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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 1, 2025 has been entered.
Detailed Action
This office action is a response to applicant’s communication submitted October 1, 2025, wherein claims 11, 13, 24, and 25 are amended, claims 12 and 14-17 are canceled, and new claim 26 is introduced. This application is a national stage application of PCT/JP2020/031357, filed August 19, 2020, which claims benefit of foreign application JP2019-156220, filed August 29, 2019.
Claims 11, 13, and 19-26 are pending in this application.
Claims 11, 13, and 19-26 as amended are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, submitted October 1, 2025, with respect to the rejection of claims 11-17 and 19-25 under 35 USC 112(b) for being unclear as to how the claims limit the amount of chemotherapeutic agent, has been fully considered and found to be persuasive to remove the rejection as the claims have been amended so as to indicate the amount of chemotherapeutic agent with respect to the occurrence of certain side effects. Therefore the rejection is withdrawn.
Applicant’s amendment, submitted October 1, 2025, with respect to the rejection of claims 11, 20, 20, 21, 23, and 24 under 35 USC 102(a)(1) for being anticipated by Hebishima-1, has been fully considered and found to be persuasive to remove the rejection as the claims have been amended to require specific chemotherapeutic agents that are not doxorubicin. Therefore the rejection is withdrawn.
Applicant’s amendment, submitted October 1, 2025, with respect to the rejection of claims 19, 22, and 25 under 35 USC 103 for being obvious over Hebishima-1 in view of Fujihara et al., has been fully considered and found to be persuasive to remove the rejection as the claims have been amended so as to require that the chemotherapeutic agent specifically be an alkylating agent. Therefore the rejection nis withdrawn.
Claim interpretation
As presently pending, independent claims 11, 24, and 25 include in their preamble the limitation, “increasing administration of an amount of chemotherapeutic agents in a living body.” These claims further refer to, “an amount of the chemotherapeutic agent in an amount increased above an amount of the chemotherapeutic agent administered had the substance with the lipopolysaccharide as the active ingredient not been administered to the living body,” “administration of the substance with the lipopolysaccharide as the active ingredient causes a reduction of a side effect of the chemotherapeutic agent to be administered at the increased amount,” and “the side effect is weight loss induced by the alkylating agent.” These limitations describe the claimed method with respect to hypothetical alternate methods, namely either wherein the chemotherapeutic agent is administered without LPS at a reduced amount, or wherein the chemotherapeutic agent is administered without LPS and exhibits a side effect, namely weight loss or decreased survival. Consideration of the scope of these claims indicates that none of the claim limitations actually require that one skilled in the art perform multiple separate administrations at different dosages. Rather the claim merely refers to a hypothetical alternate embodiment which is not actually performed, but which serves as a sort of mental reference point to which the effects of the method actually being carried out can be compared. Of all of these limitations, the only one which imposes an objective limitation on the claim scope is the last one, which is interpreted as requiring that the LPS act to reduce some particular side effect of the chemotherapeutic agent, excluding methods wherein the LPS is not one which reduces side effects of the chemotherapeutic agent.
The following rejections of record in the previous action are maintained:
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.
Claims 11, 13, 20-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Hebishima et al. (Exp Anim 2011, cited in 2/18/2025 PTO-892, herein referred to as Hebishima-1) in view of Abdella et al. (Iranian Journal of Cancer Prevention, 2008, Reference included with 2/18/2025 PTO-892)
Independent claim 11 claims a method which as described under the heading “Claim Interpretation” is interpreted as requiring administration of an alkylating chemotherapeutic agent and a lipopolysaccharide to a subject, wherein the lipopolysaccharide reduces the amount of weight loss induced by the chemotherapeutic agent. Dependent claim 13 further requires that the alkylating agent be cyclophosphamide.
