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 .
Response to Amendments / Status of Claims
The Amendments and Remarks filed 04/13/2026 in response to the Office Action of 01/22/2026 are acknowledged and have been entered.
Claims 1-9, 11-16, 18-21, 35 and 67-70 are pending
Claims 1, 5, 6, 8, 9, 11, 16, 21 and 35 have been amended by Applicant.
Claims 65-70 are newly added by Applicant.
Claims 1-9, 11-16, 18-21, 35 and 67-70 are currently under examination on the merits in the instant Office Action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Office Action contains new rejections.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/07/2026 and 05/08/2026 are being considered by the examiner.
Claim Objections - Withdrawn
Applicant has amended claims 9, 11 and 16 and so the objections have been withdrawn:
Claim Rejections - 35 USC § 112(b) - Withdrawn
Given that Applicant has now amended claims 1, 21, and 35 to delete the word “(SEGRAM)” and amended claim 5 to delete the word “SEGRAM”, the 112(b) rejections of these claims are hereby withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
The rejection of claims 1-3, 7-9, 11-16 and 18-21 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 (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779) is withdrawn. This is because some claims have been cancelled, claim 1, 21 and 35 have been amended and new claims have been added.
The rejection of claims 1-9, 11-16 and 18-21 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 (Clinical Lymphoma Myeloma and Leukemia Volume 21, Supplement 2, October 2021, Page S164) is withdrawn. This is because some claims have been cancelled, claim 1, 21 and 35 have been amended and new claims have been added. In addition, the reference of Wong et al. was published in October 2021 which is after the effective filing date of the claimed invention of January 7, 2021.
Claim Rejections - Double Patenting - Withdrawn
First NSDP Patent US 10533056
The provisional nonstatutory double patenting rejection of claims 1-9, 11-16, 18-21 and 35 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). This is because some claims have been cancelled, independent claims 1, 21 and 35 have been amended and new claims have been added. In addition, the reference of Wong et al. was published in October 2021 which is after the effective filing date of the claimed invention of January 7, 2021.
Second NSDP Patent US 11434301
The provisional nonstatutory double patenting rejection of claims 1-9, 11-16, 18-21 and 35 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). This is because some claims have been cancelled, independent claims 1, 21 and 35 have been amended and new claims have been added. In addition, the reference of Wong et al. was published in October 2021 which is after the effective filing date of the claimed invention of January 7, 2021.
Third NSDP Patent US 12325755
The provisional nonstatutory double patenting rejection of claims 1-9, 11-16, 18-21 and 35 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). This is because some claims have been cancelled, independent claims 1, 21 and 35 have been amended and new claims have been added. In addition, the reference of Wong et al. was published in October 2021 which is after the effective filing date of the claimed invention of January 7, 2021.
Fourth NSDP Patent US 12252746B2
The provisional nonstatutory double patenting rejection of claims 1-9, 11-16, 18-21 and 35 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). This is because some claims have been cancelled, independent claims 1, 21 and 35 have been amended and new claims have been added. In addition, the reference of Wong et al. was published in October 2021 which is after the effective filing date of the claimed invention of January 7, 2021.
Fifth NSDP Application No. 18/271205
The provisional nonstatutory double patenting rejection of claims 1-9, 11-16, 18-21 and 35 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). This is because some claims have been cancelled, independent claims 1, 21 and 35 have been amended and new claims have been added. In addition, the reference of Wong et al. was published in October 2021 which is after the effective filing date of the claimed invention of January 7, 2021.
Sixth NSDP Application No. 19/204124
The provisional nonstatutory double patenting rejection of claims 1-9, 11-16, 18-21 and 35 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). This is because some claims have been cancelled, independent claims 1, 21 and 35 have been amended and new claims have been added. In addition, the reference of Wong et al. was published in October 2021 which is after the effective filing date of the claimed invention of January 7, 2021.
Claim Rejections - Maintained
Claim Rejections - 35 USC § 103 - Maintained
Claim 35 remains 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 of the Non-Final Office Action dated 01/22/2026 (Pg 5-9).
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 including prostate cancer cell lines (see specifically Agents “60”, “CPA-7”, “C48” and “MMPP” that are small molecule direct inhibitors). They further teach in Table 2 (Pg. 9-10), STAT3 inhibitors that are currently in on-going clinical trials including for the treatment of bone-metastatic, castration-resistant prostate cancer (see NCT01074138). They further teach targeting STAT3 in combination with cancer immunotherapy for enhanced anti-tumor effects and reduced drug resistance as exemplified by BBI608 that has been combined with immune checkpoint inhibitors nivolumab or pembrolizumab in clinical trials for metastatic CRC (Fig. 3 Pg. 11-12 and 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 STAT3 inhibitors have been studied in clinical trials for the treatment of prostate cancer Table 2 (Pg. 9-10) and 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 on 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.
Response to Arguments
In the reply of 04/13/2026, Applicant cites that they have identified that combining an anti-CD46 antibody linked to a cytotoxic effector with a STAT3 inhibitor is highly effective in the treatment of cancer. The combination of an anti-CD46 antibody and a STAT3 inhibitor for the treatment of cancer was arrived at following the observation of a surprising technical effect occurring as a result of the interaction between an anti-CD46 antibody and a STAT3 inhibitor. In more detail, as described in Example 2 of the instant application, experiments were performed to treat the prostate cancer cell line 22Rv1 with the exemplary STAT3 inhibitor, C188- 9. It was revealed that the STAT3 inhibitor increased CD46 cell surface expression (see, FIG. 11).
Applicant also cites that as described at paragraph [0164], this finding was surprising since: STAT3 has been reported to bind directly to the promoter region of the CD46 gene and upregulate CD46 expression. However, surprisingly, at lower concentrations a STAT3 inhibitor can up-regulate CD46 expression. Thus, the inventors arrived at the combination of an antibody that specifically binds to CD46 that is linked to a cytotoxic effector with a STAT3 inhibitor for treating cancer, wherein the administration of the antibody and the STAT3 inhibitor kills more cancer cells than administration of the antibody alone (as defined in claim 35).
