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 I (claims 1 – 6, 9 – 10, 12, 15 – 16, 18 – 20, 26 – 29, and 41) drawn to a method for treating leptomeningeal metastasis in the reply filed on January 14th, 2026 is acknowledged.
Claim 45 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II (a kit for treating and/or preventing leptomeningeal metastasis), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 14th, 2026.
Claims 1 – 6, 9 – 10, 12, 15 – 16, 18 – 20, 26 – 29, 41, and 45 are currently pending in the application. However, due to a restriction requirement, claim 45 is withdrawn from further consideration and claims 1 – 6, 9 – 10, 12, 15 – 16, 18 – 20, 26 – 29, and 41 are being examined on the merits herein.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1 – 6, 9 – 10, 12, and 15 – 16 are rejected under 35 U.S.C. 103 as being unpatentable over Head et. al. ((1997), Antineoplastic drugs that interfere with iron metabolism in cancer cells, Advan. Enzyme Regul., 37, 147 – 169) in view of Oechsle et. al. ((2010), Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis, J Cancer Res Clin Oncol, 136, 1729 – 1735; cited on the IDS dated September 11th, 2023).
Regarding claims 1 – 6, 9 – 10, 12, and 16, Head et. al. teach that iron is an essential micronutrient that is required for cell division and growth in both normal and malignant cells (page 147 paragraph 1). Additionally, Head et. al. teach that the inhibition of normal iron metabolism with chelators of iron (claim 1)or antineoplastic agents bound to or covalently linked to transferrin can lead to significant inhibition of tumor cell growth in cell culture symptoms (page 147 paragraph 1). Moreover, Head et. al. teach that the iron chelator deferoxamine mesylate (claims 3 – 4) has been shown to chelate iron both outside and inside the cell and to inhibit tumor cell growth (claim 16) and division by inhibiting the activity of ribonucleotide reductase, an enzyme required for DNA synthesis (page 147 paragraph 2). Head et. al. teach that in one of the clinical trial studies using deferoxamine mesylate, deferoxamine mesylate was administered to nine neuroblastoma patients 150 mg/kg/day for 5 days and seven of the patients had responses, six had decreases in bone marrow infiltration and one had a decrease in tumor mass (page 147 paragraph 1). Furthermore, Head et. al. teach that in nude rat models of human small cell carcinoma of the lung (claim 5 and 6) abrin variant Pseudomonas exotoxin A or diphtheria toxin mutant cross-reacting material 107 complexed to human di-ferric transferrin; thus significantly delaying the onset of symptoms associated with leptomeningeal disease (claim 1) (page 151 paragraph 4). Thus, with this example Head et. al. suggest the feasibility of delaying the progression of a cancer, in particular, small cell lung cancer, towards leptomeningeal disease by sequestering iron.
Specifically, Head et. al. teach the intravenous administration of 300 mg/kg of deferoxamine mesylate into 6 week old (100 – 110 g; 0.1 – 0.11 kg) female Fisher rates that have been transplanted with 13762 NF rat mammary adenocarcinoma cells (claims 5 – 6) (page 153 paragraph 2). Moreover, Head et. al. teach that after treating the NF rats there was a 45 % reduction in tumor size as compared to the normal diet and the 25 % reduction for NF rats on a low iron diet (page 160 Table 5). Furthermore, Head et. al. teach that a Phase I – II clinical trial was conducted to determine if the sequential combination of a chelator (deferoxamine mesylate at 6 g/day in 8 hours), cisplatin transferrin complex (claim 9) and a classic cytotoxic chemotherapeutic regimen could be administered to breast cancer patients (claim 6) without unacceptable toxicity (page 154 paragraph 2). And Head et. al. teach that an alternative purpose for the Phase I – II trial was to determine whether there would be a reasonable response rate to the proposed therapeutic regimen (page 154 paragraph 2).
Specifically, Head et. al. teach that in the second clinic study in advanced breast cancer patients, the patients were administered deferoxamine mesylate, followed by the common chemotherapeutic agent cisplatin complexed to transferrin and finally FAC(5-fluorouracil, doxorubicin and cyclophosphamide at 450, 45 and 450 mg/m2, respectively) sequentially (page 161 paragraph 2). Moreover, Head et. al. teach that after the administration of this sequential therapy, seven of eight advanced breast cancer patients had a partial response with toxicities of this sequential combination therapy similar to the toxicities associated with the FAC therapy alone(page 161 paragraph 2).
