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 18-27 of Y. Akao et al., US 17/759,897 (Feb. 15, 2021) are pending. Claims 20 drawn to non-elected Group (III) is withdrawn from consideration pursuant to 37 CFR 1.142(b). Claims 1, 2, 18, 19 and 21-27 are under examination on the merits.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 13, 2026 has been entered.
Election/Restrictions
Pursuant to the restriction requirement mailed on April 8, 2025, Applicant elected Group (I), without traverse, in the reply filed on June 6, 2025. In the previous Office action, then new claim 19 was added to the invention of Group (I) and then new claim 20 was added to the invention of Group (III). New claims 21-27 are hereby added to the invention of Group (I).
Note that new claim 25 is directed to the invention of Group (II) and new claims 23 and 24 are directed to the invention of Group (IV). See Restriction mailed on April 8, 2025. In view of Applicant’s claim renumbering and in the interest of efficient prosecution, the inventions of Groups (II) and (IV) are hereby rejoined with the invention of Group (I) and restriction among Groups (II) and (III) is withdrawn.
Taking into account the rejoinder and new claims added during prosecution, the Groups of inventions are now as follows:
Group (I) Claims 1, 2, 6, 18, and 20-27 drawn to a method for inhibiting metastasis of tumor cells in a subject, comprising administering a compound represented by Chemical Formula 1A or Chemical Formula 1B (or per claim 18 Chemical Formula 2A or Chemical Formula 2B) to the subject, wherein the tumor cells are cells of malignant melanoma
Group (II) Rejoined with Group (I);
Group (III) Claims 8-10, 19 and 20 drawn to a method for enhancing an action of a glycolysis inhibitor comprising administering the compound according to Group (I);
Group (IV) Rejoined with Group (I); and
Group (V) Claims 12-13 drawn to a pharmaceutical composition wherein the pharmaceutical composition is administered in combination with a glycolysis inhibitor.
Of these, claims 3-17 are cancelled by Applicant. Claim 20 drawn to the non-elected invention of Groups (III) is 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).
Claim Objections
Withdrawn claim 20 is objected to because it recites the wrong status identifier. Claim 20 was withdrawn in the previous Office action as being drawn to non-elected Group (III). MPEP § 714(II)(C).
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, 19 and 21-27 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 fraction 3 comprises petasin (MI-A also referred to as compound 4A) and its isomer (MI-B also referred to compound 5A) a follows:
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 (petasin) and MI-B (petasin isomer) 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. Heishima teaches one of ordinary skill that petasin and neopetasin can be used to treat metastasized tumor cells
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, 19 and 21-27 Are Obvious in view of the Cited Art
Claim 1 is obvious because 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 for the following reasons. The claim 19 term “removed” in the context of “administering . . . is carried out after the malignant melanomas are removed” is broadly and reasonably interpreted, consistently with the specification, as the case where the administration is to a human patient that underwent a prior treatment, for example, surgery to remove at least a portion of malignant cells. MPEP § 2111; see specification at page 2, lines 14-22. 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.
Claim 21 recites as follows:
21. The method according to claim 1, wherein the subject has no cancer lesion.
Regarding interpretation of claim 21, the specification teaches that:
Then, while an administration target having a cancer lesion, to be administered of the "anticancer agent" is a patient it is sufficiently assumed that targets of the "metastasis inhibitor" is administered not only to a patient having a cancer lesion but also to a patient not having a cancer lesion (at least apparently) after receiving a surgery, a radiotherapy, or the like.
Specification at page 18, lines 4-11 (emphasis added). Claim 21 is obvious because one of ordinary skill is motivated to administer petasin a human patient diagnosed with malignant melanoma, after a prior treatment to remove a lesion, for example surgery or radiotherapy, in order to supplement the prior treatment.
Claim 22 recites:
22. The method according to claim 1, wherein the compound is administered in an effective amount to inhibit the metastasis in the subject.
Regarding interpretation of the claim 22 term “effective amount to inhibit the metastasis”, the specification gives no guidance as to what this amount is. Rather the specification discusses a “therapeutically effective amount”. For example, the specification states:
The dosage of the above pharmaceutical composition is determined in consideration of therapeutically effective amount. . . . Suitable dosages are, for example, 1 to 500 mg/kg body weight per day as an effective component.
Specification at page 27, lines 24-32 (emphasis added).
The specification further teaches that:
In the present description, a "therapeutically effective amount" means, when used in the present description, an amount of the effective component or pharmaceutical composition that is effective to produce any desired inhibitory effect at a reasonable benefit/risk ratio applicable to any medical treatment.
