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 .
Claim Status
Claims 1-20 are pending and under examination in the instant office action.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 30 June 2023. It is noted, however, that applicant has not filed a certified copy of the PCT/CN/2023105235 application as required by 37 CFR 1.55.
As such, the instant claims are accorded the priority date of the instant application, 7 December 2023.
Information Disclosure Statement
The IDSs dated 4/4/2024 and 11/11/2024 have been considered except where lined through. The reference CN103476941 has not been considered because no English language abstract or statement of relevance was provided.
Claim Objections
Claims 6 and 20 are objected to for the recitation of “wherein the antibody is sacituzumab” because there are two antibodies recited in claims 1 and 19, from which the claims depend. Although the antecedent basis is not indefinite because Applicant defines one as “the antibody” and the other as “the anti-human PD-1 antibody or antigen binding fragment thereof”, the Examiner suggests amending the claims to recite “wherein the antibody that binds to Trop-2 is sacituzumab” in order to further clarify the antecedent basis.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-5 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 recites “n is a decimal from 0 to 10, and represents the average number of linker/payload moieties joined to each antibody for the plurality of Immunoconjugates of Formula (I)” in lines 9-10. The recitation renders the claim indefinite because it is unclear what molecule the chemical formula represents if n is a decimal, or what an individual immunoconjugate of Formula (I) would be if “n” is a non-integer number between 0 and 10; n cannot represent both the average and the number of linker/payloads in Formula (I) because Formula (I) is a single molecule. For the purposes of expedited prosecution, the claim will be read as wherein n is an integer from 1 to 10 and the average number of linker/payload moieties joined to each antibody for the plurality of Immunoconjugates of Formula (I) is a number between 0 and 10.
Claims 3-5 are indefinite for the recitation of “the antibody” because the antecedent basis is uncertain due to two antibodies recited in claim 1: an anti-human PD-1 antibody or antigen binding fragment thereof and an antibody that binds to Trop-2 which is part of the immunoconjugate for Formula (I). The Examiner suggests obviating this rejection by amending the claims to recite “wherein the antibody that binds to Trop-2 comprises […]”.
Dependent claims are rejected for failing to resolved the indefiniteness as described.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 3-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus
Regarding instant claims 1 and 19, the disclosure teaches antibody conjugation via cysteine residues and claims structures that conjugate to antibody cysteine residues, but linker conjugates bound to the antibody are claimed as an integer or decimal, n, between 1 and 10. Instant claims 3-18 and 20 are dependent on instant claims 1 and 19 without including n to a maximum of 8.
State of the Relevant Art
The prior art has taught most ADCs are synthesized by conjugating a cytotoxic compound or “payload” to a monoclonal antibody (Behrens CR et al. (Mol. Pharmaceutics 2015, 12, 11, 3986–3998), page 3986, left column, first paragraph). Behrens teaches the payloads are conjugated using amino or sulfhydryl specific linkers that react selectively with lysines or cysteines on the antibody surface, wherein a typical antibody contains over 50 lysines and eight interchain cysteines as potential conjugation sites (page 3986, left column, first paragraph). Behrens teaches conjugation through antibody cysteines minimizes ADC heterogeneity relative to lysine conjugation because there are fewer potential conjugation sites (page 3986, right column, first paragraph). The process typically involves partial reduction of four antibody interchain disulfide bonds to generate up to eight reactive cysteine thiol groups, followed by conjugation of payloads containing thiol-specific maleimide linkers (page 3986, right column, first paragraph). Behrens teaches ADCs with suboptimal drug antibody ratios (DARs) are prone to aggregation, poor solubility, and instability, which often lead to increased toxicity and/or inadequate efficacy in vivo (page 3986, left column, first paragraph). Behrens teaches the discrepancy between the number of potential conjugation sites and the desired DAR, combined with the use of linkers that lack site-specificity, results in heterogeneous ADCs that vary in both DAR and the conjugation sites (page 3986, left to right column bridging sentence). Behrens teaches consequently, most of the ADCs in clinical development for cancer indications contain dozens or more of chemically distinct ADC molecules, each with unique pharmacological properties (page 3986, right column, first paragraph). Thus the antibody conjugation via a cysteine residue would conjugate up to 8 linker-drugs.
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification teaches an immunoconjugate of Formula (I) wherein the antibody is an anti-Trop-2 antibody and specifically sacituzumab. The specification teaches that the immunoconjugate is described in U.S. Patent No. 20200347075 [0012]. The specification prophetically teaches that n is an integer between 1 and 10 [0015]. In paragraph [0106] the specification prophetically teaches that n is between 1 and 8. The specification teaches “In a particular embodiment, the Immunoconjugate of Formula (I) comprises from about 6 to about 8 linker/drug moieties per antibody (i.e., n is from about 6 to about 8). In a specific embodiment, the Immunoconjugate of Formula (I) is Immunoconjugate A, and n is from 6 to 8” [142]. The are no specific working embodiments taught where n is greater than 8.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for immunoconjugates of Formula 1 of the antibody-drug structure conjugated to an antibody where the number of drug molecules “n” is greater than 8. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of methods and pharmaceutical compositions comprising the immunoconjugate of Formula (I) as claimed at the time of filing. Regarding claims 3-18 and 20 the claims are ultimately dependent on the rejected claims 1 and 19 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5 and 9-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating non-small cell lung cancer (NSCLC) in a patient wherein the NSCLC is without EGFR mutation and ALK fusion genes; or the NSCLC has an EGFR actionable mutation and the patient has failed prior EGFR-TKI treatment comprising administering to the patient:
a) an Immunoconjugate of Formula (I) wherein Ab is sacituzumab or comprising the anti-TROP2 CDRs of sacituzumab (SEQ ID NOs: 39-42, respectively); and
b) an anti-human PD-1 antibody or antigen binding fragment thereof wherein the anti-human PD-1 antibody or antigen binding fragment thereof blocks the interaction between PD-1 and its ligand PD-L1 or PD-L2 (e.g. wherein the anti-human PD-1 antibody is a PD-1 antagonist)
does not reasonably provide enablement for a method of treating cancer in a patient wherein the cancer is selected from ovarian cancer, cry al cancer, prostate cancer, and urothelial cancer comprising administering to the patient:
a) an Immunoconjugate of Formula (I) wherein Ab is any antibody that binds to Trop-2 and
b) The method of treating comprising administering any generic anti-human PD-1 antibody or antigen binding fragment thereof.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Scope of the claimed genus and nature of the invention
Regarding instant claim 1, the claims are directed towards a method of treating particular NSCLCs comprising an immunoconjugate of Formula (I), wherein Ab is any generic antibody that binds to Trop-2
Regarding instant claims 1, the claims are directed towards a method of treating particular NSCLCs comprising any generic anti-human PD-1 antibody or antigen binding fragment thereof
Regarding dependent claims 2 and 9-18, the claims are dependent on claim 1 without resolving the scope of enablement for both a) and b) as described. Regarding dependent claims 3-5, the claims limit the anti-Trop-2 antibody of the immunoconjugate and therefore resolve the scope of enablement of part (a), but do not resolve the scope of enablement of the anti-human PD-1 antibody or antigen binding fragment thereof as described for part (b) and therefore are rejected. Claim 6 and dependents 7-8 are not rejected because it recites particular antibodies sacituzumab and pembrolizumab and therefore resolves the scope of enablement issues as described.
State of the relevant art; level of ordinary skill; and level of predictability in the art
Regarding TROP-2 immunoconjugates, other anti-TROP-2 immunoconjugates using several TROP-2 binding antibodies are known in the art. For example, Wen Y, et. al. A literature review of the promising future of TROP2: a potential drug therapy target. Ann Transl Med. 2022 Dec;10(24):1403. doi: 10.21037/atm-22-5976. PMID: 36660684; PMCID: PMC9843409 teaches that TROP2 is overexpressed in a variety of cancers including bladder urothelial carcinoma, lung squamous cell carcinoma, head and neck squamous cell carcinoma, prostate adenocarcinoma, and lung adenocarcinoma (p. 2 right column, Fig. 1). Wen et. al. teaches anti-TROP2 ADCs with various anti-TROP2 antibodies that have anticancer effects such as hRS7 ADCs hRS7-CL2A-SN-38 and sacituzumab govitecan (IMMU-132), which has the humanized version of the hRS7 antibody (p. 9 left column ¶2-3); RN927C with is composed of a humanized anti-TROP2 IgG1 antibody (p. 9 right column ¶2); Datopotamab deruxtecan (p. 9 right column ¶3).
