DETAILED ACTION
This office action is in response to applicant’s filing dated December 7, 2022.
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 .
Status of claims
Claims 1 -19 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed December 7, 2022. Acknowledgment is made of Applicant’s addition of a new claims 11 - 19.
Priority
The present application is a 371 of PCT/CN2021/096279 filed May 27, 2021, which claims priority to Chinese Patent Application No. 202010573569.2 filed June 22, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/07/2022 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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 8 and 16are 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. The claims recite the term “preferably” , which is equivalent to phrase “such as”, renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 – 6, 11 and 13 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Deng et al (WO 2020063824 A1, hereinafter Deng).
The applied reference has a common assignee or joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
WO 2020063824 A1 (published on April 2, 2020) is the PCT counterpart to US 2021/0363165 A1 (published November 25, 2021). WO 2020063824 A1 has a 102(a)(1)) date as a result of its April 2, 2020 publication date. Because WO 2020063824 A1 and US 2021/0363165 A1appear to have identical disclosures, and because the WO document was published in Chinese language designating the United States, the US 2021/0363165 A1, which is the National Stage entry of WO 2020063824 A1, is being used as a translation of WO 2020063824 A1. As such, any reference hereinafter to column and line numbers will be based upon the US publication, but should be interpreted as referring to the corresponding disclosure of the aforementioned WO counterpart.
Instant claims are drawn to a method of preparation of compound (VII)
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, such as compound
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via reaction of compound V
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, such as compound
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with chloromethyl chlorosulfate (6) (
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) in presence of base (e.g., potassium carbonate), where molar ratio of compound V to base is 1:2.5 to 1:15; where the solvent is a binary system water/tetrahydrofuran (THF) in volume ratio 10:15 to 15:0.1; where the catalyst is quaternary ammonium phase transfer catalyst (e.g. tetrabutyl ammonium hydrogen sulfate (TBAHS)) in molar ratio compound V to catalyst 1:0.01 to 1:0.3; where the molar ratio of compound V to compound 6 is 1:1 to 1:5; where volume:mass ratio of solvent to compound V is 20 mL/g to 50mL/g and where the reaction temperature is 20°C to 35°C.
Deng teaches a method of synthesis of compound (1a)
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via reaction:
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(page 43, [0196]) in presence of potassium carbonate in aqueous tetrahydrofuran solvent (page 43, [0197] and page 45, [0215]). The reaction was conducted at temperature 20°C to 30°C (page 45, [0216]). According to example of synthesis (page 46, [0218]):
compound V was taken in molar ratio 52.59 mmol:63.15 mmol to compound 6, which is ~1:1.2;
compound V to base molar ratio is 52.59 mmol:210mmol (recalculated from solution molarity and volume), which is ~ 1:4;
volume ratio water/dichloromethane (DCM) is 60mL:100mL, which is ~ 10:16.7;
compound V to TBAHS molar ratio is 52.59mmol:5.24 mmol, which is ~1:0.1;
solvent volume to mass of compound V ratio is 160mL (total volume):10g, which is ~16mL/g.
Although, the particular synthesis example used sodium bicarbonate instead of potassium carbonate and DCM solvent instead of THF, these alkali compounds and solvents are interchangeable, according to general reaction procedure taught by Deng (page 43, [0197]). The above example uses temperature range as well as ratios of compound V to base, compound V to catalyst and compound V to compound 6 that fall within the claimed ranges. MPEP 2131.03 (I) states: "If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023). Although solvent volume to mass of compound V ratio and solvents volume ratio in the binary solvent system is slightly outside the claimed ranges, MPEP 2144.05.II(A) states: Generally, 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).
Thus, teachings of Deng anticipate method of claims 1 – 6, 11 and 13.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7 and 14 – 16 are rejected under 35 U.S.C. 103 as being obvious over Deng et al (WO 2020063824 A1) in view of Stamm et al (HCA, 89: 1841-1855, 2006, hereinafter Stamm) and Aycock (Organic Process Research & Development 2007, 11, 156−159).
