DETAILED ACTION
Applicant’s amendment submitted on 6/30/2025 is acknowledged. Claims 1 and 2 are currently amended. Claims 6-9 are canceled. Claims 10-12 are newly added. Claims 1-5 and 10-12 are currently pending in the instant application.
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 .
Priority
The instant application is a U.S. National Phase of PCT/KR2021/002039, 2/17/2021. The instant application claims foreign priority to KR10-2020-0020567 filed 2/19/2020 and a receipt of a certified copy of that document is acknowledged. An English translation of the foreign priority document has been provided on 6/30/2025 to perfect priority, therefore the effective filing date of the instant claims is considered to be the filing date of the Korean application, 2/19/2020. See 37 CFR 1.55.
Response to Amendment
Applicant’s amendment to the specification to recite “epithelial-mesenchymal transition (EMT)” overcomes the objection previously set forth in the Non-Final Rejection mailed on 4/28/2025.
The 35 U.S.C. § 101 rejections over claims 1-9 are moot in light of applicant’s amendment to the claims. Accordingly, the rejections are withdrawn.
The 35 U.S.C. § 102(a)(1) rejection of claim 6 over Cell Signaling Technology is moot in light of Applicant’s cancelation of claim 6. Accordingly, the rejection is withdrawn.
The 35 U.S.C. § 102(a)(1) rejection of claim 6 over KR102028967 is moot in light of Applicant’s cancelation of claim 6. Accordingly, the rejection is withdrawn.
The 35 U.S.C. § 102(a)(1) rejection of claims 8-9 over Cho1 is moot in light of Applicant’s cancelation of claims 8-9. Accordingly, the rejection as applied to claims 8-9 is withdrawn.
The 35 U.S.C. § 102(a)(1) rejection of claims 8-9 over Cho2 is moot in light of Applicant’s cancelation of claims 8-9. Accordingly, the rejection as applied to claims 8-9 is withdrawn.
The 35 U.S.C. § 102(a)(1) rejection of claims 8-9 over Gong is moot in light of Applicant’s cancelation of claims 8-9. Accordingly, the rejection as applied to claims 8-9 is withdrawn.
The 35 U.S.C. § 103 rejection of claim 7 over Cell Signaling Technology in view of Gong is moot in light of Applicant’s cancelation of claim 7. Accordingly, the rejection is withdrawn.
The 35 U.S.C. § 103 rejection of claim 7 over KR102028967 is moot in light of Applicant’s cancelation of claim 7. Accordingly, the rejection is withdrawn.
The 35 U.S.C. § 103 rejection of claims 8-9 over KR102028967 in view of Gong is moot in light of Applicant’s cancelation of claims 8-9. Accordingly the rejection as applied to claims 8-9 is withdrawn.
Claim Objections
Claim 10 is objected to because of the following informalities:
Claim 10 recites “STAT3” in line 4 which is not consistent with the previous recitations of “STAT-3” in claims 4 and 5. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – Indefinite
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.
New Rejection Necessitated by Amendment: Claim 12 is 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.
The term “high” in claim 12 is a relative term which renders the claim indefinite. The term “high” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification discloses that if the expression level of RIP1 in the patient’s sample is equal to or higher than that of the normal sample, lung cancer metastasis can be predicted (see p.5, lines 18-19). Claim 2 recites “determining that the metastatic potential of radiotherapy-treated lung cancer is high when the expression level of step (a) is equal to or greater than the expression level of step (b).” However, these limitations are not recited in claim 12 to objectively define the subject term “high” that is recited in claim 12. Thus, the metes and bounds of claim 12 cannot be determined, and claim 12 is indefinite.
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.
New Rejection Necessitated by Amendment: Claims 1-4 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (Cancer Res., RIP1 and its signaling network regulate radiation-induced modification of cancer microenvironment, 2019; of record in IDS filed 8/18/2022; hereinafter Cho1).
