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 .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed March 27, 2026. The amendment, filed March 27, 2026, is entered, wherein claim 1 is amended and claims 2 – 3, 6 – 7, 9, and 11 – 12 are canceled.
Claims 1, 4 – 5, 8, and 10 are pending in this application and are currently examined.
Priority
This application is a national stage application of PCT/IB2019/060642, filed December 11, 2019, which claims benefit of foreign priority document IN201841046764, filed December 11, 2018.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 365(c) or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. IN201841046764, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The foreign priority IN201841046764 does not provide support for the limitations of “sulphoxide impurity E” recited in claim 5. Thus, the priority date of claims 5 is December 11, 2019.
Withdrawn Objections
4. The objection of claim 1 in the previous Office Action, mailed December 29, 2025, is withdrawn in view of the amended claim 1.
Withdrawn Rejections
5. The rejection of claim 1 in the previous Office Action, mailed December 29, 2025, 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 has been considered and is withdrawn in view of the amended claim 1.
The following are modified / new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed March 27, 2026, wherein claim 1 is amended and claims 2 – 3, 6 – 7, 9, and 11 – 12 are canceled. Previously cited references have been used to establish the modified / new grounds of rejection.
New Objections to Specification
The disclosure is objected to because of the following informalities:
The structures of Scheme 1 and Scheme 2 on pages 2 and 6, respectively, of the specification are unclear. In particular, the portions of the chemical structures include overlapping atomic symbols and bond lines, such that the structures are not clearly readable.
The structure of sugammadex free acid in page 9 of the specification is unclear. In particular, the portions of the chemical structures include overlapping atomic symbols and bond lines, such that the structures are not clearly readable.
The structures of the impurities in page 12 of the specification are unclear. In particular, the portions of the chemical structures include overlapping atomic symbols and bond lines, such that the structures are not clearly readable.
Appropriate correction is required.
New Claim Objections
Claims 1 and 5 are objected to because of the following informalities:
Claim 1, lines 3, 8, and 12, recites chemical structures that are unclear. In particular, the portions of the chemical structures include overlapping atomic symbols and bond lines, such that the structures are not clearly readable.
Claim 1, lines 30 – 31, recites the structure of sugammadex free acid. However, the structure is blurry. Applicant is suggested to amend claim 1 to show clear structure of sugammadex free acid.
Claim 5, line 5, recites the structure of Impurity A. However, the structure is blurry. Applicant is suggested to amend claim 5 to show clear structure of Impurity A.
Appropriate correction is required.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4 – 5, 8, and 10 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.
a. Claim 1 recites the term “preferably” in step c)(iv). The claim is indefinite because the inclusion of the term “preferably” renders the scope of the claim ambiguous. The use of “preferably” introduces uncertainty as to whether the narrower range is intended to be a required limitation or merely a suggested, non-limiting embodiment of the broader range. The use of this term prevents one of ordinary skill in the art from determining the precise boundaries of the claims. Claims 4 – 5, 8, and 10 are also rejected because they depend from claim 1 and therefore incorporate the indefinite limitation of claim 1. The term “preferably” will be interpreted as “optionally”
b. Step (b) of claim 1 recites reacting compound (3) with compound (2), wherein R is hydrogen, methyl, ethyl, isopropyl, potassium, or sodium, in the presence of a base to yield sugammadex sodium (1). It is unclear how each of the recited R groups would yield sugammadex sodium. For example, when R is methyl, ethyl, or isopropyl, the reaction would appear to produce an ester derivative unless additional hydrolysis is performed. The claim does not clearly state whether such additional conversion is included in step (b). Accordingly, the scope of the claimed process is unclear. Claims 4 – 5, 8, and 10 are also rejected because they depend from claim 1 and therefore incorporate the indefinite limitation of claim 1.