Applicant further cites that contrary to the Examiner's allegation, one of ordinary skill in the art would not have been motivated to combine an anti-CD46 antibody linked to a cytotoxic effector with a STAT3 inhibitor as presently claimed and reasonably expect that such combination would kill more cancer cells than administration of the antibody alone. For example, Buettner et al. (Mol. Cancer Res., 5(8):823-832 (2007); submitted in an Information Disclosure Statement dated October 21, 2025) explicitly teaches that inhibition of STAT3 blocks CD46 cell surface protein expression (see, page 826, title of 3rd paragraph). Buettner et al. further proposes down-regulation of complement regulatory proteins (such as CD46) on tumor cells as a desirable strategy in combination with monoclonal antibody cancer immunotherapy (see, page 829, left column, 3rd paragraph). Thus, the skilled person would have been disincentivized to combine a STAT3 inhibitor with an anti- CD46 antibody as they would have expected that doing so would reduce the concentration of CD46 molecules on the cell surface, thereby diminishing the efficacy of the anti-CD46 antibody. For at least the foregoing reasons, Applicant submits that the prior art teaches away from the method recited in claim 35. Indeed, one of ordinary skill in the art would not have been motivated to combine Liu et al. and Zou et al. with a reasonable expectation of success as alleged by the Examiner in view of the finding by Buettner et al. that "activated STAT3 is required for CD46 expression in cancer cells" (see, page 829, left column, 4th paragraph; emphasis added). In short, neither the cited references nor the prior art in general (as evidenced by Buettner et al.) render obvious the unexpected finding by the inventors that use of a STAT3 inhibitor increases cell surface expression of CD46, thereby allowing for greater efficacy of anti-CD46 antibody therapy.
Examiner’s Response: The arguments found in the Reply of 04/13/2026 have been carefully considered but are not deemed persuasive. Instant claim 35 recites 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 of Transcription 3 (STAT3) inhibitor; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone.
As recited, claim 35 does not limit the claimed STAT3 inhibitor to one that specifically functions at a specific concentration with the ability to increase the expression of CD46 on cancer cells. This is because the agent of “STAT3 inhibitor” has far wider meaning and encompasses agents other than the exemplary C188- 9 that was as stated by the Applicant in the arguments. In fact, as Applicant cited, only at lower concentrations of C188-9 was it observed that this particular STAT3 inhibitor was able to upregulate CD46 expression, a finding which is unexpected and in contrast to previous findings that reported that STAT3 binding to the promoter region of CD46 gene upregulates CD46 expression. In other words, it would have been expected that a STAT3 agonist would have induced upregulation of CD46 expression. Applicant is remined that “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). In the instant case, asserted unexpected results involve a specific inhibitor at specific concentrations not required by a claim.
In addition, regarding Applicant's argument that the prior art of Buettner et al. teaches away for the method recited in claim 35 and that one of ordinary skill in the art would not have been motivated to combine Liu et al. and Zou et al. with a reasonable expectation of success as alleged by the Examiner in view of the finding by Buettner et al. that "activated STAT3 is required for CD46 expression in cancer cells" (see, page 829, left column, 4th paragraph; emphasis added); and neither the cited references nor the prior art in general (as evidenced by Buettner et al.) render obvious the unexpected finding by the inventors that use of a STAT3 inhibitor increases cell surface expression of CD46, thereby allowing for greater efficacy of anti-CD46 antibody therapy, , Buettner et al. does not “teach away” from the claim. Buettner et al. does not criticize, discredit, or otherwise discourage the claimed method. Further, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. Further, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See MPEP 2144.
Here, it would have been obvious before the filing of the instant application to one of ordinary skill in this art to use STAT3 inhibitors as taught by Zou et al., which can have different mechanisms of action and different effects on tumor cells as well as the TME that have been exploited for killing of cancer cells either alone or in combination with other agents for a variety of cancers including prostate cancer. The motivation would be to add to the anti-CD46-ADC as taught by Liu et al., an agent that is a STAT3 inhibitor as taught by Zou et al. that has a different mechanism of action to that of the anti-CD46-ADC, for the advantage of using a multi-agent approach that comprises an immunoconjugate and a small molecule drug, to target cancer cells such that the combination of anti-CD46-ADC and STAT3 inhibitor kills more cancer cells than administration of the antibody alone.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Similarly, it is obvious to combine two or more agents taught to treat prostate cancer in the prior art separately into one treatment regimen to treat the same disease.
New Rejections
Claim Rejections - 35 USC § 112(b) - New
Claim 14 recites the limitation "synthetic derivatives of the natural product Dolastatin-10” in lines 2-3. There is insufficient antecedent basis for " the natural product Dolastatin-10” in the claim. This rejection can be obviated by amending the claim to recite “synthetic derivatives of Dolastatin-10 natural product” or “synthetic derivatives of Dolastatin-10”.
Claim Rejections - 35 USC § 112(a) – New (First)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 7-9 and 68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the Claimed Genus
In the instant case, instant claims 7-9 are inclusive of a genus of a glucocorticoid receptor agonist or modulator that can induce increased expression of CD46 in cancer cells. Instant claim 68 is inclusive of a genus of a STAT3 inhibitor that can induce increased expression of CD46 in cancer cells.
Summary of Species Disclosed in the Specification
The specification at most discloses one species of a glucocorticoid receptor agonist or modulator which is dexamethasone (dex) that upregulates CD46 in mCRPC cells at 10 µM (paragraphs [0161] and [0165] and FIG. 9). In addition, the specification at most discloses one species of a STAT3 inhibitor which is C188-9 that upregulates CD46 expression in a concentration dependent manner in prostate cancer cells, wherein at low or mid concentrations (2.5 and 5 10 µM), C188-9 stimulates CD46 cell surface expression while at high concentrations of >10 M, C188-9 inhibits CD46 expression on cancer cells (paragraph [0164] and FIGs. 11-13).
Therefore, the written description in this case only reasonably sets forth one species of a glucocorticoid receptor agonist or modulator which is dexamethasone that upregulates CD46 in mCRPC cells and one species of a STAT3 inhibitor which is C188-9 that upregulates CD46 expression in a concentration dependent manner in prostate cancer cells in the instant specification. The specification does not disclose, and the art does not teach, the genus of glucocorticoid receptor agonist or modulator or STAT3 inhibitor as is broadly encompassed in the claims.
