DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/24/2025 has been entered.
3. Claims 1, 7-9, 12, 14-18, 21-28 are pending.
3. Claims 8, 12, 16-18 and 20 are withdrawn from further consideration pursuant to 37 CFR
1.142(b), as being drawn to nonelected inventions.
4. Claims 1, 7, 9-11, 14-15 and 19, 21-28 are under examination as they read on the following
species (i) eMIP (i.e., CCL3 with D27A and position 1 deleted) as the particular chemokine, (ii)
high-frequency waves as the hyperthermia source, (iii) metastatic cancer as the specific cancer,
(iv) five minutes or longer as the specific hyperthermia exposure time and (v) methods of using
probes.
5. The rejections under 102(a)(1) are hereby withdrawn in view of the claim amendment to recite “wherein the eMIP is reeatedly administered after hyperthermia”.
6. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
7. Claims 1, 7, 9-11, 14-15 and 19, 21-28 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
The “cancer metastasis in a patient who has a cancer and does not have another detectable cancer” recited in claim 1, is indefinite because the “cancer metastasis” indicates cancer spread from its original (primary) site to other parts of the body, forming new tumors, also known as secondary tumors, and is often called Stage IV cancer (see [0054] and [0055] and Fig. 6). The claims are indefinite because by definition cancer metastasis must have another detectable tumors/cancer.
9. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
10. Claims 1, 14-15, 19, 23, 25-28 are rejected under 35 U.S.C. 102(a) (1) as being anticipated by KR20170046373A (IDS# 2 and English translation attached on PTO-892).
The `373 publication teaches and claims the use of anticancer adjuvant composition comprising eMIP polypeptide of SEQ ID NO:1 ad mistered during hyperthermia therapy (by definition 41-60°C, overlap with the claimed range of 41-43oC) in the treatment of solid cancer (see published claims 4-9,[0015]- [0016]). The `373 publication teaches that if the proliferation of cancer is not controlled abnormal proliferation continues and becomes a malignant neoplasm, which is divided into epithelial tumors and non-epithelial sarcomas [0002]. Fig. 1 shows the administration of local radiation irradiation and administration of Q/C polypeptide. The `373 teaches that cancer cells metastasize to other tissues or organs and proliferate (see translation at page 2, 1st ¶). The `373 publication teach that the effect of combined radiation therapy and eMIP was confirmed to be caused by HMGB1 and HSP70 that are locally secreted due to radiation. HMGB1 and HSP70 are representative intracellular proteins known as alarmins that are released from necrotic cells and act on white blood cells and other cells to activate the body’s defense system. However, eMIP (ECI301) is a protein with 69 amino acids, and is usually manufactured as a recombinant protein and used after being frozen, which causes problems in handling [0006]. The `373 publication provides a pharmaceutical composition for preventing or treating cancer comprising Alarmin and an eMIP polypeptide represented by sequence number 1 as active ingredients [0009] [0014] [0020] or a composition for preventing or treating cancer comprising eMIP as active ingredient when inducing alarmin [0010], wherein the alarmin is HMGB1 or HSP70 [0014], wherein the cancer is solid cancer [0014]. The `373 publication teaches that alarmin such as HMGB1 and HSP70 can be induced by hyperthermia [0016] [0018]. The `373 publication teaches a daily dosage of 0.1 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be once a day or divided into several times, and the scope of the present invention is not limited thereby [0030]. The `373 publication teaches the transplanting adenocarsinoma colon26 (i.e., colorectal cancer and does not have another detectable cancer) to the right and left flank of mice, when the tumor size reaches 0.8-1 cm on the 14th day, 6 Gy of radiation is irradiated to the right flank tumor. Starting the next day, 4.4µg of Q/C polypeptide (equivalent to 10µg of eMIP), 2 µg of eMIP, or 10 µg of eMIP (each dissolved in 0.2 mgl of PBS solution) were administered via tail vein once daily for 5 days (i.e., repeatedly administered after the hyperthermia). Afer 13 days of radiation exposure, the tumor volume was calculated [0035]. The results show that compared with the control group, the irradiated group showed a decrease in tumor proliferation in the left flank as well as the right flank that was irradiated. The `373 publication teaches that the administration of combination of HSP70 and eMIP together results in significantly reduced tumor proliferation rate [0049].
The reference teachings anticipate the claimed invention.
