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 .
Summary
Claims 1-4, 10, 12, 14, and 16-18 are pending in this office action. Claims 5-9, 11, 13, and 15 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on February 2, 2024 is a 371 of PCT/KR2022/011570 filed on August 4, 2022. The current application claims foreign priority to KR10-2021-0102453 filed on August 4, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on March 4, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Claim Objections
Claims 1-4, 10, 12, 14, and 16-18 are objected to because of the following informalities:
Claim 1: After the wherein clause and prior to the text, “k is an integer from 5 to 30” should have a semicolon instead of a comma. Also, within Formula 1 adjust the terminal methyl to have a “flat” base (CH3). Within Formula 2 the terminal methyl looks boldface. Please make it normal font.
Dependent claims 2-4, 12, 14, and 16-18 are included in this objection because they do not cure the defect of claim 1.
Claim 10: Please use upper case to write the text “Formulas” to be consistent with claim 1.
Claims 12, 14, and 16: Please add the article, a, prior to the text, “….pharmaceutically acceptable salt thereof…” to be consistent with claim 1.
Appropriate correction is required.
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 non-obviousness.
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, 10, 12, 14, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Yoo et al. (US2020/0101179A1, published in April 2020) over Kendysh et al. (SU1303598A1), El-Zaria et al. (Chemistry – A European Journal, 2012), Lappano et al. (Cell Death Discovery, 2017), and Forbes et al. (International Journal of Oncology, 2014).
[The Examiner is going to introduce each new reference and then combine them where appropriate to reject the instant claims.]
1. Yoo et al.
Yoo et al. is the closest prior art to the present invention as it teaches development and application of tumor diagnostic radioactiveprobe targeting folic acid
receptor (see title). Additionally, Yoo et al. disclose that Tthe present invention pertains to a novel liposome-based contrast agent that is for suppressing absorption in the reticuloendothelial system and for tumor-specific delivery of a radiolabeled substance. More specifically, the present invention pertains to: a liposome contrast agent containing a lipid and a compound of chemical formula 1, which is a radiolabeled substance, the liposome contrast agent being characterized in that the lipid is composed of (a) cholesterol, (b) 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and (c) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethylene glycol)-2000] (DSPE-PEG2000); and a cancer diagnostic composition containing the liposome contrast agent as an active ingredient. If a liposome system, containing a contrast substance of chemical formula 1 having a unique lipid composition provided by the present invention, is manufactured, the tumor-to-organ uptake ratio of the contrast substance in the reticuloendothelial system increases significantly, thus greatly increasing the tumor diagnostic efficiency of the compound of chemical formula 1. (see abstract).
2. Kendysh et al.
Kendysh et al. teach 4-iodine-phenyl-laurate labelled with iodine radioisotopes as radioactive agent for determining fermentative activity of lipase in organism and intermediate product for producing same (see title). In addition, Kendysh et al. disclose 4-Iodophenyllaurate labeled with radioisotopes of iodine as a radioactive means for determining the enzymatic activity of lipase in the body and an intermediate product for its production (see description).
3. El-Zaria et al.
El-Zaria et al. teach synthesis, characterisation, and biodistribution of radioiodinated c-hydroxy-carboranes (see title). Furthermore, El-Zaria et al. disclose the synthesis, radiolabelling and biodistribution of iodinated C-hydroxy-nido-carborane ligands is described. Microwave heating by using NaF in aqueous ethanol was used to prepare {sodium [7-hydroxy-7,8-dicarba-nido-undecaborate], nido-carboranolj and [sodium (7-hydroxy-7,8-dicarba-nido-undceaborate-8-earboxylic acid), nido-salborin] in 97 and 90% yield, respectively. Radioiodination of these nido-carboranes was completed by using both 125I and 123I, and the products were obtained in high radiochemical purity (> 99 %) and yield (72 to 87 %). The structures of the radiolabelled products were validated through comparison to authentic standards. Biodistribution studies in BALB / c mice showed low accumulation of the labelled compounds in the liver and intestines, which arc sites where labelled carboranes typically localise. The labelled cluster bearing hydroxy and carboxylic acid groups on the two carbon vertices demonstrated preferential clearance through the kidneys and lo<w thyroid uptake. 1bis compound had substantially reduced non-specific binding than the deshydroxy analogue making it an attractive bifunctional ligand for preparing targeted molecular imaging and therapy agents (see abstract).
