DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 4, 2025 has been entered.
Claims 20, 22-24, 27, 30 and 35-40 are pending.
Claims 35-39, drawn to non-elected species and a non-elected invention are withdrawn from consideration.
Claim 29 has been cancelled.
Claim 40 has been added.
Claims 20 has been amended.
Claims 20, 22-24, 27, 30 and 40 are examined on the merits.
Withdrawn Objection
Drawings
4. The drawings are no longer objected to under 37 CFR 1.83(a) because they show Figure 5, or more specifically, “[Figure 5]” as cited on page 70 in the specification submitted June 29, 2021 (with attorney docket number and “Patent Application” at top right corner of each page) is now of record in the Drawing submitted November 4, 2025, see Remarks, page 7 submitted on same date.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 103
5. The rejection of claim(s) 20, 22-24, 27, 29 and 30 under 35 U.S.C. 103 as being unpatentable over Wokoun et al., (Oncology Reports 37: 2418-2424, 2017/ IDS reference 3 on sheet 3 submitted June 29, 2021), and further in view of Scharping et al. (Cancer Immunol. Res. 5(1): 9-16, 2016/ IDS reference 10 on sheet 2 submitted June 29, 2021), Bačić et al. (Journal of Experimental & Clinical Cancer Research 29:12, 1-5, 2010/ IDS reference 1 on sheet 2 submitted June 29, 2021) and Schneider et al., (FEBS Letters 589: 1049-1058, 2015) is withdrawn in light of the amendment to claim 20, see Amendments to the Claims submitted November 4, 2025. Claim 29 has been cancelled.
New Grounds of Objection
Claim Objections
6. Claims 20 and 40 are objected to because of the following informalities: claim 20 recites “check-point” on line 9 of the while all other claims cite this term without a hyphen, see claim 20, line 3, claims 22-27; and claim 40 does not end with a punctuation mark, a period. Hence, it is not clear if the claim has ended or additional claim text is missing.
Correction is required.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
7. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
8. Claims 20, 22-24, 27 and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. THIS IS A NEW MATTER REJECTION. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has amended claim 20 to include two wherein clauses spanning the last ten lines of the claim,
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see Amendments to the Claims submitted November 4, 2025, page 2.
However, the Specification does not support these weight ratio ranges. The Specification, page 26, last full paragraph (para.) cites “a weight ratio of metformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol hexaphosphate or a pharmaceutically acceptable salt thereof may be a range 1 : 0.2 : 0.5 : 0.5 to 1: 5: 20 : 20,” and for phenformin, spanning pages 26 and 27, “the weight ratio is cited as ““a weight ratio of phenformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol hexaphosphate or a pharmaceutically acceptable salt thereof may be a range 1 : 1 : 1 : 1 to 1: 50: 200 : 200,”. These ratios do not support the numbers Applicant has included in the new limitation of claim 20.
The lower limits of metformin (1: 0.2: 0.5) and phenformin (1: 1: 1) seems to be of record on page 26 of the Specification, however not the upper limits (metformin, 1 : 20: 20; and phenformin, 1: 200: 200). Hence, the ranges cited in the new limitation of claim 20 are not supported by the disclosure.
Applicant is requested to delete the new matter or point out where support can be found by page, section, sentence or any other identifiable unit.
Claim Rejections - 35 USC § 103
9. 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.
10. 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.
11. Claim(s) 20, 22-24, 27, 30 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Wokoun et al., (Oncology Reports 37: 2418-2424, 2017/ IDS reference 3 on sheet 3 submitted June 29, 2021), and further in view of Scharping et al. (Cancer Immunol. Res. 5(1): 9-16, 2016/ IDS reference 10 on sheet 2 submitted June 29, 2021), Bačić et al. (Journal of Experimental & Clinical Cancer Research 29:12, 1-5, 2010/ IDS reference 1 on sheet 2 submitted June 29, 2021) and Kim et al., US 2014/023559 A1 (published August 21, 2014).
Applicant submitted a declaration to obviate the previously pending 35 U.S.C. 103 that has been withdrawn in light of the amendment to independent claim 20, see preceding pages.