The applied reference has a common assignee or joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Instant claims are drawn to a method of preparation of compound VII, where step (b) is a preparation of compound 4 is obtained by hydrolysis of compound 3
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in 2-methyltetrahydrofuran/water, in presence of base (LiOH). Compound 3 is obtained by reaction (amidation):
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in DCM in presence of base triethylamine.
Deng teaches reaction of compound 18b
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with isobutyryl chloride (amidation), affording compound of ex. 20
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(pages 55 – 56, example 18 and page 57, example 20)). Reaction of compound 18b with isobutyryl chloride was conducted in DCM in presence of base triethylamine (page 56, [0297]). Although, Deng teaches reaction of alkylation of compound
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with compound (1a)
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was conducted before amidation reaction (compound 18b with isobutyryl chloride), including N-Boc deprotection step, and instant claims recite amidation (preparation of compound 3), then hydrolysis step (preparation of compound 4) and then final alkylation step (preparation of compound VIII), changing order of reactions in the multistep synthesis, which leads to the same final product is the standard laboratory practice. MPEP 2144.04. (C) states: Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). Regarding N-Boc deprotection step which is taught by prior art and does not present in the instant method, “comprising” claim language does not exclude additional, unrecited elements or steps.
Deng does not teach the method of preparation where compound 4 was obtained via reaction of hydrolysis of compound 3. However, Stamm teaches a reaction step (a)
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, where the reaction was conducted in tetrahydrofuran(THF)/water, in presence of base (LiOH) (page 1843, scheme 1, step a). Although the prior art teaches the hydrolysis reaction in THF, while instant claims used 2-methyltetrahydrofuran (2-MeTHF), these solvents have similar molecular structure with -CH3 group difference. They are both aprotic solvents and could be used alternatively. Aycock teaches several properties of THF and 2-Me THF and their application as solvents in biphasic reactions (page 156, Table 1).
Thus, since Deng teaches a method, where compound (1a) react with chloride salt of aminoacid L-proline in certain conditions and reaction components ratios, where the product of the reaction further undergoing reaction of amidation of N-atom of proline with isobutyryl chloride, Stamm teaches a method of making of isobutyryl-L-proline via hydrolysis of methyl isobutyryl-L-prolinate in basic conditions, and Aycock teaches properties of solvents, usable in this type of reactions, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to combine teachings of prior art to arrive at claimed method of synthesis with the reasonable expectation of success.
Claims 1, 8 – 10, 17 and 19 are rejected under 35 U.S.C. 103 as being obvious over Deng et al (WO 2020063824 A1).
The applied reference has a common assignee or joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The instant claims are drawn to a method of synthesis of the compound VII
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according to reaction,
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where obtained compound VII further involved into the process of synthesis of compound VIII
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via reaction of compound VII with compound 4
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, in dimethylformamide (DMF), at temperature 20°C to 30°C, in presence of potassium carbonate, where:
molar ratio of compound 4 to potassium carbonate is 1-1.5:1,
molar ratio of compound 4 to compound VII is 1-1.5:1;
solvent volume to the mass of compound 4 ratio is 8:1mL/g to 12:1 mL/g.
. The compound VIII, synthesized by the above method, further undergoes separation and purification.
Deng teaches a method of preparation of compound (1a)
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via reaction:
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. Compound (1a) further applied as reactant in the method of preparation of compound ex. 20
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( (S )-( 5-Nitroquinolin-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate) (page 57, [0304]) via reactions:
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in DMF in presence of potassium carbonate at room temperature (page 56, [0295]), obtaining compound
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, then compound 18a undergoes reaction of N-Boc deprotection, obtaining compound 18b
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and final reaction of compound 18b with isobutyryl chloride (amidation), affording compound of ex. 20 (pages 55 – 56, example 18 and page 57, example 20)). Reaction of compound 18b with isobutyryl chloride was conducted in DCM in presence of base triethylamine (page 56, [0297]). After completion of the final reaction, the reaction solution was concentrated under reduced pressure, and the resulting residues were purified by silica gel column chromatography to obtain the product, ex. 20 (page 56, [0297]).
