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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/07/2025 has been entered.
Status of the Application
Claims 1-3, 11-13 and 17-36 are pending as of the response filed 05/07/2025. Claims 8-10 and 14-16 were previously cancelled. Claims 4-7 are cancelled in the response dated 05/07/2025. Applicant’s original election of group I claims and a single species of cancer being treated with the composition as ovarian cancer is maintained. Claims 17-32 and 34-36 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or nonelected species, there being no allowable generic or linking claim. Claims 1-3, 11-13 and 33 are examined herein.
In view of the pending claims the 35 U.S.C. 103 rejections of record are maintained. It is noted that Applicants have introduced the originally elected species of microtubule polymerization inhibitor, DM4 into the claims – a new rejection has been made in this regard. Applicant’s arguments have been fully considered and are addressed below.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 11-13 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Patterson et al. (VISAGE reveals a targetable mitotic spindle vulnerability in cancer cells, 24 July 2019, hereinafter Patterson) in view of Saatci et al. (Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer, 02 February 2018, hereinafter Saatci) and Menderes et al. (Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression, 10 July 2017, hereinafter Menderes).
Regarding instant claims 1-2, 11-13 and 33, Patterson teaches pharmaceutical compositions of TH588 (a microtubule polymerization inhibitor) in combination with a PLK1 inhibitor (BI2536) that synergistically kill cancer cells both in vitro and in vivo (Pg. 74, first column, first paragraph; Pg. 75, Figure 1). Patterson teaches the MTH1 inhibitor, TH588 binding to β-tubulin impaired microtubule assembly (Pg. 74, first column, first paragraph). Patterson teaches reduced cell viability using the combination of TH588 in combination with a PLK1 inhibitor (BI2536) when compared to use of TH588 alone (Figure 1A). Patterson teaches compositions of TH588 and BI2536 in PEG hydrogel contained in a tumor implantable device implanted into CRPC xenografts grown on the flanks of NCR nude mice, to assess the greater-than-additive effects (Pg. 76, second column, last paragraph – Pg. 77, first column, continued paragraph). Patterson teaches significantly more apoptotic cell death in the tissue immediately surrounding the wells containing both drugs were observed, despite the fact that these drug combination wells contained only one-half of the amount of each drug relative to the wells containing the single drugs alone, consistent with greater-than-additive tumor cell killing (Pg. 77, first column, continued paragraph; Figure 1E; Figure 1F).
Patterson teaches TH588 also synergizes with the highly specific Plk1 inhibitor onvansertib (also known as PCM-075) (Pg. 87, second column, first full paragraph; Pg. 86, Figure 7I).
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Patterson teaches synergy between particular members of these two classes of antimitotic drugs - Plk1 inhibitors and microtubule poisons - has been observed in a few specific cancer types, including CCNE-amplified high-grade serous ovarian cancers (Pg. 88, second column, last paragraph – Pg. 89, first column, continued paragraph). Patterson teaches synergistic combination therapies, in particular, are of substantial clinical interest because of their potential for increasing efficacy and cancer cell selectivity, reducing the development of resistance, and allowing for decreases in individual drug dosage, possibly avoiding toxicity (Pg. 74, first column, last paragraph – Pg. 74, second column, continued paragraph). Patterson teaches individual drugs in these combinations are generally selected based on either their ability to target pathways required for unrestrained cell proliferation or their involvement in the acquisition and maintenance of cancer-cell-specific traits, exemplified by the hallmarks
of cancer, and can be combined to target orthogonal cancer vulnerabilities (Pg. 74, second column, continued paragraph).