Generally, the prior art has recognized that antibodies in antibody drug conjugates require internalization to be effective drug vehicles. Chalouni C et al. Fate of Antibody-Drug Conjugates in Cancer Cells (J Exp Clin Cancer Res. 2018 37(1):20) teaches antigen binding, the anti-tumor potency of cytotoxic drugs and the favorable pharmacokinetic profile of the antibody are critical for the function of the ADC (page 3, left column, third paragraph). In addition, Chalouni teaches the efficacy of an ADC also relies on its internalization and processing, the release of the drug from the intracellular compartment to the cytosol and binding to its intracellular target to trigger cell death (page 3, left column, third paragraph). Chalouni teaches ADC trafficking and processing in a classic model wherein: The ADC binds to its surface antigen (1) and the complex is internalized (2), it reaches lysosomes where its linker of the ADC is degraded leading to the release of the drug (3), the drug passes from the intracellular compartment to the cytosol (4), and binds to its target, DNA or tubulin (5) ensue apoptosis (Fig. 1b). Chalouni teaches conjugated drugs may also be released into the microenvironment via pumps or passive transfer through the cell membrane (6), capacity to enter a neighbor cancer cell (7) resulting in bystander effect. c- Endocytosis and autophagy pathways (Fig. 1c).
The prior art further teaches that antibody drug conjugates can have unpredictable effects when combined, wherein the drug can affect antibody trafficking. Chalouni teaches while the design of an ADC may rely on features specific to the trafficking of the parent antibody, this strategy can be challenging as the addition of a drug can result in subtle differences in these antibody properties such as preventing or inducing the internalization of a construct as seen for anti-CD19 antibody (page 4, left column, last paragraph).
Thus, antibody internalization is a requirement for an effective ADC and drugs may cause unpredictable effects on ADC internalization. Therefore, any generic anti-TROP2 antibody would not be expected to lead to an effective ADC.
Regarding methods of treating cancer with anti-PD-1 immunotherapy, some of these methods are known in the art. Jiang Y, et. al. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother. 2019;15(5):1111-1122. doi: 10.1080/21645515.2019.1571892. Epub 2019 Mar 19 teaches that PD-1 is a cell surface receptor that functions as a T cell checkpoint by binding its ligand PD-L1 to inhibit T cell activation and that high PD-L1 expression on tumor cells and antigen presenting cells mediates tumor immune escape (Abstract, Fig. 1). Jiang et. al. teaches that there are PD-1/PD-L1 blockade therapies including anti-PD-1 antibodies produced and approved by the FDA such as nivolumab, pembrolizumab, and cemiplimab (p. 1112 right column section 4- p. 1113 right column; Table 1).
Additionally, methods of treating cancer by combining anti-PD-1 checkpoint immunotherapy and antibody-drug conjugates comprising captothecin-based topoisomerase I inhibitors were known in the art. Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 teaches a method of treating cancer comprising an antibody conjugated to w topoisomerase I inhibitor exatecan derivative. Iwata et. al. teaches that the antibody-drug conjugate inhibited tumor growth compared to vehicle or antibody alone (Fig. 1) and that the treatment contributed to immune memory function in mouse in vivo cancer models (Fig. 2 and Fig. 3, p. 1496 right column-p. 1499 left column). Iwata et. al. teaches that treatment of the in vivo mouse model with the ADC and an anti-PD-1 antibody, survival of mice with tumors was significantly improved compared to either the ADC or anti-PD-1 antibody alone (Fig. 6 p. 1501 left column). Iwata et. al. teaches “For combination with ICIs, ADCs are considered to be better than chemotherapeutic agents because ADCs work selectively at the tumor site with reduced side effect to other organs […] In this study, DS-8201a, a HER2-targeting ADC with a topoisomerase I inhibitor showed an antitumor effect with immunostimulatory activity in a mouse model. DS-8201a also benefited from combination with anti-PD-1 antibody […] the combination of DS-8201a and anti-PD-1 antibody showed higher antitumor effect” (p. 1502 left column ¶3- right column ¶1).
Summary of species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and the quantity of experimentation needed to make or use the invention based on the content of the disclosure
Regarding anti-TROP-2 antibodies, the instant specification discloses anti-TROP2 antibodies comprising HCDRs 1-3 of SEQ ID NOs: 39-41 and LCDRs 1-3 of SEQ ID NOs: 42-44, which are the CDRs of sacituzumab as described by the instant specification ([0133-0140], Table 5). There are no other particular embodiments of anti-TROP2 antibodies disclosed. The instant specification prophetically recites “This antibody can also be obtained by screening through carrier design, construction of an antibody library displaying antibodies as disclosed in CN103476941A, or can be obtained by screening a G-MAB® library of Sorrento Therapeutics, Inc.” [0139].
Regarding anti-human PD-1 antibodies, the instant specification discloses the exemplary CDRs of and heavy/light chain of pembrolizumab and nivolumab (Table 3) as well as additional anti-PD-1 antibodies in the art of hPD-1.08A, h109A/K09A, and 409/K09A from WO2008156712 (Table 4). The specification teaches that the anti-human PD-1 antibodies are PD-1 antagonists [0107] and that the antibodies should bind to PD-1 and “block the interaction between PD-1 and its ligand PD-L1 or PD-L2” [109]. There are no PD-1 agonist antibodies or PD-1 binding antibodies that do not block the interaction with PD-L1 or PD-L2 disclosed.
Conclusion
Applicant does not have enablement for a method of treating NSCLC without EGFR mutation or ALK fusion genes or NSCLC with an EGFR actionable mutation, and the patient has failed prior EGFR-TKI treatment, comprising administering to the patient an immunoconjugate of Formula (I) wherein Ab is any generic antibody that binds to Trop-2 and comprising administering to the patient any generic anti-human PD-1 antibody or antigen binding fragment thereof, wherein the anti-human PD-1 antibody is not required to be a PD-1 antagonist.
Claim Rejections - 35 USC § 103
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 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 1-9, 11, 14, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) in view of WO2019114666 A1 to Cai et. al. published 20 June 2019 (citations refer U.S. equivalent U.S. 20200347075, of record, IDS dated 4/4/2024) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841.
NCT’974 teaches a method of treating non-small cell lung cancer without actionable genomic alterations (See “Official Title”) comprising administering a combination of a sacituzumab antibody-drug conjugate sacituzumab govitecan (synonym for IMMU-132) at 10 mg/kg on Days 1 and 8 of a 21-day cycle and 200 mg of pembrolizumab on day 1 of a 21-day cycle, administered intravenously; or (“Arms and Interventions” section). As evidenced by the instant specification, “without actionable genomic mutations” reads on no EGFR or ALK fusion gene mutations because a both EGFR and ALK fusion mutations are considered actionable ([0157], [300], [312]). Regarding claim 7, NCT’974 teaches a treatment arm with additional cisplatin or carboplatin therapy wherein there is a safety run-in at a dose of 5mg/mL (“Arms and Interventions” section).
Regarding claim 14, NCT’974 teaches experimental arms further comprising administering to the patient an additional anticancer agent which is a platinum containing chemotherapeutic agent (Carboplatin or Cisplatin, see “Arms and Interventions” section; wherein the dose of carboplatin is AUC5 (synonym for AUC 5 mg/ml/min) on Day 1 of a 21-day cycle and wherein the dose of cisplatin is 75mg/m2 on Day 1 of a 21-day cycle.
NCT’974 does not teach the method wherein the immunoconjugate comprises instant Formula (I). This deficiency is resolved by Cai et. al. and Iwata et. al.
Cai et. al. teaches a Sacituzumab antibody-drug conjugate of a TROP2 antibody conjugated to a topoisomerase I inhibitor derivative called BT001021 of the following formula (Example 32, [0424]), identical to instant Formula (I)
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Cai et. al. teaches that Sacituzumab is the anti-Trop-2 antibody (Example 32 [0424]). Cai et. al. teaches that the BT001021 antibody light chain was coupled to 0 or 1 toxin and the heavy chain is coupled with 1 to 3 toxins (reads on n is an integer between 1 and 10) (Example 53, [0483]). Cai et. al. teaches that the ADCs of the invention can be used in a method of treating cancer such as non-small cell lung cancer ([0007], [0147]) Cai et. al. teaches that in comparison to IMMU-132 (synonym for sacituzumab govitecan as evidenced by DrugBank.com), BT0001021 injected iv into mice at 3mg/kg inhibited tumor growth in a human gastric cancer subcutaneous model NCI-N87 better than IMMU-132 (Experimental Example 1, [0554-0558]); that BT0001021 injected into mice at 10mg/kg inhibited breast cancer in a HCC1806 breast cancer model better than IMMU-132 (Experimental Example 2, [0559-0565]); that BT0001021 injected into mice at 10mg/kg inhibited non-small cell lung cancer in a HCC827 NSCLC model better than IMMU-132 (Experimental Example 3, [0566-0572]). Cai et. al. further teach that BT0001021 compared to IMMU-132 had better tumor pharmacokinetic properties and tissue targeting than IMMU-132 and has a better therapeutic window [0613].