The arguments and the Declaration under 37 CFR § 1.132 filed November 4, 2025 are insufficient to overcome the instant rejection, herein based on the combination of references as set forth, herein because: the declaration fails to set forth persuasive arguments and data when compared to the closest prior art herein. It is found to be directed to latent properties and not unexpected results. It would not have been unexpected for the claimed invention to achieve the synergistic results achieved by Applicants. The combination of references does teach the claimed invention. The teachings of all these references embody all three tenets of the requirements for establishing a proper case of obviousness.
Moreover, the data is not commensurate in scope with the claims. Figures 8-10 all read on breast cancer. However, the claims read broadly on any and all cancers listed in claim 30 and it is clear from the Specification the combination reading on a biguanide-based compound, 2DG and inositol agent is dependent upon the type of cancer treated, see page 25, 3rd paragraph (para.) to page 27. Hence, one of ordinary skill in the art would clearly infer the relative amount of the pharmaceutical combination for effective treatment is dependent on the specific cancer and it is not a “one size fits all” or universal treatment.
Applicant’s Remarks and Declaration and points of view have been carefully considered, but fail to persuade.
For the reasons cited herein, the claimed combination of therapeutic agents would expectedly and predictably render synergistic effects. Hence, the rejection is set forth for the reasons of record and cited herein.
Wokoun teaches treating triple-negative breast cancer (TNBC) cancer cell lines, MDA-MB-231 and HCC1806 with glycolysis inhibitor 2-deoxy-D-glucose (2DG) in combination with metformin, see Abstract on page 2418. Metformin is art known to be a biguanide drug.
Wokoun does not teach an in vivo breast treatment method, wherein an immune checkpoint inhibitor and inositol hexaphosphate (IP6) is administered with the combinatorial treatment in a weight ratio of metformin: 2DG: IP6 as set forth in claims 20 and 40.
However, Scharping teaches treating mice with cancer with metformin in combination with 0.2 mg anti-PD-1 immunotherapy, see Abstract on page 9; paragraph bridging pages 10 and 11; page 13, paragraph bridging both columns; and Figure 4A on page 14.
Moreover, Bačić teaches treating breast cancer patients with IP6 plus inositol in combination with an additional anticancer therapeutic agent, see page 1, Title and Abstract. “IP6 has shown a significant anticancer effect against different experimental cancers” including breast cancer, see Background with Abstract on page 1; page 4, Discussion segment.
And Kim teaches the administration of another biguanide-based compound, phenformin with 2DG in a weight ratio ranging from 1:400 to 100:1, as well as a weight ratio ranging from 1:200 to 10:1, see page 3, section 0034.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the teachings of Scharping to arrive at a single dosage range of 0.01 to 25 mg/kg for the PD-1 antibody and teachings of Kim to arrive at the desired weight ratio of therapeutic agents.
Moreover, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings well known in the art, that dosages of any pharmaceutical composition must be adjusted and optimized to arrive at the desired result.
It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references to join together the four therapeutic agents to effectively treat breast cancer. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all references that a multicombinatorial method of treating breast cancer with metformin, 2DG and an immune checkpoint inhibitor, a PD-1 antibody inhibitor is able to render clinical benefits to this type of cancer, see both references in their entireties. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Wokoun, “[c]o-treatment with 2DG in combination with metformin induced a significantly higher decrease in viability and a significant higher increase in apoptosis than treatment with the respective single substances.”, see page 2423, paragraph bridging both columns. Also, Scharping teaches anti-PD1 alone or metformin alone had no impact on tumor burden, however the combination of these two anti-cancer agents exhibited tumor regression, increases TIL T-cell activation, effector function, synergistic effects on tumor clearance, as well as metformin potentiated the efficacy of PD-1 blockade and reduced tumor hypoxia, see Title; paragraph bridging pages 13 and 14; and entire document.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references in order to effectively treat breast cancer with the further administration of IP6 plus inositol. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in the references combinatorial treatment of a variety of diseases including breast cancer has been successful with the combination of anticancer therapeutic agents, see all documents and in particular, entire Bačić reference.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the teachings of Kim to arrive at the desired weight ratios for the biguanide-based compound: 2DG: inositol hexaphosphate listed in the claims. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Kim “[t]hese ingredients act in synergy with each other, thus exhibiting more potent inhibitory activity against the growth of cancer cells, compared to individual ingredients” and exerts “…a surprisingly increased anticancer effect”, see abstract; page 1, sections 0007 and 0008; page 2, sections 0022 and 0026; page 3, section 0032; page 5, section 0078; and Example 4 spanning pages 8 and 9.