Modified / New 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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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, 4 – 5, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US20180208683A1, cited in the previous Office Action) in view of Cabri et al. (WO2017/163165A1, Reference included with PTO-892), Ravi et al. (WO2014/125501A1; hereinafter ‘501A1, Reference included with PTO-892), Ravi et al. (WO2018185784A1, cited in the previous Office Action), Adam et al. (Journal of Medicinal Chemistry, 2002, Vol. 45, Issue 9, page 1806 – 1816, Reference included with PTO-892), and Overeem (WO2017/163165A1, cited in the previous Office Action mailed December 29, 2025).
a. Lee et al. discloses a process for preparing sugammadex sodium comprising reacting a gamma-cyclodextrin with a halogenating agent in the presence of DMF to provide the halogenated cyclodextrin, wherein the halogenating agent is CH3SO2Cl (para. [0008]); and reacting the halogenated cyclodextrin with 3-mercaptopropionic acid in the presence of a sodium base and an organic solvent to provide sugammadex sodium (Abstract), which correspond to the steps a) and b) of claim 1. In comparative example 1, where DMF is used as a solvent in the synthesis, the purity of the sugammadex sodium is 28.79% (page 14, Table 1). The sugammadex salt produced will be purified (para. [0015]). In some embodiments, the sodium base is a metal alkoxy, wherein the metal alkoxy is sodium methoxide (para. [0033]), which reads on the limitation of claim 4. In one example, a solution of crude sugammadex sodium is prepared in DMSO and is warmed to 70 – 80 ⁰C. After the reaction is completed, MeOH is added at 60 – 80 ⁰C. The mixture is then cooled to 20 – 30 ⁰C and stirred for 1 hour. The crude sugammadex sodium is isolated and purified. (para. [0049]). Moreover, the purification process of sugammadex salt of formula IIIa:
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comprises reacting sugammadex salt of formula IIIa with an acid in the presence of a first solvent to provide sugammadex free acid of formula IV; optionally purifying the sugammadex free acid of formula IV:
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with chromatograph column or active carbon; and treating the sugammadex free acid of formula IV with alkali metal hydroxide in the presence of a second solvent (para. [0035]). In some embodiments, the alkali metal hydroxide is sodium hydroxide (para. [0036]). In certain examples, the compound, such as sugammadex free acid, is purified with IPA/H2O/HCl at 40 – 50 ⁰C (para. [0051]), the compound is purified with RP-18 silica gel (para. [0052]), and the compound is purified with EtOH/H2O/NaOH at 40 – 50 ⁰C (para. [0053]), which reads on the step c)(vi) of claim 1 and the limitation of claim 10.
However, Lee et al. do not teach the purifying steps of c)(i) and c)(ii) and the intermediate crude sugammadex sodium (1) having purity of 93%. Lee et al. do not explicitly teach step c)(iii), which requires converting sugammadex sodium (1) obtained in step (ii) to sugammadex free acid by dissolving in a biphasic solvent system, wherein the biphasic solvent system is a mixture of water and dimethylformamide, and the purity of the isolated pure sugammadex sodium. Lee et al. do not teach the pure sugammadex sodium (1) isolated in step c)(vii) has a purity greater than 98%. Lee et al. do not teach the compound of sugammadex sodium prepared according to claim 1 has one or more of (i) impurity A less than 2.0% (w/w) and (ii) sulphoxide impurity E less than 0.1% (w/w). Lee et al. also do not teach methyl 3-mercaptopropionate to be used in the process.
Cabri et al. teach an improved process for the preparation of sugammadex (Title). Cabri et al. disclose the purification of crude sugammadex in reference example 3, which is based on the example 2 of WO2014/125501A1. The crude product is dissolved in water and methanol, treated with activated carbon and is filtered and washed with purified water. The filtrate is heated to 50 – 55 ⁰C and methanol is slowly added at the same temperature in 1 hour. The resulted suspension is cooled to 20 – 25 ⁰C and stirred for 2 hours at the same temperature. The resulted solid is filtered, washed with methanol and dried under vacuum. The obtained product has a purity of 88.5% (page 19 – 20, Reference example 3). Thus, Cabri et al. teach that the crude product is dissolved in water and methanol and the sugammadex sodium is precipitated after addition of methanol, heating to 50 – 55 ⁰C, and cooling to 20 – 25 ⁰C. Cabri et al. teach that the precipitate is then filtered and washed with methanol, which read on the steps c)(i) and c)(ii).
‘501A1 teaches the preparation of sugammadex sodium, which includes the purification of the crude sugammadex sodium. The crude product is dissolved in water and methanol, treated with activated carbon and is filtered and washed with purified water. The filtrate is heated to 50 – 55 ⁰C and methanol is slowly added at the same temperature. The contents are cooled to 20 – 25 ⁰C and stirred for 2 hours at the same temperature. The resulted solid is washed with methanol and dried under vacuum at 60 – 65 ⁰C. The obtained product has a purity of 99.43% (page 9, lines 33 – 34; page 10, lines 1 – 6).