Iwata et. al. teaches a method of treating cancer comprising an antibody conjugated to a topoisomerase I inhibitor exatecan derivative. Iwata et. al. teaches that the antibody-drug conjugate inhibited tumor growth compared to vehicle or antibody alone (Fig. 1) and that the treatment contributed to immune memory function in mouse in vivo cancer models (Fig. 2 and Fig. 3, p. 1496 right column-p. 1499 left column). Iwata et. al. teaches that treatment of the in vivo mouse model with the ADC and an anti-PD-1 antibody, survival of mice with tumors was significantly improved compared to either the ADC or anti-PD-1 antibody alone (Fig. 6 p. 1501 left column). Iwata et. al. teaches “The payload of DS-8201a has 10 times more potent topoisomerase inhibitory activity than SN-38, and this could lead to more immunologic cell death than treatment with SN-38 and other existing topoisomerase inhibitors” (p. 1501 right column ¶4) and that “Recently, three different topoisomerase I inhibitors (camptothecin, topotecan, irinotecan) have been shown to enhance tumor-killing activity of T cells” (p. 1502 left column ¶2); “For combination with ICIs, ADCs are considered to be better than chemotherapeutic agents because ADCs work selectively at the tumor site with reduced side effect to other organs […] In this study, DS-8201a, a HER2-targeting ADC with a topoisomerase I inhibitor showed an antitumor effect with immunostimulatory activity in a mouse model. DS-8201a also benefited from combination with anti-PD-1 antibody […] the combination of DS-8201a and anti-PD-1 antibody showed higher antitumor effect” (p. 1502 left column ¶3- right column ¶1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the BT0001021 sacituzumab antibody-drug conjugate of Cai et. al. in the method of treating comprising administering sacituzumab govitecan and pembrolizumab to patients with bladder cancer in order to benefit from the improved tissue targeting and therapeutic window and better anti-tumor effects in mouse models compared to IMMU-132 (synonym for sacituzumab govitecan) as taught by Cai et. al. This would have a reasonable expectation of success because both NCT’974 and Cai et. al. teach a method of treating Trop-2 positive cancers comprising administering a sacituzumab antibody drug conjugate and Iwata et. al. teaches that ADCs with topoisomerase inhibitors combined with anti-PD-1 blockade therapy increases anti-tumor immunity and cytotoxic effect. A person of ordinary skill in the art therefore would reasonably believe that the benefits of combination therapy as taught by NCT’974 and Iwata et. al. with the benefits of an improved sacituzumab ADC would result in an improved treatment for a TROP-2 positive cancer such as non-small-cell lung cancer as taught by NCT’974.
Regarding claim 2, each sacituzumab has two light chains and two heavy chains, and therefore the pool of BT0001021 of Cai et. al. contained some molecules wherein n was from 6 (e.g. 0 light chain toxins and 3 toxins per heavy chain or 1 toxin per light chain and 2 per heavy chain) to 8 (e.g. 1 toxin per light chain and 3 per heavy chain).
Regarding claims 3-5, Cai et. al. teaches that sacituzumab comprises a VH and VL of SEQ ID NOs: 19 and 20, respectively, which are 100% identical to instant SEQ ID NO: 35 and 36, comprise a VH and VL identical to instant SEQ ID NOs: 37 and 38, and comprise the HCDRs of instant SEQ ID NOs: 39-41 and LCDRs of instant SEQ ID NOs: 42-44, respectively.
Regarding claim 6, Cai et. al. teaches BT0001021 is a sacituzumab antibody-drug conjugate. Therefore, the substitution of NCT’974 in view of Cai et. al. and Iwata et. al. teaches the combination comprising the anti-TROP2 antibody sacituzumab and the anti-PD-1 antibody pembrolizumab.
Regarding claims 7 and 11, It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify the dose of the sacituzumab ADC as taught by Cai et. al. in the range of doses disclosed by Cai et. al. as effective in preclinical models (3 mg/kg and 10mg/kg) and to choose a dose lower than the clinical benchmark sacituzumab govitecan because Cai et. al. discloses that IMMU-132 has a better therapeutic window than sacituzumab govitecan. It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to therefore use the lower dose of 5mg/mL as taught by ‘974 to benefit from lowering the dose for a novel drug to determine safety and efficacy in a new combination as taught by ‘974. This would have a reasonable expectation of success because Cai et. al. discloses preclinically effective doses of 3mg/kg and 10mg/kg and that the benchmark drug sacituzumab govitecan is less effective at the lower dose than the ADC of instant formula (I), and a person of ordinary skill in the art would use preclinical data and clinical benchmarks such a sacituzumab govitecan to determine dosing.
Regarding claim 8, modified NCT’974 in view of Cai et. al. and Iwata et. al. teaches the pembrolizumab dose is 200 mg.
Regarding claim 9 and 11, modified NCT’974 in view of Cai et. al. and Iwata et. al. teaches the immunoconjugate and pembrolizumab (anti-human PD-1) are administered in 21 day cycles (reads on 3 weeks and each are administered on Day 1 of each three-week cycle).
Regarding claims 19 and 20, the composition administered on Day 1 of NCT’974 in view of Cai et. al. and Iwata et. al. reads on the pharmaceutical composition comprising the pembrolizumab (anti-human PD-1 antibody and the plurality of immunoconjugates of Formula (I) (BT001021 as taught by Cai et. al.). It would have been obvious to a person of ordinary skill in the art that the composition must also comprise a pharmaceutically acceptable carrier such as a buffer because it is administered intravenously to a human as taught by NCT’974.
Claims 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) in view of WO2019114666 A1 to Cai et. al. published 20 June 2019 (citations refer U.S. equivalent U.S. 20200347075, of record, IDS dated 4/4/2024)) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and further in view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512.
The teachings of NCT’974 in view of Cai et. al. and Iwata et. al. are in regards to claims 1 and 14 are in the 103 rejection above.
Regarding claims 15 and 16, NCT’974 describes an anti-TROP2 ADC sacituzumab govitecan is administered at a concentration of 10mg/kg, 7.5mg/kg, or 5mg/kg (safety run-in dose) on Day 1 and Day 8 of a 21-day cycle in combination with pembrolizumab 200mg on Day 1 of 21-day cycle and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle to treat NSCLC without treatable genomic alterations; Cai et. al. teaches a sacituzumab immunoconjugate of formula I administered to mice in effective doses of 3mg/kg and 10mg/kg that is more cytotoxic and has a better therapeutic window that sacituzumab govitecan (IMMU-132).
Modified NCT’974 in view of Cai et. al. does not explicitly teach the method wherein the combination wherein the cycles are 1-4 cycles.
This deficiency is resolved by Spring et. al.
Spring et. al. teaches a method of treating breast cancer with sacituzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by NCT’974 in view of Cai et. al. and Iwata et. al. by administering the ADC of Cai et. al. in the method of treating NSCLC without actionable genetic mutations at ADC safety dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because Cai et. al. teaches that SG (IMMU-132) is a benchmark sacituzumab ADC for the ADC of formula (I) and that the ADC of formula (I) has an improved efficacy and therapeutic window and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
Claims 10, 12, 13, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) in view of WO2019114666 A1 to Cai et. al. published 20 June 2019 (citations refer U.S. equivalent U.S. 20200347075, of record, IDS dated 4/4/2024) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and in further view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512; Lala, Mallika, et al. "A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation." European Journal of Cancer 131 (2020): 68-75; and NCT05347134 “SKB264 Injection vs Investigator Selected Regimens to Treat Locally Advanced, Recurrent, or Metastatic Triple-negative Breast Cancer” published 20 April 2022 (hereinafter NCT’134).
The teachings of NCT’974 in view of Cai et. al. in regarding to claims 1 and 14 are in the 103 rejection above.
NCT’974 in view of Cai et. al. does not teach the method of claim 14 wherein the immunoconjugate of Formula (I) is administered at a dose of about 5mg/kg on days 1, 15, and 29 of a 6-week cycle, the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400mg on day 1 of each six-week cycle, carboplatin is administered at a dose of AUC 5mg/ml/min or cisplatin is administered at a dose of 75mg/m2 on days 1 and 22 of each six-week cycle; and the number of cycles is from 1 to 4.
This deficiency is resolved by Spring et. al., Lala et. al., and NCT’134.