Patterson do not teach wherein the microtubule polymerization inhibitor is DM1, wherein the microtubule polymerization inhibitor is conjugated via a linker to an antibody or an antigen binding fragment thereof binding to the cancer to be treated (as in instant claim 1); wherein the antibody or an antigen binding fragment thereof specifically binds to a cell surface molecule highly expressed in a tumor cell compared to healthy cells (as in instant claim 11); wherein the antibody or an antigen binding fragment thereof specifically binds to one or more cell surface molecules selected from the group consisting of CD33, CD30, HER2, CD22, CD79b, Nectin4, trophoblast cell surface antigen (TROP-2), BCMA, folate receptor alpha (FOLR1), and CD19 (as in instant claim 12); wherein the microtubule polymerization inhibitors are conjugated via a linker to an antibody, or an antigen binding fragment thereof, selected from the group consisting of brentuximab vedotin, ado-trastuzumab emtansine, polatuzumab vedotin-piiq, enfortumab vedotin-ejfv, belantamab mafodotin-blmf, mirvetuximab soravtansine, and tisotumab vedotin-tftv (as in instant claim 13).
Saatci teaches combination treatment of acquired and de novo resistant models with T-DM1 and volasertib (a Plk1 inhibitor) resulted in synergistic growth inhibition over a wide dose range of the two drugs, both in three dimensional (3D) cell culture and in vivo, providing a promising potential of the combination in the treatment of HER2-positive breast cancers (Abstract; Pg. 2252, second column, continued paragraph). Saatci teaches Plk1 is overexpressed in a variety of solid tumors and hematological malignancies both in the context of tumor progression and drug resistance (Pg. 2265, first column, first full paragraph). Saatci emphasizes PLK1 as a clinically relevant druggable target in T-DM1 resistance by favoring evasion from drug-induced mitotic arrest, apoptosis and DNA damage both in vitro and in patients (Pg. 2257, second column, continued paragraph). Saatci teaches the maytansinoid T-DM1 is an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1 (Abstract). Saatci teaches Trastuzumab emtansine (T-DM1, Kadcyla®) is a next-generation HER2-ADC, combining trastuzumab, along with its cytostatic functions, with a potent microtubule-targeting agent, DM1 (derivative of maytansine 1) via a stable linker, MCC (Pg. 2252, first column, first full paragraph). Saatci teaches trastuzumab binds the extracellular domain IV of HER2 and prevents the activation of its intracellular tyrosine kinase domain (Pg. 2252, first column, continued paragraph). Saatci teaches these promising therapeutic agents that mostly target cancer driver proteins and thus antagonize tumor growth and increase survival (Pg. 2252, first column, continued paragraph) (therefore the teachings of Saatci read on the limitation of the microtubule polymerization inhibitor conjugated via a linker to an antibody or an antigen binding fragment thereof binding to the cancer to be treated as in claims 11-13).
Menderes teaches T-DM1 has superior anti-tumor activity in epithelial ovarian cancer (EOC) with high HER2/neu expression, compared to HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P) as single agents (Abstract; Pg. 150, Fig. 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Patterson, Saatci and Menderes, to have substituted the microtubule polymerization inhibitor of Patterson, with T-DM1 as taught by Saatci and Menderes, to arrive at the instantly claimed pharmaceutical composition for use in treating cancer patients (say, ovarian cancer), with a reasonable and predictable expectation of success that the combination composition would exhibit synergy.