Regarding claim 10-12, Cho1 teaches radiotherapy therapeutics is frequently associated with occurrence of resistance such as metastasis and might promote cancer progression and metastasis (see Abstract). Cho1 teaches ionizing radiation (IR) treatment increases migration and invasion of non-small-cell lung cancer (NSCLC) via induction of epithelial-mesenchymal transition (EMT) in A549 cells (see Abstract). Cho1 teaches measuring RIP1 expression in NSCLC A549 cells treated with ionizing radiation (IR) and reported an increased expression level of RIP1 in the A549 cells treated with IR in comparison to a control (see Abstract and Figs. 1-3). Cho1 further teaches the increase in expression of RIP1 in IR-treated A549 cells is associated with IR-induced EMT induction in vitro (see Abstract). Cho1 describes that EMT induction is dependent on RIP1 activating the EGFR-Src-STAT3 pathway (see Abstract). Cho1 further teaches a signaling analysis revealed activation of the EGFR-Src-STAT3 pathway and found NF-κB activated via increase of RIP1 as well as the overexpression of IL-1β (see Abstract and Figs. 2-6 and Summary). Cho1 further teaches down-regulation of RIP1 expression by treatment with siRNA, pharmaceutical inhibitor necrostatin (denoted nec in Fig. 3) for RIP1 kinase inihibtion, or dominant negative mutant of the kinase suppressed not only the activation of EGFR-RIP1-Src-STAT3 pathway, but also the EMT induction, reading on administering to a radiotherapy-treated lung cancer a RIP1 inhibitor therapeutic agent and wherein the RIP1 inhibitor is necrostatin or siRNA against RIP1 as recited in claim 11 (see Abstract and Figs. 3-5). siRNA was demonstrated to reduce expression of RIP1, vimentin, MMP2, MMP9, p-EGFR, EGFR, p-IKB, p-P65, p105, and IL-1B in A549 cells treated by IR, reading on reducing expression levels of RIP1, vimentin, MMP2, MMP9, p-EGFR, EGFR, p-IKB, p-P65, p105, and IL-1B as claimed (see Figs. 4 and 6). Necrostatin was demonstrated to reduce expression of RIP1, vimentin, MMP2, MMP9, p-EGFR, B-actin, p-Src, p-IKB, p-P65, p105, and IL-1B in A549 cells treated by IR, reading on reducing expression levels of RIP1, vimentin, MMP2, MMP9, p-EGFR, B-actin, p-Src, p-IKB, p-P65, p105, and IL-1B as claimed (see Figs. 3 and 6). Cho1 also teaches inhibition of EGFR, Src, STAT3, and NF-KB through inhibitors applied to NSCLC A549 cells treated by IR, reading on administering to a radiotherapy-treated lung cancer an EGFR inhibitor, a Src inhibitor, a STAT3 inhibitor, and an NF-KB inhibitor therapeutic agent (see Abstract and Figs. 2, 5 and 6). EGFR inhibitor was demonstrated to reduce expression of RIP1, vimentin, MMP2, MMP9, p-EGFR, and p-Src in A549 cells treated by IR, reading on reducing expression levels of RIP1, vimentin, MMP2, MMP9, p-EGFR, and p-Src (see Fig. 2). Src inhibitor was demonstrated to reduce expression levels of RIP1, vimentin, MMP2, MMP9, and p-Src in A549 cells treated by IR, reading on reducing expression levels of RIP1, vimentin, MMP2, MMP9, and p-Src as claimed (see Fig. 2). STAT3 inhibitor was demonstrated to reduce expression levels of RIP1, vimentin, MMP2, MMP9, and B-actin in A549 cells treated by IR, reading on reducing expression levels of RIP1, vimentin, MMP2, MMP9, and B-actin as claimed (see Fig. 2). NK-FB inhibitor was demonstrated to reduce expression levels of RIP1, vimentin, MMP2, MMP9, p-IKB, p-P65, p105, and IL-1B in A549 cells treated by IR, reading on reducing expression levels of RIP1, vimentin, MMP2, MMP9, p-IKB, p-P65, p105, and IL-1B as claimed (see Figs. 5-6). Cho1 further teaches RIP1 signals through EGFR-RIP1-Src-STAT3 axis and also through RIP1-NF-KB-IL-1B pathway, suggesting the two pathways are connected by RIP1 (see Abstract). Cho1 concludes RIP1 has a role as a novel biomarker as well as a molecular target for suppressing lung cancer metastasis (see Abstract). While Cho1 does not teach their method in a radiotherapy-treated lung cancer patient, it would have been obvious to administer one or more of a RIP1 inhibitor, EGFR inhibitor, Src inhibitor, STAT3 inhibitor, and an NF-KB inhibitor to a radiotherapy-treated lung cancer patient in order to inhibit metastasis, since Cho1 teaches each of these inhibitors decreases expression levels of RIP1 and RIP1 is a molecular target for suppressing lung cancer and because RIP1 bridges the EGFR-RIP1-Src-STAT3 and RIP1-NF-KB-IL-1B pathways implicated in EMT induction and lung cancer metastasis, yielding predictable results. Regarding claim 12, the radiotherapy-treated lung cancer is considered to read on a high metastatic potential since Cho1 teaches IR treatment increases RIP1 expression and RIP1 expression influences EMT induction and invasion and migration of cancer cells (i.e. metastasis).