Applicant’s arguments, filed 10/24/2025, have been fully considered, but have not been found convincing.
Applicant submits that claims 1 has been amended to include the subject matter previously recite in claim 11. Claim 11 was not included in the above anticipation rejection, thus the Official Action has effectively acknowledged that Kanegasaki and Tsuchiya ` 373 fail to disclose a method of suppressing or preventing cancer metastasis in a patient who has a cancer, and does not have another detectable cancer, that comprises repeatedly administering eMIP in a combination with performing a hyperthermia on a cancer. The incorporation of the subject matter of claim 11 into claim 1 was also discussed with Examiner Haddad during the interview and found to overcome the above anticipation rejections.
However, after reconsideration, the Examiner notes that the examples in the `373 are limited to adenocarsinoma colon26 (i.e., does not have another detectable cancer). Also, the `373 publication teaches the eMIP was administered daily or via tail vein once daily for 5 days (i.e., repeatedly administered) [0030][0035].
11. 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.
12. Claims 1, 7, 9-11, 14-15 and 19, 21-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kanegasaki et al, (OncoImmunology 3:10, e958956; November 1, 2014, of record) or KR20170046373A, each in view of Adkins et al (Oncoimmunology, (2017, 6(5): e1311433 (13 pages) and Cabuy E (Reliable Cancer Therapies. Energy-based therapies. 2011;1(2):1-48).
The teachings of the `373 publication have been discussed, supra.
Kanegasaki et al teach ECI301 (eMIP), a single amino-acid substituted CCL3 (MIP-1a/, enhanced tumor growth inhibition and the abscopal effect (an effect distal to the target) following local antitumor therapy such as radiation, radiofrequency ablation (RFA), or hyperthermia treatment. The recent elucidation of the underlying mechanism may lead to a better antitumor therapy (abstract). Kanegasaki et al found that eMIP-enhanced tumor growth inhibition could be caused by hyperthermia treatment (42oC for 30 min) (page 2, 2nd col., top ¶). Kanegasaki et al teach the alarmins released during local antitumor treatments play an essential role in enhancing tumor growth inhibition at treated and non-treated sites via a derivative of CCL3 (see title).
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Fig. 1 shows a possible action mechanism of the combination therapy. Local antitumor treatments induce apoptosis and necrosis of rapidly dividing tumor cells. HSP70 released from dying tumor cells traps intravenous-administrated eMIP, and eMIP-HSP70 complex induces HMGB1 release from dying tumor cells. HMGB1 also binds eMIP. eMIP-HSP70 and eMIP-HMGB1 promote eradication of tumor cells that may evade the treatments by stimulating NK cells and CD4C and CD8C cells, directly or indirectly.
Fig. 1 shows locally performing the hyperthermia on tumor cells would induce apoptosis/necrosis followed by eMIP treatment.
The reference teachings differ from the claimed invention only in the recitation of that the eMIP is repeatedly administered after the hyperthermia in claim 1, the heated using electromagnetic waves or ultrasonic waves in the hyperthermia in claim 7, the cancer is irradiated with high-frequence waves in the hyperthermia in claim 9, the treatment reduces the number of newly generated metastatic colonies of the cancer in claims 14 and 25, a temperature of a heated site is being monitored in claim 21, using a probe inserted to a position near an affected site in claims 22 and 24.
Adkins et al showed that mHS (42oC) treatment induces HSP70, as well as the release of low amounts of other DAMPs (i.e., alarmin) such as HMGB1. Adkins et al teach that HSP70 was detected on the cell surface of mHS-treated cells, albeit at lower amounts than on cells treated with sHS (47oC) (see page -4, right col, 3rd ¶ and page -9, right col., 1st ¶). Similarly, they detected HMGB1 release in mHS-treated OV90, but profound release of HMGB1 in both A549 and OV90 cancer cell lines 24 h after HS treatment (Fig. 2D) (page -5, left col, top ¶). Mouse and human tumor cells subjected to mild HS (mHS) ≤ 42 oC showed increased immunogenicity as well as the induction of tumor-antigen specific T-cell responses in vitro and in vivo, which has been attributed mainly to the action of HS proteins such as HSP70 (page -1, last ¶). HSP70 was not detectable in sHS-treated tumor cells, but was strongly induced by mHS treatment pointing at possible differences in immunogenic molecules exposure/release in mouse tumor cells under various HS conditions (page -8, left col., ¶).
