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 .
Priority
This Application is a 371 of PCT/KR2021/014360, filed Oct. 15, 2021, and claims foreign priority to KR10-2020-0139432, filed Oct. 26, 2020 and KR10-2021-0135651, filed Oct. 13, 2021, in the Republic of Korea.
Claim Status
Claims 1 and 9 are pending and subject to examination.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim(s) 1 and 9-10 under 35 U.S.C. 103 as being unpatentable over Wang & Xu (CN 110404077 A, Published Nov. 5, 2019) (of record) in view of Jain et al. (AU 2011329638 A1, published May 30, 2013) (of record) is withdrawn.
Claim Rejections – 35 USC § 103 – New Grounds of Rejection Necessitated By Amendment
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.
Claim(s) 1 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang & Xu (CN 110404077 A, Published Nov. 5, 2019) (of record) in view of Jain et al. (AU 2011329638 A1, published May 30, 2013) (of record) and Tamura et al. (Journal of Nuclear Medicine, November 2013, Vol. 54, No. 11, p. 1869-1875.
Claim 1 is directed towards:
A method of enhancing tumor penetration of an anticancer drug in a subject having a solid tumor comprising:
subcutaneously administering to the subject at a site outside the solid tumor a composition comprising a pharmaceutically acceptable amount of losartan as an active ingredient daily for at least 25 days; and
intravenously administering to the subject a single dose of trastuzumab as the anticancer drug, wherein the trastuzumab is conjugated to a chelator DOTA and labeled with a radioisotope copper-64;
wherein losartan is systemically distributed to the solid tumor and degrades collagen and hyaluronic acid in an extracellular matrix of the solid tumor to enhance uniform intratumoral penetration and distribution of the trastuzumab throughout an entire volume of the solid tumor
wherein the solid tumor is selected from the group consisting of
gastric cancer, lung cancer, brain tumor, lymphoma, colorectal cancer, and pancreatic cancer.
Wang teaches a method of enhancing tumor penetration of an anticancer drug in a subject having cancer comprising administering a composition comprising losartan as an active ingredient, wherein the anticancer drug is trastuzumab (Herceptin), and wherein the cancer is a solid tumor such as breast cancer, gastric cancer, lung cancer, colon cancer, brain cancer, or pancreatic cancer. Wang specifically demonstrates the anti-tumor effects of a combination of losartan and trastuzumab (Herceptin), wherein the oral dose of losartan is 40 mg/kg. Wang teaches the intratumoral injection of losartan every other day and oral losartan daily for 6 days (extratumoral administration of losartan), which is initiated at the same time as Herceptin therapy, then administer losartan by injection, every other day for 3 weeks:
In the present invention, preferably, independent system may be selected in tumour ECM degradation and/or inhibitor and anti-tumor drug Agent product. Tumour ECM
degradation and/or inhibitor can use preceding or simultaneously or after apply in anti-tumor drug With the specific time is first 48 hours to latter 48 hours that anti-tumor
drug uses time point. The frequency of use of hyaluronidase compared with It goodly is to arrive once a day monthly.
The present invention also provides a kind of application of complete kit in the drug for being used to prepare treating cancer.
In the present invention, as known to those skilled in the art, the cancer is generally solid tumor The cancer may include pancreas Cancer, oophoroma, lung cancer, colon cancer, prostate cancer, cervix cancer, head and neck cancer, carcinoma mesothelial, glioblastoma, breast cancer, liver Cancer and/or gastric cancer etc..
…
The positive effect of the present invention is that:
Tumour ECM provided by the present invention degradation and/or inhibitor can wide spectrum effectively degrade outside tumor tissue cell Matrix or inhibit tumor tissue cell's epimatrix generation, improve tumor tissues penetrability, allow drug effectively into Enter tumor tissues, contact and kill tumour cell, to improve the therapeutic effect of drug.
Wang, Translation, Specification, p. 6 (emphasis added);
In the present invention, the anti-tissue fibers agent is anti-tissue fibers agent commonly used in the art, preferably TGF β Inhibitor (transforming growth factor-β (transforming growth factor- β, TGF-β) inhibitor)；The TGF β inhibits Agent be preferably pirfenidone (Pirfenidone, 5- methyl-1-phenyl-2- (1H)-pyridone), Losartan (Losartan), Candesartan (Candesartan, 2- ethyoxyl -3- [[4- [2- (1H-TETRAZOLE -5- base) phenyl] phenyl] methyl] -3H- benzo Imidazoles -4- carboxylic acid) and one of melbine (Merformin) or a variety of；More preferably it is Losartan (Losartan).
Wang, Translation, Specification, p. 4 (emphasis added);
In the present invention, the anti-tumor drug is anti-tumor drug commonly used in the art, the anti-tumor drug Effective component is preferably oncolytic virus, immunocyte, CAR-T cell (Chimeric antigen receptor T cell (Chimeric Antigen Receptor-T cell, CAR-T)), TCR-T cell (T cell antigen receptor (T cell receptor, TCR)), antitumor chemical drug, targeting antibodies drug, ADC antibody drug (antibody drug conjugates (antibody-drug Conjugate, ADC)), immunologic test point inhibitor, one of nanoparticulate drug and corticosteroid or a variety of.