Regarding claim 1, Cho1 teaches measuring the expression level of RIP1 kinase before administration of the therapeutic agent, labeled as IR (10 Gy) or IR in the figures, and measuring an expression level of RIP1 in a control sample which reads on a normal control sample (see Figs. 2-6). Cho1 discloses plots of these measured expression values, which is an act of comparison, reading on steps (a)-(c) of claim 1.
Regarding claim 2, Cho1 demonstrates the expression level of RIP1 is greater in IR treated samples than the RIP1 expression in normal control samples, reading on a high metastatic potential as claimed (see Abstract and Figs. 2-6).
Regarding claim 3, Cho1 performs western blots which are a measure of an expression level of RIP1 protein amount (see Figs. 2-6).
Regarding claim 4, Cho1 teaches measuring the expression levels of EGFR, NF-KB, STAT-3, Src, and IL-1B in samples of IR treated lung cancer before administration of the therapeutic agent and in samples of normal controls and discloses plots of these measured expression values, which is an act of comparison, reading on claim 4 (see Figs. 2-6).
Thus, claims 1-4 and 10-12 are prima facie obvious over Cho1.
New Rejection Necessitated by Amendment: Claims 1-4 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (Preprints, 2020 Jan. 22, Vol. 1, p.1-29; hereinafter Cho2; of record).
Regarding claim 10, Cho2 teaches RIP1 expression is increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to ionizing radiation (IR) as compared to a control (see Abstract, paragraph bridging p.4-5, p.7, last paragraph, p.10, 1st paragraph, Fig. 1E, 2A, 3, and Fig. 7). Cho2 further teaches that IR activates EGFR and NF-κB and subsequently triggers the RIP1-Src/STAT3-EMT pathway, ultimately promoting metastasis (see Abstract, p.3, last paragraph, p.4, last paragraph-p.6, 1st passage, and paragraph bridging p.8-9). Cho2 further teaches measuring the expression of NF-κB, EGFR, Src, and STAT3 in IR exposed A549 cells and control cells (see Abstract, p.4, 1st paragraph, paragraph bridging p.5-6, p.7, last paragraph, p.10, 1st paragraph, Figs. 3-5). Cho2 further teaches treating IR-exposed A549 cells with the RIP1 inhibitor, necrostatin, suppresses IR-induced invasion/migration, on administering to a radiotherapy-treated lung cancer a RIP1 inhibitor therapeutic agent and wherein the RIP1 inhibitor is necrostatin as recited in claim 11 (see p.6, 1st paragraph and Figs. 4A-4B). Treatment with necrostatin reduced expression of RIP1, vimentin, MMP2, MMP9, p-EGFR, and p-Src (see Fig. 4D-E). Cho2 also teaches treating IR exposed A549 cells with siRNA targeting RIP1 suppressed EMT induction and proposes RIP1 expression as well as kinase activity is critically involved in IR-induced invasion/migration, i.e. metastasis, reading on administering to a radiotherapy-treated lung cancer a RIP1 inhibitor therapeutic agent and wherein the RIP1 inhibitor is siRNA against RIP1 as recited in claim 11 (see paragraph bridging p.6-7 and Fig. 5). Treatment with siRNA targeting RIP1 reduced expression of RIP1, vimentin, MMP2, MMP9, p-EGFR, EGFR, and p-Src (see Fig. 5C-D). Cho2 further teaches EGFR inhibitors lead to a decrease in IR-induced RIP1 in A549 cells treated by IR (see paragraph bridging p.5-6 and Fig. 3). Treatment with EGFR inhibitor reduced expression of RIP1, vimentin, MMP2, MMP9, p-EGFR, and p-Src (see Fig. 3B). Cho2 further teaches Src and STAT3 inhibitors suppressed IR-induced phosphorylation of Src and STAT3 and expression of MMP-2, MMP-9, and vimentin (see paragraph bridging p.5-6 and Fig. 3). Treatment with Src inhibitor reduced expression of RIP1, vimentin, MMP2, MMP9, and p-Src (see