Although method of Deng teaches synthesis of compound ex. 20, reaction of alkylation of compound
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with compound (1a) was conducted before amidation reaction (compound 18b with isobutyryl chloride), including N-Boc deprotection step, and instant claims recite reactions in order: amidation (preparation of compound 3), then hydrolysis step (preparation of compound 4) and then final alkylation step (preparation of compound VIII), changing order of reactions in the multistep synthesis, which leads to the same final product is the standard laboratory practice. MPEP 2144.04. (C) states: Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). Regarding N-Boc deprotection step which is taught by prior art and does not present in the instant method, “comprising” claim language does not exclude additional, unrecited elements or steps.
Regarding ratios of components of the reaction mixture, Deng teaches:
molar ratio of L-Boc-proline to compound (1a) is 9.4 mmol:6.3 mmol, which is ~1.5:1;
molar ratio of L-Boc-proline to potassium carbonate is 9.4mmol:12.6 mmol, which is ~ 1:1.3;
solvent volume to the mass of L-Boc-proline ratio is 15 mL:2.02 g which is ~7.4 mL/g.
The amounts, taught by prior art are within the range, overlapping or close to the claimed ranges. MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Similarly, 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). "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."
Thus, since Deng teaches a method of preparation of prodrug (target compound) from nitroxoline drug, using multistep synthesis, where first reaction is alkylation of nitroxoline with chloromethyl chlorosulfate, where resulting product react with aminoacid proline in certain conditions and reaction components ratios, , it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to slightly modify teachings of prior art to arrive at claimed method of synthesis with the reasonable expectation of success.
Claims 1, 8, 12 and 18 are rejected under 35 U.S.C. 103 as being obvious over Deng et al (WO 2020063824 A1) in view of Chern et al (WO 2014/163622 A1, hereinafter Chern).
The applied reference (WO 2020063824 A1) has a common assignee or joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Instant claims are drawn to a method of synthesis of compound VII
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where A is an aromatic or heteroaromatic ring, R1 = R2 and R2 is C1-C6 alkyl, k = 1 via reaction:
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, where -OH group in compound V is attached to a carbon atom of the ring. The reaction was conducted in presence of base and catalyst, where the solvent is a binary system water/tetrahydrofuran (THF). The instant claims are further drawn to a method of synthesis of compound VIII
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where A is an aromatic or heteroaromatic ring, R1 = R2 and R2 is C1-C6 alkyl, k = 1, via reaction:
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, where -OCH2Cl group in compound VII is attached to a carbon atom of the ring. The reaction was conducted in dimethylformamide (DMF), at temperature 20°C to 30°C, in presence of potassium carbonate, where:
molar ratio of compound 4 to potassium carbonate is 1-1.5:1,
molar ratio of compound 4 to compound VII is 1-1.5:1;
solvent volume to the mass of compound 4 ratio is 8:1mL/g to 12:1 mL/g.
The compound VII is previously prepared according to reaction
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.
Deng teaches a method of synthesis of compound (1a)
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via reaction:
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(page 43, [0196]) in presence of potassium carbonate in aqueous tetrahydrofuran solvent (page 43, [0197] and page 45, [0215]). After being synthesized, compound (1a) is further applied in a method of preparation of compound ex. 20
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( (S )-( 5-Nitroquinolin-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate) (page 57, [0304]) via reactions:
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in DMF in presence of potassium carbonate at room temperature (page 56, [0295]), obtaining compound
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(alkylation), then compound 18a undergoes reaction of N-Boc deprotection, obtaining compound 18b
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and final reaction of compound 18b with isobutyryl chloride (amidation), affording compound of ex. 20 (pages 55 – 56, example 18 and page 57, example 20)). Reaction of compound 18b with isobutyryl chloride was conducted in DCM in presence of base triethylamine (page 56, [0297]). Although method of Deng teaches synthesis of compound ex. 20, where reaction of alkylation of compound
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with compound (1a) was conducted before amidation reaction (compound 18b with isobutyryl chloride), including N-Boc deprotection step, and instant claims recite amidation (preparation of compound 3), before alkylation step (preparation of compound VIII), changing order of reactions in the multistep synthesis, which leads to the same final product is the standard laboratory practice. MPEP 2144.04. (C) states: Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). Regarding N-Boc deprotection step which is taught by prior art and does not present in the instant method, “comprising” claim language does not exclude additional, unrecited elements or steps.