Regarding claim 15, recitation for a method wherein the iron chelator is administered to the subject at a dose from about 0.05 mg/kg to about 100 mg/kg; as stated previously, Head et. al. teach the use of deferoxamine mesylate at 150 mg/kg/day to treat a cancer. Now while the value of 150 mg/kg is slightly larger than 100 mg/kg the two values are within the same magnitude of value. Thus a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)). Moreover, in general differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).(MPEP 2144.05(II)A).
However, while Head et. al. taught that in nude rat models of human small cell carcinoma of the lung (claim 5 and 6) complexing human di-ferric transferrin significantly delayed the onset of symptoms associated with leptomeningeal disease Head et. al. fail to teach a method of treating leptomeningeal metastasis in a subject (claim 1) wherein an iron chelator is administered.
Nevertheless, Oechsle et. al. teach that Leptomeningeal metastases are a rare clinical picture occurring in only 5-8% of all patients with malignant diseases (page 1729 column 2 paragraph 3). Oechsle et. al. teach that Leptomeningeal metastases occurrence always imply a very limited prognosis with median survival times of 1.8 – 5.8 months (page 1729 column 2 paragraph 3). Moreover, Oechsle et. al. teach that leptomeningeal metastases are associated with advanced disease and are observed in patients with primary tumor entities, which tend to form out solid parenchymal cerebral metastases frequently, e.g. malignant melanoma, lung and breast cancer with rates of development of leptomeningeal metastases up to 20% (page 1729 column 2 paragraph 3). Furthermore, Oechsle et. al. teach that once malignant cells have entered into the cerebrospinal fluid (CSF) by hematogenous spread, endoor perineural spread along peripheral nerves, or by direct spread from parenchymal cerebral metastases, they can extend at every location in the neurospinal axis (page 1730 column 1 paragraph 1). Hence, Oechsle et. al. teach that leptomeningeal metastasis can cause almost any neurologic symptom originating in the different areas of the central nervous system, brain, cranial nerves and spinal cord (page 1730 column 1 paragraph 1). Additionally, Oechsle et. al. teach that usual treatment of leptomeningeal metastases includes different treatment modalities, such as intrathecal (claim 2) and systemic chemotherapy, radiotherapy (claim 10) and surgery (page 1730 column 1 paragraph 2).
Oechsle et. al. teach that the purpose of their study is to determine prognostic factors in patients with leptomeningeal metastasis and to retrospectively analyze the efficacy of different treatment modalities administered within daily clinical practice in patients with leptomeningeal metastases of different malignant diseases (page 1730 column 1 paragraph 4). Also, Oechsle et. al. teach that out of the 135 consecutive patients evaluated in the study patients that received the systemic chemotherapy at the time of leptomeningeal metastases was first-line chemotherapy in 16 patients (25% ), second-line for relapsed or progressive disease (claim 12) in 42 patients (65%) and more than second-line in 7 patients (10%) (page 1730 column 2 paragraph 2). Furthermore, Oechsle et. al. teach that based on the treatment modalities applied to these patients, regardless of the primary disease, the median survival was longest in patients undergoing systemic plus intrathecal chemotherapy (5.6 months) and patients with three-fold combination treatment including additional irradiation (5.8 months) (page 1732 column 2 paragraph 3).
Regarding claim 16, recitation for a method wherein administration of the iron chelator reduces the proliferation and/or survival of metastatic cancer cells in the cerebrospinal fluid of the subject; as taught above, Head et. al. teach that the iron chelator deferoxamine mesylate has been shown to chelate iron both outside and inside the cell and to inhibit tumor cell growth (claim 16) and division by inhibiting the activity of ribonucleotide reductase, an enzyme required for DNA synthesis (page 147 paragraph 2).