Fig. 3C). Treatment with STAT3 inhibitor reduced expression of RIP1, vimentin, MMP2, and MMP9 (see Fig. 3D). Cho2 also teaches NF-KB inhibitor treatment in IR-treated A549 cells suppresses IR-induced invasion/migration and decreases IR-induced RIP1 protein expression (see paragraph bridging p.7-8 and Fig. 6). Treatment with NF-KB inhibitor reduced expression of RIP1, vimentin, MMP2, MMP9, p-IKB, p-P65, and p105 (see Fig. 6D). While Cho2 does not teach their method in a radiotherapy-treated lung cancer patient, it would have been obvious to administer one or more of a RIP1 inhibitor, EGFR inhibitor, Src inhibitor, STAT3 inhibitor, and an NF-KB inhibitor to a radiotherapy-treated lung cancer patient in order to inhibit metastasis, since Cho2 teaches each of these inhibitors decreases expression levels of RIP1 and increased RIP1 expression is known to influence metastasis in IR-treated lung cancer, yielding predictable results.
Regarding claim 1, Cho2 teaches measuring the expression level of RIP1 kinase before administration of the therapeutic agent, labeled as IR (10 Gy) or IR in the figures, and measuring an expression level of RIP1 in a control sample which reads on a normal control sample (see Figs. 3-6). Cho2 discloses plots of these measured expression values, which is an act of comparison, reading on steps (a)-(c) of claim 1.
Regarding claim 2, Cho2 demonstrates the expression level of RIP1 is greater in IR treated samples than the RIP1 expression in normal control samples, reading on a high metastatic potential as claimed (see Figs. 3-6).
Regarding claim 3, Cho2 performs western blots which are a measure of an expression level of RIP1 protein amount (see Figs. 3-6).
Regarding claim 4, Cho2 teaches measuring the expression levels of EGFR, NF-KB, STAT-3, Src, and IL-1B in samples of IR treated lung cancer before administration of the therapeutic agent and in samples of normal controls and discloses plots of these measured expression values, which is an act of comparison, reading on claim 4 (see Figs. 3-6).
Thus, claims 1-4 and 10-12 are prima facie obvious over Cho2.
New Rejection Necessitated by Amendment: Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (Preprints, 2020 Jan. 22, Vol. 1, p.1-29; hereinafter Cho2; of record), as applied to claims 1-4 and 10-12 above, and further in view of Setrerrahmane et al. (Molec. Cancer, 2017, Vol. 16, p.1-17; of record).
Cho2 teaches the invention of claims 4 and 10 as outlined in the rejection above.
Regarding claim 5, Cho2 teaches that ionizing radiation (IR) activates EGFR and NF-κB and subsequently triggers the RIP1-Src/STAT3-EMT pathway, ultimately promoting metastasis (see Abstract, p.3, last paragraph, p.4, last paragraph-p.6, 1st passage, and paragraph bridging p.8-9). Cho2 further teaches measuring the expression of NF-κB, EGFR, Src, and STAT3 in IR exposed A549 cells and control cells (see Abstract, p.4, 1st paragraph, paragraph bridging p.5-6, p.7, last paragraph, p.10, 1st paragraph, Figs. 3-5).
Cho2 does not teach measuring IL-1RI and IL-1RII.
Setrerrahmane teaches that IL-1 receptors are expressed on cancer cells and that IL-1 has affinity to the receptors IL-1R1 and IL-1R2 (see p.5, right column, last paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have further tested for the expression of IL-1R1 and IL-1R2, as taught by Setrerrahmane, in the signaling and pathway analysis performed on the A549 non-small-cell lung cancer cells of Cho2, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to detect receptors known to be expressed on cancer cells, yielding predictable results.
Thus, claim 5 is prima facie obvious over Cho2 in view of Setrerrahmane.
