DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 03/06/2026, in which claims 11-13, 15, 18-19, and 21 are amended and claims 1-10 are canceled.
Claims 11-21 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/JP2021/022709, filed on 06/15/2021, which claims foreign priority to JP 2020-104116 filed on 06/16/2020 and JP 2020-136861 filed on 08/13/2020, and JP 2021-051608 filed on 03/25/2021.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 112(a) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, JP 2020-104116 filed on 06/16/2020 and JP 2020-136861 filed on 08/13/2020, and JP 2021-051608 filed on 03/25/2021, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
JP 2020-104116 filed on 06/16/2020 teaches altering the inflammatory pathways leading to cytokine storm. JP 2020-136861 filed on 08/13/2020 teaches Aureobasidium pullulans AFO-202 derived β-glucan as a vaccine to combat COVID-19. JP 2021-051608 filed on 03/25/2021 teaches Aureobasidium pullulans AFO-202 derived β-glucan as a vaccine to treat cancer. The disclosures of these three prior-filed applications fail to provide support for specifically increasing the ratio of lymphocytes to C-reactive-protein (LCR) and decreasing the ratio of neutrophils to lymphocytes (NLR), decreasing C-reactive protein (CRP) levels, increasing CD11b integrin levels, increasing mitochondrial ATPase production, increasing anti-CD69 antibody, or increasing anti-candida antibody in a subject as recited in instant claim 11. Similarly, they fail to provide support for treating a solid cancer and increasing T cell count and B cell count in the subject as recited in instant claim 13, treating renal carcinoma as recited in instant claim 14, treating a liquid cancer or administering a chemotherapy agent selected from the group consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or alleviating a nausea as recited in instant claim 15, treating lymphoma as recited in instant claim 16, decreasing expression of ACE2, CD13, or PDL-1 as recited in instant claim 20.
JP 2020-104116 filed on 06/16/2020 further teaches administering the beta-1,3-1,6 glucan only as a monotherapy and fails to provide support for administering teaches Aureobasidium pullulans AFO-202 derived β-glucan as an adjuvant to a conventional COVID-19 therapy as recited in instant claim 21. Support for this limitation is found in JP 2020-136861 filed on 08/13/2020.
Accordingly, claims 11-21 are not entitled to the benefit of the prior application and the earliest effective filing date afforded to the claims is 06/15/2021, which is the filing date of PCT/JP2021/022709 which provides support for the limitations of base claim 11. As the limitations of claim 11 are required in each of the dependent claims, dependent claims 12-21 are entitled to the same filing date of 06/15/2021.
Information Disclosure Statement
The information disclosure statement (IDS) dated 12/31/2025 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statement has been considered by the examiner.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 03/06/2026, with respect that the specification is objected to as containing a hyperlink has been fully considered and is persuasive, as amendments to the specification have been submitted. This objection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 11-21 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention has been fully considered and is persuasive, as claim 11 has been amended to remove the parenthetical and now recite ND1, and claim 15 has been amended to recite “a nausea”. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 12-16 and 18 are rejected under 35 U.S.C. 112(a), as because the specification, while being enabling for treating cancer or a viral infection, does not reasonably provide enablement for preventing cancer or a viral infection has been fully considered and is persuasive, as claims 12 and 13 have been amended to remove the scope of preventing cancer and claim 18 has been amended to remove the scope of preventing a viral infection. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claim 11 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Uenokawa has been fully considered and is persuasive, as claim 11 has been amended to require administration of the AFO-202 strain of Aureobasidium pullulans. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 11-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park has been fully considered and is persuasive, as claim 11 has been amended to require administration of the AFO-202 strain of Aureobasidium pullulans. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 11 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Park has been fully considered and is persuasive, as the scope of the claim has been amended to require administration of the AFO-202 strain of Aureobasidium pullulans. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 11-12 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Abidi in view of Park has been fully considered and is persuasive, as the scope of the claim has been amended to require administration of the AFO-202 strain of Aureobasidium pullulans. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 11 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chao in view of Uenokawa has been fully considered and is persuasive, as the scope of the claim has been amended to require administration of the AFO-202 strain of Aureobasidium pullulans. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 17 is rejected under 35 U.S.C. 103 as being unpatentable over Chao in view of Uenokawa as applied to claim 11, further in view of Han has been fully considered and is persuasive, as the scope of the claim has been amended to require administration of the AFO-202 strain of Aureobasidium pullulans. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/06/2026, with respect that claims 21 is rejected under 35 U.S.C. 103 as being unpatentable over Chao in view of Uenokawa as applied to claims 19-20, further in view of Cohen has been fully considered and is persuasive, as the scope of the claim has been amended to require administration of the AFO-202 strain of Aureobasidium pullulans. This rejection has been withdrawn.
