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 .
Status of Claims
Claims 1-9, 11-16, 18-21 and 35 are pending
Claims 7, 9, 11-14, 16 and 18-20 are amended.
Claims 1-9, 11-16, 18-21 and 35 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 01/07/2021 based on the provisional application 63/134,817 (filed 01/07/2021).
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 9, 11, and 16 are objected to because of the following informalities:
Claim 9 is objected to because the word "days" has been deleted after "1-30" in line 2. This appears to be a typographical error, and the word should be replaced so that line 2 recites “….time comprises 1-30 days before administering the antibody.
Claim 11 is objected to because of the following typographical issues: (i) the word "an" in line 5 should be deleted since there are three HC CDR sequences recited in the sentence; (ii) the word “sequence” in line 5 should be in the plural form of "sequences" since there are three HC CDR sequences recited in the sentence; (iii) the word "an" in line 7 should be deleted since there are three LC CDR sequences recited in the sentence; and (iv) the word “sequence” in line 7 should be in the plural form of "sequences" since there are three LC CDR sequences recited in the sentence.
Claim 16 is objected to because of the following typographical issues: (i) the word "an" in line 5 should be deleted since there are three HC CDR sequences recited in the sentence; (ii) the word “sequence” in line 5 should be in the plural form of "sequences" since there are three HC CDR sequences recited in the sentence; (iii) the word "an" in line 7 should be deleted since there are three LC CDR sequences recited in the sentence; and (iv) the word “sequence” in line 7 should be in the plural form of "sequences" since there are three LC CDR sequences recited in the sentence; and (v) the phrase "is the cytotoxic effector" should be included after the term “(MMAE)” in line 9.
Appropriate correction is required.
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 1-9, 11-16, 18-21 and 35 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.
Claims 1-9, 11-16, 18-21 and 35 are rejected because claims 1, 21, and 35 recite the term “SEGRAM” in parenthesis. It is unclear how, or if, the term in parenthesis limits the claims.
Claim 5 is rejected as being indefinite because it is unclear how dexamethasone, prednisone, and cortisol can be members of a Markush group of SEGRAMs when dexamethasone, prednisone, and cortisol do not appear to be SEGRAMs.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-3, 7-9, 11-16 and 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20170362330A1 Date Published 2017-12-21) in view of Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072) and Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779).
Liu et al. teaches Embodiment 1: An isolated human antibody that specifically binds CD46 and is internalized into a cell expressing or overexpressing CD46, wherein said antibody can be YS5 (paragraph [0009]). Liu et al. also teaches Embodiment 215: An immunoconjugate including an antibody according to Embodiment 1 attached to an effector that can be a cytotoxin or cytostatic agent, or a drug (paragraph [0224]).
Liu et al. also teaches Embodiment 249: A method of inhibiting the growth and/or proliferation of a cancer cell that expresses or overexpresses CD46, said method include: contacting said cancer cell with an immunoconjugate including an antibody according to Embodiment 1 attached to an effector that has cytostatic and/or cytotoxic activity (paragraph [0258]). They also teach Embodiment 252: The method of Embodiment 249, wherein said cell is a cancer cell, and Embodiment 255: The method of embodiment 252, wherein said cancer cell is a prostate cancer cell.
Liu et al. also teaches Embodiment 275: The method according to any one of Embodiments 249, 252 and 255, wherein said immunoconjugate or antibody is administered in a pharmaceutical composition including a pharmaceutically acceptable carrier (paragraph [0284]). They also teach Embodiment 276: The method according to any one of Embodiments 249, 252 and 255, wherein said administering comprises administering to a human (paragraph [0285]). They further teach that for the method that involves contacting a cell that expresses or overexpresses CD46 (e.g., a cancer cell such as a prostate cancer cell) with the construct, the “contacting” can comprise administering the antibody or the construct to a human subject in need thereof (paragraph [0419]).
Liu et al. also teaches Embodiment 281: The method according to Embodiments 249, 252 and 255, wherein said antibody and/or immunoconjugate is administered in conjunction with another anti-cancer drug and/or a hormone (paragraph [0290]). They also teach Embodiment 282: The method of Embodiment 281, wherein said antibody and/or immunoconjugate is administered in conjunction with abiraterone and/or enzalutamide (paragraph [0291]). Therefore, Liu et al. teaches a method of treating cancer cells comprising contacting an anti-CD46 antibody attached to an effector that has cytotoxic activity i.e. an immunoconjugate, wherein said immunoconjugate is administered in conjunction with abiraterone and/or enzalutamide. As taught by Antonarakis et al., enzalutamide is an inhibitor of androgen-receptor signaling that exerts its activity by binding avidly to the ligand-binding domain of the androgen receptor, competing with and displacing the natural ligands of this receptor while also inhibiting translocation of the androgen receptor into the nucleus and impairing transcriptional activation of androgen-responsive target genes; while abiraterone is an inhibitor of cytochrome P450 17A1 (CYP17A1) that impairs androgen-receptor signaling by depleting adrenal and intratumoral androgens (Pg. 1029 column left paragraph first), thereby confirming that enzalutamide and abiraterone are androgen signaling inhibitors.
Liu et al. also teaches in Fig. 41 that abiraterone (Abi)-treated LNCaP C4-2B cells are more sensitive to CD46 antibody-drug conjugated (ADC) to MMAF such that LNCaP-C4-2B cells that were initially incubated with 10 μM of abiraterone for 7 days, then subsequently incubated with CD46 ADC without abiraterone for an additional 96 hours had enhanced killing of tumor cells, where EC50 values dropped from 169 pM to 21 pM when compared to cells without initial exposure to abiraterone (paragraphs [0402] and [0671]). They also teach that in LNCaP-C4-2B cells that had prior incubation with 10 μM of abiraterone for 7 days there was a significant upregulation of surface CD46 expression (FIG. 40; paragraph [0671]). Liu et al. further teaches that when the neuroendocrine prostate cancer cell line H660 was incubated with 10 μM enzalutamide for 7 days, a significant upregulation of cell surface CD46 was observed (FIG. 42), whereby the H660 cells became more sensitive to CD46 ADC post enzalutamide treatment with EC50 dropping by 4-5 fold (paragraph [0671]).
Therefore, Liu et al. teaches a method of treating LNCaP C4-2B and H660 human cancer cells comprising contacting or treating said cancer cells with an anti-CD46 antibody conjugated to a cytotoxic drug after said cells were treated with an androgen signaling inhibitor that is enzalutamide or abiraterone for 7 days which significantly upregulated expression of cell surface CD46.
Liu et al. also teaches in Fig. 1A the VH framework and CDR regions for YS5 (SEQ ID NO:1), and in Fig. 1B the VL framework and CDR regions for YS5 (SEQ ID NO:22) (paragraph [0362] and Table 1). When the instant HC CDR1 (SEQ ID NO: 80), HC CDR2 (SEQ ID NO: 81) and HC CDR3 (SEQ ID NO: 82) were aligned with the VH amino acid sequence of antibody YS5 as set forth in SEQ ID NO:1 of Liu et al. that comprises the VH specific CDR regions shown in Fig 1A, it was noted that the instant HC CDRs are an exact match to the VH CDR regions of antibody YS5 as taught by Liu et al. Similarly. Similarly, when the instant LC CDR1 (SEQ ID NO: 83), LC CDR2 (SEQ ID NO: 84) and LC CDR3 (SEQ ID NO: 85) were aligned with the VL amino acid sequence of antibody YS5 as set forth in SEQ ID NO:22 of Liu et al. that comprises the VL specific CDR regions shown in Fig 1B, it was also noted that the instant LC CDRs are an exact match to the VL CDR regions of antibody YS5 as taught by Liu et al. Therefore, Liu et al. teaches the instant HC and LC CDRs as recited in instant claims 11 and 16.
Liu et al. further teaches that anti-CD46 immunoconjugates can be formed by conjugating the antibody to an effector that is a cytotoxic or cytostatic agent such as a chemotherapeutic agent, microtubule inhibitors, DNA-damaging agents, polymerase inhibitors, auristatin, Dolastatin-10, synthetic derivatives of the natural product Dolastatin-10, maytansine or a maytansine derivative (paragraphs [0224]-[227], [0229]-[0232], [0235], [0515], [0542] and [0543]). They further teach that the auristatin can be selected from Auristatin E (AE), Monomethylauristatin E (MMAE), Monomethylauristatin F (MMAF), vcMMAE, and vcMMAF (paragraphs [0233] and [0544]). They further specifically teach that the anti-CD46 antibody YS5 IgG1 was conjugated to monomethylauristatin F (MMAF) via the mc-vc-PAB linker and showed potent in vitro tumor-killing activities on a panel of metastatic castration resistant prostate cancer cell lines (LNCaP-C4-2B and Du145) (Figs. 11-13 and paragraphs [0372] and [0657]). As confirmed by Dagvadorj et al., DU145 cells are androgen receptor negative prostate cancer cell lines, whereas LNCaP cells express androgen receptor protein i.e. are androgen receptor positive (Pg. 9 paragraph first). Further, Decker et al. confirms that C4-2B is a castration-resistant prostate cancer (CRPC) cell line derived from a LNCaP xenograft that relapsed and metastasized to bone after castration, and that C4-2B is androgen receptor positive (Pg. 10768 column right paragraph first lines 4-11). In addition, Liu et al. further teaches that in vivo anti-tumor activity of the anti-CD46 ADC on LNCaP-C4-2B subcutaneous xenograft model showed potent inhibition of tumor growth and survival, where tumor volume reduced to non-detectable levels following 5 doses at 5 mg/kg, with no tumor recurrence during the indicated period post ADC injection (Fig. 14 and paragraph [0658]).
Liu et al. does not specifically demonstrate administering an antibody that specifically binds to CD46 that is linked to a cytotoxic effector and an agent that is an androgen signaling inhibitor to a human with cancer wherein administration of the antibody linked to a cytotoxic effector and the androgen signaling inhibitor kills more cancer cells than administration of the antibody alone.
Liu et al. also does not specifically teach the method of instant claim 8, wherein administering the antibody further comprises administering an androgen signaling inhibitor, SEGRAM, or both with the antibody.
However, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to performed a combined method of administering an antibody that specifically binds to CD46 that is linked to a cytotoxic effector and an agent that is an androgen signaling inhibitor to a human with cancer and one would predict that administration of the antibody linked to a cytotoxic effector and the androgen signaling inhibitor would kill more cancer cells than administration of the antibody alone because the CD46 antibody linked to a cytotoxic effector is able to specifically target a cytotoxic moiety to CD46 expressing cancer cells to kill the cells when compared to a CD46 antibody alone which does not have any cytotoxic moiety that can mediate killing of cancer cells. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said androgen signaling inhibitor kills more cancer cells than administration of the antibody linked to a cytotoxic effector alone because Liu et al. teaches that LNCaP-C4-2B cells pre-treated with 10 μM of abiraterone for 7 days followed by treating with CD46-MMAF for an additional 96 hours had enhanced killing of tumor cells where EC50 values dropped from 169 pM to 21 pM when compared to cells without prior exposure to abiraterone. Further Liu et al. teaches that neuroendocrine prostate cancer cell line H660 pretreated with 10 μM enzalutamide for 7 days became more sensitive to CD46 ADC post enzalutamide treatment with EC50 dropping by 4-5 fold (paragraphs [0402] and [0671]). This is an example of (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claims 7 and 9, it would have been obvious to administer to a human with cancer the agent that is enzalutamide or abiraterone for 7 days without the antibody and before administering the antibody, because Liu et al. teaches that significant upregulation of the expression of cell surface CD46 on cancer cell lines was observed when treated with enzalutamide or abiraterone for 7 days which sensitized the cancer cells to antibody ADC cytotoxicity.
With regards to claim 8, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further administer an androgen signaling inhibitor with the antibody, because Liu et al. teaches that administration of enzalutamide or abiraterone alone to cancer cell lines significantly upregulated expression of cell surface CD46 in said cells, therefore continued administration of enzalutamide or abiraterone together with the antibody would provide further upregulated expression of cell surface CD46 on cancer cells when administered to human subjects, thus further enhancing the cytotoxic ability of the treatment method.
With regards to claim 16, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to substitute the MMAF that is conjugated to antibody YS5 via the mc-vc-PAB linker as taught by Liu et al. (Figs. 11-13 and paragraphs [0372] and [0657]) with MMAE also taught by Liu et al. (paragraphs [0233] and [0544]) to arrive at an antibody that comprises instant HC and LC CDRs (SEQ ID NOs: 80, 81, 82, 83, 84 and 85) conjugated to MMAE via an mc-vc-PAB linker as recited in instant claim 16. This is an example of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143.
With regards to claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to combine the anti-CD46 antibody conjugated to a cytotoxic effector comprised in a pharmaceutical composition as taught by Liu et al. (paragraph [0284]) with an agent that is an androgen signaling inhibitor which can be enzalutamide or abiraterone also as taught by Liu et al., that is to be administered in conjunction with the said anti-CD46 antibody conjugate (paragraph [0291]). This combination pharmaceutical composition would have the advantage of increased ease of administration of two therapeutic compounds to a human subject in a single composition or in a single administration. This is an example of (A) Combining prior art elements according to known methods to yield predictable results. See MPEP 2143.
