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 .
Priority
The instant application, filed 07/12/2024, is the national stage entry of International Application No. PCT/KR2023/000549, filed 01/12/2023, which claims priority to KR Patent Application No. KR10-2022-0005965, filed 01/14/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55. A certified translation of the KR10-2022-0005965 application has not been received.
Status of Claims
Claims 1-19 were originally presented on 07/12/2024 and are pending.
Information Disclosure Statement
Two separate Information Disclosure Statements (“IDSs”) have been submitted, one on 07/12/2024, and one on 04/06/2026. The IDSs are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs have been considered by the examiner.
Claim Rejections - 35 USC § 112(b)
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 4 and 5 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.
Claims 4-5 Indefinite – “the reaction”
Regarding claims 4 and 5, they recite the claim term “the reaction”. It is unclear which reaction is “the reaction” referred to in these claims.
For example, claim 4 recites the “method of claim 2, wherein the reaction is performed” in various solvent systems. It is unclear which reaction is referred to in this claim because independent claim 1 recites at least 3 separation reactions (producing Chemical Formula 9, obtaining Chemical Formula 6, and obtaining Chemical Formula 6).
For claim 4, while Applicant may intend the claim to be interpreted as reciting solvents used for the reaction for obtaining a compound of Chemical Formula 6 from a compound of Chemical Formula 5, the claim could reasonably be interpreted as reciting reaction solvents (and amounts) for the other reactions, each of which are “a reaction”, and without clear antecedent basis, may be interpreted as “the reaction”. For example, “the reaction” recited in claim 1, where “reacting a compound of Chemical Formula 7 with the compound of Chemical Formula 6 to obtain a compound of Chemical Formula 8”, is also exemplified in the Specification at 47 as using THF as a solvent.
The same issue arises with respect to claim 5, wherein “the reaction” may refer to any number of reactions, with conditions specific to temperature instead of solvent.
Therefore, it is unclear which reaction “the reaction” refers to in claims 4 and 5, and as a result, claim 4 and 5 are rejected as indefinite.
For an example of where “the reaction” was clearly identified, see claim 13 (“…the reaction of the transition metal salt with the diazonium salt of the compound of Chemical Formula 4 is performed at 30° C. to 80° C.”).
Claim Rejections - 35 USC § 102(a)(1)
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.
Claims 14 and 17 Anticipated by WO’382
Claim(s) 14 and 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO’382.1
Regarding independent claim 14, it recites a method of producing a Chemical Formula 9, shown below in a table form (left is claim text, right are structures depicted in the claim):
A method for producing a compound of Chemical Formula 9, comprising the following steps:
obtaining a compound of Chemical Formula 11 from a compound of Chemical Formula 10;
reacting a compound of Chemical Formula 12 with the compound of Chemical Formula 11 to obtain a compound of Chemical Formula 13; and
obtaining the compound of Chemical Formula 9 from the compound of Chemical Formula 13
X, Y, and R4 are each independently a halogen, and other variables are too broad to list.
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The examiner generally interprets these steps as follows (from Specification at 54):
obtaining a compound of Chemical Formula 11 from a compound of Chemical Formula 10;
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reacting a compound of Chemical Formula 12 with the compound of Chemical Formula 11 to obtain a compound of Chemical Formula 13;
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obtaining the compound of Chemical Formula 9 from the compound of Chemical Formula 13
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Regarding claim 17, it recites
The method of claim 14, wherein the compound of Chemical Formula 10 is obtained by carboxylating a compound of Chemical Formula 14
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, where R5 is alkyl and X/Y are halo.
WO’382 at 31 teaches this entire reaction,
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Accordingly, claims 14 and 17 are anticipated by WO’382.
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.
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 1-5 and 10-13 Obvious over US’390 in view of CN’253
Claim(s) 1-5 and 10-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’3902 in view of CN’253.3
Claims 1-5
Claim 1 is directed to a multi-step synthesis. The left column below is the claim text, center are the structures, and right are the designated exemplary compounds from the Specification:
A method for producing a compound of Chemical Formula 9, comprising the following steps:
obtaining a compound of Chemical Formula 6 from a compound of Chemical Formula 5; and
reacting a compound of Chemical Formula 7 with the compound of Chemical Formula 6 to obtain a compound of Chemical Formula 8:
wherein R2, R3, X, and Y are each independently a halogen, and other variables are too broad to list.
