Reference application claims 39-40, 42-44, and 48 all structurally limit the ADC of claim 1, wherein a full structure for said ADC is reproduced below (see claim 48):
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wherein L- represents the antibody or antigen binding fragment thereof and (i) p is from 1 to 10; (ii) p is from 2 to 8; (iii) p is from 3 to 5; (iv) p is from 3 to 4; (v) p is about 4; or (vi) the average p value of the effective amount of the antibody drug conjugates is about 3.8. Reference application claim 54 further limits the method of claim 1 wherein (i) the ADC is administered at a dose of about 1 to about 10 mg/kg of the subject's body weight, about 1 to about 5 mg/kg of the subject's body weight, about 1 to about 2.5 mg/kg of the subject's body weight, or about 1 to about 1.25 mg/kg of the subject's body weight; (ii) the ADC is administered at a dose of about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2.0 mg/kg, about 2.25 mg/kg, or about 2.5 mg/kg of the subject's body weight; (iii) the ADC is administered at a dose of about 1 mg/kg of the subject's body weight; or (iv) the ADC is administered at a dose of about 1.25 mg/kg of the subject's body weight. Claim 58 of the reference application further limits the method of claim 1 wherein the ADC is administered by: (i) an intravenous (IV) injection or infusion; (ii) an IV injection or infusion three times every four-week cycle; (iii) an IV injection or infusion on Days 1, 8 and 15 of every four-week cycle;(iv) an IV injection or infusion over about 30 minutes three times every four-week cycle; and/or (v) an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four- week cycle. Reference application claim 63 further limits the method of claim 1 wherein the ADC is formulated in a pharmaceutical composition comprising: (i) L-histidine, polysorbate-20, and trehalose dihydrate; (ii) about 20 mM L-histidine, about 0.02% (w/v) polysorbate-20, about 5.5% (w/v) trehalose dihydrate, and hydrochloride, and wherein the pH of the pharmaceutical composition is about 6.0 at 25°C; or (iii) about 9 mM histidine, about 11 mM histidine hydrochloride monohydrate, about 0.02% (w/v) polysorbate-20, and about 5.5% (w/v) trehalose dihydrate, and wherein the pH of the pharmaceutical composition is about 6.0 at 25°C. Claim 66 of the reference application further limits the method of claim 1 wherein the ADC has
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the following structure:
wherein L- represents the antibody or antigen binding fragment thereof and p is from about 3 to about 4, the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8, wherein the ADC is administered at a dose of about 1.25 mg/kg of the subject's body weight, and wherein the dose is administered by an IV injection or infusion over about 30 minutes on Days 1, 8 and 15 of every four-week cycle. Claim 67 further limits the method of claim 1 wherein (i) the subject has a complete response following the treatment; (ii) the subject has a partial response following the treatment; (iii) the subject has a complete response or a partial response following the treatment; (iv) the subject has a stable disease following the treatment; (v) the subject has a duration of response of at least or about 10 months following the treatment; (vi) the subject has a duration of response of at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, or at least 22 months following the treatment; (vii) the subject has a progression free survival of at least or about 5 months following the treatment; (viii) the subject has a progression free survival of at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at U.S. Application No. 18/030,225 least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, or at least 22 months following the treatment;(ix) the subject has an overall survival of at least or about 14 months following the treatment; or (x) the subject has an overall survival of at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, or at least 28 months following the treatment. Reference application claim 77 further limits the method of claim 1 wherein the subject is in a population of subjects treated by the method, and wherein: (i) the percentage of complete response in the population of subjects is at least or about 20%; (ii) the percentage of partial response in the population of subjects is at least or about 31%; (iii) the objective response rate in the population of subjects is at least or about 51%; (iv) the objective response rate in the population of subjects ranges from 40% to 63%; (v) the percentage of stable disease in the population of subjects is at least or about 30%; (vi) the median duration of response in the population of subjects is at least or about 10 months; (vii) the duration of response in the population of subjects is at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 U.S. Application No. 18/030,225 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, or at least 22 months;(viii) the median progression free survival in the population of subjects is at least or about 5 months;(ix) the progression free survival in the population of subjects is at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, or at least 22 months;(x) the median overall survival in the population of subjects is at least or about 14 months; or (xi) the overall survival in the population of subjects is at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, or at least 28 months. Reference application claim 88 further