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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 30 April 2026 has been entered.
This Office action is responsive to Applicant’s amendment and remarks, filed 30 April 2026, in which claims 6 and 10 are amended to change the scope and breadth of the claim, and claim 5 is canceled.
This application is the national stage entry of PCT/JP2021/025112, filed 02 July 2021; and claims benefit of foreign priority document JAPAN 2020-115074, filed 02 July 2020. This foreign priority document is not in English.
Claims 1, 3-4, 6, and 10-12 are pending in the current application and are examined on the merits herein.
Objections Withdrawn
Applicant’s amendment, filed 30 April 2026, with respect that claim 10 is objected to because of informalities has been fully considered and is persuasive, as amended claim 10 does not recite the indicated informalities.
This objection has been withdrawn.
Rejections Withdrawn
Applicant’s amendment, filed 30 April 2026, with respect that claims 10-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been fully considered and is persuasive, as amended claim 10 does not recite the full scope of preventing the diseases as claimed.
This rejection has been withdrawn.
Applicant’s amendment, filed 30 April 2026, with respect that claims 10-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite has been fully considered and is persuasive, as amended claim 10 clarifies to who or what the composition is administered.
This rejection has been withdrawn.
The following are new grounds of rejection responsive to Applicant’s amendment, filed 30 April 2026, in which claims 6 and 10 are amended to change the scope and breadth of the claim, and claim 5 is canceled.
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:
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.
Amended Claims 1, 6, and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Kakeya et al. (WO 2018/003857 A1, published 04 Jan 2018, English language equivalent US 2019/0224325, both provided by Applicant in IDS filed 30 Dec 2022) in view of Bastin et al. (Organic Process Research & Development, 2000, 4, p427-435, of record), Elder et al. (International Journal of Pharmaceutics, 2013, 453, p88-100, cited in PTO-892), and Waterman et al. (Pharmaceutical Development and Technology, 2002, 7(2), p113-146, cited in PTO-892).
WO 2018/003857 A1 is not in English, therefore citations to Kakeya et al. will be found in US 2019/0224325. Kakeya et al. teaches a curcumin pharmaceutical preparation that is highly water soluble, can maintain the concentration of free curcumin in the blood sufficiently high by being administered parenterally, can effectively obtain a pharmacological action of curcumin, and is highly safe, and a pharmaceutical composition for parenteral administration including the water-soluble substance conjugate of curcumin as an active component (abstract). The working example of the conjugate of curcumin is the curcumin monoglucuronide
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(example 1 at paragraph 59 spanning page 3 to 5), corresponding to the free acid form of the claimed formula (I) rotated 180° along a vertical axis. Curcumin includes both of keto and enol forms of curcumin, which are tautomers (page 2, paragraph 44), and one of skill in the art would have understood that the enol form depicted in Kakeya et al. is necessarily in tautomeric equilibrium with the keto form depicted in claim 1. The composition for parenteral administration may also include water and an acid or an alkali, such as a water-soluble inorganic acid or a water-soluble inorganic acid salt (page 3, paragraphs 54-55), addressing limitations of claims 5-6 and 11. Kakeya et al. teaches a working example of administering the composition intravenously in order to treat the disease of cancer (example 2 at page 6, paragraphs 76-83), addressing limitations of claims 10-12. Kakeya et al. further teaches the curcumin therapy of the invention to be selected from cancer therapy, an anti-inflammatory therapy, a cholesterol-lowering therapy, an anti-allergic therapy, a cognitive function improving therapy, and a heart disease preventive therapy (page 2, paragraph 34), addressing limitations of claim 10.
Kakeya et al. does not specifically disclose a sodium salt of the curcumin monoglucuronide (claim 1).
Bastin et al. teaches selection of an appropriate salt form for a new chemical entity provides the pharmaceutical chemist and formulation scientist with the opportunity to modify the characteristics of the potential drug substance and to permit the development of dosage forms with good bioavailability, stability, manufacturability, and patient compliance. Salts are most commonly employed for modifying aqueous solubility (page 427, abstract). The choice of salt is governed largely by the acidity or basicity of the ionizable group of the drug substance, and common pharmaceutical salt cations include sodium (page 428).
Elder et al. teaches for ionizable drugs (anionic, cationic and zwitterionic) salt formation is the simplest, most cost-effective strategy to address poor aqueous solubility and enhance bioavailability. In addition to the positive impact on solubility, salts can beneficially affect the purity of the active pharmaceutical ingredient (API), isolation of the API, stability (both chemical and physical), manufacturability (particularly flow) and can influence irritancy/toxicity of the dosage form (page 88, paragraph spanning left and right columns). For drugs with dissolution rate limited absorption, a salt/cocrystal strategy facilitates the bioavailability of the compound by increasing the dissolution rate, which is described by the Nernst (1904) equation. However, there is often a compromise to be made between solubility and stability and the most soluble form may not be the optimal form, due to enhanced hydrolysis, which is a common degradation pathway, citing Waterman et al. (Section 2 from page 89, right column to page 90, left column, especially page 89, right column, paragraphs 3-4).