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Exemplary compounds
Formula 5 (c50)
Formula 6 (c36)
Formula 7 (
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Formula 8 (c39)
Formula 9 (c40)
The examiner generally interprets these steps as follows:
obtaining a compound of Chemical Formula 6 from a compound of Chemical Formula 5; and
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Specification at 36.
reacting a compound of Chemical Formula 7 with the compound of Chemical Formula 6 to obtain a compound of Chemical Formula 8:
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Specification at 47
US’390 at 22-23 teaches the process of the instant claim 1, i.e., a method for preparing 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (compound c40) through the reaction pathway, see left column below, right column are assignments explained below):
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c36 (Chemical Formula 6)
c38 (Chemical Formula 7) as a Grignard reagent
c39 (Chemical Formula 8)
c40 (Chemical Formula 9)
does not teach preferred Chemical Formula 5 (
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), Specification at 36.
US’390 at 23, left column.
The instant claim 1 differs from US’390 wherein the instant claim, Chemical Formula 6 is obtained from a Chemical Formula 5,
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.
However, CN’253 teaches a method of producing a compound of Chemical Formula 6 (see compound 1 below, which is c36) from a compound of Chemical Formula 5 (see left compound below, which is c50), wherein X and Y are Br, and R2 is Cl.
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CN’253 at paragraph [0017].
The compound of Chemical Formula 5 from CN’253 is the preferred intermediate designated c50 used in the exemplified embodiments of the instant methods depicted in the Specification at 36:
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Specification at 36.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in obtaining the subject matter of the instant claim 1 because both US’390 and CN’253 derive from analogous art (preparation of SGLT inhibitors), and CN’253 at 4, paragraph [0027]-[0029] teaches that the synthetic modification disclosed increases yield, has fewer reactions, and was trivial to perform using the skills of an ordinary chemist at the time of filing. See annexed Machine Translation from Google Translate at 7 (top of page), hereinafter CN’253 Translation.4 Combining the teachings results in the process claimed in the instant claim 1 and many other claims.
Accordingly, claim 1 was obvious at the time of filing
Regarding claim 2, it recites:
The method of claim 1, wherein the obtaining of the compound of Chemical Formula 6 from the compound of Chemical Formula 5 comprises:
selectively converting the substituent X in the compound of Chemical Formula 5 to an aldehyde group using an organomagnesium reagent and dimethylformamide (DMF) as reaction reagents.
The examiner interprets this claim as being generally directed to the following transformation which appears in the method exemplified in the Specification at 36,
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Specification at 36.
This step appears to be identical to the following reaction taught in CN’253, where it teaches using an organomagnesium reagent and dimethylformamide (DMF) as reaction reagents to selectively convert the substituent X in the compound of Chemical Formula 5 to an aldehyde group. See CN’253 Translation at 8, Example 5, text appearing at center of page:
[0043] 3.5 g of 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran and 35 mL of tetrahydrofuran were added to a 100 mL reaction flask. Under nitrogen protection, 18 mL of a 2.5 M solution of isopropyl magnesium chloride in tetrahydrofuran was added dropwise. After the addition was complete, the mixture was kept warm and stirred for 1 hour. Then, 5 mL of N,N dimethylformamide was added dropwise while the mixture was kept warm, and the reaction was continued for 30 minutes. The reaction solution was poured into 3 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to obtain 2.73 g of compound 1, with a yield of 93.2%, as a white solid.
CN’253 Translation at 8 (emphases added).
Accordingly, claim 2 was obvious at the time of filing.
Regarding claim 3 (interpreted as the amount the organomagnesium reagent is used in claim 2 step) and claim 5 (interpreted as the reaction temperature in claim 2 step), the subject matter of these claims represent ordinary and routine experimentation following the methods of CN’253, well within the grasp of an ordinary chemist at the time of filing.
The amount the organomagnesium reagent is a result effective variable. If no organomagnesium reagent is used, no reaction occurs; if excess organomagnesium reagent is used, synthetic costs increase.
The reaction temperature is a result effective variable. For example, different reaction temperatures require different apparatuses, which increase or decrease the cost of the synthesis, and/or change the product yield.
While shown for a different process, it was routine to vary reaction temperatures and reagent amounts to optimize conditions. See, e.g., US’390 at 36, Table 4, showing that it was routine to vary reaction temperatures and reagent amounts to change product yield. Further, synthetic cost is a result effective variable, see, e.g., CN’253 Translation at 7, indicating that a benefit of its procedure was “low cost”; the cost also includes specialized reactors, indicated in the same section of CN’253 Translation.
The MPEP states that merely modifying the process conditions such as temperature and concentration is not patentable absent a showing of criticality or unexpected results.
See, e.g., MPEP 2144.05, subsection II.A
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)….