The following are new grounds of rejection necessitated by Applicant’s amendment, in which claim 11 is amended to require administration of the AFO-202 strain of Aureobasidium pullulans.
Claim Objections
Claim 11 is objected to because of the following informalities: claim 11 does not indicate all amended subject matter using underline. In claim 11 the new limitation “AFO-202 strain” is not underlined on page 2 lines 12 and 19. 37 CFR 1.121 (c) (2) states that all claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn— currently amended.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 11-21 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.
Claim 11 recites AFO-202 strain (accession number: FERM BP-19327)” on lines 12-13. It is not clear whether the parentheticals are used to define the term or provide an optional example. Thus, it is unclear whether the limitations in the parentheticals are part of the claimed invention. Under the broadest reasonable interpretation the claim will be examined using the non-parenthetical limitation AFO-202 strain. Claims 12-21 depend from claim 11 and are indefinite for the same reason.
Claim Rejections - 35 USC § 102/103
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.
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.
Claim 11 is rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Ikewaki et al. (Microbiol. Immunol., 2007; IDS 01/31/2024, hereafter Ikewaki-1).
Ikewaki-1 provides a study of the immunological actions of Sophy β-glucan as disclosed in Ikewaki-1 N., et al. United States Patent 6956120 and Japan Patent 2004–329077. Sophy β-glucan is a type of β-1,3-1,6 glucan produced by the black yeast Aureobasidium pullulans (A. pullulans) strain AFO-202, currently available commercially as a health food supplement (abstract). Ikewaki-1 reports that, in general, the actions of β-glucans are not due to direct actions on cancer cells as is the case with chemical anti-cancer drugs, but rather to acting as a biological response modifier (BRM) to enhance the immunity of living organisms (page 862, paragraph 1). The complement component type-3 receptor (CR3) on leukocytes, monocytes, macrophages, granulocytes, and dendritic cells has been identified as a β-glucan receptor (page 862, paragraph 2). Sophy β-glucan, a β-1,3-1,6 glucan, currently available commercially as a health food supplement, has BRM and immunoregulatory functions. Sophy β-glucan appears to be an excellent candidate for future research by the health food, pharmaceutical and medical industries as an auxiliary health food for the maintenance and enhancement of human health (page 871, paragraph 2). Ikewaki-1 further teaches that Beta glucan is a powerful immune stimulator known to activate macrophages and have positive immune actions on B lymphocytes, natural killer cells and suppressor T cells in the immune system (page 862, paragraph 1). Although Ikewaki-1 does not expressly teach oral administration of Sophy β-glucan, Ikewaki-1 does teach Sophy β-glucan as a health food supplement. As such, one of ordinary skill in the art would immediately recognize that the Sophy β-glucan of Ikewaki-1 would have been administered orally.
Alternatively, to the extent that it is argued that Ikewaki-1 does not anticipate the method of instant claim 11, it would have been prima facie obvious before the effective filing date of the claimed invention for one of ordinary skill in the art to regulate an immune response in a subject by orally administering the Sophy β-glucan of Ikewaki-1, which is produced by Aureobasidium pullulans strain AFO-202, to arrive at the instantly claimed invention because Ikewaki-1 teaches that Sophy β-glucan is a health food supplement that has BRM and immunoregulatory functions. One of ordinary skill in the art would have a reasonable expectation of success because Ikewaki-1 teaches that Sophy β-glucan is an excellent candidate for future research by the health food, pharmaceutical and medical industries as an auxiliary health food for the maintenance and enhancement of human health.
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.
Claims 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Sier et al. (Int. J. Cancer, 2004; PTO-892) in view of Ikewaki et al. (Microbiol. Immunol., 2007; IDS 01/31/2024, hereafter Ikewaki-1).