New Rejection Necessitated by Amendment: Claims 1-4 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Gong et al. (Molecul. Cancer, 2019, Vol. 18(100), p.1-17; of record).
Regarding claims 10-12, Gong teaches that necroptosis – a regulated necrotic cell death modality – is mainly mediated by RIP1, RIP3, and mixed lineage kinase domain-like (MLKL), and that necroptosis is reported to promote cancer metastasis (see Abstract and p.2, left column, 1st passage and 2nd paragraph). Gong further teaches that radiotherapy is known to induce necroptosis in cancer therapy (see p.11, left column, 1st passage-3rd paragraph and Table 3). Gong further teaches that RIPK1 expression is markedly elevated in both human lung cancer samples and mouse lung tumor models (see p.6, right column, 1st paragraph). Thus, Gong implicitly teaches measuring RIP1 protein expression in lung cancer patients treated by radiotherapy to check for a cancer necroptosis and potential for metastasis since an elevated level of RIP1 is known to be indicative of necroptosis and lung cancer. Gong further teaches RIP1 ultimately induces the canonical NF-κB pathway, and thus teaches further measuring an expression of NF- κB, as recited in claim 4 (see p.2, right column, 1st passage and Table 1). Gong teaches necrostatin-1 is a well-defined necroptosis inhibitor that exclusively inhibits RIP1 activity, reading on administering RIP1 inhibitor as recited in claim 10 and necrostatin in claim 11 (see p.2, left column, 1st passage). Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have inhibited metastasis of radiotherapy-treated lung cancer by administering the RIP1 inhibitor necrostatin to inhibit RIP1 in a radiotherapy-treated lung cancer patient because Gong teaches necroptosis is mediated by RIP1 and promotes cancer metastasis, radiotherapy induces necroptosis, and RIP1 is markedly elevated in human lung cancer samples, yielding predictable results.
Regarding claims 1 and 3-4, it would have been prima facie obvious to one of ordinary skill in the art to measure the expression levels of RIP1 and NF-KB in a sample from the radiotherapy-treated lung cancer patient prior to administering necrostatin, to measure RIP1 and NF-KB expression levels in a normal control sample, and to compare the expression levels in order to provide an expression profile of RIP1 and NF-KB useful for tracking the progression of the lung cancer disease and metastatic potential. One of ordinary skill in the art would have been motivated to because Gong teaches that RIP1 expression is markedly elevated in both human lung cancer samples and that RIP1 ultimately induces the canonical NF-κB pathway, yielding predictable results.
Regarding claim 2, Gong teaching necroptosis is mainly mediated by RIP1 and necroptosis promotes metastasis (see Abstract and p.2, left column, 1st passage and 2nd paragraph), that radiotherapy is known to induce necroptosis in cancer therapy (see p.11, left column, 1st passage-3rd paragraph and Table 3), and that RIP1 expression is markedly elevated in both human lung cancer samples is interpreted to read on a high metastatic potential as recited in claim 2 (see p.6, right column, 1st paragraph).
Thus, claims 1-4 and 10-12 are prima facie obvious over Gong.
New Rejection Necessitated by Amendment: Claims 1-4 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over KR102028967 to Park et al. (Of record in IDS filed 8/18/2022; citations corresponding to English translation) in view of Gong et al. (Molecul. Cancer, 2019, Vol. 18(100), p.1-17; of record).