Moreover, as taught above, Oechsle et. al. teach that regardless of the primary disease, patients with leptomeningeal metastasis that were treated with systemic plus intrathecal chemotherapy or the three-fold combination treatment which included additional irradiation had a median survival rate of 5.6 months and 5.8 months respectively. Thus given that the skill of one of ordinary skill in the art is relatively high as that of a clinical researcher or research physician, and given the teachings of Head et.al. and Oechsle et. al. as taught above, it would have been reasonable to expectation that deferoxamine mesylate can inhibit tumor cell growth in tumor cells that have made it to the cerebrospinal fluid (CSF), that is leptomeningeal metastasis.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the treatment regime of Heads et. al. for a method of treating cancer in view of Oechsle et. al. for the treatment of leptomeningeal metastasis. One of ordinary skill in the art would have been motivated to make this modification to improve the median survival times of patients suffering with advanced cancers that have development leptomeningeal metastasis. One of ordinary skill in the art would have had a reasonable expectation of success because the median survival rate of patients undergoing systemic plus intrathecal chemotherapy was 5.6 months and 5.8 months for patients with three-fold combination treatment which included additional irradiation.
Claims 18 – 20, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Head et. al. ((1997), Antineoplastic drugs that interfere with iron metabolism in cancer cells, Advan. Enzyme Regul., 37, 147 – 169) in view of Oechsle et. al. ((2010), Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis, J Cancer Res Clin Oncol, 136, 1729 – 1735; cited on the IDS dated September 11th, 2023).
The prior art teachings of Head et. al. and Oechsle et. al. as they relate to claims 1 – 6, 9 – 10, 12, and 16, are given previously in this office action and are fully incorporated here.
Regarding claim 18, recitation for a method for preventing or reducing the risk of leptomeningeal metastasis in a subject having cancer, comprising administering a therapeutically effective amount of an iron chelator to the subject; as taught above, Head et. al. teach that the iron chelator deferoxamine mesylate (claim20) has been shown to chelate iron both outside and inside the cell and to inhibit tumor cell growth and division by inhibiting the activity of ribonucleotide reductase, an enzyme required for DNA synthesis (page 147 paragraph 2). Head et. al. teach that in one of the clinical trials deferoxamine mesylate was administered to nine neuroblastoma patients 150 mg/kg/day for 5 days and seven of the patients had responses, six had decreases in bone marrow infiltration and one had a decrease in tumor mass (page 147 paragraph 1).
Furthermore, Head et. al. teach that a Phase I – II clinical trial was undertaken to determine if the sequential combination of a chelator (deferoxamine mesylate at 6 g/day in 8 hours), cisplatin transferrin complex and a classic cytotoxic chemotherapeutic regimen could be administered to breast cancer patients without unacceptable toxicity. Moreover, Head et. al. teach that another purpose of the Phase trial was to determine whether there would be a reasonable response rate to the therapeutic regimen (page 154 paragraph 2). Head et. al. teach that said clinic trial the sequential administration of deferoxamine mesylate, cisplatin complexed to transferrin, and finally FAC therapy led to a partial repose in seven of eight advanced breast cancer patients with toxicities similar to those associated with the FAC therapy alone (page 161 paragraph 2).
Moreover, Oechsle et. al. teach that Leptomeningeal metastases are a rare clinical picture occurring in only 5-8% of all patients with malignant diseases (page 1729 column 2 paragraph 3) but that the occurrence always imply a very limited prognosis with median survival times of 1.8 – 5.8 months (page 1729 column 2 paragraph 3). Additionally, Oechsle et. al. teach that leptomeningeal metastases are associated with advanced disease and are observed in patients with primary tumor entities, which tend to form out solid parenchymal cerebral metastases frequently, e.g. malignant melanoma, lung and breast cancer, with rates of development of up to 20% (page 1729 column 2 paragraph 3). Thus given that the skill of one of ordinary skill in the art is relatively high as that of a clinical researcher or research physician, and given the teachings of both Head et.al. and Oechsle et. al. as taught above, it would have been obvious to one of ordinary skill in the art to try and administer the iron chelator to patients with breast or lung cancers in particular to treat the cancer before it would progress to leptomeningeal metastasis.
Regarding claim 19, recitation for a method of claim 18, wherein the iron chelator is administered intrathecally; as taught above, Head et. al. teach the intravenous administration of 300 mg/kg of deferoxamine mesylate into 6 week old (100 – 110 g; 0.1 – 0.11 kg) female Fisher rates that have been transplanted with 13762 NF rat mammary adenocarcinoma cells (page 153 paragraph 2). Moreover, Head et. al. teach that after treating the NF rats there was a 45 % reduction in tumor size as compared to the normal diet and the 25 % reduction for NF rats on a low iron diet (page 160 Table 5).
