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 .
Detailed Action
The Amendments and Remarks filed 11/13/25 in response to the Office Action of 8/13/25 are acknowledged and have been entered.
Claim 21 has been added by Applicant.
Claims 1, 4, 6, 10-15, and 21 are pending.
Claims 1, 4, 6, and 10 have been amended by Applicant.
Claims 1, 4, 6, 10-15, and 21 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The following Office Action contains NEW GROUNDS of rejections Necessitated by Amendments.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103
Claims 1, 4, 6, and 10-15 are rejected under 35 U.S.C. 103(a) as being unpatentable over Li et al (Hepatology, 2017, 66: 157-167) in view of Tian et al (Cell Biosci, 2019, 9(79): 1-10), Yan et al (Journal of Experimental & Clinical Cancer Research, 2018, 37(203): 1-13), Castro et al (NEJM, 2018, 378: 2486-2496), Zhao et al (J Cell Mol Med, 2011, 15(3): 691-700), and Chen et al (Tumor Biol, 2015, 36: 973-981).
Li et al teaches CCL2 is highly expressed in human hepatocellular cancer/carcinoma (HCC) and elevated levels of CCL2 in HCC correlate with poor survival (Figure 1, in particular). Li et al further teaches CCR2 is the only known receptor of CCL2 (left column on page 158, in particular) and that blocking CCL2/CCR2 signaling with a CCR2 antagonist (which is an inhibitor of CCL2 because the antagonist inhibits CCL2/CCR2 signaling) suppresses HCC tumor growth and metastasis in vivo (Abstract, Figure 3, and supplementary figure S3, in particular). Li et al further teaches an antibody targeting CCL2 has entered clinical trials for the treatment of prostate cancer (left column on page 158, in particular).
Li et al does not specifically describe administering an inhibitor of IL-13 or teach over-expression of Twist1. However, these deficiencies are made up in the teachings of Tian et al, Yan et al, Castro et al, Zhao et al, and Chen et al.
Tian et al teaches TAMs in the HCC tumor microenvironment that are polarized toward M2 phenotype by IL-4 and IL-13 contribute to poor prognosis in HCC and promote tumor growth, invasion, and metastasis (Figure 1 and pages 4-5, in particular).
Yan et al teaches the TAM M2 phenotype, which promotes tumor invasion and metastasis, tends to predominate in the tumor microenvironment (right column on page 2, in particular). Yan et al further teaches E-cadherin is a connecting structure among epithelial cells and has strong and stable adhesion properties, while N-cadherin can be defined as a connecting structure among mesenchymal cells and shows weaker adhesion ability, a characteristic that is one of the causes underlying the increase in cell migration and invasion following EMT (paragraph spanning columns on page 2, in particular). Yan et al further teaches the most significant feature of a cell following EMT is the decrease in E-cadherin expression and increase in N-cadherin expression, which leads to an increase in cell migration and invasion following EMT (paragraph spanning columns on page 2, in particular). Yan et al further teaches the transcription factor Twist reduces E-cadherin expression (right column on page 2, in particular).
Castro et al teaches dupilumab is a human antibody that blocks both IL-4 and IL-13 signaling that has been approved to treat humans (left column on page 2486, in particular).
Zhao et al teaches testing for nuclear overexpression of Twist1 in HCC samples and that Twist1 nuclear overexpression in the samples correlates with HCC metastasis (page 694, in particular). Zhao et al further teaches elevated nuclear expression of Twist1 in HCC correlates with (i) elevated Twist1 cytoplasmic expression, (ii) elevated MMP-9 expression, and (iii) decreased E-cadherin expression (Fig. 5, in particular). Zhao et al further teaches elevated expression of Twist1 in HCC results in increased MMP9 and MMP2 activity (Fig. 3, in particular). Zhao et al further hypothesizes that Twist1 induces EMT-mediated metastasis through E-cadherin repression (page 696, in particular).
Chen et al teaches CCL2 enhances IL-6 induced EMT and cell invasion, decreases E-cadherin expression, and increases N-cadherin expression (Fig. 1, in particular). Figure 4 of Chen et al further teaches CCL2 greatly enhances IL-6-induced EMT events mainly by upregulating expression of Twist (same as “Twist1”).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of therapeutically inhibiting HCC tumor growth, invasion, and metastasis in a mammalian patient, such as a human or mouse, with HCC in a synergistic manner comprising administering the CCR2 antagonist and/or the antibody targeting CCL2 of Li et al in combination with dupilumab of Castro et al because Li et al teaches that blocking CCL2/CCR2 signaling, which can be done with the CCR2 antagonist and/or the antibody targeting CCL2 of Li et al, suppresses HCC tumor growth and metastasis in vivo, and Tian et al teaches TAMs in the HCC tumor microenvironment that are polarized toward M2 phenotype by IL-4 and IL-13 contribute to poor prognosis in HCC and promote tumor growth, invasion, and metastasis, and dupilumab of Castro et al is an antibody approved to treat humans that blocks both IL-4 and IL-13 signaling and would predictably inhibit tumor growth, invasion, and metastasis by blocking IL-4/IL-13 stimulation of TAMs toward the M2 phenotype.
