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 .
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 6/25/2026 is acknowledged. The election H01L03 as antibody and Zn-DTPA as drug species are also acknowledged. Claims 2-13 and 17-35 are pending, of which claims 2-13 and 17 are withdrawn from consideration at this time as being directed to a non-elected invention. Claims 24 and 27-29 are withdrawn as being directed to non-elected species of drug and sequence modified antibody. Claims 18-23, 25, 26 and 30-35 encompass the elected invention and species and are examined herein on the merits for patentability.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 18-23, 25, 26 and 30-35 are rejected under 35 U.S.C. 103 as being unpatentable over Nakata et al. (US 2021/0338852) in view of Jaggi et al. (Cancer Res, 2005, 65(11), p. 4888-4895).
Nakata teaches an RI-labeled anti-MUC5AC humanized antibody as a conjugate of a chelating agent chelated with a radionuclide and an antibody (the radionuclide is a metal nuclide that emits α particle or positron, and the antibody is a humanized antibody specifically binding to MUC5AC), and is superior in specificity for MUC5AC and accumulation in tumor. Therefore, it is extremely useful for the treatment and/or diagnosis of diseases in which MUC5AC is overexpressed, particularly cancer (abstract).
The radionuclide contained in the conjugate of the present invention is a metal nuclide that emits α particles. The metal nuclide may be any nuclide that emits α particles in the decay process of a radioactive metal. Specifically, 212Bi, 213Bi, 227Th, 225Ac, or the like is preferably used. More preferred is 227Th or 225Ac, and further preferred is 225Ac (actinium-225) (paragraph 0059).
The heavy chain variable region of the humanized antibody preferred in the present invention consists of the amino acid sequence shown in any one of SEQ ID NO: 1 to SEQ ID NO: 4, and the light chain variable region consists of the amino acid sequence shown in any one of SEQ ID NO: 5 to SEQ ID NO: 8. That is, the humanized antibody used in the present invention consists of a combination of the above-mentioned four heavy chain variable regions (H01-H04) and four light chain variable regions (L01-L04). A preferable humanized antibody in the present invention has heavy chain variable region H01, H03, or H04, and any one of L01-L04 as the light chain variable region (paragraph 0064-6).
As a preferred target disease, cancer can be mentioned. Examples of the cancer to be treated and diagnosed by the present invention include pancreatic cancer, thyroid cancer, liver cancer, colorectal cancer, gastric cancer, urothelial cancer, breast cancer, cervical cancer, ovarian cancer, and endometrial carcinoma, and particularly, application to pancreatic cancer is preferred (paragraph 0159).
The accumulation in the tumor was highest when the humanized antibody (H01L03) was administered, and lowest when the chimeric antibody was administered. The accumulation in the liver was highest when chimeric antibody was administered, and lower when any humanized antibody was administered as compared to the chimeric antibody. When the humanized antibody (H01L03) was administered, the excretion was the slowest and the blood retention was high. Regardless of which antibody was administered, the accumulation in the liver and spleen was high among the normal organs, followed by the accumulation in the lung and kidney.
In Example 5, 225Ac-labeled monovalent antibody using tumor-bearing mice was evaluated. The 225Ac-labeled monovalent antibody (H01L03) produced according to Example 1 was used. The 225Ac-labeled monovalent antibody showed a dose-dependent tumor growth inhibitory effect and statistically significantly suppressed tumor growth at all doses (paragraph 0223). Low kidney toxicity is stated in paragraph 0229.
Nakata does not specifically recite administration of a metal chelating drug (DTPA) that reduces renal toxicity.
Jaggi teaches that alpha-particle immunotherapy by targeted A-emitters or A emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radio nuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction in the renal 213Bi uptake; however, DMPS was more effective than DMSA. Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters (abstract).
In this study, we show the effectiveness of metal chelation in scavenging and, therefore, preventing the renal accumulation of free, radioactive bismuth. We also show the value of pharmacologic inhibition of metal reabsorption in different segments of the nephron in accelerating the clearance of the radioactive 225Ac daughters. Lastly, we report the effectiveness of competitive metal blockade and the role of tumor burden in altering the pharmaco kinetics and uptake of the daughter radionuclides in the kidneys. Each of these interventions could reduce the renal accumulation of 225Ac daughters (page 4889).
