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 the Claims
Currently, claims 1-10 are pending in the instant application.
Priority
The instant application is a CON of application 17/819,157, filed on 08/11/2022 and claims foreign priority to CN202110924393.5, filed on 08/12/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/26/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 9 objected to because of the following informalities: Grammar. The instant claim currently recites “E is CH group”. This objection may be overcome by amending the claim to read “E is CH” or “E is a CH group”. Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Second Paragraph
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 1-5 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.
Claim 1 is indefinite for reciting the following:
“Sol-1 is selected from: DMSO, DMF, or THF”
“Sol-2 is selected from: DMSO, DMF, or THF”
“Sol-3 is selected from: DMSO, DMF, or MeCN”
Because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. The above recitations provide improper antecedence because Synthetic Method 1 and Synthetic Method 2 of the instant claim do not recite the inclusion or use of any of Sol-1, Sol-2, or Sol-3.
Claim 2 is indefinite for reciting the following:
“Sol-1 is DMSO”
“Sol-2 is DMF”
“Sol-3 is MeCN”
Because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. The above recitations provide improper antecedence because Synthetic Method 1 and Synthetic Method 2 of claim 1 do not recite the inclusion or use of any of Sol-1, Sol-2, or Sol-3.
Claim 3 is indefinite for reciting “wherein the following two intermediate compounds RM1 and RM1b are obtained by the first reaction step in both synthetic methods 1 and 2, respectively”, because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. The instant claim recites the result of carrying out the first step of synthetic methods 1 and 2 of claim 2, however does not provide any material structure to the method. Accordingly, the instant claim does not further limit the method recited in claim 2. See MPEP 2111.04(I):
In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Claim 4 is indefinite for reciting the “method of claim 3”, because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. As indicated in the 112b rejection of claim 3, claim 3 is not further limiting of claim 2 or claim 1. As the instant claim is attempting to further limit a non-limiting claim, the instant claim is also not further limiting.
Claim 5 is indefinite for reciting “wherein the following multi-substitutional functional compound SM2-01 is prepared by any of the following methods”, because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. The instant claim provides improper antecedence because claim 1 does not recite a compound SM2-01. Applicant may overcome this rejection by amending the claim to include a statement indicating that SM2-01 is a compound of SM2 (i.e., “wherein SM2 is a compound of SM2-01”, etc.).
Claim Rejections - 35 USC § 102
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 1-2 and 7-8 are rejected under pre-AIA 35 U.S.C. 102(a)(1) as being anticipated by Jia (CN 107266363 A).
Claim 1 recites a method for preparing a compound of formula III:
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Wherein the method comprises any one of the following synthetic methods:
Synthetic Method 1:
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Synthetic Method 2:
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Jia teaches a compound of formula III and methods of synthesis thereof. More specifically, Jia teaches synthesis of lenvatinib (specification [0008] and [0010]):
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Lenvatinib is a compound of Formula III wherein:
E is CH
G1 is H
G2 is C1 alkoxy
G3 is C(O)NH2
G4 and G5 are each H
R1 is H
R2 is H
R3 is C3 cycloalkyl
X1, X3, and X4 are each H
X2 is halogen (Cl)
Furthermore, the teachings of Jia appear to anticipate at least synthetic method 1 per the following reactions (due to low image quality of the original document, the following are reactions received from the CAS database, and indexed to CN 107266363 A):
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The original reaction scheme diagram is provided below for reference:
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As can be seen from the reactions above, all of the compounds used and their corresponding variables are the same as in lenvatinib above. Each of compounds SM1, SM2, RM1, and formula III are anticipated by the reagents in the above reactions. Additionally, Jia teaches the use of potassium tert-butoxide corresponding to the recited base-1 and the use of pyridine corresponding to base-2. With regards to base-3, Jia indicates the use of cyclopropylamine in the above third reaction scheme (i.e., conversion from LVTN-2 to LVTN-3) (specification [0009])1.