State of the Prior Art
The state of the art teaches that CD46 can be targeted for the treatment of both adenocarcinoma and neuroendocrine prostate cancers (Su et al., see Title and Abstract). Su et al. also teaches that androgen signaling inhibitors such as abiraterone and enzalutamide, when used to treat mCRPC cells, causes upregulation of cell surface CD46 expression (Abstract and Figure 6). Moreover, the state of the art teaches that a set of anti-STAT-3 oligonucleotides inhibitors decreased the expression of STAT3-regulated gene product of CD46 (Lewis et al., see Figure 4). It means that Lewis et al. teaches that STAT3 inhibitors had the opposite effect to what is claimed in instant claim 68. Further, the state of the art is lacking in the teachings of the effect of glucocorticoid receptor agonist or modulators on the expression of CD46. Therefore, there is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of which glucocorticoid receptor agonist or modulator; or which STAT3 inhibitor, can induce increased expression of CD46 in cancer cells.
Guidance on When Disclosed Species are Representative of the Claimed Genus
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor' s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.' ”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”). The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim' s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Further, Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). Even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification that discloses only one species provides neither a representative number of species glucocorticoid receptor agonist or modulator; or number of species STAT3 inhibitor, that encompass the genus of glucocorticoid receptor agonists or modulators; or the genus of STAT3 inhibitors, that is capable of inducing increased expression of CD46 in cancer cells, nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
Conclusion
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus can be highly variant, the disclosure of only one species of glucocorticoid receptor agonist or modulator, and only one species of STAT3 inhibitor, found in the specification is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as is broadly claimed. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims without any variability.
Claim Rejections - 35 USC § 112(a) – New (Second)
Claims 7-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the agent that is a glucocorticoid receptor agonist or modulator that is dexamethasone which is capable of inducing increased expression of CD46 in cancer cells, does not reasonably provide enablement for just any glucocorticoid receptor agonist or modulator that is capable of inducing increased expression of CD46 in cancer cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 68 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor that is C188-9 which is capable of inducing increased expression of CD46 in cancer cells, does not reasonably provide enablement for just any STAT3 inhibitor that is capable of inducing increased expression of CD46 in cancer cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
The instant claims 7-8 are drawn to any glucocorticoid receptor agonist or modulator that is capable of inducing increased expression of CD46 in cancer cells, while instant claim 68 is drawn to any STAT3 inhibitor that is capable of inducing increased expression of CD46 in cancer cells.
The nature of the invention
The above claims are drawn to agents that are either (i) a glucocorticoid receptor agonist or modulator; or (ii) a STAT3 inhibitor, that can induce increased expression of CD46 in cancer cells.
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The breadth of the claims
The claims are broad in that they encompass any glucocorticoid receptor agonist or modulator or any STAT3 inhibitor.
The amount of direction provided by the inventor/the existence of working examples
The specification at most discloses one species of a glucocorticoid receptor agonist or modulator which is dexamethasone (dex) that upregulates CD46 in mCRPC cells at 10 µM (paragraphs [0161] and [0165] and FIG. 9). In addition, the specification at most discloses one species of a STAT3 inhibitor which is C188-9 that upregulates CD46 expression in a concentration dependent manner in prostate cancer cells, wherein at low or mid concentrations (2.5 and 5 µM), C188-9 stimulates CD46 cell surface expression while at high concentrations of >10 µM, C188-9 inhibits CD46 expression on cancer cells (paragraph [0164] and FIGs. 11-13).
However, these teachings do not enable the full breadth of the claims because any glucocorticoid receptor agonist or modulator or any STAT3 inhibitor would not predictably be capable of upregulating the expression of CD46 in cancer cells. Specifically, the instant specification teaches that STAT3 has been reported to bind directly to the promoter region of the CD46 gene and upregulate CD46 expression (paragraph [0164]), and only the STAT3 inhibitor of C188-9, at low or mid concentrations of 2.5 and 5 pM, is able to stimulate CD46 expression on cancer cells.
The state of the art/the level of predictability in the art
The state of the art teaches that CD46 can be targeted for the treatment of both adenocarcinoma and neuroendocrine prostate cancers (Su et al. JCI Insight. 2018 Sep 6;3(17):e121497, see Title and Abstract). Su et al. also teaches that androgen signaling inhibitors such as abiraterone and enzalutamide, when used to treat mCRPC cells, causes upregulation of cell surface CD46 expression (Abstract and Figure 6). Moreover, the state of the art teaches that a set of anti-STAT-3 oligonucleotides inhibitors decreased the expression of STAT3-regulated gene product of CD46 (Lewis et al. Mol Cancer Ther. 2008 Jun;7(6):1543-50, see Figure 4). It means that Lewis et al. teaches that STAT3 inhibitors had the opposite effect to what is claimed in instant claim 68. Further, the state of the art is lacking in the teachings of the effect of glucocorticoid receptor agonist or modulators on the expression of CD46. Therefore, there is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of which glucocorticoid receptor agonist or modulator; or which STAT3 inhibitor, can induce increased expression of CD46 in cancer cells.
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Not knowing and absent further experimentation, which glucocorticoid receptor agonist or modulator; or which STAT3 inhibitor can upregulate CD46 expression on cancer cells, leads to one having no predictability or expectation of success for the function of any given glucocorticoid receptor agonist or modulator; or any given STAT3 inhibitor, to induce increased expression of CD46 in cancer cells. Such random experimentation to identify at a later time which glucocorticoid receptor agonist or modulator; or which STAT3 inhibitor, and at which concentrations is able to upregulate CD46 expression, and is embraced by Applicant’s claims is undue experimentation.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict or otherwise envisage (1) which glucocorticoid receptor agonist or modulator other than dexamethasone at 10 µM; or (2) which STAT3 inhibitor other than C188-9 at 2.5 µM or 5 µM, can induce increased expression of CD46 in cancer cells.
Examiner confirms that Applicant is enabled for the glucocorticoid receptor agonist or modulator of dexamethasone at 10 µM and the STAT3 inhibitor of C188-9 at 2.5 µM or 5 µM, as agents that can induce increased expression of CD46 in cancer cells.
Conclusion
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to any glucocorticoid receptor agonist or modulator or any STAT3 inhibitor, and Applicant has not enabled just any glucocorticoid receptor agonist or modulator or just any STAT3 inhibitor because it has not been shown that any glucocorticoid receptor agonist or modulator or any STAT3 inhibitor at which concentrations can induce increased expression of CD46 in cancer cells.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require an unreasonable amount of experimentation by one of skill in the art to determine with any predictability, that the method would function as claimed. This is because the art teaches that androgen signaling inhibitors and STAT3 can induce CD46 expression, but does not teach glucocorticoid receptor agonists or modulators or STAT3 inhibitors can induce CD46 expression in cancer cells and therefore, one would be burdened with undue experimentation to perform the method of the instant claims as broadly as they are currently claimed.