Sier teaches a method of enhancing the killing of renal cell carcinoma micrometastases by monoclonal antibody G250 directed complement activation. Seir teaches that metastases from renal cell carcinomas (RCC) are resistant to radiation and chemotherapy but are relatively immunogenic (abstract). Seir investigates the possibility of using the patient’s own complement system to eliminate RCC using MAb G250 where the efficiency of the complement system against tumor cells is enhanced by using immune response modifiers such as β-glucan (page 900, paragraph 3). Specifically, Seir discloses administration of G250 to a spheroid model system of RCC where complement assisted cellular cytotoxicity (CACC) was not detectable after administration of G250 alone, but addition of soluble β-glucan induced the killing of MAb and iC3b opsonized spheroids by effector cells (abstract). Seir further elaborates that addition of soluble β-glucan, isolated from yeasts, mushrooms or plants, to phagocytic cells seems to function as a signal necessary to prime CR3 for binding of iC3b on opsonized tumor cells (page 907, paragraph 1). Seir concludes that for CACC the presence of CR3-priming β-glucan seems to be obligatory (abstract).
Seir states that other studies have shown that orally administered yeast β-glucan inhibited the growth of mouse colon tumors in mice and pulmonary metastasis of Lewis lung carcinoma, and elsewhere that anti-tumor antibodies in combination with soluble β-glucan therapy of mice implanted with mouse mammary tumors showed more than 57% reduction in tumor weight, whereas therapy failed in C3 or CR3 deficient mice, and teaches that their study using MAb G250 and β-glucan suggests that similar results might be obtained in RCC carcinoma patients (page 907, paragraph 1).
The teachings of Sier differ from that of the instantly claimed invention in that they do not teach oral administration of beta-1,3-1,6 glucan produced by Aureobasidium pullulans AFO-202 strain to a subject.
Ikewaki-1 provides a study of the immunological actions of Sophy β-glucan as disclosed in Ikewaki N., et al. United States Patent 6956120 and Japan Patent 2004–329077. Sophy β-glucan is a type of β-1,3-1,6 glucan produced by the black yeast Aureobasidium pullulans (A. pullulans) strain AFO-202, currently available commercially as a health food supplement (abstract). Ikewaki-1 reports that, in general, the actions of β-glucans are not due to direct actions on cancer cells as is the case with chemical anti-cancer drugs, but rather to acting as a biological response modifier (BRM) to enhance the immunity of living organisms (page 862, paragraph 1). The complement component type-3 receptor (CR3) on leukocytes, monocytes, macrophages, granulocytes, and dendritic cells has been identified as a β-glucan receptor (page 862, paragraph 2). Sophy β-glucan, a β-1,3-1,6 glucan, currently available commercially as a health food supplement, has BRM and immunoregulatory functions. Sophy β-glucan appears to be an excellent candidate for future research by the health food, pharmaceutical and medical industries as an auxiliary health food for the maintenance and enhancement of human health (page 871, paragraph 2). Ikewaki-1 further teaches that Beta glucan is a powerful immune stimulator known to activate macrophages and have positive immune actions on B lymphocytes, natural killer cells and suppressor T cells in the immune system (page 862, paragraph 1).
It would have been prima facie obvious before the effective filing date of the claimed invention for one of ordinary skill in the art to administer the Sophy β-glucan of Ikewaki-1, which is produced by Aureobasidium pullulans strain AFO-202, to the RCC patients suggested by Sier to arrive at the instantly claimed invention because Ikewaki-1 teaches that Sophy β-glucan is a health food supplement that is a BRM and suggests that it acts as a BRM by binding the complement component type-3 receptor (CR3). One of ordinary skill in the art would have a reasonable expectation of success because Sier teaches a method of treating RCC patients comprising administering CR3-priming β-glucan. Furthermore, one of ordinary skill in that art would expect to orally administer the Sophy β-glucan of Ikewaki-1 because Ikewaki-1 teaches that Sophy β-glucan is a health food, which suggests oral administration.
Claims 11 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Geller et al. (Frontiers in Immunology, 2020; PTO-892) in view of Ikewaki et al. (J. of Kyushu Univ. of Health and Welfare, 2018; PTO-892, hereafter Ikewaki-2) and Tang et al. (J. Thromb. Haemost. 2020; PTO-892).
