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 .
Specification
The spacing of the lines of the specification is such as to make reading difficult. New application papers with lines 1 1/2 or double spaced (see 37 CFR 1.52(b)(2)) are required.
The use of the terms “Chiral Pak” on page 25 line 19, “Cell titer Glo” on page 33 line 16, and “GraphPad Prism 8” on page 33 line 24, which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
The claims are objected to because the lines are crowded too closely together, making reading difficult. Substitute claims with lines one and one-half or double spaced on good quality paper are required. See 37 CFR 1.52(b).
Claims 1, 16, 20, 22, 24 – 25, and 30 – 32 are objected to because of the following informalities: the compound labels do not appear directly under the compound that the label refers to. Appropriate correction is required.
Claim 14 is objected to because of the following informalities: contains periods within the body of the claim. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). See MPEP 608.01(m). Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 - 2, 4 – 7, 14 – 16, 20, 22 – 26, and 28 – 32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 2, 7, 16, 22, 26, and 30 – 32, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 29 contains the trademark/trade name “CHIRALPAK®”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the type of chromatographic column used to separate the enantiomers and, accordingly, the identification/description is indefinite.
Claims 1, 4 – 5, 16, 20, 22, 24 – 25, and 30 – 32 recite, lists of compounds or structural formulae. However, all the claims are missing a conjunction between the last two structures recited in the claims. Thus without the missing conjunctions the claims recite non-closed list of alternatives. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of whether the compound or method can contain or be only the recited compounds or whether any AKR1C3 reductase modulator falls within the scope of the invention.
Claim 14 recites the limitation "the AKR1C3 reductase content" in line 3. There is insufficient antecedent basis for this limitation in the claim; since claim 6, from which claim 14 depends does not recite AKR1C3 reductase content. Furthermore since the determining step in claim 14 does not require the subject to have a AKR1C3 reductase content claim 14 is indefinite. Moreover the determining step in claim 14 which recites “if the measured AKRlC3 reductase content is equal to or greater than a predetermined value;” is indefinite because it is unclear whether that determining step requires that the cancer cells and tumors to exhibit AKR1C3 reductase content. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of whether the subject is required to have cancer cells and tumors that exhibits AKR1C3 reductase content. Therefore, given the insufficient antecedent basis claim 14 is rejected under 35 U.S.C. 112(b). Additionally, given the uncertainty around determining step of claim 14; claim 14 is rejected under 35 U.S.C. 112(b).
Claim 14 recites the limitation "the corresponding RNA expression " in line 5. There is insufficient antecedent basis for this limitation in the claim; since claim 6, from which claim 14 depends does not recite corresponding RNA expression. Furthermore since the determining step in claim 14 does not require the subject to have RNA expression of AKR1C3 reductase content; claim 14 is indefinite. Moreover the determining step in claim 14 which recites “if the measured corresponding RNA expression of AKR1C3 reductase content is equal to or greater than a predetermined value;” is indefinite because it is unclear whether that determining step requires that the cancer cells and tumors to exhibit RNA expression of AKR1C3 reductase content. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of whether the subject is required to have cancer cells and tumors that exhibits RNA expression of AKR1C3 reductase content. Therefore, given the insufficient antecedent basis claim 14 is rejected under 35 U.S.C. 112(b). Additionally, given the uncertainty around determining step of claim 14; claim 14 is rejected under 35 U.S.C. 112(b).
Moreover with regards to claim 14, the preamble recites a method for treating cancer , comprising step a or b with a determining step; however the active step of administering the drug according to claim 6 is a conditional and dependent on whether the AKR1CE reductase content or RNA expression level meets a predetermined value. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of what is the required step if the reductase content is less than “a predetermined value” or outside of the RNA range. Therefore, given the uncertainty around determining step of claim 14; claim 14 is rejected under 35 U.S.C. 112(b).
.
Claim 15 recites the limitation " the AKR1C3 reductase content" in line 2. There is insufficient antecedent basis for this limitation in the claim; since claim 6, from which claim 15 depends does not recite AKR1C3 reductase content. Therefore, given the insufficient antecedent basis claim 15 is rejected under 35 U.S.C. 112(b). Furthermore, claim 15 recites a method for treating cancer or tumor, comprising a step of adjusting the AKR1C3 reductase content or expression level, wherein the drug according to claim 6 is administered to the patient when the AKR1C3 reductase content or expression level is adjusted to be equal to or greater than a predetermined value; however, the only active step in the claim is the adjusting of the AKR1C3 level. Moreover, this active step is conditional and dependent on the AKR1C3 reductase content or expression level being equal to or greater than a predetermined value. Furthermore the limitation of the drug according to claim 6 is administered to the patient is conditional and dependent on the AKR1C3 reductase content or expression level being equal to or greater than a predetermined value. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of what is the required step if the AKR1C3 reductase content or expression level is less than “a predetermined value”. Therefore, given the uncertainty around determining step of claim 15; claim 15 is rejected under 35 U.S.C. 112(b).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 14 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recites a method for treating cancer or tumor, comprising step a or step b: a. determining the AKR1C3 reductase content of cancer cells or tissues in a patient, and administering the drug according to claim 6 to the patient if the measured AKRlC3 reductase content is equal to or greater than a predetermined value; b. determining the corresponding RNA expression level of AKRlC3 reductase of cancer cells or tissues in a patient, and administering the drug according to claim 6 to the patient if the measured RNA expression level is in a predetermined range. The claim sets forth a mental process abstract idea judicial exception that requires the comparison of the observed AKR1C3 protein level or RNA level to a standard. Comparing is also a mathematical concept.
This judicial exception is not integrated into a practical application because of the inclusion of the conditional term “if” in the determination step which makes the treatment step conditional, and not required in all embodiments. Therefore, when the treatment step is not required, the claim does not apply or use the judicial exception in any way. The conditional recitation in claim 14 is interpreted to mean that there are two distinct patient populations: (1) a population with the AKR1C3 reductase content equal to or greater that of a predetermined value or a population with the corresponding RNA expression level of AKR1C3 reductase is at a predetermined value and (2) a population with the AKR1C3 reductase content below that of a predetermined value or a population where the corresponding RNA expression level of AKR1C3 reductase is not at a predetermined value.