Now while Head et. al. does not teach the intrathecally administration; the prior art of Oechsle et. al. teach that regardless of the primary disease, patients with leptomeningeal metastasis that were treated with systemic plus intrathecal chemotherapy or the three-fold combination treatment which included additional irradiation had a median survival rate of 5.6 months and 5.8 months respectively. Thus given that the skill of one of ordinary skill in the art is relatively high as that of a clinical researcher or research physician, and given the teachings of both Head et.al. and Oechsle et. al. as taught above, it would have been obvious to one of ordinary skill in the art to try and administer the iron chelator intrathecally at least in combination with systemic or three-fold combination treatment since the prior art taught that such treatment had a median survival rate of 5.6 months and 5.8 months respectively.
Regarding claim 20, recitation for a method of claim 18, wherein the iron chelator is deferoxamine or a salt thereof; as taught above, Head et. al. teach the intravenous administration of 300 mg/kg of deferoxamine mesylate into 6 week old (100 – 110 g; 0.1 – 0.11 kg) female Fisher rates that have been transplanted with 13762 NF rat mammary adenocarcinoma cells (page 153 paragraph 2). Moreover, Head et. al. teach that after treating the NF rats there was a 45 % reduction in tumor size as compared to the normal diet and the 25 % reduction for NF rats on a low iron diet (page 160 Table 5).
Additionally, Head et. al. teach that in one of the clinical trial studies using deferoxamine mesylate, deferoxamine mesylate was administered to nine neuroblastoma patients 150 mg/kg/day for 5 days and seven of the patients had responses, six had decreases in bone marrow infiltration and one had a decrease in tumor mass (page 147 paragraph 1). Thus given that the skill of one of ordinary skill in the art is relatively high as that of a clinical researcher or research physician, and given the teachings Head et.al. and Oechsle et. al. as taught above, it would have been obvious to one of ordinary skill in the art to try and administer deferoxamine mesylate as the iron chelator for the preventing or reducing the risk of leptomeningeal metastasis since the prior art demonstrated that using deferoxamine mesylate, at 150 mg/kg/day for 5 days produced partial response in seven of the nine patients with six patients having decreased bone marrow infiltration and one having a decrease in tumor mass (page 147 paragraph 1).
Regarding claims 26, recitation for a method of claim 18, wherein : (a) wherein the iron chelator is administered to the subject at a dose from about 0.05 mg/kg to about 100 mg/kg; (b) wherein the cancer is selected from breast cancer and lung cancer; (c) wherein the subject was not known to have leptomeningeal metastasis prior to treatment with the iron chelator; and (d) further comprising administering a therapeutically effective amount of an anticancer agent to the subject; and/or (e) wherein the subject was previously treated with radiation therapy; as stated previously, Head et. al. teach the use of deferoxamine mesylate at 150 mg/kg/day to treat a cancer. Now while the value of 150 mg/kg is slightly larger than 100 mg/kg the two values are within the same magnitude of value. Thus a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)). Moreover, in general differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).(MPEP 2144.05(II)A).
Moreover, regarding claim 26 recitation wherein the cancer is breast cancer or lung cancer; the prior art of Head et. al. taught that in a second clinic study in advanced breast cancer patients when the patients were administered a sequential administration of the chelator deferoxamine mesylate, followed by the common chemotherapeutic agent cisplatin complexed to transferrin and finally FAC (5-fluorouracil, doxorubicin and cyclophosphamide at 450, 45 and 450 mg/m2, respectively) therapy; seven of eight advanced breast cancer patients had a partial response (page 161 paragraph 2).