Claim 2 further limits the method of claim 1 wherein Base-1 is potassium tert-butoxide, Sol-1 is DMSO, Base-2 is pyridine, Sol-2 is DMF, Base-3 is cyclopropylamine, Sol-3 is MeCN.
As iterated previously, Jia teaches a synthesis scheme wherein the corresponding Base-1 is potassium tert-butoxide, Base-2 is pyridine, and Base-3 is cyclopropylamine.
Claim 7 further limits the method of claim 1 wherein:
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As indicated in the claim 1 rejection above, Jia teaches the synthesis of lenvatinib wherein:
E is CH
G1 is H
G2 is C1 alkoxy
G3 is C(O)NH2
G4 and G5 are each H
R1 is H
R2 is H
R3 is C3 cycloalkyl
X1, X3, and X4 are each H
X2 is halogen (Cl)
Claim 8 further limits the method of claim 7 wherein:
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As indicated in the claim 1 rejection above, Jia teaches the synthesis of lenvatinib wherein:
E is CH
G1 is H
G2 is C1 alkoxy
G3 is C(O)NH2
G4 and G5 are each H
R1 is H
R2 is H
R3 is C3 cycloalkyl
X1, X3, and X4 are each H
X2 is halogen (Cl)
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jia (CN 107266363 A) in view of Richaradson (EXPERT OPINION ON DRUG DISCOVERY 2021, VOL. 16, NO. 11, 1261–1286).
Claim 4 recites the method of claim 3 wherein the structures of RM1 and RM1b are as follows:
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As indicated in the rejection of claims 1 and 2, the teachings of Jia anticipate a method of claim 1 because Jia teaches the use of such a method to synthesize lenvatinib. Jia does not explicitly teach the structures of RM1 and RM1b. However, it would have been obvious to utilize at least RM1 because Richardson teaches that fluorine is isosteric with hydrogen, and there would have been a reasonable expectation of success in using the method of Jia to synthesize fluorinated lenvatinib analogs.
The synthesis method of Jia corresponds to method 1 as recited in claim 1, wherein the following structure corresponds to RM1:
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For comparison RM1 of the instant claim is provided below:
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As can be seen from the above compounds, the main difference is the presence of fluorine atoms on the right most aryl ring. By providing a synthesis method utilizing an almost identical compound, Jia provides a certain amount of predictability in said synthesis pathway.
Richardson teaches the general effects of fluorine substitution in drug discovery. In particular, Richardson teaches that utilizing fluorine as a substitute for hydrogen is a common practice in drug discovery because fluorine is an isosteric replacement for hydrogen (page 1263)2. Furthermore, Richardson indicates that fluorine has a van der Waal’s radius that is intermediate in size, lying between hydrogen and the oxygen of a hydroxyl group, and as a result, does not induce significant steric changes when directly substituted with hydrogen. Given the teachings of Jia and Richardson, a person of ordinary skill in the art would have reasonable expectation of success in synthesizing a fluorinated lenvatinib analog from at least compound RM1, as there would be a further reasonable expectation that the fluorine atoms would not interfere with Jia’s synthesis method due to lack of significant steric effect.
Without evidence of the contrary, a person of ordinary skill in the art would reasonably expect that the method of Jia would be effective in both utilizing and producing halogenated versions of the indicated reagent and product compounds by the same mechanisms when viewed through the lens of Richardson. Accordingly, it would have been prima facie obvious for a person of ordinary skill in the art to be able to utilize fluorinated or otherwise halogenated analogs of the compounds taught by Jia as there would have been a reasonable expectation of success in producing halogenated lenvatinib analogs.
Claim(s) 5-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jia in view of Hao (CN104326924A) and Richardson.
Claim 5 further limits the method of claim 1 wherein SM2-01 is prepared by any of the following methods 10-1 or 10-2:
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As indicated previously, Jia anticipates a method of claim 1. Jia does not explicitly teach wherein SM-2 of claim 1 is SM2-01, or the recited methods of synthesis for said compound. However, it would be obvious to incorporate such a synthesis because Hao teaches an analogous synthesis method to method 10-1 and Richardson teaches that fluorine is isosteric with hydrogen, and there would be a reasonable expectation of success in synthesizing a compound of SM2-01.
