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 November 24, 2025. The amendment, filed November 24, 2025, is entered, wherein claims 14, 16 – 17, and 20 – 21 are 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.
Withdrawn Objections
4. The objections of claims 14 and 16 in the previous Office Action, mailed June 23, 2025, is withdrawn in view of the amended claims 14 and 16.
Withdrawn Rejections
5. The rejection of claim 17 in the previous Office Action, mailed June 23, 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for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention has been considered and is withdrawn in view of the amended claim 17.
The rejection of claim 21 in the previous Office Action, mailed June 23, 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for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention has been considered and is withdrawn in view of the amended claim 21.
The rejection of claims 14 – 24 in the previous Office Action, mailed June 23, 2025, under 35 U.S.C. 103 as being unpatentable over Lopez Cremades in view of Sakhardande et al. and Zhang et al. has been considered and is withdrawn because Zhang et al. do not support the limitation “a pressure of 5 to 8 bar”.
The rejection of claims 25 – 26 in the previous Office Action, mailed June 23, 2025, under 35 U.S.C. 103 as being unpatentable over Lopez Cremades in view of Sakhardande et al. and Zhang et al. as applied to claims 14 – 24 above, and further in view of Schmid et al. has been considered and is withdrawn because claims 25 – 26 depends from claims 14 and the rejection of claims 14 – 24 is withdrawn.
The following are modified / new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed November 24, 2025, wherein claims 14, 16 – 17, and 20 – 21 are amended and claims 1 – 13 are canceled. Previously cited references have been used to established the modified / new grounds of rejection.
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 14 – 24 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).
Regarding claims 14 – 24, 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 sequent 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 (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, it is used a iodine compound selected from molecular iodine, sodium iodide, and mixture thereof (para. [0038]). 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]).
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 is 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).
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. For the pressure, the examples disclose in the instant specification indicate the use of the claimed range of pressure during the deacetylation step, which converts acetylated diosmin to diosmin (page 5, lines 20 – 25; page 6, lines 22 – 27; page 7, lines 5 – 9; page 8, lines 4 – 9). It would have been prima facie obvious for a person of ordinary skill in the art to modify the reaction condition 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 condition 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. 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%. The amounts of 6-iododiosmin and isorhoifolin are expected to be less than the recited amount in claim 16. 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.
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).
Regarding claims 25 – 26, the references teach the limitations discussed above.
However, the references 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 November 24, 2025, has been fully considered and are found to be not persuasive.
Regarding Lopez Cremades, Applicant argues that Lopez Cremades teaches away from the claimed invention because Lopez Cremades teaches a method of manufacturing diosmin with improved purity, namely with low iodine and bromine content without the need to use organic solvents during the process. The examiner asserts that there is no teaching away because the addition of methanol is targeting the reduction of isorhoifolin. Lopez Cremades discloses that the treatment simply using inorganic base would reduce the iodine or bromine content of less than 0.1% (para. [0057]). The disclosure does not address the reduction of isorhoifolin. Therefore, one of the ordinary skill in the art would have been motivated to incorporate methanol for the purpose of reducing the content of impurities other than impurities containing iodine or bromine.
Regarding Zhang et al., Applicant argues that Zhang et al. relates to pressurized liquid extraction of flavonoids from the natural product Hottuynia cordata Thunb, and one skilled in the art would not have looked an extraction method to modify a synthetic process simply because the extraction method produce flavonoids. However, the argument is not persuasive because Zhang et al. is no long relied upon. As explained above, No et al. teach to apply an elevated pressure during deacetylation to increase the degree of deacetylation. The disclosure provides a motivation for one of the ordinary skill in the art to consider modifying the reaction condition of diosmin preparation by increasing the pressure for achieving higher degree of acetylation. Therefore, the combination of Lopez Cremades, Sakhardande et al., No et al., and Margetic renders the claimed invention obvious.
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