Geller discloses an evaluation of the use of oral β-glucan in a prophylactic setting could be an effective way to boost immune responses and abrogate symptoms in COVID-19 (abstract). Geller teaches that it has been shown throughout the literature that the induction of trained immunity (TRIM) using such inducers as the BCG vaccine and β-glucan can provide protection through altered immune responses against a range of viral infections (abstract). β-glucans of various sources have also been widely shown to have significant antiviral effects, and have been shown to decrease the severity of both upper and lower respiratory tract viral infections. Geller teaches that these anti-viral effects are likely be due to the induction of TRIM (page 2, paragraph 2). Geller states that considering that β-glucan can be administered orally, has an extremely high safety profile, does not require a person to access healthcare to receive the treatment, and is known to act similarly to the BCG vaccine in terms of augmenting innate immune responses, there is a strong argument to be made in favor of the use of β-glucan to prophylactically treat against COVID-19 (page 2, paragraph 4). Geller teaches that the activation of macrophages, DCs, NK cell and neutrophils due to TRIM induced by β-glucan may result in more effective initial responses to infection, enhanced T and B-cell responses against SARS-CoV-2, and an overall decrease in the duration and severity of symptoms in COVID-19 (page 6, paragraph 2). Geller further teaches that patients with severe disease have been shown to have increased levels of IL-6, TNF-α, MCP1, MIP1A, and IP10, which is also correlated with endothelial dysfunction and increased levels of D-dimer (page 6, paragraph 3).
The teachings of Geller differ from that of the instantly claimed invention in that they do not teach beta-1,3-1,6 glucan produced by Aureobasidium pullulans AFO-202 strain.
Ikewaki-2 discloses a clinical study examining the serum levels of β-1,3-1,6 glucan (BG)-specific antibodies (IgG, IgA2 and IgM) and the peripheral blood (PB) levels of immune biomarkers, including the serum total immunoglobulin (IgG, IgA and IgM), interleukin-6 (IL-6), IL-12 and soluble-form CD44 (sCD44) in normal individuals (abstract). Ikewaki teaches that examination of the serum titers of BG-specific antibodies (IgG, IgA2 and IgM) in normal individuals shows correlations between the serum titers of BG-specific antibodies and the serum levels of various immune biomarkers strongly suggest the possible involvement of BG-specific antibodies in the regulation of the immune system (page 90, paragraph 2). Ikewaki-2 teaches that because the serum titers of BG-specific IgA2 were significantly correlated with the serum levels of IL-6, it is probable that BG-specific IgA2 influences IgA antibody production under IL-6 action in the mucosal and gut immune systems (page 89, paragraph 7).
Ikewaki-2 further teaches that the serum titers of BG-specific IgG, IgA2 and IgM showed a tendency to be correlated with the serum levels of IL-12 (page 89, paragraph 5). IL-12 is a cytokine produced by the dendritic cells (DCs), macrophages and neutrophils in response to antigenic stimulation. IL-12 plays an important role in the activities of NK cells and cytotoxic T-lymphocytes (CTLs), and directly mediates enhancement of the cytotoxic activity of NK cells. Ikewaki-2 teaches that because the serum titers of BG-specific IgG, IgA2 and IgM showed a tendency to be correlated with the serum levels of IL-12, BG-specific antibodies also indirectly regulate NK cell and CTL functions in the immune system. (Page 90, paragraph 1). Ikewaki-2 teaches that the β-1,3-1,6 glucans used in this study were synthesized by Sophy Co. from Aureobasidium pullulans strain AFO-202 and is currently available commercially as a health food supplement (page 88, paragraph 3).
Tang teaches that novel coronavirus infection demonstrates significantly abnormal coagulation parameters in severe novel coronavirus pneumonia (NCP) cases and describes the coagulation feature of patients with novel coronavirus pneumonia (NCP) (abstract). Tang discloses a study of patients with confirmed NCP (page 844, paragraph 2), wherein coagulation tests were collected on admission and during the hospital stay and normally and abnormally distributed quantitative variables were compared between survivors and non-survivors (paragraph bridging page 844-845). Tang teaches that at the late stages of NCP non-survivors revealed significantly higher D-dimer and fibrin degradation product levels, and longer prothrombin time compared to survivors on admission (page 845, paragraph 5).
One of ordinary skill in the art would have been motivated to orally administer the β-1,3-1,6 glucans derived from Aureobasidium pullulans strain AFO-202 as disclosed in Ikewaki-2 to the patients of Geller, who are at risk of developing severe novel coronavirus pneumonia, in order to decrease D-dimer levels and the risk of blood coagulation because Tang teaches that at the late stages of NCP non-survivors have significantly higher D-dimer levels and significantly abnormal coagulation, Geller teaches that the duration and severity of symptoms in COVID-19 can be decreased by the activation of TRIM by orally administering β-glucans and that β-glucans are additionally advantageous for treating COVID-19 because they can be administered orally and have an extremely high safety profile. One of ordinary skill in the art would have a reasonable expectation of success because Geller teaches that induction of TRIM involves activation of macrophages, DCs, NK cells and neutrophils and gives enhanced T and B-cell responses against SARS-CoV-2 and Ikewaki-2 teaches that BG-specific IgG, IgA2 and IgM are correlated with the serum levels of IL-12 and IL-12 plays an important role in the activities of NK cells and cytotoxic T-lymphocytes in the immune system.
