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 May 13, 2026. The amendment, filed May 13, 2026, has been entered, wherein no claim is amended and claims 1 – 13 are canceled.
Claims 14 – 26 are pending in this application and are currently examined.
Priority
This application is a national stage application of PCT/EP2021/068970, filed July 8, 2021, which claims benefit of foreign priority document EP20315345.7, filed July 9, 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The following are the maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed May 13, 2026, wherein no claim is amended and claims 1 – 13 are canceled. Previously cited references have been used to establish the maintained / modified grounds of rejection.
Maintained / Modified 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 14 – 24 are rejected under 35 U.S.C. 103 as being unpatentable over Lopez Cremades (EP3053930A1, cited in the PTO-892 on June 23, 2025) in view of Sakhardande et al. (WO2010/092592A2, cited in the PTO-892 on June 23, 2025), No et al. (Journal of Agricultural and Food Chemistry, 2000, Vol. 48, Issue 6, page 2625 – 2627, cited in the PTO-892 on February 19, 2026), and Margetic (Walter de Gruyter GmbH & Co KG, 2019, cited in the PTO-892 on February 19, 2026).
Lopez Cremades teaches a process for the preparation of diosmin from hesperidin. The process involves oxidation of acylated hesperidin with iodine in C2-C4 carboxylic acid medium and subsequent treatment with an inorganic base to partially neutralized the acidic media. The process allows obtaining diosmin with low iodine content (Abstract). This process for the preparation of diosmin from hesperidin comprising a) acylating hesperidin with a C2-C4 carboxylic acid anhydride; b) treating the mixture obtained in step a) with an oxidant and a halogen; c) treating the mixture obtained in step b) with an inorganic base; d) deacylating the acylated diosmin obtained by step c) by treating with an aqueous solution of an inorganic base (para. [0023]). The C2-C4 carboxylic acid anhydride is acetic anhydride with a catalyst that is sodium acetate(para. [0029]; para. [0031]), wherein the molar ratio of anhydride to hesperidin is about 8 (para. [0028]). The reaction a) is carried out at a temperature between 90 ⁰C and 150 ⁰C (para. [0032]). In step b), the reaction mixture obtained in step a) without isolation of the acylated hesperidin, is directly treated with an oxidant and a halogen, iodine (para. [0035]). The halogen used in step b) can be added in the form of molecular halogen or as halogen precursor, namely an alkali metal halide, which is oxidized in the reaction media by the oxidant, so that the molecular halogen is formed in situ. The halogen precursor is sodium iodide (para. [0037]). The halogen is preferably in a molar ratio in the range of 0.01 – 0.2 relative to acylated hesperidin (para. [0036]) and the oxidant is preferably used in 1 – 1.5 molar equivalent amount relative to acylated hesperidin (para. [0041]). In more preferred embodiment, step b) involves treating the mixture obtained from step a) with hydrogen peroxide and a iodine compound, such as iodine, sodium iodide, and mixtures thereof (para. [0065]). In a preferred embodiment, the oxidant of step b) is preferably carried out at reflux conditions (para. [0046]). In step c), the reaction mixture obtained in step b) is treated with an inorganic base (para. [0047]). The inorganic base is sodium hydroxide in aqueous solution (para. [0049]). This treatment is carried out at a temperature between 90 ⁰C to 125 ⁰C (para. 0052]). Lopez Cremades further discloses that treatment with an hydroalcoholic alkaline solution is used previously (para. [0054]). The diosmin obtained after step d) may be subsequently purified by one or more crystallization in aqueous media. For example, in an alkaline solution comprising water/alkali hydroxide/sulphuric acid; wherein the alkali hydroxide is sodium hydroxide (para. [0073 – 0074]). Moreover, Lopez Cremades teaches that the