Moreover, as taught by Oechsle et. al. leptomeningeal metastases are associated with advanced disease and are observed in patients with primary tumor entities, which tend to form out solid parenchymal cerebral metastases frequently, e.g. malignant melanoma, lung and breast cancer with rates of development of leptomeningeal metastases up to 20% (page 1729 column 2 paragraph 3). Therefore since the prior art of Head et. al. establishes that the iron chelator deferoxamine mesylate was useful in advanced breast cancer patients; and since the prior art of Oechsle et. al. establishes that leptomeningeal metastases forms in advanced cancer patients especially those with lung and breast primary tumors it would have been obvious to one of ordinary skill in the art to attempt to treat preemptively treat said patients to prevent the breast cancer from progressing to leptomeningeal metastasis . One of ordinary skill in the art would have been motivated to try since the median survival times for leptomeningeal metastasis 1.8 – 5.8 months (page 1729 column 2 paragraph 3). Moreover, one of ordinary skill in the art would have had a reasonable expectation for success because in a nude rat model of human small cell carcinoma of the lung when variant Pseudomonas exotoxin A or diphtheria toxin mutant cross-reacting material 107 complexed to human di-ferric transferrin; there was a significant delay in the onset of symptoms associated with leptomeningeal disease.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the treatment regime of Heads et. al. for a method of treating cancer in view of Oechsle et. al. for the treatment of leptomeningeal metastasis. One of ordinary skill in the art would have been motivated to make this modification to avoid cancers like lung cancer and breast cancer developing leptomeningeal metastasis. One of ordinary skill in the art would have had a reasonable expectation of success because in a clinical trial when deferoxamine mesylate was administered to nine neuroblastoma patients at 150 mg/kg/day for 5 days and seven of the patients had responses, six had decreases in bone marrow infiltration and one had a decrease in tumor mass.
Claims 27 – 29, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Head et. al. ((1997), Antineoplastic drugs that interfere with iron metabolism in cancer cells, Advan. Enzyme Regul., 37, 147 – 169) in view of Oechsle et. al. ((2010), Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis, J Cancer Res Clin Oncol, 136, 1729 – 1735; cited on the IDS dated September 11th, 2023).
The prior art teachings of Head et. al. and Oechsle et. al. as they relate to claims 1 – 6, 9 – 10, 12, and 16, are given previously in this office action and are fully incorporated here.
Regarding claim 27, recitation for a method for lengthening the period of survival of a subject having a cancer, comprising administering a therapeutically effective amount of an iron chelator to the subject; as taught above, Head et. al. teach that the iron chelator deferoxamine mesylate (claim20) has been shown to chelate iron both outside and inside the cell and to inhibit tumor cell growth and division by inhibiting the activity of ribonucleotide reductase, an enzyme required for DNA synthesis (page 147 paragraph 2). Head et. al. teach that in one of the clinical trials deferoxamine mesylate was administered to nine neuroblastoma patients 150 mg/kg/day for 5 days and seven of the patients had responses, six had decreases in bone marrow infiltration and one had a decrease in tumor mass (page 147 paragraph 1).
Furthermore, Head et. al. teach that a Phase I – II clinical trial was undertaken to determine if the sequential combination of a chelator (deferoxamine mesylate at 6 g/day in 8 hours), cisplatin transferrin complex and a classic cytotoxic chemotherapeutic regimen could be administered to breast cancer patients without unacceptable toxicity. Moreover, Head et. al. teach that another purpose of the Phase trial was to determine whether there would be a reasonable response rate to the therapeutic regimen (page 154 paragraph 2). Head et. al. teach that said clinic trial the sequential administration of deferoxamine mesylate, cisplatin complexed to transferrin, and finally FAC therapy led to a partial repose in seven of eight advanced breast cancer patients with toxicities similar to those associated with the FAC therapy alone (page 161 paragraph 2).
Moreover, Oechsle et. al. teach that Leptomeningeal metastasis are a rare clinical picture occurring in only 5-8% of all patients with malignant diseases (page 1729 column 2 paragraph 3) but that the occurrence always imply a very limited prognosis with median survival times of 1.8 – 5.8 months (page 1729 column 2 paragraph 3). Additionally, Oechsle et. al. teach that leptomeningeal metastasis are associated with advanced disease and are observed in patients with primary tumor entities, which tend to form out solid parenchymal cerebral metastasis frequently, e.g. malignant melanoma, lung and breast cancer, with rates of development of up to 20% (page 1729 column 2 paragraph 3). Oechsle et. al. teach that the purpose of their study is to determine prognostic factors in patients with leptomeningeal metastasis and to retrospectively analyze the efficacy of different treatment modalities administered within daily clinical practice in patients with leptomeningeal metastasis of different malignant diseases (page 1730 column 1 paragraph 4). Also, Oechsle et. al. teach that out of the 135 consecutive patients evaluated in the study patients that received the systemic chemotherapy at the time of leptomeningeal metastasis was first-line chemotherapy in 16 patients (25% ), second-line for relapsed or progressive disease (claim 12) in 42 patients (65%) and more than second-line in 7 patients (10%) (page 1730 column 2 paragraph 2). Furthermore, Oechsle et. al. teach that based on the treatment modalities applied to these patients, regardless of the primary disease, the median survival was longest in patients undergoing systemic plus intrathecal chemotherapy (5.6 months) and patients with three-fold combination treatment including additional irradiation (5.8 months) (page 1732 column 2 paragraph 3).