Regarding claims 1-4 and 10-12, Park teaches a method for diagnosing lung cancer metastasis by measuring the RIP1 expression level from a lung cancer patient sample, measuring the RIP1 expression level from a normal control sample, and comparing the expression level from each measurement (see p.5, 8th passage). Park teaches when the expression level of the normal control sample is equal to greater than the expression level of lung cancer patient sample, then it may be determined that lung cancer metastasis ability is high, reading on claims 2 and 12 (see p.5, 9th passage). Park teaches RIP1 expression is measured from the amount of protein or mRNA, reading on claim 11 (see p.6, 3rd passage). Park further teaches determining the expression of RIP1, NF-κB, EGFR, STAT3, Src, and IL-1β in lung cancer cells and comparing to a control, reading on claims 1 and 4 (see p.3, 2nd and 5th passages, p.9, 9th and last passage, p.10, 2nd passage, p.11-13, and Figs. 5-9). Park further teaches treatment of elevated RIP1 with the RIP1 inhibitor necrostatin (see p.8, 10th-last passages, p.10, 5th and 9th passages, p.11, 10th-11th passages, and Figs. 4-7). Park also teaches administering STAT3, Src, EGFR, and NF-KB inhibitors to A549 and H460 lung cancer cells lines overexpressing RIP1 (see p.7, 8th passage-p.14, 4th passage). Park demonstrates that necrostatin decreases expression levels of RIP1, vimentin, MMP2, MMP9, p-Src and p-EGFR (see Figs. 3C, 6B and 7F). Park demonstrates that STAT3 inhibitor decreases expression levels of RIP1, vimentin, MMP2, MMP9, and p-Src (see Fig. 6E). Park demonstrates that Src inhibitor decreases expression levels of RIP1, vimentin, MMP2, MMP9, and p-Src (see Fig. 6F). Park demonstrates that EGFR inhibitor decreases expression levels RIP1, vimentin, p-EGFR, MMP2, MMP9, and p-Src (see Figs. 7C-E). Park demonstrates that NF-KB inhibitor decreases expression levels of vimentin, MMP2, and MMP9 (see Fig. 9D). Park teaches STAT3 inhibitor reduces cell infiltration and migration (see passage bridging p.10-11). Park teaches EGFR inhibitor reduces cell infiltration and migration (see p.11, 10th passage). Park teaches NF-KB inhibitor reduces cell invasion and migration (see p.14, 2nd passage). Park further teaches RIP1 induces epithelial-mesenchymal transition (EMT) and that EMT induction is implicated in increased cancer cell migration and invasion (see p.3, passage 5, and p.11, 3rd passage). Therefore, it would have been obvious to one of ordinary skill in the art to administer one or more of necrostatin, EGFR inhibitor, Src inhibitor, STAT3 inhibitor, and NF-KB inhibitor to a lung cancer patient in order to inhibit cell invasion and migration, otherwise, metastasis of the cancer.
Park does not teach the lung cancer sample is from a patient who has undergone radiotherapy.
Gong teaches that necroptosis – a regulated necrotic cell death modality – is mainly mediated by RIP1, RIP3, and mixed lineage kinase domain-like (MLKL), and that necroptosis is reported to promote cancer metastasis (see Abstract and p.2, left column, 1st passage and 2nd paragraph). Gong further teaches that radiotherapy is known to induce necroptosis in cancer therapy (see p.11, left column, 1st passage-3rd paragraph and Table 3). Gong further teaches that RIPK1 expression is markedly elevated in both human lung cancer samples and mouse lung tumor models (see p.6, right column, 1st paragraph). Gong further teaches RIP1 ultimately induces the canonical NF-κB pathway (see p.2, right column, 1st passage and Table 1). Gong teaches necrostatin-1 is a well-defined necroptosis inhibitor that exclusively inhibits RIP1 activity, reading on a metastasis inhibitor (see p.2, left column, 1st passage).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have performed the method of Park on a lung cancer patient who has undergone radiotherapy, as taught by Gong, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to inhibit metastasis of radiotherapy-treated lung cancer using the method described by Park to inhibit RIP1 in lung cancer because Gong teaches radiotherapy is known to induce necroptosis that promotes metastasis and RIP1 is markedly elevated in lung cancer. One of ordinary skill in the art would have had a reasonable expectation of success because Gong teaches necroptosis is mediated by RIP1 and both Park and Gong teach RIP1 is elevated in lung cancer.
Thus, claims 1-4 and 10-12 are prima facie obvious over Park in view Gong.
New Rejection Necessitated by Amendment: Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over KR102028967 to Park et al. (Of record in IDS filed 8/18/2022; citations corresponding to English translation) in view of Gong et al. (Molecul. Cancer, 2019, Vol. 18(100), p.1-17; of record), as applied to claims 1-4 and 10-12 above, and further in view of Setrerrahmane et al. (Molec. Cancer, 2017, Vol. 16, p.1-17; of record).
Park in view of Gong teach the invention of claims 4 and 10 as outlined in the rejection above.