preparation of diosmin may be done in a reactor while maintaining the reflux conditions (para. [0089]). Thus, Lopez Cremades teaches step a) acylating hesperidin with a C2-C4 carboxylic acid anhydride in the presence of sodium acetate as a catalyst at a temperature between 90 ⁰C and 150 ⁰C, wherein the C2-C4 carboxylic acid anhydride is acetic anhydride, wherein the molar ratio of anhydride to hesperidin is about 8, which corresponds to the claimed step a) of claims 14 and 17 – 18. Lopez Cremades teaches step b) treating the mixture obtained in step a) with hydrogen peroxide and sodium iodide at reflux conditions, wherein the halogen has a molar ratio of 0.01 – 0.2 relative to acylated hesperidin and the oxidant is preferably used in 1 – 1.5 molar equivalent amount relative to acylated hesperidin, which corresponds to the claimed step b) of claims 14, 19, and 21. Lopez Cremades teaches step c) the reaction mixture obtained in step b) is treated with an inorganic base at a temperature between 90 ⁰C to 125 ⁰C, wherein the inorganic base is sodium hydroxide in aqueous solution, which corresponds to step c) of claims 14 and 23. Lopez Cremades teaches step d) deacylating the acylated diosmin obtained by step c) by treating with an aqueous solution of an inorganic base, wherein the inorganic base is sodium hydroxide, and the preparation of diosmin may be done in a reactor while maintaining the reflux conditions, which correspond to step d) of claim 14. Finally, Lopez Cremades teaches that the diosmin obtained after step d) may be subsequently purified by one or more crystallization in aqueous media, wherein the aqueous media is water/alkali hydroxide/sulphuric acid, which corresponds to step e) of claim 14.
However, Lopez Cremades does not teach that the diosmin obtained contains other flavonoids, wherein the diosmin obtained contains less than 0.6% of 6-iododiosmin and less than 3.0% of isorhoifolin. Lopez Cremades also does not teach the acetylated diosmin obtained at the end of the oxidation step b) is isolated by precipitation in water before used in step c) and the alcohol used in step c) is methanol. Lopez Cremades does not explicitly teach the pressure used in the process.
Sakhardande et al. teach a process for preparation of diosmin wherein methanol is used and levels of impurities such as isorhoifolin and diosmetin in diosmin are reduced (page 5, para. 4). Many processes are often found to contain impurities, such as isorhoifolin and 6-iododiosmin (page 3, para. 5). In particular, the process comprises (a) reacting hesperidin with iodine in presence of base by recovering pyridine and then treating reaction mass with alcohol to reduce the impurities, such as isorhoifolin and diosmetin and treating the resulting solid from step (a) with sodium thiosulfate solution to isolate crude diosmin which is crystallized using DMF:water mixture (page 6, para. 4). In precise, example 1 demonstrates that the diosmin has been collected as a solid before charging methanol (page 7, para. 6). The obtained solid has a purity of 99.9% in example 2 (page 8, para. 3). Thus, Sakhardande et al. teach a step of treating the reaction mass with alcohol in the presence of base, wherein the alcohol is methanol, which correspond to step c) of claim 14 and 24. Sakhardande et al. teach that the crude diosmin obtained after the reaction of iodine in the presence of base may be isolated by crystallization using DMF:water mixture, which corresponds to claim 22. Sakhardande et al. also teach that the preparation of diosmin will result in the production of impurities, such as isorhoifolin and 6-iododiosmin, which corresponds to claim 15.
No et al. teach a deacetylation process under autoclaving conditions at 15 psi and 120 ⁰C. The deacetylation process is for preparing chitosan from chitin and the deacetylation requires an alkalizing agent, which is NaOH. The deacetylation is effectively achieved under elevated temperature and pressure and the product has a 90.4% degree of deacetylation (Abstract).