Thus given that the skill of one of ordinary skill in the art is relatively high as that of a clinical researcher or research physician, and given the teachings of both Head et.al. and Oechsle et. al. as taught above, it would have been obvious to one of ordinary skill in the art to try and administer the iron chelator to patients with breast or lung cancers in particular to treat the cancer before it would progress to leptomeningeal metastasis to lengthen the period of survival of the subject.
Regarding claim 28, recitation for a method of claim 27, wherein the iron chelator is administered intrathecally; as taught above, Head et. al. teach the intravenous administration of 300 mg/kg of deferoxamine mesylate into 6 week old (100 – 110 g; 0.1 – 0.11 kg) female Fisher rates that have been transplanted with 13762 NF rat mammary adenocarcinoma cells (page 153 paragraph 2). Moreover, Head et. al. teach that after treating the NF rats there was a 45 % reduction in tumor size as compared to the normal diet and the 25 % reduction for NF rats on a low iron diet (page 160 Table 5).
Now while Head et. al. does not teach the intrathecally administration; the prior art of Oechsle et. al. teach that regardless of the primary disease, patients with leptomeningeal metastasis that were treated with systemic plus intrathecal chemotherapy or the three-fold combination treatment which included additional irradiation had a median survival rate of 5.6 months and 5.8 months respectively. Thus given that the skill of one of ordinary skill in the art is relatively high as that of a clinical researcher or research physician, and given the teachings of both Head et.al. and Oechsle et. al. as taught above, it would have been obvious to one of ordinary skill in the art to try and administer the iron chelator intrathecally at least in combination with systemic or three-fold combination treatment since the prior art taught that such treatment had a median survival rate of 5.6 months and 5.8 months respectively.
Regarding claim 29, recitation for a method of claim 27, wherein the iron chelator is deferoxamine or a salt thereof; as taught above, Head et. al. teach the intravenous administration of 300 mg/kg of deferoxamine mesylate into 6 week old (100 – 110 g; 0.1 – 0.11 kg) female Fisher rates that have been transplanted with 13762 NF rat mammary adenocarcinoma cells (page 153 paragraph 2). Moreover, Head et. al. teach that after treating the NF rats there was a 45 % reduction in tumor size as compared to the normal diet and the 25 % reduction for NF rats on a low iron diet (page 160 Table 5).
Additionally, Head et. al. teach that in one of the clinical trial studies using deferoxamine mesylate, deferoxamine mesylate was administered to nine neuroblastoma patients 150 mg/kg/day for 5 days and seven of the patients had responses, six had decreases in bone marrow infiltration and one had a decrease in tumor mass (page 147 paragraph 1). Thus given that the skill of one of ordinary skill in the art is relatively high as that of a clinical researcher or research physician, and given the teachings Head et.al. and Oechsle et. al. as taught above, it would have been obvious to one of ordinary skill in the art to try and administer deferoxamine mesylate since using deferoxamine mesylate, at 150 mg/kg/day for 5 days produced partial response in seven of the nine patients with six patients having decreased bone marrow infiltration and one having a decrease in tumor mass (page 147 paragraph 1).