Animals received either 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) in drinking water (1.2 and 1.5 mg/mL, respectively) starting 1 day before injection with 225Ac generator and continued until the animals were sacrificed. The control animals received regular drinking water. The water bottles were replaced with fresh DMPS or regular water every 12 hours. The average water consumption was slightly lower in the DMPS-treated group (3.5 mL/mouse/d) compared with control animals (4 mL/mouse/d). For i.p. chelation therapy, 1.2 mg calcium-diethylenetriamine pentaacetate (Ca-DTPA) or DMPS was administered per animal in 2-hourly divided doses over 24 hours (page 4889).
Ca-DTPA treatment significantly prevented the renal 213Bi accumulation, but it was less potent than DMPS in doing so. Similar experiments conducted up to 8 days postinjection with the radiolabeled antibody showed similar reduction (58.4%, 65.3%, and 60.7% at 120, 144, and 192 hours, respectively) in the renal bismuth activity, thus confirming the results obtained at early time points (page 4890).
The doses of DMPS used in our studies are in the recommended 0.1 to 1 mmol/kg/d range for the treatment of heavy metal poisoning. Although the effective half-lives of many radio labeled antibodies in humans are usually measured in several days, the 10-day half-life of 225Ac and continuous generation of daughters may require that patients treated with 225Ac in vivo generator be administered chelation therapy for a relatively longer period. DMPS has been shown to be safe when used long term (months) for heavy metal detoxification trials in humans. The interexperimental variance in the tissue daughter activities at a given time point was expected owing to possible age-related variability in the capacity of the reticuloendothelial system to metabolize the labeled antibody (page 4894).
In summary, we tested the value of different pharmacologic agents and the role of tumor burden in altering the pharmacoki netics of the 225Ac-labeled antibody and the released decay daughters. The results suggest that chelation and diuretic therapy, alone or in combination, and competitive metal blockade to a certain extent can reduce the renal accumulation of 225Ac daughters. Therefore, these approaches could possibly enhance the therapeutic index of the 225Ac immunoconjugates. The findings support the use of dithiol chelators, thiazide diuretics, and furosemide as possible adjuvants for future clinical trials with 225Ac in vivo generators (page 4894).
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform a method of treating a tumor, comprising administering, to a mammal, an effective amount of a 225 Ac-labeled anti-MUC5AC humanized antibody (H01L03) and an effective amount of a drug that reduces renal toxicity when the teaching of Nakata is taken in view of Jaggi. One would have been motivated to do so, with a reasonable expectation of success, because Nakata teaches 225Ac-labeled anti-MUC5AC antibody for use in tumor therapy, including some accumulation in kidney as well as tumor, and Jaggi teaches that coadministration of a chelator for use with 225Ac immunotherapy can reduce the renal accumulation of 225Ac daughters and could enhance the therapeutic index of the 225Ac immunoconjugates.
Regarding claim 21 the steps of administering 225Ac antibody and metal chelate are taught by Jaggi, as such the time frame or late toxicity after administration would necessarily be met. With regard to claims 31-35, it would have been obvious to modify the order of addition of renal protectant such as simultaneous or sequential or coadministered in a formulation, as selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results). See MPEP 2144. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Claim(s) 18-23 and 30-35 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (US 2016/0090413) in view of Jaggi et al. (Cancer Res, 2005, 65(11), p. 4888-4895).
Liu teaches a chimeric, humanized or human antibody or antigen-binding fragment thereof that binds to an epitope located within the second to fourth cysteine-rich domains of MUC5ac (amino acid residues 1575-2052), wherein the antibody binds to 85% or more of pancreatic adenocarcinomas (claim 1). A method for diagnosing or treating cancer, comprising: (a) administering to a subject any one of the multivalent, multispecific antibodies or fragments thereof claimed herein that have an affinity toward an epitope located within the second to fourth cysteine-rich domains of MUC5ac (amino acid residues 1575-2052) and comprise one or more hapten binding sites; (b) waiting a sufficient amount of time for an amount of the non-bound antibody to clear the subject's blood stream; and (c) administering to said subject a carrier molecule comprising a diagnostic agent, a therapeutic agent, or a combination thereof, that binds to a binding site of the antibody. In a preferred embodiment the cancer is pancreatic cancer (paragraph 0037). Further taught is a method of treating a malignancy in a subject comprising administering to said subject a therapeutically effective amount of an antibody or fragment thereof that binds to an epitope located within the second to fourth cysteine-rich domains of MUC5ac (amino acid residues 1575-2052), optionally conjugated to at least one therapeutic agent. The antibody or fragment thereof may alternatively be a naked antibody or fragment thereof. In more preferred embodiments, the antibody or fragment is administered either before, simultaneously with, or after administration of another therapeutic agent as described above (paragraph 0038).