Spring et. al. teaches a method of treating breast cancer with sacituzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by NCT’974 in view of Cai et. al. and Iwata et. al. by administering the ADC of Cai et. al. in the method of treating NSCLC without actionable genetic mutations at ADC de-escalation dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because Cai et. al. teaches that SG (IMMU-132) is a benchmark sacituzumab ADC for the ADC of formula (I) and that the ADC of formula (I) has an improved efficacy and therapeutic window and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
NCT’974 in view of Cai et. al., Iwata et. al., and Spring et. al. dose not teach a dose of pembrolizumab 400 mg every 6 weeks and wherein the ADC is administered on Days 1, 15, and 29 of a 6-week cycle.
Lala et. al. teaches a method of treating cancer comprising administering pembrolizumab 400 mg dose every 6 weeks (Abstract). Lala et. al. teaches “In conclusion, the pembrolizumab 400 mg Q6W dosing regimen is expected to produce similar efficacy and safety across all clinical treatment settings in which pembrolizumab 200 mg (or 2 mg/kg) is currently used. Overall, pembrolizumab 400 mg Q6W is expected to have a similar benefit-risk profile as the approved 200 mg Q3W dosing regimen while allowing physicians added flexibility and convenience to dose at a frequency that meets the clinical need of patients with cancer” (p. 74 right column).
NCT’134 teaches a method of treating locally advanced or metastatic breast cancer comprising administering an anti-TROP2 ADC wherein the anti-TROP2 ADC is administered at 5mg/kg IV on Day 1 and 15 of each 28 day cycle (which is equivalent to every 2 weeks).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the dose timing and schedule of the combination of the ADC of Cai et. al. and pembrolizumab as taught by modified NCT’974 by administering 400 mg of pembrolizumab every six weeks in order to benefit from the increased flexibility and decreased visit frequency for cancer patients as taught by Lala et. al. This would have a predictable effect because Lala et. al. teaches that the safety and pharmacokinetic profile of 400 mg Q6W is similar to the current standard of administering every third week. A person of ordinary skill in the art would also understand that dosing every 6 weeks would be advantageous in a combination therapy because it allows more flexibility in the dose timing of the second drug without increasing the visit frequency or needing extra visits for administering the drugs individually. It would have been further obvious to modify the dose timing of the ADC of Cai et. al. from the dose timing of the ADC of NCT’974 because Cai et. al. teaches that the ADC has a favorable pharmacokinetic profile compared to IMMU-132, and therefore a person of ordinary skill in the art would expect to adjust the dosing frequency and amount to arrive at the most efficacious and best treatment of cancer, including a possible dosing schedule of every two weeks as taught by a different anti-TROP2 ADC in NCT’134 in order to benefit from less frequent dosing for an ADC with a stronger cytotoxic effect as taught by Cai et. al. This combination would result in a six week cycle with pembrolizumab dosed every Day 1 at 400 mg and the ADC of Cai et. al. dosed at 5mg/mL every 2 weeks, which is days 1, 15, and 29 of a six-week cycle, and carboplatin or cisplatin dosed at AUC5 or 75mg/m2, respectively day 1 every 3 weeks, which is Days 1 and 22 of a 6-week cycle. This would have a reasonable expectation of success because an artisan of ordinary skill would adjust the dosing amounts and schedules based on clinical benchmarks of similar drugs and the preclinical strength of the drug in order to arrive at the most effective and safest dosing schedule.
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.
U.S. Patent No. 11970506
Claims 1-9, 11, 14, 19, and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11970506 B2 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841.
The ‘506 patent teaches an antibody-drug conjugate, wherein the conjugate is:
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Identical to instant Formula (I), wherein γ is an integer from 1 to 10 and mAb is an anti-Trop-2 monoclonal antibody. Claims 2 and 17 teaches an antibody-drug conjugated to the same drug, wherein A1 is an anti-TROP2 antibody comprising a heavy chain SEQ ID NO: 19 and a light chain SEQ ID NO: 20 or the CDRs of SEQ ID NOs: 19 and 20 (identical to instant SEQ ID NOs: 35 and 36, comprising VH and VL instant SEQ ID NOs: 37 and 38 and HCDRs SEQ ID NOs: 39-41 and LCDRs 42-44; reads on instant claims 3-5), wherein A1 is linked via one or more thiol groups to form the conjugate and γ is an integer from 1 to 8. Claim 3 teaches the conjugate of claim 2 wherein γ is 6 to 8 (reads on instant claim 2). Claim 6 teaches a pharmaceutical composition comprising one or more of the conjugate of claim 2 and one or more pharmaceutical excipients. Claim 9 teaches wherein the antibody A1 is sacituzumab (reads on instant claim 6). Claim 12 teaches a pharmaceutical composition comprising one or more of the conjugate of claim 9 and one or more pharmaceutical excipients.
The ‘506 patent does not teach a method of treating NSCLC without an EGFR mutation or ALK fusion, said method comprising administering an anti-human PD-1 antibody or antigen-binding fragment thereof and an immunoconjugate of instant Formula (I). This deficiency is resolved by NCT’974 and Iwata et. al.
NCT’974 teaches a method of treating non-small cell lung cancer without actionable genomic alterations (See “Official Title”) comprising administering a combination of a sacituzumab antibody-drug conjugate sacituzumab govitecan (synonym for IMMU-132) at 10 mg/kg on Days 1 and 8 of a 21-day cycle and 200 mg of pembrolizumab on day 1 of a 21-day cycle, administered intravenously; or (“Arms and Interventions” section). As evidenced by the instant specification, “without actionable genomic mutations” reads on no EGFR or ALK fusion gene mutations because a both EGFR and ALK fusion mutations are considered actionable ([0157], [300], [312]). Regarding claim 7, NCT’974 teaches a treatment arm with additional cisplatin or carboplatin therapy wherein there is a safety run-in at a dose of 5mg/mL (“Arms and Interventions” section).
Regarding claim 14, NCT’974 teaches experimental arms further comprising administering to the patient an additional anticancer agent which is a platinum containing chemotherapeutic agent (Carboplatin or Cisplatin, see “Arms and Interventions” section; wherein the dose of carboplatin is AUC5 (synonym for AUC 5 mg/ml/min) on Day 1 of a 21-day cycle and wherein the dose of cisplatin is 75mg/m2 on Day 1 of a 21-day cycle.
Iwata et. al. teaches a method of treating cancer comprising an antibody conjugated to w topoisomerase I inhibitor exatecan derivative. Iwata et. al. teaches that the antibody-drug conjugate inhibited tumor growth compared to vehicle or antibody alone (Fig. 1) and that the treatment contributed to immune memory function in mouse in vivo cancer models (Fig. 2 and Fig. 3, p. 1496 right column-p. 1499 left column). Iwata et. al. teaches that treatment of the in vivo mouse model with the ADC and an anti-PD-1 antibody, survival of mice with tumors was significantly improved compared to either the ADC or anti-PD-1 antibody alone (Fig. 6 p. 1501 left column). Iwata et. al. teaches “The payload of DS-8201a has 10 times more potent topoisomerase inhibitory activity than SN-38, and this could lead to more immunologic cell death than treatment with SN_38 and other existing topoisomerase inhibitors” (p. 1501 right column ¶4) and that “Recently, three different topoisomerase I inhibitors (camptothecin, topotecan, irinotecan) have been shown to enhance tumor-killing activity of T cells” (p. 1502 left column ¶2); “For combination with ICIs, ADCs are considered to be better than chemotherapeutic agents because ADCs work selectively at the tumor site with reduced side effect to other organs […] In this study, DS-8201a, a HER2-targeting ADC with a topoisomerase I inhibitor showed an antitumor effect with immunostimulatory activity in a mouse model. DS-8201a also benefited from combination with anti-PD-1 antibody […] the combination of DS-8201a and anti-PD-1 antibody showed higher antitumor effect” (p. 1502 left column ¶3- right column ¶1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the sacituzumab antibody-drug conjugate of ‘506 in the method of treating comprising administering sacituzumab govitecan and pembrolizumab to patients with bladder cancer in order to benefit from a TROP2 targeted ADC conjugated to a topoisomerase I inhibitor as taught by ‘506 in a method of treatment using the ADC as suggested by NCT’974 and Iwata et. al. This would have a reasonable expectation of success because both NCT’974 and ‘506 teach a method or a composition for use in treating Trop-2 positive cancers (a sacituzumab antibody conjugated to a topoisomerase I inhibitor/camptothecin derivative) and Iwata et. al. teaches that ADCs with topoisomerase inhibitors combined with anti-PD-1 blockade therapy increases anti-tumor immunity and cytotoxic effect. A person of ordinary skill in the art therefore would reasonably believe that the benefits of combination therapy as taught by NCT’974 and Iwata et. al. with the benefits of an improved sacituzumab ADC would result in an improved treatment for a TROP-2 positive cancer such as bladder cancer as taught by NCT’974.