Claim Rejections - 35 USC § 103 (Second)
Claim(s) 1-9, 11-16 and 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20170362330A1 Date Published 2017-12-21), Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072) and Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779) as applied to claims 1-3, 7-9, 11-16 and 18-21 above and further in view of Sundahl et al. (Oncoscience 2016 Jul 27; 3(7-8): 188–202) and Wong et al. (Clinical Lymphoma Myeloma and Leukemia Volume 21, Supplement 2, October 2021, Page S164).
The combined teachings of Liu et al., Antonarakis et al., Dagvadorj et al. and Decker et al. render obvious instant claims 1-3, 7-9, 11-16 and 18-21 as discussed above.
However, Liu et al., Antonarakis et al., Dagvadorj et al. and Decker et al. do not specifically teach the method of claim 1, wherein the agent is a SEGRAM or wherein the SEGRAM is selected from the group consisting of dexamethasone, prednisone, cortisol, mapracorat, fosdagrocorat (PF-04171327), and dagrocorat. However, these deficiencies are made up in the teachings of Sundahl et al. and Wong et al.
Sundahl et al. teaches that selective glucocorticoid receptor agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed and could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer by inhibiting proliferation, migration and invasion, and by inducing apoptosis of cancer cells (Abstract and Figure 3).
Wong et al. teaches that CD46 is highly expressed in multiple myeloma, especially in patients with gain of chromosome 1q and in the refractory setting (Background). They teach that in vitro studies showed upregulation of CD46 and enhanced cytotoxicity upon treatment with dexamethasone (Background). They also teach that FOR46, an anti-CD46 antibody-drug conjugated with vc-MMAE, recognizes a tumor selective epitope of CD46, is taken up by malignant cells by micropinocytosis (Background) and demonstrated an acceptable toxicity profile using adjusted body weight (ABW) dosing in patients with multiple myeloma (Conclusion).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector as taught by Liu et al. and an agent that is a SEGRAM as taught by Sundahl et al.; or an agent that is dexamethasone as taught by Wong et al.; or an agent that comprises both an androgen signaling inhibitor and a SEGRAM as taught by Liu et al. and Sundahl et al. respectively, because Sundahl et al. teaches that SEGRAMs have a more restricted GR activity profile that could improve the therapy regimens for cancers by inhibiting proliferation, migration and invasion, and by inducing apoptosis of cancer cells (Abstract and Figure 3), and Wong et al. teaches that dexamethasone upregulated the expression of CD46 on multiple myeloma cells and enhanced the cytotoxicity on said cells in vitro (Background). The advantage of a combined method of Liu et al. and Sundahl et al. (CD46 immunoconjugate/ADC and SEGRAM) would be to combine different therapeutic agents that can mediate killing of cancer cells through different mechanisms of actions for an enhanced therapeutic method. The advantage of a combined method of Liu et al. and Wong et al. (CD46 immunoconjugate/ADC and dexamethasone) would be that the administration of dexamethasone can upregulate CD46 expression on cancer cells thus increasing the amount of expressed CD46 on cancer cells and localization of the administered anti-CD46 immunoconjugate/ADC at the cancer site, thereby arriving at a more potent cancer therapeutic method. The advantage of a combined method of Liu et al., Liu et al. and Sundahl et al. (CD46 immunoconjugate/ADC, androgen signaling inhibitor and SEGRAM) would be to upregulate CD46 expression on cancer cells with the androgen signaling inhibitor to sensitize them to the cytotoxicity of the CD46 immunoconjugate/ADC while combining the effect that SEGRAM has on cancer cells to inhibit proliferation, migration and invasion, thereby killing cancer cells through different mechanisms of actions for an enhanced therapeutic method. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claim 6, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating cancer in a human, the method comprising administering the combination of an antibody that specifically binds to CD46 that is linked to a cytotoxic effector as taught by Liu et al., an androgen signaling inhibitor also taught by Liu et al. and a SEGRAM that is dexamethasone that is taught by Wong et al. (CD46 immunoconjugate/ADC and enzalutamide or abiraterone and dexamethasone) because Liu et al. teaches that cancer cells had a significant upregulation of surface CD46 expression and became more sensitive to CD46 ADC post abiraterone or enzalutamide treatment (paragraphs [0402] and [0671]) and Wong et al. teaches that dexamethasone upregulated the expression of CD46 of multiple myeloma cells in vitro and enhanced cytotoxicity (Background). Therefore, administering both enzalutamide or abiraterone and dexamethasone would be expected to provide an additive effect in upregulating the surface expression of CD46 to further enhance sensitization of cancer cells to CD46 immunoconjugate/ADC.
Claim Rejections - 35 USC § 103 (Third)
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20170362330A1 Date Published 2017-12-21) in view of Zou et al. (Mol Cancer Vol 19, Article 145, 1-19, 2020).
The teachings of Liu et al. have already been discussed in the first 103 rejection above.
Liu et al. does not specifically teach a method of treating cancer in a human, the method comprising administering an agent that is a Signal Transducer And Activator or Transcription 3 (STAT3) inhibitor, wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone. However, these deficiencies are made up in the teachings of Zou et al.
Zou et al. teaches that signal transducer and activator of transcription 3 (STAT3) is broadly hyperactivated both in cancer and non-cancerous cells such as immune cells and cancer-associated fibroblasts within the tumor microenvironment (TME) and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors (Abstract, Pg. 4 column left paragraph second, and Fig. 2). They teach that targeting STAT3 is expected to offer multiple benefits, including reduced tumor cell intrinsic proliferation, enhanced anti-tumor effects of tumor-infiltrating immune cells, and improve the immunosuppressive crosstalk within the TME (Pg. 14 column left paragraph second). They also teach in Table 1 (Pg. 7-8) STAT3 inhibitors that have been studied in pre-clinical cancer models and in Table 2 (Pg. 9-10) STAT3 inhibitors that are currently in on-going clinical trials. They further teach that BBI608, a small molecule STAT3 inhibitor, has had excellent outcome as a monotherapy in advanced colorectal cancer and has been approved as an orphan drug by the FDA for the treatment of gastric and pancreatic cancer (Pg. 8 column left paragraph third). They further also teach targeting STAT3 in combination with cancer immunotherapy for enhanced anti-tumor effects and reduced drug resistance (Fig. 3 Pg. 11-12) as exemplified by BBI608 that has been combined with immune checkpoint inhibitors nivolumab or pembrolizumab in clinical trials for metastatic CRC (Table 2 Pg. 9).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector as taught by Liu et al. and an agent that is a STAT3 inhibitor as taught by Zou et al. because Zou et al. teaches that STAT3 plays a critical role in tumor cell survival and immune evasion in the TME, therefore inhibition of STAT3 can lower tumor survival and proliferation, enhance anti-tumor effects of tumor-infiltrating immune cells, and improve the immunosuppressive crosstalk within the TME (Abstract, Pg. 4 column left paragraph second, Fig. 2 and Pg. 14 column left paragraph second). Further, Zou et al. teaches that monotherapy of STAT3 inhibitors have been approved for the treatment of gastric and pancreatic cancer and combination of STAT3 inhibitors with immunotherapy are being studied in the clinical trial setting for metastatic CRC (Pg. 8 column left paragraph third and Table 2 Pg. 9). The advantage of a combined method of Liu et al. and Zou et al. would be to combine different therapeutic agents that can target the killing of tumors through different mechanisms of actions on both cancer cells and non-cancerous cells within the TME for an enhanced therapeutic method of treating cancer. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said STAT3 inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because the combination therapy uses two agents to kill cancer cells wherein one of the agents can also kill cells in the surrounding TME. The first agent serves to target delivery of a cytotoxic drug through a CD46 antibody that recognizes CD46 that are highly expressed in cancer cells and the second agent inhibits STAT3 that is expressed in cancer and surrounding cells in the TME that are responsible for tumor survival and immune evasion, whereas the method of administering the antibody linked to a cytotoxic effector alone can only effect killing of cancer cells that express CD46. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
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.
First NSDP Patent US 10533056
Claims 1-9, 11-16, 18-21 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 11, 12, 33, 35, 36, 37, 38, 39, 40, 41, 45, 47, 48, 49, 54, 55, 56, 57, 62 and 64 of U.S. Patent No. 10533056 in view of Liu et al. (US20170362330A1 Date Published 2017-12-21), Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072), Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779), Sundahl et al. (Oncoscience 2016 Jul 27; 3(7-8): 188–202), Wong et al. (Clinical Lymphoma Myeloma and Leukemia Volume 21, Supplement 2, October 2021, Page S164) and Zou et al. (Mol Cancer Vol 19, Article 145, 1-19, 2020).
Patent 10533056 claim 1 is drawn in part to an isolated recombinant human antibody that specifically binds CD46 wherein: said isolated recombinant human antibody specifically binds cells that express or overexpress a CD46, and wherein said isolated recombinant human antibody comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of an antibody selected from the group consisting of YS5 (represented by SEQ ID NOs: 1 and 22).
Patent 10533056 claim 10 is drawn in part to the antibody of claim 1, wherein said isolated recombinant human antibody comprises the variable light (VL) chain of antibody YS5.
Patent 10533056 claim 11 is drawn in part to the antibody of claim 1, wherein said isolated recombinant human antibody comprises the variable light (VH) chain of antibody YS5.
Patent 10533056 claim 12 is drawn to the antibody of claim 1, wherein said isolated recombinant human antibody comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of the YS5 antibody.
Patent 10533056 claim 33 is drawn to a pharmaceutical formulation said formulation comprising: a pharmaceutically acceptable excipient and an antibody according to claim 1.
Patent 10533056 claim 35 is drawn in part to an immunoconjugate comprising an antibody according to claim 1 attached to an effector that can be selected from a group comprising of a cytotoxin or cytostatic agent.
Patent 10533056 claim 36 is drawn to the immunoconjugate of claim 35, wherein said antibody is attached to a cytotoxic and/or cytostatic drug.
Patent 10533056 claim 37 is drawn in part to the immunoconjugate of claim 35, wherein said antibody is attached directly or through a linker to said drug.
Patent 10533056 claim 38 is drawn to the immunoconjugate of claim 37, wherein said drug is an anti-cancer drug.
Patent 10533056 claim 39 is drawn to the immunoconjugate of claim 37, wherein said drug is selected from the group consisting of a microtubule inhibitor, a DNA-damaging agent, and a polymerase inhibitor.
Patent 10533056 claim 40 is drawn to the immunoconjugate of claim 39, wherein the drug comprises a tubulin inhibitor.
Patent 10533056 claim 41 is drawn in part to the immunoconjugate of claim 40, wherein the drug comprises: a drug selected from the group consisting of an auristatin, Dolastatin-10, synthetic derivatives of the natural product Dolastatin-10, and maytansine or a maytansine derivative; or a drug selected from the group consisting of Monomethylauristatin F (MMAF), Auristatin E (AE), Monomethylauristatin E (MMAE), vcMMAE, and vcMMAF.
Patent 10533056 claim 45 is drawn in part to the immunoconjugate of claim 37, wherein said drug is selected from the group consisting of auristatin and dolastatin.
Patent 10533056 claim 47 is drawn to a method of inhibiting the growth and/or proliferation of a cancer cell that expresses or overexpresses CD46, said method comprising: contacting said cancer cell with an immunoconjugate comprising an antibody according to claim 1 attached to an effector that has cytostatic and/or cytotoxic activity.
Patent 10533056 claim 48 is drawn in part to the method of claim 47, wherein said cancer cell is prostate cancer.
Patent 10533056 claim 49 is drawn the method of claim 47, wherein said cancer cell is a prostate cancer cell.
Patent 10533056 claim 54 is drawn in part to the method of claim 47, wherein said effector comprises a cytostatic drug.
Patent 10533056 claim 55 is drawn in part to the method of claim 54, wherein said effector comprises one or more of a cytotoxic and/or cytostatic drug.
Patent 10533056 claim 56 is drawn to the method of claim 55, wherein said drug is an anti-cancer drug.
Patent 10533056 claim 57 is drawn in part to the method of claim 56, wherein said drug is selected from the group consisting of auristatin and dolastatin.
Patent 10533056 claim 62 is drawn to the method of claim 47, wherein said antibody and/or immunoconjugate is administered in conjunction with another anti-cancer drug and/or a hormone.
Patent 10533056 claim 64 is drawn in part to an isolated recombinant human antibody that specifically binds CD46, wherein said isolated recombinant human antibody comprises: the variable light (VL) chain of the YS5 antibody and the variable heavy (VH) chain of the YS5 antibody.
Alignment of Patent 10533056 antibody YS5 comprising VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 and represented by SEQ ID NOs: 1 and 22 with instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprising instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85 respectively shows that SEQ ID NO: 1 of Patent 10533056 comprises instant HC CDR1, HC CDR2 and HC CDR3 as set forth in instant SEQ ID NOs: 80, 81 and 82, and SEQ ID NO: 22 of Patent 10533056 comprises instant LC CDR1, LC CDR2, and LC CDR3 as set forth in instant SEQ ID NOs: 83, 84 and 85. Moreover, instant specification defines YS5 as an antibody that recognizes CD 46 on the cell surface of prostate cancer cells (paragraph 0053) and defines YS5 as having the VH domain as set forth in instant SEQ ID NO: 1 and the VL domain as set forth in instant SEQ ID NO: 22 (paragraph [0074] Table 1 Novel human anti-CD46 antibody sequences). Comparison of instant SEQ ID NOs: 1 and 22 with Patent 10533056 SEQ ID NOs: 1 and 22 showed that these are an exact match. Therefore, the antibody YS5 as recited by Patent 10533056 is the same antibody claimed in instant claims 11 and 16 that specifically binds to CD46.