For the population with the AKR1C3 reductase content equal to or greater that of a predetermined value or a population with the corresponding RNA expression level of AKR1C3 reductase is at a predetermined value, this population will receive the drug according to claim 6 which yields a claim as a whole that is sufficiently amounts to significantly more than the judicial exception of a mental process. However, a population with the AKR1C3 reductase content below that of a predetermined value or a population where the corresponding RNA expression level of AKR1C3 reductase is not at a predetermined value the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the only active step in the method as claimed by claim 14 is the judicial exception, of a mental processes step. To overcome this 101 rejection applicant may amend the claims to clearly require administering the drug in all embodiments.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 16, 20, and 22 – 26, are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).
Regarding claims 1, 16, 20, and 22 – 26, Duan’685 teach compounds of the disclosure as specific substrates of the aldehyde-ketone reductase AKR1C3, that can be rapidly and effectively reduced only in cancer cells with high AKR1C3 expression. See translation page 2 paragraph 0008. Additionally, Duan’685 teach that because of the specificity, compounds of the disclosure release cytotoxins resulting in highly selective cancer cell killing effects. See translation page 2 paragraph 0008. Specifically, Duan’685 teach compound species 16 of the structure
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. See Duan’685 page 5 row 4 column 1. See claims 1 limitation for a compound of structure A
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. Moreover, Duan’685 teach that compound species 16 has an IC50 value of 0.3518 nM in H460 cancer cells. See Duan’685 page 11 compound 16. Also, Duan’685 teach that the present invention also provides a medicine or preparation containing the above mentioned compounds II and III which includes compound 16 for treating tumors and cancer. See translation page 7 paragraph 0037. Furthermore, Duan’685 teach that the compounds of the disclosure which includes compound 16 can be provided as a basic salt or an acidic salt. See translation page 7 paragraph 0033. Moreover, Duan’685 teach that the compounds of the disclosure, which include compound 16, can be made into the solvate or solvate forms. See translation page 7 paragraph 0035. Additionally, Duan’685 teach that the compounds of the disclosure, which include compound 16, can also be used in the form of solvates, i.e., pharmaceutically acceptable solvates of compounds II and III provided herein, wherein the solvates are hydrates, alcohols, etc., and alcohols include ethanol compounds. See translation page 7 paragraph 0035.
Also Duan’685 teach that cancer includes lung cancer, pancreatic cancer, liver cancer, stomach cancer, esophageal cancer, non-small cell lung cancer, tumors of the central nervous system, or bile duct carcinoma. See translation page8 paragraph 0038. Additionally, Duan’685 teach that a method for treating cancer or tumors, comprising the steps of administering the aforementioned drug or preparation, which includes compound 16; and the steps of measuring the AKR1C3 reductase content or expression level in the patient's cancer cells using an AKR1C3 antibody. See translation page 8 paragraph 0040. Furthermore, Duan’685 teach that if the AKR1C3 reductase content or expression level is measured to be equal to or greater than a predetermined value, the aforementioned drug or preparation shall be administered to the patient. See translation page 8 paragraph 0040.
Additionally, Duan’685 teach a method for treating cancer or tumors, comprising the steps of administering the aforementioned drug or preparation; and the step of regulating AKR1C3 reductase levels. See translation page 9 paragraph 0044. Furthermore, Duan’685 teach that when the adjustment results in the AKR1C3 reductase content being equal to or greater than a predetermined value, the aforementioned drug or preparation is administered to the patient. See translation page 9 paragraph 0044.
Furthermore, Duan’685 teach that compound 16 is was prepared by the following scheme:
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. See Duan’685 page 27 paragraph 4. See claim 16 limitation for a method of preparing the compound of structure A
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comprising subjecting compound I-1
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[AltContent: rect][AltContent: rect]to a ring closures reaction where X is bromine. See claim 20 limitation for a compound with the structure
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. See claim 22 limitation for a method of preparing
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from reacting compound II-1
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BrCH2CH2NH2·HBr, that is bromoethylamine hydrobromide. See claim 23 limitation for a method where X are bromine and the haloethylamine hydrohalide is bromoethylamine hydrobromide. See claim 24 limitation for a compound of structure II-1
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. See claim 25 limitation for a method for preparing II-1
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by reacting the compound of II I-3, that is 16-A2 with TMSCF3
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.
Furthermore, Duan’685 teach that after deprotecting with TBAF 2 mL of 3N hydrochloric acid was added to the reaction and the reaction was allowed to warm to room temperature for an hour. See translation page 32 paragraph 0160. See claim 26 limitation for a method where the deprotecting reagent use is tetrabutylammonium fluoride, that is TBAF and hydrochloric acid is used in the hydrolysis operation. Moreover, Duan’685 teach that the above compounds which include compound 16 also include isotope Z-substituted compounds with typical Z-substitution being that of a substitution of hydrogen, or Halogen - H bonds by deuterium atom D. See translation page 5 paragraph 0019.
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.
Claims 2, 4 – 7, 14 – 15, 30 – 31 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used)..
Regarding claims 2, 4 – 7, 14 – 15, 30 – 31, Duan’685 teach compounds of the disclosure as specific substrates of the aldehyde-ketone reductase AKR1C3, that can be rapidly and effectively reduced only in cancer cells with high AKR1C3 expression. See translation page 2 paragraph 0008. Additionally, Duan’685 teach that because of the specificity, compounds of the disclosure release cytotoxins resulting in highly selective cancer cell killing effects. See translation page 2 paragraph 0008. Specifically, Duan’685 teach compound species 16 of the structure
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. See Duan’685 page 5 row 4 column 1. See claims 1 limitation for a compound of structure A
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. Moreover, Duan’685 teach that compound species 16 has an IC50 value of 0.3518 nM in H460 cancer cells. See Duan’685 page 11 compound 16. Also, Duan’685 teach that the present invention also provides a medicine or preparation containing the above mentioned compounds II and III which includes compound 16 for treating tumors and cancer. See translation page 7 paragraph 0037. See claim 6 limitation for a drug containing the compound according to claim 1. While the prior art does not specifically teach an example embodiment of compound 16 as a drug, the prior art does teach the use of compound 16 in inhibiting H460 cancer cells. Moreover, Duan’685 does teach that the compounds of the disclosure, which include compound 16, can be prepared as medicine for the treatment of tumors and cancer. Thus it would be obvious to one of ordinary skill in the art given the above teachings to prepare a drug containing compound 16; as recited in claim 6.