Wherein, preferably, the targeting antibodies drug preferably targets the anti-of ErbB-2 (Her-2) Body drug such as Herceptin.
Wang, Translation, Specification, p. 6 (emphasis added);
Experiment 5. intra-tumoral injection preparation of embodiment increases Herceptin (targeting ErbB-2 (Her- 2), Roche) to the growth inhibition effect of high expression hyaluronic acid breast cancer nude mouse subcutaneous transplantation tumor
BALB/c nude mouse, female, 6-8 week old, 20 ± 2g of weight, before inoculated tumour 2 days in the left back of every nude mouse Dorsal sc embeds estrogen sustained release tablets. Human breast carcinoma BT474/HAS2 obtained in embodiment 4 is inoculated in nude mouse after 2 days Right back, cell inoculation amount are 1 × 10 7 / only. Nude mouse subcutaneous transplantation tumor vernier caliper measurement transplantable tumor diameter, to tumour Grow to 150mm3Animal is grouped at random by gross tumor volume behind left and right.
Compare the test group of animals grouping of different preparation effects are as follows: solvent control group 10, administration group 6.Wherein it is administered Group Herceptin (15mg/kg) is intra-tumoral injection, respectively 1) Herceptin；2) Herceptin and preparation 1 are (real It applies in example 3 and is made)；3) Herceptin and preparation 2 (being made in embodiment 3)；4) Herceptin and preparation 3 are (in embodiment 3 It is made)；5) Herceptin+Mouse oral Losartan (40mg/kg, D-1 start to take orally daily, continuous 6 days). Intratumor injection In, preparation shifts to an earlier date 12hr and is injected, per injection 100 μ l, it is subsequent every other day, injection is primary. Herceptin is weekly It is administered twice, successive administration 3 weeks；Solvent control group then gives same amount of normal saline. In whole experiment process, measurement is moved 2 times a week It plants tumor diameter (including major diameter and minor axis), while weighing mouse weight
Wang, Translation, Specification, p. 7 (emphasis added).
Wang shows that the combination of Herceptin and losartan slows tumor growth as compared to losartan alone:
Gross tumor volume such as Fig. 1 of the different time of each experimental group of human breast carcinoma BT474/HAS2 Nude Mice, 2 institutes Show, as can be seen from Figure, in the tumor tissues of high ECM content, is individually used together Herceptin with PH20, or When individually Herceptin being used together with Losartan, tumour can only be made to increases slowly and not gross tumor volume be made to become smaller, And when preparation 2 or preparation 3 are used in combination with Herceptin respectively, the volume of tumour starts to become smaller as time goes by.
Wang, Translation, Specification, p. 8.
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Wang, Translation, Figures 1-2.
Formulation 3 also comprises losartan as an active ingredient:
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Wang, Translation, Table 3.
Wang teaches that the cancer includes: “cancer of pancreas, oophoroma, lung cancer, colon cancer, forefront Gland cancer, cervix cancer, head and neck cancer, carcinoma mesothelial, glioblastoma, breast cancer, gastric cancer and liver cancer.” (Wang, Translation, p. 2).
While Wang only teaches the extratumoral administration of losartan by an oral route, one of ordinary skill in the art would have a reasonable expectation of success to administer the losartan extratumorally and subcutaneously because it is commonly known in the art to administer losartan subcutaneously and extratumorally to enhance the penetration of an anti-tumor drug such as Herceptin.
For example, Jain teaches that losartan is an anti-hypertensive and/or a collagen modifying agent (AHCM) and angiotensin receptor blocker (ARB) that “normalizes the collagen, interstitial matrix of solid tumors and facilitates the distribution and/or penetration of 20 chemotherapeutics, including large molecular weight chemotherapeutics, e.g., nanotherapeutics.” (Jain, Specification, p. 2). Jain thus discloses “methods and compositions for improving the delivery and/or efficacy of therapeutics (e.g., cancer therapeutics)” comprising administering losartan with the therapeutic (id., p. 2-3). Jain teaches a method of treating a cancer in a subject comprising administering losartan in combination with a cancer therapy:
The inventors have discovered, inter alia, that losartan normalizes the collagen, interstitial matrix of solid tumors and facilitates the distribution and/or penetration of chemotherapeutics, including large molecular weight chemotherapeutics, e.g., nanotherapeutics. For example, losartan reduced collagen I levels in (e.g., reduced collagen production by) carcinoma associated fibroblasts (CAFs) isolated from breast cancer biopsies, and caused a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic and skin tumors in mice. Losartan also improved the distribution, therapeutic efficacy and/or penetration of nanopartices (e.g., oncolytic herpes simplex viruses (FISV) and pegylated liposomal doxorubicin (DOXIL®)). The inventors have also discovered that losartan facilitates decompression of blood vessels and vascular normalization, and improves tumor perfusion and delivery of low molecular weight chemotherapeutics, thus enhancing the therapeutic effect of radiation and chemotherapeutics.
