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 .
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.
This office action is a response to applicant’s communication submitted April 26, 2024. This application is a 371 of PCT/IB2022/060197 filed 10/24/2022 and claims benefit to US provisional application 63/271,808 filed10/26/2021
Claims 1-9 are pending in this application.
Claim Objections
Claims 1, 3-4 and 6 are objected to because of the following informalities:
Claim 1 which recites “Pharmaceutical composition comprising” should recite “A pharmaceutical composition comprising” to better differentiate the claim as an independent claim.
Claim 3 which recites “Method for” should recite “A method for” to better differentiate the claim as an independent claim.
Claim 4 which recites “Method for” should recite “The method for” to better differentiate the claim as an dependent claim.
Claim 6 which recites “Use according to” should recite “The use according” to better differentiate the claim as an dependent claim. See 101 and 112 issues below regarding use claims.
Appropriate correction is required.
Claim Interpretation
With respect to instant claim 8, which is directed to a pharmaceutical composition and recites the phrase “for use in in the treatment of hepatocellular carcinoma (HCC)”. The Examiner notes that it is well settled that “intended use” of a composition or product, e.g., “for use in the treatment of hepatocellular carcinoma”, will not further limit claims drawn to a composition, so long as the prior art discloses the same composition comprising the same ingredients in an effective amount, as the instantly claimed (See MPEP 2111.02 (II)).
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5-7 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.
Claims 5-7 attempt to claim a process without setting forth any steps involved in the process. The claims merely recite a use without any active, positive steps delimiting how this use is actually practiced, such as “administering” or “mixing”. Thus claims 5-7 are rendered indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 8 are rejected under 35 U.S.C. 101 because: The claimed invention is directed to a natural product without significantly more.
Claim 1 is directed to a pharmaceutical composition comprising a diglycosylated coumarin derivative and pharmaceutically acceptable excipients, wherein the diglycosylated coumarin derivative is a rutinosylated coumarin derivative. Claim 8 recites the pharmaceutical composition according to claim 1, for use in the treatment of hepatocellular carcinoma, which is interpreted as an intended use.
According to Ouyang (Chem. Biodiversity, 2016, cited on PTO-892),
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is a natural product isolated from the stems of Clausena emarginata (abstract, pg. 1179, figure 1). The compound is a coumarin derivative that is diglycosylated with rutinose.
According to Xu (Yao Xue Xue Bao., 2012, abstract, cited on PTO-892) 7-[[6-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl]oxy]-2H-1-benzopyran-2-one is a natural product isolated from the twigs of Chamaecyparis obtusa var. breviramea f. crippsii. The methanol extract of this plant showed cytotoxicity on cancer cell lines (abstract), demonstrating it exists in a composition of nature that exhibits biological activity (abstract).
This judicial exception is not integrated into a practical application because claims 1 and 8 recite a composition comprising the compound and a pharmaceutically acceptable excipient, in a generic level of detail which is no more than generally linking the use of the natural product to a field of use. The composition is described in a generic level of detail that would have been well-understood, routine, or conventional activity in the pertinent field of art concerning compounds or agents having a biological activity. Moreover, there is no evidence in the specification inclusion of the compound in a composition with an excipient has markedly different characteristics from its natural state.
Therefore claims claim 1 and 8 are drawn to the judicial exception which is not markedly different from the product of nature, and claims 1 and 8 do not integrate the judicial exception into a practical application and do not include additional elements that are sufficient to amount to significantly more than the judicial exception itself.
Claims 5-7 are rejected under 35 U.S.C. 101 because: The claimed invention is directed to non-statutory subject matter.
The claims do not fall within at least one of the four categories of patent eligible subject matter because the claims are “use” claims. one cannot claim a new use per se, because it is not among the categories of patentable inventions (process, machine, manufacture, or composition of matter) specified in 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 5-6, and 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mazzaferro (Carbohydrate Research, 2012, available online 2011, IDS filed May 13, 2024) as evidenced by McKim (Pharmaceutical Technology, 2008, cited on PTO-892).