Ravi et al. teaches an improved process for the preparation of sugammadex sodium and its purification process (Abstract). Ravi et al. demonstrate that the crude sugammadex sodium obtained from example 3 is purified and is further converted to sugammadex free acid by dissolving in a mixture of water and acetic acid (page 22, Example 8, lines 7 – 12), which indicates that purified sugammadex sodium may be converted to sugammadex free acid in order to perform further purification. The sugammadex free acid obtained is dissolved in water and neutralized by using aqueous sodium hydroxide solution. Methanol is added to the resulting mixture at 25 – 30 ⁰C and stirred for 1 hour at the same temperature. The resulting reaction mixture is filtered and washed with method. The obtained wet compound is dissolved in a mixture of DMF and water and is stirred for 1 hour at 25 – 30 ⁰C. The precipitated solid is filtered and washed with methanol. The obtained compound is dissolved in water at 25 – 30 ⁰C and is lyophilized to get the final compound. The obtained final compound may undergo a chromatography (page 23, lines 4 – 14). Thus, Ravi et al. teach that the conversions from sugammadex sodium to sugammadex free acid and from sugammadex free acid back to sugammadex sodium is conducted in a mixture of DMF and water at 25 – 30 ⁰C and further teach that the sugammadex sodium obtained at the end is dissolved in water and the mixture may undergo chromatography, which read on the limitation of step c)(iii), c)(iv), and c(v) of claim 1 and the limitation of claim 8. The provided process for the purification of sugammadex sodium, wherein the sugammadex sodium is obtained with a purity greater than 99% (page 19, lines 1 – 2). Ravi et al. also teaches that the purification step includes using HPLC with silica column of C18 bulk media with 10 or 16 μm obtained pure sugammadex free acid having purity more than 99% (page 8, lines 15 – 16; page 18, lines 6 – 7). The disclosure correspond to step c)(vi) and c)(vii) of claim 1 and the limitations of claims 5 and 10.
Adam et al. teach the synthesis of 6-perdeoxy-6-per(2-carboxy-ethyl)thio-γ-cyclodextrin sodium salt, wherein methyl-3-mercaptopropionate in DMF is added to the solution of 6-perdeoxy-6-perbromo-γ-cyclodextrin and cesium carbonate (page 1812, Right Col., para. 4). Furthermore, Overeem discloses that γ-cyclodextrin has 8 primary hydroxyl groups (groups attached to a CH2-) and 16 secondary hydroxyl groups (groups attached to a CHR-). The 8 primary hydroxyl groups are substituted to form sugammadex. Overeem acknowledges that the synthesis of sugammadex is complicated by the fact that it requires the complete conversion of eight identical functional groups per molecule, giving rise to high levels of impurities. Most of these impurities are structurally related γ-cyclodextrin and have physico-chemical characteristics and molecular weighs comparable to that of the active substance. This explains why the structurally related impurities are difficult to fully identify and to remove from the active substance. (page 8, lines 1 – 8).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method for preparing sugammadex sodium as taught by Lee et al. with the purification procedures of sugammadex sodium in view of Cabri et al. and ‘501A1 because both Cabri et al. and ‘501A1 explicitly teach purification of crude sugammadex sodium through the same water/methanol precipitation, filtration, washing, and isolation step to obtain sugammadex sodium products with higher purity. Lee et al. teach the preparation of sugammadex sodium from gamma-cyclodextrin, including reaction in DMF, and further teach that the produced sugammadex salt may be purified. Lee et al. also show in comparative example 1 that the resulting sugammadex sodium has a purity of 28.79% when DMF is used as solvent. Therefore, one would have been motivated to implement these additional purification steps disclosed by Cabri et al. and ‘501A1 to the method for preparing sugammadex sodium as taught by Lee et al. because Cabri et al. and ‘501A1 teaches the purifying steps that are known in the art and a skilled artisan would have recognized that doing so would result in a higher purity product, which is a routine and desirable objective in the field. One of ordinary skill in the art would have had a reasonable expectation of success to combine the method for preparing sugammadex sodium as taught by Lee et al. with the purification procedures of sugammadex sodium in view of Cabri et al. and ‘501A1 because each reference teaches the same target compound, sugammadex sodium, and Cabri et al. and ‘501A1 explicitly teach purification of crude sugammadex sodium using water/methanol precipitation and isolation techniques. Since Lee et al. teach that sugammadex salt produced may be purified, and Cabri et al. and ‘501A1 provide known purification procedures for crude sugammadex sodium, applying those purification steps to the process of Lee et al. would have predictably yielded a purified sugammadex sodium product.