Patterson teaches pharmaceutical compositions of TH588 (a microtubule polymerization inhibitor) in combination with a PLK1 inhibitor (BI2536) that synergistically kill cancer cells both in vitro and in vivo. Patterson teaches significantly more apoptotic cell death in the tissue immediately surrounding the wells containing both drugs were observed, despite the fact that these drug combination wells contained only one-half of the amount of each drug relative to the wells containing the single drugs alone, consistent with greater-than-additive tumor cell killing. Patterson teaches TH588 synergizes with the highly specific Plk1 inhibitor onvansertib (also known as PCM-075). Patterson teaches synergy between particular members of these two classes of antimitotic drugs - Plk1 inhibitors and microtubule poisons - has been observed in a few specific cancer types, including CCNE-amplified high-grade serous ovarian cancers. Patterson teaches synergistic combination therapies, in particular, are of substantial clinical interest because of their potential for increasing efficacy and cancer cell selectivity, reducing the development of resistance, and allowing for decreases in individual drug dosage, possibly avoiding toxicity. Saatci teaches combination treatment of acquired and de novo resistant models with T-DM1 and volasertib (a Plk1 inhibitor) resulted in synergistic growth inhibition over a wide dose range of the two drugs, both in three dimensional (3D) cell culture and in vivo, providing a promising potential of the combination in the treatment of HER2-positive breast cancers. Saatci teaches Plk1 is overexpressed in a variety of solid tumors and hematological malignancies both in the context of tumor progression and drug resistance. Saatci emphasizes PLK1 as a clinically relevant druggable target in T-DM1 resistance by favoring evasion from drug-induced mitotic arrest, apoptosis and DNA damage both in vitro and in patients. Saatci teaches the maytansinoid T-DM1 is an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. Saatci teaches Trastuzumab emtansine (T-DM1, Kadcyla®) is a next-generation HER2-ADC, combining trastuzumab, along with its cytostatic functions, with a potent microtubule-targeting agent, DM1 (derivative of maytansine 1) via a stable linker, MCC (Pg. 2252, first column, first full paragraph). Saatci teaches trastuzumab binds the extracellular domain IV of HER2 and prevents the activation of its intracellular tyrosine kinase domain (Pg. 2252, first column, continued paragraph). Saatci teaches these promising therapeutic agents that mostly target cancer driver proteins and thus antagonize tumor growth and increase survival. Menderes teaches T-DM1 showed superior anti-tumor activity in epithelial ovarian cancer (EOC) with high HER2/neu expression.
According to MPEP 2144.06 (II), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. In the instant case, the TH588 of Patterson and T-DM1 of Saatci/Menderes, are both microtubule polymerization inhibitors, and are considered equivalents in the art.
Therefore, one of ordinary skill in the art would have been motivated to formulate a pharmaceutical composition for use in treating cancers, (say, ovarian cancer), comprising a Plk1 inhibitor, say onvansertib, and a microtubule polymerization inhibitor, say T-DM1 (an antibody-drug conjugate), with a reasonable expectation of success that administration of such a combination would result in a more than additive effect when compared to the effect obtained by use of only any one of the inhibitors. The motivation being to provide combinations for targeted therapy of HER2 positive cancers with recurrent disease resistant to chemotherapy, thereby improving treatment outcomes (Menderes, Pg. 151, first column, second paragraph).
Regarding instant claim 3, Patterson in view of Saatci and Menderes render obvious the pharmaceutical composition of instant claim 1. Patterson do not explicitly teach wherein the microtubule polymerization inhibitor binds a site on tubulin selected from the group consisting of laulimalide, taxane/epithilone, vinca alkaloid, and colchicine sites.
Saatci teaches the maytansinoid T-DM1 (Abstract). DM1, by virtue of its inherent property, binds at the vinca alkaloid site, since maytansines are competitive inhibitors of binding for the vinca alkaloids.
According to MPEP 2112.01(II), “Products of identical chemical composition can not have mutually exclusive properties.” Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). In the instant case, the microtubule polymerization inhibitor taught by Saatci, DM1 (a maytansinoid), is identical to the instantly claimed species of microtubule polymerization inhibitor. Therefore, it will inherently be expected to bind at the vinca alkaloid site.
Claims 1-3, 11-13 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Patterson et al. (VISAGE reveals a targetable mitotic spindle vulnerability in cancer cells, 24 July 2019, hereinafter Patterson) in view of Ponte et al. (Mirvetuximab soravtansine (IMGN853), a folate receptor alpha–targeting antibody-drug conjugate, potentiates the activity of standard of care therapeutics in ovarian cancer models, December 2016, hereinafter Ponte).