The teachings of Hao are directed towards synthesis methods for intermediates of the compound tivozanib which is also a compound of Formula III:
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Two such methods are for the synthesis of 4-[2-(2-Chloro-4-hydroxyphenyl)diazenyl]benzenesulfonic acid and 4-Amino-3-chlorophenol (specification [0048]-[0049], [0054]-[0055])3. The reactions corresponding to said syntheses are provided below:
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As can be seen above, the synthesis of Hao corresponds to method 10-1 of the instant claim where [H] is zinc. The only difference is that SM2-01 is a halogenated analog of 4-amino-3-chlorophenyl.
Richardson teaches the general effects of fluorine substitution in drug discovery. In particular, Richardson teaches that utilizing fluorine as a substitute for hydrogen is a common practice in drug discovery because fluorine is an isosteric replacement for hydrogen (page 1263). Furthermore, Richardson indicates that fluorine has a van der Waal’s radius that is intermediate in size, lying between hydrogen and the oxygen of a hydroxyl group, and as a result, does not induce significant steric changes when directly substituted with hydrogen. Given the teachings of Hao and Richardson, a person of ordinary skill in the art would have reasonable expectation of success in synthesizing SM2-01 from a fluorinated analog of m-chlorophenol using the method of Hao because there would be further expectation that such fluorine substitutions would not interfere with Hao’s synthesis method due to lack of significant steric effect.
Given that Jia discloses the use of 4-amino-3-chlorophenyl in the synthesis of lenvatinib, Hao discloses a method of synthesizing 4-amino-3-chlorophenyl, and Richardson teaches the isosteric replacement of hydrogen with fluorine, it would have been prima facie obvious for a person of ordinary skill in the art to utilize the teachings of Hao to produce 4-amino-3-chlorophenyl or a halogenated analog thereof, and use said compound per the teachings of Jia to produce a compound of Formula III, because there would have been a reasonable expectation of success in producing the target compound.
Claim 6 further limits the method of claim 5 wherein:
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As previously discussed, Hao essentially teaches method 10-1 recited in claim 5. Hao does not explicitly teach the use of Fe powder and HCl as a reducing agent. However, it would be obvious to use said components because Hao teaches Fe powder as an alternate reducing agent (specification [0018])4, and there would be a reasonable expectation of success in forming the target compound SM2-01.
As discussed above, the teachings of Hao indicate alternate reducing agents other than Zn powder. One of the alternates taught by Hao is Fe powder. While Hao does not explicitly teach the combination of Fe powder and HCl, a person of ordinary skill in the art would recognize that the combination of iron and HCl is a ubiquitous combination in the art for redox, and carrying out reductions. As Hao explicitly teaches the use of reducing agents in order to form 4-amino-3-chlorophenyl, a person of ordinary skill in the art would look to obvious techniques found in the art. The inclusion of HCl alongside Fe powder would have been obvious to a person of ordinary skill in the art, and there would have been a reasonable expectation that the inclusion would successfully form the target compound.
Claim(s) 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jia in view of Richardson.
Claim 9 further limits the method of claim 8 wherein:
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As discussed previously, the teachings of Jia anticipate a method of claim 8. Jia does not explicitly teach the synthesis of a compound of the instant claim. However it would be obvious to utilize the method of Jia to synthesize such a compound because the compound of the instant claim encompasses fluorinated analogs of lenvatinib, and there would be a reasonable expectation of success in synthesizing such fluorinated compounds because Richardson teaches that fluorine is an isosteric replacement for hydrogen.
Lenvatinib, as taught by Jia, meets all the limitations of the instant claim save for variables X1 and X3. In lenvatinib, X1 and X3 are H rather than halogen, alkoxy, or alkylamino. In other words, the instant claim targets structural analogs of lenvatinib.