Claims 11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Ikewaki et al. (US 6,956,120 B2; IDS 01/31/2024, hereafter ‘120) in view of Ikewaki et al. (Microbiol. Immunol., 2007; IDS 01/31/2024, hereafter Ikewaki-1) and Ikewaki et al. (J. of Kyushu Univ. of Health and Welfare, 2018; PTO-892, hereafter Ikewaki-2).
‘120 discloses β-glucans derived from Aureobasidium medium that have a variety of industrial and commercial uses, including applications in pharmaceutical or medical products or treatments (abstract). ‘120 further teaches that the β-1,3-1,6 glucan may be used in a method for treating inflammatory, infectious, or neoplastic diseases. These disease include, among others, viral infections (col. 7, lines 63-67). ‘120 specifically discloses a β-1,3-1,6 glucan that down-regulates the expression or function of CD11a molecules and is useful to prevent the attachment or adsorption of rotavirus (col. 4, lines 29-33). It may be administered orally in a food product and may also be combined with other pharmaceutical products or drugs (col. 8., lines 5-15).
The teachings of ‘120 differ from that of the instantly claimed invention in that they do not teach that the beta-1,3-1,6 glucan is produced by Aureobasidium pullulans AFO-202 strain or teach that IgA is increased in a subject.
Ikewaki-1 provides a study of the immunological actions of Sophy β-glucan as disclosed in Ikewaki N., et al. United States Patent 6956120 and Japan Patent 2004–329077. Sophy β-glucan is a type of β-1,3-1,6 glucan produced by the black yeast Aureobasidium pullulans (A. pullulans) strain AFO-202, currently available commercially as a health food supplement (abstract). Ikewaki-1 reports that, in general, the actions of β-glucans are not due to direct actions on cancer cells as is the case with chemical anti-cancer drugs, but rather to acting as a biological response modifier (BRM) to enhance the immunity of living organisms (page 862, paragraph 1). The complement component type-3 receptor (CR3) on leukocytes, monocytes, macrophages, granulocytes, and dendritic cells has been identified as a β-glucan receptor (page 862, paragraph 2). Sophy β-glucan, a β-1,3-1,6 glucan, currently available commercially as a health food supplement, has BRM and immunoregulatory functions. Sophy β-glucan appears to be an excellent candidate for future research by the health food, pharmaceutical and medical industries as an auxiliary health food for the maintenance and enhancement of human health (page 871, paragraph 2). Ikewaki-1 further teaches that the β-glucan receptor is involved in innate and adaptive immune responses to foreign antigens and pathogens, including β-glucan as an immune function stimulator (page 826, paragraph 2).
Ikewaki-2 discloses a clinical study examining the serum levels of β-1,3-1,6 glucan (BG)-specific antibodies (IgG, IgA2 and IgM) and the peripheral blood (PB) levels of immune biomarkers, including the serum total immunoglobulin (IgG, IgA and IgM), interleukin-6 (IL-6), IL-12 and soluble-form CD44 (sCD44) in normal individuals (abstract). Ikewaki teaches that examination of the serum titers of BG-specific antibodies (IgG, IgA2 and IgM) in normal individuals shows correlations between the serum titers of BG-specific antibodies and the serum levels of various immune biomarkers strongly suggest the possible involvement of BG-specific antibodies in the regulation of the immune system (page 90, paragraph 2). Ikewaki-2 teaches that because the serum titers of BG-specific IgA2 were significantly correlated with the serum levels of IL-6, it is probable that BG-specific IgA2 influences IgA antibody production under IL-6 action in the mucosal and gut immune systems (page 89, paragraph 7).
Ikewaki-2 further teaches that the serum titers of BG-specific IgG, IgA2 and IgM showed a tendency to be correlated with the serum levels of IL-12 (page 89, paragraph 5). IL-12 is a cytokine produced by the dendritic cells (DCs), macrophages and neutrophils in response to antigenic stimulation. IL-12 plays an important role in the activities of NK cells and cytotoxic T-lymphocytes (CTLs), and directly mediates enhancement of the cytotoxic activity of NK cells. Ikewaki-2 teaches that because the serum titers of BG-specific IgG, IgA2 and IgM showed a tendency to be correlated with the serum levels of IL-12, BG-specific antibodies also indirectly regulate NK cell and CTL functions in immune system. (Page 90, paragraph 1). Ikewaki-2 teaches that the β-1,3-1,6 glucans used in this study were synthesized by Sophy Co. from Aureobasidium pullulans strain AFO-202 (page 88, paragraph 3).