Cabuy teaches hyperthermia is a therapeutic procedure used to raise the body or local tissue temperature to about 41-43°C through the application of electromagnetic or ultrasound energy for a defined period of time to sensitize cells for additional therapies. Hyperthermia is almost always used with other forms of cancer therapies as it provides a possibility for synergy with different actions of conventional therapies. Significant improvement in clinical outcome has been demonstrated for tumors of the bladder, breast, cervix, head and neck, and soft tissue sarcomas. Cabuy provides biological rationale for the application of hyperthermia to human cancer treatment (see abstract). Hyperthermia, also often called thermal therapy or thermotherapy, is a cancer treatment in which cancer tissue or the whole body is exposed to temperatures between 41-43°C through the application of electromagnetic energy for a defined period of time to damage and kill cancer cells. Thermal ablation is using much higher temperatures of >45°C (section 2.2). Cabuy teaches that mechanisms of heating include thermal conduction of heat way from a source at higher temperature (section 2.3). Cabuy teaches that modes of application of hyperthermia includes localized hyperthermia (Section 2.4). Cabuy teaches that external local hyperthermia is used to treat tumors that are in or just below the skin. Superficial lesions are the least difficult to heat adequately because of their accessibility and proximity to external energy sources. Heat is usually applied using high-frequency energy waves generated from a source outside the body (such as a radiofrequency or microwave source) (section 2.4.1.1). Cabuy teaches that local hyperthermia causes changes in the tumor microvasculature including increased perfusion and changes in endothelial gap size. Cabuy teaches that there is no evidence that local-regional hyperthermia causes an increase in metastases (section 4.2). Cabuy teaches that to ensure that the desired temperature is reached, but not exceeded, the temperature of the tumor and surrounding tissue is monitored throughout hyperthermia treatment (Section 2.5.2). This technique allows the tumor to be heated to higher temperatures than external techniques. Under anesthesia, probes or needles are inserted into the tumor (sections 2.5.2 and 2.4.1.3).
Given that HSP70 released from dying tumor cells traps intravenous-administrated eMIP, and eMIP-HSP70 complex induces HMGB1 release from dying tumor cells. HMGB1 also binds eMIP. eMIP-HSP70 and eMIP-HMGB1 promote eradication of tumor cells that may evade the treatments by stimulating NK cells and CD4C and CD8C cells, directly or indirectly as taught by Kanegasaki et al, those of skill in the art would have a reason to combined the eMIP polypeptide taught by the `373 publication and Kanegasaki et al with the mHS treatment that induces HSP70 and HMGB1 as taught by Adkins et al to inhibit cancer proliferation and hence cancer metastasis with reasonable expectation of success, the results would have been predictable, as that is precisely the teaching of the primary reference. It is noted that Kanegasaki et al teaches that hyperthermia induces the release of HSP70 and HMGB1 which binds to eMIP (see Fig. 1) which results in promoting eradication of tumor cells.
Those of skill in the art would have had a reason to apply high-frequency waves/electromagnetic techniques/ultrasound beams as the source of superficial lesions outside the body heat taught by Cabuy reference to treat cancer Kanegasaki et al and KR20170046373 based on the cancer location. Those skilled in the art would monitor the temperature of a heated site as taught by Kanegasaki et al and KR20170046373 to make sure that the temperatures are reached in the target tissue volume. It would have been obvious to use probes inserted deep within the body of tumors to allow the tumor to be heated to higher temperatures than external techniques.
Claim 14 is included because the claimed functional properties are considered inherent property of the combined treatment.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments, filed 10/24/2025, have been fully considered, but have not been found convincing.
Applicant submits that a person ordinarily skilled in the art would not have expected that suppression or prevention of cancer metastasis could occur in a patient being treated with the claimed methods. This surprising discovery is supported by the fact that hyperthermia at 41-43oC for 5-30 minutes as claimed alone could not kill cancer (as illustrated in Fig. 1 of Okumura, see ¶7 of Dr. Kanegasaki’s Declaration filed June 05, 2005, and could not suppress the metastasis of cancer cells (see Example 3, FIGs. 6 and 7 of PG Pub). The discovery made by the inventors of the present applicantion is further surprising given that an abscopal effect was believed to require a treatment known to be capable of killing cancer cells, e.g., radiation therapy (see¶8 and 17 of Kanegasaki’s Declaration 1).