As indicated previously, Richardson teaches that utilizing fluorine as a substitute for hydrogen is a common practice in drug discovery because fluorine is an isosteric replacement for hydrogen (page 1263). Furthermore, Richardson indicates that fluorine has a van der Waal’s radius that is intermediate in size, lying between hydrogen and the oxygen of a hydroxyl group, and as a result, does not induce significant steric changes when directly substituted with hydrogen.
Accordingly, it would have been prima facie obvious for a person of ordinary skill in the art to be able to apply Jia’s methods to the synthesis of at least fluorinated analogs of lenvatinib because there would be a reasonable expectation of success in forming such compounds per the teachings of Richardson.
Claim 10 further limits the method of claim 9 wherein the compound is:
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The above compound is a fluorinated analog of lenvatinib wherein the corresponding X1 and X3 positions are fluorine. Accordingly, the instant claim would be obvious for the same reasons as iterated in the claim 9 rejection. Namely that a person of ordinary skill in the art would reasonably expect that the methods of Jia would be successful in forming a halogenated analog of lenvatinib due to the combined teachings of Richardson which indicate isosteric replacement of hydrogen with fluorine.
Conclusion
Claims 1-10 are rejected.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “Intermediate-2 is then subjected to a substitution reaction with cyclopropylamine to give Intermediate-3: 4- (3-chloro-4- (N'-cyclopropylureido) phenoxy) -6-carboxylic acid amide (LVTN-3, levignine free base)”
2 “The unique properties of fluorine have long been recognized within drug discovery and given that it typically does not resemble those of the other halogens, it is often employed as an isosteric replacement for hydrogen Although, often stated to be sterically analogous to hydrogen, from its van der Waal’s radius, fluorine is intermediate in size between a hydrogen and the oxygen of a hydroxyl group, and as such direct substitution does not induce significant changes from a steric perspective.”
3 “Weigh p-aminobenzenesulfonic acid (17.4g, 0.1mol), add water (150ml), slowly add sodium carbonate powder (5.8g, 0.055mol), stir to dissolve into a clear solution, reduce the temperature of the solution to 0 ° C, drop Add sodium nitrite (7.25g, 0.105mol) in water (20ml) solution, continue to add concentrated hydrochloric acid (25ml) slowly after the addition, the temperature of the two drops does not exceed 5 ° C, after the addition is completed, at 0 The reaction was stirred at -5 ° C for 40 min. After the reaction is completed, the reaction solution is refrigerated for use. Weighed m-chlorophenol (6.4g, 0.1mol) was added to water (150ml) to dissolve, add 20% NaOH solution (20ml, 0.1mol) and sodium carbonate powder (8g, 0.075mol), the solution was cooled to 0 ° C, at 0 The reaction liquid prepared above was slowly added dropwise at -5 ° C, and after completion of the dropwise addition, the reaction was stirred at 0 to 5 ° C for 3 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5 with concentrated hydrochloric acid, stirred for 0.5 hr, filtered, and filtered, washed with water (20 ml), and dried under reduced pressure at 40 ° C to yield a yield of a solid red solid (15.4 g, 98.7%).”
“4-(2-Chloro-4-hydroxy-phenylazo)benzenesulfonic acid (12.5 g, 0.04 mol) was weighed, and methanol (125 ml) was added thereto, respectively, ammonium formate (12.6 g, 0.2 mol) and zinc powder ( 6.5 g, 0.1 mol), and reacted at room temperature for 2 h. After the reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The liquid phase was separated, and the organic phase was washed with water, brine and dried over anhydrous sodium sulfate. The dried solution was evaporated to dryness EtOAc. Yield: 87%, m.p. 159-160 ° C”
4 “In another preferred example, the reducing agent in step (3) is selected from the group consisting of hydrogen, sodium persulfite (sodium hydrosulfite), sodium hydrosulfide, iron powder, zinc powder and ammonium formate or zinc powder and formic acid; more Preferably, the reducing agent is selected from the mixture of zinc powder and ammonium formate or the mixture of zinc powder and formic acid.”
Prosecution Insights