In particular regards to claim 12, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further perform said combined method wherein the HCC is tested for expression of targets to be inhibited by the combined method (including IL-4, IL-13, and CCL2) in order to determine whether targets are present in the cancer to be therapeutically treated. As evidenced by the instant specification, such testing tests the cancer for “expression of a cytokinome associated with Twist1”, because the instant specification discloses Twist1 cytokinome includes CCL2 and IL13 (see [124] on page 32, in particular).
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of inhibiting HCC tumor growth, invasion, and metastasis wherein the patient is first tested for nuclear overexpression of Twist1 in HCC samples and found to have nuclear overexpression of Twist1 in the samples because identifying patients that have nuclear overexpression of Twist1 in HCC samples would predictably identify HCC patients that would benefit from inhibition of metastasis of the combined method because (i) Zhao et al teaches nuclear overexpression in HCC samples correlates with HCC metastasis and the combined method treats HCC metastasis and (ii) Chen et al teaches CCL2 greatly enhances IL-6-induced EMT events mainly by upregulating expression of Twist. Inhibiting upregulated Twist1 by the combined method that administers a CCR2 antagonist and/or the antibody targeting CCL2 would prevent CCL2 from enhancing upregulation of Twist and prevent an otherwise upregulated Twist1 from reducing E-cadherin expression (as taught by Yan et al) in an effort to prevent invasion by maintaining strong and stable adhesion by E-cadherin (as taught by Yan et al). This is an example of both (i) combining prior art elements according to known methods to yield predictable results and (ii) some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teaching to arrive at the claimed invention.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 4, 6, 10-15, and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (Hepatology, 2017, 66: 157-167) in view of Tian et al (Cell Biosci, 2019, 9(79): 1-10), Yan et al (Journal of Experimental & Clinical Cancer Research, 2018, 37(203): 1-13), Castro et al (NEJM, 2018, 378: 2486-2496), Zhao et al (J Cell Mol Med, 2011, 15(3): 691-700), and Chen et al (Tumor Biol, 2015, 36: 973-981), as applied to claims 1, 4, 6, and 10-15 above, and further in view of Teng et al (Molecular Cancer Therapeutics, 2016, 16(2): 312-322).
The teachings of Li et al, Tian et al, Yan et al, Castro et al, Zhao et al, and Chen et al are discussed above.
Li et al, Tian et al, Yan et al, Castro et al, Zhao et al, and Chen et al do not specifically teach patients treated by the combined method overexpress MYC. However, these deficiencies are made up in the teachings of Teng et al.
Teng et al teaches c-MYC (same as “MUC”) is a well-known oncogene that promotes hepatocellular carcinoma (HCC) proliferation (right column on page 318, in particular). Teng et al further teaches a neutralizing antibody that inhibits CCL2, resulting in CCL2-CCR2 blockade, suppresses HCC development and reduces overexpression of c-MYC in a mouse HCC model (Figure 5, in particular). Teng et al further postulates inhibition of HCC growth by targeting CCL2 is, at least in part, through inhibition of c-MYC expression (right column on page 318, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Li et al, Tian et al, Yan et al, Castro et al, Zhao et al, and Chen et al of therapeutically inhibiting HCC tumor growth, invasion, and metastasis in a patient with HCC comprising administering the CCR2 antagonist and/or the antibody targeting CCL2 of Li et al wherein the patient with HCC overexpresses c-MYC (same as “MYC”) because the CCR2 antagonist and/or the antibody targeting CCL2 of the combined method function by causing CCL2-CCR2 blockade and Teng et al teaches a neutralizing antibody that inhibits CCL2, resulting in CCL2-CCR2 blockade, suppresses HCC development and reduces overexpression of c-MYC (a well-known oncogene that promotes HCC proliferation) and postulates inhibition of HCC growth by targeting CCL2 is, at least in part, through inhibition of c-MYC expression (right column on page 318, in particular). This is an example of both (i) combining prior art elements according to known methods to yield predictable results and (ii) some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teaching to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SEAN E AEDER/Primary Examiner, Art Unit 1642