Hebishima- 1 teaches that doxorubicin suppresses host immune cells and that LPS exhibits potent protective effects against doxorubicin-induced immunosuppression, such as the inhibition of macrophage growth (page 107, paragraph 1). Hebishima- 1 discloses a method administering LPS and doxorubicin to mice which significantly prolonged the survival compared to mice that were only administered doxorubicin (page 105, paragraph 2). Hebishima- teaches that this effect is due to the modulation of the chemotherapy induced anti-tumor immunity suppression (figure 4). Hebishima-1 also teaches that the LPS is administered orally (page 103, paragraph 3). Hebishima-1 teaches that the LPS is derived from the bacterium Pantoea agglomerans (page 102, paragraph 3). Hebishima-1 teaches that the LPS is a supportive drug (page 102, paragraph 4). Hebishima- also teaches that LPS was effective for protecting against doxorubicin induced immunosuppression because it induces recovery in the immune system through TLR-4 signaling and increasing serum levels of TNF-α (page 106, paragraph 1). Hebishima-1 does not teach chemotherapeutic agents including an alkylating agent (instant claim 11) which is streptozotocin or cyclophosphamide (instant claim 13).
Abdella teaches that treatment with cyclophosphamide predisposes cancer patients to risk of bacterial, fungal, and viral infection (abstract). Cyclophosphamide is an alkylating agent used as an anticancer chemotherapeutic (page 155, paragraph 1). Abdella teaches that pretreatment with LPS induces an immune response which increases cellular resistance to the effects of immunosuppression by cyclophosphamide (page 162, paragraph 3). The response of the host to LPS is mediated by the immune modulating molecules such as TNF- α, members of interleukin family, reactive oxygen species, and lipids (page 156, paragraph 1). Furthermore, Abdella teaches that the treatment with LPS decreases the immunosuppressor effects of cyclophosphamide in mice (page 163, paragraph 1), thereby indicating that the treatment is suitable for administration to a subject. A person of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to orally administer a composition comprising LPS as an active ingredient to cancer patients who are being treated with cyclophosphamide because Abdella teaches that cyclophosphamide is a chemotherapeutic agent causing immunosuppression in cancer patients, and that this immunosuppression can be decreased by administration of LPS, and Hebishima-1 teaches a method of inducing recovery in the immune system to protect against chemotherapeutic agent induced immunosuppression by orally administering an LPS comprising composition. A person of ordinary skill in the art would have had a reasonable expectation of success because both Abdella and Hebishima-1 teach that LPS modulates TNF- α to induce an immune response, and that this immune response helps decrease chemotherapeutic agent induced immunosuppression.
Response to Arguments: Applicant’s arguments, submitted October 1, 2025, with respect to the above ground of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant does not separately traverse this rejection, but rather argues that it is improper for the same reasons given with respect to the now withdrawn rejection under 35 USC 102 over Hebishima-1 alone. The only argument given traversing this rejection is that Hebishima-1 describes the side effect of the chemotherapeutic agent as being immunosuppression rather than weight loss or reduced survival. However, Abdella specifically describes cyclophosphamide as an immunosuppressive agent (p. 155 left column first paragraph) and further describes LPS as ameliorating cyclophosphamide immunosuppression. Furthermore while Abdella does not specifically measure the body weights of the treated animals, a review of the art indicates that reversing immunosuppression would be reasonably considered to also reverse weight loss. For example Shruthi et al. (Reference included with PTO-892) discloses that cyclophosphamide and cisplatin both exert immunosuppressive effects. (p. 151 right column first and second paragraphs) Animals treated with these agents lost body weight, an effect which was mitigated by gallic acid, an agent which acts to reduce the immunosuppressive effects of these drugs. (p. 153 left column third and fourth paragraphs) Similarly Kim et al. (Reference included with PTO-892) discloses that reduction of the immune suppression caused by cisplatin by a herbal preparation also led to reduced weight loss. (see p. 3 figures 1 and 2) Finally Jang et al. (Reference included with PTO-892) observes a similar effect when the probiotic L. casei is used to ameliorate cyclophosphamide-induced weight loss. (See p. 399 figure 2) Therefore it is clear from the art that immunosuppression by chemotherapeutic agents including cyclophosphamide leads to weight loss and that treatments that ameliorate the immunosuppression also reduce the weight loss. As a result it is reasonably expected that if Hebashima-1 or Abdella did measure the body weights of the animals it would be revealed that the LPS did in fact reduce weight loss caused by the immunosuppressive agents. Therefore the rejection is deemed proper and maintained.