MPEP 2144.05, subsection II.A.
In discussing this reaction (Step 5), the instant Specification at 43 states that the amounts of reagents and reaction temperatures “were important factors.” It does not state that such factors were critical, nor that unexpected results occurred. Further, CN’253, through its translation states “the mixture was kept warm” after addition of the organomagnesium reagent, see above excerpt from CN’253 Translation at 8. While a specific temperature is not explicitly recited, “warm” generally means neither cold nor hot, which appears to be well within the range recited in claim 5.
Accordingly, claims 3 and 5 were obvious at the time of filing.
Regarding claim 4, it recites:
The method of claim 2, wherein the reaction is performed using tetrahydrofuran (THF), diethyl ether, 2-methyl tetrahydrofuran, and a mixture thereof as a reaction solvent, and the reaction solvent is used in an amount that is 5- to 15-fold (w/v) the amount of the compound of Chemical Formula 5.
CN’253 teaches 3.5 g of the compound of Chemical Formula 5 and 35 mL THF (using density of THF at 0.89 g/mL, there is 8.9 fold more THF than the Chemical Formula 5). See above excerpt from CN’253 Translation at 8. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in obtaining the subject matter of claim 4, by following the procedures of CN’253, and utilizing mere ordinary and routine experimentation by selection of solvent systems and amounts of reagents and solvents used for handling Grignard reagents, and their skills as just an ordinary chemist at the time of filing.
Accordingly, claim 4 was obvious at the time of filing.
Claims 10-13
Regarding claim 10, it recites
The method of claim 1, wherein the reacting of the compound of Chemical Formula 7 with the compound of Chemical Formula 6 to obtain the compound of Chemical Formula 8 comprises:
obtaining a compound of Chemical Formula 7' from the compound of Chemical Formula 7; and
coupling the compound of Chemical Formula 7' with the compound of Chemical Formula 6,
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The examiner interprets this claim as being generally directed to the following transformation which appears in the method exemplified in the Specification at 47, where c37 is the compound of Chemical Formula 7, and c36 is the compound of Chemical Formula 6, the Grignard formed is the Chemical Formula 7’, and c39 is the Chemical Formula 8.
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The reaction represents no more than trivial formation and reaction of Grignard reagent taught in US’390,
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US’390 at 11.
US’390 teaches what appears to be the exact same synthesis in the previously cited excerpt at 23,
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US’390 at 23, left column.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in incorporating the formation of a Grignard and reacting it as taught in US’390 because US’390 teaches how to perform the reaction.
Accordingly, claim 10 was obvious at the time of filing.
Regarding claims 11 and 12, they recite:
11. The method of claim 1, wherein the compound of Chemical Formula 5 is obtained by halogenating the amine in a compound of Chemical Formula 4 through the Sandmeyer reaction:
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12. The method of claim 11, wherein the Sandmeyer reaction includes reacting the compound of Chemical Formula 4 with NaNO2 to form a diazonium salt of the compound of Chemical Formula 4 and reacting the diazonium salt with a transition metal salt to obtain the compound of Chemical Formula 5.
The examiner interprets these claims as being generally directed to the following transformation which appears in the method exemplified in the Specification at 42:
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This exact reaction is taught in CN’253 at Example 3 and claim 1. See, e.g., CN’253 Translation at 7-8, Example 3, where the text teaches NaNO2 solution and copper chloride.
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One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in incorporating the teachings of CN’253 into a method of synthesizing an SGLT intermediate as immediately claimed for the reasons stated regarding claim 1.
Accordingly, claims 11-12 were obvious at the time of filing.
Regarding claim 13, it recites
The method of claim 12, wherein the NaNO2 is used in an amount of 1 to 2 equivalents relative to the compound of Chemical Formula 4, and the reaction of the transition metal salt with the diazonium salt of the compound of Chemical Formula 4 is performed at 30oC to 80oC.
CN’253 teaches 2.47 g NaNO2, i.e., 0.0358 mol NaNO2, using mol. weight 68.9953 g/mol; and 10 g amine, mol. weight 292.95 g/mol, i.e., 0.0341 mol. amine. Ratio is ~ 1.05 NaNO2 to amine, directly in line with the instant claims. Addition of NaNO2 occurred at 0-5oC, exactly as described in the Specification at 42. Reaction proceeded at room temperature after addition of NaNO2. For an un-temped reaction at “room temperature”, 30oC could easily be reached given either a hot room or a reaction that generates heat.