limits the method of claim 1, wherein: (i) complete response rate is at least or about 20% for the subject in a population of subjects treated with the method; (ii) partial response rate is at least or about 31% for the population of subjects treated with the method; (iii) objective response rate is at least or about 51% for the population of subjects treated with the method; (iv) objective response rate is from 40% to 63% for the population of subjects treated with the method;(v) stable disease rate is at least or about 30% for the population of subjects treated with the method;(vi) median duration of response is at least or about 10 months for the population of subjects treated with the method;(vii) duration of response is at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, or at least 22 months for the population of subjects treated with the method;(viii) median progression free survival is at least or about 5 months for the population of subjects treated with the method;(ix) progression free survival is at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, or at least 22 months for the population of subjects treated with the method;(x) median overall survival is at least or about 14 months for the population of subjects treated with the method; or (xi) overall survival is at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, or at least 28 months for the population of subjects treated with the method. Reference application claim 100 further limits the method of claim 11 wherein the subject is in a population of subjects treated by the methods, and wherein: (i) the objective response rate in the treated population is at least or about 48%; or (ii) the objective response rate in the treated population is at least or about 43%. Thus, the limitations of the above-listed claims of the reference patent read directly the method, patient population, ADC doses, schedule, and formulation, and outcomes thereof of instant claims 1, 14, 16, 19, 22, 26, 45-46, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 47 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 11, 16, 19, 22, 24, 26, 30, 35-36, 39-40, 42-44, 48, 54, 58, 63, 66-67, 77, 88, and 100 of copending Application No. 18/030,225 (reference application), as applied to claims 1, 14, 16, 19, 22, 26, 45-46, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 above, and in further view of non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107").
The claims of the reference application read directly on a method of instant claim 1. However, the reference application does not claim a method wherein the patient has an absolute neutrophil count of no less that 1500/mm3. This deficiency is remedied by NCT03474107.
NCT03474107 discloses an open label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (Study Identification, Official Title; emphasis added). Experimental arm A comprises administration of enfortumab vedotin (i.e., ASG-22ME, ASG-2CE) to subjects intravenously on days 1, 8, and 15 of each 28 day cycle (Arms and Interventions; emphasis added). The inclusion criteria for the study include the following: (i) subjects having histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra) wherein subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible; (ii) subjects have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease; (iii) subjects have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting; (iv) subjects have radiologically documented metastatic or locally advanced disease at baseline; and (v) the subjects have baseline laboratory data of an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 x109/L, hemoglobin ≥ 9 g/dL, serum total bilirubin ≤1.5 x upper limit of normal or ≤ 3 x upper limit of normal for subjects with Gilbert’s disease, creatinine clearance ≥30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection, and alanine aminotransferase (ALT) and aspartate aminotransferase ≤2.5 x upper limit of normal or ≤3 x upper limit of normal for subjects with liver metastases (Eligibility; emphasis added). The exclusion criteria for the study include: (i) subjects having preexisting sensory or motor neuropathy Grade ≥2; (ii) subjects having active central nervous system metastases; (iii) subjects having a history of uncontrolled diabetes mellitus within 3 months of the first dose of study drug wherein uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (Id.; emphasis added).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the invention of the reference application such that the method for treating cancer encompassed by the claims is further limited to a patient population having an ANC of no less than 1500/mm3. One of ordinary skill in the art would have been motivated to make such a modification, and would have had a reasonable expectation of success, because enfortumab vedotin (an ADC that the reference application claims read on) is indicated for use in patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by NCT03474107), and modifying the requirement of the reference application (1x109/L) to that suggested by NCT03474107 would reasonably be expected to achieve similar therapeutic outcomes and be effective in treating cancer.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”), non-patent literature PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as “PADCEV”, non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107"), and US 8,637,642 (US patent document citation A01 on 10/10/2023 IDS; herein after referred to as “Satpayev”).