A therapeutic agent may comprise one or more radioactive isotopes useful for treating diseased tissue. Particularly useful therapeutic radionuclides include 111In, 177Lu, 212Bi, 213Bi, …225Ac, etc. Preferred are radionuclides that substantially decay with generation of alpha-particles. Such radionuclides include, but are not limited to: Dy-152, At-211, Bi-212, Ra-223, Rn-219, Po-215, Bi-211, Ac-225 (paragraph 0192-0194). See also claim 5 wherein the antibody or fragment thereof is conjugated to at least one therapeutic or diagnostic agent, including 225Ac.
Liu does not specifically recite administration of a metal chelating drug (DTPA) that reduces renal toxicity.
Jaggi teaches that alpha-particle immunotherapy by targeted A-emitters or A emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radio nuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction in the renal 213Bi uptake; however, DMPS was more effective than DMSA. Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters (abstract).
In this study, we show the effectiveness of metal chelation in scavenging and, therefore, preventing the renal accumulation of free, radioactive bismuth. We also show the value of pharmacologic inhibition of metal reabsorption in different segments of the nephron in accelerating the clearance of the radioactive 225Ac daughters. Lastly, we report the effectiveness of competitive metal blockade and the role of tumor burden in altering the pharmaco kinetics and uptake of the daughter radionuclides in the kidneys. Each of these interventions could reduce the renal accumulation of 225Ac daughters (page 4889).
Animals received either 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) in drinking water (1.2 and 1.5 mg/mL, respectively) starting 1 day before injection with 225Ac generator and continued until the animals were sacrificed. The control animals received regular drinking water. The water bottles were replaced with fresh DMPS or regular water every 12 hours. The average water consumption was slightly lower in the DMPS-treated group (3.5 mL/mouse/d) compared with control animals (4 mL/mouse/d). For i.p. chelation therapy, 1.2 mg calcium-diethylenetriamine pentaacetate (Ca-DTPA) or DMPS was administered per animal in 2-hourly divided doses over 24 hours (page 4889).
Ca-DTPA treatment significantly prevented the renal 213Bi accumulation, but it was less potent than DMPS in doing so. Similar experiments conducted up to 8 days postinjection with the radiolabeled antibody showed similar reduction (58.4%, 65.3%, and 60.7% at 120, 144, and 192 hours, respectively) in the renal bismuth activity, thus confirming the results obtained at early time points (page 4890).
The doses of DMPS used in our studies are in the recommended 0.1 to 1 mmol/kg/d range for the treatment of heavy metal poisoning. Although the effective half-lives of many radio labeled antibodies in humans are usually measured in several days, the 10-day half-life of 225Ac and continuous generation of daughters may require that patients treated with 225Ac in vivo generator be administered chelation therapy for a relatively longer period. DMPS has been shown to be safe when used long term (months) for heavy metal detoxification trials in humans. The interexperimental variance in the tissue daughter activities at a given time point was expected owing to possible age-related variability in the capacity of the reticuloendothelial system to metabolize the labeled antibody (page 4894).
In summary, we tested the value of different pharmacologic agents and the role of tumor burden in altering the pharmacokinetics of the 225Ac-labeled antibody and the released decay daughters. The results suggest that chelation and diuretic therapy, alone or in combination, and competitive metal blockade to a certain extent can reduce the renal accumulation of 225Ac daughters. Therefore, these approaches could possibly enhance the therapeutic index of the 225Ac immunoconjugates. The findings support the use of dithiol chelators, thiazide diuretics, and furosemide as possible adjuvants for future clinical trials with 225Ac in vivo generators (page 4894).
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform a method of treating a tumor, comprising administering, to a mammal, an effective amount of a 225 Ac-labeled anti-MUC5AC humanized antibody and an effective amount of a drug that reduces renal toxicity when the teaching of Liu is taken in view of Jaggi. One would have been motivated to do so, with a reasonable expectation of success, because Liu teaches 225Ac to be a preferred radionuclide conjugated to an anti-MUC5AC antibody for use as a cancer therapeutic, and Jaggi teaches that coadministration of a chelator for use with 225Ac immunotherapy can reduce the renal accumulation of 225Ac daughters and could enhance the therapeutic index of the 225Ac immunoconjugates.
Regarding claim 21 the steps of administering 225Ac antibody and metal chelate are taught by Jaggi, as such the time frame or late toxicity after administration would necessarily be met. With regard to claims 31-35, it would have been obvious to modify the order of addition of renal protectant such as simultaneous or sequential or coadministered in a formulation, as selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results). See MPEP 2144. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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