Furthermore, Duan’685 teach that the compounds of the disclosure which includes compound 16 cam be provided as a basic salt or an acidic salt. See translation page 7 paragraph 0033. Moreover, Duan’685 teach that the compounds of the disclosure, which include compound 16, can be made into the solvate or solvate forms. See translation page 7 paragraph 0035. Additionally, Duan’685 teach that the compounds of the disclosure, which include compound 16, can also be used in the form of solvates, i.e., pharmaceutically acceptable solvates of compounds II and III provided herein, wherein the solvates are hydrates, alcohols, etc., and alcohols include ethanol compounds. See translation page 7 paragraph 0035. See claim 2 limitation for a basic salt, an acidic salt, or a solvate. While the prior art does not specifically teach an example embodiment of compound 16 as a basic salt, acidic salt, or solvate the prior art does teach that compounds of the disclosure can be prepared as a basic salt, acidic salt, solvate or ethanolate. Thus it would be obvious to one of ordinary skill in the art given the above teachings to prepare compound 16 as basic salt, acidic salt, solvate or ethanolate as recited in claim 2.
Also Duan’685 teach that cancer includes lung cancer, pancreatic cancer, liver cancer, stomach cancer, esophageal cancer, non-small cell lung cancer, tumors of the central nervous system, or bile duct carcinoma. See translation page 8 paragraph 0038. See claim 7 limitation for a method where the cancer is lung cancer, pancreatic cancer, liver cancer, or gastric cancer. Additionally, Duan’685 teach that a method for treating cancer or tumors, comprising the steps of administering the aforementioned drug or preparation, which includes compound 16; and the steps of measuring the AKR1C3 reductase content or expression level in the patient's cancer cells using an AKR1C3 antibody. See translation page 8 paragraph 0040. See claim 7 limitation for a method of treating cancer comprising administering a compound of claim 1. While the prior art does not specifically teach an example where compound 16 is used in a method of treating cancer comprising the steps of administering compound 16, the prior art does teach that compounds of the disclosure, that includes compound 16, can be in method for treating cancer. Thus it would be obvious to one of ordinary skill in the art given the above teachings to administer compound 16 as in a method of treating cancer with a reasonable expectation of success because the prior art does teach that compound 16 is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer.
Furthermore, Duan’685 teach that if the AKR1C3 reductase content or expression level is measured to be equal to or greater than a predetermined value, the aforementioned drug or preparation shall be administered to the patient. See translation page 8 paragraph 0040. See claim 14 limitation for a method for treating cancer comprising determining the AKR1C3 reductase content or RNA expression levels before administering a compound according claim 1. While the prior art does not specifically teach an example where compound 16 is used in a method of treating cancer comprising a determining step where AKR1C3 content or RNA expression based on a predetermined value then administering compound 16, the prior art does teach that compounds of the disclosure, that includes compound 16, can be administered in a method for treating cancer based on a step where the AKR1C3 reductase content or expression level is measured to be equal to or greater than a predetermined value. Thus it would be obvious to one of ordinary skill in the art given the above teachings to administer compound 16 in a method of treating cancer which also includes a step where the AKR1C3 reductase content or expression level is measured to be equal to or greater than a predetermined value. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art does teach that compound 16 is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer.
Additionally, Duan’685 teach a method for treating cancer or tumors, comprising the steps of administering the aforementioned drug or preparation; and the step of regulating AKR1C3 reductase levels. See translation page 9 paragraph 0044. Furthermore, Duan’685 teach that when the adjustment results in the AKR1C3 reductase content being equal to or greater than a predetermined value, the aforementioned drug or preparation is administered to the patient. See translation page 9 paragraph 0044. See claim 15 limitation for a method for treating cancer or tumor, comprising a step of adjusting the AKRlC3 reductase content or expression level, wherein the drug according to claim 6 is administered to the patient when the AKRlC3 reductase content or expression level is adjusted to be equal to or greater than a predetermined value. While the prior art does not specifically teach an example where compound 16 is used in a method of treating cancer comprising an adjusting step where the AKRlC3 reductase content or expression level, wherein the drug according to claim 6 is administered to the patient when the AKR1C3 reductase content or expression level is adjusted, the prior art does teach that the AKR1C3 reductase content can be adjusted to have the AKR1C3 reductase content or expression level being equal to or greater than a predetermined value, the aforementioned drug or preparation is administered to the patient. Thus it would be obvious to one of ordinary skill in the art given the above teachings to administer compound 16 in a method of treating cancer which also includes a step where the AKR1C3 reductase content or expression level is adjusted when the values are found to be equal to or greater than a predetermined value. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art does teach that compound 16 is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer.
Moreover, Duan’685 teach that the above compounds which include compound 16 also include isotope Z-substituted compounds with typical Z-substitution being that of a substitution of hydrogen, or Halogen - H bonds by deuterium atom D. See translation page 5 paragraph 0019. Additionally, Duan’685 teach compounds of formula II of structure
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can accommodate a D atom in the R8 position. See translation page 5 paragraph 0014. See Duan’685 page 2. See claim 4 limitation for an isotopic variant
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wherein at least one of the nine As is D. See claim 5 limitation for a compound according to claim 1 where the isotopic variant corresponds to the deuterated compound of the structures as delineated which includes
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. While the prior art does not specifically teach an example embodiment of compound 16 as a deuterated isotopic variant the prior art does teach that compounds of the disclosure can be prepared as deuterated isotopic variants in particular to the R8 position. Thus it would be obvious to one of ordinary skill in the art given the above teachings to prepare compound 16 an isotopic variant particularly of the structure
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.
Furthermore, Duan’685 teach that compound 16 is was prepared by the following scheme:
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. See Duan’685 page 27 paragraph 4. See claim 30 limitation for a method of preparing the compound of structure V-I
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comprising subjecting compound IV-1
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[AltContent: rect]to a ring closures reaction where X is bromine. See claim 31 limitation for a method of preparing
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from reacting compound II-1a
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with BrCH2CH2NH2·HBr, that is bromoethylamine hydrobromide. See claim 23 limitation for a method where X are bromine and the haloethylamine hydrohalide is bromoethylamine hydrobromide. See claim 24 limitation for a compound of structure II-1
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. See claim 25 limitation for a method for preparing II-1
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by reacting the compound of II I-3, that is 16-A2 with TMSCF3
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. Furthermore, Duan’685 teach that after deprotecting with TBAF 2 mL of 3N hydrochloride acid was added it the reaction and the reaction was allowed to warm to room temperature for an hour. See translation page 32 paragraph 0160.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the teachings of Duan’685 for a compound based on compound 16 that is an acid salt or basic salt, and/ or deuterated isotopic variant. Moreover, it would have been obvious before the effective filing date of the instant application to modify the teachings of Duan’685 for a method for treating cancer comprising administering compound 16 as an acid salt or basic salt, and/ or deuterated isotopic variant further comprising a step to determine the AKR1C3 reductase content or corresponding RNA expression level of AKR1C3 reductase or a step of adjusting the AKR1C3 reductase content or expression level. Furthermore, it would have been obvious before the effective filing date of the instant application to modify the teachings of Duan’685 for a method for preparing compound 16 as deuterated isotopic variant. One of ordinary skill in the art would have been motivated to make the above modifications because the prior art of Duan’685 suggested the feasibility of each of the above modifications. One of ordinary skill in the art would have had a reasonable expectation of success because the formation of deuterated isotopic and acid/base/solvate forms of compounds is well established in the prior art are routine synthetic strategies. Additionally, as taught above compound 16 is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer. Thus one of ordinary skill in the art would have had a reasonable expectation of success in targeting cancers where AKR1C3 is expressed.