Margetic discloses the maximum pressures may be used in experiments for alcohol and the pressure varies based on the reaction temperature and time (page 13, Table 1.6):
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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 process for the preparation of diosmin from hesperidin as taught by Lopez Cremades with the process for preparing diosmin using methanol in view of Sakhardande et al. because Lopez Cremades discloses that hydroalcoholic alkaline solution has been previously used and Sakhardande et al. teach that the addition of methanol in the process will reduce the amount of other flavonoids. One would have been motivated to combine the processes because the process by Sakhardande et al. yield high purity diosmin. It would have been prima facie obvious for a person of ordinary skill in the art to modify the reaction conditions as taught by Lope Cremades by increasing the pressure in view of No et al. because No et al. teach the reaction conditions for deacetylation. One would have been motivated to modify the reaction conditions as taught by Lope Cremades by increasing the pressure in view of No et al. because No et al. specifically indicate that the deacetylation under autoclave at elevated pressure will increase the degree of deacetylation. Margetic teaches the maximum pressures for common alcoholic solvents. One would have considered the information provided by Margetic and would have performed routine experimentation to discover the best pressure to be used in the deacetylation of acetylated diosmin for the optimal degree of acetylation. For the temperature and reaction (reflux) condition, one would also have performed routine experimentation to discover the best conditions for the optimal preparation of diosmin. Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success to combine the process for the preparation of diosmin from hesperidin as taught by Lopez Cremades with the process for preparing diosmin using methanol in elevated pressure in view of Sakhardande et al. because Lopez Cremades teaches the process of preparing diosmin, Sakhardande et al. also teach the preparation of diosmin, but with improved purity due to the addition of methanol, No et al. disclose a reaction condition of deacetylation that would increase the degree of deacetylation, and Margetic provides the maximum pressures of some common alcoholic solvents for one to consider.
Regarding claim 16, Sakhardande et al. recognize 6-iododiosmin and isorhoifolin as known impurities associated with diosmin preparation. Thus, the recited impurities are not newly identified impurities, but known diosmin-related impurities that one of ordinary skill in the art would have understood to monitor and reduce when preparing high purity diosmin. Both references do not explicitly disclose the amount of other flavonoids, however, the obtained product from Sakhardande et al. has the purity of 99.9% and Sakhardande et al. teach that its process reduces impurity levels. Accordingly, the amounts of 6-iododiosmin and isorhoifolin are expected to be less than the recited amount in claim 16.
Regarding claim 20, Lopez Cremades teaches that the halogen has a molar ratio of 0.01 – 0.2 relative to acylated hesperidin, which falls within the claimed molar ratio range. In the context of Lopez, Cremades, NaI is defined to be the halogen precursor. One would have been performed routine experimentation to discover the molar ratio of NaI, the halogen precursor, relative to acylated hesperidin for the optimal reaction characteristics based on the disclosed molar ratio of halogen to acylated hesperidin of Lopez Cremades.
Claims 25 – 26 are rejected under 35 U.S.C. 103 as being unpatentable over Lopez Cremades (EP3053930A1) in view of Sakhardande et al. (WO2010/092592A2), No et al. (Journal of Agricultural and Food Chemistry, 2000, Vol. 48, Issue 6, page 2625 – 2627, Reference included with PTO-892), and Margetic (Walter de Gruyter GmbH & Co KG, 2019, Reference included with PTO-892) as applied to claims 14 – 24 above, and further in view of Schmid et al. (US4078137).
Lopez Cremades and Sakhardande et al. teach the limitations discussed above.
However, Lopez Cremades and Sakhardande et al. do not teach the amount of base used in step c) is between 0.5 and 2.5 molar equivalents relative to the hesperidin used and the amount of base added to the deacetylation step d) is between 2 and 4.5 molar equivalents relative to the hesperidin used.
Schmid et al. teach a process for manufacturing pure diosmin comprising acetylating hesperidin, brominating the acetylation production, followed by hydrolysis (Abstract). In one embodiment, 72 g hesperidin and 25 g NaOH are used in the presence of methanol and another 24 g of NaOH is used in the process (Col. 3, para. 2 – 5).
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 process for the preparation of diosmin from hesperidin as taught by Lopez Cremades with the amount of base used in the process of preparation of diosmin in view of Schmid et al. because both processes are for preparation of diosmin. The combination of the process will yield predictable results. The calculated molar equivalents for 25 g NaOH and 24 g NaOH relative to hesperidin used are 5.29 and 5.08, respectively. One would have performed a routine experimentation to discover the best molar equivalents for the optimal production characteristics. Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success to combine the process for the preparation of diosmin from hesperidin as taught by Lopez Cremades with the amount of base used in the process of preparation of diosmin in view of Schmid et al. because Lopez Cremades teaches the process of preparing diosmin and Schmid et al. teach a process for manufacturing pure diosmin.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed May 13, 2026, has been fully considered and are found to be not persuasive.