Regarding ratios of components of the reaction mixture, Deng teaches:
molar ratio of L-Boc-proline to compound (1a) is 9.4 mmol:6.3 mmol, which is ~1.5:1;
molar ratio of L-Boc-proline to potassium carbonate is 9.4mmol:12.6 mmol, which is ~ 1:1.3;
solvent volume to the mass of L-Boc-proline ratio is 15 mL:2.02 g which is ~7.4 mL/g.
The amounts, taught by prior art are within the range, overlapping or close to the claimed ranges. MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Similarly, 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). "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."
Deng does not teach where R1 = R2 and R2 is C1-C6 alkyl and k= 1.
However, Chern teaches compound of Formula (l) or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof:
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, where R1 is hydrogen or C1-C8 haloalkyl, R3 and R4 are independently hydrogen or C1-C8 alkyl; R2, R7, R5 and R6 is hydrogen. The compound of formula (I) of Chern is equivalent of compound of formula VII of instant claims if R1 is C1 haloalkyl (e.g. -CH2Cl) and R3 or R4 is C1-C6 alkyl. The compound of formula (I) of Chern is equivalent of compound of formula V of instant claims if R1 is H and either R3 and R4 is C1-C6 alkyl.
Chern does not teach the same method of synthesis of compound of formula (I) as method of synthesis of instant claims.
Nevertheless, since Deng teaches a method of synthesis of compound (1a), which is further converted into compound of ex. 20 via multistep synthesis, and Chern teaches a compound of formula (I), where heteroaromatic ring has C1-C6 alkyl and (-O-CH2Cl) substituents, which structure corresponds to the compound of formula VII or compound of formula V of instant claims, and where -O-CH2Cl group is the reaction center in synthesis of target compound (compound VIII of instant claims), it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to take compounds of Formula (I) of Chern and employ them into a method of synthesis taught by Deng to obtain compound VIII of instant claims 12 and 18 with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 11, 13 – 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Clark et al (US 8,436,009 B2, hereinafter Clark), in view of Qin et al (US 9,517,988 B2, hereinafter Qin), Wijma et al (J Antimicrob Chemother 2018; 73: 2916–2926, hereinafter Wijma), Vig et al (Advanced Drug Delivery Reviews 65 (2013) 1370–1385), Stamm et al (HCA, 89: 1841-1855, 2006, hereinafter Stamm), Aycock (Organic Process Research & Development 2007, 11, 156−159) and Luykx et al (HCA, 79: 527-540, hereinafter Luykx).
Instant claims are drawn to a method of synthesis of compound VII are drawn to a method of synthesis of the compound VII
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according to reaction,
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where obtained compound VII further involved into the process of synthesis of compound VIII
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via reaction of compound VII with compound 4
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.
:
The synthesis steps were conducted under following conditions:
1. Preparation of compound VII (7). Compound V (5)
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and 6
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reacted in in presence of base (e.g., potassium carbonate), where molar ratio of compound V to base is 1:2.5 to 1:15; where the solvent is a binary system water/tetrahydrofuran (THF) in volume ratio 10:15 to 15:0.1; where the catalyst is quaternary ammonium phase transfer catalyst (e.g. tetrabutyl ammonium hydrogen sulfate (TBAHS)) in molar ratio compound V to catalyst 1:0.01 to 1:0.3; where the molar ratio of compound V to compound 6 is 1:1 to 1:5; where volume:mass ratio of solvent to compound V is 20 mL/g to 50mL/g and where the reaction temperature is 20°C to 35°C.
2. Preparation of compound VIII (8). Compound VII (7) and 4 reacted in dimethylformamide (DMF), at temperature 20°C to 30°C, in presence of potassium carbonate, where:
molar ratio of compound 4 to potassium carbonate is 1-1.5:1,
molar ratio of compound 4 to compound VII is 1-1.5:1;
solvent volume to the mass of compound 4 ratio is 8:1mL/g to 12:1 mL/g.