Enablement can be met by amending claims 7-8 to recite explicitly the glucocorticoid receptor agonist or modulator of dexamethasone, at which specific concentrations, that can induce expression of CD46 in cancer cells. Further, enablement can be met by amending claim 68 to recite explicitly the STAT3 inhibitor of C188-9, at which specific concentrations, that can induce expression of CD46 in cancer cells.
Claim Rejections - 35 USC § 103 (First) - New
Claims 1, 5, 6, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 65, 66 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), Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779) and Dorff and Crawford (Annals of Oncology, 24, 31-38; January 2013).
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; and 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 and had enhanced killing of tumor cells 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]). They further teach that neuroendocrine prostate cancer cell line H660 incubated with 10 μM enzalutamide for 7 days was observed to have a significant upregulation of cell surface CD46 accompanied by increased sensitivity to CD46-ADC cytotoxicity post enzalutamide treatment (FIG. 42 and 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, wherein enzalutamide or abiraterone
Liu et al. also teaches in Fig. 1A the VH framework and CDR regions for antibody YS5 (SEQ ID NO:1), and in Fig. 1B the VL framework and CDR regions for antibody 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, 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]).
Liu et al. 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 teach administering said antibody that specifically binds to CD46 that is linked to a cytotoxic effector and an agent that is a glucocorticoid receptor agonist or modulator; wherein administration of said antibody linked to a cytotoxic effector and a glucocorticoid receptor agonist or modulator kills more cancer cells than administration of the antibody alone.
Liu et al. also does not specifically teach the method of instant claim 5, wherein the glucocorticoid receptor agonist or modulator is prednisone.
However, these deficiencies are made up in the teachings of Dorff and Crawford.
Dorff and Crawford teaches the use of corticosteroids in combination with FDA approved drugs for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). They teach that corticosteroids are commonly used in the treatment of cancer, primarily for their anti-inflammatory activities because they can mimic endogenous cortisol thus activating the glucocorticoid receptor to up-regulate expression of anti-inflammatory proteins and down-regulate expression of proinflammatory proteins (Pg 31 right column first full paragraph; Section: Corticosteroids in cancer). They also teach that in prostate cancer, corticosteroids also may have a direct effect on tumor-induced pain thus are used both to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms such as improve appetite to reduce weight loss (Pg 31 right column first and second full paragraphs; Section: Corticosteroids in cancer). They further teach the significant improvement of appetite with dexamethasone in advanced gastrointestinal cancer patients and the concomitant use of dexamethasone with docetaxel in mCRPC patients (Pg 32 left column lines 8-12 and Pg 34 left column lines 1-5). Even further, they teach in Table 3 and Figure 1, various therapeutic regimens and options comprising prednisone that have been commonly used for mCRPC.
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 comprising administering to the human an antibody that specifically binds to CD46 that is linked to a cytotoxic effector as taught by Liu et al. and an agent that is a glucocorticoid receptor agonist or modulator such as dexamethasone and prednisone as taught by Dorff and Crawford because Liu et al. teaches that the antibody YS5, an anti-CD46 antibody, when used alone can inhibit growth and/or proliferation of prostate cancer cells, or when coupled to drugs as an immunoconjugate can provide efficient and specific delivery of the cytotoxic effector (paragraph [0514]), and because Dorff and Crawford teaches that glucocorticoid receptor agonists or modulators including prednisone are commonly used in combination therapies for treating cancers and specifically for prostate cancer to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms, and because combination therapy of other drugs with prednisone has been shown to provide progression-free survival advantage in mCRPC (Pg 31 right column first and second full paragraphs and Pg 35 right column third full paragraph lines 18-22). In addition, one would predict that administration of said antibody linked to a cytotoxic effector and the glucocorticoid receptor agonist or modulator would kill more cancer cells than administration of the antibody alone because said CD46 antibody linked to a cytotoxic effector can specifically target a cytotoxic moiety to CD46 expressing cancer cells for cell killing when compared to said CD46 antibody alone which can only inhibit proliferation of cancer cells. 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 instant claims 6 and 65, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Liu et al. and Dorff and Crawford above, wherein the method further comprises administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) glucocorticoid receptor agonist or modulator; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC. This is an example of (A) Combining prior art elements according to known methods to yield predictable results. See MPEP 2143.
With regards to instant 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 instant claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as taught by Liu et al. (paragraph [0284]) and an agent that is a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford. 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. Further, with regards to instant claim 66, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making a pharmaceutical composition comprising said anti-CD46 antibody conjugated to a cytotoxic effector and an agent that is a glucocorticoid receptor agonist or modulator as taught by Liu et al. and Dorff and Crawford respectively as described above, and further combining an androgen signaling inhibitor of enzalutamide or abiraterone also as taught by Liu et al. into the pharmaceutical composition. This combination pharmaceutical composition would have the advantage of increased ease of administration of three 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) - New
Claims 35, 67, 69 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20170362330A1 Date Published 2017-12-21) and 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 new 103 rejection above. While the teachings of Liu et al. and Zou et al. have been discussed in the maintained 103 rejection above.
Liu et al. and Zou et al. do not specifically teach the method of instant claim 35, further comprising administering an androgen signaling inhibitor.
Liu et al. and Zou et al. also do not specifically teach the method of instant claim 35, wherein the cancer is prostate cancer.
Liu et al. and Zou et al. further do not specifically teach a pharmaceutical composition comprising: an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the 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., further comprising administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) STAT3 inhibitor; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC. This is an example of (A) Combining prior art elements according to known methods to yield predictable results. See MPEP 2143.
With regards to instant claim 69, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human comprising administering to the human an antibody that specifically binds to CD46 that 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., wherein the cancer is prostate cancer as taught by both Liu et al. and Zou et al. because Liu et al. teaches that CD46 is over expressed on prostate cancer cells and Zou et al. teaches that STAT3 inhibitors have been studied in pre-clinical prostate cancer models and that STAT3 inhibitors have been studied in clinical trials for the treatment of (Tables 1 and 2). 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 instant claim 70, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as taught by Liu et al. and an agent that is a STAT3 inhibitor as taught by Zou 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. This is an example of (A) Combining prior art elements according to known methods to yield predictable results. See MPEP 2143.