Further, reaction temperature is a result effective variable that one of ordinary skill in the art at the time of filing could tune utilizing simple ordinary and routine experimentation and the skills of an ordinary chemist at the time of filing. See discussion of claims 3 and 5 (temperature specific to claim 5).
The MPEP states that merely modifying the process conditions such as temperature is not patentable absent a showing of criticality or unexpected results. See, e.g., MPEP 2144.05, subsection II.A
Further, the specification at 42 does not indicate that the temperature was critical or that any unexpected results occurred. Instead, the exact same product was obtained as taught by CN’253 Example 3.
Accordingly, claim 13 was obvious at the time of filing.
Claims 1 and 6-9 Obvious over US’390 in view of CN’253 and Iida 2011 as Evidenced by US’559
Claim(s) 1 and 6-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’390 in view of CN’253 and Iida 20115 as Evidenced by US’559.6
The rejection of claim 1 under 35 U.S.C. 103 as being unpatentable over US’390 in view of CN’253 is incorporated herein.
Regarding claim 6, it recites
The method of claim 1, wherein the reacting of the compound of Chemical Formula 7 with the compound of Chemical Formula 6 to obtain the compound of Chemical Formula 8 comprises:
lithiating a halogen position of the compound of Chemical Formula 7 and then coupling the same with the compound of Chemical Formula 6.
Claims 7-9 are directed to reaction conditions for claim 6, i.e.,
claim 7 requiring 1-1.3 equivalents of an organolithium reagent relative to one equivalent of the compound of Chemical Formula 7,
claim 8 reciting adding butylmagnesium chloride or tert-butylmagnesium chloride to the compound of Chemical Formula 7 in a solvent prior to the lithiation reaction, and
claim 9 reciting the butylmagnesium chloride or tert-butylmagnesium chloride is used in an amount of 0.2 to 1 equivalent relative to one equivalent of the compound of Chemical Formula 7.
The examiner interprets these claims as being generally directed to the following transformation which appears in the method exemplified in the Specification at 45, where c37 is the compound of Chemical Formula 7, and c36 is the compound of Chemical Formula 6:
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Specification at 45.
The recited reaction conditions of claims 6-9 are essentially the reverse of CN’253, Example 6, shown below. CN’253 teaches the lithium magnesate prepared from c50/CN’253 compound. See CN’253 Translation at 8, Example 6:
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[0046] 3.5 g of 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran and 35 mL of tetrahydrofuran were added to a 100 mL reaction flask. Under nitrogen protection, the mixture was cooled to -30 °C, and 2.25 mL of a 2.5 M solution of isopropyl magnesium chloride in tetrahydrofuran was added dropwise, followed by 4.6 mL of a 2.5 M solution of n-butyllithium in n-hexane. After the addition was complete, the mixture was kept warm and stirred for 30 minutes, and then 1.96 g of a 10 mL solution of 4-cyclopropylbenzaldehyde in tetrahydrofuran was added dropwise. After the addition was complete, the reaction was kept warm for another 30 minutes. The reaction solution was poured into 3 M hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried with anhydrous sodium sulfate. After concentration, column chromatography was used to obtain 3.70 g of compound 2, yielding a yield of [86.9%].
CN’253 Translation at 8, Example 6 (emphases added).
In CN’253, the ratio of the isopropyl magnesium chloride to n-butyllithium was ~ 1:2 per mol (5.625 mmol / 11.5 mmol), i.e., the same ratio exemplified in the Specification at 45.
While CN’253 does not appear to expressly teach the reverse reaction as required for the instant claims, Iida 2001 explains that preparing an aldehyde from an aryl halide utilizing a Grignard reagent and DMF leads to unwanted products and slow reactions in certain cases. See, e.g., Iida 2001 at 4842, Scheme 2, and surrounding text.
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Iida 2001 at 4842, Scheme 2.
As explained below, the teachings of Iida 2001 apply to standard Grignard reactions, such as C-C bond formation by reacting with an aldehyde, which result in a secondary alcohol, like that depicted in US’390 at 23.