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the process of Lee et al., including the purification steps of Cabri et al. and ‘501A1, with the additional purification steps based on the conversion between sugammadex sodium and sugammadex free acid in view of Ravi et al. because Lee et al. teach that sugammadex salt may be converted to sugammadex free acid and then treated with alkali metal hydroxide, such as sodium hydroxide, to form the corresponding sodium salt and Ravi et al. teach purifying sugammadex sodium by converting purified sugammadex sodium to sugammadex free acid and reconverting the sugammadex free acid to sugammadex sodium in the medium of water and DMF. One would have been motivated to incorporate the step disclosed by Ravi et al. into the process of Lee et al., including the purification steps of Cabri et al. and ‘501A1, because Ravi et al. explicitly teach an improved process for preparing and purifying sugammadex sodium and teach obtaining sugammadex sodium having purity greater than 99%. Lee et al. teach the conversion of sugammadex free acid to sugammadex sodium and both Lee et al. and Ravi et al. teach the purification of sugammadex free acid via flash column chromatography loaded with RP-18 silica gel. The purity of sugammadex free acid is more than 99%. One would have been motivated to implement this purification step for isolating the product because the high purity of sugammadex free acid that is obtained after the flash column chromatography. One of ordinary skill in the art would have had a reasonable expectation of success in combining these teachings because Lee et al., Cabri et al., ‘501A1, and Ravi et al. are directed to the same compound, sugammadex sodium, and each reference teaches compatible purification or conversion steps for the same sugammadex sodium/free acid system. Lee et al. and Ravi et al. both teach conversion between sugammadex sodium and sugammadex free acid, and Ravi et al. teach that the process provides sugammadex sodium having purity greater than 99%. Therefore, applying the known additional purification steps of Ravi et al. after the purification steps as taught by Cabri et al. and ‘501A1 would have predictably produced purified sugammadex sodium having purity greater than 98%.
It would also have been obvious for a skilled artisan to substitute 3-mercaptopropionic acid as taught by Lee et al. with methyl 3-mercaptopropionate in view of Adam et al. because Adam et al. teach that methyl 3-mercaptopropionate is used to react with halogenated gamma cyclodextrin in the presence of DMF and base to yield sugammadex sodium. It would have been obvious for one of ordinary skill in the art to substitute 3-mercaptopropionic acid as taught by Lee et al. with methyl 3-mercaptopropionate in view of Adam et al. because both 3-mercaptopropionic acid and methyl 3-mercaptopropionate are known separately in the prior art for the purpose of reacting with halogenated gamma cyclodextrin to yield sugammadex sodium, and it would have been obvious to substitute equivalent reactant to yield the same product. This substitution will lead to predictable results. Therefore, one of the ordinary skill in the art would have a reasonable expectation of success to substitute 3-mercaptopropionic acid as taught by Lee et al. with methyl 3-mercaptopropionate in view of Adam et al. because it is a well known to substitute equivalent reactant for the synthesis of the same product.
Regarding the temperatures used in steps c)(ii) and c)(iv), Cabri et al. and ‘501A1 teach the filtrate is heated to 50 – 55 ⁰C and the resulted suspension is cooled to 20 – 25 ⁰C. These disclosure overlaps the claimed temperature ranges. One of ordinary skill in the art would have performed a routine experimentation to discover the best temperature for optimal reaction profile.
Regarding the “sugammadex sodium (1) having purity of 93% in step c)(ii) of claim 1, Cabri et al. and ‘501A1 teach the same preliminary purification process of crude sugammadex sodium using water/methanol dissolution, activated carbon treatment, filtration, methanol addition/precipitation, cooling, filtration, methanol washing, and drying. Cabri et al. report that this purification process provides sugammadex sodium having a purity of 88.5%, while ‘501A1 reports that substantially the same purification process provides sugammadex sodium having HPLC purity of 99.43%. Thus, the prior art demonstrate that the known water/methanol purification and precipitation process is capable of producing sugammadex sodium products with purities below, above, or at the claimed 93%. Therefore, the claimed intermediate purity of 93% would have been an obvious result of applying and optimizing the known purification process taught by Cabri et al. and ‘501A1. A person of ordinary skill in the art seek to purify the crude sugammadex sodium prepared by the method of Lee et al. would have been motivated to adjust routine purification parameters to obtain an intermediate material of suitable purity before further purification.