4. Lappano et al.
Lappano et al. teach lauric acid-activated signaling prompts apoptosis in
cancer cells (see title). Also, Lappano disclose the saturated medium-chain fatty-acid lauric acid (LA) has been associated to certain health-promoting benefits of coconut oil intake, including the improvement of the quality of life in breast cancer patients during chemotherapy. As it concerns the potential to hamper tumor growth, LA was shown to elicit inhibitory effects only in colon cancer cells. Here, we provide novel insights regarding the molecular mechanisms through which LA triggers antiproliferative and pro-apoptotic effects in both breast and endometrial cancer cells. In particular, our results demonstrate that LA increases reactive oxygen species levels, stimulates the phosphorylation of EGFR, ERK and c-Jun and induces the expression of c-fos. In addition, our data evidence that LA via the Rho-associated kinase-mediated pathway promotes stress fiber formation, which exerts a main role in the morphological changes associated with apoptotic cell death. Next, we found that the increase of p21Cip1/WAF1 expression, which occurs upon LA exposure in a p53-independent manner, is involved in the apoptotic effects prompted by LA in both breast and endometrial cancer cells. Collectively, our findings may pave the way to better understand the anticancer action of LA, although additional studies are warranted to further corroborate its usefulness in more comprehensive therapeutic approaches (see abstract).
5. Forbes et al.
Forbes et al. teach synthesis and anticancer activity of new flavonoid analogs and inconsistencies in assays related to proliferation and viability measurements (see title). Furthermore, Forbes et al. disclose that flavonoids have been studied intensely for their ability to act as anti-carcinogenic, anti-inflammatory, anti-viral and anti-aging agents and are often marketed as supplements related to their anti-inflammatory activity. Previous studies have primarily focused on the effects of polar natural flavonoids. We examined the activity of novel hydrophobic and lipophilic flavonols against human DU-145 and PC-3 prostate cancer cell lines. All flavonol analogs were more active than the naturally occurring flavonols quercetin, kaempferol, kaempferide and galangin. The most potent analogs were 6.5-fold more active against DU-145 and PC-3 cells than quercetin and fell within the biologically relevant concentration range (low micromolar). We also evaluated the potential toxic effects of flavonol analogs on normal cells, an assessment that has frequently been ignored when studying the anticancer effects of flavonoids. During these analyses, we discovered that various metabolic and DNA staining assays were unreliable methods for assessing cell viability of flavonoids. Flavonoids reduce colorimetric dyes such as MTT and Alamar Blue in the absence of cells. We showed that flavonol-treated prostate cancer cells were stained less intensely with crystal violet than untreated cells at non-toxic concentrations. The trypan blue exclusion assay was selected as a reliable alternative for measuring cell viability (see abstract).
Combination of Yoo et al. and Kendysh et al.
Regarding instant claim 1, Yoo et al. and Kendysh et al. teach a novel radioactive compound. The necessary citations within Yoo et al. and Kendysh et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Yoo et al. and Kendysh et al. Citations
A novel radioactive compound selected from the group consisting of Formula 1 or a pharmaceutically acceptable salt thereof:
Yoo et al. is considered to be the closest prior art to the subject-matter of claims 2, 3, 11, and 13 and discloses a liposome contrast agent comprising laurylbenzoate labeled with an iodine radioisotope, cholesterol, 1,2-dipalmitoylsn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000), which is partially attached to folate (see claims 1-13, paragraph [0031-0064], and Examples 1-6 within Yoo et al.). These liposome contrast agents are used for in vivo imaging and for diagnosing a cancer (see Figures 1-13 within Yoo et al.).
The subject-matter of claims 2, 3, 11, and 13 differs from Yoo et al. in that a different radiolabeled compound is used. The compound is the reverse ester analogue of Formula 1:
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(see paragraph [0011] within Yoo et al.).