Iida 2001 exemplifies the preparation of lithium magnesates, also referred to in the literature and particularly in as “magnesium ate” complexes and other variants, which were known to be preferred in these cases where the Grignard may lead to unwanted products. See Iida 2001 at 4842-4843 (discussing advantages of using lithium magnesates over Grignards):
The magnesium–bromine exchange reaction of 1 with i-PrMgCl at ambient temperature has been reported recently by Que´guiner et al.4 We applied their protocol to the preparation of 3. However, even using our optimized conditions (Scheme 2), the desired exchange reaction was relatively sluggish (>5 h at 20°C) and a slight excess of i-PrMgCl was necessary to complete the reaction. In addition, the formation of an alkylated side product 4 (>5%) was not prevented.5 On the other hand, it should be noted that the organomagnesium intermediate(2: M= MgCl) was very stable at 20°C and no significant decomposition was observed, even after aging for 24h. Knochel et al. have recently reported that the analogous i-Pr2 Mg-induced exchange reaction shows a similar reactivity to i-PrMgCl.6 These results prompted us to investigate a magnesiumate complex (R3MgLi), which should exhibit the reactivity between n-BuLi and i-PrMgCl/i-Pr2 Mg, giving a stable metalated species under non-cryogenic conditions.
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Iida 2001 at 4842-4843 (emphases added).
The method of CN’253 starting from the preparation of the Grignard through
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, i.e., c50, or a compound of Chemical Formula 5, represented a poor starting material for preparing a Grignard reagent because of the multiple aryl halides, which under Iida 2001, despite showing the process for a different chemical, would reasonably lead to unwanted products.
The inventors of CN’253 therefore teach the preparation of the lithium magnesate through the additional step of adding n-BuLi, and used a 1:2 ratio. Iida 2001 teaches that this ratio consistently works, see, e.g., Iida 2001 at 4843, Table 2. See also, Iida 2001 at 4844, reference 10 (teaching that n-Bu2Mg and n-BuLi (1:1) works as well), and at 4842 (“We therefore prepared n-Bu3MgLi by mixing n-BuMgCl(in THF) and n-BuLi (in hexane) in the ratio of 1:2;10”).
These reagents were known to be advantageous because they avoid cryogenic conditions. See Iida 2001 at 4843 (“This novel reaction can be carried out under non-cryogenic conditions (at −10°C) and therefore offers a significant advantage for large-scale production.”); see also, CN’253 Translation at 8 (translating to that the reaction was kept warm).
Iida 2001 references in footnote 7 a patent application (by the authors of Iida 2001) and a paper by Kitagawa (separate set of inventors), which further explain the generality of the reaction exemplified in Iida 2001. The referenced patent application (JP 2000-024613) resulted in PCT/JP01/00463 (WO 01/57046 Pub. No), which entered the US national stage and resulted in the US 6,946,559 B2 patent (i.e., US’559, cited in this rejection).
US’559 at col. 2, teaches “an exchange reagent” prepared from the standard Grignard form R1-Mg-X1 designated formula (I), wherein R1 is an “optionally substituted hydrocarbon residue”, and X1 is a halogen. The Grignard reacts with an “an organolithium compound”, R2-Li designated formula (II), wherein R2 is an optionally “optionally substituted hydrocarbon residue”. Preferred hydrocarbons are n-butyl and tert-butyl. See US’559 at col. 6, lines 10-15. Standard secondary alcohols result when the “exchange reagent”/ lithium magnesates/“magnesium ate” complexes react with aryl aldehydes. See, e.g., US’559 at col. 25 (teaching the formation of a secondary alcohol from benzaldehyde, wherein an “exchange reagent” was prepared from n-BuMgCl and n-BuLi, which formed a complex with 2,6-Dibromopyridine, which was then reacted with benzaldehyde to yield the secondary alcohol). In the reaction, the exemplified 2,6-Dibromopyridine corresponds to what US’559 designates as a compound of formula (VII), which can be a benzene ring substituted with a halogen and a cycloalkyl group. See, e.g., US’559 at col 3 (discussing “the exchange process”), items (5) and (7) and related text.
Accordingly, Iida 2001 as Evidenced by US’559 teaches the motivation to reverse the Example 6 reaction of CN’253 (to avoid unwanted side products), and that there would be a reasonable expectation of success that the reaction would proceed to yield the main product already known from the Grignard reaction exemplified in US’390 at 23 (excerpted previously, shown again here):
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US’390 at 23, left column.
Therefore, claims 6-9 were obvious at the time of filing.
Claims 14 and 17 Obvious over WO’382
Claim(s) 14 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’382.
The discussion and rejection of claims 14 and 17 as being anticipated by WO’382 is referenced and incorporated herein.
Regarding independent claim 14, as explained, it recites another method of producing a Chemical Formula 9:
A method for producing a compound of Chemical Formula 9, comprising the following steps:
obtaining a compound of Chemical Formula 11 from a compound of Chemical Formula 10;
reacting a compound of Chemical Formula 12 with the compound of Chemical Formula 11 to obtain a compound of Chemical Formula 13; and
obtaining the compound of Chemical Formula 9 from the compound of Chemical Formula 13
X, Y, and R4 are each independently a halogen, and other variables are too broad to list.