Application No.
Pertinent Claims
Summary of Pertinent Claims
Deficiencies of the Pertinent Claims
17634026
1, 25, 32, 35, 38, 41-42, 44, 46, 49, 52, 57-59
Method of treating cancer comprising administering an ADC that binds 191P4D12 conjugated to MMAE. The claimed method reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed is the treatment of patients previously treated with platinum-based chemotherapy and/or PD-1/PD-L1 inhibitors, and ADC doses/dosing schedules.
No treatment of bladder or endothelial cancer, liver metastases, ADC formulations, outcomes/responses, or inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria.
17779068
1-2, 9, 16, 19-20, 29, 32, 34, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, 214-215
Method of treating urothelial cancer in a human subject that previously received CPI therapy and chemotherapy comprising administering an ADC that binds 191P4D12 conjugated to MMAE. The claimed method reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed are ADC doses/dosing schedules and exclusion criteria (e.g., diabetes and/or neuropathy).
No liver metastases, ADC formulations, outcomes/responses, or inclusion criteria (ANC).
18010970
1, 134-137, 139-143, 146-148, 152, 168, 173, 176, 181-182, 184
Method of treating cancer comprising administering an ADC. The claimed method reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed are ADC doses/dosing schedules and formulations that read on those of the instant claims. Also claimed is the treatment of bladder and/or endothelial cancer.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), outcomes/responses, or inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria.
19521551
1, 6-8, 10-13, 17, 20, 30-31, 36-73, 79-81, 88
Method of treating bladder or urothelial cancer in a subject ineligible for cisplatin treatment comprising administering an ADC comprising an anti-191P4D12 antibody conjugated to MMAE. The claimed method reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed are subjects with visceral/liver metastases, ADC doses/dosing schedules, ADC formulations, exclusion criteria (CNS metastases), and outcomes/responses.
No exclusion criteria regarding neuropathy and/or uncontrolled diabetes, inclusion criteria (ANC), or the instantly claimed 4-week dosing schedule.
18724594
1, 3, 8-9, 11, 13-14, 18, 21-24, 28, 30-31, 34, 36, 42, 45, 50, 54
Method of treating bladder or urothelial cancer in a subject ineligible for cisplatin treatment comprising administering an ADC comprising an anti-191P4D12 antibody conjugated to MMAE. The claimed method reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed are ADC doses/dosing schedules, ADC formulations, previous standard of care therapies including CPI therapy and/or chemotherapy, and outcomes/responses.
No liver metastases, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, or the instantly claimed 4-week dosing schedule.
18682886
1, 6, 16, 20, 22-24, 28, 33, 37, 43-44, 46-48, 59
Method of treating bladder cancer in a human subject comprising administering an ADC comprising an anti-191P4D12 antibody conjugated to MMAE. The claimed method reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed are the treatment of urothelial carcinoma, inclusion (ANC) criteria, ADC doses/dosing schedules, and ADC formulations.
No liver metastases, exclusion (diabetes, neuropathy, CNS metastases) criteria, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), outcomes/responses, or the instantly claimed ADC doses or 4-week dosing schedule.
19057775
115-128, 130-133, 136-138, 141-145
Pharmaceutical composition comprising an ADC that comprises an antibody that binds to 191P4D12 conjugated to MMAE, specific formulations thereof, and method of treating cancer in a human subject comprising administering the ADC. The ADC claimed reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed is the treatment of bladder and/or endothelial cancer in the methods of treatment, ADC doses/dosing schedules, and ADC formulations.
No liver metastases, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), or outcomes/responses.