Regarding claim 5, Park and Gong render obvious a method of administering at least one or more of necrostatin, EGFR inhibitor, Src inhibitor, STAT3 inhibitor, and NF-KB inhibitor to a lung cancer patient treated by radiotherapy to inhibit metastasis for the reasons set forth above in the rejection of claims 1-4 and 10-12. Park teaches determining the expression of RIP1, NF-κB, EGFR, STAT3, Src, and IL-1β in lung cancer cells and comparing to a control, reading on claims 1 and 4, as it is induced by RIP1 (see p.3, 2nd and 5th passages, p.9, 9th and last passage, p.10, 2nd passage, p.11-13, and Figs. 5-9).
Park does not teach measuring IL-1RI and IL-1RII.
Setrerrahmane teaches that IL-1 receptors are expressed on cancer cells and that IL-1 has affinity to the receptors IL-1R1 and IL-1R2 (see p.5, right column, last paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have further tested for the expression of IL-1R1 and IL-1R2, as taught by Setrerrahmane, in the method rendered obvious by Park and Gong to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to detect receptors known to be expressed on cancer cells, yielding predictable results.
Thus, claim 5 is prima facie obvious over Park in view of Gong and Setrerrahmane.
Response to Arguments
Applicant's arguments filed 6/30/2025 have been fully considered but they are not persuasive.
In Applicant’s Remarks, see p.7, 4th-last paragraphs, Applicant argues that since Cho1 and Cho2 are each published within 1 year of the effective filing date of the claimed invention and the inventors of the present application are listed as authors in both Cho1 and Cho2, neither Cho1 nor Cho2 are available as prior art according to 35 U.S.C. § 102(b)(1)(A). This is not found persuasive. Cho1 lists the authors Ju Yeon Kim, EunAh Lee, Young Do Yoo, and Yu-Jin Jung which are not listed as inventors in the instant application. Cho2 lists the authors A-Ram Kang, Na-Gyeong Lee, and Dae-Hae Lee which are not listed as inventors in the instant application. Applicant must submit a declaration under 37 CFR 1.130(a) in order to show that the potential prior art disclosure was the work of the inventors to invoke exceptions under 35 U.S.C. § 102(b)(1)(A). In the absence of the declarations, Cho1 and Cho2 remain applicable as prior art for having authors listed that are not listed as inventors in the instant application.
In Applicant’s Remarks, see paragraph bridging p.8-9, Applicant argues there is no teaching in Gong that the necroptosis caused by radiotherapy is also the type of necroptosis that would result in metastasis. Applicant further submits even if RIP1 mediates necroptosis and is elevated in lung cancer, there is no teaching in Gong that RIP1 expression levels are indicative of metastasis, especially radiotherapy-induced metastasis. Applicant further argues even if necrostatin-1 is a well-defined necroptosis inhibitor, Gong does not implicitly teach that necrostatin-1 can also inhibit metastasis, and thus does not disclose inhibition of RT-induced metastasis. This is not found persuasive. Gong teaches that necroptosis – a regulated necrotic cell death modality – is mainly mediated by RIP1, RIP3, and mixed lineage kinase domain-like (MLKL), and that necroptosis is reported to promote cancer metastasis (see Abstract and p.2, left column, 1st passage and 2nd paragraph). Gong further teaches that radiotherapy is known to induce necroptosis in cancer therapy (see p.11, left column, 1st passage-3rd paragraph and Table 3). Gong further teaches that RIPK1 expression is markedly elevated in both human lung cancer samples and mouse lung tumor models (see p.6, right column, 1st paragraph). Thus, it would logically follow from the teachings of Gong that lung cancer patients treated by radiotherapy would have an elevated risk of metastasis since Gong teaches that radiotherapy induces necroptosis in which necroptosis is RIP1-mediated and promotes metastasis and RIP1 is already found to be markedly elevated in lung cancer patients, yielding predictable results. Therefore, one of ordinary skill in the art would find it obvious that RIP1 inhibitor necrostatin-1 would be useful in inhibiting metastasis by inhibiting RIP1-mediated necroptosis. Applicant has not provided any evidence that the necroptosis described in Gong is not the type of necroptosis that results in metastasis, and there is good reason to believe that it is the kind that results in metastasis based on Gong’s disclosure. Therefore, Gong remains applicable to the claimed invention.