Claims 28 – 29 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used) as applied to claims 1, 2, 4 – 7, 14 – 16, 20, 22 – 26, and 30 – 31 above, and in further view of Pradere et. al. ((2014), Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs, Chemical Reviews, 114, 9154 – 9218) and Ellington et. al. ((2001), High-performance liquid chromatographic separation of the enantiomers of organophosphorus pesticides on polysaccharide chiral stationary phases, J. Chromatogr. A., 928, 145 – 154).
The teachings of Duan’685 as it relates to claim 1, from which claims 28 – 29 depend, are given previously in this office action and are fully incorporated here.
However, while Duan’685 teach the synthesis of the racemate of prior art compound 16 of structure
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; Duan’685 fail to teach a method for separating the racemate of the compound according to claim 1:
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to obtain an enantiomer or to increase the concentration of either of the enantiomers of the racemate in the compound to be excessive, comprising the following steps: subjecting the racemic compound to optical resolution operation, wherein the operation is performed by chiral chromatography comprising stationary phase and mobile phase, wherein the stationary phase comprises silica gel impregnated with a functionalized polysaccharide, and wherein the mobile phase comprises an alcohol and a further solvent; wherein the alcohol is ethanol, and the further solvent is n-hexane; wherein the temperature of the chromatography column during the operation of the chiral chromatography is 38°C; wherein the functionalized polysaccharide is amylase tris(3,5-dimethylphenylcarbamate). See claim 28. Moreover, Duan’685 fail to teach an HPLC method for separating the racemate of the compound according to claim 1:
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, to obtain an enantiomer or to increase the concentration of either of the enantiomers of the racemate in the compound to be excessive, wherein the chromatography column is CHIRALPAK® AD, and the mobile phase is ethanol, and the column temperature is 35°C. See claim 29.
Nevertheless, Pradere et. al. teach that for nucleoside monophosphate prodrugs are designed to efficiently cross the biological barriers (as opposed to nucleoside monophosphates; Figure 1, eq 1) and reach the targeted cells or tissues. See page 9154 column 2 paragraph 1. Furthermore, Pradere et. al. teach that once inside the cell, the bio-labile protecting groups are then degraded enzymatically and/or chemically, releasing the free nucleoside analog in the monophosphate form, which can often efficiently express its therapeutical potency by intracellular conversion to the corresponding nucleoside triphosphate (Figure 1, eq 2). See page 9154 column 2 paragraph 1. Furthermore, Pradere et. al. teach that phosphate prodrugs can have a variety of moieties such as those illustrated here:
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.See page 9156 column 1 Table 1. Thus, Pradere et. al. teach that phosphate prodrugs can have P(V) moieties with 2 P-N bonds, 1 O-P bond, and 1 O=P bond which is similar to the P-center of prior art compound 16 of Duan’685 of structure
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.
Moreover, Pradere et. al. teach that it has been proven over time that Sp and Rp diastereoisomers can display different biological profiles, and it is not uncommon to see 10-fold or more difference in terms of in vitro potency between two phosphorus diastereomers. See page 9195 column 2 paragraph 3. Additionally, Pradere et. al. teach that the separation of phosphorus diastereomeric mixtures can be realized, in some cases, by HPLC, selective crystallization, or flash chromatography on silica gel. See page 9195 column 2 paragraph 3. Thus, Pradere et. al. suggest the need to separate phosphorus diastereomeric mixtures which result from reactions forming phosphate prodrugs of which compound 16 of prior art Duan’685 belongs.
However, while Pradere et. al. suggest the need to separate phosphorus diastereomeric mixtures using HPLC; Pradere et. al. fail to teach a method for separating the racemate comprising subjecting the racemic compound to optical resolution operation, wherein the operation is performed by chiral chromatography comprising stationary phase and mobile phase, wherein the stationary phase comprises silica gel impregnated with a functionalized polysaccharide, and wherein the mobile phase comprises an alcohol and a further solvent; wherein the alcohol is ethanol, and the further solvent is n-hexane; wherein the temperature of the chromatography column during the operation of the chiral chromatography is 38°C; wherein the functionalized polysaccharide is amylase tris(3 ,5-dimethylphenylcarbamate). See claim 28. Moreover, Pradere et. al. fail to teach an HPLC method for separating the racemate where the chromatography column is CHIRALPAK® AD, and the mobile phase is ethanol, and the column temperature is 35°C. See claim 29.
Nevertheless, Ellington et. al. teach that some of these organophosphorus (OPs) based pesticides are sold as the racemate (i.e. an equimolar mixture of the pair of enantiomers). See page 145 column 2 paragraph 1. Moreover, Ellington et. al. teach that the stereogenic (chiral) center in OPs may be pentavalent phosphorus (PV) or carbon, sulfur, or other atoms as a substituent of phosphorus of structures
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. See page 145 column 2 paragraph 1 and page 148 Figure 1. Thus, Ellington et. al. teach OPs examples with base P(V) phosphorus cores that are taught by Pradere et. al. to belong to phosphate prodrugs from which prior art compound 16 of Duan’685 of structure
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also belongs.