Regarding claims 41, recitation for a method of claim 27, wherein : (a) wherein the iron chelator is administered to the subject at a dose from about 0.05 mg/kg to about 100 mg/kg; (b) wherein the cancer is selected from breast cancer and lung cancer; (c) wherein the subject was not known to have leptomeningeal metastasis prior to treatment with the iron chelator; and (d) further comprising administering a therapeutically effective amount of an anticancer agent to the subject; and/or (e) wherein the subject was previously treated with radiation therapy; as stated previously, Head et. al. teach the use of deferoxamine mesylate at 150 mg/kg/day to treat a cancer. Now while the value of 150 mg/kg is slightly larger than 100 mg/kg the two values are within the same magnitude of value. Thus a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)). Moreover, in general differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).(MPEP 2144.05(II)A).
Moreover, regarding claim 41 recitation wherein the cancer is breast cancer or lung cancer; the prior art of Head et. al. taught that in a second clinic study in advanced breast cancer patients when the patients were administered a sequential administration of the chelator deferoxamine mesylate, followed by the common chemotherapeutic agent cisplatin complexed to transferrin and finally FAC (5-fluorouracil, doxorubicin and cyclophosphamide at 450, 45 and 450 mg/m2, respectively) therapy; seven of eight advanced breast cancer patients had a partial response (page 161 paragraph 2).
Moreover, as taught by Oechsle et. al. leptomeningeal metastasis are associated with advanced disease and are observed in patients with primary tumor entities, which tend to form out solid parenchymal cerebral metastasis frequently, e.g. malignant melanoma, lung and breast cancer with rates of development of leptomeningeal metastases up to 20% (page 1729 column 2 paragraph 3). Therefore since the prior art of Head et. al. establishes that the iron chelator deferoxamine mesylate was useful in advanced breast cancer patients; and since the prior art of Oechsle et. al. establishes that leptomeningeal metastases forms in advanced cancer patients especially those with lung and breast primary tumors it would have been obvious to one of ordinary skill in the art to attempt to treat preemptively treat said patients to prevent the breast cancer from progressing to leptomeningeal metastases. Furthermore, given that the prior art of Oechsle et. al. teach that based on the treatment modalities applied to these patients, regardless of the primary disease, the median survival was longest in patients undergoing systemic plus intrathecal chemotherapy (5.6 months) and patients with three-fold combination treatment including additional irradiation (5.8 months) (page 1732 column 2 paragraph 3), which is about it would have been obvious to one of ordinary skill in the art to try and administer the iron chelator to patients with breast or lung cancers in particular to treat the cancer before it would progress to leptomeningeal metastasis to lengthen the period of survival of the subject.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the treatment regime of Heads et. al. for a method of treating cancer in view of Oechsle et. al. for the lengthening the treatment of leptomeningeal metastasis. One of ordinary skill in the art would have been motivated to make this modification to avoid cancers like lung cancer and breast cancer developing leptomeningeal metastasis. One of ordinary skill in the art would have had a reasonable expectation of success because the median survival was longest in patients undergoing systemic plus intrathecal chemotherapy (5.6 months) and patients with three-fold combination treatment including additional irradiation (5.8 months) (page 1732 column 2 paragraph 3).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1 – 6, 9 – 10, 12, 15 – 16, 17 – 20, 26 – 29, and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, and 5 – 6 of U.S. Patent No. US 11305014 B2 to Boire et. al. (herein after Boire’014) in view of Head et. al. ((1997), Antineoplastic drugs that interfere with iron metabolism in cancer cells, Advan. Enzyme Regul., 37, 147 – 169) and Oechsle et. al. ((2010), Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis, J Cancer Res Clin Oncol, 136, 1729 – 1735; cited on the IDS dated September 11th, 2023).
Boire’014 recite a method of treating leptomeningeal metastasis (instant claims 1 and 18) in a subject with cancer (instant claim 5), comprising diagnosing leptomeningeal metastasis in the subject and administering an effective inhibitory amount of an antagonist of C3 or C3aR to the subject (reference claim 1) wherein the cancer is breast cancer (instant claims 6, 26, and 41), lung cancer, or melanoma (reference claim 2); comprising further treating the subject with a second therapeutic agent (reference claim 5; instant claims 9, 26, and 41); and wherein the second therapeutic agent is a chemotherapeutic agent (reference claim 6; instant claim 9, 26, and 41).