Waterman et al. teaches a review of hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients (page 113, abstract). Hydrolysis is the cleavage of a chemical species by water. Since water, either as a solvent or in the form of moisture in the air, contacts most pharmaceutical dosage forms to some degree, the potential for this degradation pathway exists for most drugs and excipients (page 113, left column). Table 2 offers examples of potentially hydrolyzable functional groups and examples of drugs containing these functional groups (page 116, right column, paragraph 3; page 118, table 2), such as the acetal group. A number of drugs (e.g., macrolide antibiotics) contain acetal, hemi-acetal, ketal, and hemi-ketal functionalities, all of which are subject to either base-catalyzed hydrolysis (paragraph spanning page 120-121) or acid-catalyzed hydrolysis (page 121, right column, paragraphs 4-5). Rate constants for hydrolysis of several drugs are listed in Table 3, including the values for the acetal-containing erythromycin. The pseudo first-order rate constants for the hydrolysis of the drug predicts the half-life of the drug (page 119, paragraph spanning left and right columns, and table 3). Different salt and hydrate forms of the drug can result in different hydrolytic reactivity based on several factors. For salt forms, differences in aqueous solubility, microenvironmental pH, and hygroscopicity can lead to differences in reactivity (page 115, left column, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Kakeya et al. in view of Bastin et al., Elder et al., and Waterman et al. in order to formulate the drug compound of Kakeya et al. as a sodium salt form. One of ordinary skill in the art would have been motivated to combine Kakeya et al. in view of Bastin et al., Elder et al., and Waterman et al. with a reasonable expectation of success because Kakeya et al. teaches the desire to prepare a curcumin pharmaceutical preparation that is highly water soluble with good bioavailability; Bastin et al. teaches selection of the appropriate salt form for a drug permits the development of dosage forms with modified aqueous solubility and good bioavailability and stability, and teaches common pharmaceutical salts include sodium; Elder et al. teaches the specific measure of aqueous solubility would have predictable and expected for the formation of pharmaceutical salts; and Waterman et al. teaches hydrolysis is a common degradation pathway of active pharmaceutical ingredients such as those containing an acetal group of a glycosidic bond such as in erythromycin or the claimed monoglucuronide, differences in aqueous solubility, microenvironmental pH, and hygroscopicity can lead to differences in reactivity for salt forms, and that the specific measure of drug stability such as half-life would have predictable and expected. It would have been obvious to apply the known technique of selection of an appropriate salt form for a drug to improve the invention of Kakeya et al. in the same way as the desired improvements of Kakeya et al. to give predictable results taught by Bastin et al., Elder et al., and Waterman et al.
Response to Applicant’s Remarks:
Applicant’s remarks, filed 30 April 2026, have been fully considered and not found to be persuasive.
Applicant again remarks that Kakeya et al. does not specifically describe the stability of the curcumin glucuronide sodium salt, and that Bastin et al. does not describe the specific measure of improved stability for the sodium salt form of curcumin glucuronide, and that this improvement would have been unpredictable. However, the court of Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007) rejected the notion that unpredictability could be equated with nonobviousness here, because there were only a finite number (53) of pharmaceutically acceptable salts to be tested for improved properties, in response to Pfizer arguing that the results of forming amlodipine besylate would have been unpredictable and therefore nonobvious. By analogous reasoning, Kakeya et al. in view of Bastin et al. teaches a finite number of pharmaceutically acceptable salts to be tested for improved properties, where the improvements are predicted to be in the properties of bioavailability and stability. Further, newly cited Elder et al. and Waterman et al. teach that these properties are predictable and expected for the formation of pharmaceutical salts. Therefore the
evidence of improvement in stability described in the application, and the specific measure of stability also expressed in terms of half-life and the specific measure of solubility would not have been unexpected results, but rather the expected measurements of an optimized property from the selection within a finite number of pharmaceutically acceptable salts, where newly cited Elder et al. and Waterman et al. teach the results were both expected and predictable.
Amended Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Kakeya et al. (WO 2018/003857 A1, published 04 Jan 2018, English language equivalent US 2019/0224325, both provided by Applicant in IDS filed 30 Dec 2022) in view of Bastin et al. (Organic Process Research & Development, 2000, 4, p427-435, of record), Elder et al. (International Journal of Pharmaceutics, 2013, 453, p88-100, cited in PTO-892), and Waterman et al. (Pharmaceutical Development and Technology, 2002, 7(2), p113-146, cited in PTO-892) as applied to claims 1, 6, and 10-12 above, and further in view of Lam et al. (Ind. Eng. Chem. Res., 2010, 49(24), p12503-12512, of record).
Kakeya et al. in view of Bastin et al., Elder et al., and Waterman et al. teaches as above.
Kakeya et al. in view of Bastin et al., Elder et al., and Waterman et al. does not specifically teach reacting curcumin monoglucuronide with a base represented by chemical formula (II) (claim 3).
Lam et al. teaches salt formation is frequently employed to improve the solubility and bioavailability of pharmaceutical compounds (page 12503, abstract). Salt formation is the most common and effective method employed in the pharmaceutical industry to modify and optimize the physicochemical properties of these lead compounds (page 12503, left column, paragraph 2). Lam et al. teaches preparation of the salt by reacting a carboxylic acid-containing drug with a metal hydroxide such as NaOH or KOH (page 12504, right column).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Kakeya et al. in view of Bastin et al., Elder et al., and Waterman et al. further in view of Lam et al. to prepare the salt by commonly used methods. One of ordinary skill in the art would have been motivated to combine Kakeya et al. in view of Bastin et al., Elder et al., and Waterman et al. further in view of Lam et al. with a reasonable expectation of success because Lam et al. teaches salt formation is the most common and effective method employed in the pharmaceutical industry and teaches preparation of the sodium or potassium salt of a carboxylic acid-containing drug by reaction with the metal hydroxide base.
Response to Applicant’s Remarks:
Applicant’s remarks, filed 30 April 2026, have been fully considered and not found to be persuasive.
Applicant’s remarks regarding Kakeya et al. in view of Bastin et al. as applicable to the new rejection over Kakeya et al. in view of Bastin et al., Elder et al., and Waterman et al. are addressed as above.
Conclusion
No claim is found to be allowable.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693
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