The Kanegasaki Declaration under 37 CFR §1.132, filed 10/24/2025, is insufficient to overcome the 103 rejection over Kanegasaki et al, (OncoImmunology 3:10, e958956; November 1, 2014, of record) or KR20170046373A, each in view of Cabuy E (Reliable Cancer Therapies. Energy-based therapies. 2011;1(2):1-48) for the following reasons:
The declaration under ¶5 states that due to differences between the mechanisms of hyperthermia and radiation therapy, those skilled in the art would not have expected that the effects achieved by the combination of radiation and eMIP could also be obtained by the combination of hyperthermia and eMIP. Under ¶6, the declaration states that cell death caused by radiation is considered to be primarily reproductive death dure to DNA damage, whereby cells are no longer able to proliferate after cell division. In such cases, cells may undergo one or several divisions, and even thereafter nucleic acid and protein synthesis continues. Accordingly, cells injured by radiation can continue to release alarmins (i.e., damage-associated molecular patterns). The production of these alarmins are needed to make eMIP an effective cancer treatment. That is, eMIP binds to these alarmins to create complexes that activate immune cells like natural killer (NK) cells and T-cells. These activated immune cells create a mobilized immune response that attacks the cancer cells in the body. Therefore, without alarmin production, eMIP cannot overcome the complex defense mechanisms of cancer cells and assert its therapeutic effect. A 5 day administration of eMIP in combination with radiation is considered to be an effective cancer treatment. By contrast, cell death induced by hyperthermia occurs through denaturation caused by protein conformational changes and alterations in membrane structures, resulting in an almost immediate cessation of cellular metabolism. Therefore, cells damaged by hyperthermia were considered unable to generate alarmins in a sustained manner needed for eMIP to create a mobilized immune response against the cancer cells. For this reason, alarmin production by hyperthermia was regarded as transient and insufficient for treating cancer. Thus, those skilled in the art would not have exected that the effects obtained by the combination of radiation and eMIP would also be achievable with the combination of hyperthermia and eMIP.
This is not found persuasive because Adkins et al (Oncoimmunology, (2017, 6(5): e1311433 (13 pages) showed that mHS (42oC) treatment induces HSP70, as well as the release of low amounts of other DAMPs (i.e., alarmin) such as ATP or HMGB1. Adkins et al teach that HSP70 was detected on the cell surface of mHS-treated cells, albeit at lower amounts than on cells treated with sHS (47oC) (see page -4, right col, 3rd ¶ and page -9, right col., 1st ¶). Similarly, they detected HMGB1 release in mHS-treated OV90, but profound release of HMGB1 in both A549 and OV90 cancer cell lines 24 h after HS treatment (Fig. 2D) (page -5, left col, top ¶). Mouse and human tumor cells subjected to mild HS (mHS) ≤ 42 oC showed increased immunogenicity as well as the induction of tumor-antigen specific T-cell responses in vitro and in vivo, which has been attributed mainly to the action of HS proteins such as HSP70 (page -1, last ¶). HSP70 was not detectable in sHS-treated tumor cells, but was strongly induced by mHS treatment pointing at possible differences in immunogenic molecules exposure/release in mouse tumor cells under various HS conditions (page -8, left col., ¶). Also, Kanegasaki et al found that eMIP-enhanced tumor growth inhibition could be caused by hyperthermia treatment (42oC for 30 min) (page 2, 2nd col., top ¶) Lamegasalo et al reference teaches that HSP70 released from dying tumor cells traps intravenous-administrated eMIP, and eMIP-HSP70 complex induces HMGB1 release from dying tumor cells. HMGB1 also binds eMIP. eMIP-HSP70 and eMIP-HMGB1 promote eradication of tumor cells that may evade the treatments by stimulating NK cells and CD4C and CD8C cells, directly or indirectly. Moreover, the `373 publication teaches that HMGB1 and HSP70 are representative intracellular proteins known as alarmins that are released from necrotic cells and act on white blood cells and other cells to activate the body’s defense system. The `373 publication provides a pharmaceutical composition for preventing or treating cancer comprising Alarmin and an eMIP polypeptide represented by sequence number 1 as active ingredients [0009] [0014] [0020] or a composition for preventing or treating cancer comprising eMIP as active ingredient when inducing alarmin [0010], wherein the alarmin is HMGB1 or HSP70 [0014], wherein the cancer is solid cancer [0014]. Those of skill in the art would have a reason to combined the eMIP polypeptide taught by the `373 publication and Kanegasaki et al with the mHS treatment that induces HSP70 and HMGB1 as taught by Adkins et al to inhibit cancer proliferation and hence cancer metastasis with reasonable expectation of success, the results would have been predictable, as that is precisely the teaching of the primary reference.