Regarding instant claims 1-2, 11-13 and 33, Patterson teaches pharmaceutical compositions of TH588 (a microtubule polymerization inhibitor) in combination with a PLK1 inhibitor (BI2536) that synergistically kill cancer cells both in vitro and in vivo (Pg. 74, first column, first paragraph; Pg. 75, Figure 1). Patterson teaches the MTH1 inhibitor, TH588 binding to β-tubulin impaired microtubule assembly (Pg. 74, first column, first paragraph). Patterson teaches reduced cell viability using the combination of TH588 in combination with a PLK1 inhibitor (BI2536) when compared to use of TH588 alone (Figure 1A). Patterson teaches compositions of TH588 and BI2536 in PEG hydrogel contained in a tumor implantable device implanted into CRPC xenografts grown on the flanks of NCR nude mice, to assess the greater-than-additive effects (Pg. 76, second column, last paragraph – Pg. 77, first column, continued paragraph). Patterson teaches significantly more apoptotic cell death in the tissue immediately surrounding the wells containing both drugs were observed, despite the fact that these drug combination wells contained only one-half of the amount of each drug relative to the wells containing the single drugs alone, consistent with greater-than-additive tumor cell killing (Pg. 77, first column, continued paragraph; Figure 1E; Figure 1F).
Patterson teaches TH588 also synergizes with the highly specific Plk1 inhibitor onvansertib (also known as PCM-075) (Pg. 87, second column, first full paragraph; Pg. 86, Figure 7I).
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Patterson teaches synergy between particular members of these two classes of antimitotic drugs - Plk1 inhibitors and microtubule poisons - has been observed in a few specific cancer types, including CCNE-amplified high-grade serous ovarian cancers (Pg. 88, second column, last paragraph – Pg. 89, first column, continued paragraph). Patterson teaches synergistic combination therapies, in particular, are of substantial clinical interest because of their potential for increasing efficacy and cancer cell selectivity, reducing the development of resistance, and allowing for decreases in individual drug dosage, possibly avoiding toxicity (Pg. 74, first column, last paragraph – Pg. 74, second column, continued paragraph). Patterson teaches individual drugs in these combinations are generally selected based on either their ability to target pathways required for unrestrained cell proliferation or their involvement in the acquisition and maintenance of cancer-cell-specific traits, exemplified by the hallmarks
of cancer, and can be combined to target orthogonal cancer vulnerabilities (Pg. 74, second column, continued paragraph).
Patterson do not teach wherein the microtubule polymerization inhibitor is DM4, wherein the microtubule polymerization inhibitor is conjugated via a linker to an antibody or an antigen binding fragment thereof binding to the cancer to be treated (as in instant claim 1); wherein the antibody or an antigen binding fragment thereof specifically binds to a cell surface molecule highly expressed in a tumor cell compared to healthy cells (as in instant claim 11); wherein the antibody or an antigen binding fragment thereof specifically binds to one or more cell surface molecules selected from the group consisting of CD33, CD30, HER2, CD22, CD79b, Nectin4, trophoblast cell surface antigen (TROP-2), BCMA, folate receptor alpha (FOLR1), and CD19 (as in instant claim 12); wherein the microtubule polymerization inhibitors are conjugated via a linker to an antibody, or an antigen binding fragment thereof, selected from the group consisting of brentuximab vedotin, ado-trastuzumab emtansine, polatuzumab vedotin-piiq, enfortumab vedotin-ejfv, belantamab mafodotin-blmf, mirvetuximab soravtansine, and tisotumab vedotin-tftv (as in instant claim 13).