19080308
2-20, 23, 29-30
An ADC comprising an anti-191P4D12 antibody conjugated to MMAE, pharmaceutical composition thereof, and method of treating cancer comprising administering the ADC. The ADC claimed reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed is the treatment of bladder cancer.
No treatment of endothelial cancer, liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC doses/dosing schedules, ADC formulations, outcomes/responses, or inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria.
Claims 1, 14, 16, 19, 22, 26, 45-47, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the copending claims above over related subject matter only further supports this obviousness.
It is noted that all of the above-listed copending applications are generally drawn to ADCs comprising antibodies or antigen binding fragments thereof that specifically bind 191P4D12 (i.e., Nectin-4) that are conjugated to MMAE, which read directly on the ADC of the instant claims.
However, it is noted that not all of the copending applications claim a method for treating bladder and/or urothelial cancer in a human subject, wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the inventions of the above-listed copending applications to arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because the prior art recognizes (i) the use of enfortumab vedotin (e.g., 1.25 mg/kg body weight via IV injection/infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle) in the treatment of patients with metastatic or locally advanced urothelial carcinoma, including patients with liver metastases, who have previously been treated with immune checkpoint inhibitors and platinum-based chemotherapy is taught by Rosenberg, patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see PADCEV and Satpayev). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, wherein (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and (iv) estimated median overall survival was 11.7 months.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed U.S. Patent Nos. in view of Rosenberg et. al. (J. Clin. Oncol., 2019, 37(29), 2592-2600, including Authors’ Disclosures and Appendix; publication associated with Clinical Trial NCT03219333; NPL citation C201 of 06/01/2026 IDS; herein after referred to as “Rosenberg”), non-patent literature PADCEV Prescribing Information (Revised Label from December 2019; NPL citation C171 on 06/01/2026 IDS; herein after referred to as “PADCEV”, non-patent literature NCT03474107 (retrieved from ClinicalTrials.gov, Version 39 dated 08/20/2019; herein after referred to as "NCT03474107"), and US 8,637,642 (US patent document citation A01 on 10/10/2023 IDS; herein after referred to as “Satpayev”).
Patent No.
Pertinent Claims
Summary of Pertinent Claims
Deficiencies of the Pertinent Claims
8637642
1-10, 13
ADC, pharmaceutical composition thereof, and method of treatment comprising administering the ADC. The claimed ADC comprises an antibody that reads directly on the instantly claimed antibody that binds 191P4D12, comprises the cytotoxic agent MMAE as a drug, and is formulated in a pharmaceutical composition in human unit dose form for the treatment of cancer, including bladder cancer.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC doses/dosing schedules, ADC structure, ADC formulations, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or treatment of urothelial cancer.
9078931
1-8
Anti-191P4D12 antibody or fragment thereof, ADC comprising said antibody conjugated to a cytostatic agent, and a pharmaceutical composition thereof. The claimed anti-191P4D12 antibody reads directly on the instantly claimed antibody that binds 191P4D12 and the ADC claimed can comprise the antibody conjugated to MMAE.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC doses/dosing schedules, ADC structure, ADC formulations, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or methods of treating bladder or urothelial cancer.
9314538
1-8, 10-12, 15-33
Polynucleotide encoding an antibody, host cell, and method of making said antibody and a method of making an ADC comprising said antibody. The claimed antibody reads directly on the instantly claimed antibody that binds 191P4D12, and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC doses/dosing schedules, ADC formulations, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or methods of treating bladder or urothelial cancer.
9962454
1-5
ADC and ADC produced by a method. The ADC claimed reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC doses/dosing schedules, ADC formulations, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or methods of treating bladder or urothelial cancer.
10894090
1-10, 13-17, 25-38
ADC, pharmaceutical composition thereof, and method of treatment comprising administering the ADC. The ADC claimed reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed is the treatment of bladder cancer and dosages of the ADC.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC dosing schedules, ADC formulations, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or methods of treating urothelial cancer.