Regarding step c)(vii) of claim 1, both Lee et al. and Ravi et al. teach the purification using chromatography. It is expected that some fractions will be collected after the flash column chromatography, which reads on the limitation “to collect a plurality of fractions”. For the isolating step by evaporating, ‘501A1 teaches that the sugammadex sodium is obtained via drying in vacuum at 60 – 65 ⁰C. With the raised temperature, one of ordinary skill in the art would have understood that heating results in evaporation of the solvent. It would have been obvious for one of ordinary skill in the art to modify the method as taught by Lee et al. with the drying and evaporating step in view of ‘501A1 to obtain the sugammadex sodium solid after flash column chromatography.Regarding claim 5, Ravi et al. teach obtaining sugammadex sodium having purity greater than 99%. A product having purity greater than 99% necessarily contains less than 1% total impurities. Therefore, the amount of any individual impurity, including structurally related impurity A, would be less than 2.0%. As claim 5 recites that the compound of sugammadex sodium prepared according to claim 1 has purity greater than 98.0% by HPLC and “one or more” of impurity A less than 2.0% (w/w) and sulfoxide impurity E less than 0.1% (w/w), claim 5 do not require both impurity A and sulfoxide impurity E to be present at the recited levels. Thus, this meets at least the limitation of claim 5 requiring impurity A less than 2.0% (w/w). Overeem teaches that synthesis of sugammadex requires complete conversion of eight identical primary hydroxyl groups on γ-cyclodextrin and that incomplete or difficult conversion gives rise to structurally related γ-cyclodextrin impurities having physiochemical characteristics and molecular weights comparable to sugammadex. Thus, Overeem recognizes that incomplete conversion of the γ-cyclodextrin starting material produces partially substituted sugammadex-related impurities. Impurity A shown in claim 5 is a partially substituted sugammadex-related cyclodextrin structure. Specifically, impurity A retains the γ-cyclodextrin core but has fewer substituted side chains than fully substituted sugammadex sodium. Accordingly, impurity A is the type of incomplete-conversion impurity encompassed by Overeem. Therefore, one of ordinary skill in the art would have recognized that incomplete conversion during sugammadex synthesis would produce impurities, such as impurity A, and would have been motivated to apply the purification processes taught by the cited art to reduce such incomplete-conversion impurities.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed March 27, 2026, have been fully considered and are not found to be persuasive.
Regarding the rejection, Applicant argues that Overeem, either alone or in combination with other cited art, do not disclose all the elements of the presently amended claim 1. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding Lee et al., Applicant argues that Lee et al. is silent on the nature and possible impurities and that purification is optional and not detailed. However, this argument is not persuasive because Lee et al. is relied upon for teaching the preparation of sugammadex sodium, including reacting gamma-cyclodextrin with methane sulfonyl chloride in DMF and reacting the halogenated cyclodextrin with 3-mercaptopropionic acid in the presence of a sodium base. Lee et al. also teach that the sugammadex salt produced may be purified. The additional purification teachings are supplied by Cabri et al., ‘501A1, and Ravi et al., which expressly address purification and impurity removal.
Regarding Overeem, Application argues that Overeem discloses impurity formation in a DMSO-based process and that the present invention does not use DMSO. This argument is not moot because Overeem is no longer relied upon for its synthetic process or for the particular DMSO-based reaction conditions. Overeem is relied upon for teaching that sugammadex synthesis produces structurally related impurities due to incomplete conversion of the eight primary hydroxyl groups of γ-cyclodextrin. Applicant’s arguments regarding DMSO, reaction temperature, NaOH, and impurity formation during the synthesis disclosed by Overeem do not address the portion of Overeem actually relied upon in the rejection.