It would have been prima facie obvious before the effective filing date of the claimed invention to treat a viral infection such as a rotavirus infection by orally administering the β-1,3-1,6 glucan of ‘120 and that administration of the β-1,3-1,6 glucan of ‘120 in the treatment of viral infection such as a rotavirus infection would increase IgA antibody infection because ‘120 teaches a β-1,3-1,6 glucan that may be administered orally and may be used to treat a rotavirus infection, Ikewaki-1 teaches that the β-1,3-1,6 glucan of ‘120 is derived from Aureobasidium pullulans strain AFO-202 and binds to a β-glucan receptor involved in innate and adaptive immune responses, and Ikewaki-2 teaches that the β-1,3-1,6 glucan from Aureobasidium pullulans strain AFO-202 have a BG-specific IgA2 antibody that influences IgA antibody production. Thus one of ordinary skill in the art would understand that the adaptive immunity of the patient would product IgA2 antibodies in response to the administration of the β-1,3-1,6 glucan of ‘120, resulting in increased IgA production.
Claims 11 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Geller et al. (Frontiers in Immunology, 2020; PTO-892) in view of Ikewaki et al. (J. of Kyushu Univ. of Health and Welfare, 2018; PTO-892, hereafter Ikewaki-2).
Geller discloses an evaluation of the use of oral β-glucan in a prophylactic setting could be an effective way to boost immune responses and abrogate symptoms in COVID-19 (abstract). Geller teaches that it has been shown throughout the literature that the induction of trained immunity (TRIM) using such inducers as the BCG vaccine and β-glucan can provide protection through altered immune responses against a range of viral infections (abstract). β-glucans of various sources have also been widely shown to have significant antiviral effects, and have been shown to decrease the severity of both upper and lower respiratory tract viral infections. Geller teaches that these anti-viral effects are likely be due to the induction of TRIM (page 2, paragraph 2). Geller states that considering that β-glucan can be administered orally, has an extremely high safety profile, does not require a person to access healthcare to receive the treatment, and is known to act similarly to the BCG vaccine in terms of augmenting innate immune responses, there is a strong argument to be made in favor of the use of β-glucan to prophylactically treat against COVID-19 (page 2, paragraph 4). Geller teaches that the activation of macrophages, DCs, NK cell and neutrophils due to TRIM induced by β-glucan may result in more effective initial responses to infection, enhanced T and B-cell responses against SARS-CoV-2, and an overall decrease in the duration and severity of symptoms in COVID-19 (page 6, paragraph 2). Geller further teaches that patients with severe disease have been shown to have increased levels of IL-6, TNF-α, MCP1, MIP1A, and IP10, which is also correlated with endothelial dysfunction and increased levels of D-dimer (page 6, paragraph 3).
The teachings of Geller differ from that of the instantly claimed invention in that they do not teach beta-1,3-1,6 glucan produced by Aureobasidium pullulans AFO-202 strain.
Ikewaki-2 discloses a clinical study examining the serum levels of β-1,3-1,6 glucan (BG)-specific antibodies (IgG, IgA2 and IgM) and the peripheral blood (PB) levels of immune biomarkers, including the serum total immunoglobulin (IgG, IgA and IgM), interleukin-6 (IL-6), IL-12 and soluble-form CD44 (sCD44) in normal individuals (abstract). Ikewaki teaches that examination of the serum titers of BG-specific antibodies (IgG, IgA2 and IgM) in normal individuals shows correlations between the serum titers of BG-specific antibodies and the serum levels of various immune biomarkers strongly suggest the possible involvement of BG-specific antibodies in the regulation of the immune system (page 90, paragraph 2). Ikewaki-2 teaches that because the serum titers of BG-specific IgA2 were significantly correlated with the serum levels of IL-6, it is probable that BG-specific IgA2 influences IgA antibody production under IL-6 action in the mucosal and gut immune systems (page 89, paragraph 7).