11559582
1-24, 27-29
ADC, pharmaceutical composition thereof, and method of treatment comprising administering the ADC. The ADC claimed reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed is the treatment of bladder cancer in the methods of treatment.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC doses/dosing schedules, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or methods of treating urothelial cancer.
12257340
1-14, 16-18, 21-23
Pharmaceutical compositions comprising an ADC, specific formulations thereof, and method of treatment comprising administering the ADC. The ADC claimed reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed is the treatment of bladder and/or endothelial cancer and ADC doses/dosing schedules.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or methods of treating urothelial cancer.
RE48389
1-28, 37-40, 42-62, 64-67, 70-73, 75-85, 88-110
ADC, pharmaceutical composition thereof, and method of treatment comprising administering the ADC. The ADC claimed reads directly on the instantly claimed antibody that binds 191P4D12 and the structure of the ADC is also claimed and reads directly on the instantly claimed structure and, in view of the claimed antibody, also reads directly on an ADC that is enfortumab vedotin. Also claimed is the treatment of bladder cancer and dosages of the ADC.
No liver metastases, previous therapeutic intervention (e.g., CPI therapy or chemotherapy), ADC dosing schedules, or ADC formulations, inclusion (ANC)/exclusion (diabetes, neuropathy, CNS metastases) criteria, outcomes/responses, or methods of treating urothelial cancer.
Claims 1, 14, 16, 19, 22, 26, 45-47, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims above over related subject matter only further supports this obviousness.
It is noted that all of the above-listed patents are generally drawn to ADCs comprising antibodies or antigen binding fragments thereof that specifically bind 191P4D12 (i.e., Nectin-4) that are conjugated to MMAE, which read directly on the ADC of the instant claims.
However, it is noted that not all of the patents claim a method for treating bladder and/or urothelial cancer in a human subject, wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the inventions of the above-listed patents to arrive at a method for treating urothelial and/or bladder cancer in a human subject wherein the method comprises administering a therapeutically effective amount of the ADC, wherein the ADC is enfortumab vedotin, specifically according to the instantly claimed formulations, dosages, and/or administration route and schedule, and further wherein the subject has (i) liver metastases; (ii) been previously treated with an immune checkpoint inhibitor and/or platinum-based chemotherapy; (iii) has an ANC of no less than 1500/mm3; (iv) has no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes; and wherein the subject, or a population of subjects, who receive(s) the treatment experience the instantly claimed therapeutic outcomes regarding progression free survival, complete response, partial response, and/or duration of response. One would have been motivated to make such modifications because the prior art recognizes (i) the use of enfortumab vedotin (e.g., 1.25 mg/kg body weight via IV injection/infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle) in the treatment of patients with metastatic or locally advanced urothelial carcinoma, including patients with liver metastases, who have previously been treated with immune checkpoint inhibitors and platinum-based chemotherapy is taught by Rosenberg, patients having an ANC no less than 1500/mm3, no more than Grade 2 sensory or motor neuropathy, no active CNS metastases, and/or no uncontrolled diabetes are indicated for treatment (as suggested by Rosenberg and NCT03474107), wherein the antibody and the structure of enfortumab vedotin, and its formulation, were known in the art (see PADCEV and Satpayev). One of ordinary skill in the art would have a reasonable expectation of success because the method of Rosenberg yielded favorable therapeutic outcomes in the population (and sub-populations) of patients treated, wherein (i) confirmed objective response rate was 44%, including 12% complete responses, wherein similar responses were observed in prespecified subgroups, such as those patients with liver metastases; (ii) median duration of response was 7.6 months; (iii) estimated median progression-free survival was 5.8 months; and (iv) estimated median overall survival was 11.7 months.
Conclusion
Claims 1, 14, 16-19, 22, 24, 26-28, 45-48, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are pending. Claims 17-18, 24, 27-28, and 48 are withdrawn. Claims 1, 14, 16, 19, 22, 26, 45-47, 50, 53-55, 57-64, 67-68, 70-72, 76-77, 82, 86, 91, and 94-95 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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