In Applicant’s Remarks, see p.9, 1st paragraph, Applicant argues that p.9, left column, last paragraph, of Gong clearly suggests that one of skill in the art would have no way of knowing from Gong whether inhibiting necroptosis would have a metastatic or anti-metastatic effect. This is not found persuasive. As discussed above, Gong does teach a relationship found in RIP-1-mediated necroptosis that promotes metastasis, that radiotherapy also induces necroptosis, and that RIP1 is markedly elevated in lung cancer. One of ordinary skill in the art would find it obvious to explore RIP1-mediated necroptosis and metastasis in lung cancer given Gong teaches RIP1 is markedly elevated in lung cancer, regardless of whether the net effects of necroptosis and cancer metastasis are defined and whether necroptosis facilitates or suppresses tumor growth and metastasis not be conclusively determined. This admission in Gong does not prevent one of ordinary skill in the art from further exploration of RIP1-mediated necroptosis and metastasis in lung cancer, and the person of ordinary skill in the art would have reason to believe the necroptosis of lung cancer is also involved in metastasis based on Gong’s teachings.
In Applicant’s Remarks, see p. 9, 2nd paragraph, Applicant argues that the study Gong references to teach that radiotherapy is known to induce necroptosis does not elucidate how necroptosis promotes metastasis since the study is silent with respect to metastasis. This is not found persuasive. The rejection relies upon Gong as a whole to teach the link between RIP1-mediated necroptosis and metastasis, as discussed in the previous replies. Applicant argues from a point of silence and claims necroptosis is highly unpredictable with regards to its role in metastasis, but does not provide any evidence of these claims. MPEP § 2145(I) sets forth that argument does not replace evidence where evidence is necessary. Thus, Applicant’s arguments are not found persuasive.
In Applicant’s Remarks, see paragraph bridging p.9-10, Applicant concludes there is no teaching in Gong that RT-induced necroptosis promotes metastasis and there is no teaching of RT-induced metastasis. Applicant further argues Gong does not demonstrate RT-induced necroptosis, or any resulting metastasis, in lung cancer. Applicant further argues Gong teaches inhibition of necroptosis would likely increase metastasis or cancer cell survival based on the reference Gong uses. Applicant argues Gong concludes pronecroptotic agents might enhance anti-tumor effects of radiotherapy and that Gong discloses lung metastasis was markedly reduced by shikonin probably by inducing RIPK1- and RIPK3-dependent necroptosis. Applicant concludes Gong teches inhibiting RIPK1-dependent necroptosis would increase metastasis, and an increase in RIPK1 expression indicates a reduction in metastasis. This is not found persuasive. The rejection relies upon Gong as a whole to teach the link between RIP1-mediated necroptosis and metastasis as discussed in the previous replies. Applicant’s argument that the study Gong cites teaching that inhibition of radiotherapy-induced necroptosis via necrostatin increasing cancer cell survival would lead one of ordinary skill in the art to avoid this when treating cancer metastasis does not sufficiently demonstrate how cell survival is implicated in metastasis to thereby prevent one of skill in the art from inhibiting necroptosis. Indeed, when looking to Gong as a whole, it is evident that necroptosis actually promotes metastasis and thus it follows that it should be inhibited. With regards to Applicant’s arguments with respect to the study using shikonin, there is no evidence provided that shikonin acts on RIPK1 and Gong only speculates. Thus, it is maintained that Gong does provide sufficient objective evidence to suggest a role of RIP1-mediated necroptosis that promotes metastasis with necroptosis induced by radiotherapy and their link with elevated RIP1 in lung cancer.
In Applicant’s Remarks, see paragraph bridging p.12-13-p.14, last paragraph, Applicant repeatedly argues that there is no teaching in Gong that the necroptosis caused by radiotherapy is also the type of necroptosis that would result in metastasis. Applicant further argues Gong does not teach or suggest inhibiting necroptosis to treat radiotherapy-induced metastasis, and thus collapses the rejection over Park in view of Gong. This is not found persuasive. The arguments with respect to Gong have been previously addressed in the replies above.
In Applicant’s Remarks, see p.15, 1st paragraph, Applicant argues Gong teaches away from inhibiting necroptosis/RIP1 because doing so would increase metastasis and promote cancer survival. This is not found persuasive. The arguments with respect to Gong suggesting necroptosis should not be inhibited because it improves lung cancer cell survivability have been previously addressed in the replies above.
Therefore, Gong remains applicable to the claimed invention.
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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/J.P.S./Examiner, Art Unit 1657
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1657