Furthermore, Ellington et. al. teach that the enantioselective biological recognition or bio discrimination of enantiomers is often observed in biological systems. See page 145 column 2 paragraph 1. Ellington et. al. teach that pharmacological and environmental fate studies are increasingly conducted on enantiomers because of the possible stereoselective efficacy and metabolism of each enantiomer. See page 146 column 1 paragraph 2. Thus, Ellington et. al. teach that chromatographic separation of the enantiomers can be used to monitor enantiomerically selective degradation of racemates. See page 146 column 1 paragraph 2. Specifically, Ellington et.al. teach that a standard column selection procedure that utilized the same chromatographic conditions on CHIRALPAK® AD, CHIRALPAK ®AS, CHIRALCEL ®OD and CHIRALCEL ®OJ columns was used to determine polysaccharide chiral stationary phases (CSP) selectivity for the OP enantiomers. See page 146 column 1 paragraph 3. See claim 29 limitation for an HPLC method for separating the racemate where the chromatography column is CHIRALPAK® AD. Furthermore, Ellington et.al. teach that CHIRALPAK® AD functionalized polysaccharide is amylase tris(3 ,5-dimethylphenylcarbamate). See page 147 column 1 paragraph 2. See claim 28 limitation for a method where the stationary phase comprises silica gel impregnated with a functionalized polysaccharide where the functionalized polysaccharide is amylase tris(3,5-dimethylphenylcarbamate). Moreover, Ellington et. al. teach that for the comparison a mobile phase of heptane/ethanol (EtOH) at (90/10 v/v) at a flow-rate of 1 ml/min at room temperature or 25oC was used for initial evaluation or screening of columns with the optical rotation in the mobile phase for each enantiomer being determined by using a polarimeter detector. See page 147 column 2 paragraph 3. See claim 28 limitation for a method for separating the racemate comprising subjecting the racemic to optical resolution operation, where the mobile phase comprises an alcohol and a further solvent; where the alcohol is ethanol. Furthermore, Ellington et. al. teach that using the screening conditions lead to baseline resolution of the enantiomers for example organophosphorus compounds 1 – 5, 7, 8, and 10 of Table 1. See page 148 column 1 paragraph 1.
Now while claim 28 recites the solvent as hexane; the prior art taught the use of heptane which is one carbon unit longer than hexane. Thus given that the only difference between claim 28 solvent of hexane and the prior art solvent of heptane is a single carbon unit; both hexane and heptane are homologs of each other. Therefore, compounds which are homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). See MPEP 2144.09(II). Thus the prior art teaching of heptane as a HPLC solvent renders obvious the claim 28 limitation for hexane.
Now while claim 28 recites the chromatogram temperature of 35oC the prior art method of Ellington et. al. teach that the column was kept at room temperature of 25oC. Thus the prior art teaching of 25oC renders obvious the 35oC as recited in claim 28 since there two temperatures are sufficiently close to each other. 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). See MPEP 2144.05(I). Thus the prior art teaching of 25oC renders obvious the 35oC as recited in claim 28.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the synthesis of Duan’685 for prior art compound 16 of structure
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in view of Pradere et. al. that is to separate the resulting phosphorus diastereomeric mixture using an HPLC in further view of Ellington et. al. that is using an HPLC method where the racemic compound is subjected to optical resolution by polarimeter detector, where the stationary phase is CHIRALPAK® AD with functionalized polysaccharide is amylase tris(3 ,5-dimethylphenylcarbamate) where the mobile phase comprises ethanol and heptane, and where the column is between 25 oC – 38°C. One of ordinary skill in the art would have been motivated to make this modification to sperate the racemic mixture into separate pure enantiomers that potential have stereoselective efficacy and metabolism of each enantiomer. One of ordinary skill in the art would have had a reasonable expectation of success because using the screening conditions lead to baseline resolution of the enantiomers or example organophosphorus compounds.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used) as applied to claims 1, 2, 4 – 7, 14 – 16, 20, 22 – 26, and 30 – 31 above, and in further view of Frost et. al. ((1998), Recent developments in aromatic heteroatom coupling reactions, J. Chem. Soc. Perkin Trans., 1, 2615 – 2623).
The teachings of Duan’685 as it relates to claim 1, from which claim 32 depend, are given previously in this office action and are fully incorporated here.
However, while the prior art of Duan’685 teach the limitation for a method for preparing compound A
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, comprising the following steps: reacting compound
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as the starting material to obtain compound
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; Duan’685 fail to teach reacting the compound
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with formula I-7-1 , that is
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to obtain the corresponding compound of formula A
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where Y2 are halogen or OM, and M is hydrogen, sodium, potassium, magnesium, or calcium. See claim 32.
Frost et. al. teach highlights recent advances in the addition of heteroatom nucleophiles to aromatic or heteroaromatic substrates throughout the period 1/6/96 to 31/12/97. See page 2615 column 1 paragraph 1. Moreover, Frost et. al. teach an example of a Pd(dba)2/DPPF catalyst system as effective in the preparation of diaryl ethers such as 60, by coupling aryl bromide 58 with sodium aryl oxide 59 (Scheme 15) as shown here
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. See page 2619 column 2 paragraph 1 and page 2620 column 1 Scheme 15. Given the relatively high skill level of one of ordinary skill in the organic synthetic arts and that one of ordinary skill in the art would be familiar with C-O bond formation between aryl groups it would be within the purview of such artisan to work retro-synthetically to build prior art compound 16. Moreover it would be obvious to one of ordinary skill in the art that another strategic strategy for forming compound 16 would be to separate the two aromatic units along the O-C bond to form the two starting materials
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and
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where X is a halogen and a good leaving group. Additionally coupled with the teachings of Frost et.al. for generic C-O bond formation it would have been obvious to one of ordinary skill in the art to substituted prior art compound 16-0A of Duan’685 for prior art compound 59 of Frost et. al.. Moreover, it would have been obvious to one of ordinary skill in the organic synthetic to then substitute
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for prior art compound 58 to complete the reaction as taught by Frost et.al..
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Duan’685 for preparing compound A
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, comprising reacting the compound
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in view of Frost et. al. with
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. One of ordinary skill in the art would have been motivated to make this modification in retro-synthetically determining how to make prior art compound A. One of ordinary skill in the art would have been motivated to make this modification since O-C coupling conditions are were taught by Frost et. al.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 – 2, and 4 – 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 11 of U.S. Patent No. US 12595275 B2 to Duan et. al.(Duan’275).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the invention of Duan’275 and the copending examined application direct to the same compound of structure
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. Specifically, the issued Duan’275, exemplifies the compound of
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as well as the deuterated isotopic form. See reference claims 1 – 9. See examined claims 1 – 2, and 4 – 5. Moreover, Duan’275 recite a medicament or formulation containing the solid compound according to (reference) claim 1. See reference claim 10. See examined claim 6. Furthermore, Duan’275 recite a method of treating non-small cell lune cancer in a patient, the method comprising administering to the patient in need thereof the medicament or formulation according to (reference) claim 10. See reference claim 11. See examined claim 7.
Claims 14 – 16, 20, 22 – 26, and 30 – 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11 – 16 of U.S. Patent No. U.S. Patent No. US 12595275 B2 to Duan et. al.(Duan’275) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).