Kendysh et al. disclose 4-iodophenyl laurate labeled with iodine radioisotopes. The radioisotopes 125I and 131I are located in 4-position of the phenyl moiety of the ester (see Examples 1-2, table 1, and claim 1 within Kendysh et al.). The radiolabeled compound is a substrate for lipase (see paragraphs introduction and [0001] within Kendysh et al.) and is suitable for imaging, diagnosis and treating cancer. Kendysh et al. disclose the use of the identical compound as in instant claim 1, Formula 1, the 4-iodophenyl laurate analogue:
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(see column 1, lines 6-8 within Kendysh et al. and PTO-892 NPL W).
The objective technical problem to be solved by the present invention may therefore be regarded as the provision of alternative radiolabeled compounds and liposomes suitable for in vivo imaging and diagnosing a cancer.
However, the skilled person would replace the radiolabeled laurylbenzoate of Yoo et al. by the radiolabeled compound of Kendysh et al. without exercising inventive skill thereby arriving at liposomes and methods according to claims 2, 3, 11, and 13 within Yoo et al.
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[in order to save space the Examiner is only illustrating the compound mapped for rejection purposes]
wherein, in the Formula 1, X is a diagnostically active radioisotope selected from the group consisting of43Sc,44Sc,51Mn,52Mn, 64Cu,67Ga, 68Ga,86Y, 89Zr, 94mTc,99mTc, 111In, 152Tb, 155Tb,201TI, 203Pb, 18F, 76Br, 77Br, 123I,124I and 125I; or a therapeutically active radioisotope selected from the group consisting of 47Sc, 67Cu, 89Sr, 90Y, 153Sm, 149Tb, 161Tb, 177Lu, 186Re, 188Re,212Pb, 213Bi, 223Ra, 225Ac, 226Th, 227Th, 131I and 211At, k is an integer from 5 to 30.
It would have been obvious to one of ordinary skill in the art [skilled artisan; POSITA (person of ordinary skill in the art)] prior to the effective filing date of the claimed invention to modify Yoo et al. with the teachings of Kendysh to disclose a novel radioactive compound for the diagnosis, imaging, and treatment of cancer. The motivation for doing so would have been to develop a novel radioactive compound by simple substitution as described within Table I.
Regarding instant claims 2-4, Yoo et al. and Kendysh et al. teach a liposome comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and lipids comprising a) cholesterol; (b) 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC); and (c) 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)- 2000(DSPE-PEG2000).
Yoo et al. disclose a liposome contrast agent consisting of a compound defined by a laurylbenzoate analogue and lipids, wherein the lipid is characterized by consisting essentially of (a) cholesterol; (b) 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC); and (c) 1,2-di stearoyl-sn-glycero-3-phosphoethanolamine-N[ methoxy(polyethylene-glycol)-2000 (DSPE-PEG2000) (see paragraph [0022] within Yoo et al.). In addition, Yoo et al. disclose covalent attachment of folate to DSPE-PEG2000 (see paragraphs [0055-0056] and claim 5 within Yoo et al.).
Combination of Yoo et al., Kendysh et al., and El-Zaria et al.
Regarding instant claim 10, Yoo et al., Kendysh et al., and El-Zaria et al. teach a compound of formula 9 or 10, or a pharmaceutically acceptable salt:
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El-Zaria et al. disclose the following derivatives within Scheme 1:
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Compounds 4 and 6 could be esterified under routine experimental conditions to obtain the desired analogues corresponding to Formulas 9 and 10, respectively. The motivation being that a skilled artisan (POSITA) would want to increase the “organic portion” of the derivative and protect the carboxylic acid moiety for binding similar to instant claim 1 (having an extended ester chain) within the folate receptor (see PTO-892 NPL 2V).
Combination of Yoo et al. and Kendysh et al.
Regarding instant claims 12, 14 and 17, Yoo et al. and Kendysh et al. teach a method for in vivo imaging comprising the steps of: i) administering the compound of instant claim 1 or a pharmaceutically acceptable salt thereof, a liposome comprising said compound or a pharmaceutically acceptable salt thereof and lipids, to a subject; ii) waiting for a sufficient time to allow the compound or liposome to be introduced into the subject's body; and iii) imaging an area where the compound or liposome is detected in the subject; and a method for diagnosing a cancer comprising the steps of: a) administering the compound of instant claim 1 or a pharmaceutically acceptable salt thereof, or a liposome comprising said compound or pharmaceutically acceptable salt thereof and lipids, to a subject; b) waiting for a sufficient time to allow the compound or liposome to be introduced into cancer cells; c) detecting proliferative cells by imaging an area where the compound or liposome is detected in the subject; and d) diagnosing the subject as having cancer when the compound or liposome is detected in the subject.
