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
Claims 1, 2, and 7-20 of Y. Akao et al., US 17/759,897 (Feb. 15, 2021) are pending. Claims 7-17 and 20 drawn to non-elected Groups (II)-(V) are withdrawn from consideration pursuant to 37 CFR 1.142(b). Claims 1, 2 and 18-19 are under examination on the merits.
Election/Restrictions
Pursuant to the restriction requirement, Applicant elected Group (I), (now claims 1, 2, 6 18 and 19, without traverse, in the reply filed on June 6, 2025. New claim 19 is added to the invention of Group (I). New claim 20 is added to the invention of Group (III).
Claims 7-17 and 20 drawn to non-elected Groups (II)-(V) are maintained as withdrawn from consideration pursuant to 37 CFR 1.142(b). The restriction requirement is maintained as FINAL.
Pursuant to the election of species requirement, Applicant elected petasin, for prosecution on the merits.
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See specification at page 14 for structure of petasin. Claims 1, 2 and 18-19 of elected Group (I) read on the elected species. The provisional election of species requirement is maintained in effect and no elected claims are withdrawn as not reading on the elected species. MPEP § 803.02(III)(A).
Withdrawal Claim Rejections - 35 USC § 102 (AIA )
Rejection of claims 1, 2, 6 and 18 under 35 U.S.C. 102(a)(1) as being anticipated by X. Lyu et al., 132 Chinese Medical Journal, 1071- 1078 (2019) (“Lyu”) is withdrawn in view of Applicant’s amendments and argument.
Rejection of claims 1, 2, 6 and 18 under 35 U.S.C. 102(a)(1) as being anticipated by A. Ikemoto et al., JP 2014198683A (2014) (“Ikemoto”) is withdrawn in view of Applicant’s amendments and argument.
New 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under AIA 35 U.S.C. 103(a) 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.
Claims 1, 2, 18 and 19 are rejected under AIA 35 U.S.C. 103 as being unpatentable over A. Ikemoto et al., JP 2014198683A (2014) (“Ikemoto”) in view of secondary references HEISHIMA, Kazuki et al., Anti-Cancer Activity of Petasites japonicus Extract. Proceedings of the 77th Annual Meeting of the Japanese Cancer Association (2018) (“Heishima”); E. Alvarez e al., B16 Murine Melanoma (Ch. 4), in Tumor Models in Cancer Research, 73-89 (B. Teicher ed., 2002) (“Alvarez”); C. Danciu et al., 96 International Journal of Experimental Pathology, 73-80 (2015) (“Danciu”); X. Lyu et al., 132 Chinese Medical Journal, 1071- 1078 (2019) (“Lyu”); and T. Sinnberg et al., 129 Journal of Investigative Dermatology, 1500-1515 (2009).
A. Ikemoto et al., JP 2014198683A (2014) (“Ikemoto”)
An English-language machine translation (by Google Patents) is attached as the second half of reference A. Ikemoto et al., JP 2014198683A (2014) (“Ikemoto”). Ikemoto thus consists of 76 total pages (including the English-language translation portion). Accordingly, this Office action references Ikemoto page numbers in the following format “xx of 76”.
Ikemoto teaches a melanin production inhibitor/anticancer agent following formulae (4A) to (6A) (in which one of the two adjacent chemical bonds shown by dotted lines is a double bond):
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Ikemoto at pages 42-43 of 76; Id at pages 44-45 of 76. Ikemoto compound (4A) encompasses petasin:
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See specification at page 14 for structure of petasin. Ikemoto teaches one of ordinary skill that compounds (4A) to (6A) (and petasin) are MITF inhibitors, melanin production inhibitors and anticancer agents. Ikemoto at page 45 of 76, lines 29-31.
Ikemoto teaches that
In the present invention, by incorporating the above-mentioned alicyclic compound in a drug, the drug can be used as an MITF inhibitor, or as a melanin production inhibitor (or a melanin production inhibitor). It may also be used as a cosmetic composition containing a biosuppressant, or as an anti-cancer agent.
Ikemoto at pages 55, line 49 to page 56, line 1. Ikemoto teaches that melanin production inhibitor containing the above-mentioned alicyclic compound inhibits MITF,
which is a master transcription factor of the enzymes and proteins necessary for melanin pigment production, as shown in FIG. 2, and can therefore effectively inhibit melanin production from its roots. Ikemoto at page 56 of 76, lines 3-5.
In a working example, Ikemoto teaches extraction of Job’s tears with ethanol, followed by fractionation with using a synthetic adsorption resin, Diaion HP-20 to give four fractions, which Ikemoto summarizes as follows:
The fraction that passed through was designated "fraction 1" (30% methanol eluate).
The fraction that was then eluted with 300 ml of 75% (v/v) methanol water was designated "fraction 2".
The fraction that was further eluted with 300 ml of methanol was designated "fraction 3".
The fraction was eluted with 300 ml of ethyl acetate and designated as "fraction 4" (ethyl acetate eluate).
Ikemoto at page 57 of 76, lines 26-30.