Ikewaki-2 further teaches that the serum titers of BG-specific IgG, IgA2 and IgM showed a tendency to be correlated with the serum levels of IL-12 (page 89, paragraph 5). IL-12 is a cytokine produced by the dendritic cells (DCs), macrophages and neutrophils in response to antigenic stimulation. IL-12 plays an important role in the activities of NK cells and cytotoxic T-lymphocytes (CTLs), and directly mediates enhancement of the cytotoxic activity of NK cells. Ikewaki-2 teaches that because the serum titers of BG-specific IgG, IgA2 and IgM showed a tendency to be correlated with the serum levels of IL-12, BG-specific antibodies also indirectly regulate NK cell and CTL functions in the immune system. (Page 90, paragraph 1). Ikewaki-2 teaches that the β-1,3-1,6 glucans used in this study were synthesized by Sophy Co. from Aureobasidium pullulans strain AFO-202 and is currently available commercially as a health food supplement (page 88, paragraph 3).
One of ordinary skill in the art would have been motivated to orally administer the β-1,3-1,6 glucans derived from Aureobasidium pullulans strain AFO-202 as disclosed in Ikewaki-2 to COVID-19 patients because Geller teaches that the duration and severity of symptoms in COVID-19 can be decreased by the activation of TRIM by orally administering β-glucans and that β-glucans are additionally advantageous for treating COVID-19 because they can be administered orally, have an extremely high safety profile, and do not require a person to access healthcare to receive the treatment. One of ordinary skill in the art would have a reasonable expectation of success because Geller teaches that induction of TRIM involves activation of macrophages, DCs, NK cells and neutrophils and gives enhanced T and B-cell responses against SARS-CoV-2. Ikewaki-2 teaches that BG-specific IgG, IgA2 and IgM are correlated with the serum levels of IL-12 and IL-12 plays an important role in the activities of NK cells and cytotoxic T-lymphocytes in the immune system.
Regarding instant claim 20, it is noted that neither Geller nor Ikewaki-2 expressly teach that the method results in decreasing expression of ACE2, CD13, or PDL-1. However, these effects describe mechanistic outcomes caused by administration of the glucan. As the combined teachings of the prior art suggest the administration of the same active ingredients (a β-1,3-1,6-glucan derived from Aureobasidium pullulans) to the same patient population (COVID19 patients), a decrease in expression of ACE2, CD13, or PDL-1 would necessarily flow, thereby meeting the instant claim limitations. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2154(II) states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. Thus the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.
Claims 11 and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Expert Review of Vaccines, 2021; PTO-892) in view of Hoa et al. (J. Microbiol. Biotechnol., 2011; PTO-892).
Zhang teaches that adjuvants are essential to vaccines for immunopotentiation in the elicitation of protective immunity and provides a review of several carbohydrates with immunomodulatory properties include chitosan, β-glucan, mannan, and saponins, which have been used in vaccine formulation (abstract). Zhang teaches that β-glucan is a natural polysaccharide with immunostimulatory properties. Nanoparticles (NPs) containing β-glucan can be prepared through different methods and have shown great potential in antigen delivery and enhancement of the immune response. β-glucan-based NPs have the advantage of targeting immune cells and thus could be an appropriate choice for antigen delivery (page 802, paragraph 1). Zhang teaches that test vaccines against COVID-19 have shown great promise. Therefore, the application of carbohydrate containing NPs in nucleic acid-based vaccines could be a key advancement (page 807, paragraph 4). Zhang concludes teaching that carbohydrate-containing NPs are valuable in vaccines such as SARS-CoV-2 and influenza virus vaccines (page 807, paragraph 5).
The teachings of Zhang differ from that of the instantly claimed invention in that they do not teach beta-1,3-1,6 glucan produced by Aureobasidium pullulans AFO-202 strain.
Hoa discloses the adjuvant effect of sophy β-glucan (SBG), β-1,3-1,6 glucan produced by the black yeast Aureobasidium pullulans strain AF0-202, on antibody response in avian influenza A H5N1 and H5N2 vaccines (abstract). Hoa teaches that SBG offers a way of modulating immune cells in their response to avian influenza vaccines to enhance the immune response (page 410, paragraph 4). β-glucan[(1→3)-β-glucan] is an adjuvant that improves the immune response by modulating the immune system and the effector cells to produce cytokines (page 406, paragraph 1), and the immunogenicity of inactivated vaccines was improved by using the immunomodulatory adjuvant SBG (paragraph bridging page 409-410).