Given that mHS (42oC) treatment induces HSP70, as well as the release of low amounts of other DAMPs (i.e., alarmin) such as HMGB1,those of skilled in the art would have had a reason to combine the eMIP polypeptide treatment with mHS in the treatment of cancer to inhibit cancer proliferation and hence metastasis.
The declaration under ¶7 states that as shown in the Examples, I discovered that, by controlling hyperthermia conditions carefully to employ a sublethal temperature that avoids killing cells, the combination of hyperthermia and eMIP can suppress cancer metastasis, which led me to file the present patent application.
The declaration under ¶8 states that it should also be noted that the types of radiation that, in combination with eMIP, provide a tumor growth suppressive effect are limited to X-rays and electron beams. As shown in the figure below, the combination of eMIP with carbon-ion radiation, which likewise induces reproductive death, does not achieve growth suppression. Thus, combining eMIP with a treatment that induces cell damage does not necessarily yield a tumor growth suppressive effect. Those skilled in the art should have recognized, in view of this, the metastasis suppressing effect produced by the combination of hyperthermia and eMIP as a surprising and unexpected effect.
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Figure: Even when eMIP was administered after carbon-ion irradiation of the tumor at 3Gy (C3Gy) or Gy (C6Gy), tumor growth was not suppressed, still less any metastasis-supressing effect.
This is not found persuasive because the showing in the specification is limited to adenocarcinoma Colon 26, however the claims are directed to a genus of cancer metastasis. The showing in the specification is not commensurate with the scope of the claimed invention. Importantly, Adkins et al (Oncoimmunology, (2017, 6(5): e1311433 (13 pages) showed that colon cancer treated with mHS (42oC) treatment induces HSP70, as well as the release of low amounts of other DAMPs (i.e., alarmin) such as HMGB1, it would have been obvious to those of skill in the art to combined to eMIP polypeptide taught by Kanegasaki et al and the `373 publication with the mHS (42oC) treatment that induces HSP70, as well as the release of low amounts of other DAMPs (i.e., alarmin) such as HMGB1 to inhibit cancer growth as taught by Kanegasaki and the `373 publication.
Further, the claims are directed to suppressing or preventing cancer metastasis of cancer using hyperthermia and eMIP. The provided figure does not indicate the type of cancer used in the experiment also the Figure does not show whether cancer metastasis was prevented/suppressed or not using the claimed combination. The showing is directed to irradiation for inhibiting cancer. No showing for inhibiting cancer metastasis is provided in the figure as claimed as required by the claimed invention.
At ¶9 of the declaration states that even if the tumor volume at the primary site is reduced by the combination of hyperthermia and eMIP, those skilled in the art would not have expected that such reduction leads to a decrease in metastasis. Accordingly, those skilled in the art could not have expected a reduction in the number of metastases.
This is not found persuasive because Adkins et al show that mHS (42oC) treatment induces HSP70, as well as the release of low amounts of other DAMPs (i.e., alarmin) such as HMGB1,those of skilled in the art would have had a reason to combine the eMIP polypeptide treatment with mHS in the treatment of cancer to inhibit cancer proliferation and hence metastasis. The abscopal effect taught by the primary references means treatment of metastatic cancer by inhibiting bother treated and untreated cancer in different area.
Paragraph 10 of the declaration illustrates the abscopal effect of the eMIP and hyperthermia treatment. Applicant conclusion that the reduction in tumor volume at the primary site cannot be said to also reduce the total number of metastatic colonies at secondary sites unless the treatment at the primary site was shown to produce an abscopal effect. Based on such knowledge, those skilled in the art would have concluded tht , even if a combination treatment reduced the tumor volume at the primary site, this dose not imply a reduction in metastasis. This is not convincing simply because Kanegasaki et al teach ECI301 (eMIP) enhanced tumor growth inhibition and the abscopal effect (an effect distal to the target) following local antitumor therapy such as hyperthermia treatment. Accordingly, the eMIP is know to have abscopal effect prior to Applicant claimed invention/Example 3.