Double Patenting - New
First NSDP Patent US 10533056 (New)
Claims 1, 5, 6, 11-16, 18-21, 35, 65-67 and 69-70 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), Dorff and Crawford (Annals of Oncology, 24, 31-38; January 2013) 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 a glucocorticoid receptor agonist or modulator; 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 glucocorticoid receptor agonist or modulator is dexamethasone or prednisone (instant claim 5);
The method of instant claim 1, further comprising administering an androgen signaling inhibitor (instant claim 6);
The method of instant claim 1, wherein the antibody comprises the recited HC CDRs and LC CDRs; and MMAE is the cytotoxic effector 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 a glucocorticoid receptor agonist or modulator (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; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35);
The method of instant claim 6, wherein the androgen signaling inhibitor is enzalutamide or abiraterone (instant claim 65);
The pharmaceutical composition of instant claim 21, wherein the pharmaceutical composition further comprises an androgen signaling inhibitor (instant claim 66);
The method of instant claim 35, further comprising administering an androgen signaling inhibitor (instant claim 67);
The method of instant claim 35, wherein the cancer is prostate cancer (instant claim 69); and
A pharmaceutical composition comprising: an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor (instant claim 70);
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford 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 a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford to a human with cancer because Liu et al. teaches that the antibody YS5, an anti-CD46 antibody, when used alone can inhibit growth and/or proliferation of prostate cancer cells, or when coupled to drugs as an immunoconjugate can provide efficient and specific delivery of the cytotoxic effector (paragraph [0514]), and because Dorff and Crawford teaches that glucocorticoid receptor agonists or modulators including prednisone are commonly used in combination therapies for treating cancers and specifically for prostate cancer to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms, and because combination therapy of other drugs with prednisone has been shown to provide progression-free survival advantage in mCRPC (Pg 31 right column first and second full paragraphs and Pg 35 right column third full paragraph lines 18-22). In addition, one would predict that administration of said antibody linked to a cytotoxic effector and the glucocorticoid receptor agonist or modulator would kill more cancer cells than administration of the antibody alone because said CD46 antibody linked to a cytotoxic effector can specifically target a cytotoxic moiety to CD46 expressing cancer cells for cell killing when compared to said CD46 antibody alone which can only inhibit proliferation of cancer cells.
With regards to instant claims 6 and 65, 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, and a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford, and further administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) glucocorticoid receptor agonist or modulator; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
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 perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Patent 10533056 and an agent that is a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford. 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. Further, with regards to instant claim 66, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making a pharmaceutical composition comprising said anti-CD46 antibody conjugated to a cytotoxic effector and an agent that is a glucocorticoid receptor agonist or modulator as recited by Patent 10533056 and Dorff and Crawford respectively as described above, and further combining an androgen signaling inhibitor of enzalutamide or abiraterone as taught by Liu et al. into the pharmaceutical composition. This combination pharmaceutical composition would have the advantage of increased ease of administration of three 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 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 taught 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 STAT3 inhibitors have been studied in clinical trials for the treatment of prostate cancer Table 2 (Pg. 9-10) and 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 on 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.
With regards to instant claim 67, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the 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 recited by Patent 10533056 and an agent that is a STAT3 inhibitor as taught by Zou et al., further comprising administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) STAT3 inhibitor; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
With regards to instant claim 69, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human comprising administering to the human an antibody that specifically binds to CD46 that 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., wherein the cancer is prostate cancer as recited by Patent 10533056 and as taught by Liu et al. and Zou et al. because Liu et al. teaches that CD46 is over expressed on prostate cancer cells and Zou et al. teaches that STAT3 inhibitors have been studied in pre-clinical prostate cancer models and that STAT3 inhibitors have been studied in clinical trials for the treatment of (Tables 1 and 2).
With regards to instant claim 70, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Patent 10533056 and an agent that is a STAT3 inhibitor as taught by Zou 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.
Second NSDP Patent US 11434301 (New)
Claims 1, 5, 6, 11-16, 18-21, 35, 65-67 and 69-70 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 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), Dorff and Crawford (Annals of Oncology, 24, 31-38; January 2013) 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 a glucocorticoid receptor agonist or modulator; 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 glucocorticoid receptor agonist or modulator is dexamethasone or prednisone (instant claim 5);
The method of instant claim 1, further comprising administering an androgen signaling inhibitor (instant claim 6);
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 a glucocorticoid receptor agonist or modulator (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; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35);
The method of instant claim 6, wherein the androgen signaling inhibitor is enzalutamide or abiraterone (instant claim 65);
The pharmaceutical composition of instant claim 21, wherein the pharmaceutical composition further comprises an androgen signaling inhibitor (instant claim 66);
The method of instant claim 35, further comprising administering an androgen signaling inhibitor (instant claim 67);
The method of instant claim 35, wherein the cancer is prostate cancer (instant claim 69); and
A pharmaceutical composition comprising: an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor (instant claim 70);
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford 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 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 a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford because Liu et al. teaches that the antibody YS5, an anti-CD46 antibody, when used alone can inhibit growth and/or proliferation of prostate cancer cells, or when coupled to drugs as an immunoconjugate can provide efficient and specific delivery of the cytotoxic effector (paragraph [0514]), and because Dorff and Crawford teaches that glucocorticoid receptor agonists or modulators including prednisone are commonly used in combination therapies for treating cancers and specifically for prostate cancer to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms, and because combination therapy of other drugs with prednisone has been shown to provide progression-free survival advantage in mCRPC (Pg 31 right column first and second full paragraphs and Pg 35 right column third full paragraph lines 18-22). In addition, one would predict that administration of said antibody linked to a cytotoxic effector and the glucocorticoid receptor agonist or modulator would kill more cancer cells than administration of the antibody alone because said CD46 antibody linked to a cytotoxic effector can specifically target a cytotoxic moiety to CD46 expressing cancer cells for cell killing when compared to said CD46 antibody alone which can only inhibit proliferation of cancer cells.
With regards to instant claims 6 and 65, 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, and a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford, and further administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) glucocorticoid receptor agonist or modulator; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
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 11434301 (Patent claims 11, 16, 27, 28 and 29) 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 perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Patent 11434301 (claim 1) and an agent that is a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford. 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. Further, with regards to instant claim 66, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making a pharmaceutical composition comprising said anti-CD46 antibody conjugated to a cytotoxic effector and an agent that is a glucocorticoid receptor agonist or modulator as recited by Patent 11434301 and Dorff and Crawford respectively as described above, and further combining an androgen signaling inhibitor of enzalutamide or abiraterone as taught by Liu et al. into the pharmaceutical composition. This combination pharmaceutical composition would have the advantage of increased ease of administration of three 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 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 taught 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 STAT3 inhibitors have been studied in clinical trials for the treatment of prostate cancer Table 2 (Pg. 9-10) and 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 on 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.