Regarding claim 8, modified ‘506 in view of NCT’974 and Iwata et. al. teaches the pembrolizumab dose is 200 mg.
Regarding claim 9, modified ‘506 in view of NCT’974 and Iwata et. al. teaches the immunoconjugate and anti-human PD-1 are administered in 21 day cycles (reads on 3 weeks and each are administered on Day 1 of each three-week cycle).
Regarding claims 19 and 20, the composition administered on Day 1 of ‘506 in view of NCT’974 and Iwata et. al. reads on the pharmaceutical composition comprising the pembrolizumab (anti-human PD-1 antibody and the plurality of immunoconjugates of Formula (I) (of the claims of ‘506).
Claims 15 and 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11970506 B2 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and further in view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512.
The teachings of ‘506 in view of NCT’974 and Iwata et. al. in regards to claim 1 and 14 are in the NSDP rejection above.
Regarding claims 15 and 16, NCT’974 describes an anti-TROP2 ADC sacituzumab govitecan administered at a concentration of 10mg/kg, 7.5mg/kg, or 5mg/kg (safety run-in dose) on Day 1 and Day 8 of a 21-day cycle in combination with pembrolizumab 200mg on Day 1 of 21-day cycle and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle to treat NSCLC without treatable genomic alterations; Cai et. al. teaches a sacituzumab immunoconjugate of formula I administered to mice in effective doses of 3mg/kg and 10mg/kg that is more cytotoxic and has a better therapeutic window that sacituzumab govitecan (IMMU-132).
Modified ‘506 in view of NCT’974 and Iwata et. al. does not explicitly teach the method wherein the combination wherein the cycles are 1-4 cycles.
This deficiency is resolved by Spring et. al.
Spring et. al. teaches a method of treating breast cancer with sacitzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by ‘506 in view of NCT’974 and Iwata et. al. by administering the ADC of ‘506 in the method of treating NSCLC without actionable genetic mutations at ADC safety dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because ‘506 teaches both NCT’978, ‘506, and Spring et. al. teach sacituzumab ADCs conjugated to camptothecin derivatives and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
Claims 10, 12, 13, 17 and 18 are rejected are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11970506 B2 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and in further view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512; Lala, Mallika, et al. "A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation." European Journal of Cancer 131 (2020): 68-75; and NCT05347134 “SKB264 Injection vs Investigator Selected Regimens to Treat Locally Advanced, Recurrent, or Metastatic Triple-negative Breast Cancer” published 20 April 2022.
The teachings of ‘506 in view of NCT’974 and Iwata et. al. in regards to claim 1 and 14 are in the NSDP rejection above.
‘506 in view of NCT’974 and Iwata et. al. does not teach the method of claim 14 wherein the immunoconjugate of Formula (I) is administered at a dose of about 5mg/kg on days 1, 15, and 29 of a 6-week cycle, the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400mg on day 1 of each six-week cycle, carboplatin is administered at a dose of AUC 5mg/ml/min or cisplatin is administered at a dose of 75mg/m2 on days 1 and 22 of each six-week cycle; and the number of cycles is from 1 to 4.
This deficiency is resolved by Spring et. al., Lala et. al., and NCT’134.
Spring et. al. teaches a method of treating breast cancer with sacituzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by ‘506 in view of NCT’974 and Iwata et. al. by administering the ADC of ‘506 in the method of treating NSCLC without actionable genetic mutations at ADC safety dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because ‘506 teaches both NCT’978, ‘506, and Spring et. al. teach sacituzumab ADCs conjugated to camptothecin derivatives and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
‘506 in view of NCT’974 and Iwata et. al., and Spring et. al. dose not teach a dose of pembrolizumab 400 mg every 6 weeks and wherein the ADC is administered on Days 1, 15, and 29 of a 6-week cycle.
Lala et. al. teaches a method of treating cancer comprising administering pembrolizumab 400 mg dose every 6 weeks (Abstract). Lala et. al. teaches “In conclusion, the pembrolizumab 400 mg Q6W dosing regimen is expected to produce similar efficacy and safety across all clinical treatment settings in which pembrolizumab 200 mg (or 2 mg/kg) is currently used. Overall, pembrolizumab 400 mg Q6W is expected to have a similar benefit-risk profile as the approved 200 mg Q3W dosing regimen while allowing physicians added flexibility and convenience to dose at a frequency that meets the clinical need of patients with cancer” (p. 74 right column).
NCT’134 teaches a method of treating locally advanced or metastatic breast cancer comprising administering an anti-TROP2 ADC wherein the anti-TROP2 ADC is administered at 5mg/kg IV on Day 1 and 15 of each 28 day cycle (which is equivalent to every 2 weeks)
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the dose timing and schedule of the combination of the ADC of ‘506 and pembrolizumab as taught by modified NCT’974 by administering 400 mg of pembrolizumab every six weeks in order to benefit from the increased flexibility and decreased visit frequency for cancer patients as taught by Lala et. al. This would have a predictable effect because Lala et. al. teaches that the safety and pharmacokinetic profile of 400 mg Q6W is similar to the current standard of administering every third week. A person of ordinary skill in the art would also understand that dosing every 6 weeks would be advantageous in a combination therapy because it allows more flexibility in the dose timing of the second drug without increasing the visit frequency or needing extra visits for administering the drugs individually. It would have been further obvious to modify the dose timing of the ADC of ‘506 from the dose timing of the ADC of NCT’974 because a person of ordinary skill in the art would expect to adjust the dosing frequency and amount to arrive at the most efficacious and best treatment of cancer, including a possible dosing schedule of every two weeks as taught by a different anti-TROP2 ADC in NCT’134 in order to benefit from less frequent dosing for an ADC with a stronger cytotoxic effect as taught by ‘506. This combination would result in a six week cycle with pembrolizumab dosed every Day 1 at 400 mg and the ADC of Cai et. al. dosed at 5mg/mL every 2 weeks, which is days 1, 15, and 29 of a six-week cycle, and carboplatin or cisplatin dosed at AUC5 or 75mg/m2, respectively day 1 every 3 weeks, which is Days 1 and 22 of a 6-week cycle. This would have a reasonable expectation of success because an artisan of ordinary skill would adjust the dosing amounts and schedules based on clinical benchmarks of similar drugs and the preclinical strength of the drug in order to arrive at the most effective and safest dosing schedule.
Co-pending Application No. 18719435
Claims 1-9, 11, 14, 19, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-61 of copending Application No. 18719435 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841.
This is a provisional non-statutory double patenting rejection.
The claims of ‘435 teach a method for treating cancer is a subject comprising a step of administering to the subject a therapeutically effective amount of a combination of an anti-TROP-2 antibody drug conjugate and an additional therapeutic agent, wherein the additional therapeutic agent is one or more selected from the group consisting of an PD-L1 antibody or an antibody-binding fragment thereof and a chemotherapeutic agent; wherein the anti-TROP2 ADC comprises a camptothecin drug and an anti-TROP2 antibody comprising HCDR1-3 SEQ ID NO: 1-3 or variants thereof and LCDR1-3 of SEQ ID NOs: 4-6 or variants thereof (identical to instant CDRs SEQ ID NOs: 39-44) (claim 1); wherein the antibody-drug conjugate has the following structure:
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Wherein γ is in the range of 6 to 10, Identical to instant Formula (I) (claim 34), wherein the average number of γ is between 6 and 8 (reads on instant claim 2). Claims 38-46 teach different types of cancer including lung cancer and NSCLC (claims 39, 40, 41). Claim 43 teaches wherein the NSCLC is selected from EGFR wild type or EGFR mutated NSCLC. Claim 45 teaches wherein the NSCLC is negative for ALK rearrangements. Claim 47 teaches the method wherein the ADC and anti-PD-L1 antibody have an administration cycle of 14 to 42 days; claim 48 teaches wherein the cycle is 21, 28, or 42 days (reads on 3 weeks and 6 weeks). Claims 49 and 50 teaches wherein the ADC is administered at a dose of 1mg/kg to 10mg/kg. Claims 57 and 58 teach a kit and a pharmaceutical composition comprising the TROP-2 ADC and the additional therapeutic agent wherein the additional therapeutic agent includes the anti-PD-L1 antibody (reads on the pharmaceutical compositions of claims 19 and 20). Claim 53 teaches the method further comprises administering carboplatin at a dose of AUC 1mg/ml/min to 10mg/ml/min or cisplatin at a dose of 50mg/m2 to 150mg/m2. Claim 58 teaches the composition comprising one or more therapeutic agent selected from an anti-PD-L1 antibody and a chemotherapeutic agent. Claim 59 teaches the composition with pharmaceutically acceptable carriers.