Thus, methods and compositions for improving the delivery and/or efficacy of therapeutics (e.g., cancer therapeutics) are disclosed. Methods and compositions for treating or preventing a cancer (e.g., a solid tumor such as a desmoplastic tumor) by administering to a subject an anti-hypertensive and/or collagen modifying agent, as a single agent or in combination with a therapeutic agent (for example, a cancer therapeutic agent ranging in size from a large nanotherapeutic to a low molecular weight chemotherapeutics and/or oxygen radicals) are disclosed.
Jain, Specification, p. 2-3.
Jain teaches the anticancer agents include denosumab (Jain, Specification, p. 54, line 27), olaratumab (id., p. 55, line 3), panitumumab (id., p. 18, line 34), trastuzumab (id., p. 53, line 18), pertuzumab (id., p. 55, line 4), cetuximab (id., p. 18, line 34), rituximab (id., p. 55, line 6), and bevacizumab (id., p. 53, line 30).
Jain specifically teaches that the AHCM can be administered by a subcutaneous route:
In one embodiment, the AHCM is formulated as a tablet (e.g., an oral tablet). In other embodiments, the AHCM is formulated for other routes of administration, e.g., subcutaneous or intravenous administration.
Jain, Specification, p. 8;
The AHCM and/or the anticancer agent described herein can be administered to the subject systemically (e.g., orally, parenterally, subcutaneously…
Jain, Specification, p. 20.
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Jain, Specification, p. 66;
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Jain, Specification, p. 68;
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Jain, Specification, p. 71.
While Wang does not teach intratumor/subcutaneous injection daily for at least 25 days, one of ordinary skill in the art would have a reasonable expectation of success to administer the injection daily for at least 25 days because every other day dosing for 21 days is very similar to daily dosing for 25 days and Wang also teaches daily oral dosing for more than 25 days. It would be prima facie obvious to one of ordinary skill in the art to optimize the dosing schedule given the very similar teachings of Wang (see MPEP 2144.05). Furthermore, Jain teaches daily dosing:
In the present methods, losartan can be administered orally in a daily schedule (once or twice a day), alone or in combination with a cancer therapy described herein.
Jain, Specification, p. 6.
While Wang does not explicitly teach administering the losartan prior to the Herceptin, one of ordinary skill in the art would have a reasonable expectation of success to administer the losartan prior to the Herceptin because this is commonly known in the art.
For example, Jain teaches to administer the losartan prior to the anticancer agent:
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Jain, Specification, p. 3;
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Jain, Specification, p. 15;
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Jain, Specification, p. 16.
It is well known in the art that losartan would degrade collagen and hyaluronic acid in an extracellular matrix of the solid tumor, which enhances the intratumoral penetration and distribution of the trastuzumab throughout an entire volume of the solid tumor. This is an inherent property of systemic administration of losartan. For example, Jain teaches that systemically administered losartan normalizes the collagen and interstitial matrix of tumors and enhances the penetration of antitumor drugs:
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Jain, Specification, p. 77-80.
While Wang does not teach that the Herceptin is conjugated to the chelator DOTA and labelled with a radioisotope copper 64, one of ordinary skill in the art would have a reasonable expectation of success to administer to the subject a single dose of trastuzumab conjugated to the chelator DOTA and labelled with a radioisotope copper 64, because it is known in the art to administer radiolabeled antibodies for diagnostic and therapeutic purposes in conjunction with losartan and because Cu64-DOTA-trastuzumab is commonly known in the art.
For example, Jain teaches that the antibody may be radiolabeled for diagnostic imaging:
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Jain, Specification, p. 59.
For example, Tamura teaches to administer a single intravenous dose of Cu64-DOTA-Trastuzumab PET imaging in patients with metastatic HER2-Positive Breast Cancer: “All patients had received intravenous injections of 64Cu-DOTA trastuzumab.” (Tamura, p. 1870, col. 2);
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Tamura, Abstract.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 9 recites:
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As shown in the rejection of claim 1 above, Wang teaches a method of treating cancer, including pancreatic cancer, ovarian cancer, lung cancer, colon cancer, prostate cancer, cervix cancer, head and neck cancer, carcinoma mesothelial, glioblastoma, breast cancer, liver Cancer and/or gastric cancer etc., comprising administering a combination of losartan and trastuzumab (Herceptin). As shown above, Wang teaches that the losartan administration is started with the Herceptin administration and continued for six days (oral) and three weeks (intratumoral injection).
As shown in the rejection above, while Wang only teaches the oral administration of losartan to systemically deliver losartan, one of ordinary skill in the art would have a reasonable expectation of success to use subcutaneous administration instead of oral administration because Jain teaches systemic administration includes subcutaneous administration, which can continue for time periods of more than 25 days.
As shown in the rejection of claim 1, while Wang does not teach Cu64-DOTA-trastuzumab, one of ordinary skill in the art would have a reasonable expectation of success to administer Cu64-DOTA-trastuzumab because it is known in the art to administer radiolabeled antibodies for diagnostic and therapeutic purposes in conjunction with losartan and because Cu64-DOTA-trastuzumab is commonly known in the art.
Therefore, claim 9 was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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 extension fee 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 date of this final action.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629