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Exemplary compounds
Formula 9 (c40)
Formula 10 (c51)
Formula 11 (c52)
Formula 12 (
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Formula 13 (c53)
The examiner generally interprets these steps as follows (from Specification at 54):
obtaining a compound of Chemical Formula 11 from a compound of Chemical Formula 10;
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reacting a compound of Chemical Formula 12 with the compound of Chemical Formula 11 to obtain a compound of Chemical Formula 13;
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obtaining the compound of Chemical Formula 9 from the compound of Chemical Formula 13
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Regarding claim 17, it recites
The method of claim 14, wherein the compound of Chemical Formula 10 is obtained by carboxylating a compound of Chemical Formula 14
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, where R5 is alkyl and X/Y are halo (e.g., c34, Specification at 60).
WO’382 at 31 teaches this entire reaction,
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Accordingly, claims 14 and 17 were obvious at the time of filing.
Claims 14 and 15 Obvious over WO’382 in view of CN’253 and Menzel 2006
Claim(s) 14 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’382 in view of CN’253 and Menzel 2006.7
The above discussion of claim 14 and rejection is incorporated herein.
Regarding claim 15, it recites
The method of claim 14, wherein the compound of Chemical Formula 10 is obtained by carboxylating a compound of Chemical Formula 5,
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, where R2 and X/Y are halo (e.g., compound c50).
The examiner interprets this claim as being generally directed to the following transformation which appears in the method exemplified in the Specification at 54
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As stated previously, CN’253 teaches the key intermediates c50 and c51 for the synthesis of SGLT inhibitors (the below left and right compounds, respectively):
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CN’253 at paragraph [0017].
As stated previously, the above transformation of CN’253 uses selectively forming a Grignard reagent at the aryl C-bromine adjacent to the aryl C-Cl bond, utilizing the reagent isopropyl magnesium chloride, which is a Grignard reagent itself. CN’253 teaches that the reaction with the Grignard reagent isopropyl magnesium chloride occurs at a specific position (the aryl C-Br bond adjacent to the aryl C-Cl bond).
CN’253 does not teach carboxylating the intermediate formed by reacting c50 with isopropyl magnesium chloride. Instead, it teaches formylation using DMF in a second step.
However, carboxylating a Grignard reagent to form a carboxylic acid by bubbling in CO2 was textbook, elementary organic chemistry. See, e.g., Menzel 2006 at 1949, excerpts below and surrounding text, providing an example teaching how well known it was to react a Grignard reagent with CO2 to form a carboxylic acid. Depicted below is the exact same Grignard reagent used by CN’253, and it shown as reacting with a similar tri-halo aryl group (see 1a of Table 2 below):
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Menzel 2006 at 1949.
These were standard reactions that were obvious to try to one of ordinary skill in the art at the time of filing. There were clear market pressures to solve for new ways to cut down on the synthetic steps for forming SGLT inhibitors. See CN’253 Translation at 7, top of page discussing such factors.
Once the intermediate c50 was known from the disclosure of CN’253, there were a limited number of predictable ways that one could incorporate such an intermediate into a known synthetic process for making SGLT inhibitors.
One known synthetic process utilizes the formation of a carboxylic acid as a key intermediate. See WO’382 at 31.
There would have been a reasonable expectation of success to one of ordinary skill in the art at the time of filing that the reaction would result in the formation of the carboxylic acid because CN’253 teaches that the Grignard reagent isopropyl magnesium chloride specifically reacted at the aryl C-bromine of c50 that was adjacent to the aryl C-Cl bond, and because bubbling in CO2 to form a carboxylic acid from a Grignard reagent was standard, elementary textbook organic chemistry as exemplified by Menzel 2006.
Therefore, claims 14 and 15 were obvious at the time of filing.
Claims 14, 16, and 18 Obvious over WO’382 in view of CN’253, and Gandhari 2007 as Evidenced by Travis 2003
Claim(s) 14, 16, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’382 in view of CN’253, and Gandhari 20078 as Evidenced by Travis 2003.9
Regarding claim 16, it recites
The method of claim 14, wherein the compound of Chemical Formula 10 is obtained by converting the aldehyde group in a compound of Chemical Formula 6 to a carboxyl group,
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, R2 and Y are halo (e.g., c36).
The examiner interprets this claim as being generally directed to the following transformation which appears in the method exemplified in the Specification at 56
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Regarding claim 18, it recites
The method of claim 16, wherein the compound of Chemical Formula 6 is obtained by selectively converting the substituent X in a compound of Chemical Formula 5 to an aldehyde group,
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, where R2 and X/Y are halo (e.g., c50).