The ‘435 application does not teach a method of treating NSCLC without an EGFR mutation or ALK fusion, said method comprising administering an anti-human PD-1 antibody or antigen-binding fragment thereof and an immunoconjugate of instant Formula (I). This deficiency is resolved by NCT’974 and Iwata et. al.
NCT’974 teaches a method of treating non-small cell lung cancer without actionable genomic alterations (See “Official Title”) comprising administering a combination of a sacituzumab antibody-drug conjugate sacituzumab govitecan (synonym for IMMU-132) at 10 mg/kg on Days 1 and 8 of a 21-day cycle and 200 mg of pembrolizumab on day 1 of a 21-day cycle, administered intravenously; or (“Arms and Interventions” section). As evidenced by the instant specification, “without actionable genomic mutations” reads on no EGFR or ALK fusion gene mutations because a both EGFR and ALK fusion mutations are considered actionable ([0157], [300], [312]). Regarding claim 7, NCT’974 teaches a treatment arm with additional cisplatin or carboplatin therapy wherein there is a safety run-in at a dose of 5mg/mL (“Arms and Interventions” section).
Regarding claim 14, NCT’974 teaches experimental arms further comprising administering to the patient an additional anticancer agent which is a platinum containing chemotherapeutic agent (Carboplatin or Cisplatin, see “Arms and Interventions” section; wherein the dose of carboplatin is AUC5 (synonym for AUC 5 mg/ml/min) on Day 1 of a 21-day cycle and wherein the dose of cisplatin is 75mg/m2 on Day 1 of a 21-day cycle.
Iwata et. al. teaches a method of treating cancer comprising an antibody conjugated to w topoisomerase I inhibitor exatecan derivative. Iwata et. al. teaches that the antibody-drug conjugate inhibited tumor growth compared to vehicle or antibody alone (Fig. 1) and that the treatment contributed to immune memory function in mouse in vivo cancer models (Fig. 2 and Fig. 3, p. 1496 right column-p. 1499 left column). Iwata et. al. teaches that treatment of the in vivo mouse model with the ADC and an anti-PD-1 antibody, survival of mice with tumors was significantly improved compared to either the ADC or anti-PD-1 antibody alone (Fig. 6 p. 1501 left column). Iwata et. al. teaches “The payload of DS-8201a has 10 times more potent topoisomerase inhibitory activity than SN-38, and this could lead to more immunologic cell death than treatment with SN_38 and other existing topoisomerase inhibitors” (p. 1501 right column ¶4) and that “Recently, three different topoisomerase I inhibitors (camptothecin, topotecan, irinotecan) have been shown to enhance tumor-killing activity of T cells” (p. 1502 left column ¶2); “For combination with ICIs, ADCs are considered to be better than chemotherapeutic agents because ADCs work selectively at the tumor site with reduced side effect to other organs […] In this study, DS-8201a, a HER2-targeting ADC with a topoisomerase I inhibitor showed an antitumor effect with immunostimulatory activity in a mouse model. DS-8201a also benefited from combination with anti-PD-1 antibody […] the combination of DS-8201a and anti-PD-1 antibody showed higher antitumor effect” (p. 1502 left column ¶3- right column ¶1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the sacituzumab antibody-drug conjugate of ‘435 in the method of treating comprising administering sacituzumab govitecan and pembrolizumab to patients with bladder cancer in order to benefit from a TROP2 targeted ADC conjugated to a topoisomerase I inhibitor as taught by ‘435 in a method of treatment using the ADC as suggested by NCT’974 and Iwata et. al. This would have a reasonable expectation of success because both NCT’974 and ‘435 teach a method or a composition for use in treating Trop-2 positive cancers (a sacituzumab antibody conjugated to a topoisomerase I inhibitor/camptothecin derivative) and Iwata et. al. teaches that ADCs with topoisomerase inhibitors combined with anti-PD-1 blockade therapy increases anti-tumor immunity and cytotoxic effect. A person of ordinary skill in the art therefore would reasonably believe that the benefits of combination therapy as taught by NCT’974 and Iwata et. al. with the benefits of an improved sacituzumab ADC would result in an improved treatment for a TROP-2 positive cancer such as bladder cancer as taught by NCT’974.
Regarding claim 8, modified ‘435 in view of NCT’974 and Iwata et. al. teaches the pembrolizumab dose is 200 mg.
Regarding claim 9, modified ‘435 in view of NCT’974 and Iwata et. al. teaches the immunoconjugate and anti-human PD-1 are administered in 21 day cycles (reads on 3 weeks and each are administered on Day 1 of each three-week cycle).
Regarding claims 19 and 20, the composition administered on Day 1 of ‘435 in view of NCT’974 and Iwata et. al. reads on the pharmaceutical composition comprising the pembrolizumab (anti-human PD-1 antibody and the plurality of immunoconjugates of Formula (I) (of the claims of ‘435).
Claims 15 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-61 of copending Application No. 18719435 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and further in view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512.
The teachings of ‘435 in view of NCT’974 and Iwata et. al. in regards to claim 1 and 14 are in the NSDP rejection above.
Regarding claims 15 and 16, NCT’974 describes an anti-TROP2 ADC sacituzumab govitecan administered at a concentration of 10mg/kg, 7.5mg/kg, or 5mg/kg (safety run-in dose) on Day 1 and Day 8 of a 21-day cycle in combination with pembrolizumab 200mg on Day 1 of 21-day cycle and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle to treat NSCLC without treatable genomic alterations; Cai et. al. teaches a sacituzumab immunoconjugate of formula I administered to mice in effective doses of 3mg/kg and 10mg/kg that is more cytotoxic and has a better therapeutic window that sacituzumab govitecan (IMMU-132).
Modified ‘435 in view of NCT’974 and Iwata et. al. does not explicitly teach the method wherein the combination wherein the cycles are 1-4 cycles.
This deficiency is resolved by Spring et. al.
Spring et. al. teaches a method of treating breast cancer with sacituzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by ‘435 in view of NCT’974 and Iwata et. al. by administering the ADC of ‘435 in the method of treating NSCLC without actionable genetic mutations at ADC safety dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because ‘435 teaches both NCT’978, ‘435, and Spring et. al. teach sacituzumab ADCs conjugated to camptothecin derivatives and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
Claims 10, 12, 13, 17 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-61 of copending Application No. 18719435 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and in further view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512; Lala, Mallika, et al. "A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation." European Journal of Cancer 131 (2020): 68-75; and NCT05347134 “SKB264 Injection vs Investigator Selected Regimens to Treat Locally Advanced, Recurrent, or Metastatic Triple-negative Breast Cancer” published 20 April 2022.
The teachings of ‘435 in view of NCT’974 and Iwata et. al. in regards to claim 1 and 14 are in the NSDP rejection above.
‘435 in view of NCT’974 and Iwata et. al. does not teach the method of claim 14 wherein the immunoconjugate of Formula (I) is administered at a dose of about 5mg/kg on days 1, 15, and 29 of a 6-week cycle, the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400mg on day 1 of each six-week cycle, carboplatin is administered at a dose of AUC 5mg/ml/min or cisplatin is administered at a dose of 75mg/m2 on days 1 and 22 of each six-week cycle; and the number of cycles is from 1 to 4.
This deficiency is resolved by Spring et. al., Lala et. al., and NCT’134.
Spring et. al. teaches a method of treating breast cancer with sacitzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by ‘435 in view of NCT’974 and Iwata et. al. by administering the ADC of ‘435 in the method of treating NSCLC without actionable genetic mutations at ADC safety dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because ‘435 teaches both NCT’978, ‘435, and Spring et. al. teach sacituzumab ADCs conjugated to camptothecin derivatives and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
‘435 in view of NCT’974 and Iwata et. al., and Spring et. al. dose not teach a dose of pembrolizumab 400 mg every 6 weeks and wherein the ADC is administered on Days 1, 15, and 29 of a 6-week cycle.
Lala et. al. teaches a method of treating cancer comprising administering pembrolizumab 400 mg dose every 6 weeks (Abstract). Lala et. al. teaches “In conclusion, the pembrolizumab 400 mg Q6W dosing regimen is expected to produce similar efficacy and safety across all clinical treatment settings in which pembrolizumab 200 mg (or 2 mg/kg) is currently used. Overall, pembrolizumab 400 mg Q6W is expected to have a similar benefit-risk profile as the approved 200 mg Q3W dosing regimen while allowing physicians added flexibility and convenience to dose at a frequency that meets the clinical need of patients with cancer” (p. 74 right column).
