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 .
Response to Amendments and Arguments
2. Claims 20, 22-24, 27 and 35-39 are pending.
Claims 35-39, drawn to non-elected species and a non-elected invention are withdrawn from consideration.
Claims 30 and 40 have been cancelled.
Claims 20 and 22-24 have been amended.
Claims 20, 22-24 and 27 are examined on the merits.
3. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Grounds of Objection
Claim Objections
4. Claims 20 and 40 are no longer objected to because claim 20 recites “checkpoint” on line 9 and claim 40 has been cancelled.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 112
5. The NEW MATTER REJECTION of claims 20, 22-24 and 27 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or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement has been withdrawn in light of the amendment to claim 20 deleting the new matter, see Amendments to the Claims (page 2); and Remarks (paragraph bridging page 6 and 7), both in submitted July 8, 2026. Claim 30 has been cancelled.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
6. 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.
7. 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.
8. The rejection of claim(s) 20, 22-24 and 27 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) is maintained. Claims 30 and 40 have been cancelled.
The arguments and the Declaration under 37 CFR § 1.132 filed July 8, 2026 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 attained by Applicant.
In particular, the Supplementary Experiment 1 (SE1) reading on in vitro breast cancer assays (4T1) consists of 12 Figures (S1-01 through S1-12) with details spanning pages 2-8 of the Declaration. Only one figure, S1-12 on page 8 seems to show synergism, wherein the relative expression of C-C motif chemokine ligand 5 (CCL5) was statistically lower when exposed to the 4-agent combination, aPD-1+MET+2DG+IP6 as compared to the other three controls/combination groups. However, this experimental design is based on laboratory (outside of the body) assessment of one biomarker art known to be correlated with tumor progression and poor prognosis exposed to the 4-agent combination utilizes aPD-1 (as the other declaration figures) and no other immune checkpoint inhibitor (ICI). All other figures within SE1 seem to show additive and not synergism. Moreover, these figures also read on expression of markers, however it is not clear how the results translate clinically.
Supplementary Experiment 2 (SE2) reads on an in vivo study, wherein the 4-agent combination, aPD-1+MET+2DG+IP6 as compared to the other three controls/combination groups exhibits a synergistic effect in which colon cancer (colon 26) tumor volume is significantly lower over the days of aPD-1+MET+2DG+IP6 treatment, see page 9, Fig. S2-01.
Supplementary Experiment 2 (SE3) reads on an in vivo study, wherein the 4-agent combination, aPD-1+MET+2DG+IP6 as compared to the other three controls/combination groups exhibits a synergistic effect in which liver cancer (H22) tumor volume is significantly lower over the days of aPD-1+MET+2DG+IP6 treatment, see page 10, Fig. S3-01.
The data herein is not commensurate in scope with the claims, wherein all the data revealed utilizes only one ICI, aPD-1. One of ordinary skill in the art cannot extrapolate the results rendered with one ICI to another especially in combination with other therapeutic agents. Moreover, the figures within SE1 do not exemplify any in vivo data as the claims read on.
The claims read on three distinct cancers and it is clear from the Specification the combination reading on a biguanide-based compound, 2DG and inositol agent at dose ranges are 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. The figures within the declaration do not set forth any dosage ranges. The combination of references teaches the claimed invention. The teachings of all these references embody all three tenets of the requirements for establishing a proper case of obviousness.
Applicant’s Remarks, 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 claim 20.
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; and 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 (cols.). 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.
9. The rejection of claim(s) 20, 22-24 and 27 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) is maintained. Claims 30 and 40 have been cancelled.
The arguments and the Declaration under 37 CFR § 1.132 filed July 8, 2026 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 attained by Applicant.
In particular, the Supplementary Experiment 1 (SE1) reading on in vitro breast cancer assays (4T1) consists of 12 Figures (S1-01 through S1-12) with details spanning pages 2-8 of the Declaration. Only one figure, S1-12 on page 8 seems to show synergism, wherein the relative expression of C-C motif chemokine ligand 5 (CCL5) was statistically lower when exposed to the 4-agent combination, aPD-1+MET+2DG+IP6 as compared to the other three controls/combination groups. However, this experimental design is based on laboratory (outside of the body) assessment of one biomarker art known to be correlated with tumor progression and poor prognosis exposed to the 4-agent combination utilizes aPD-1 (as the other declaration figures) and no other immune checkpoint inhibitor (ICI). All other figures within SE1 seem to show additive and not synergism. Moreover, these figures also read on expression of markers, however it is not clear how the results translate clinically.
Supplementary Experiment 2 (SE2) reads on an in vivo study, wherein the 4-agent combination, aPD-1+MET+2DG+IP6 as compared to the other three controls/combination groups exhibits a synergistic effect in which colon cancer (colon 26) tumor volume is significantly lower over the days of aPD-1+MET+2DG+IP6 treatment, see page 9, Fig. S2-01.
Supplementary Experiment 2 (SE3) reads on an in vivo study, wherein the 4-agent combination, aPD-1+MET+2DG+IP6 as compared to the other three controls/combination groups exhibits a synergistic effect in which liver cancer (H22) tumor volume is significantly lower over the days of aPD-1+MET+2DG+IP6 treatment, see page 10, Fig. S3-01.
The data herein is not commensurate in scope with the claims, wherein all the data revealed utilizes only one ICI, aPD-1. One of ordinary skill in the art cannot extrapolate the results rendered with one ICI to another especially in combination with other therapeutic agents. Moreover, the figures within SE1 do not exemplify any in vivo data as the claims read on.
The claims read on three distinct cancers and it is clear from the Specification the combination reading on a biguanide-based compound, 2DG and inositol agent at dose ranges are 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. The figures within the declaration do not set forth any dosage ranges. The combination of references teaches the claimed invention. The teachings of all these references embody all three tenets of the requirements for establishing a proper case of obviousness.
Applicant’s Remarks, 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.
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; page 2, section 0026; and 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 “…breast cancer, …colon 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 claim 20 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; and 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
10. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
11. 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
21 September 2026
/Alana Harris Dent/
Primary Examiner, Art Unit 1643