With regards to instant claim 67, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the 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 recited by Patent 10533056 and an agent that is a STAT3 inhibitor as taught by Zou et al., further comprising administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) STAT3 inhibitor; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
With regards to instant claim 69, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human comprising administering to the human an antibody that specifically binds to CD46 that 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., wherein the cancer is prostate cancer as recited by Patent 10533056 and as taught by Liu et al. and Zou et al. because Liu et al. teaches that CD46 is over expressed on prostate cancer cells and Zou et al. teaches that STAT3 inhibitors have been studied in pre-clinical prostate cancer models and that STAT3 inhibitors have been studied in clinical trials for the treatment of (Tables 1 and 2).
With regards to instant claim 70, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Patent 10533056 and an agent that is a STAT3 inhibitor as taught by Zou 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.
Third NSDP Patent US 12325755 (New)
Claims 1, 5, 6, 11-16, 18-21, 35, 65-67 and 69-70 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 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), Dorff and Crawford (Annals of Oncology, 24, 31-38; January 2013) 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 a glucocorticoid receptor agonist or modulator; 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 glucocorticoid receptor agonist or modulator is dexamethasone or prednisone (instant claim 5);
The method of instant claim 1, further comprising administering an androgen signaling inhibitor (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);
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 a glucocorticoid receptor agonist or modulator (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; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35);
The method of instant claim 6, wherein the androgen signaling inhibitor is enzalutamide or abiraterone (instant claim 65);
The pharmaceutical composition of instant claim 21, wherein the pharmaceutical composition further comprises an androgen signaling inhibitor (instant claim 66);
The method of instant claim 35, further comprising administering an androgen signaling inhibitor (instant claim 67);
The method of instant claim 35, wherein the cancer is prostate cancer (instant claim 69); and
A pharmaceutical composition comprising: an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor (instant claim 70);
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford 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 a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford because Liu et al. teaches that the antibody YS5, an anti-CD46 antibody, when used alone can inhibit growth and/or proliferation of prostate cancer cells, or when coupled to drugs as an immunoconjugate can provide efficient and specific delivery of the cytotoxic effector (paragraph [0514]), and because Dorff and Crawford teaches that glucocorticoid receptor agonists or modulators including prednisone are commonly used in combination therapies for treating cancers and specifically for prostate cancer to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms, and because combination therapy of other drugs with prednisone has been shown to provide progression-free survival advantage in mCRPC (Pg 31 right column first and second full paragraphs and Pg 35 right column third full paragraph lines 18-22). In addition, one would predict that administration of said antibody linked to a cytotoxic effector and the glucocorticoid receptor agonist or modulator would kill more cancer cells than administration of the antibody alone because said CD46 antibody linked to a cytotoxic effector can specifically target a cytotoxic moiety to CD46 expressing cancer cells for cell killing when compared to said CD46 antibody alone which can only inhibit proliferation of cancer cells.
With regards to instant claims 6 and 65, 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 a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford, and further administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) glucocorticoid receptor agonist or modulator; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
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 perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Patent 12325755 (claims 19 and 27) and an agent that is a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford. 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. Further, with regards to instant claim 66, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making a pharmaceutical composition comprising said anti-CD46 antibody conjugated to a cytotoxic effector and an agent that is a glucocorticoid receptor agonist or modulator as recited by Patent 12325755 and Dorff and Crawford respectively as described above, and further combining an androgen signaling inhibitor of enzalutamide or abiraterone as taught by Liu et al. into the pharmaceutical composition. This combination pharmaceutical composition would have the advantage of increased ease of administration of three 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 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 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 STAT3 inhibitors have been studied in clinical trials for the treatment of prostate cancer Table 2 (Pg. 9-10) and 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 on 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.
With regards to instant claim 67, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the 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 recited by Patent 12325755 and an agent that is a STAT3 inhibitor as taught by Zou et al., further comprising administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) STAT3 inhibitor; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
With regards to instant claim 69, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human comprising administering to the human an antibody that specifically binds to CD46 that is linked to a cytotoxic effector as recited by Patent 12325755 and an agent that is a STAT3 inhibitor as taught by Zou et al., wherein the cancer is prostate cancer as recited by Patent 12325755 (claim 24) and as taught by Liu et al. and Zou et al. because Liu et al. teaches that CD46 is over expressed on prostate cancer cells and Zou et al. teaches that STAT3 inhibitors have been studied in pre-clinical prostate cancer models and that STAT3 inhibitors have been studied in clinical trials for the treatment of (Tables 1 and 2).
With regards to instant claim 70, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Patent 12325755 and an agent that is a STAT3 inhibitor as taught by Zou 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.
Fourth NSDP Patent US 12252746B2 (New)
Claims 1, 5, 6, 11-16, 18-21, 35, 65-67 and 69-70 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 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), Dorff and Crawford (Annals of Oncology, 24, 31-38; January 2013) 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 a glucocorticoid receptor agonist or modulator; 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 glucocorticoid receptor agonist or modulator is dexamethasone or prednisone (instant claim 5);
The method of instant claim 1, further comprising administering an androgen signaling inhibitor (instant claim 6);
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 a glucocorticoid receptor agonist or modulator (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; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35);
The method of instant claim 6, wherein the androgen signaling inhibitor is enzalutamide or abiraterone (instant claim 65);
The pharmaceutical composition of instant claim 21, wherein the pharmaceutical composition further comprises an androgen signaling inhibitor (instant claim 66);
The method of instant claim 35, further comprising administering an androgen signaling inhibitor (instant claim 67);
The method of instant claim 35, wherein the cancer is prostate cancer (instant claim 69); and
A pharmaceutical composition comprising: an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor (instant claim 70);
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford 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 a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford because Liu et al. teaches that the antibody YS5 which is the same antibody recited by Patent 12252746B2, when used alone can inhibit growth and/or proliferation of prostate cancer cells, or when coupled to drugs as an immunoconjugate can provide efficient and specific delivery of the cytotoxic effector (paragraph [0514]), and because Dorff and Crawford teaches that glucocorticoid receptor agonists or modulators including prednisone are commonly used in combination therapies for treating cancers and specifically for prostate cancer to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms, and because combination therapy of other drugs with prednisone has been shown to provide progression-free survival advantage in mCRPC (Pg 31 right column first and second full paragraphs and Pg 35 right column third full paragraph lines 18-22). In addition, one would predict that administration of said antibody linked to a cytotoxic effector and the glucocorticoid receptor agonist or modulator would kill more cancer cells than administration of the antibody alone because said CD46 antibody linked to a cytotoxic effector can specifically target a cytotoxic moiety to CD46 expressing cancer cells for cell killing when compared to said CD46 antibody alone which can only inhibit proliferation of cancer cells.