One of ordinary skill in the art would have been motivated to select a β-glucan such as the SBG of Hoa as the adjuvant for the adjuvanted SARS-CoV-2 vaccines suggested by Zhang because Zhang teaches that β-glucan-based NPs have the advantage of targeting immune cells and are valuable in vaccines such as SARS-CoV-2 and influenza virus vaccines. One of ordinary skill in the art would have a reasonable expectation of success because Zhang teaches that β-glucan-based NPs have the advantage of targeting immune cells and Hoa teaches that SBG modulates immune cells.
Regarding instant claim 20, it is noted that neither Zhang nor Hoa expressly teach that the method results in decreasing expression of ACE2, CD13, or PDL-1. However, these effects describe mechanistic outcomes caused by administration of the glucan. As the combined teachings of the prior art suggest the administration of the same active ingredients (a β-1,3-1,6-glucan derived from Aureobasidium pullulans) to the same patient population (COVID19 patients), a decrease in expression of ACE2, CD13, or PDL-1 would necessarily flow, thereby meeting the instant claim limitations. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2154(II) states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. Thus the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.
Response to Arguments
Applicant's arguments filed 03/06/2026 have been fully considered but they are not persuasive.
Applicant argues that none of Uenokawa, Park, Abidi, Chao, Han, or Cohen teach increasing LCR, decreasing NLR, decreasing CRP and D-dimer, increasing CD11b level, the production of mitochondrial ATPase and ND-1, anti-CD69 antibody, and anti-candida antibody by administering beta-1,3-1,6-glucan as they are recited in instant claim 11 (Remarks, page 36, paragraph 1). This is not persuasive.
Applicant’s arguments are moot, as new grounds of rejections are necessitated by the claim amendments requiring the new limitation of administration glucan derived from the AFO-202 strain. In so far as Applicant’s argument is applicable to the newly applied rejections the argument is not persuasive because the recitations of increasing LCR, CD11b, the production of mitochondrial ATPase, ND-1, anti-CD69 antibody, and anti-candida antibody, and decreasing NLR, decreasing CRP, IL-6, and D-dimer, as well as the newly introduced limitation of increasing the production of antiviral cytokine as they are recited in instant claim 11 describe mechanistic outcomes caused by administration of the recited glucan. Where the combined teachings of the prior art suggest the administration of the same active ingredients to the same patient population, these results recited in instant claim 11 would necessarily flow, thereby meeting the instant claim limitations. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2154(II) states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. Thus the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 03/06/2026.
Allowable Subject Matter
Claims 15-16 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The following is a statement of reasons for the indication of allowable subject matter.
Claims 15 and 16 are drawn to a method of treatment of a liquid cancer comprising administering chemotherapy selected from rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and an effective amount of beta-1,3-1,6 glucan produced by the Aureobasidium pullulans AFO-202 strain wherein a nausea from the chemotherapy in the subject is alleviated. Thus both claims 15 and 16 require alleviating a chemotherapy induced nausea. The closest prior art is Ikewaki et al. (US 6,956,120 B2; IDS 01/31/2024) which discloses Aureobasidium pullulans AFO-202 strain β-1,3-1,6-glucan as being useful for clinical therapy of cancer (col. 4, lines 17-18), including leukemia (col. 4, lines 12-19 and Figures 3-6). However, ‘120 does not disclose administration of the β-glucan with another chemotherapy agent and does not suggest reduction of chemotherapy induced nausea. The prior art broadly does not provide a teaching regarding the capacity of beta-1,3-1,6 glucan produced by the Aureobasidium pullulans AFO-202 strain – or other Aureobasidium pullulans strains – to alleviate chemotherapy induced nausea. The art also does not provide a predictable way of determining which β-glucans alleviate αchemotherapy induced nausea. Furthermore, Steimbach et al. (Clinical Nutrition, 2021; PTO-892) teaches that β-glucans as an adjuvant to chemotherapy are generally known to increase rather than decrease nausea during chemotherapy treatment (paragraph bridging pages 3111-3112 and Figure 2) such that one of ordinary skill in the art would not have a reasonable expectation of success in alleviating the nausea due to chemotherapy using rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone by the administration of beta-1,3-1,6 glucan produced by the Aureobasidium pullulans AFO-202 strain. Thus claims 15 and 16 are not obvious over the prior art.
Conclusion
No claims are allowed.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah Grace Hibshman whose telephone number is (703)756-5341. The examiner can normally be reached Monday-Thursday 7:30am-5:30pm (EST). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached on (571) 270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format.
For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
Prosecution Insights