The compound VIII, synthesized by the above method, further undergoes separation and purification.
The instant claims are further drawn to a method of preparation of compound 3 via reaction:
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in DCM in presence of base triethylamine; and a preparation of compound 4 via reaction:
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in 2-methyltetrahydrofuran/water, in presence of base (LiOH).
Clark teaches a method of synthesis of prodrugs from drug of formula (IV)
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, where the method steps are:
1.
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, the reaction was conducted in a binary solvent system water/tetrahydrofuran (THF) or mixture of solvents with water, in presence of base (e.g., potassium carbonate) with catalyst phase transfer catalyst (e.g. tetrabutyl ammonium hydrogen sulfate (TBAHS)), at temperature 10°C to 30°C, where the ratios are:
- base to compound B-2 is 5 – 15 fold molar amount;
- solvents (DCM/THF/water) are in volume ratio ~1:1:1 example (column 40, lines 35 – 39);
- compound B-2 to catalyst 1:0.01 to 1:0.3 molar amount;
- compound B-2 to compound C-1 is 1:1 to 1:5 molar amount (column 19, step 1c);
- volume:mass ratio of solvent to compound B-2 is 60mL/g (recalculated from mass of compound B-2 and total volume of solvent mixture) (column 40, lines 35 – 39).
2. Reaction of compound C-2
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with carboxylic acid C-3, yielding compound of formula C-4
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, where A1 is a bond and R5 is C1-C6 alkyl or C3-C8 cycloalkyl, optionally substituted. The reaction was conducted in DMF in presence of potassium carbonate, at temperature 20°C to 60°C where:
molar ratio of carboxylic acid C-3 to compound C-2 is 1 to 5 fold molar amount (column 20, step 2c);
molar ratio of carboxylic acid C-3 to potassium carbonate is 88.3 mg (0.76 mmol):109 mg (~1.1 mmol), which is ~1:1.4;
solvent volume to the mass of carboxylic acid C-3 ratio is ~ 100 – 150 mL/g.
The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (columns 47 lines 53 - 67 and 48, lines 1 - 5).
Although, the structure of the drug, taught by Clark is not similar to the structure of instant claims, the compound (IV) of Clark has the same fragment (heteroaromatic ring (1,2,4-triazole) with -OH group, and only this fragment of the molecule participates in the reactions, described above. Although, the compound (IV) shown in the figure in -NH-C(=O)- form, this compound exists in two tautomeric forms, where C=O group and C-OH group easily interconvert by tautomeric proton transfer, where -OH group attached to the carbon atom of the heteroaromatic ring, undergoing reaction with chloromethyl chlorosulfate (compound C-1), forming compound C-2, which further converted into prodrug (C-4) via reaction with carboxylic acid (C-3), where only -O-CH2Cl group of compound C-2 participates.
Although some reaction component amounts are outside the claimed ranges, MPEP 2144.05.II(A) states: Generally, 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).
Regarding presence of DCM in solvent mixture, used by Clark in particular example, which is applied herein for amount calculation purposes, instant claims do not recite DCM. However, according to general procedure in step 1c, the solvents are selected from THF, dioxane etc., or mixture thereof with water (column 19, lines 15 – 24).
Clark does not teach the preparation method where carboxylic acid (C-3) is L-proline or isobutyryl-L-proline. Clark does not teach method of synthesis of isobutyryl-L-proline (4) from compound 3 or making compound 3 from compounds 1 and 2. Clark also does not teach nitroxoline as a drug to prepare prodrug from.
However, Qin teaches prodrugs of phenol derivative drugs useful for local
anesthesia, anti-arrhythmia and anti-convulsion (column 2, lines 27 – 62) where the prodrugs have a structure:
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or
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, where proline or N-Boc proline is attached to the phenol derivative drug via -CH2- linker (column 66, lines 35 – 40 and column 72, lines 35 – 40).