Patent 10533056 claims do not specifically recite:-
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM); wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 1);
The method of instant claim 1, wherein the agent is an androgen signaling inhibitor (instant claim 2);
The method of instant claim 2, wherein the agent is enzalutamide or abiraterone (instant claim 3);
The method of instant claim 1, wherein the agent is a SEGRAM (instant claim 4);
The method of instant claim 4, wherein the SEGRAM is dexamethasone (instant claim 5);
The method of instant claim 1, comprising administering an androgen signaling inhibitor and a SEGRAM (instant claim 6);
The method of instant claim 1, wherein the administering comprises administering the agent without the antibody for a time sufficient to induce increased expression of CD46 in cancer cells followed by administering the antibody in an amount sufficient to kill cancer cells in the human (instant claim 7);
The method of instant claim 7, wherein administering the antibody further comprises administering an androgen signaling inhibitor, SEGRAM, or both with the antibody (instant claim 8);
The method of instant claim 7, wherein the time comprises 1-30 days before administering the antibody (instant claim 9);
The method of instant claim 1, wherein the antibody comprises the recited HC CDRs and LC CDRs; and MMAE that is conjugated to said antibody via a maleimidocaproyl-valine-citruline-para-amino benzyloxycarbonyl (mc-vc-PAB) linker (instant claim 16);
The method of instant claim 1, wherein the cancer is androgen receptor negative (instant claim 18);
The method of instant claim 1, wherein the cancer is androgen receptor positive (instant claim 19);
A pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM) (instant claim 21);
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is a Signal Transducer And Activator or Transcription 3 (STAT3) inhibitor, optionally in combination with an androgen signaling inhibitor, a glucocorticoid receptor agonist or modulator (SEGRAM), or both; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35).
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al. are discussed above in the 103 rejections.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of administering an antibody that specifically binds to CD46 that is linked to a cytotoxic effector as recited by Patent 10533056 and an agent that is an androgen signaling inhibitor as taught by Liu et al. to a human with cancer because Liu et al. teaches that administration of enzalutamide or abiraterone sensitized cancer cells to the killing of subsequently administered CD46 immunoconjugate. Also, one would predict that administration of the antibody linked to a cytotoxic effector and the androgen signaling inhibitor kills more cancer cells than administration of the antibody alone because the CD46 antibody linked to a cytotoxic effector is able to specifically target a cytotoxic moiety to CD46 expressing cancer cells to kill the cells compared to a CD46 antibody alone which does not have any cytotoxic moiety that can mediate killing of cancer cells. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said androgen signaling inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because Liu et al. teaches that LNCaP-C4-2B cells pre-treated with 10 μM of abiraterone for 7 days followed by treating with CD46-MMAF for an additional 96 hours had enhanced killing of tumor cells with EC50 values dropping from 169 pM to 21 pM when compared to cells without prior exposure to abiraterone, and that neuroendocrine prostate cancer cell line H660 pretreated with 10 μM enzalutamide for 7 days became more sensitive to CD46 ADC post enzalutamide treatment with EC50 dropping by 4-5 fold (paragraphs [0402] and [0671]).
With regards to instant claims 4 and 5, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector as recited by Patent 10533056 and an agent that is a SEGRAM as taught by Sundahl et al. or an agent that is dexamethasone as taught by Wong et al. or an agent that comprises both an androgen signaling inhibitor and a SEGRAM as taught by Liu et al. and Sundahl et al. respectively, because Sundahl et al. teaches that SEGRAMs have a more restricted GR activity profile that could improve the therapy regimens for cancers by inhibiting proliferation, migration and invasion, and by inducing apoptosis of cancer cells (Abstract and Figure 3), and Wong et al. teaches that dexamethasone upregulated the expression of CD46 on multiple myeloma cells and enhanced the cytotoxicity on said cells in vitro (Background). The advantage of a combined method of Patent 10533056 and Sundahl et al. (CD46 immunoconjugate/ADC and SEGRAM) would be to combine different therapeutic agents that can mediate killing of cancer cells through different mechanisms of actions for an enhanced therapeutic method. The advantage of a combined method of Patent 10533056 and Wong et al. (CD46 immunoconjugate/ADC and dexamethasone) would be that the administration of dexamethasone can upregulate CD46 expression on cancer cells thus increasing the amount of expressed CD46 on cancer cells and localization of the administered anti-CD46 immunoconjugate/ADC at the cancer site, thereby arriving at a more potent cancer therapeutic method. The advantage of a combined method of Patent 10533056, Liu et al. and Sundahl et al. (CD46 immunoconjugate/ADC, androgen signaling inhibitor and SEGRAM) would be to upregulate CD46 expression on cancer cells with the androgen signaling inhibitor to sensitize them to the cytotoxicity of the CD46 immunoconjugate/ADC while combining the effect that SEGRAM has on cancer cells to inhibit proliferation, migration and invasion, thereby killing cancer cells through different mechanisms of actions for an enhanced therapeutic method.
Further, with regards to instant claim 6, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering the combination of an antibody that specifically binds to CD46 that is linked to a cytotoxic effector as recited by Patent 10533056, an androgen signaling inhibitor taught by Liu et al. and a SEGRAM that is dexamethasone that is taught by Wong et al. (CD46 immunoconjugate/ADC and enzalutamide or abiraterone and dexamethasone) because Liu et al. teaches that cancer cells had a significant upregulation of surface CD46 expression and became more sensitive to CD46 ADC post abiraterone or enzalutamide treatment (paragraphs [0402] and [0671]) and Wong et al. teaches that dexamethasone upregulated the expression of CD46 of multiple myeloma cells in vitro and enhanced cytotoxicity (Background), therefore administering both enzalutamide or abiraterone and dexamethasone would be expected to provide an additive effect in upregulating the surface expression of CD46 to further enhance sensitization of cancer cells to CD46 immunoconjugate/ADC.
With regards to instant claims 7 and 9, it would have been obvious to administer to a human with cancer the agent that is enzalutamide or abiraterone for 7 days without the antibody and before administering the antibody as recited by Patent 10533056, because Liu et al. teaches that significant upregulation of the expression of cell surface CD46 on cancer cell lines was observed when treated with enzalutamide or abiraterone for 7 days which sensitized the cancer cells to antibody ADC cytotoxicity.
With regards to instant claim 8, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further administer an androgen signaling inhibitor with the antibody ADC of Patent 10533056, because Liu et al. teaches that administration of enzalutamide or abiraterone alone to cancer cell lines significantly upregulated expression of cell surface CD46 in said cells, therefore continued administration of enzalutamide or abiraterone together with the antibody would provide further upregulated expression of cell surface CD46 on cancer cells when administered to human subjects, thus further enhancing the cytotoxic ability of the treatment method.
With regards to instant claim 16, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to conjugate antibody YS5 to MMAE as recited by Patent 10533056 (Patent claim 41) via the mc-vc-PAB linker as taught by Liu et al. (Figs. 11-13 and paragraphs [0372] and [0657]) to arrive at an antibody that comprises instant HC and LC CDRs (SEQ ID NOs: 80, 81, 82, 83, 84 and 85) conjugated to MMAE via an mc-vc-PAB linker as recited in instant claim 16.
With regards to instant claims 18 and 19, Liu et al. teaches that the anti-CD46 antibody YS5, the same antibody recited by Patent 10533056, was conjugated to MMAF via the mc-vc-PAB linker and showed potent in vitro tumor-killing activities on LNCaP-C4-2B and Du145 metastatic castration resistant prostate cancer cell lines (Figs. 11-13 and paragraphs [0372] and [0657]). As confirmed by Dagvadorj et al., DU145 cells are androgen receptor negative prostate cancer cell lines, whereas LNCaP cells are androgen receptor positive (Pg. 9 paragraph first). Further, Decker et al. confirms that C4-2B is a castration-resistant prostate cancer (CRPC) cell line derived from a LNCaP xenograft that relapsed and metastasized to bone after castration, and that C4-2B is androgen receptor positive (Pg. 10768 column right paragraph first lines 4-11).
With regards to instant claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to combine the anti-CD46 antibody conjugated to a cytotoxic effector comprised in a pharmaceutical composition as recited by Patent 10533056 (claim 33) with an agent that is an androgen signaling inhibitor which can be enzalutamide or abiraterone as taught by Liu et al. (paragraph [0291]). This combination pharmaceutical composition would have the advantage of increased ease of administration of two therapeutic compounds to a human subject in a single composition or in a single administration.
With regards to instant claim 35, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector as recited by Patent 10533056 and an agent that is a STAT3 inhibitor as taught by Zou et al. because Zou et al. teaches that STAT3 plays a critical role in tumor cell survival and immune evasion in the TME, therefore inhibition of STAT3 can lower tumor survival and proliferation, enhance anti-tumor effects of tumor-infiltrating immune cells, and improve the immunosuppressive crosstalk within the TME (Abstract, Pg. 4 column left paragraph second, Fig. 2 and Pg. 14 column left paragraph second). Further, Zou et al. teaches that monotherapy of STAT3 inhibitors have been approved for the treatment of gastric and pancreatic cancer and combination of STAT3 inhibitors with immunotherapy are being studied in the clinical trial setting for metastatic CRC (Pg. 8 column left paragraph third and Table 2 Pg. 9). The advantage of a combined method of Patent 10533056 and Zou et al. would be to combine different therapeutic agents that can target the killing of tumors through different mechanisms of actions on both cancer cells and non-cancerous cells within the TME for an enhanced therapeutic method of treating cancer. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said STAT3 inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because the combination therapy uses two agents to kill cancer cells wherein one of the agents can also kill cells in the surrounding TME. The first agent serves to target delivery of a cytotoxic drug through a CD46 antibody that recognizes CD46 that are highly expressed in cancer cells and the second agent inhibits STAT3 that is expressed in cancer and surrounding cells in the TME that are responsible for tumor survival and immune evasion, whereas the method of administering the antibody linked to a cytotoxic effector alone can only effect killing of cancer cells that express CD46.
Second NSDP Patent US 11434301
Claims 1-9, 11-16, 18-21 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 15, 16, 26, 27, 28 and 29 of U.S. Patent No. 11434301 in view of Liu et al. (US20170362330A1 Date Published 2017-12-21), Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072), Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779), Sundahl et al. (Oncoscience 2016 Jul 27; 3(7-8): 188–202), Wong et al. (Clinical Lymphoma Myeloma and Leukemia Volume 21, Supplement 2, October 2021, Page S164) and Zou et al. (Mol Cancer Vol 19, Article 145, 1-19, 2020).
Patent 11434301 claim 1 is drawn in part to a method of treating a subject having a cancer, said method comprising: administering to said subject a therapeutically effective amount of a CD46-targeted therapy, wherein the CD46-targeted therapy comprises a pharmaceutical composition comprising an anti-CD46 antibody.
Patent 11434301 claim 11 is drawn in part to the method of claim 1, wherein the anti-CD46 antibody is YS5 antibody comprising the sequences of SEQ ID No: 1 and 2.
Patent 11434301 claim 15 is drawn to the method of claim 1, wherein the anti-CD46 antibody further comprises at least one payload, and wherein the payload comprises a cytotoxic or cytostatic drug, or a tubulin inhibitor.
Patent 11434301 claim 16 is drawn to the method of claim 15, wherein the at least one payload comprises: one or more drugs selected from the group consisting of a microtubule inhibitor, a DNA-damaging agent, and a polymerase inhibitor; or one or more drugs selected from the group consisting of Monomethylauristatin F(MMAF), Auristatin E (AE), and Monomethylauristatin E (MMAE).
Patent 11434301 claim 26 is drawn to the method of claim 1, wherein the subject is a human.
Patent 11434301 claim 27 is drawn in part to the method of claim 1, wherein the anti-CD46 antibody comprises: a heavy chain variable region comprising a variable heavy (VH) CDR1 that comprises the amino acid sequence of SEQ ID NO: 3, a variable heavy (VH) CDR2 that comprises the amino acid sequence of SEQ ID NO: 4, and a variable heavy (VH) CDR3 that comprises the amino acid sequence of SEQ ID NO: 5; and a light chain variable region comprising a variable light (VL) CDR 1 that comprises the amino acid sequence of SEQ ID NO: 6, a variable light (VL) CDR 2 that comprises the amino acid sequence of SEQ ID NO: 7, and a variable light (VL) CDR 3 that comprises the amino acid sequence of SEQ ID NO: 8.
Patent 11434301 claim 28 is drawn to the method of claim 27, wherein the anti-CD46 antibody comprises a variable heavy region comprising the amino acid sequence of SEQ ID NO: 1; and a variable light region comprising the amino acid sequence of SEQ ID NO:2.
Patent 11434301 claim 29 is drawn in part to the method of claim 1, wherein the anti-CD46 antibody comprises variable heavy chain CDR domains VH CDR1, VH CDR2, VH CDR3 and variable light chain CDR domains VL CDR1, VL CDR2 and VL CDR3 SEQ ID NOS:3-8, respectively.