NCT’134 teaches a method of treating locally advanced or metastatic breast cancer comprising administering an anti-TROP2 ADC wherein the anti-TROP2 ADC is administered at 5mg/kg IV on Day 1 and 15 of each 28 day cycle (which is equivalent to every 2 weeks)
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the dose timing and schedule of the combination of the ADC of ‘435 and pembrolizumab as taught by modified NCT’974 by administering 400 mg of pembrolizumab every six weeks in order to benefit from the increased flexibility and decreased visit frequency for cancer patients as taught by Lala et. al. This would have a predictable effect because Lala et. al. teaches that the safety and pharmacokinetic profile of 400 mg Q6W is similar to the current standard of administering every third week. A person of ordinary skill in the art would also understand that dosing every 6 weeks would be advantageous in a combination therapy because it allows more flexibility in the dose timing of the second drug without increasing the visit frequency or needing extra visits for administering the drugs individually. It would have been further obvious to modify the dose timing of the ADC of ‘435 from the dose timing of the ADC of NCT’974 because a person of ordinary skill in the art would expect to adjust the dosing frequency and amount to arrive at the most efficacious and best treatment of cancer, including a possible dosing schedule of every two weeks as taught by a different anti-TROP2 ADC in NCT’134 in order to benefit from less frequent dosing for an ADC with a stronger cytotoxic effect as taught by ‘435. This combination would result in a six week cycle with pembrolizumab dosed every Day 1 at 400 mg and the ADC of Cai et. al. dosed at 5mg/mL every 2 weeks, which is days 1, 15, and 29 of a six-week cycle, and carboplatin or cisplatin dosed at AUC5 or 75mg/m2, respectively day 1 every 3 weeks, which is Days 1 and 22 of a 6-week cycle. This would have a reasonable expectation of success because an artisan of ordinary skill would adjust the dosing amounts and schedules based on clinical benchmarks of similar drugs and the preclinical strength of the drug in order to arrive at the most effective and safest dosing schedule.
Co-pending Application No. 18557900
Claims 1-9, 11, 14, 19, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-32 of copending Application No. 18557900 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841
This is a provisional NSDP rejection.
The claims of ‘900 teach a method of treating a tumor disease comprising administering a therapeutically effective amount of an antibody-drug conjugate of Formula (I)
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110
506
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wherein D is a bioactive molecular fragment, γ is an integer from 1 to 10, and A is a TROP-2 monoclonal antibody or an antigen binding fragment thereof (claim 1). Claim 2 teaches the method wherein the tumor disease is an unresectable locally advanced or metastatic solid tumor that has failed standard treatments. Claims 3, 20, and 22 teach the method of claim 2 wherein the tumor disease comprises one of a group of cancers including lung cancer and particularly NSCLC or small-cell lung cancer. Claims and 5 teach the method of claim 1 with particular structures of the antibody-drug conjugate of Formula (I) including:
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187
819
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Which is identical to instant Formula (I). Claim 6 teaches a method for treating a tumor disease comprising administering the antibody-drug conjugate according to claim 1 and a pharmaceutically acceptable carrier. Claims 8 and 25 teaches wherein the ADC is administered every 7-35 days, once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once every 35 days. Claims 10 and 27 teach doses of the ADC from 1 mg/kg to 30mg/kg, 1 mg/kg to 20 mg/kg, 2 mg/kg to 12 mg/kg, 2 to 5 mg/kg, 4 to 7 mg/kg, 6 to 9 mg/kg, 8 to 11 mg/kg, 10 to 13 mg/kg, or 12 to 15 mg/kg. Claims 12 and 13 teaches wherein γ is an integer from 5 to 8. Claim 15 teaches wherein the ADC is administered once every 7-28 days. Claim 16 teaches a method of treating a tumor disease comprising administering a pharmaceutical composition comprising the ADC of claim 5 and a pharmaceutically acceptable carrier. Claim 19 teaches wherein the tumor disease is locally advanced or metastatic solid tumor that has failed standard treatments. Claim 20 teaches wherein the tumor disease comprises one of a group of cancers including lung cancer.
The ‘900 application does not teach a method of treating NSCLC without an EGFR mutation or ALK fusion, said method comprising administering an anti-human PD-1 antibody or antigen-binding fragment thereof and an immunoconjugate of instant Formula (I). This deficiency is resolved by NCT’974 and Iwata et. al.
NCT’974 teaches a method of treating non-small cell lung cancer without actionable genomic alterations (See “Official Title”) comprising administering a combination of a sacituzumab antibody-drug conjugate sacituzumab govitecan (synonym for IMMU-132) at 10 mg/kg on Days 1 and 8 of a 21-day cycle and 200 mg of pembrolizumab on day 1 of a 21-day cycle, administered intravenously; or (“Arms and Interventions” section). As evidenced by the instant specification, “without actionable genomic mutations” reads on no EGFR or ALK fusion gene mutations because a both EGFR and ALK fusion mutations are considered actionable ([0157], [300], [312]). Regarding claim 7, NCT’974 teaches a treatment arm with additional cisplatin or carboplatin therapy wherein there is a safety run-in at a dose of 5mg/mL (“Arms and Interventions” section).
Regarding claim 14, NCT’974 teaches experimental arms further comprising administering to the patient an additional anticancer agent which is a platinum containing chemotherapeutic agent (Carboplatin or Cisplatin, see “Arms and Interventions” section; wherein the dose of carboplatin is AUC5 (synonym for AUC 5 mg/ml/min) on Day 1 of a 21-day cycle and wherein the dose of cisplatin is 75mg/m2 on Day 1 of a 21-day cycle.
Iwata et. al. teaches a method of treating cancer comprising an antibody conjugated to w topoisomerase I inhibitor exatecan derivative. Iwata et. al. teaches that the antibody-drug conjugate inhibited tumor growth compared to vehicle or antibody alone (Fig. 1) and that the treatment contributed to immune memory function in mouse in vivo cancer models (Fig. 2 and Fig. 3, p. 1496 right column-p. 1499 left column). Iwata et. al. teaches that treatment of the in vivo mouse model with the ADC and an anti-PD-1 antibody, survival of mice with tumors was significantly improved compared to either the ADC or anti-PD-1 antibody alone (Fig. 6 p. 1501 left column). Iwata et. al. teaches “The payload of DS-8201a has 10 times more potent topoisomerase inhibitory activity than SN-38, and this could lead to more immunologic cell death than treatment with SN_38 and other existing topoisomerase inhibitors” (p. 1501 right column ¶4) and that “Recently, three different topoisomerase I inhibitors (camptothecin, topotecan, irinotecan) have been shown to enhance tumor-killing activity of T cells” (p. 1502 left column ¶2); “For combination with ICIs, ADCs are considered to be better than chemotherapeutic agents because ADCs work selectively at the tumor site with reduced side effect to other organs […] In this study, DS-8201a, a HER2-targeting ADC with a topoisomerase I inhibitor showed an antitumor effect with immunostimulatory activity in a mouse model. DS-8201a also benefited from combination with anti-PD-1 antibody […] the combination of DS-8201a and anti-PD-1 antibody showed higher antitumor effect” (p. 1502 left column ¶3- right column ¶1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the sacituzumab antibody-drug conjugate of ‘900 in the method of treating comprising administering sacituzumab govitecan and pembrolizumab to patients with bladder cancer in order to benefit from a TROP2 targeted ADC conjugated to a topoisomerase I inhibitor as taught by ‘900 in a method of treatment using the ADC as suggested by NCT’974 and Iwata et. al. This would have a reasonable expectation of success because both NCT’974 and ‘900 teach a method or a composition for use in treating Trop-2 positive cancers (a sacituzumab antibody conjugated to a topoisomerase I inhibitor/camptothecin derivative) and Iwata et. al. teaches that ADCs with topoisomerase inhibitors combined with anti-PD-1 blockade therapy increases anti-tumor immunity and cytotoxic effect. A person of ordinary skill in the art therefore would reasonably believe that the benefits of combination therapy as taught by NCT’974 and Iwata et. al. with the benefits of an improved sacituzumab ADC would result in an improved treatment for a TROP-2 positive cancer such as bladder cancer as taught by NCT’974.
Regarding claim 8, modified ‘900 in view of NCT’974 and Iwata et. al. teaches the pembrolizumab dose is 200 mg.
Regarding claim 9, modified ‘900 in view of NCT’974 and Iwata et. al. teaches the immunoconjugate and anti-human PD-1 are administered in 21 day cycles (reads on 3 weeks and each are administered on Day 1 of each three-week cycle).