Yoo et al. disclose a method for diagnosing a cancer in a subject, the method comprising administering an effective amount of the liposome contrast agent of claim 1 to the subject in need thereof (see claim 13 within Yoo et al.). Furthermore, Yoo et al. disclose wherein the contrast agent is used for optical imaging, positron emission
tomography (PET) scanning, or single photon tomography (SPECT) scanning (see claim 11 within Yoo et al.). A skilled artisan (POSITA) would be able to reconstruct instant claim 12, 14, and 17 with the aid of the above citations from Yoo et al.
Combination of Yoo et al., Kendysh et al., Lappano et al., and Forbes et al.
Regarding instant claim 16, Yoo et al., Kendysh et al., Lappano et al., and Forbes et al. teach a method for treating a cancer, the method comprising administering an effective amount of a composition comprising the compound of instant claim 1 or a pharmaceutically acceptable salt thereof, or a liposome comprising said compound or pharmaceutically acceptable salt thereof and lipids, to a subject in need thereof.
Both the Lappano et al. and Forbes et al. references support the anticancer activity within the 4-iodophenyl laurate analogue (see title and abstract within Lappano et al.; and title, abstract, and Figure 2). Additionally, Kendysh et al. supports the therapeutically active 131I radioisotope within the 4-position (see Examples 1-2, table 1, and claim 1 within Kendysh et al.). Finally, addition of the Yoo et al. reference would allow for lipids (see instant claims 2-4). Therefore, combination of these four references would disclose a method for treating cancer to a skilled artisan (POSITA).
Combination of Yoo et al. and Kendysh et al.
Regarding instant claim 18, Yoo et al. and Kendysh et al. teach wherein the cancer is pancreatic cancer.
Yoo et al. disclose wherein the folate receptor-overexpressing tumor is pancreatic cancer (see claim 10 within Yoo et al.).
Analogous Art
The Yoo et al., Kendysh et al., El-Zaria et al., Lappano et al., and Forbes et al. references are directed to the same field of endeavor as the instant claims, that is, a novel radioactive compound, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the diagnostic radioactive probe disclosed by Yoo et al., using the teachings of Kendysh et al., Lappano et al., and Forbes et al. in order to arrive at the subject matter of the instant claims.
The Yoo et al., Kendysh et al., El-Zaria et al., Lappano et al., and Forbes et al. references all have considerable overlap in the radiotherapy arts. In this instance, Yoo et al. supplies the template for folic acid receptor targets, Kendysh et al. supplies the required 4-iodophenyl laurate derivative, El-Zaria et al. supplies the claim-specific nido-carboranes, while Lappano et al. and Forbes et al. supply the support for the anticancer activity of the laurate analogue. All references are directed to radiotherapy and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the five references when seeking to develop a novel radioactive compound.
Given these teachings, a POSITA would have been motivated to combine the template for folic acid receptor targets as disclosed by Yoo et al., the required 4-iodophenyl laurate derivative supplied by Kendysh, the claim-specific nido-carboranes disclosed by El-Zaria, and the support for the anticancer activity of the laurate analogue disclosed by Lappano et al. and Forbes et al.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar device in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the diagnostic radioactive probe taught by Yoo et al. along with the use of the necessary claim limitations taught by Kendysh et al., El-Zaria et al., Lappano et al., and Forbes et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Kendysh et al., El-Zaria et al., Lappano et al., and Forbes et al. would have been viewed by a POSITA as routine design optimizations or known modifications for radiotherapy compounds. The motivation for doing so would have been to develop a novel radioactive compound by simple substitution as described within Table I. Implementing these features in Yoo et al.’s diagnostic radioactive probe would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Yoo et al., Kendysh et al., El-Zaria et al., Lappano et al., and Forbes et al. provides all the elements of the claimed invention. The resulting novel radioactive compound and methods of use, constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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