Alignment of Patent 11434301 antibody YS5 comprising the sequences of SEQ ID NOs: 1 and 2 with instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprising instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85 respectively shows that SEQ ID NO: 1 of Patent 11434301 comprises instant HC CDR1, HC CDR2 and HC CDR3 as set forth in instant SEQ ID NOs: 80, 81 and 82, and SEQ ID NO: 2 of Patent 11434301 comprises instant LC CDR1, LC CDR2, and LC CDR3 as set forth in instant SEQ ID NOs: 83, 84 and 85. Moreover, instant specification defines YS5 as an antibody that recognizes CD 46 on the cell surface of prostate cancer cells (paragraph 0053) and defines YS5 as having the VH domain as set forth in instant SEQ ID NO: 1 and the VL domain as set forth in instant SEQ ID NO: 22 (paragraph [0074] Table 1. Novel human anti-CD46 antibody sequences). Comparison of instant SEQ ID NOs: 1 and 22 with Patent 11434301 SEQ ID NOs: 1 and 2 showed that these are an exact match. Further, YS5 VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NOS:3-8, respectively as recited by Patent 11434301 are 100% identical to instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as set forth in instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85 respectively. Therefore, the antibody YS5 as recited by Patent 11434301 is the same antibody claimed in instant claims 11 and 16 that specifically binds to CD46.
Patent 11434301 claims do not specifically recite:-
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM); wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 1);
The method of instant claim 1, wherein the agent is an androgen signaling inhibitor (instant claim 2);
The method of instant claim 2, wherein the agent is enzalutamide or abiraterone (instant claim 3);
The method of instant claim 1, wherein the agent is a SEGRAM (instant claim 4);
The method of instant claim 4, wherein the SEGRAM is dexamethasone (instant claim 5);
The method of instant claim 1, comprising administering an androgen signaling inhibitor and a SEGRAM (instant claim 6);
The method of instant claim 1, wherein the administering comprises administering the agent without the antibody for a time sufficient to induce increased expression of CD46 in cancer cells followed by administering the antibody in an amount sufficient to kill cancer cells in the human (instant claim 7);
The method of instant claim 7, wherein administering the antibody further comprises administering an androgen signaling inhibitor, SEGRAM, or both with the antibody (instant claim 8);
The method of instant claim 7, wherein the time comprises 1-30 days before administering the antibody (instant claim 9);
The method of instant claim 1, wherein the antibody comprises the recited HC CDRs and LC CDRs; and MMAE that is conjugated to said antibody via a maleimidocaproyl-valine-citruline-para-amino benzyloxycarbonyl (mc-vc-PAB) linker (instant claim 16);
The method of instant claim 1, wherein the cancer is androgen receptor negative (instant claim 18);
The method of instant claim 1, wherein the cancer is androgen receptor positive (instant claim 19);
The method of instant claim 18, wherein the cancer is prostate cancer (instant claim 20);
A pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM) (instant claim 21);
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is a Signal Transducer And Activator or Transcription 3 (STAT3) inhibitor, optionally in combination with an androgen signaling inhibitor, a glucocorticoid receptor agonist or modulator (SEGRAM), or both; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35).
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al. are discussed above in the 103 rejections.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the patented method of treating cancer in a human comprising administering to the human a CD46-targeted therapy wherein the anti-CD46 antibody further comprises a payload/cytotoxic effector as recited by Patent 11434301 and an agent that is an androgen signaling inhibitor as taught by Liu et al. because Liu et al. teaches that administration of enzalutamide or abiraterone sensitized cancer cells to the killing of subsequently administered CD46 immunoconjugate. Also, one would predict that administration of the antibody linked to a cytotoxic effector and the androgen signaling inhibitor kills more cancer cells than administration of the antibody alone because the CD46 antibody linked to a cytotoxic effector is able to specifically target a cytotoxic moiety to CD46 expressing cancer cells to kill the cells compared to a CD46 antibody alone which does not have any cytotoxic moiety that can mediate killing of cancer cells. Moreover, one would also predict that a combined method of administering the said antibody linked to a payload/cytotoxic effector and the said androgen signaling inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because Liu et al. teaches that LNCaP-C4-2B cells pre-treated with 10 μM of abiraterone for 7 days followed by washing and treating with CD46-MMAF for an additional 96 hours had enhanced killing of tumor cells with EC50 values dropping from 169 pM to 21 pM when compared to cells without prior exposure to abiraterone, and that neuroendocrine prostate cancer cell line H660 pretreated with 10 μM enzalutamide for 7 days became more sensitive to CD46 ADC post enzalutamide treatment with EC50 dropping by 4-5 fold (paragraphs [0402] and [0671]).
With regards to instant claims 4 and 5, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering to the human an anti-CD46 antibody that further comprises a payload/cytotoxic effector as recited by Patent 11434301 and an agent that is a SEGRAM as taught by Sundahl et al.; or an agent that is dexamethasone as taught by Wong et al.; or an agent that comprises both an androgen signaling inhibitor and a SEGRAM as taught by Liu et al. and Sundahl et al. respectively, because Sundahl et al. teaches that SEGRAMs have a more restricted GR activity profile that could improve the therapy regimens for cancers by inhibiting proliferation, migration and invasion, and by inducing apoptosis of cancer cells (Abstract and Figure 3), and Wong et al. teaches that dexamethasone upregulated the expression of CD46 on multiple myeloma cells and enhanced the cytotoxicity on said cells in vitro (Background). The advantage of a combined method of Patent 11434301 and Sundahl et al. (CD46 immunoconjugate/ADC and SEGRAM) would be to combine different therapeutic agents that can mediate killing of cancer cells through different mechanisms of actions for an enhanced therapeutic method. The advantage of a combined method of Patent 11434301 and Wong et al. (CD46 immunoconjugate/ADC and dexamethasone) would be that the administration of dexamethasone can upregulate CD46 expression on cancer cells thus increasing the amount of expressed CD46 on cancer cells and localization of the administered anti-CD46 immunoconjugate/ADC at the cancer site, thereby arriving at a more potent cancer therapeutic method. The advantage of a combined method of Patent 11434301, Liu et al. and Sundahl et al. (CD46 immunoconjugate/ADC, androgen signaling inhibitor and SEGRAM) would be to upregulate CD46 expression on cancer cells with the androgen signaling inhibitor to sensitize them to the cytotoxicity of the CD46 immunoconjugate/ADC while combining the effect that SEGRAM has on cancer cells to inhibit proliferation, migration and invasion, thereby killing cancer cells through different mechanisms of actions for an enhanced therapeutic method.
Further, with regards to instant claim 6, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering the combination of an antibody that specifically binds to CD46 that is linked to a cytotoxic effector as recited by Patent 11434301, an androgen signaling inhibitor taught by Liu et al. and a SEGRAM that is dexamethasone that is taught by Wong et al. (CD46 immunoconjugate/ADC and enzalutamide or abiraterone and dexamethasone) because Liu et al. teaches that cancer cells had a significant upregulation of surface CD46 expression and became more sensitive to CD46 ADC post abiraterone or enzalutamide treatment (paragraphs [0402] and [0671]) and Wong et al. teaches that dexamethasone upregulated the expression of CD46 of multiple myeloma cells in vitro and enhanced cytotoxicity (Background), therefore administering both enzalutamide or abiraterone and dexamethasone would be expected to provide an additive effect in upregulating the surface expression of CD46 to further enhance sensitization of cancer cells to CD46 immunoconjugate/ADC.
With regards to instant claims 7 and 9, it would have been obvious to administer to a human with cancer the agent that is enzalutamide or abiraterone for 7 days without the antibody and before administering the antibody as recited by Patent 11434301, because Liu et al. teaches that significant upregulation of the expression of cell surface CD46 on cancer cell lines was observed when treated with enzalutamide or abiraterone for 7 days which sensitized the cancer cells to antibody ADC cytotoxicity.
With regards to instant claim 8, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further administer an androgen signaling inhibitor with the antibody ADC of Patent 11434301, because Liu et al. teaches that administration of enzalutamide or abiraterone alone to cancer cell lines significantly upregulated expression of cell surface CD46 in said cells, therefore continued administration of enzalutamide or abiraterone together with the antibody would provide further upregulated expression of cell surface CD46 on cancer cells when administered to human subjects, thus further enhancing the cytotoxic ability of the treatment method.
With regards to instant claim 16, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to conjugate antibody YS5 as recited by Patent 11434301 (Patent claims 11, 27, 28 and 29) to MMAE also as recited by Patent 11434301 (Patent claim 16) via the mc-vc-PAB linker as taught by Liu et al. (Figs. 11-13 and paragraphs [0372] and [0657]) to arrive at an antibody that comprises instant HC and LC CDRs (SEQ ID NOs: 80, 81, 82, 83, 84 and 85) conjugated to MMAE via an mc-vc-PAB linker as recited in instant claim 16.
With regards to instant claims 18, 19 and 20, Liu et al. teaches that the anti-CD46 antibody YS5, the same antibody recited by Patent 11434301, was conjugated to MMAF via the mc-vc-PAB linker and showed potent in vitro tumor-killing activities on LNCaP-C4-2B and Du145 metastatic castration resistant prostate cancer cell lines (Figs. 11-13 and paragraphs [0372] and [0657]). As confirmed by Dagvadorj et al., DU145 cells are androgen receptor negative prostate cancer cell lines, whereas LNCaP cells are androgen receptor positive (Pg. 9 paragraph first). Further, Decker et al. confirms that C4-2B is a castration-resistant prostate cancer (CRPC) cell line derived from a LNCaP xenograft that relapsed and metastasized to bone after castration, and that C4-2B is androgen receptor positive (Pg. 10768 column right paragraph first lines 4-11).
With regards to instant claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to conjugate the anti-CD46 antibody to a cytotoxic effector as recited by Patent 11434301 (claims 15 and 16) and combine it with an agent that is an androgen signaling inhibitor which can be enzalutamide or abiraterone as taught by Liu et al. (paragraph [0291]) to be comprised in a pharmaceutical composition as recited by Patent 11434301 (claim 1). This combination pharmaceutical composition would have the advantage of increased ease of administration of two therapeutic compounds to a human subject in a single composition or in a single administration.
With regards to instant claim 35, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector as recited by Patent 11434301 and an agent that is a STAT3 inhibitor as taught by Zou et al. because Zou et al. teaches that STAT3 plays a critical role in tumor cell survival and immune evasion in the TME, therefore inhibition of STAT3 can lower tumor survival and proliferation, enhance anti-tumor effects of tumor-infiltrating immune cells, and improve the immunosuppressive crosstalk within the TME (Abstract, Pg. 4 column left paragraph second, Fig. 2 and Pg. 14 column left paragraph second). Further, Zou et al. teaches that monotherapy of STAT3 inhibitors have been approved for the treatment of gastric and pancreatic cancer and combination of STAT3 inhibitors with immunotherapy are being studied in the clinical trial setting for metastatic CRC (Pg. 8 column left paragraph third and Table 2 Pg. 9). The advantage of a combined method of Patent 11434301 and Zou et al. would be to combine different therapeutic agents that can target the killing of tumors through different mechanisms of actions on both cancer cells and non-cancerous cells within the TME for an enhanced therapeutic method of treating cancer. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said STAT3 inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because the combination therapy uses two agents to kill cancer cells wherein one of the agents can also kill cells in the surrounding TME. The first agent serves to target delivery of a cytotoxic drug through a CD46 antibody that recognizes CD46 that are highly expressed in cancer cells and the second agent inhibits STAT3 that is expressed in cancer and surrounding cells in the TME that are responsible for tumor survival and immune evasion, whereas the method of administering the antibody linked to a cytotoxic effector alone can only effect killing of cancer cells that express CD46.
Third NSDP Patent US 12325755
Claims 1-9, 11-16, 18-21 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 6, 7, 8, 9, 13, 16, 17, 18, 19, 22, 23, 24, 26, 27, 28, 32, 33, 34, 35, 36, 38, 39 and 42, of U.S. Patent No. 12325755in view of Liu et al. (US20170362330A1 Date Published 2017-12-21), Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072), Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779), Sundahl et al. (Oncoscience 2016 Jul 27; 3(7-8): 188–202), Wong et al. (Clinical Lymphoma Myeloma and Leukemia Volume 21, Supplement 2, October 2021, Page S164) and Zou et al. (Mol Cancer Vol 19, Article 145, 1-19, 2020).
Patent 12325755 claim 1 is drawn to an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising the amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising the amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising the amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising the amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising the amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising the amino acid sequence of SEQ ID NO. 231.
Patent 12325755 claim 5 is drawn in part to an immunoconjugate comprising an antibody according to claim 1 and an effector wherein the effector is selected from a cytotoxic agent, a cytostatic agent, or a drug.
Patent 12325755 claim 6 is drawn in part to the immunoconjugate of claim 5, wherein said antibody is attached to the effector, wherein the effector is selected from the group consisting of the cytotoxic agent, the cytostatic agent, and combinations thereof.
Patent 12325755 claim 7 is drawn in part to an immunoconjugate comprising an antibody according to claim 1, a linker, and a drug.
Patent 12325755 claim 8 is drawn in part to the immunoconjugate of claim 7, wherein said drug is selected from the group consisting of an anti-cancer drug, a microtubule inhibitor, a tubulin inhibitor, a DNA-damaging agent, a polymerase inhibitor, and combinations thereof.