Wijma teaches nitroxoline
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(page 2917, Figure 1(b)) as an antibiotic for the treatment or prophylaxis of acute urinary tract infections (abstract).
Moreover, Vig teaches amino acid prodrugs, based on natural (page 1372, Fig. 2) or synthetic aminoacids, which are used to improve poor solubility, poor permeability, sustained release etc., of the parent drug, where structurally amino acids are directly conjugated to the parent drugs or bifunctional linkers have been used to further increase the structural diversity of parent drugs that could be linked to amino acids (page 1372, right column, 1st paragraph). The prodrug linkage structures of aminoacid (AA)
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and R’-OH parent drug producing prodrug of structure R’-O-AA are illustrated in Fig. 3 (page 1373).
Regarding a method of preparation of compound 4 via reaction of hydrolysis of compound 3, Stamm teaches a reaction step (a)
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, where the reaction was conducted in tetrahydrofuran(THF)/water, in presence of base (LiOH) (page 1843, scheme 1, step a). Although the prior art teaches the hydrolysis reaction in THF, while instant claims used 2-methyltetrahydrofuran (2-MeTHF), these solvents have similar molecular structure with -CH3 group difference, and could be used alternatively.
Aycock teaches several properties of THF and 2-MeTHF and their application as solvents in biphasic reactions, where MeTHF is being used in biphasic chemical processes replacing THF. (page 156, Table 1).
The method of preparation of compound 3 from 1 and 2 has been taught by Luykx:
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(page 528, scheme 1). Luykx teaches conducting the reaction in EtOAc solvent instead of DCM, in presences of TEA at room temperature (page 533, experimental part 1). However, the conditions of the reaction of preparation of compound 3, in DCM solvent, in presence of TEA at room temperature are well-known in the laboratory practice:
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(https://commonorganicchemistry.com/Rxn_Pages/Amine_to_Amide/Amine_to_AmiAm_Index.htm).
Thus, since prior art teaches a method of synthesis of prodrugs from R-OH drugs by linking them with aminoacids, where all method steps are taught by prior art, where reactions conducted under certain conditions, utilizing certain amounts of reaction components, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to combine teachings of prior art and make a prodrug (compound VIII) from known drug (nitroxoline) by linking it with known fragment (isobutyryl-L-proline), utilizing known method, to arrive at the claimed invention. The one of ordinary skills would be motivated to do so pursuing improvement of desired properties of the drug with the reasonable expectation of success.
Claims 1, 8, 12 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Clark et al (US 8,436,009 B2), in view of Qin et al (US 9,517,988 B2), Chern et al (WO 2014/163622 A1), Vig et al (Advanced Drug Delivery Reviews 65 (2013) 1370–1385) and Stamm et al (HCA, 89: 1841-1855, 2006).
Instant claims are drawn to a method of synthesis of compound VII
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where A is an aromatic or heteroaromatic ring, R1 = R2 and R2 is C1-C6 alkyl, k = 1, via reaction:
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, where -OH group in compound V is attached to a carbon atom of the ring. The reaction was conducted in presence of base and catalyst, where the solvent is a binary system water/tetrahydrofuran (THF). Instant claims are further drawn to a method of synthesis of compound VIII
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where A is an aromatic or heteroaromatic ring, R1 = R2 and R2 is C1-C6 alkyl, k= 1, via reaction:
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, where -OCH2Cl group in compound VII is attached to a carbon atom of the ring. The reaction was conducted in dimethylformamide (DMF), at temperature 20°C to 30°C, in presence of potassium carbonate, where:
molar ratio of compound 4 to potassium carbonate is 1-1.5:1,
molar ratio of compound 4 to compound VII is 1-1.5:1;
solvent volume to the mass of compound 4 ratio is 8:1mL/g to 12:1 mL/g.
The compound VII is previously prepared according to reaction
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.
Clark teaches a method of synthesis of prodrugs from drug of formula (IV)
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, where the method steps are:
1.
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, the reaction was conducted in a binary solvent system water/tetrahydrofuran (THF) or mixture of solvents with water, in presence of base (e.g., potassium carbonate) with catalyst phase transfer catalyst (e.g. tetrabutyl ammonium hydrogen sulfate (TBAHS)).