Ikemoto summarizes the above four fractions in Table 1.
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Ikemoto at page 57 of 76, lines 34-45. With respect to fraction 3, Ikemoto teaches that:
Cell proliferation inhibitory effect (anticancer effect) of Job's tears extract (fraction 3) The proliferation of various cancer cell lines was measured using cells cultured with the addition of fraction 3. The results are shown in Figure 13. As shown in Figure 13, fraction 3 was confirmed to have a strong cell proliferation inhibitory effect on malignant melanoma B16 melanoma 4A5 and human lung cancer cell line A549. On the other hand, the same concentration range had almost no effect on the cell proliferation of mouse-derived mesenchymal stem cells C3H/10T1/2, human liver cancer cell line HepG2, human leukemia cell line U937, and mouse-derived adipose precursor cells 3T3-L 1. As described above, it was found that fraction 3 selectively exhibits anti-cancer effects against malignant melanoma and lung cancer.
Ikemoto at page 60 of 76, lines 10-20 (emphasis added). Ikemoto teaches that:
Since the HPLC analysis showed that TLC fractions 1, 3, and 7 contained two common substances, ii was determined that these two substances had various inhibitory effects. These two substances were named Ml-A and MI-B in descending order of amount.
Ikemoto at page 61 of 76, lines 2-4.
Ikemoto teaches that the structural identify of the two substances MI-A and MI-B were determined by spectral analysis to be the following compounds (4A) and (5A).
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Ikemoto at page 62 of 76, lines 10-30. In further experiments, Ikemoto teaches that as shown in Figures 24(A) and (8), both Ml-A and Ml-8 were confirmed to have an inhibitory effect on melanin production, with Ml-A being slightly more effective. Ikemoto at page 63 of 76, lines 10-12.
HEISHIMA, Kazuki et al., Anti-Cancer Activity of Petasites japonicus Extract. Proceedings of the 77th Annual Meeting of the Japanese Cancer Association (2018)
Heishima (a one page abstract) identifies four active ingredients in Petasfles japonicus extract (PJE); that is petasin, neopetasin, neo-S-Petasin, and S-petasin. Heishima teaches orally administered PJE in three cases of canine melanoma, where one case showed regression of metastatic lung lesion. Heishima states that the present results suggest that PJE has the potential to be a chemopreventive agent for a broad range of cancers.
E. Alvarez e al., B16 Murine Melanoma (Ch. 4), in Tumor Models in Cancer Research, 73-89 (B. Teicher ed., 2002) (“Alvarez”)
Alvarez teaches that syngeneic tumors in mice offer an important model for oncology research and although the use of murine models of neoplastic disease has been raised to the level of a fundamental paradigm in oncology research, it is to be considered with all the care and diligence afforded to us by any biological model. Alvarez at page 73. Alvarez teaches that:
The knowledge gained from these efforts has directly led to the use of the B16 model to ask more questions regarding the nature of metastasis, with the added benefit of time to provide newer tools to answer such questions. It is also important to keep in mind that the overall selection and the acceptance of the model in the scientific community has been influenced by the already existing scientific framework of the time. The B16 melanoma tumor line has most definitely made a profound impact in the field of oncology research. It has served as a model for basic biological research, and has helped in the identification of distinct pathways now available as potential therapeutic targets.
Alvarez at page 87 (emphasis added). Alvarez thus teaches one of ordinary skill that the B16 model is accepted by the scientific community as predictive of melanoma metastasis and in identifying potential therapeutic targets.
C. Danciu et al., 96 International Journal of Experimental Pathology, 73-80 (2015) (“Danciu”)
Danciu teaches the behavior of four different B16 murine melanoma cell sublines after inoculation into C57BL/6J mice; and, more specifically to analyze skin changes. Danciu at Abstract. Danciu teaches that both non-invasive and invasive analysis showed that B164A5 [as tested by Ikemoto] is the most aggressive melanoma cell line for C57BL/6J’s skin.
X. Lyu et al., 132 Chinese Medical Journal, 1071- 1078 (2019) (“Lyu”)
Lyu teaches a study aimed to investigate the anticolon cancer activity of petasin both in vitro and in vivo models. Lyu at Abstract.
Lyu teaches that human colon carcinoma cell lines (i.e., Caco-2, LoVo, SW-620, and HT-29 cell lines) were used to detect the inhibitory effect of petasin:
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on colon cancer proliferation using a MTT assay. Lyu at page 1072 (“Cell viability assay”). Lyu teaches that Western blotting assays were employed to evaluate the expression levels of proteins in the protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling pathway. Lyu at page 1073 (“Western blotting analysis”).