Ponte teaches the maytansinoid DM4 (the originally elected species of microtubule polymerization inhibitor) as a potent agent that induces mitotic arrest by suppressing microtubule dynamics (Abstract). Ponte teaches mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate (ADC) that consists of the maytansinoid DM4, coupled to a humanized anti-FRα monoclonal antibody via a linker that is stable in the circulation but readily cleaved within cells to release the payload (Pg. 776, first column, third full paragraph). Ponte teaches elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC) in contrast to its restricted expression in normal tissues (Abstract; Pg. 776, first column, first full paragraph). Ponte teaches folate receptor alpha as a cell surface glycoprotein (FRα) (Pg. 776, first column, first full paragraph). Ponte teaches high-affinity binding of IMGN853 to FRα followed by its internalization results in accumulation of a high cytotoxic intracellular concentration of DM4, which subsequently acts as a potent antimitotic agent through its ability to suppress microtubule dynamics (Pg. 776, first column, third full paragraph) (therefore the teachings of Ponte read on the limitation of the microtubule polymerization inhibitor conjugated via a linker to an antibody or an antigen binding fragment thereof binding to the cancer to be treated as in claims 11-13). Ponte teaches an antibody-drug conjugate of the maytansinoid DM4 (IMGN853), holds considerable promise in the treatment of epithelial ovarian cancers (EOC), particularly as novel combinatorial treatments with existing standard-of-care regimens (Pg. 783, first column, first full paragraph). Ponte teaches targeted therapy combinations of IMGN853 with clinically approved agents confer superior therapeutic activity over corresponding single-agent treatments in preclinical models of EOC (including patient-derived xenografts) in both the platinum-sensitive and platinum-resistant disease settings (Pg. 781, second column, first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Patterson and Ponte to have substituted the microtubule polymerization inhibitor of Patterson, with T-DM4 as taught by Ponte, to arrive at the instantly claimed pharmaceutical composition for use in treating cancer patients (say, ovarian cancer), with a reasonable and predictable expectation of success that the combination composition would exhibit synergy.
Patterson teaches pharmaceutical compositions of TH588 (a microtubule polymerization inhibitor) in combination with a PLK1 inhibitor (BI2536) that synergistically kill cancer cells both in vitro and in vivo. Patterson teaches significantly more apoptotic cell death in the tissue immediately surrounding the wells containing both drugs were observed, despite the fact that these drug combination wells contained only one-half of the amount of each drug relative to the wells containing the single drugs alone, consistent with greater-than-additive tumor cell killing. Patterson teaches TH588 synergizes with the highly specific Plk1 inhibitor onvansertib (also known as PCM-075). Patterson teaches synergy between particular members of these two classes of antimitotic drugs - Plk1 inhibitors and microtubule poisons - has been observed in a few specific cancer types, including CCNE-amplified high-grade serous ovarian cancers. Patterson teaches synergistic combination therapies, in particular, are of substantial clinical interest because of their potential for increasing efficacy and cancer cell selectivity, reducing the development of resistance, and allowing for decreases in individual drug dosage, possibly avoiding toxicity. Ponte teaches the maytansinoid DM4 as a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Ponte teaches an antibody-drug conjugate of the maytansinoid DM4, holds considerable promise in the treatment of epithelial ovarian cancers (EOC), particularly as novel combinatorial treatments with existing standard-of-care regimens.
According to MPEP 2144.06 (II), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. In the instant case, the TH588 of Patterson and T-DM4 of Ponte, are both microtubule polymerization inhibitors, and are considered equivalents in the art.
Therefore, one of ordinary skill in the art would have been motivated to formulate a pharmaceutical composition for use in treating cancers, especially ovarian cancers by administering to the subject, a pharmaceutical composition comprising a Plk1 inhibitor, say onvansertib, and a microtubule polymerization inhibitor, say DM4, in the treatment of ovarian cancers, with a reasonable expectation of success that the combination composition would exhibit synergy. The motivation being to provide combinations for targeted therapy against FRα-expressing tumors, thereby improving patient outcomes (Ponte, Abstract; Pg. 776, first column, third full paragraph).
Regarding instant claim 3, Patterson in view of Ponte renders obvious the pharmaceutical composition of instant claim 1. Patterson do not explicitly teach wherein the microtubule polymerization inhibitor binds a site on tubulin selected from the group consisting of laulimalide, taxane/epithilone, vinca alkaloid, and colchicine sites.