12. Claim(s) 20, 22-24, 27, 30 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al., US 2014/023559 A1 (published August 21, 2014), and further in view of Scharping et al. (Cancer Immunol. Res. 5(1): 9-16, 2016/ IDS reference 10 on sheet 2 submitted June 29, 2021), and Bačić et al. (Journal of Experimental & Clinical Cancer Research 29:12, 1-5, 2010/ IDS reference 1 on sheet 2 submitted June 29, 2021). Kim teaches a method of treating cancer compromising phenformin and 2-deoxy-D-glucose (2DG), as well as with another anticancer agent “…by which a therapeutically synergistic effect can be obtained…”, see page 1, sections 0007, 0008, 0010 and 0011; and page 2, section 0026; Table 7 and sections 0115, 0116, 0121 on page 9. The anticancer agent may be immunotherapy and biological agents, see page 5, section 0079.
The taught combination of therapeutic agents is able to treat “…uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer, and liver cancer,”, see page 2, section 0021.
“[T]he pharmaceutical composition may comprise phenformin hydrochloride and 2-deoxy-D-glucose preferably at a weight ratio of from 1:400 to 100:1, and more preferably at a weight ratio of from 1:200 to 10:1.”, see page 3, section 0034.
Kim does not the claimed method, wherein the biguanide-based compound is metformin, the anticancer agent is an immune checkpoint inhibitor in a single dosage in a range of 0.01 to 25 mg/kg with inositol hexaphosphate (IP6) and the combinatorial pharmaceutical composition administered for treatment in the weight ratios set forth in claims 20 and 40 for the biguanide-based compound: 2DG: IP6.
However, Scharping teaches treating mice with cancer with another biguanide-based compound, metformin in combination with 0.2 mg anti-PD-1 immunotherapy, see Abstract on page 9; paragraph bridging pages 10 and 11; page 13, paragraph bridging both columns; and Figure 4A on page 14.
Scharping teaches anti-PD1 alone or metformin alone had no impact on tumor burden, however the combination of these two anti-cancer agents exhibited tumor regression, increases TIL T-cell activation, effector function, synergistic effects on tumor clearance, as well as metformin potentiated the efficacy of PD-1 blockade and reduced tumor hypoxia, see Title; paragraph bridging pages 13 and 14; and entire document.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the teachings of Scharping to arrive at a single dosage range of 0.01 to 25 mg/kg for the PD-1 antibody, as well as substitute the phenformin of Kim with the metformin of Scharping.
Bačić teaches treating breast cancer patients with IP6 plus inositol in combination with an additional anticancer therapeutic agent, see page 1, Title and Abstract. “IP6 has shown a significant anticancer effect against different experimental cancers” including breast cancer, see Background with Abstract on page 1; page 4, Discussion segment.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references in order to effectively treat breast cancer with the further administration of IP6 plus inositol. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in the references combinatorial treatment of a variety of diseases including breast cancer has been successful with the combination of anticancer therapeutic agents, see all documents and in particular, entire Bačić reference.
It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references to join together the four therapeutic agents to effectively treat breast cancer. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all references that a multicombinatorial method of treating breast cancer with one of the two taught biguanide-based compounds, 2DG and an immune checkpoint inhibitor, a PD-1 antibody inhibitor is able to render clinical benefits to this type of cancer, see both references in their entireties. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Kim “[t]hese ingredients act in synergy with each other, thus exhibiting more potent inhibitory activity against the growth of cancer cells, compared to individual ingredients” and exerts “…a surprisingly increased anticancer effect”, see abstract; page 1, sections 0007 and 0008; page 2, sections 0022 and 0026; page 3, section 0032; page 5, section 0078; and Example 4 spanning pages 8 and 9.
Conclusion
13. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached between the hours, 8AM-8PM, Monday through Friday.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
Alana Harris Dent
January 2, 2026
/Alana Harris Dent/
Primary Examiner, Art Unit 1643