Applicant argues that the impurities disclosed in Overeem differ from the impurities of the present invention and that the purity levels are not comparable because impurities are process-dependent. This argument is not persuasive. The rejection does not rely on Overeem to disclose the identical impurity profile or the exact numerical impurity amounts. Rather, Overeem is relied upon for teaching that sugammadex synthesis requires complete conversion of eight identical primary hydroxyl groups on γ-cyclodextrin and that incomplete conversion gives rise to structurally related γ-cyclodextrin impurities. Overeem further teaches that such structurally related impurities have physiochemical characteristics and molecular weights comparable to the active substance, making them difficult to identify and remove. Impurity A recited in claim 5 is a structurally related sugammadex impurity having the γ-cyclodextrin core and fewer complete substitutes than fully converted sugammadex sodium. Thus, impurity A is the type of incomplete-conversion impurity that Overeem recognizes as being formed during sugammadex synthesis.. The cited references collectively teach applying purification techniques to sugammadex sodium, including precipitation, conversion to free acid and back to sodium salt, and reverse-phase silica chromatography. Overeem teaches that the structurally related γ-cyclodextrin impurities are very difficult to remove, which affects the purity of the sugammadex sodium produced. Ravi et al. further teaches obtaining sugammadex sodium having purity greater than 99%. Therefore, the prior art provides motivation and reasonable expectation of success for reducing structurally related sugammadex impurities to low levels. Ravi et al. further teach obtaining sugammadex sodium having purity greater than 99%, which meets the claimed purity greater than 98%.
Regarding Ravi et al., Applicant argues that Ravi et al. disclose a 7-step process, whereas the present invention provides a shorter process. Applicant argues that Ravi et al. disclose the use of water and DMF in the purification step, whereas the present invention use water, methanol, or a mixture thereof. However, the arguments are not persuasive. Ravi et al. is relied upon for teaching purification using mixed biphasic solvent system, including water and DMF. Overeem teach water addition followed by addition or organic solvent such as methanol, cooling to obtain sugammadex solid. Thus, the cited references teach or suggest the claimed solvent purification steps.
Applicant then argues that the claimed biphasic solvent treatment is not suggested by Overeem and that Overeem only teach alcohol washing or precipitation. This argument is not persuasive. Overeem is not relied upon alone for the biphasic solvent limitation. Ravi et al. teach purification of sugammadex sodium using a mixture of solvents such as water and DMF, which addresses the claimed biphasic solvent system. The combination of purification as taught by Overeem with the purification in view of Ravi et al. would have been obvious to one of ordinary skill in the art seeking to improve purity of sugammadex.
Applicant argues that column chromatography is deliberately selected by the inventors and is not obvious. This argument is not persuasive. Lee et al. teach purification using RP-18 silica gel, and Ravi et al. teach use of C18 silica column chromatography. Claim 10 recites reverse phase silica gel selected from C8 and C18 silica gel. Thus, the claimed chromatography medium is taught by the prior art for purification of sugammadex compounds.
Applicant argues that Overeem teaches away from Lee et al. because Overeem prefers DMSO over DMF and teach lower reaction temperatures. This argument is not persuasive. Teaching away requires more than a preference for one embodiment. DMSO disclosed by Overeem. as a preferred solvent does not criticize, discredit, or prohibit the DMF-based process taught by Lee et al. Moreover, Overeem is relied upon for purification teachings, not for replacing they synthesis disclosed by Lee et al. Therefore, Applicant’s argument is not responsive to the actual basis of the rejection.
Applicant then argues that methyl 3-mercaptopropionate is not equivalent to 3-mercaptopropionic acid and that its selection is not suggested by the prior art. However, this argument is moot because Brown is no longer included in the rejection. Adam et al. teach the synthesis of sugammadex sodium by reacting the halogenated gamma cyclodextrin with methyl 3-mercaptopropionate in the presence of DMF and base. It would have been obvious for one of ordinary skill in the art to substitute 3-mercaptopropionic acid with methyl 3-mercaptopropionate because Adam et al. explicitly teach the use of methyl 3-mercaptopropionate in the synthesis of sugammadex sodium. One of ordinary skill in the art would have had a reasonable expectation of success to substitute 3-mercaptopropionic acid with methyl 3-mercaptopropionate because it is known in the art to substitute equivalent reactant for the synthesis of the same product.
Applicant argues that the claimed combination provides unexpected reductions in impurity A, sulphoxide impurity E, and other impurities. This argument is not persuasive. Applicant’s assertions of unexpected results and synergy are not supported by sufficient comparative evidence against the closest prior art. Ravi et al. already teach sugammadex sodium having purity greater than 99%. The claimed purity greater than 98% and impurity reductions would have been expected from applying known purification methods, including precipitation, free-acid conversion, and reverse-phase chromatography.
Finally, Applicant argues that the rejection relies on hindsight and improper mosaicking. The argument is not persuasive. The references share a common objective, which is preparing and purifying sugammadex sodium. The motivation to combine arises from the recognized desire to remove impurities and to obtain higher purity product. The combination applies known purification techniques to a known sugammadex sodium process to achieve the predictable result of improved purity. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE NON-FINAL.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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