Duan’275 recite a recite a method of treating non-small cell lung cancer in a patient, the method comprising administering to the patient in need thereof the medicament or formulation according to (reference) claim 10. See reference claim 11. Additionally, Duan’275 recite a method for preparing the solid compound according to (reference) claim 1, characterized in that compounds V and VI are subjected to condensation reaction to close rings to provide the compounds of above formulae II and III:
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wherein Y is a leaving group and further reaction conditions defined in dependent (reference) claims 13 – 14. See reference claim 12.
However, Duan’275 fails to recite a method of treating comprising a determination step nor does Duan’275 recite a method of treating cancer comprising an adjusting step. See examined claims 14 – 15. Moreover, Duan’275 fails to recite a method of preparing the anticipated compound
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as delineated in examined claims 16, 20, 22 – 26, and 30 – 31.
Nevertheless, the teachings of Duan’685 as they relate to the prior art rection of examined claims 14 – 16, 20, 22 – 26, and 30 – 31, 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 the invention of Duan’275 for a method for treating non-small cell lung cancer in view of Duan’685 for a method for treating cancer comprising administering
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further comprising a step to determine the AKR1C3 reductase content or corresponding RNA expression level of AKR1C3 reductase or a step of adjusting the AKR1C3 reductase content or expression level. Furthermore, it would have been obvious before the effective filing date of the instant application to modify the teachings of Duan’685 for a method for preparing
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as deuterated isotopic variant. One of ordinary skill in the art would have been motivated to make the above modifications because the prior art of Duan’685 suggested the feasibility of each of the above modifications. One of ordinary skill in the art would have had a reasonable expectation of success because the formation of deuterated isotopic forms of compounds is well established in the prior art are routine synthetic strategies. Additionally, as taught above
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is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer. Thus one of ordinary skill in the art would have had a reasonable expectation of success in targeting cancers where AKR1C3 is expressed.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15 – 16 of U.S. Patent No. U.S. Patent No. US 12595275 B2 to Duan et. al.(Duan’275) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used)and Frost et. al. ((1998), Recent developments in aromatic heteroatom coupling reactions, J. Chem. Soc. Perkin Trans., 1, 2615 – 2623).
Alternatively, Duan’275 recite a method for preparing the solid compound according to (reference) claim 1, characterized by making
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with further reaction conditions defined in dependent (reference) claim 16. See reference claim 15.
However, Duan’275 fails to recite a method of preparing the anticipated compound
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as delineated in examined claim 32.
Nevertheless, the teachings of Duan’685 and Frost et. al. as they relate to the prior art rection of examined claim 32, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of Duan’275 for a method of preparing the anticipated compound
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using
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as a starting material in view of Duan’685 for preparing either racemate comprising reacting the compound
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in view of Frost et. al. with
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. One of ordinary skill in the art would have been motivated to make this modification in retro-synthetically determining how to make prior art compound A. One of ordinary skill in the art would have been motivated to make this modification since O-C coupling conditions are were taught by Frost et. al.
Claims 28 – 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12 – 16 of U.S. Patent No. U.S. Patent No. US 12595275 B2 to Duan et. al.(Duan’275) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used), Pradere et. al. ((2014), Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs, Chemical Reviews, 114, 9154 – 9218), and Ellington et. al. ((2001), High-performance liquid chromatographic separation of the enantiomers of organophosphorus pesticides on polysaccharide chiral stationary phases, J. Chromatogr. A., 928, 145 – 154).
Duan’275 recite a recite a method of treating non-small cell lung cancer in a patient, the method comprising administering to the patient in need thereof the medicament or formulation according to (reference) claim 10. See reference claim 11. Additionally, Duan’275 recite a method for preparing the solid compound according to (reference) claim 1, characterized in that compounds V and VI are subjected to condensation reaction to close rings to provide the compounds of above formulae II and III:
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wherein Y is a leaving group and further reaction conditions defined in dependent (reference) claims 13 – 14. See reference claim 12. Alternatively, Duan’275 recite a method for preparing the solid compound according to (reference) claim 1, characterized by making
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with further reaction conditions defined in dependent (reference) claim 16. See reference claim 15.
However, Duan’275 fail to recite a method for separating the racemate of the compound according to claim 1:
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to obtain an enantiomer or to increase the concentration of either of the enantiomers of the racemate in the compound to be excessive, comprising the following steps: subjecting the racemic compound to optical resolution operation, wherein the operation is performed by chiral chromatography comprising stationary phase and mobile phase, wherein the stationary phase comprises silica gel impregnated with a functionalized polysaccharide, and wherein the mobile phase comprises an alcohol and a further solvent; wherein the alcohol is ethanol, and the further solvent is n-hexane; wherein the temperature of the chromatography column during the operation of the chiral chromatography is 38°C; wherein the functionalized polysaccharide is amylase tris(3,5-dimethylphenylcarbamate). See claim 28. Moreover, Duan’275 fail to teach an HPLC method for separating the racemate of the compound according to claim 1:
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, to obtain an enantiomer or to increase the concentration of either of the enantiomers of the racemate in the compound to be excessive, wherein the chromatography column is CHIRALPAK® AD, and the mobile phase is ethanol, and the column temperature is 35°C. See claim 29.
Nevertheless, the teachings of Duan’685, Pradere et. al., and Ellington et. al. as they relate to the prior art rection of examined claims 28 – 29, 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 the invention of Duan’275 for a method of making
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in view of Duan’685, that is for a method of making either racemate, in view of Pradere et. al. that is to separate the resulting phosphorus diastereomeric mixture using an HPLC in further view of Ellington et. al. that is using an HPLC method where the racemic compound is subjected to optical resolution by polarimeter detector, where the stationary phase is CHIRALPAK® AD with functionalized polysaccharide is amylase tris(3 ,5-dimethylphenylcarbamate) where the mobile phase comprises ethanol and heptane, and where the column is between 25 oC – 38°C. One of ordinary skill in the art would have been motivated to make this modification to sperate the racemic mixture into separate pure enantiomers that potential have stereoselective efficacy and metabolism of each enantiomer. One of ordinary skill in the art would have had a reasonable expectation of success because using the screening conditions lead to baseline resolution of the enantiomers or example organophosphorus compounds.
Claims 1, and 4 – 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 – 15 of copending Application No. 18/209314 to Duan et. al. (reference application; Duan’314).