The examiner interprets claim 18 as being generally directed to the following transformation which appears again in the method exemplified in the Specification at 56:
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Therefore, claim 18 is claims 14 and 16 combined into one claim, adding the step that was already known from CN’253 (the c50 -> c36 transformation through isopropyl magnesium chloride and DMF). Accordingly, claims 14, 16, and 18 can be addressed together here.
CN’253 already taught the c50 -> c36 transformation. Incorporating it into a synthesis of a SGLT inhibitor was obvious at the time of filing. See discussion of claim 1, and discussion of claim 15. There were clear market pressures to solve for new ways to cut down on the synthetic steps for forming SGLT inhibitors. See CN’253 Translation at 7, top of page discussing such factors.
Once the intermediate c50 was known from the disclosure of CN’253, there were a limited number of predictable ways that one could incorporate such an intermediate into a known synthetic process for making SGLT inhibitors.
One known synthetic process utilizes the formation of a carboxylic acid as a key intermediate. See WO’382 at 31.
Converting an aryl-aldehyde to a carboxylic acid was textbook, elementary organic chemistry. Many oxidizing agents work, see, e.g., Gandhari 2007 at 852 (discussing in a teaching example the oxidizing agents KMnO4 and K2Cr2O7, and noting that “[t]hese heavy metal-based reagents are hazardous and the protocols produce metal wastes that require special handling owing to their toxicities.”). Ghandari 2007 teaches the preferred oxidizing agent Oxone as “a nontoxic and eco-friendly reagent.” Ghandari 2007 at 852. It was well known for API syntheses to avoid toxic reagents (e.g., K2Cr2O7) when possible per safety regulations.
Citation 9 in Gandhari 2007 is to a paper by Travis et al., that teaches “a convenient procedure for oxidation of aromatic aldehydes using Oxone in dimethylformamide (9).” See Gandhari 2007 at 852, top right. This paper is the Travis 2003 article cited in this rejection. Travis 2003 at 1032 teaches standard procedure for utilizing Oxone as an oxidizing agent for aryl aldehydes, and specifically teaches that “Halogenated benzaldehydes were also oxidized effortlessly to their corresponding halogenated benzoic acids in good yields (Table 1, entries 8−10)” (emphasis added). Compound 8 of Travis 2003 has an aryl-Cl bond adjacent to the aryl-aldehyde bond, and therefore exhibited similar properties to c36 of CN’253. Tavis 2003 describes the protocol as characterized by “inherent simplicity”. Travis 2003 at 1032, middle right.
These were standard reactions that were obvious to try to one of ordinary skill in the art at the time of filing. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in utilizing the procedures set forth in Gandhari 2007 as Evidenced by Travis 2003 for oxidizing c36 of CN’253 to a carboxylic acid for use in the synthetic procedures of WO’382 because Oxone represented a “a nontoxic and eco-friendly reagent” that oxidized “[h]alogenated benzaldehydes … effortlessly”, which was exemplified for structurally similar benzaldehydes.
Accordingly, claims 14, 16, and 18 were obvious at the time of filing.
Claims 14, 16, and 19 Obvious over WO’382 in view of CN’253 as Evidenced by US’496, and Gandhari 2007 as Evidenced by Travis 2003
Claim(s) 14, 16, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’382 in view of CN’253 as Evidenced by US’496,10 and Gandhari 2007 as Evidenced by Travis 2003.
The above rejections of claims 14 and 16 under 35 U.S.C. 103 as being unpatentable over WO’382 in view of CN’253, and Gandhari 2007 as Evidenced by Travis 2003 are incorporated herein.
Regarding claim 19, it recites
The method of claim 16, wherein the compound of Chemical Formula 6 is obtained by:
obtaining a compound of Chemical Formula 15 from a compound of Chemical Formula 14, and
obtaining the compound of Chemical Formula 6 from the compound of Chemical Formula 15:
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, where X/Y hare halo and R5 is alkyl.
From claim 16, Chemical Formula 6 is
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, R2 and Y are halo (e.g., c36).
The examiner interprets claim 19 as being generally directed to the following transformation which appears in the method exemplified in the Specification at 58:
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According to the exemplified method in the Specification at 58-59, the c34->c54 reduction utilizes standard NaBH4 conditions, and the c54->c36 oxidation utilizes standard PCC in DCM.