2. Reaction of compound C-2
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with carboxylic acid C-3, yielding compound of formula C-4
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, where A1 is a bond and R5 is C1-C6 alkyl or C3-C8 cycloalkyl, optionally substituted. The reaction was conducted in DMF in presence of potassium carbonate, at temperature 20°C to 60°C where:
molar ratio of carboxylic acid C-3 to compound C-2 is 1 to 5 fold molar amount (column 20, step 2c);
molar ratio of carboxylic acid C-3 to potassium carbonate is 88.3 mg (0.76 mmol):109 mg (~1.1 mmol), which is ~1:1.4;
solvent volume to the mass of carboxylic acid C-3 ratio is ~ 100 – 150 mL/g.
Although, the structure of the drug, taught by Clark is not similar to the structure of instant claims, the compound (IV) of Clark has the same fragment (heteroaromatic ring (1,2,4-triazole) with -OH group, and only this fragment of the molecule participates in the reactions, described above. Although, the compound (IV) shown in the figure in -NH-C(=O)- form, this compound exists in two tautomeric forms, where C=O group and C-OH group easily interconvert by tautomeric proton transfer, where -OH group attached to the carbon atom of the heteroaromatic ring, undergoing reaction with chloromethyl chlorosulfate (compound C-1), forming compound C-2, which further converted into prodrug (C-4) via reaction with carboxylic acid (C-3), where only -O-CH2Cl group of compound C-2 participates.
Although some reaction component amounts are outside the claimed ranges, MPEP 2144.05.II(A) states: Generally, 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).
Regarding presence of DCM in solvent mixture, used by Clark in particular example, which is applied herein for amount calculation purposes, instant claims do not recite DCM. However, according to general procedure in step 1c, the solvents are selected from THF, dioxane etc., or mixture thereof with water (column 19, lines 15 – 24).
Clark does not teach the preparation method where carboxylic acid is L-proline or isobutyryl-L-proline. Clark also does not teach the drug of formula
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where R1 = R2, R2 is C1-C6 alkyl substituents in aromatic or heteroaromatic ring A and k>=0. However, Qin teaches prodrugs of phenol derivative drugs useful for local anesthesia, anti-arrhythmia and anti-convulsion (column 2, lines 27 – 62) where the prodrugs have a structure:
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or
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, where proline or N-Boc proline is attached to the phenol derivative drug via -CH2- linker (column 66, lines 35 – 40 and column 72, lines 35 – 40). Chern teaches compound of Formula (l) or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof:
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, where R1 is hydrogen or C1-C8 haloalkyl, R3 and R4 are independently hydrogen or C1-C8 alkyl; R2, R7, R5 and R6 is hydrogen. The compound of formula (I) of Chern is equivalent of compound of formula VII of instant claims if R1 is C1 haloalkyl (-CH2Cl) and either R3 and R4 is C1-C6 alkyl or equivalent to a compound of formula V if R1 is hydrogen and either R3 and R4 is C1-C6 alkyl.
Moreover, Vig teaches amino acid prodrugs, based on natural (page 1372, Fig. 2) or synthetic aminoacids, which are used to improve poor solubility, poor permeability, sustained release etc., of the parent drug, where structurally amino acids are directly conjugated to the parent drugs or bifunctional linkers have been used to further increase the structural diversity and expand the types of parent drugs that could be linked to amino acids (page 1372, right column, 1st paragraph). The prodrug linkage structures of aminoacid (AA)
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and R’-OH parent drug producing prodrug of formula: R’-O-AA are illustrated in Fig. 3 (page 1373).
Additionally, Stamm teaches isobutyryl-L-proline (compound 6)
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, which was prepared via reaction of hydrolysis of compound 5 (page 1843, scheme 1, step a).
Thus, since prior art teaches a method of synthesis of prodrugs from R-OH drugs by linking them with aminoacids, where all method steps are taught by prior art, where reactions conducted under certain conditions, utilizing certain amounts of reaction components, it would have been prima facie obviou