Patent 12325755 claim 9 is drawn in part to the immunoconjugate of claim 7, wherein said drug is selected from the group consisting of an auristatin, Dolastatin-10, synthetic derivatives of a natural product Dolastatin-10, maytansine, a maytansine derivative, Monomethylauristatin F (MMAF), Auristatin E (AE), Monomethylauristatin E (MMAE), vcMMAE, and vcMMAF.
Patent 12325755 claim 13 is drawn to the immunoconjugate of claim 7, wherein said drug is selected from the group consisting of auristatin and dolastatin.
Patent 12325755 claim 16 is drawn in part to the antibody of claim 1, wherein the isolated recombinant human antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Patent 12325755 claim 17 is drawn to the immunoconjugate of claim 5, wherein the antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Patent 12325755 claim 18 is drawn to the immunoconjugate of claim 7, wherein said antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Patent 12325755 claim 19 is drawn to a pharmaceutical formulation said formulation comprising: a pharmaceutically acceptable excipient and the antibody according to claim 1.
Patent 12325755 claim 22 is drawn to the formulation of claim 19, wherein the antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO: 1.
Patent 12325755 claim 23 is drawn to a method of inhibiting growth and/or proliferation of a cancer cell that expresses or overexpresses CD46, said method comprising: contacting the cancer cell with immunoconjugate comprising the antibody according to claim 1 and an effector wherein the effector has cytostatic or cytotoxic activity.
Patent 12325755 claim 24 is drawn the method of claim 23, wherein the cancer cell that expresses or overexpresses CD46 is a metastatic castration resistant prostate cancer cell.
Patent 12325755 claim 26 is drawn to the method of claim 23, wherein the antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Patent 12325755 claim 26 is drawn to the method of claim 23, wherein the antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Patent 12325755 claim 27 is drawn in part to an immunoconjugate comprising: an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising the amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising the amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising the amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising the amino acid sequence of SEQ ID NO. 227, VL CDR2 SEQ ID NO. 229, and VL CDR3 comprising the amino acid sequence of SEQ ID NO. 231; and an effector comprising a drug selected from Monomethylauristatin F (MMAF), Auristatin E (AE), Monomethylauristatin E (MMAE), vcMMAE, vcMMAF , and combinations thereof.
Patent 12325755 claim 28 is drawn in part to the immunoconjugate of claim 27, wherein the isolated recombinant human antibody is covalently coupled to the effector through a MC-vc-PAB linker.
Patent 12325755 claim 32 is drawn to the immunoconjugate of claim 27, wherein the isolated recombinant human antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Patent 12325755 claim 33 is drawn to the immunoconjugate of claim 27, wherein said effector is Monomethylauristatin E (MMAE).
Patent 12325755 claim 34 is drawn in part to the immunoconjugate of claim 33, wherein the isolated recombinant human antibody is covalently coupled to the effector through a MC-vc-PAB linker.
Patent 12325755 claim 35 is drawn to the immunoconjugate of claim 33, wherein the isolated recombinant human antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Patent 12325755 claim 36 is drawn in part to the immunoconjugate of claim 35, wherein the isolated recombinant human antibody is covalently coupled to the effector through a MC-vc-PAB linker.
Patent 12325755 claim 38 is drawn in part to an immunoconjugate comprising: an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising the amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising the amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising the amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising the amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising the amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising the amino acid sequence of SEQ ID NO. 231; and an effector comprising Monomethylauristatin E (MMAE) or Monomethylauristatin F (MMAF).
Patent 12325755 claim 39 is drawn to the immunoconjugate of claim 38, wherein the isolated recombinant human antibody is covalently coupled to the effector through a MC-vc-PAB linker.
Patent 12325755 claim 42 is drawn to the immunoconjugate of claim 38, wherein the isolated recombinant human antibody comprises a variable light (VL) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising the amino acid sequence of SEQ ID NO:1.
Alignment of Patent 12325755 recombinant human antibody that specifically binds CD46 comprising VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NOS:80, 82, 84, 227, 229 and 231, respectively with instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as set forth in instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85, respectively shows that the CDRs are 100% identical to each other. Further, antibody YS5 comprising the sequences of SEQ ID NOs: 1 and 22 as recited by Patent 12325755 was found to comprise instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 such that SEQ ID NO: 1 of Patent 12325755 comprises instant HC CDR1, HC CDR2 and HC CDR3 as set forth in instant SEQ ID NOs: 80, 81 and 82, and SEQ ID NO: 22 of Patent 12325755 comprises instant LC CDR1, LC CDR2, and LC CDR3 as set forth in instant SEQ ID NOs: 83, 84 and 85. Moreover, instant specification defines YS5 as an antibody that recognizes CD 46 on the cell surface of prostate cancer cells (paragraph 0053) and defines YS5 as having the VH domain as set forth in instant SEQ ID NO: 1 and the VL domain as set forth in instant SEQ ID NO: 22 (paragraph [0074] Table 1. Novel human anti-CD46 antibody sequences). Comparison of instant SEQ ID NOs: 1 and 22 with Patent 12325755 SEQ ID NOs: 1 and 22 showed that these are an exact match. Therefore, the antibody YS5 comprising VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NOS:80, 82, 84, 227, 229 and 231, respectively, VH chain comprising SEQ ID NO:1 and VL chain comprising SEQ ID NO:22 as recited by Patent 12325755 is the same antibody claimed in instant claims 11 and 16 that specifically binds to CD46.
Patent 12325755 claims do not specifically recite:-
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM); wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 1);
The method of instant claim 1, wherein the agent is an androgen signaling inhibitor (instant claim 2);
The method of instant claim 2, wherein the agent is enzalutamide or abiraterone (instant claim 3);
The method of instant claim 1, wherein the agent is a SEGRAM (instant claim 4);
The method of instant claim 4, wherein the SEGRAM is dexamethasone (instant claim 5);
The method of instant claim 1, comprising administering an androgen signaling inhibitor and a SEGRAM (instant claim 6);
The method of instant claim 1, wherein the administering comprises administering the agent without the antibody for a time sufficient to induce increased expression of CD46 in cancer cells followed by administering the antibody in an amount sufficient to kill cancer cells in the human (instant claim 7);
The method of instant claim 7, wherein administering the antibody further comprises administering an androgen signaling inhibitor, SEGRAM, or both with the antibody (instant claim 8);
The method of instant claim 7, wherein the time comprises 1-30 days before administering the antibody (instant claim 9);
The method of instant claim 1, wherein the cancer is androgen receptor negative (instant claim 18);
The method of instant claim 1, wherein the cancer is androgen receptor positive (instant claim 19);
The method of instant claim 18, wherein the cancer is prostate cancer (instant claim 20);
A pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM) (instant claim 21);
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is a Signal Transducer And Activator or Transcription 3 (STAT3) inhibitor, optionally in combination with an androgen signaling inhibitor, a glucocorticoid receptor agonist or modulator (SEGRAM), or both; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35).
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al. are discussed above in the 103 rejections.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of administering an antibody that specifically binds to CD46 comprising recited CDRs, VH and VL chains as recited by Patent 12325755 that is covalently linked to an effector such as MMAE through a MC-vc-PAB linker (to form an immunoconjugate) also as recited by Patent 12325755 and an agent that is an androgen signaling inhibitor as taught by Liu et al. to a human with cancer because Liu et al. teaches that administration of enzalutamide or abiraterone sensitized cancer cells to the killing of subsequently administered CD46 immunoconjugate. Also, one would predict that administration of the antibody linked to a cytotoxic effector and the androgen signaling inhibitor kills more cancer cells than administration of the antibody alone because the CD46 antibody linked to a cytotoxic effector is able to specifically target a cytotoxic moiety to CD46 expressing cancer cells to kill the cells compared to a CD46 antibody alone which does not have any cytotoxic moiety that can mediate killing of cancer cells. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said androgen signaling inhibitor kills more cancer cells than administration of the antibody linked to a cytotoxic effector alone because Liu et al. teaches that LNCaP-C4-2B cells pre-treated with 10 μM of abiraterone for 7 days followed by washing and treating with CD46-MMAF for an additional 96 hours had enhanced killing of tumor cells with EC50 values dropping from 169 pM to 21 pM when compared to cells without prior exposure to abiraterone, and that neuroendocrine prostate cancer cell line H660 pretreated with 10 μM enzalutamide for 7 days became more sensitive to CD46 ADC post enzalutamide treatment with EC50 dropping by 4-5 fold (paragraphs [0402] and [0671]).
With regards to instant claims 4 and 5, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46 comprising recited CDRs, VH and VL chains as recited by Patent 12325755 that is covalently linked to an effector such as MMAE through a MC-vc-PAB linker (to form an immunoconjugate) also as recited by Patent 12325755 and an agent that is a SEGRAM as taught by Sundahl et al.; or an agent that is dexamethasone as taught by Wong et al.; or an agent that comprises both an androgen signaling inhibitor and a SEGRAM as taught by Liu et al. and Sundahl et al. respectively, because Sundahl et al. teaches that SEGRAMs have a more restricted GR activity profile that could improve the therapy regimens for cancers by inhibiting proliferation, migration and invasion, and by inducing apoptosis of cancer cells (Abstract and Figure 3), and Wong et al. teaches that dexamethasone upregulated the expression of CD46 on multiple myeloma cells and enhanced the cytotoxicity on said cells in vitro (Background). The advantage of a combined method of Patent 12325755 and Sundahl et al. (CD46 immunoconjugate/ADC and SEGRAM) would be to combine different therapeutic agents that can mediate killing of cancer cells through different mechanisms of actions for an enhanced therapeutic method. The advantage of a combined method of Patent 12325755 and Wong et al. (CD46 immunoconjugate/ADC and dexamethasone) would be that the administration of dexamethasone can upregulate CD46 expression on cancer cells thus increasing the amount of expressed CD46 on cancer cells and localization of the administered anti-CD46 immunoconjugate/ADC at the cancer site, thereby arriving at a more potent cancer therapeutic method. The advantage of a combined method of Patent 12325755, Liu et al. and Sundahl et al. (CD46 immunoconjugate/ADC, androgen signaling inhibitor and SEGRAM) would be to upregulate CD46 expression on cancer cells with the androgen signaling inhibitor to sensitize them to the cytotoxicity of the CD46 immunoconjugate/ADC while combining the effect that SEGRAM has on cancer cells to inhibit proliferation, migration and invasion, thereby killing cancer cells through different mechanisms of actions for an enhanced therapeutic method.
Further, with regards to instant claim 6, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering the combination of an antibody that specifically binds to CD46 comprising recited CDRs, VH and VL chains as recited by Patent 12325755 that is covalently linked to an effector such as MMAE through a MC-vc-PAB linker (to form an immunoconjugate) also as recited by Patent 12325755 and an androgen signaling inhibitor taught by Liu et al. and a SEGRAM that is dexamethasone that is taught by Wong et al. (CD46 immunoconjugate/ADC and enzalutamide or abiraterone and dexamethasone) because Liu et al. teaches that cancer cells had a significant upregulation of surface CD46 expression and became more sensitive to CD46 ADC post abiraterone or enzalutamide treatment (paragraphs [0402] and [0671]) and Wong et al. teaches that dexamethasone upregulated the expression of CD46 of multiple myeloma cells in vitro and enhanced cytotoxicity (Background), therefore administering both enzalutamide or abiraterone and dexamethasone would be expected to provide an additive effect in upregulating the surface expression of CD46 to further enhance sensitization of cancer cells to CD46 immunoconjugate/ADC.
With regards to instant claims 7 and 9, it would have been obvious to administer to a human with cancer the agent that is enzalutamide or abiraterone for 7 days without the antibody and before administering the antibody as recited by Patent 12325755, because Liu et al. teaches that significant upregulation of the expression of cell surface CD46 on cancer cell lines was observed when treated with enzalutamide or abiraterone for 7 days which sensitized the cancer cells to antibody ADC cytotoxicity.
With regards to instant claim 8, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further administer an androgen signaling inhibitor with the antibody ADC of Patent 12325755, because Liu et al. teaches that administration of enzalutamide or abiraterone alone to cancer cell lines significantly upregulated expression of cell surface CD46 in said cells, therefore continued administration of enzalutamide or abiraterone together with the antibody would provide further upregulated expression of cell surface CD46 on cancer cells when administered to human subjects, thus further enhancing the cytotoxic ability of the treatment method.
With regards to instant claims 18 and 19, Liu et al. teaches that the anti-CD46 antibody YS5, the same antibody recited by Patent 12325755, was conjugated to MMAF via the mc-vc-PAB linker and showed potent in vitro tumor-killing activities on LNCaP-C4-2B and Du145 metastatic castration resistant prostate cancer cell lines (Figs. 11-13 and paragraphs [0372] and [0657]). As confirmed by Dagvadorj et al., DU145 cells are androgen receptor negative prostate cancer cell lines, whereas LNCaP cells are androgen receptor positive (Pg. 9 paragraph first). Further, Decker et al. confirms that C4-2B is a castration-resistant prostate cancer (CRPC) cell line derived from a LNCaP xenograft that relapsed and metastasized to bone after castration, and that C4-2B is androgen receptor positive (Pg. 10768 column right paragraph first lines 4-11).