The declaration under ¶11 points to two documents deal with cancer intravasation. The declaration states that the skilled person would not have understood that suppressing the growth of the implanted tumor cells would reduce metastasis. This is not found persuasive simply because eMIP is know to have abscopal effect prior to the claimed invention. In other words, eMIP would inhibit cancer proliferation of both treated and untreated cells. While the two documents show that cancer metastasis occur event after the removal/excision of cancer, simply because the cancer already intravasated into a blood or lymphatic vessel. The instant claims are directed to treatment of sold cancer with the claimed combination wherein the hyperthermia would induce cancer cells to induce the production HSP70 and other DAMPs (i.e., alarmin) such as HMGB1 that complex with eMIP and inhibit treated and untreated cancer proliferation.
Under ¶13 of the specification, the declaration states that in Example 3 of the specification, although the growth inhibition of the implanted tumor achieved by the combination of hyperthermia and eMIP was only about 40%, suppression of lung metastasis was ≥ 96%, and in 3 of the 6 mice no metastatic colonies were observed in the lung at all. Such large quantitate effects would also have been unpredictable to those skilled in the art.
This is not found persuasive because the `373 publication teaches and claims the use of anticancer adjuvant composition comprising eMIP polypeptide of SEQ ID NO:1 administered during hyperthermia therapy (by definition 41-60°C, overlap with the claimed range of 41-43oC) in the treatment of solid cancer (see published claims 4-9,[0015]- [0016]). The `373 publication provides a pharmaceutical composition for preventing or treating cancer comprising Alarmin and an eMIP polypeptide represented by sequence number 1 as active ingredients [0009] [0014] [0020] or a composition for preventing or treating cancer comprising eMIP as active ingredient when inducing alarmin [0010], wherein the alarmin is HMGB1 or HSP70 [0014], wherein the cancer is solid cancer [0014]. The `373 publication teaches that alarmin such as HMGB1 and HSP70 can be induced by hyperthermia [0016] [0018].
Adkins et al (Oncoimmunology, (2017, 6(5): e1311433 (13 pages) showed that mHS (42oC) treatment induces HSP70, as well as the release of low amounts of other DAMPs (i.e., alarmin) such as ATP or HMGB1 in cancer cells. Adkins et al teach that HSP70 was detected on the cell surface of mHS-treated cells, albeit at lower amounts than on cells treated with sHS (47oC) (see page -4, right col, 3rd ¶ and page -9, right col., 1st ¶). Similarly, they detected HMGB1 release in mHS-treated OV90, but profound release of HMGB1 in both A549 and OV90 cancer cell lines 24 h after HS treatment (Fig. 2D) (page -5, left col, top ¶). Mouse and human tumor cells subjected to mild HS (mHS) ≤42 oC showed increased immunogenicity as well as the induction of tumor-antigen specific T-cell responses in vitro and in vivo, which has been attributed mainly to the action of HS proteins such as HSP70 (page -1, last ¶). HSP70 was not detectable in sHS-treated tumor cells, but was strongly induced by mHS treatment pointing at possible differences in immunogenic molecules exposure/release in mouse tumor cells under various HS conditions (page -8, left col., ¶).
Those of skill in the art would have a reason to combined the eMIP polypeptide taught by the `373 publication with the mHS treatment that induces HSP70 and HMGB1 to inhibit cancer proliferation and hence cancer metastasis with reasonable expectation of success, the results would have been predictable, as that is precisely the teaching of the primary reference.
Applicant at page 11 of the remarks argues that Kanegasaki reference merely states that eMIP exposure enhanced tumor growth inhibition by hyperthermia but did not comment on the degree of tumor growth inhibition (see ¶7 of Kanegasaki’s declaration 1). That is, Kanegasaki is silent on whether the tumor growth inhibition involved merely slowing the growth of the cancer or completely eradicating the cancer, Tsuchiya `373 publication also only discloses that the growth of a cancer at an untreated site became slower but continued even with a compabinatin foe MIP and radiotherapy (see F.1 of Tsuchiya `373). Because neither Kanegasaki nor Tsuchiya `373 disclose that eMIP with hyperthermia can completely eradicate cancer, a person ordinarily skilled in the art would not have considered the result of Kanegasaki and Tsuchiya `373 as particularly promising.