With regards to instant claims 6 and 65, 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, and a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford, and further administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) glucocorticoid receptor agonist or modulator; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
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 perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody attached to a payload such as auristatin or MMAE as recited by Patent 12252746B2 (claims 1, 9 and 10) and an agent that is a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford. 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. Further, with regards to instant claim 66, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making a pharmaceutical composition comprising said anti-CD46 antibody conjugated to a payload and an agent that is a glucocorticoid receptor agonist or modulator as recited by Patent 12252746B2 and Dorff and Crawford respectively as described above, and further combining an androgen signaling inhibitor of enzalutamide or abiraterone as taught by Liu et al. into the pharmaceutical composition. This combination pharmaceutical composition would have the advantage of increased ease of administration of three 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 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 STAT3 inhibitors have been studied in clinical trials for the treatment of prostate cancer Table 2 (Pg. 9-10) and 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 on 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.
With regards to instant claim 67, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the 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 attached to a payload as recited by Patent 12252746B2 and an agent that is a STAT3 inhibitor as taught by Zou et al., further comprising administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) STAT3 inhibitor; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
With regards to instant claim 69, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human comprising administering to the human an antibody that specifically binds to CD46 that is conjugated to a payload as recited by Patent 12252746B2 and an agent that is a STAT3 inhibitor as taught by Zou et al., wherein the cancer is prostate cancer as taught by Liu et al. and Zou et al. because Liu et al. teaches that CD46 is over expressed on prostate cancer cells and Zou et al. teaches that STAT3 inhibitors have been studied in pre-clinical prostate cancer models and that STAT3 inhibitors have been studied in clinical trials for the treatment of (Tables 1 and 2).
With regards to instant claim 70, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition comprising an anti-CD46 antibody conjugated to a payload as recited by Patent 12252746B2 and an agent that is a STAT3 inhibitor as taught by Zou 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.
Fifth NSDP Application No. 18/271205 (New)
Claims 1, 5, 6, 11-16, 18-21, 35, 65-67 and 69-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5 and 7-14 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), Decker et al. (Nucleic Acids Research, 2012, Vol. 40, No. 21 10765–10779), Dorff and Crawford (Annals of Oncology, 24, 31-38; January 2013) and Zou et al. (Mol Cancer Vol 19, Article 145, 1-19, 2020).
Copending 18/271205 claim 1 is drawn in part to a method of treating prostate 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, optionally in combination with a glucocorticoid receptor agonist or modulator, wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone.
Copending 18/271205 claim 5 is drawn to the method of claim 1, wherein the glucocorticoid receptor agonist or modulator is dexamethasone or prednisone.
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.
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 a glucocorticoid receptor agonist or modulator; 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 1, further comprising administering an androgen signaling inhibitor (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);
A pharmaceutical composition comprising an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a glucocorticoid receptor agonist or modulator (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; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35);
The method of instant claim 6, wherein the androgen signaling inhibitor is enzalutamide or abiraterone (instant claim 65);
The pharmaceutical composition of instant claim 21, wherein the pharmaceutical composition further comprises an androgen signaling inhibitor (instant claim 66);
The method of instant claim 35, further comprising administering an androgen signaling inhibitor (instant claim 67);
The method of instant claim 35, wherein the cancer is prostate cancer (instant claim 69); and
A pharmaceutical composition comprising: an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor (instant claim 70);
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford 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 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 in combination with a glucocorticoid receptor agonist as recited by Copending 18/271205 because Liu et al. teaches that the antibody YS5 which is the same antibody recited by Copending 18/271205, when used alone can inhibit growth and/or proliferation of prostate cancer cells, or when coupled to drugs as an immunoconjugate can provide efficient and specific delivery of the cytotoxic effector (paragraph [0514]), and because Dorff and Crawford teaches that glucocorticoid receptor agonists or modulators including prednisone are commonly used in combination therapies for treating cancers and specifically for prostate cancer to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms, and because combination therapy of other drugs with prednisone has been shown to provide progression-free survival advantage in mCRPC (Pg 31 right column first and second full paragraphs and Pg 35 right column third full paragraph lines 18-22). In addition, one would predict that administration of said antibody linked to a cytotoxic effector and the glucocorticoid receptor agonist or modulator would kill more cancer cells than administration of the antibody alone because said CD46 antibody linked to a cytotoxic effector can specifically target a cytotoxic moiety to CD46 expressing cancer cells for cell killing when compared to said CD46 antibody alone which can only inhibit proliferation of cancer cells.
With regards to instant claims 6 and 65, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a method of treating cancer in a human, the method comprising administering the combination of an antibody that specifically binds to CD46 and a glucocorticoid receptor agonist or modulator as recited by Copending 18/271205, and further administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) glucocorticoid receptor agonist or modulator; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
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).
With regards to instant claim 21, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition as taught by Liu et al. comprising (i) an anti-CD46 antibody attached to a cytotoxic effector and (ii) a glucocorticoid receptor agonist or modulator as recited by Copending 18/271205. 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. Further, with regards to instant claim 66, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making a pharmaceutical composition comprising (i) said anti-CD46 antibody conjugated attached to a cytotoxic effector and (ii) a glucocorticoid receptor agonist or modulator as recited by Copending 18/271205 as described above, and further combining (ii) an androgen signaling inhibitor of enzalutamide or abiraterone as taught by Liu et al. into the pharmaceutical composition. This combination pharmaceutical composition would have the advantage of increased ease of administration of three 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 cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46 conjugated to a cytotoxic effector as recited by Copending 18/271205 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 STAT3 inhibitors have been studied in clinical trials for the treatment of prostate cancer Table 2 (Pg. 9-10) and 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 18/271205 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 on 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.