With regards to instant claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to combine the anti-CD46 antibody conjugated to an effector as recited by Patent 12325755 (claim 27) and combine it with an agent that is an androgen signaling inhibitor which can be enzalutamide or abiraterone as taught by Liu et al. (paragraph [0291]) to be comprised in a pharmaceutical composition as recited by Patent 12325755 (claim 19). This combination pharmaceutical composition would have the advantage of increased ease of administration of two therapeutic compounds to a human subject in a single composition or in a single administration.
With regards to instant claim 35, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering the combination of an antibody that specifically binds to CD46 comprising recited CDRs, VH and VL chains as recited by Patent 12325755 that is covalently linked to an effector such as MMAE through a MC-vc-PAB linker (to form an immunoconjugate) also as recited by Patent 12325755 and an agent that is a STAT3 inhibitor as taught by Zou et al. because Zou et al. teaches that STAT3 plays a critical role in tumor cell survival and immune evasion in the TME, therefore inhibition of STAT3 can lower tumor survival and proliferation, enhance anti-tumor effects of tumor-infiltrating immune cells, and improve the immunosuppressive crosstalk within the TME (Abstract, Pg. 4 column left paragraph second, Fig. 2 and Pg. 14 column left paragraph second). Further, Zou et al. teaches that monotherapy of STAT3 inhibitors have been approved for the treatment of gastric and pancreatic cancer and combination of STAT3 inhibitors with immunotherapy are being studied in the clinical trial setting for metastatic CRC (Pg. 8 column left paragraph third and Table 2 Pg. 9). The advantage of a combined method of Patent 12325755 and Zou et al. would be to combine different therapeutic agents that can target the killing of tumors through different mechanisms of actions on both cancer cells and non-cancerous cells within the TME for an enhanced therapeutic method of treating cancer. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said STAT3 inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because the combination therapy uses two agents to kill cancer cells wherein one of the agents can also kill cells in the surrounding TME. The first agent serves to target delivery of a cytotoxic drug through a CD46 antibody that recognizes CD46 that are highly expressed in cancer cells and the second agent inhibits STAT3 that is expressed in cancer and surrounding cells in the TME that are responsible for tumor survival and immune evasion, whereas the method of administering the antibody linked to a cytotoxic effector alone can only effect killing of cancer cells that express CD46.
Fourth NSDP Patent US 12252746B2
Claims 1-9, 11-16, 18-21 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 9 and 10 of U.S. Patent No. 12252746B2 in view of Liu et al. (US20170362330A1 Date Published 2017-12-21), Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072), Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779), Sundahl et al. (Oncoscience 2016 Jul 27; 3(7-8): 188–202), Wong et al. (Clinical Lymphoma Myeloma and Leukemia Volume 21, Supplement 2, October 2021, Page S164) and Zou et al. (Mol Cancer Vol 19, Article 145, 1-19, 2020).
Patent 12252746B2 claim 1 is drawn in part to a method comprising: administering to a human with cancer a therapeutically effective amount of the CD46-targeted therapy, wherein the CD46-targeted therapy is a pharmaceutical composition comprising (i) an anti-CD46 antibody comprising a heavy chain variable region comprising a variable heavy (VH) CDR1 that comprises an amino acid sequence of SEQ ID NO: 3, a VH CDR2 that comprises an amino acid sequence of SEQ ID NO: 4, and a VH CDR3 that comprises an amino acid sequence of SEQ ID NO: 5; and a light chain variable region comprising a variable light (VL) CDR 1 that comprises an amino acid sequence of SEQ ID NO: 6, a VL CDR 2 that comprises an amino acid sequence of SEQ ID NO: 7, and a VL CDR 3 that comprises an amino acid sequence of SEQ ID NO: 8; attached to (ii) at least one payload wherein the at least one payload comprises an auristatin.
Patent 12252746B2 claim 8 is drawn to the method of claim 1, wherein the subject is a human.
Patent 12252746B2 claim 9 is drawn to the method of claim 1, wherein the auristatin is selected from the group consisting of Monomethylauristatin F (MMAF), Auristatin E (AE), and Monomethylauristatin E (MMAE).
Patent 12252746B2 claim 10 is drawn to the method of claim 1, wherein the auristatin is MMAE.
Alignment of Patent 12252746B2 anti-CD46 antibody comprising VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NOs: 3, 4, 5, 6, 7 and 8, respectively with instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprising instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85, respectively shows that the antibody CDRs of Patent 12252746B2 are an exact match to instant antibody CDRs. Moreover, Patent 12252746B2 specification in Table 1 (Column 22) discloses that VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NOs: 3, 4, 5, 6, 7 and 8 corresponds to the CDRs of antibody YS5 which comprises VH and VL amino acid sequence of SEQ ID NOs: 1 and 2 respectively. Further, instant specification defines YS5 as an antibody that recognizes CD 46 on the cell surface of prostate cancer cells (paragraph 0053) and defines YS5 as having the VH domain as set forth in instant SEQ ID NO: 1 and the VL domain as set forth in instant SEQ ID NO: 22 (paragraph [0074] Table 1. Novel human anti-CD46 antibody sequences). It is also noted that instant HC CDR1, HC CDR2 and HC CDR3 as set forth in instant SEQ ID NOs: 80, 81 and 82 respectively are comprised within instant SEQ ID NO: 1 (YS5 VH), while instant LC CDR1, LC CDR2, and LC CDR3 as set forth in SEQ ID NOs: 83, 84 and 85, respectively are comprised within instant SEQ ID NO: 22 (YS5 VL). Comparison of instant SEQ ID NOs: 1 and 22 with Patent 12252746B2 SEQ ID NOs: 1 and 2 showed that these are an exact match. Therefore, the antibody YS5 as recited by Patent 12252746B2 is the same antibody claimed in instant claims 11 and 16 that specifically binds to CD46.
Patent 12252746B2 claims do not specifically recite:-
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM); wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 1);
The method of instant claim 1, wherein the agent is an androgen signaling inhibitor (instant claim 2);
The method of instant claim 2, wherein the agent is enzalutamide or abiraterone (instant claim 3);
The method of instant claim 1, wherein the agent is a SEGRAM (instant claim 4);
The method of instant claim 4, wherein the SEGRAM is dexamethasone (instant claim 5);
The method of instant claim 1, comprising administering an androgen signaling inhibitor and a SEGRAM (instant claim 6);
The method of instant claim 1, wherein the administering comprises administering the agent without the antibody for a time sufficient to induce increased expression of CD46 in cancer cells followed by administering the antibody in an amount sufficient to kill cancer cells in the human (instant claim 7);
The method of instant claim 7, wherein administering the antibody further comprises administering an androgen signaling inhibitor, SEGRAM, or both with the antibody (instant claim 8);
The method of instant claim 7, wherein the time comprises 1-30 days before administering the antibody (instant claim 9);
The method of instant claim 1, wherein the antibody comprises the recited HC CDRs and LC CDRs; and MMAE that is conjugated to said antibody via a maleimidocaproyl-valine-citruline-para-amino benzyloxycarbonyl (mc-vc-PAB) linker (instant claim 16);
The method of instant claim 1, wherein the cancer is androgen receptor negative (instant claim 18);
The method of instant claim 1, wherein the cancer is androgen receptor positive (instant claim 19);
A pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM) (instant claim 21);
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is a Signal Transducer And Activator or Transcription 3 (STAT3) inhibitor, optionally in combination with an androgen signaling inhibitor, a glucocorticoid receptor agonist or modulator (SEGRAM), or both; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35).
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al. are discussed above in the 103 rejections.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of administering to a human with cancer a therapeutically effective amount of a CD46-targeted therapy, wherein the CD46-targeted therapy is a pharmaceutical composition comprising an anti-CD46 antibody comprising a heavy chain variable region comprising a variable heavy (VH) CDR1 that comprises an amino acid sequence of SEQ ID NO: 3, a VH CDR2 that comprises an amino acid sequence of SEQ ID NO: 4, and a VH CDR3 that comprises an amino acid sequence of SEQ ID NO: 5; and a light chain variable region comprising a variable light (VL) CDR 1 that comprises an amino acid sequence of SEQ ID NO: 6, a VL CDR 2 that comprises an amino acid sequence of SEQ ID NO: 7, and a VL CDR 3 that comprises an amino acid sequence of SEQ ID NO: 8; attached to (ii) at least one payload wherein the at least one payload comprises an auristatin which is MMAE as recited by Patent 12252746B2 and an agent that is an androgen signaling inhibitor as taught by Liu et al. because Liu et al. teaches that administration of enzalutamide or abiraterone sensitized cancer cells to the killing of subsequently administered CD46 immunoconjugate. Also, one would predict that administration of the anti-CD46 antibody attached to auristatin or MMAE and the androgen signaling inhibitor would kill more cancer cells than administration of the antibody alone because the CD46 antibody attached to auristatin or MMAE is able to specifically target a cytotoxic moiety to CD46 expressing cancer cells to kill the cells compared to a CD46 antibody alone which does not have any cytotoxic moiety that can mediate killing of cancer cells. Moreover, one would also predict that a combined method of administering the said antibody attached to auristatin or MMAE and the said androgen signaling inhibitor would kill more cancer cells than administration of the antibody attached to auristatin or MMAE alone because Liu et al. teaches that LNCaP-C4-2B cells pre-treated with 10 μM of abiraterone for 7 days followed by washing and treating with CD46-MMAF for an additional 96 hours had enhanced killing of tumor cells with EC50 values dropping from 169 pM to 21 pM when compared to cells without prior exposure to abiraterone, and that neuroendocrine prostate cancer cell line H660 pretreated with 10 μM enzalutamide for 7 days became more sensitive to CD46 ADC post enzalutamide treatment with EC50 dropping by 4-5 fold (paragraphs [0402] and [0671]).
With regards to instant claims 4 and 5, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46, wherein the antibody is attached to auristatin or MMAE as recited by Patent 12252746B2 and an agent that is a SEGRAM as taught by Sundahl et al.; or an agent that is dexamethasone as taught by Wong et al.; or an agent that comprises both an androgen signaling inhibitor and a SEGRAM as taught by Liu et al. and Sundahl et al. respectively, because Sundahl et al. teaches that SEGRAMs have a more restricted GR activity profile that could improve the therapy regimens for cancers by inhibiting proliferation, migration and invasion, and by inducing apoptosis of cancer cells (Abstract and Figure 3), and Wong et al. teaches that dexamethasone upregulated the expression of CD46 on multiple myeloma cells and enhanced the cytotoxicity on said cells in vitro (Background). The advantage of a combined method of Patent 12252746B2 and Sundahl et al. (CD46 immunoconjugate/ADC and SEGRAM) would be to combine different therapeutic agents that can mediate killing of cancer cells through different mechanisms of actions for an enhanced therapeutic method. The advantage of a combined method of Patent 12252746B2 and Wong et al. (CD46 immunoconjugate/ADC and dexamethasone) would be that the administration of dexamethasone can upregulate CD46 expression on cancer cells thus increasing the amount of expressed CD46 on cancer cells and localization of the administered anti-CD46 immunoconjugate/ADC at the cancer site, thereby arriving at a more potent cancer therapeutic method. The advantage of a combined method of Patent 12252746B2, Liu et al. and Sundahl et al. (CD46 immunoconjugate/ADC, androgen signaling inhibitor and SEGRAM) would be to upregulate CD46 expression on cancer cells with the androgen signaling inhibitor to sensitize them to the cytotoxicity of the CD46 immunoconjugate/ADC while combining the effect that SEGRAM has on cancer cells to inhibit proliferation, migration and invasion, thereby killing cancer cells through different mechanisms of actions for an enhanced therapeutic method.
Further, with regards to instant claim 6, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering the combination of an antibody that specifically binds to CD46 that is attached to auristatin or MMAE as recited by Patent 12252746B2, an androgen signaling inhibitor taught by Liu et al. and a SEGRAM that is dexamethasone that is taught by Wong et al. (CD46 immunoconjugate/ADC and enzalutamide or abiraterone and dexamethasone) because Liu et al. teaches that cancer cells had a significant upregulation of surface CD46 expression and became more sensitive to CD46 ADC post abiraterone or enzalutamide treatment (paragraphs [0402] and [0671]) and Wong et al. teaches that dexamethasone upregulated the expression of CD46 of multiple myeloma cells in vitro and enhanced cytotoxicity (Background), therefore administering both enzalutamide or abiraterone and dexamethasone would be expected to provide an additive effect in upregulating the surface expression of CD46 to further enhance sensitization of cancer cells to CD46 immunoconjugate/ADC.
With regards to instant claims 7 and 9, it would have been obvious to administer to a human with cancer the agent that is enzalutamide or abiraterone for 7 days without the antibody and before administering the antibody as recited by Patent 12252746B2, because Liu et al. teaches that significant upregulation of the expression of cell surface CD46 on cancer cell lines was observed when treated with enzalutamide or abiraterone for 7 days which sensitized the cancer cells to antibody ADC cytotoxicity.
With regards to instant claim 8, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further administer an androgen signaling inhibitor with the antibody ADC of Patent 12252746B2, because Liu et al. teaches that administration of enzalutamide or abiraterone alone to cancer cell lines significantly upregulated expression of cell surface CD46 in said cells, therefore continued administration of enzalutamide or abiraterone together with the antibody would provide further upregulated expression of cell surface CD46 on cancer cells when administered to human subjects, thus further enhancing the cytotoxic ability of the treatment method.