This is not found persuasive because Applicant is arguing limitations that are not claimed. The instant claims do not set a degree of suppression and/or prevention of cancer metastasis. Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023) (“A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘a new property dissimilar to the known property,’ rather than producing a predictable result but to an unexpected extent.”).
Applicant argues that the `373 publication also clearly discloses the cancer at the untreated site continued to grow even with a combination of hyperthermia and radiotherapy (Fig.2), which would have dissuaded a person ordinarily skilled in the art from expecting suppression of prevention of cancer metastasis.
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This is not found persuasive because the `373 publication teaches that in the irradiated right flank tumor proliferation and tumor volume were statistically significantly reduced compared to the non-irradiated control group. In the group treated with radiation therapy plus Q/C polypeptide or eMIP, the tumor volume in the right flank was statistically significantly reduced compared to the group treated with radiation therapy alone. Moreover, the tumor volume in the non-irradiated left flank was also statistically significantly reduced in the groups administered Q/C polypeptide or eMIP. The `373 publication conclude that the A/C polypeptide inhibits cancer proliferation not only in the irradiated area but also in other areas (abscopal effect). In contrast to applicant’s assertions of teaching away by the prior art because the references indicate a successful method of reducing tumor volume using irradiation and eMIP; there is no discouragement nor skepticism in the prior art for using eMIP plus hyperthermia, particularly in light of the prior art teachings to provide the inhibition of cancer proliferation not only in the irradiated area but also in other areas.
Applicant points to surprising discovery that the claimed methods can suppress cancer metastasis via a synergistic action between eMIP and some proteins released from the cancer cells during hyperthermia. Applicant points to Example 3 and Figs 6 and 7 which shows that a significant increase in cancer metastasis. Applicant points that those of ordinary skill in the art would envisage the surprising results shown in Example 3 of the application extending to other cancers. In particular every cancer has the capability of mutating and acquiring metastatic traits.
However, the `373 publication confirmed that Q/C polypeptide or eMIP polypeptide significantly inhibited cancer cell proliferation when administered together with HSP70 (Fig. 3). Fig. 2 show the tumor volume of Colon 26 cells in the right and left flanks 13 days after radiation exposure. In the irradiated right flank, tumor proliferation and tumor volume were statistically significantly reduced compared to the non-irradiated control group. In the group treated with radiation therapy plus Q/C polypeptide roe MIP, the tumor volume in the right flank was statistically significantly reduced compared to the group treated with radiation therapy alone. Moreover, the tumor volume in the non-irradiated left flank was also statistically significantly reduced in the groups administered Q/C polypeptide or eMIP. From the above results, it was confirmed that the Q/C polypeptide inhibits cancer proliferation not only in the irradiated area but also in other areas [0043]. Given that cancer proliferation fuels metastasis, the highter proliferation fuels the massive cell numbers needed for metastasis, and the higher the colonies formation in the lungs. Since eMIP has abscopal effect on cancer cell treated with hyperthermia which result in release of HSP70 and HMGB1 wherein HMGB1 binds eMIP. eMIP-HSP70 and eMIP-HMGB1 promote eradication of tumor cells that may evade the treatments by stimulating NK cells and CD4C and CD8C cells, directly or indirectly as taught by Kanegasaki reference. Accordingly, Applicant fails to provide persuasive reasoning or credible evidence that the claimed invention achieves any advantage over, or even any Kanegasaki reference and the `373 publication.
Further, the showing of surprising discovery is not commensurate in scope with the invention as claimed. The claims are directed to a genus of cancer metastasis in a patient, while the showings of surprising result is limited to adenocarcinoma Colon 26 cells. MPEP §716.02(d). Not all the cancers would result in the unexpected surprising discovery of suppressing cacer metastasis via a synergistic action between eMIP and some proteins released from the cancer cells during hyperthermia. Besides adenocarcinoma Colon 26 cells, neither the specification not the prior art shows all cancer cells produced alarmines that bind to eMIP to promote eradication of tumor cells and thus suppress cancer metastasis / colony formation in the lung. While every cancer has the capability to metastasis, however, Applicant fails to show that every cancer has the capability to release alarmins in response to hyperthermia that would bind to eMIP which promotes the suppression and prevention of cancer metastasis via abscopal effect.
12. No claim is allowed.
13. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Iida et al (Cancer Res 2010;70:6556–66).