Lyu teaches that the result of this in vitro cell-line study is that petasin inhibited proliferation of human colon carcinoma cell lines, including SW-620, Caco-2, Lovo, andHT-29. Lyu at page 1073 (“Results”). Lyu teaches that treatment with petasin (1, 5, 25 mmol/L) exerted dose-dependent cytotoxicity on all four cell lines [Figure 1]. Lyu at page 1073 (“Results”). Lyu further teaches that the results indicate that treatment with 25 mmol/L petasin for 24 h significantly decreased the phosphorylation of Akt. Lyu at page 1074 (“Petasin inactivates Akt/mTOR signaling pathway in SW-620 cells”). Lyu teaches that this inhibition of the Akt/ mTOR pathway could activate an intrinsic apoptotic program. Id. Lyu teaches that Akt regulates the expression of matrix metalloproteinase (MMP) genes that promote p65- and p52-DNA-binding activities of NF-kB; MMPs are thus vital enzymes for extracellular matrix degradation during tumor invasion and metastasis. Id. Lyu teaches that these results suggested that the anticancer effects of petasin may be partly due to the inactivation of the Akt/mTOR signaling pathway. Id.
Lyu teaches that SW-620 cells were suspended in 200 mL growth medium/Matrigel and hypodermically injected into right axillaries of Balb/c athymic (nu+/nu+) male mice (4 weeks old). Lyu at page 1073 (“Tumorigenicity assay in nude mice”). Lyu reports that the study result was that mice treated with 10 mg/kg petasin exhibited significant reduction in tumor size compared to untreated mice at days 21 and 28. Lyu at page 1074 (“The in vivo anticolon cancer effect of petasin”).
Lyu concludes that the antitumor activity of petasin on human colon cancer cells both in vitro and in vivo suggests petasin as a possible candidate for human colon cancer therapy and this activity of petasin might be partially due to the inactivation of the Akt/mTOR pathway. Lyu at page 1077, col. 2.
T. Sinnberg et al., 129 Journal of Investigative Dermatology, 1500-1515 (2009)
Sinnberg teaches a study to determine whether targeting the PI3K-AKT-mTOR (AKT) or the RAF-MEK-ERK (MAPK) pathway, which are both constitutively activated in melanoma and appear to play a relevant role in tumor chemoresistance, would efficiently enhance melanoma chemosensitivity. Sinnberg at page 1511, col. 1.
As a result, Sinnberg found that inhibition of PI3K-AKT-mTOR signaling may downmodulate Mcl-1 and enhance melanoma chemosensitivity. Sinnberg at Abstract; Id. at page 1512, col. 2; Id. at page 1513, col. 1 (summary paragraph).
Claims 1, 2, 18, and 19 Are Obvious in view of the Cited Art
One of ordinary skill is motivated by Ikemoto to treat (and inhibit metastasis in) a human patient diagnosed with the malignant melanoma by administering petasin to the human patient:
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in view of Ikemoto’s teaching that fraction 3 (containing compounds (4A) and (5A), i.e., petasin and its isomer) selectively exhibits anti-cancer effects against malignant melanoma B16 melanoma 4A5 cells. One of ordinary skill is particularly motivated because Alvarez teaches one of ordinary skill that the B16 model is accepted by the scientific community as predictive of melanoma metastasis and in identifying potential therapeutic targets and Danciu teaches that both non-invasive and invasive analysis showed that B164A5 [as tested by Ikemoto] is the most aggressive melanoma cell line for C57BL/6J’s skin. One of ordinary skill is further motivated in view of Heishima teaching that orally administered Petasfles japonicus extract (PJE) (which comprises petasin, neopetasin, neo-S-Petasin, and S-petasin) in three cases of canine melanoma, where one case showed regression of metastatic lung lesion.
One of ordinary skill is further motivated to so administer petasin to a human patient with malignant melanoma in view of Lyu’s teaching that the antitumor activity of petasin on human colon cancer cells suggests the activity of petasin might be partially due to the inactivation of the Akt/mTOR pathway. Lyu at page 1077, col. 2. In this regard, Sinnberg found that inhibition of PI3K-AKT-mTOR signaling may downmodulate Mcl-1 and enhance melanoma chemosensitivity. Sinnberg at Abstract; Id. at page 1512, col. 2; Id. at page 1513, col. 1 (summary paragraph). In other words, the Akt/mTOR pathway mechanism of petasin in human colon carcinoma could be reasonably expected by one of ordinary skill to extend to the treatment of melanoma, based on the teachings of Sinnberg.
One of ordinary skill so administering petasin to a human patient thereby practices each and every limitation of claim 1, where the claim 1 preamble recitation of “inhibiting metastasis of tumor cells” is “the natural result flowing from the operation as taught [in the prior art] would result in”1 the claimed subject matter. See Bristol-Myers Squibb Co. v. Ben Venue Lab'ys, Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001) (“the claimed process here is not directed to a new use; it is the same use, and it consists of the same steps as described by Kris. Newly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.”).
The further limitations of claim 2 and 18 are clearly met by administration of petasin to a human patient as proposed above.
Claim 19 is obvious because one of ordinary skill is motivated to administer petasin to the human patient after a prior melanoma treatment in order to supplement or replace the prior melanoma treatment; for example, if the prior melanoma treatment was merely a holistic treatment (e.g., vitamins), failed, or was only partially successful.
Conclusion
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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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343–44 (Fed. Cir. 2005) (alteration in original; citation omitted).