With regards to instant claim 16, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to conjugate the anti-CD46 antibody to MMAE as recited by Patent 12252746B2 (Patent claims 1 and 9) via the mc-vc-PAB linker as taught by Liu et al. (Figs. 11-13 and paragraphs [0372] and [0657]) to arrive at an antibody that comprises instant HC and LC CDRs (SEQ ID NOs: 80, 81, 82, 83, 84 and 85) conjugated to MMAE via an mc-vc-PAB linker as recited in instant claim 16.
With regards to instant claims 18, 19 and 20, Liu et al. teaches that the anti-CD46 antibody YS5, the same antibody recited by Patent 12252746B2, was conjugated to MMAF via the mc-vc-PAB linker and showed potent in vitro tumor-killing activities on LNCaP-C4-2B and Du145 metastatic castration resistant prostate cancer cell lines (Figs. 11-13 and paragraphs [0372] and [0657]). As confirmed by Dagvadorj et al., DU145 cells are androgen receptor negative prostate cancer cell lines, whereas LNCaP cells are androgen receptor positive (Pg. 9 paragraph first). Further, Decker et al. confirms that C4-2B is a castration-resistant prostate cancer (CRPC) cell line derived from a LNCaP xenograft that relapsed and metastasized to bone after castration, and that C4-2B is androgen receptor positive (Pg. 10768 column right paragraph first lines 4-11).
With regards to instant claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to combine the anti-CD46 antibody attached to a payload such as auristatin or MMAE comprised in a pharmaceutical composition as recited by Patent 12252746B2 (claims 1, 9 and 10) with an agent that is an androgen signaling inhibitor which can be enzalutamide or abiraterone as taught by Liu et al. (paragraph [0291]). This combination pharmaceutical composition would have the advantage of increased ease of administration of two therapeutic compounds to a human subject in a single composition or in a single administration.
With regards to instant claim 35, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a patented method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46, wherein the antibody is attached to a payload such as auristatin or MMAE as recited by Patent 12252746B2 and an agent that is a STAT3 inhibitor as taught by Zou et al. because Zou et al. teaches that STAT3 plays a critical role in tumor cell survival and immune evasion in the TME, therefore inhibition of STAT3 can lower tumor survival and proliferation, enhance anti-tumor effects of tumor-infiltrating immune cells, and improve the immunosuppressive crosstalk within the TME (Abstract, Pg. 4 column left paragraph second, Fig. 2 and Pg. 14 column left paragraph second). Further, Zou et al. teaches that monotherapy of STAT3 inhibitors have been approved for the treatment of gastric and pancreatic cancer and combination of STAT3 inhibitors with immunotherapy are being studied in the clinical trial setting for metastatic CRC (Pg. 8 column left paragraph third and Table 2 Pg. 9). The advantage of a combined method of Patent 12252746B2 and Zou et al. would be to combine different therapeutic agents that can target the killing of tumors through different mechanisms of actions on both cancer cells and non-cancerous cells within the TME for an enhanced therapeutic method of treating cancer. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said STAT3 inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because the combination therapy uses two agents to kill cancer cells wherein one of the agents can also kill cells in the surrounding TME. The first agent serves to target delivery of a cytotoxic drug through a CD46 antibody that recognizes CD46 that are highly expressed in cancer cells and the second agent inhibits STAT3 that is expressed in cancer and surrounding cells in the TME that are responsible for tumor survival and immune evasion, whereas the method of administering the antibody linked to a cytotoxic effector alone can only effect killing of cancer cells that express CD46.
Fifth NSDP Application No. 18/271205
Claims 1-9, 11-16, 18-21 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 26 of copending Application No. 18/271205 in view of Liu et al. (US20170362330A1 Date Published 2017-12-21), Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072) and Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779).
Copending 18/271205 claim 1 is drawn in part to a method of treating multiple myeloma, lymphoma, acute myeloid leukemia (AML), prostate cancer or metastatic renal cell carcinoma (mRCC) in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent, optionally in combination with a glucocorticoid receptor agonist or modulator (SEGRAM), wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone.
Copending 18/271205 claim 3 is drawn to the method of claim 1, wherein the administering comprises administering the agent without the antibody for a time sufficient to induce increased expression of CD46 in cancer cells followed by administering the antibody in an amount sufficient to kill myeloma cells in the human.
Copending 18/271205 claim 4 is drawn in part to the method of claim 3, wherein administering the antibody further comprises administering an agent, a SEGRAM, or both with the antibody.
Copending 18/271205 claim 5 is drawn to the method of claim 1, wherein the SEGRAM is selected from the group consisting of dexamethasone, prednisone, cortisol, mapracorat, fosdagrocorat (PF-04171327), and dagrocorat.
Copending 18/271205 claim 6 is drawn to the method of claim 3, wherein the time comprises 1-30 days (e.g., 2-20, or 3-15, 5-10 days) before administering the antibody.
Copending 18/271205 claim 7 is drawn in part to the method of claim 1, wherein the antibody comprises heavy chain CDRs 1, 2 and 3 and light chain CDRs 1, 2, and 3 of YS5.
Copending 18/271205 claim 8 is drawn to the method of claim 1, wherein the antibody comprises a heavy chain (HC) variable region that comprises three complementarity determining regions (CDRs): HC CDR1, HC CDR2 and HC CDR3 and a light chain (LC) variable region that comprises three CDRs: LC CDR1, LC CDR2, and LC CDR3, wherein said HC CDR1, HC CDR2, HC CDR3 comprise an amino acid sequence of SEQ ID NO: 80, SEQ ID NO: 81, and SEQ ID NO: 82, respectively, and said LC CDR1, LC CDR2, and LC CDR3 comprise an amino acid sequence of SEQ ID NO: 83, SEQ ID NO: 84, and SEQ ID NO: 85, respectively.
Copending 18/271205 claim 9 is drawn to the method of claim 1, wherein the cytotoxic effector is a chemotherapeutic agent.
Copending 18/271205 claim 10 is drawn to the method of claim 1, wherein the cytotoxic effector is a microtubule inhibitor, a DNA-damaging agent, or a polymerase inhibitor.
Copending 18/271205 claim 11 is drawn to the method of claim 1, wherein the cytotoxic effector is selected from the group consisting of an auristatin, Dolastatin-10, synthetic derivatives of the natural product Dolastatin-10, and maytansine or a maytansine derivative.
Copending 18/271205 claim 12 is drawn to the method of claim 11, wherein the cytotoxic effector is selected from the group consisting of Monomethylauristatin F (MMAF), Auristatin E (AE), Monomethylauristatin E (MMAE), vcMMAE, and vcMMAF.
Copending 18/271205 claim 13 is drawn to the method of claim 1, wherein the antibody comprises a heavy chain (HC) variable region that comprises three complementarity determining regions (CDRs): HC CDR1, HC CDR2 and HC CDR3 and a light chain (LC) variable region that comprises three CDRs: LC CDR1, LC CDR2, and LC CDR3, wherein said HC CDR1, HC CDR2, HC CDR3 comprise an amino acid sequence of SEQ ID NO: 80, SEQ ID NO: 81, and SEQ ID NO: 82, respectively, and said LC CDR1, LC CDR2, and LC CDR3 comprise an amino acid sequence of SEQ ID NO: 83, SEQ ID NO: 84, and SEQ ID NO: 85, respectively; and (b) monomethylauristatin E (MMAE) that is conjugated to said antibody via a maleimidocaproyl-valine-citrulline-para-amino benzyloxycarbonyl (mc-vc-PAB) linker.
Copending 18/271205 claim 14 is drawn to the method of claim 13, wherein the HC comprises SEQ ID NO:86 and the LC comprises SEQ ID NO:87.
Copending 18/271205 claim 15 is drawn in part to a pharmaceutical composition comprising {a) an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent, optionally in combination with a glucocorticoid receptor agonist or modulator (SEGRAM); or (b) an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor, optionally in combination with a glucocorticoid receptor agonist or modulator (SEGRAM).
Copending 18/271205 claim 26 is drawn in part to a method of treating multiple myeloma, lymphoma, acute myeloid leukemia (AML), prostate cancer or metastatic renal cell carcinoma (mRCC) in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent, wherein the agent is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor, optionally in combination with a glucocorticoid receptor agonist or modulator (SEGRAM), wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone.
Alignment of Copending 18/271205 antibody comprising HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as set forth in SEQ ID NOs: 80, 81, 82, 83, 84 and 85, respectively with instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprising instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85, respectively shows the CDRs are an exact match. Moreover, instant specification defines YS5 as an antibody that recognizes CD 46 on the cell surface of prostate cancer cells (paragraph 0053) and defines YS5 as having the VH domain as set forth in instant SEQ ID NO: 1 and the VL domain as set forth in instant SEQ ID NO: 22 (paragraph [0074] Table 1. Novel human anti-CD46 antibody sequences). Comparison of instant SEQ ID NOs: 1 and 22 (which comprises instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as set forth in instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85, respectively) with Copending 18/271205 SEQ ID NOs: 86 and 87 showed that these are an exact match. Therefore, the antibody YS5 as recited by Copending 18/271205 is the same antibody claimed in instant claims 11 and 16 that specifically binds to CD46.
Copending 18/271205 claims do not specifically recite:-
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM); wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 1);
The method of instant claim 1, wherein the agent is an androgen signaling inhibitor (instant claim 2);
The method of instant claim 2, wherein the agent is enzalutamide or abiraterone (instant claim 3);
The method of instant claim 1, comprising administering an androgen signaling inhibitor and a SEGRAM (instant claim 6);
The method of instant claim 1, wherein the cancer is androgen receptor negative (instant claim 18);
The method of instant claim 1, wherein the cancer is androgen receptor positive (instant claim 19);
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al. and Decker et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al. and Decker et al. are discussed above in the 103 rejections.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating cancer in a human, the method comprising administering an antibody that specifically binds to CD46 wherein the antibody is linked to a cytotoxic effector; and an agent, optionally in combination with a glucocorticoid receptor agonist or modulator (SEGRAM) as recited by Copending 18/271205 wherein the agent is an androgen signaling inhibitor as taught by Liu et al. and wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone as recited by Copending 18/271205. This is an example of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143.
With regards to instant claims 18 and 19, Liu et al. teaches that the anti-CD46 antibody YS5, the same antibody recited by Copending 18/271205, was conjugated to MMAF via the mc-vc-PAB linker and showed potent in vitro tumor-killing activities on LNCaP-C4-2B and Du145 metastatic castration resistant prostate cancer cell lines (Figs. 11-13 and paragraphs [0372] and [0657]). As confirmed by Dagvadorj et al., DU145 cells are androgen receptor negative prostate cancer cell lines, whereas LNCaP cells are androgen receptor positive (Pg. 9 paragraph first). Further, Decker et al. confirms that C4-2B is a castration-resistant prostate cancer (CRPC) cell line derived from a LNCaP xenograft that relapsed and metastasized to bone after castration, and that C4-2B is androgen receptor positive (Pg. 10768 column right paragraph first lines 4-11).
This is a provisional nonstatutory double patenting rejection.
Sixth NSDP Application No. 19/204124
Claims 1-9, 11-16, 18-21 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 101, 102, 103, 104, 105, 106, 107, 110, 111 and 114 of copending Application No. 19/204124 in view of Liu et al. (US20170362330A1 Date Published 2017-12-21), Antonarakis et al. (N Engl J Med 2014; 371: 1028-1038), Dagvadorj et al. (Clin Cancer Res. 2008 Oct 1;14(19):6062–6072), Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779), Sundahl et al. (Oncoscience 2016 Jul 27; 3(7-8): 188–202), Wong et al. (Clinical Lymphoma Myeloma and Leukemia Volume 21, Supplement 2, October 2021, Page S164) and Zou et al. (Mol Cancer Vol 19, Article 145, 1-19, 2020).
Copending 19/204124 claim 101 is drawn in part to a method of treating a subject having cancer, the method comprising: administering to the subject an effective amount of an immunoconjugate comprising: an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising an amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising an amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising an amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising an amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising an amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising an amino acid sequence of SEQ ID NO. 231; and an effector comprising Monomethylauristatin E (MMAE) or Monomethylauristatin F (MMAF); wherein the isolated recombinant human antibody specifically binds to cells that express or over express CD46 and are cancer cells.
Copending 19/204124 claim 102 is drawn to the method of claim 101, wherein the cancer cells are selected from the group consisting of ovarian cancer, colorectal cancer, breast cancer, lung cancer, prostate cancer, kidney cancer, pancreatic cancer, mesothelioma, lymphoma, liver cancer, urothelial cancer, stomach cancer, multiple myeloma, glioblastoma multiforme, glioma, neuroblastoma, and cervical cancer.
Copending 19/204124 claim 103 is drawn to the method of claim 101, wherein the cancer cells are prostate cancer cells.
Copending 19/204124 claim 104 is drawn to the method of claim 101, wherein the cancer cells are castration-resistant prostate cancer cells.
Copending 19/204124 claim 105 is drawn to the method of claim 102, wherein the cancer cells are metastatic cancer cells.