Specification at page 28, lines 15-20 (emphasis added). Claim 22 is obvious because the term “effective amount to inhibit the metastasis” is interpreted, consistently with the specification as any amount that would kill at least one metathesizing cancer cell. MPEP § 2111. Claim 22 is obvious for the same reasons as claim 1 because it merely recites “the natural result flowing from the operation as taught [in the prior art] would result in”2 administration of petasin a human patient diagnosed with malignant melanoma. 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.”).
Claim 23 requires that “the compound is formulated as a human health food”. The specification does not limit the meaning of “human health food”. The specification teaches that:
The form of the food and drink composition for suppressing the metastasis of tumor cells is not particularly limited, and the food and drink composition may be added to a liquid, gel or solid food (for example, juice, soft drink, tea, soup, soy milk, salad oil, dressing, yogurt, jelly, pudding, Furikake, powdered milk for child care, cake mix, powdered or liquid dairy product, bread, cookies, and the like), or may be processed into pellets, tablets, granules, or the like together with excipients such as dextrin, lactose, or starch, a fragrance, a pigment, or the like as necessary. In addition, at least one of the compounds represented by Chemical Formula lA or Chemical Formula 1B described above can be coated with gelatin or the like and molded into a capsule to be used as a health food, a nutritional supplement, or the like.
Specification at page 37, lines 14-23 (emphasis added). The “human health food” composition of claim 23 encompasses standard pharmaceutical compositions. Claim 23 is obvious because one of ordinary skill is motivated to administer of petasin to a human patient diagnosed with malignant melanoma in a “health food” form, for example, as a pharmaceutical composition.
Claim 24 recites:
24. The method according to claim 1, wherein the compound is formulated as a pet food composition.
However, base claim 1 requires “administering . . . to the subject in need thereof . . . the subject is a human patient diagnosed with the malignant melanomas”. Though, generally, it is not seen why a human patient could not ingest a “pet food composition”. The specification defines “pet food composition” as “a food and drink composition intended for ingestion by pets”. Specification at page 38, [0078]. The specification does not describe any structural difference between a “pet food” and a “human health food” (where “human health food” was discussed above as encompassing standard pharmaceutical compositions). The only difference between the two is the subject intended in the mind of the claim practitioner, or what is printed on the composition. Further, there does not appear to be any functional relationship between labelling a composition as “pet food” and its intended use (per claim 1) of “administering . . . to the subject in need thereof . . . the subject is a human patient diagnosed with the malignant melanomas”. MPEP § 2111.05(I)(A) (To be given patentable weight, the printed matter and associated product must be in a functional relationship. Accordingly, under the instant facts, the claim 24 term “formulated as a pet food composition” cannot be given patentable weight. MPEP § 2111.05(I)(A). Claim 24 is therefore obvious for the same reasons as claim 23.
Claims 25 and 26 are obvious for the same reasons as claim 22; that is, these claims merely recites “the natural result flowing from the operation as taught [in the prior art] would result in” administration of petasin a human patient diagnosed with malignant melanoma. See Bristol-Myers Squibb Co. v. Ben Venue Lab'ys, Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001).
Claim 27 recites:
27. The method according to claim 1, wherein the compound is administered for preventing or delaying the metastasis in the subject.
Here the claim 27 term “for preventing or delaying the metastasis in the subject” does not limit claim 27 to any particular structure; rather it is directed solely to the intent of the claim practitioner. Claim scope is not limited by claim language that does not limit a claim to a particular structure. MPEP § 2111.04(I). As such, the claim 27 term “for preventing or delaying the metastasis in the subject” cannot be given weight as a claim limitation. Claim 27 is therefore obvious for the same reasons as claim 1.
Applicant’s Argument
Applicant argues that claim 1 patentable over the cited references at least because the claimed metastasis inhibition is an unexpected result that could not have been expected from Ikemoto's antiproliferative activity. Reply at page 6. Applicant argues that based on these teachings, a person of ordinary skill in the art would have expected, at most, that petasin-type compounds suppress the proliferation of melanoma cancer cells through MITF inhibition and the person of ordinary skill would not have expected that these compounds would also inhibit metastasis of tumor cells. Reply at page 7. Applicant argues one of ordinary skill would not have expected that the migration of tumor cells from a primary focus to a remote site because Ikemoto provides no teaching, suggestion, or data whatsoever regarding metastasis, cell migration, or any mechanism related to metastasis inhibition.