Although the claims at issue are not identical, they are not patentably distinct from each other because both conflicting applications direct to a compound of the structure
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. Specifically, Duan’314 recites a method of synthesizing a compound selected from Compound B of structure
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to further synthesis compound B selected from compounds having the following structure
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which anticipates the compounds of examined claims 1, and 4 – 5. See reference claims 13 – 15. See examined claims 1, and 4 – 5.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2, 6, 16, 20, 22 – 26, 30, and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 – 15 of copending Application No. 18/209314 to Duan et. al. (reference application; Duan’314) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).Duan’314 recites a method of synthesizing a compound selected from Compound B of structure
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to further synthesis compound B selected from compounds having the following structure
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. See reference claims 13 – 15. Moreover, Duan’314 recites a method of synthesizing a compound using
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where (reference) compound B2 renders obvious the species of examined compound 20. See reference claim 14. See examined claim 20.
However, Duan’314 fails to recite
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as a basic salt, acid salt, hydrate, and/ or solvate. See examined claim 2. Moreover, Duan’314 fails to recite a method of preparing the anticipated compound
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as delineated in examined claims 16, 20, 22 – 26, and 30 – 31.
Nevertheless, the teachings of Duan’685 as they relate to the prior art rection of examined claims 2, 6, 16, 20, 22 – 26, and 30 – 31, 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 of Duan’314 for a method for synthesizing
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in view of Duan’685 to prepare the compound as a basic salt, acid salt, hydrate, and/ or solvate using the synthetics method. One of ordinary skill in the art would have been motivated to synthesis the compound using the modified method because the prior art of Duan’685 suggested the feasibility of each of the above modifications. One of ordinary skill in the art would have had a reasonable expectation of success because the formation of deuterated isotopic forms of compounds is well established in the prior art are routine synthetic strategies.
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 2, and 4 – 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 – 15 of copending Application No. 18/693111 to Duan et. al. (reference application; Duan’111).
Although the claims at issue are not identical, they are not patentably distinct from each other because both conflicting applications direct to a compound of the structure
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. Specifically, Duan’111 recite a treatment method which uses a drug monotherapy containing an AKR1C3-activated DNA alkylating agent prodrug compound or in combination with other therapeutic drugs for treating cancer and tumor patients having KRAS mutations. See reference claim 1. See examined claim 7. Furthermore, Duan’111 recite a treatment method where the compound is
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which anticipates the compounds of examined claims 1 – 2, and 4 – 6. See reference claims 1 – 7. See examined claims 1 – 2, and 4 – 5. Moreover, Duan’111 recite a pharmaceutical use of an AKR1C3-activated DNA alkylating agent prodrug compound, wherein the compound is used in the manufacture of a drug monotherapy or in combination with other therapeutic drugs for treating cancer and tumor patients having KRAS mutations. See examined claims 8 – 13. See examined claim 6.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 14 – 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 13 of copending Application No. 18/693111 to Duan et. al. (reference application; Duan’111) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).
Duan’111 recite a treatment method which uses a drug monotherapy containing an AKR1C3-activated DNA alkylating agent prodrug compound or in combination with other therapeutic drugs for treating cancer and tumor patients having KRAS mutations. See reference claim 1. Furthermore, Duan’111 recite a treatment method where the compound is
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.See reference claims 1 – 7.
However, Duan’111 fails to recite a method of treating cancer
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as delineated in examined claims 14 – 15.
Nevertheless, the teachings of Duan’685 as they relate to the prior art rection of examined claims 14 – 15, 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 of Duan’111 for a method of treating cancer using
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in view of Duan’685 for the cancer to be as delineated in examined claims 14 – 15. One of ordinary skill in the art would have been motivated to because as taught above
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is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer. Thus one of ordinary skill in the art would have had a reasonable expectation of success in targeting cancers where AKR1C3 is expressed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 2, and 4 – 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 – 15 of copending Application No. 18/846565 to Duan et. al. (reference application; Duan’565).
Although the claims at issue are not identical, they are not patentably distinct from each other because both conflicting applications direct to a compound of the structure
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. Specifically, Duan’565 recite a method for treating BRCA gene-mutated cancer, which uses a drug monotherapy containing hypoxia-activated prodrug compounds of formulas (1), (2), (3) or AKR1C3 enzyme activated prodrug compounds of formulas (4), (5), (6), (7), (8), (9), (10), (11), (12) and salts, esters, solvates, and isotopic isomers thereof or in combination with other drugs to treat patients with BRCA gene-mutated cancer and tumors. See reference claim 1. See examined claim 7. Furthermore, Duan’565 recite a treatment method where the compound is
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which anticipates the compounds of examined claims 1 – 2, and 4 – 6. See reference claims 1 – 13. See examined claims 1 – 2, and 4 – 5.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 14 – 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 14 of copending Application No. 18/846565 to Duan et. al. (reference application; Duan’565) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).
Duan’565 recite a method for treating BRCA gene-mutated cancer, which uses a drug monotherapy containing hypoxia-activated prodrug compounds of formulas (1), (2), (3) or AKR1C3 enzyme activated prodrug compounds of formulas (4), (5), (6), (7), (8), (9), (10), (11), (12) and salts, esters, solvates, and isotopic isomers thereof or in combination with other drugs to treat patients with BRCA gene-mutated cancer and tumors. See reference claim 1. Furthermore, Duan’565 recite a treatment method where the compound is
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.See reference claims 1 – 13.
However, Duan’565 fails to recite a method of treating cancer
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as delineated in examined claims 14 – 15.
Nevertheless, the teachings of Duan’685 as they relate to the prior art rection of examined claims 2, and 14 – 15, 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 of Duan’565 for a method of treating cancer using
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in view of Duan’685 for the cancer to be as delineated in examined claims 14 – 15 One of ordinary skill in the art would have been motivated to because as taught above
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is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer. Thus one of ordinary skill in the art would have had a reasonable expectation of success in targeting cancers where AKR1C3 is expressed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 2, and 4 – 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 7 – 9, and 11 of copending Application No. 18/872718 to Li et. al. (reference application; Li’718).
Although the claims at issue are not identical, they are not patentably distinct from each other because both conflicting applications direct to a compound of the structure
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. Specifically, Li’718 recite a treatment method for cancer patients with an AKR1C3 enzyme-activated prodrug, characterized in that: the tumor or cancer tissue of the patients is detected to have a gene mutation capable of upregulating or activating NRF2; or the patients are detected to have a gene mutation capable of up-regulating or activating NRF2. See reference claim 1. See examined claim 7. Furthermore, Li’718 recite a treatment method where the compound is
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which anticipates the compounds of examined claims 1 – 2, and 4 – 6. See reference claims 1 – 5, 8 – 9, and 11. See examined claims 1 – 2, and 4 – 5. Additionally, Li’718 recite a medicament comprising AKR1C3 enzyme-activated prodrug compound, which is used to treat cancer patients, wherein the tumor or cancer tissue of the patients is detected to have a gene mutation capable of up-regulating or activating NRF2; or the patients are detected to have a gene mutation capable of up-regulating or activating NRF2. See reference claim 7. See examined claim 6.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 14 – 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 7 – 9, and 11 of copending Application No. 18/872718 to Li et. al. (reference application; Li’718) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).