Copending 19/204124 claim 106 is drawn to the method of claim 105, wherein the metastatic cancer cells are selected from a bone metastasis, a liver metastasis, a bladder metastasis, and/or a lymph node metastasis.
Copending 19/204124 claim 107 is drawn to the method of claim 101, wherein the cancer cells are solid tumor cells.
Copending 19/204124 claim 110 is drawn to the method of claim 101, wherein the antibody is administered in conjunction with another anti-cancer drug and/or a hormone.
Copending 19/204124 claim 111 is drawn to the method of claim 101, wherein the isolated recombinant human antibody is covalently coupled to the effector through a MC-vc-PAB linker.
Copending 19/204124 claim 114 is drawn to the method of claim 101, wherein the isolated recombinant human antibody comprises a variable light (VL) chain of a YS5 antibody comprising an amino acid sequence of SEQ ID NO:22 and a variable heavy (VH) chain of a YS5 antibody comprising an amino acid sequence of SEQ ID NO:1.
Alignment of Copending 19/204124 anti-CD46 antibody comprising VH CDR1 comprising an amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising an amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising an amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising an amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising an amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising an amino acid sequence of SEQ ID NO. 231 with instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprising instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85, respectively shows the CDRs are an exact match. Moreover, instant specification defines YS5 as an antibody that recognizes CD 46 on the cell surface of prostate cancer cells (paragraph 0053) and defines YS5 as having the VH domain as set forth in instant SEQ ID NO: 1 and the VL domain as set forth in instant SEQ ID NO: 22 (paragraph [0074] Table 1. Novel human anti-CD46 antibody sequences). Comparison of instant SEQ ID NOs: 1 and 22 (which comprises instant HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as set forth in instant SEQ ID NOs: 80, 81, 82, 83, 84 and 85, respectively) with Copending 19/204124 SEQ ID NOs: 1 (VH chain) and 22 (VL chain) showed that these are also an exact match. Therefore, the antibody YS5 as recited by Copending 19/204124 is the same antibody claimed in instant claims 11 and 16 that specifically binds to CD46.
Copending 19/204124 claims do not specifically recite:-
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM); wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 1);
The method of instant claim 1, wherein the agent is an androgen signaling inhibitor (instant claim 2);
The method of instant claim 2, wherein the agent is enzalutamide or abiraterone (instant claim 3);
The method of instant claim 1, wherein the agent is a SEGRAM (instant claim 4);
The method of instant claim 4, wherein the SEGRAM is dexamethasone (instant claim 5);
The method of instant claim 1, comprising administering an androgen signaling inhibitor and a SEGRAM (instant claim 6);
The method of instant claim 1, wherein the administering comprises administering the agent without the antibody for a time sufficient to induce increased expression of CD46 in cancer cells followed by administering the antibody in an amount sufficient to kill cancer cells in the human (instant claim 7);
The method of instant claim 7, wherein administering the antibody further comprises administering an androgen signaling inhibitor, SEGRAM, or both with the antibody (instant claim 8);
The method of instant claim 7, wherein the time comprises 1-30 days before administering the antibody (instant claim 9);
The method of instant claim 1, wherein the cancer is androgen receptor negative (instant claim 18);
The method of instant claim 1, wherein the cancer is androgen receptor positive (instant claim 19);
A pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is an androgen signaling inhibitor and/or a glucocorticoid receptor agonist or modulator (SEGRAM) (instant claim 21);
A method of treating cancer in a human, the method comprising administering to the human: an antibody that specifically binds to CD46, wherein the antibody is linked to a cytotoxic effector; and an agent that is a Signal Transducer And Activator or Transcription 3 (STAT3) inhibitor, optionally in combination with an androgen signaling inhibitor, a glucocorticoid receptor agonist or modulator (SEGRAM), or both; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35).
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Sundahl et al., Wong et al. and Zou et al. are discussed above in the 103 rejections.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject having cancer, the method comprising: administering to the subject an effective amount of an immunoconjugate comprising: an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising an amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising an amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising an amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising an amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising an amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising an amino acid sequence of SEQ ID NO. 231; coupled via the MC-vc-PAB linker to an effector comprising Monomethylauristatin E (MMAE) or Monomethylauristatin F (MMAF) as recited by Copending 19/204124 and an agent that is an androgen signaling inhibitor as taught by Liu et al. because Liu et al. teaches that administration of enzalutamide or abiraterone sensitized cancer cells to the killing of subsequently administered CD46 immunoconjugate. Also, one would predict that administration of the antibody linked to a cytotoxic effector and the androgen signaling inhibitor kills more cancer cells than administration of the antibody alone because the CD46 antibody linked to a cytotoxic effector is able to specifically target a cytotoxic moiety to CD46 expressing cancer cells to kill the cells compared to a CD46 antibody alone which does not have any cytotoxic moiety that can mediate killing of cancer cells. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said androgen signaling inhibitor kills more cancer cells than administration of the antibody linked to a cytotoxic effector alone because Liu et al. teaches that LNCaP-C4-2B cells pre-treated with 10 μM of abiraterone for 7 days followed by washing and treating with CD46-MMAF for an additional 96 hours had enhanced killing of tumor cells with EC50 values dropping from 169 pM to 21 pM when compared to cells without prior exposure to abiraterone, and that neuroendocrine prostate cancer cell line H660 pretreated with 10 μM enzalutamide for 7 days became more sensitive to CD46 ADC post enzalutamide treatment with EC50 dropping by 4-5 fold (paragraphs [0402] and [0671]).
With regards to instant claims 4 and 5, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject having cancer, the method comprising: administering to the subject an effective amount of an immunoconjugate comprising: an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising an amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising an amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising an amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising an amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising an amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising an amino acid sequence of SEQ ID NO. 231; and an effector comprising Monomethylauristatin E (MMAE) or Monomethylauristatin F (MMAF) as recited by Copending 19/204124 and an agent that is a SEGRAM as taught by Sundahl et al.; or an agent that is dexamethasone as taught by Wong et al.; or an agent that comprises both an androgen signaling inhibitor and a SEGRAM as taught by Liu et al. and Sundahl et al. respectively, because Sundahl et al. teaches that SEGRAMs have a more restricted GR activity profile that could improve the therapy regimens for cancers by inhibiting proliferation, migration and invasion, and by inducing apoptosis of cancer cells (Abstract and Figure 3), and Wong et al. teaches that dexamethasone upregulated the expression of CD46 on multiple myeloma cells and enhanced the cytotoxicity on said cells in vitro (Background). The advantage of a combined method of Copending 19/204124 and Sundahl et al. (CD46 immunoconjugate/ADC and SEGRAM) would be to combine different therapeutic agents that can mediate killing of cancer cells through different mechanisms of actions for an enhanced therapeutic method. The advantage of a combined method of Copending 19/204124 and Wong et al. (CD46 immunoconjugate/ADC and dexamethasone) would be that the administration of dexamethasone can upregulate CD46 expression on cancer cells thus increasing the amount of expressed CD46 on cancer cells and localization of the administered anti-CD46 immunoconjugate/ADC at the cancer site, thereby arriving at a more potent cancer therapeutic method. The advantage of a combined method of Copending 19/204124, Liu et al. and Sundahl et al. (CD46 immunoconjugate/ADC, androgen signaling inhibitor and SEGRAM) would be to upregulate CD46 expression on cancer cells with the androgen signaling inhibitor to sensitize them to the cytotoxicity of the CD46 immunoconjugate/ADC while combining the effect that SEGRAM has on cancer cells to inhibit proliferation, migration and invasion, thereby killing cancer cells through different mechanisms of actions for an enhanced therapeutic method.
Further, with regards to instant claim 6, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject having cancer, the method comprising: administering to the subject an effective amount of an immunoconjugate comprising: an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising an amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising an amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising an amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising an amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising an amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising an amino acid sequence of SEQ ID NO. 231; and an effector comprising Monomethylauristatin E (MMAE) or Monomethylauristatin F (MMAF) as recited by Copending 19/204124, an androgen signaling inhibitor taught by Liu et al. and a SEGRAM that is dexamethasone that is taught by Wong et al. (CD46 immunoconjugate/ADC and enzalutamide or abiraterone and dexamethasone) because Liu et al. teaches that cancer cells had a significant upregulation of surface CD46 expression and became more sensitive to CD46 ADC post abiraterone or enzalutamide treatment (paragraphs [0402] and [0671]) and Wong et al. teaches that dexamethasone upregulated the expression of CD46 of multiple myeloma cells in vitro and enhanced cytotoxicity (Background), therefore administering both enzalutamide or abiraterone and dexamethasone would be expected to provide an additive effect in upregulating the surface expression of CD46 to further enhance sensitization of cancer cells to CD46 immunoconjugate/ADC.
With regards to instant claims 7 and 9, it would have been obvious to administer to a human with cancer the agent that is enzalutamide or abiraterone for 7 days without the antibody and before administering the antibody conjugated to MMAE or MMAF as recited by Copending 19/204124, because Liu et al. teaches that significant upregulation of the expression of cell surface CD46 on cancer cell lines was observed when treated with enzalutamide or abiraterone for 7 days which sensitized the cancer cells to antibody ADC cytotoxicity.
With regards to instant claim 8, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further administer an androgen signaling inhibitor with the antibody coupled to MMAE or MMAF of Copending 19/204124, because Liu et al. teaches that administration of enzalutamide or abiraterone alone to cancer cell lines significantly upregulated expression of cell surface CD46 in said cells, therefore continued administration of enzalutamide or abiraterone together with the antibody would provide further upregulated expression of cell surface CD46 on cancer cells when administered to human subjects, thus further enhancing the cytotoxic ability of the treatment method.
With regards to instant claims 18 and 19, Liu et al. teaches that the anti-CD46 antibody YS5, the same antibody recited by Copending 19/204124, was conjugated to MMAF via the mc-vc-PAB linker and showed potent in vitro tumor-killing activities on LNCaP-C4-2B and Du145 metastatic castration resistant prostate cancer cell lines (Figs. 11-13 and paragraphs [0372] and [0657]). As confirmed by Dagvadorj et al., DU145 cells are androgen receptor negative prostate cancer cell lines, whereas LNCaP cells are androgen receptor positive (Pg. 9 paragraph first). Further, Decker et al. confirms that C4-2B is a castration-resistant prostate cancer (CRPC) cell line derived from a LNCaP xenograft that relapsed and metastasized to bone after castration, and that C4-2B is androgen receptor positive (Pg. 10768 column right paragraph first lines 4-11).
With regards to instant claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to combine the anti-CD46 antibody conjugated to a cytotoxic effector as recited by Copending 19/204124 with an agent that is an androgen signaling inhibitor which can be enzalutamide or abiraterone as taught by Liu et al. (paragraph [0291]) to be comprised in a pharmaceutical composition as taught by Liu et al. This combination pharmaceutical composition would have the advantage of increased ease of administration of two therapeutic compounds to a human subject in a single composition or in a single administration.
With regards to instant claim 35, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject having cancer, the method comprising: administering to the subject an effective amount of an immunoconjugate comprising: an isolated recombinant human antibody that specifically binds CD46 comprising VH CDR1 comprising an amino acid sequence of SEQ ID NO. 80, VH CDR2 comprising an amino acid sequence of SEQ ID NO. 82, VH CDR3 comprising an amino acid sequence of SEQ ID NO. 84, VL CDR1 comprising an amino acid sequence of SEQ ID NO. 227, VL CDR2 comprising an amino acid sequence of SEQ ID NO. 229, and VL CDR3 comprising an amino acid sequence of SEQ ID NO. 231; and an effector comprising Monomethylauristatin E (MMAE) or Monomethylauristatin F (MMAF) as recited by Copending 19/204124 and an agent that is a STAT3 inhibitor as taught by Zou et al. because Zou et al. teaches that STAT3 plays a critical role in tumor cell survival and immune evasion in the TME, therefore inhibition of STAT3 can lower tumor survival and proliferation, enhance anti-tumor effects of tumor-infiltrating immune cells, and improve the immunosuppressive crosstalk within the TME (Abstract, Pg. 4 column left paragraph second, Fig. 2 and Pg. 14 column left paragraph second). Further, Zou et al. teaches that monotherapy of STAT3 inhibitors have been approved for the treatment of gastric and pancreatic cancer and combination of STAT3 inhibitors with immunotherapy are being studied in the clinical trial setting for metastatic CRC (Pg. 8 column left paragraph third and Table 2 Pg. 9). The advantage of a combined method of Copending 19/204124 and Zou et al. would be to combine different therapeutic agents that can target the killing of tumors through different mechanisms of actions on both cancer cells and non-cancerous cells within the TME for an enhanced therapeutic method of treating cancer. Moreover, one would also predict that a combined method of administering the said antibody linked to a cytotoxic effector and the said STAT3 inhibitor would kill more cancer cells than administration of the antibody linked to a cytotoxic effector alone because the combination therapy uses two agents to kill cancer cells wherein one of the agents can also kill cells in the surrounding TME. The first agent serves to target delivery of a cytotoxic drug through a CD46 antibody that recognizes CD46 that are highly expressed in cancer cells and the second agent inhibits STAT3 that is expressed in cancer and surrounding cells in the TME that are responsible for tumor survival and immune evasion, whereas the method of administering the antibody linked to a cytotoxic effector alone can only effect killing of cancer cells that express CD46.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642