However, Boire’014 fails to recite a method for treating leptomeningeal metastasis in a subject, comprising administering a therapeutically effective amount of an iron chelator to the subject (instant claim 1); a method for preventing or reducing the risk of leptomeningeal metastasis in a subject having cancer, comprising administering a therapeutically effective amount of an iron chelator to the subject (instant claim 18); or a method for lengthening the period of survival of a subject having a cancer, comprising administering a therapeutically effective amount of an iron chelator to the subject (instant claim 27).
Nevertheless, the prior art of Head et. al. and Oechsle et. al. as they relate to the prior art rejections of instant claims 1 – 6, 9 – 10, 12, 15 – 16, 17 – 20, 26 – 29, and 41, are given previously in this office action and are fully incorporated here.
Therefore it would have been obvious before the effective filing date of the instant application to modify copending Boire’014 for a method for treating/preventing leptomeningeal metastasis or lengthening the period of survival of a subject with cancer in view of Head et. al., that is to include the iron chelator of deferoxamine mesylate in further view of Oechsle et. al. to administer the iron chelator intrathecally. One of ordinary skill in the art would have been motivated to make this modification to improve the median survival times of patients suffering with advanced cancers that have development leptomeningeal metastasis. One of ordinary skill in the art would have had a reasonable expectation of success because the median survival rate of patients undergoing systemic plus intrathecal chemotherapy was 5.6 months and 5.8 months for patients with three-fold combination treatment which included additional irradiation.
Claims 1 – 6, 9 – 10, 12, 15 – 16, 18 – 20, 26 – 29, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16 – 23, and 38 of copending Application No. 19/161882 to Boire et. al. (herein after Boire’882) in view of Head et. al. ((1997), Antineoplastic drugs that interfere with iron metabolism in cancer cells, Advan. Enzyme Regul., 37, 147 – 169) and Oechsle et. al. ((2010), Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis, J Cancer Res Clin Oncol, 136, 1729 – 1735; cited on the IDS dated September 11th, 2023).
Boire’882 recite a method of treating leptomeningeal metastasis (reference claim 3, 21 – 23, and 38; instant claims 1 and 18) in a subject afflicted with cancer (instant claim 5), the method comprising administering to the subject a viral vector that encodes for at least one IL-12 peptide, at least one IL-15 peptide, and/or at least one interferon peptide (reference claims 1 and 19); wherein the cancer is breast cancer (instant claims 6, 26, and 41), lung cancer, a colon cancer, a cervical cancer, a pancreatic cancer, a renal cancer, a stomach cancer, a GI cancer, a liver cancer, a bone cancer, a hematological cancer, a neural tissue cancer, a melanoma, a thyroid cancer, a ovarian cancer, a testicular cancer, a prostate cancer, a cervical cancer, a vaginal cancer, or a bladder cancer (reference claim 16); wherein the cancer comprises a tumor (reference claims 17 and 18).
However, Boire’882 fails to recite a method for treating leptomeningeal metastasis in a subject, comprising administering a therapeutically effective amount of an iron chelator to the subject (instant claim 1); a method for preventing or reducing the risk of leptomeningeal metastasis in a subject having cancer, comprising administering a therapeutically effective amount of an iron chelator to the subject (instant claim 18); or a method for lengthening the period of survival of a subject having a cancer, comprising administering a therapeutically effective amount of an iron chelator to the subject (instant claim 27).
Nevertheless, the prior art of Head et. al. and Oechsle et. al. as they relate to the prior art rejections of instant claims 1 – 6, 9 – 10, 12, 15 – 16, 17 – 20, 26 – 29, and 41, are given previously in this office action and are fully incorporated here.
Therefore it would have been obvious before the effective filing date of the instant application to modify copending Boire’882 for a method for treating/preventing leptomeningeal metastasis or lengthening the period of survival of a subject with cancer in view of Head et. al., that is to include the iron chelator of deferoxamine mesylate in further view of Oechsle et. al. to administer the iron chelator intrathecally. One of ordinary skill in the art would have been motivated to make this modification to improve the median survival times of patients suffering with advanced cancers that have development leptomeningeal metastasis. One of ordinary skill in the art would have had a reasonable expectation of success because the median survival rate of patients undergoing systemic plus intrathecal chemotherapy was 5.6 months and 5.8 months for patients with three-fold combination treatment which included additional irradiation.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1 – 6, 9 – 10, 12, 15 – 16, 18 – 20, 26 – 29, and 41 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627