Claims 24 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Hebishima et al. (Exp Anim 2011, cited in 2/18/2025 PTO-892, herein referred to as Hebishima-1) in view of Hebishima et al. (Anticancer Research, 2010, Reference included with 2/18/2025 PTO-892, herein referred to as Hebishima-2)
Independent claims 24 and 25 claim a method which as described under the heading “Claim Interpretation” is interpreted as requiring administration of cisplatin or 5-fluorouracil and a lipopolysaccharide to a subject, wherein the lipopolysaccharide reduces the amount of weight loss induced by the chemotherapeutic agent.
Hebishima- 1 teaches that doxorubicin suppresses host immune cells and that LPS exhibits potent protective effects against doxorubicin-induced immunosuppression, such as the inhibition of macrophage growth (page 107, paragraph 1). Hebishima- 1 discloses a method administering LPS and doxorubicin to mice which significantly prolonged the survival compared to mice that were only administered doxorubicin (page 105, paragraph 2). Hebishima- teaches that this effect is due to the modulation of the chemotherapy induced anti-tumor immunity suppression (figure 4). Hebishima-1 also teaches that the LPS is administered orally (page 103, paragraph 3). Hebishima-1 teaches that the LPS is derived from the bacterium Pantoea agglomerans (page 102, paragraph 3). Hebishima-1 teaches that the LPS is a supportive drug (page 102, paragraph 4). Hebishima- also teaches that LPS was effective for protecting against doxorubicin induced immunosuppression because it induces recovery in the immune system through TLR-4 signaling and increasing serum levels of TNF-α (page 106, paragraph 1). Hebishima-1 does not teach chemotherapeutic agents including cisplatin or fluorouracil.
Hebishima-2 teaches the LPS protects cells from doxorubicin, cisplatin, and 5- fluorouracil mediated growth inhibition (page 2038, paragraph 4), and that LPS has immunoenhancing effects for subjects (page 2034, paragraph 1). Hebishima-2 teaches that administration of LPS produced TNF-α and that this is responsible for the immunopotentiation effects (Figure 1D, and page 2038, paragraph 3). Hebishima-2 also teaches that LPS may provide protection through TLR-4 signaling (page 2038, paragraph 4). Regarding claims 14-17, Hebishima-2 teaches that LPS particularly confers protection against chemotherapeutic agent induced inhibition of macrophage growth by not only doxorubicin, but also cisplatin and 5-fluorouracil (paragraph bridging pages 2036-2037). It would have been prima facie obvious to apply the method of reducing the negative immunosuppression effect of chemotherapy by administration of LPS to a subject as taught by Hebishima-1, to chemotherapy treatments involving cisplatin and 5-fluorouracil, as taught by Hebishima-2, because both reference teach a combination treatment of a chemotherapy and LPS to reduce the negative chemotherapeutic effect of immunosuppression. A person of ordinary skill in the art before the effective filing date of the claimed invention would have a reasonable expectation of success in selecting a subject being treated with cisplatin and 5-fluorouracil for administration of LPS because Hebishima-1 teaches that LPS protects the immune system of a subject from chemotherapeutic induced suppression by improving TLR-4 and TNF-α signaling, and Hebishima-2 teaches that LPS acts through TLR-4 and TNF-α signaling to protect against immunosuppression by cisplatin and 5-fluorouracil.
Response to Arguments: Applicant’s arguments, submitted October 1, 2025, with respect to the above ground of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant’s arguments are the same as those made with respect to the rejection over Hebishima-1 in view of Abdella above, and are found not persuasive for the same reasons, namely that one of ordinary skill in the art would have understood immunosuppression as leading to weight loss and reversal of immunosuppression as reversing weight loss. Additionally, Hebishima-1 (p. 106 figure 3A-B) shows that co-administration of a chemotherapeutic agent and a LPS improves survival compared to the chemotherapeutic agent alone. For these reasons the rejection is deemed proper and maintained.
The following new grounds of rejection are introduced:
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.