Regarding claims 19 and 20, the composition administered on Day 1 of ‘900 in view of NCT’974 and Iwata et. al. reads on the pharmaceutical composition comprising the pembrolizumab (anti-human PD-1 antibody and the plurality of immunoconjugates of Formula (I) (of the claims of ‘900).
Claims 15 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-32 of copending Application No. 18557900 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and further in view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512.
The teachings of ‘900 in view of NCT’974 and Iwata et. al. in regards to claim 1 and 14 are in the NSDP rejection above.
Regarding claims 15 and 16, NCT’974 describes an anti-TROP2 ADC sacituzumab govitecan administered at a concentration of 10mg/kg, 7.5mg/kg, or 5mg/kg (safety run-in dose) on Day 1 and Day 8 of a 21-day cycle in combination with pembrolizumab 200mg on Day 1 of 21-day cycle and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle to treat NSCLC without treatable genomic alterations; Cai et. al. teaches a sacituzumab immunoconjugate of formula I administered to mice in effective doses of 3mg/kg and 10mg/kg that is more cytotoxic and has a better therapeutic window that sacituzumab govitecan (IMMU-132).
Modified ‘900 in view of NCT’974 and Iwata et. al. does not explicitly teach the method wherein the combination wherein the cycles are 1-4 cycles.
This deficiency is resolved by Spring et. al.
Spring et. al. teaches a method of treating breast cancer with sacitzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by ‘900 in view of NCT’974 and Iwata et. al. by administering the ADC of ‘900 in the method of treating NSCLC without actionable genetic mutations at ADC safety dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because ‘900 teaches both NCT’978, ‘900, and Spring et. al. teach sacituzumab ADCs conjugated to camptothecin derivatives and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
Claims 10, 12, 13, 17 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-32 of copending Application No. 18557900 in view of NCT05186974 "Study of Sacituzumab Govitecan Combinations in First-line Treatment of Participants With Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (EVOKE-02)" published 24 June 2022 (hereinafter NCT’974) and Iwata TN, et. al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018 Jul;17(7):1494-1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841 as applied to claims 1 and 14 above, and in further view of Spring, Laura, et al. "Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial." (2022): 512-512; Lala, Mallika, et al. "A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation." European Journal of Cancer 131 (2020): 68-75; and NCT05347134 “SKB264 Injection vs Investigator Selected Regimens to Treat Locally Advanced, Recurrent, or Metastatic Triple-negative Breast Cancer” published 20 April 2022.
The teachings of ‘900 in view of NCT’974 and Iwata et. al. in regards to claim 1 and 14 are in the NSDP rejection above.
‘900 in view of NCT’974 and Iwata et. al. does not teach the method of claim 14 wherein the immunoconjugate of Formula (I) is administered at a dose of about 5mg/kg on days 1, 15, and 29 of a 6-week cycle, the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400mg on day 1 of each six-week cycle, carboplatin is administered at a dose of AUC 5mg/ml/min or cisplatin is administered at a dose of 75mg/m2 on days 1 and 22 of each six-week cycle; and the number of cycles is from 1 to 4.
This deficiency is resolved by Spring et. al., Lala et. al., and NCT’134.
Spring et. al. teaches a method of treating breast cancer with sacitzumab govitecan (SG) wherein primary objection was to assess pathological complete response and secondary objective was safety and tolerability of SG administered IV of days 1 and 8 of a 21-day cycle for 4 cycles (Background, Methods sections). After 4 cycles, patients with biopsy-proven residual disease had the option to receive additional NA therapy at the discretion of the treating physician (Methods).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer as taught by ‘900 in view of NCT’974 and Iwata et. al. by administering the ADC of ‘900 in the method of treating NSCLC without actionable genetic mutations at ADC safety dose 5.0mg/mL on Days 1 and 8 of a 21-day cycle, pembrolizumab 200 mg on Day 1 of a 21-day cycle, and either carboplatin AUC5 or cisplatin 75mg/m2 on Day 1 of a 21-day cycle, for 4 cycles as taught by Spring et. al. in order to benefit from a rational endpoint to reassess for whether additional or alternative therapy is needed as taught by Spring et. al. This would have a reasonable expectation of success because ‘900 teaches both NCT’978, ‘900, and Spring et. al. teach sacituzumab ADCs conjugated to camptothecin derivatives and Spring et. al. teaches that 4 cycles is a beneficial point to choose alternative therapy for the benefit of the patient.
‘900 in view of NCT’974 and Iwata et. al., and Spring et. al. dose not teach a dose of pembrolizumab 400 mg every 6 weeks and wherein the ADC is administered on Days 1, 15, and 29 of a 6-week cycle.
Lala et. al. teaches a method of treating cancer comprising administering pembrolizumab 400 mg dose every 6 weeks (Abstract). Lala et. al. teaches “In conclusion, the pembrolizumab 400 mg Q6W dosing regimen is expected to produce similar efficacy and safety across all clinical treatment settings in which pembrolizumab 200 mg (or 2 mg/kg) is currently used. Overall, pembrolizumab 400 mg Q6W is expected to have a similar benefit-risk profile as the approved 200 mg Q3W dosing regimen while allowing physicians added flexibility and convenience to dose at a frequency that meets the clinical need of patients with cancer” (p. 74 right column).
NCT’134 teaches a method of treating locally advanced or metastatic breast cancer comprising administering an anti-TROP2 ADC wherein the anti-TROP2 ADC is administered at 5mg/kg IV on Day 1 and 15 of each 28 day cycle (which is equivalent to every 2 weeks)
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the dose timing and schedule of the combination of the ADC of ‘900 and pembrolizumab as taught by modified NCT’974 by administering 400 mg of pembrolizumab every six weeks in order to benefit from the increased flexibility and decreased visit frequency for cancer patients as taught by Lala et. al. This would have a predictable effect because Lala et. al. teaches that the safety and pharmacokinetic profile of 400 mg Q6W is similar to the current standard of administering every third week. A person of ordinary skill in the art would also understand that dosing every 6 weeks would be advantageous in a combination therapy because it allows more flexibility in the dose timing of the second drug without increasing the visit frequency or needing extra visits for administering the drugs individually. It would have been further obvious to modify the dose timing of the ADC of ‘900 from the dose timing of the ADC of NCT’974 because a person of ordinary skill in the art would expect to adjust the dosing frequency and amount to arrive at the most efficacious and best treatment of cancer, including a possible dosing schedule of every two weeks as taught by a different anti-TROP2 ADC in NCT’134 in order to benefit from less frequent dosing for an ADC with a stronger cytotoxic effect as taught by ‘900. This combination would result in a six week cycle with pembrolizumab dosed every Day 1 at 400 mg and the ADC of Cai et. al. dosed at 5mg/mL every 2 weeks, which is days 1, 15, and 29 of a six-week cycle, and carboplatin or cisplatin dosed at AUC5 or 75mg/m2, respectively day 1 every 3 weeks, which is Days 1 and 22 of a 6-week cycle. This would have a reasonable expectation of success because an artisan of ordinary skill would adjust the dosing amounts and schedules based on clinical benchmarks of similar drugs and the preclinical strength of the drug in order to arrive at the most effective and safest dosing schedule.
Additional Provisional NSDP Rejections:
Copending Application No.:
Rejected over Application Claims:
Summary of Claim teachings
Application/Patent with similar (prov.) NSDP rejections:
18532428
1-20
Claims teach a method of treating ovarian, cervical, prostate, or urothelial cancer comprising an immunoconjugate identical to Formula I wherein the antibody is sacituzumab and a pharmaceutical composition comprising the immunoconjugate, a pharmaceutically acceptable carrier, and an anti-human PD-1 antibody
Co-pending 18719435
18833326
1-10, 12, 17-24, 30, 35, 42-48
Claims teach pharmaceutical compositions comprising an immunoconjugate identical to the instant Formula I, wherein the antibody is Sacituzumab and a method for treating a tumor disease, wherein the disease is metastatic or for which treatment fails; lists ovarian, urothelial, cervical, bladder cancer
Co-pending 18557900 and 18719435
19587842
1-26
Claims teach a method of treating non-small cell lung cancer comprising administering an anti-human PD-1 antibody and an Immunoconjugate of Formula (I) identical to instant formula 1; a composition comprising the anti-human PD-1 antibody, a carrier, and the immunoconjugate of Formula (I); only difference to the instant claims is NSCLC
Co-pending 18719435
19583452
1-12
A method of treating endometrial cancer comprising administering an immunoconjugate of Formula (I) identical to instant Formula (I)
U.S. Patent 11970506 and Co-pending 18719435
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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