Ponte teaches the maytansinoid DM4 (Abstract). DM4, by virtue of its inherent property, binds at the vinca alkaloid site, since maytansines are competitive inhibitors of binding for the vinca alkaloids.
According to MPEP 2112.01(II), “Products of identical chemical composition can not have mutually exclusive properties.” Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). In the instant case, the microtubule polymerization inhibitor taught by Ponte, DM4, is identical to the instantly claimed species of microtubule polymerization inhibitor. Therefore, it will inherently be expected to bind at the vinca alkaloid site.
Response to Arguments
Applicants argue on pages 9-12 of the response dated 05/07/2025, that “ (i) the Office Action contains no evidence (e.g., peer-reviewed publications) that a person of ordinary skill in the art would have expected that T-DM1 and TH588 interacted with tubulin at the same binding site to have effected the same downstream biochemical and/or physiological effects”. Applicants argue “As an initial matter, it is unclear what “inherent property” is being referenced in the Office Action. Further, proof of inherency is not met by a mere showing of a possibility or probability that the missing element or function is present”. Applicants argue “(ii) even if T-DM1 and TH588 interacted with tubulin at the same binding site, the Office Action contains no evidence that the interactions would have similarly led to a contributing synergistic effect”. Applicants argue “Lastly, and more importantly, Patterson teaches that its TH588 inhibits tubulin polymerization through binding to the colchicine binding site (Patterson, page 84, left col., second para., until page 87, right col., first para) a distinct binding site from the vinca alkaloid binding site. Saatci and Menderes are silent regarding the binding site of their T-DM1 to tubulin, other than a generic statement in Saatci indicating that DM1 is a microtubule- targeting agent. To the extent that the assessment in the Office Action attempts to equate the colchicine binding site with the vinca alkaloid site, Applicant respectfully submits that the colchicine binding site and vinca alkaloid site are distinct sites on tubulin, such that a person of ordinary skill in the art would not arrive at a conclusion that binding to two distinct sites on a target would lead to the same biochemical and/or physiological downstream effects”. Applicant's arguments have been fully considered but they are not persuasive.
Regarding Applicant’s contention that one of ordinary skill in the art would not have expected both TH588 and T-DM1 to have effected the same downstream biochemical and/or physiological effects, the examiner does not dispute the fact that TH588 and T-DM1 have distinct binding sites on tubulin. Despite different structural effects on tubulin, post binding to a vinca alkaloid site on tubulin by T-DM1 or colchicine binding site on tubulin by TH588, both the microtubule agents disrupt microtubule dynamics and lead to cell cycle arrest and apoptosis in the context of cancer. Therefore, a person of ordinary skill in the art would have been motivated to substitute the TH588 of Patterson with T-DM1 taught by Saatci, to arrive at the instantly claimed pharmaceutical composition, with a reasonable expectation of success.
Regarding Applicant’s contention of the “inherent property” referenced in the rejection, as discussed in the 103 rejection above, the combined teachings of Patterson, Saatci and Menderes render obvious a pharmaceutical composition comprising a microtubule polymerization inhibitor, DM1 (as an antibody-drug conjugate, T-DM1) and a Plk inhibitor, onvansertib, as instantly claimed. The trastuzumab portion of T-DM1 delivers the drug conjugate to HER2-expressing cancer cells, and once inside, the DM1 payload by binding to the vinca domain of tubulin exerts its cytotoxic effect by inhibiting microtubule polymerization. The T-DM1 binding to the vinca domain of tubulin is considered an inherent property of DM1. The examiner asserts that a reference to “inherent property” has been used in the correct context.