Here, Applicant proffers specification Example 13 in support of unexpected results. Reply at page 9; see specification at pages 58-59. Specification Example 13 recites the following procedure:
In this test example, neopetasin (NP) was previously reacted with B16F10 cells that are derived from the mouse melanoma at a concentration of 3 μM in vitro. Thereafter, the uniform numbers of living cells were injected into the tail vein of the mice, and thereafter, no treatment was performed, and the number of metastasis lesions formed in the lung after a two-week non-treatment period was counted.
Specification at page 58, lines 8-15. Applicant summarizes Example 13 as follows:
The experimental protocol of Test Example 13 was as follows:
(1) B16F10 melanoma cells (a highly metastatic malignant melanoma cell line) were pre-treated with [neo]3petasin (3 μM) in vitro.
(2) After pre-treatment, the number of living cells was uniformly aligned between the petasin group and the control (DMSO) group, and the cells were injected into the tail vein of mice.
(3) Crucially, no further treatment was administered during the subsequent two-week period.
(4) After the two-week non-treatment period, the number of metastasis lesions formed in the lung was counted.
Reply at page 9 (emphasis added) (apparently citing specification at page 10, lines 22-29).
Applicant summarizes the Example 13 results as follows:
In the control (DMSO) group, many metastatic lesions were formed in the lungs, as expected for a highly metastatic cell line.
In the neopetasin-treated group, no metastatic lesions [in the lung]4 were observed even after the two-week non-treatment period (para. 0132; Fig. 20).
Reply at page 11 (citing specification at page 58, lines 18-24).
Applicant argues that the design of this experiment is critical to understanding the unexpected nature of the results. Because the number of living cells was uniformly aligned between the two groups before injection, any difference in metastasis cannot be attributed to the [neo]petasin group simply having fewer viable cells. Moreover, because no further treatment was administered during the two-week period, any difference in metastasis cannot be attributed to ongoing antiproliferative suppression of tumor cell growth at the metastatic site. Reply at page 10.
Examiner Response
A greater than expected result and evidence of unobvious or unexpected advantageous properties are evidentiary factors pertinent to the legal conclusion of obviousness of the claims at issue. MPEP § 716.02(a)(I)/(II). However, the burden is on Appellant to establish that the evidence relied upon demonstrates that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. MPEP § 716.02(b). Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. MPEP § 716.02(b)(III).
Here, Applicant’s proffer of Example 13 is not probative of unexpected results because Applicant has made no comparison with the prior art. MPEP § 716.02(e) (an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness.). Rather proffered Example 13 demonstrates that living neopetasin-treated B16F10 melanoma cells are less able to proliferate from mouse tail to mouse lung than the same number of untreated B16F10 melanoma cells. Here, Applicant is proffering that neopetasin’s ability to inhibit proliferation is not taught in the prior art and thus was previously unappreciated. However, this is not the type of proffer effective to overcome a § 103 rejection because it involves no comparison with the prior art. MPEP § 716.02(e). Rather, the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. MPEP 2112(I).
The Examiner notes that, as explained by Applicant, in proffered Example 13 only living B16F10 melanoma cells were uniformly injected in the mouse tail. Thus, Example 13 demonstrates that living neopetasin-treated B16F10 melanoma cells are less able to proliferate to the mouse lung than the same number of living but untreated B16F10 melanoma cells. Reply at page 10. But, absent further explanation, Applicant’s conclusion that this is unexpected is not convincing. One of ordinary skill may well expect, based on the cited art, that living neopetasin-treated B16F10 melanoma cells, being in a weaker state, may be less able to proliferate. For example, Ikemoto teaches that fraction 3, comprising petasin (referred to as either MI-A or 4A) and its isomer (referred to as either MI-B or 5A), selectively exhibits anti-cancer effects against malignant melanoma and lung cancer. Ikemoto at page 60 of 76, lines 10-20. In sum, Applicant has not explained why non-proliferation of living neopetasin-treated B16F10 cells versus proliferation of the same number of living untreated B16F10 cells is unexpected and has therefore not met its burden. MPEP § 716.02(b
The proffered results are further not persuasive because the proffered results with neopetasin are clearly not commensurate with claim 1 genus where R3 is “an optionally substituted hydrocarbon group”. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. MPEP § 716.02(d)
Applicant’s further argument respecting amended claim 19 and new claims 21-27 are addressed above in the § 103 rejection.
Conclusion
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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).
2 SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343–44 (Fed. Cir. 2005) (alteration in original; citation omitted).
3 Example 13 was performed with neopetasin not petasin. See specification at page 10, lines 22-29; Id. at page 58.
4 The specification teaches that “the number of metastasis lesions formed in the lung after a two-week non-treatment period was counted”. Specification at page 58, lines14-15.