Li’718 recite a treatment method for cancer patients with an AKR1C3 enzyme-activated prodrug, characterized in that: the tumor or cancer tissue of the patients is detected to have a gene mutation capable of upregulating or activating NRF2; or the patients are detected to have a gene mutation capable of up-regulating or activating NRF2. See reference claim 1. Furthermore, Li’718 recite a treatment method where the compound is
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.See reference claims 1 – 5, 8 – 9, and 11.
However, Li’718 fails to recite a method of treating cancer
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as delineated in examined claims 14 – 15.
Nevertheless, the teachings of Duan’685 as they relate to the prior art rection of examined claims 14 – 15, 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 of Li’718 for a method of treating cancer using
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in view of Duan’685 for the cancer to be as delineated in examined claims 14 – 15. One of ordinary skill in the art would have been motivated to because as taught above
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is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer. Thus one of ordinary skill in the art would have had a reasonable expectation of success in targeting cancers where AKR1C3 is expressed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 2, and 4 – 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 4 – 8, 12 – 14, 16 – 21 of copending Application No. 19/120073 to Duan et. al. (reference application; Duan’073).
Although the claims at issue are not identical, they are not patentably distinct from each other because both conflicting applications direct to a compound of the structure
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. Specifically, Duan’073 recite a method for treating cancer patients accompanied by pain by combining a drug containing an AKR1C3-activated anticancer prodrug compound or its salt, ester, solvate or isotope isomer with a non-steroidal analgesic drug. See reference claim 1. See examined claim 7. Furthermore, Duan’073 recite a treatment method where the compound is
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which anticipates the compounds of examined claims 1 – 2, and 4 – 6. See reference claims 1 – 2, 4 – 8, and 19. See examined claims 1 – 2, and 4 – 5. Additionally, Duan’073 recite a drug combination, characterized in that the following substances are comprised as active ingredients: an AKR1C3-activated prodrug compound or its salt, ester, solvate or isotope isomer, and a non-steroidal analgesic drug; wherein, the active ingredients are formulated together or separately for combined use, simultaneous use or separate use. See reference claim 12 – 14, 16 – 18, and 20 – 21. See examined claim 6.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 14 – 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 4 – 8, 12 – 14, 16 – 21 of copending Application No. 19/120073 to Duan et. al. (reference application; Duan’073) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).
Duan’073 recite a method for treating cancer patients accompanied by pain by combining a drug containing an AKR1C3-activated anticancer prodrug compound or its salt, ester, solvate or isotope isomer with a non-steroidal analgesic drug. See reference claim 1. Furthermore, Duan’073 recite a treatment method where the compound is
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See reference claims 1 – 5, 8 – 9, and 11.
However, Duan’073 fails to recite a method of treating cancer
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as delineated in examined claims 14 – 15.
Nevertheless, the teachings of Duan’685 as they relate to the prior art rection of examined claims 14 – 15, 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 of Duan’073 for a method of treating cancer using
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in view of Duan’685 for the cancer to be as delineated in examined claims 14 – 15. One of ordinary skill in the art would have been motivated to because as taught above
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is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer. Thus one of ordinary skill in the art would have had a reasonable expectation of success in targeting cancers where AKR1C3 is expressed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 2, and 4 – 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, and 4 – 16 of copending Application No. 19/490563 to Li et. al. (reference application; Li’563).
Although the claims at issue are not identical, they are not patentably distinct from each other because both conflicting applications direct to a compound of the structure
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. Specifically, Li’563 recite a method for cancer, tumor, or disorders or cell proliferative diseases caused by cancer or tumor, including administering an AKRIC3 enzyme-activated prodrug to a patient when the tumor or cancer tissue of the patient is detected to have a KRAS gene mutation or the patient is detected to have a KRAS gene mutation, without detecting the AKRIC3 protein expression level or the AKRIC3 RNA content in the tumor or cancer tissue of the patient. See reference claim 1. See examined claim 7. Furthermore, Li’563 recite a treatment method where the compound is
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which anticipates the compounds of examined claims 1 – 2, and 4 – 6. See reference claims 1 – 2, 4 – 8, and 12 – 16. See examined claims 1 – 2, and 4 – 5. Additionally, Li’563 recite a formulation unit package comprising an AKR1C3-activated prodrug compound or its salt, ester, solvate or isotope isomer, and a non-steroidal analgesic drug; wherein, the active ingredients are formulated together or separately for combined use, simultaneous use or separate use. See reference claims 9 – 11. See examined claim 6.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 14 – 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 4 – 8, and 12 – 16 of copending Application No. 19/490563 to Li et. al. (reference application; Li’563) in view of International Publication Number WO 2020/228685 A1 to Duan et. al. (Duan’685; cited on the ISR form; English Espacenet translation for WO 2020/228685 A1 submitted by applicant on August 5th, 2024 was used).
Li’563 recite a method for cancer, tumor, or disorders or cell proliferative diseases caused by cancer or tumor, including administering an AKRIC3 enzyme-activated prodrug to a patient when the tumor or cancer tissue of the patient is detected to have a KRAS gene mutation or the patient is detected to have a KRAS gene mutation, without detecting the AKRIC3 protein expression level or the AKRIC3 RNA content in the tumor or cancer tissue of the patient. See reference claim 1. See examined claim 7. Furthermore, Li’563 recite a treatment method where the compound is
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. See reference claims 1 – 2, 4 – 8, and 12 – 16.
However, Li’563 fails to recite a method of treating cancer
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as delineated in examined claims 14 – 15.
Nevertheless, the teachings of Duan’685 as they relate to the prior art rection of examined claims 14 – 15, 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 of Li’563 for a method of treating cancer using
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in view of Duan’685 for the cancer to be as delineated in examined claims 14 – 15. One of ordinary skill in the art would have been motivated to because as taught above
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is capable of inhibiting AKR1C3 and AKR1C3 is target of interested for treating cancer. Thus one of ordinary skill in the art would have had a reasonable expectation of success in targeting cancers where AKR1C3 is expressed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1 – 2, 4 – 7, 14 – 16, 20, 22 – 26, and 28 – 32 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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