Iida et al teach that radiofrequency ablation (RFA) is used to locally eliminate cancers such as hepatocellular carcinoma (HCC), renal cell carcinoma, and lung cancer. Because HCC often recurs even after an eradicative treatment with RFA, additional immunotherapy is necessary. We treated tumor-bearing mice by administering ECI301, an active variant of CC chemokine ligand 3, after RFA. Mice were injected s.c. with BNL 1ME A.7R.1, a murine hepatoma cell line, in the bilateral flank. After the tumor became palpable, RFA was done on the tumor of one flank with or without ECI301. RFA alone eliminated the treated ipsilateral tumors and retarded the growth of contralateral non–RFA-treated tumors accompanied by massive T-cell infiltration. Injection of ECI301 augmented RFA-induced antitumor effect against non–RFA-treated tumors when administered to wild-type or CCR5-deficient but not CCR1-deficient mice (abstract). RFA treatments were done using a radiofrequency generator at a power output of 25 W for 1.5 minutes and the temperature of the needle tips reached 70°C to 80°C (page 6557, under Radiofrequency ablation). RFA induces the expression of heat shock proteins 70 and 90 on ablated tumor cells, and these proteins can activate toll-like receptor– expressing antigen-presenting cells (41, 42). In addition, we showed that RFA treatment alone caused local production of CCL3 in RFA-treated tumors accompanied by accumulation of T cells and CD11c+ dendritic cells. These mechanisms may also account for the observed RFA-induced generation of tumor-specific immune responses (page 6564, right col., 1st ¶).
WO 2012023631
The `631 publication provided is a cancer therapeutic agent which can treat solid cancer and various diseases or disorders associated with solid cancer without inducing any adverse side effect. Provided is a pharmaceutical compound for treating cancer, which comprises a heat shock protein (HSP) and a polypeptide (ECI301) as active ingredients. HSP70 and ECI301 can be administered in a same or different compound. The `631 publication claims a pharmaceutical composition for treating cancer, comprising heat shock protein (HSP) 70 and a polypeptide represented by SEQ ID NO: 1 (ECI301), wherein the cancer is a solid cancer, wherein the solid cancer is lung cancer, colon cancer, or fibrosarcoma, comprising heat shock protein (HSP) 70 and polypeptide represented by SEQ ID NO: 1 (ECI301) in a weight ratio of 1: 0.4 to 16.
Tsuchiya et al. Identification of the active portion of the CCL3 derivative reported to induce antitumor abscopal effect. Clinical and translational radiation oncology, (2018 Mar) Vol. 10, pp. 7-12.
Tsuchiya et al teach that intravenous administration of a single amino acid-substituted chemokine CCL3 derivative named eMIP elicits the abscopal effect (an effect distal to the target), after local irradiation at a tumor-bearing site. To distinguish the active portion of eMIP, we tested the antitumor activity of chemically synthesized partial peptides of eMIP. Synthetic peptide has various advantages in its clinical application. Colon26 adenocarcinoma cells were implanted subcutaneously in the right and left flanks of mice. eMIP, CCL3 or any of synthesized peptides was administered intravenously, either after irradiating the right flank. The effect was evaluated by tumor-growth inhibition. Q/C peptide, a synthetic peptide of amino acids 22-51 of eMIP has no chemotaxis-inducing ability but yet enhanced tumor growth inhibition at the non-irradiated sites, recapitulating the effect of eMIP with local irradiation. Co-administration of this peptide and HSP70 also inhibited tumor growth.
Kanegasaki et al. Macrophage Inflammatory Protein Derivative ECI301 Enhances the Alarmin-Associated Abscopal Benefits of Tumor Radiotherapy. Cancer Res (2014) 74 (18): 5070–5078.
Kanegasaki et al report that i.v. administration of ECI301 after intratumoral injection of tumor cell lysates can inhibit tumor growth, not only at the site of injection but also at nontreated sites. Effects of the tumor lysate were further recapitulated by i.v. administration of the alarmins HSP70 or HMGB1, but not HSP60, and combinations of ECI301 + HSP70 were sufficient to inhibit tumor growth. Our results suggest a model in which sequential release of the alarmins HSP70 and HMGB1 from a tumor by irradiation may trap circulating ECI301, thereby licensing or restoring tumor immunosurveillance capabilities of natural killer cells or CD4+ and CD8+ T cells against tumor cells that may evade irradiation (abstract).
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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December 30, 2025
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644