Regarding claims 1-2, 5-6, and 8-9: Mazzaferro teaches the synthesis of 4-methylumbelliferyl-rutinoside in DMSO (pg. 72, figure 2b, pg. 73, figure 4). Concentration of 4-methylumbelliferyl-rutinoside reached concentrations of approximately 400 µM (pg. 73, figure 4). According to McKim, DMSO is an excipient in pharmaceutical compositions (pg. 4, para. 3). According to the instant specification concentrations ranging from 0.1 mM to 1 mM are effective in killing hepa129 cells (i.e. 100-1000 µM, pgs. 15-16, bridging paras.). Thus the composition of Mazzaferro comprises 4-methylumbelliferyl-rutinoside in an effective amount as the instantly claimed composition.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Piccioni (Glycobiology, 2011, IDS filed May 13, 2024) in view of Thuan (J. Ind. Microbiol. Biotechnol., 2013, IDS filed May 13, 2024), Stanisic (Studies in Natural Products Chemistry, 2018, cited on PTO-892), Mazzaferro (Carbohydrate Research, 2012, available online 2011, IDS filed May 13, 2024).
Regarding claims 1-9: Piccioni teaches 4-Methylumbelliferone (4MU) is an inhibitor of HA synthesis and has anticancer activity (abstract). Piccioni teaches 4MU is a modified coumarin (pg. 826, col. 1, para. 1). Piccioni teaches 4MU has antitumor activity in vivo and is an orally available molecule with potential for hepatocellular carcinoma (HCC) treatment (abstract). Piccioni teaches the oral administration of 4MU to mice orthotopically inoculated with Hepa129 tumor cells (abstract). Piccioni teaches 4MU was administered via oral gavage at a dose of 400 mg/kg/day wherein saline was used as control (i.e. water is an excipient, pg. 827, figure 1, pg. 832, col. 2, para. 1). Thus, it would have been prima facie obvious to apply the method of Piccioni for the treatment of HCC in a subject via oral administration of 4MU as suggested by Piccioni. A person of ordinary skill in the art would have had the motivation to do so as Piccioni suggests 4MU is an orally available molecule with potential for HCC treatment.
Piccioni does not teach wherein 4-Methylumbelliferone (4MU) is rutinosylated.
However, Thuan teaches glycosylation is one of the most important post-modification processes of small molecules and enables the parent molecule to have increased solubility, stability, and bioactivity (abstract). Thuan teaches coumarins are a known class of compounds that show anti-neoplastic effects (pg. 1339, col. 2, last para.). Thuan teaches coumarin glycosides show better solubility and stability than their aglycon derivatives (pg. 1341, col. 1, para. 1). Stanisic teaches hesperidin is a known molecule which is comprised of hesperidin which is glycosidased by rutinose, a disaccharide that gives hesperidin the form of a pro-drug, which, upon being hydrolyzed in the intestines, is released as an active and more bioavailable glycone hesperetin (pg. 164, para. 2). Stanisic teaches the rutinoside group allows for hesperidin to be selective for cancerous cells (pg. 174, last para.). Stanisic teaches hesperidin is known to be effective against human hepatocellular carcinoma (pg. 177, para. 1). Additionally, Mazzaferro teaches the synthesis of 4-methylumbelliferyl-rutinoside in DMSO (pg. 72, figure 2b, pg. 73, figure 4), establishing that such a molecule is known in the art and demonstrates effective rutinosylation of 4-MU. Mazzaferro teaches the preparation of 4-methylumbelliferyl-rutinoside from hesperidin (pg. 72, figure 2b).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the method of Piccioni such that 4MU is replaced with 4-methylumbelliferyl-rutinoside as suggested by Thuan, Stanisic, and Mazzaferro for the purpose of treating hepatocellular carcinoma in a subject. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes glycosylation of small molecules is a known technique in the art in order to improve solubility, stability and bioactivity, and rutinose is a known pro-drug moiety which is selective for cancer cells. One of ordinary skill in the art would have been capable of applying this known method of enhancement to 4MU in the prior art and the results would have been predictable to one of ordinary skill in the art given that glycosylation of coumarins is a known technique in the art (See MPEP 2143 (IC)).
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
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/SAMUEL L GALSTER/Examiner, Art Unit 1693
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