Regarding Lopez Cremades, Applicant argues that Lopez Cremades clearly teaches away from the use of methanol in the disclosed process because the process disclosed and claimed in the Lopez Cremades relates to a process for the preparation of diosmin wherein no organic solvent is used. Applicant states that the disclosure of Lopez Cremades relates to a process for manufacturing diosmin which avoids the use of organic solvents and the organic solvents include methanol. However, the argument is not persuasive. Lopez Cremades merely discloses that extensive use of different organic solvents results in residual organic solvents, which is not desirable for its use as a drug, high environmental impact, and potential occupational health hazards for workers, apart from an increase in the manufacturing cost (para. [0019]). Lopez Cremades prefers not to use organic solvents in order to reduce residual solvent, cost, environmental impact, and worker hazards. However, Lopez Cremades does not teach that methanol is unsuitable, inoperative, or incapable of being used in the diosmin process. Instead, Lopez Cremades only expresses a preference for avoiding organic solvents. See In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016), “The applicant argued that modifying the primary reference in the manner suggested by the secondary reference would forego the benefits taught by the primary reference, thereby teaching away from the combination. The court held that both prior art references suggest[ed] that hydrolysis time may be adjusted to achieve different fiber properties. Nothing in the prior art teaches that the proposed modification would have resulted in an “inoperable” process or a dietary fiber product with undesirable properties. Moreover, the rejection does not rely on Lopez Cremades alone for the use of methanol. Sakhardande et al. explicitly teaches that the use of methanol in the process would reduce 6-iododiosmin and isorhoifolin. Thus, one of ordinary skill in the art would have had a motivation or a reason to employ methanol in the process of Lopez Cremades in order to reduce 6-iododiosmin and isorhoifolin, with a reasonable expectation of success because Sakhardande et al. teach that the incorporation of methanol achieves that very result. At most, Lopez Cremades only identifies a known tradeoff associated with organic solvents. Such a tradeoff does not amount to teaching away wherein the prior art also teaches another benefit, which is the reduction of impurities. A person of ordinary skill in the art would have reasonably selected methanol when reduction of impurities is desired.
Regarding No et al., Applicant argues that No et al. is limited to deacetylation of chitin to chitosan and do not teach its conditions are suitable for deacetylation of any and all substrates. This argument is not persuasive because the rejection does not rely on No et al. as teaching the deacetylation of acetylated diosmin. Lopez Cremades is relied upon for that teaching. No et al. is relied upon only for its disclosure that particular reaction conditions may be used in a deacetylation process to adjust process performance, such as efficiency. Thus, No et al. is not being applied as a universal teaching that its conditions are suitable for every substrate, but as evidence that the recited process condition is known to be useful in deacetylation chemistry. One of ordinary skill in the art, starting from deacetylation process of Lopez Cremades and seeking to improve the reaction efficiency would have had considered No et al. because No et al. teach that deacetylation under the disclosed conditions will be effectively achieved.
Regarding Margetic, Applicant argues that Margetic is a general reference related to high-pressure organic synthesis and merely discloses that methanol may be used at elevated pressures. This argument is not persuasive. The rejection does not rely on Margetic as teaching the entire claimed diosmin process, nor as teaching deacetylation of acetylated diosmin. Instead, Margetic is relied upon for the narrower teaching that methanol is known to be suitable for use a reaction medium under elevated pressure organic synthesis conditions. Thus, Margetic is used to support the reasonable expectation and predictability of carrying out the modified process under elevated pressure conditions in the presence of methanol.
Regarding claims 25 – 26, Applicant argues that the instantly claimed process is not rendered obvious by the combined disclosure of Lopez Cremades, Sakhardande et al., No et al., and Margetic in view of Schmid et al. because of the arguments above. The arguments are not persuasive and they have been addressed above.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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