CN’253 Translation at 5 teaches this entire reaction. See below:
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CN’253 Translation at 4 states that the entire reaction was known from Chinese Patent CN109311861A. This referenced Chinese patent is in family with US’496.
See, e.g., US’496 at cols. 42 (bottom right) – 43 (top left) (teaching the reaction):
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One of ordinary skill would have a reasonable expectation of success in copying the reaction conditions taught by US’496 using the exact same compounds to perform the exact same transformation.
Accordingly, claims 14, 16, and 19 were obvious at the time of filing.
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.
NSDP to US’406
Claims 14 and 17 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,661,406 B2 (“US’406”).11 Although the claims at issue are not identical, they are not patentably distinct from each other.
US’406 teaches at claim 1 the same reaction recited in claims 14 and 17.
Accordingly, claims 14 and 17 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’406.
NSDP to US’360
Claims 1-19 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 12,448,360 B2 (“US’360”).12 Although the claims at issue are not identical, they are not patentably distinct from each other.
US’360 at claim 1 teaches the key synthetic intermediates
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(c36) and
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(c39) and “4,6-dibromo-7-chloro-2,3-dihydrobenzofuran” (c50).
One of ordinary skill in the art at the time of filing the application that led to the US’360 patent, and in possession of its subject matter, would have a reasonable expectation of success in incorporating the synthetic intermediates disclosed in US’360 into methods of preparing SGLT inhibitor intermediates as instantly claimed, because the reaction intermediates are identical and are used for the same purpose of preparing SGLT inhibitors.
Accordingly, claim 1-19 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’360.
Conclusion
No claims allowed.
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/C.E.R./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
1 LI, QING RI and YOON, HEE KYOON, “METHOD FOR PRODUCING INTERMEDIATE USEFUL FOR SYNETHESIS OF SGLT INHIBITOR”, International Publication No. WO 2020036382 A, published 2020-02-20, hereinafter “WO’382”, cited in the IDS received on 07/12/2024 as FOR Cite 3. A copy of a translation is annexed hereto, obtained from WIPO PatentScope.
2 YOON; Hee-kyoon, et al., “METHOD FOR PRODUCING DIPHENYLMETHANE DERIVATIVE”, U.S. Patent Application Publication No. US 20190382390 A1, published 2019-12-19, hereinafter “US’390”..
3 HUANG, Zhi-ning, “Synthetic Method For Preparing SGLT Inhibitor Intermediate”, Chinese Patent Application Publication No. CN 112094253 A, published 2020-12-18, hereinafter “CN’253”.
4 Referenced page numbers used herein refer to the PDF page number, printed at the bottom center of the document.
5 Iida, Takehiko, et al. "Tributylmagnesium ate complex-mediated novel bromine–magnesium exchange reaction for selective monosubstitution of dibromoarenes." Tetrahedron Letters 42.29 (2001): 4841-4844, hereinafter “Iida 2011”.
6 Iida, Takehiko, et al., “Method Of Converting Functional Group Through Halogen-metal Exchange Reaction”, U.S. Patent No. US 6946559 B2, published 2005-09-20, hereinafter “US’559”.
7 Menzel, Karsten, et al. "Regioselective halogen-metal exchange reaction of 3-substituted 1, 2-dibromo arenes: The synthesis of 2-substituted 5-bromobenzoic acids." Synlett 2006.12 (2006): 1948-1952, hereinafter “Menzel 2006”.
8 Gandhari, Rajani, Padma P. Maddukuri, and Thottumkara K. Vinod. "Oxidation of aromatic aldehydes using oxone." Journal of chemical education 84.5 (2007): 852-854, hereinafter “Gandhari 2007”.
9 Travis, Benjamin R., et al. "Facile oxidation of aldehydes to acids and esters with oxone." Organic letters 5.7 (2003): 1031-1034, hereinafter “Travis 2003”.
10 Yoon; Hee-kyoon, et al., “Method For Producing Diphenylmethane Derivative”, U.S. Patent No. US 10640496 B2, published 2020-05-05, hereinafter “US’496”.
11 Li; Qing Ri and Yoon; Hee Kyoon, “Method For Producing Intermediate Useful For Synthesis Of SGLT Inhibitor”, U.S. Patent No. US 11661406 B2, published 2023-05-30, Daewoong Pharmaceutical Co., Ltd. Assignee, hereinafter US’406.
12 Huang; Zhining, et al., “Method For Producing Intermediate Useful For Synthesis Of SGLT Inhibitor”, U.S. Patent No. US 12448360 B2, published 2025-10-21, Daewoong Pharmaceutical Co., Ltd. Assignee, hereinafter US’360.
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