With regards to instant claim 67, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46 attached to a cytotoxic effector as recited by Copending 18/271205 and an agent that is a STAT3 inhibitor as taught by Zou et al., further comprising administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) STAT3 inhibitor; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
With regards to instant claim 69, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human comprising administering to the human an antibody that specifically binds to CD46 that is conjugated to a cytotoxic effector as recited by Copending 18/271205 and an agent that is a STAT3 inhibitor as taught by Zou et al., wherein the cancer is prostate cancer as taught by Copending 18/271205 and Zou et al. because Liu et al. teaches that CD46 is over expressed on prostate cancer cells and Zou et al. teaches that STAT3 inhibitors have been studied in pre-clinical prostate cancer models and that STAT3 inhibitors have been studied in clinical trials for the treatment of (Tables 1 and 2).
With regards to instant claim 70, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition as taught by Liu et al. comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Copending 18/271205 and an agent that is a STAT3 inhibitor as taught by Zou 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.
This is a provisional nonstatutory double patenting rejection.
Sixth NSDP Application No. 19/204124 (New)
Claims 1, 5, 6, 11-16, 18-21, 35, 65-67 and 69-70 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), Dorff and Crawford (Annals of Oncology, 24, 31-38; January 2013) 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 in part to the method of claim 101, wherein the cancer cells is prostate 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 a glucocorticoid receptor agonist or modulator; 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 glucocorticoid receptor agonist or modulator is dexamethasone or prednisone (instant claim 5);
The method of instant claim 1, further comprising administering an androgen signaling inhibitor (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);
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; wherein administration of the antibody and the agent kills more cancer cells than administration of the antibody alone (instant claim 35);
The method of instant claim 6, wherein the androgen signaling inhibitor is enzalutamide or abiraterone (instant claim 65);
The pharmaceutical composition of instant claim 21, wherein the pharmaceutical composition further comprises an androgen signaling inhibitor (instant claim 66);
The method of instant claim 35, further comprising administering an androgen signaling inhibitor (instant claim 67);
The method of instant claim 35, wherein the cancer is prostate cancer (instant claim 69); and
A pharmaceutical composition comprising: an anti-CD46 antibody conjugated to a cytotoxic effector; and an agent that is a Signal Transducer And Activator of Transcription 3 (STAT3) inhibitor (instant claim 70);
However, these deficiencies are made up in the teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford and Zou et al.
The teachings of Liu et al., Antonarakis et al., Dagvadorj et al., Decker et al., Dorff and Crawford 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 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 a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford because Liu et al. teaches that the antibody YS5 which is the same antibody recited by Copending 19/204124, when used alone can inhibit growth and/or proliferation of prostate cancer cells, or when coupled to drugs as an immunoconjugate can provide efficient and specific delivery of the cytotoxic effector (paragraph [0514]), and because Dorff and Crawford teaches that glucocorticoid receptor agonists or modulators including prednisone are commonly used in combination therapies for treating cancers and specifically for prostate cancer to counteract toxic effects associated with specific cancer therapeutics and to manage tumor-related symptoms, and because combination therapy of other drugs with prednisone has been shown to provide progression-free survival advantage in mCRPC (Pg 31 right column first and second full paragraphs and Pg 35 right column third full paragraph lines 18-22). In addition, one would predict that administration of said antibody linked to a cytotoxic effector and the glucocorticoid receptor agonist or modulator would kill more cancer cells than administration of the antibody alone because said CD46 antibody linked to a cytotoxic effector can specifically target a cytotoxic moiety to CD46 expressing cancer cells for cell killing when compared to said CD46 antibody alone which can only inhibit proliferation of cancer cells.
With regards to instant claims 6 and 65, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform 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) as recited by Copending 19/204124, and a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford, and further administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) glucocorticoid receptor agonist or modulator; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
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 perform a combine method of making a pharmaceutical composition as taught by Liu et al. comprising (i) an anti-CD46 antibody attached to a cytotoxic effector as recited by Copending 19/204124 and (ii) a glucocorticoid receptor agonist or modulator as taught by Dorff and Crawford. 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. Further, with regards to instant claim 66, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making a pharmaceutical composition comprising (i) said anti-CD46 antibody conjugated attached to a cytotoxic effector and (ii) a glucocorticoid receptor agonist or modulator as recited by as recited by Copending 19/204124 as described above, and further combining (ii) an androgen signaling inhibitor of enzalutamide or abiraterone as taught by Liu et al. into the pharmaceutical composition. This combination pharmaceutical composition would have the advantage of increased ease of administration of three 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 STAT3 inhibitors have been studied in clinical trials for the treatment of prostate cancer Table 2 (Pg. 9-10) and 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 on 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.
With regards to instant claim 67, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human, the method comprising administering to the human an antibody that specifically binds to CD46 attached to a cytotoxic effector as recited by Copending 19/204124 and an agent that is a STAT3 inhibitor as taught by Zou et al., further comprising administering an androgen signaling inhibitor that is enzalutamide or abiraterone as taught by Liu et al. because Liu et al. teaches that treatment of prostate cancer cell lines with enzalutamide or abiraterone significantly upregulated surface expression of CD46 on said cells and enhanced their killing by said CD46 antibody-drug conjugate thus the combined method of (i) CD46-ADC; (ii) STAT3 inhibitor; and (iii) androgen signaling inhibitor, would be capable of being an even more superior cancer therapeutic when enzalutamide or abiraterone administration can sensitize cancer cells to the concomitantly administered CD46-ADC.
With regards to instant claim 69, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating cancer in a human comprising administering to the human an antibody that specifically binds to CD46 that is conjugated to a cytotoxic effector as recited by Copending 19/204124 and an agent that is a STAT3 inhibitor as taught by Zou et al., wherein the cancer is prostate cancer as taught by Copending 18/271205 and Zou et al. because Liu et al. teaches that CD46 is over expressed on prostate cancer cells and Zou et al. teaches that STAT3 inhibitors have been studied in pre-clinical prostate cancer models and that STAT3 inhibitors have been studied in clinical trials for the treatment of (Tables 1 and 2).
With regards to instant claim 70, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combine method of making a pharmaceutical composition as taught by Liu et al. comprising an anti-CD46 antibody conjugated to a cytotoxic effector as recited by Copending 19/204124 and an agent that is a STAT3 inhibitor as taught by Zou 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.
This is a provisional nonstatutory double patenting rejection.
Claim Objections
Claims 7-9 and 68 are objected to as being dependent on a rejected base claim (claim 1 and claim 35).
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
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