Claims 19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Hebishima-1 in view of Abdella as applied to claims 11, 13, and 20-21 above, and further in view of Fujihara et al. and Jetiyanon et al. (References of record in previous action)
The disclosures of Hebishima-1 and Abdella are discussed above. Hebishima-1 in view of Abdella does not specifically disclose a method wherein the LPS is from the family Enterobacteriaceae, or the species Enterobacter asburiae.
Fujihara teaches that LPS is a major component of the outer membrane of gram- negative bacteria (page 172, paragraph 1). Enterobacterial LPS causes cell signaling through TLR-4 (table 1 and page 174 paragraphs 3-4), which in turn signals TNF-α (table 3). Jetiyanon teaches that LPS may be isolated from the gram-negative bacteria Enterobacter asburiae (sections 1 and 2.4). It would have been prima facie obvious to use the LPS isolated from Enterobacter asburiae as taught by Jetiyanon in the method of reducing immunosuppression effects of chemotherapy by administering LPS as taught by Hebishima because Fujihara teaches that Enterobacterial LPS causes cell signaling through TLR-4 and TNF-α. A person of ordinary skill in the art before the effective filing date of the claimed invention would have a reasonable expectation of success in administering the LPS of Jetiyanon in the method Hebishima-1 of because both Hebishima-1 and Fujihara teach an LPS that increases TLR-4 and TNF-α signaling.
Therefore the invention taken as a whole is prima facie obvious.
Claims 11, 13, 21, 22-24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Hebishima-1 in view of Abdalla as applied to claims 11, 13, 20-21, and 23 above, and further in view of Nunes. (PCT international publication 2012/0251441, cited in PTO-892)
The disclosures of Hebishima-1 and Abdalla are discussed above. Hebishima-1 in view of Abdalla does not disclose embodiments wherein the alkylating agent is streptozotocin or cisplatin.
Nunes discloses using an immuomodulator as an antitumor therapy. (p. 13 paragraph 254 – p. 14 paragraph 255) This compound is disclose as inducing endogenous cytokines, similar to the description of the effects of LPS in the disclosures of Hebishima-1 and Abdalla. (p. 14 paragraphs 263-267) These compounds are additionally described as correcting problems caused by adverse effects of other agents used to treat cancer. (p. 15 paragraph 270) One benefit of this therapy is that it allows for higher doses of other chemotherapeutic agents to be used in view of the reduction of the harmful effects of other chemotherapeutic agents. (p. 15 paragraph 273 and 274, also p. 16 paragraph 282) Specific adverse effects described as being ameliorated include immunosuppression and cachexia, which includes weight loss. (p. 16 paragraph 284, p. 9 paragraph 170) Specific chemotherapy agents this can be applied to (p. 49 paragraph 801) include alkylating agents such as cyclophosphamide and streptozotocin, as well as platinum complexes including cisplatin. Furthermore platinum complexes such as cisplatin are described elsewhere in the reference as being alkylating agents as well. (p. 2 paragraph 37)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer streptozotocin or cisplatin in combination with the LPS agent described by Hebashima-1 and Abdalla. One of ordinary skill in the art would have been motivated to do so because as described by Nunes these are also alkylating agents used in chemotherapy, and the disclosure of Nunes describes a similar method in which an immunomodulator that produces endogenous cytokines is used to reduce effects of these compounds including immunosuppression and cachexia.
Furthermore while as discussed previously, claims 11, 24, and 25 and their dependent claims are interpreted as merely requiring that both agents be administered to the same subject in a manner that results in decreased adverse effects compared to administering the chemotherapeutic agent alone, even assuming for the sake of argument that the claims were interpreted in such a way as to positively require the administration of the chemotherapeutic agent at an increased dose compared to what would be administered alone, it would still have been obvious to one of ordinary skill in the art to administer such an increased dose in view of the disclosure of Nunes. In particular, one of ordinary skill in the art would have seen that Nunes describes one of the benefits of a similar immunomodulator as being to allow for administration of increased dosages of the chemotherapeutic by reducing its adverse effects, suggesting that a similar benefit could be realized with coadministration of chemotherapeutic agents with LPS.
Therefore the invention taken as a whole is prima facie obvious.
Conclusion
No claims are allowed in this action.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 1/22/2026