Regarding Applicant’s contention that even if T-DM1 and TH588 interacted with tubulin at the same binding site, the Office Action contains no evidence that the interactions would have similarly led to a contributing synergistic effect AND that a person of ordinary skill in the art would not arrive at a conclusion that binding to two distinct sites on a target would lead to the same biochemical and/or physiological downstream effects, the examiner would like to emphasize that Patterson teaches strong synergy specific to the combination of inhibitors of Plk1 and microtubule polymerization that likely functions by targeting an inherent mitotic vulnerability present in a wide variety of cancer cells of disparate origin (Pg. 89, first column, continued paragraph). Saatci teaches Plk1 is overexpressed in a variety of solid tumors and hematological malignancies both in the context of tumor progression and drug resistance (Pg. 2265, first column, first full paragraph). Saatci emphasizes PLK1 as a clinically relevant druggable target in T-DM1 resistance by favoring evasion from drug-induced mitotic arrest, apoptosis and DNA damage both in vitro and in patients (Pg. 2257, second column, continued paragraph).
Accordingly, in view of the teachings of the prior art, a person of ordinary skill in the art would have had a reasonable and predictable expectation of a synergistic benefit using a combination of a microtubule polymerization inhibitor and a Plk inhibitor.
In other words, different microtubule polymerization inhibitors target microtubules by binding to slightly different sites or exert their effects through variations in their mechanism of action - as is the case with T-DM1 and TH588 binding to different sites on tubulin. However, different microtubule polymerization inhibitors combined with PLK1 inhibitors could potentially exploit different vulnerabilities in the mitotic pathway, leading to a synergistic effect.
According to MPEP 2141 (III), The "mere existence of differences between the prior art and an invention does not establish the invention’s nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). Further, according to MPEP 2143(I)(E), “the mere existence of a large number of options does not in and of itself lead to a conclusion of nonobviousness. Where the prior art teachings lead one of ordinary skill in the art to a narrower set of options, then that reduced set is the appropriate one to consider when determining obviousness using an obvious to try rationale”. In the instant case, the teachings of Patterson indicate synergy observed between the two classes of inhibitors - Plk1 inhibitors and microtubule polymerization inhibitors – in the treatment of various cancers including ovarian cancer. Patterson exemplifies synergy between TH588 (a microtubule polymerization inhibitor) in combination with Plk1 inhibitor, onvansertib. Saatci teaches the maytansinoid T-DM1 is an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. Saatci emphasizes PLK1 as a clinically relevant druggable target in T-DM1 resistance by favoring evasion from drug-induced mitotic arrest, apoptosis and DNA damage both in vitro and in patients with cancer. Menderes teaches T-DM1 has superior anti-tumor activity in epithelial ovarian cancer (EOC) with high HER2/neu expression. As such, the examiner maintains that claimed pharmaceutical combination is prima facie obvious.
Further, the claims are drawn broadly to a pharmaceutical composition for treating any type of cancer using the claimed combination of microtubule polymerization inhibitor and Plk inhibitor. And, Applicants have not provided a clear and convincing evidence of nonobviousness or unexpected results to overcome the 35 U.S.C. 103 rejection of record.
Therefore, the 35 U.S.C. 103 rejections of record are maintained.
Miscellaneous
Reference made of record but not relied upon in this rejection.
Jemaa et al. (Preferential Killing of Tetraploid Colon Cancer Cells by Targeting the Mitotic Kinase PLK1, Cellular Physiology and Biochemistry, Vol. 54, 303-320, 22 March 2020, hereinafter Jemaa). Jemaa teaches synergistic effect of co-treatment of the tetraploid colon cancer cells with a PLK1 inhibitor and a microtubule polymerisation inhibitor (Abstract; Pg. 313, last paragraph, Fig. 5D). Jemaa teaches the combination of PLK1 inhibitors and microtubule poisons as a promising therapeutic strategy based on mitotic catastrophe for the treatment of colon cancer (Pg. 316, last paragraph).
Conclusion
Claims 1-3, 11-13 and 33 are rejected.
No claims are allowed.
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/P.S.R./Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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