DETAILED ACTION
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 .
Priority
The application claims priority to U.S. provisional application, 63/348,389, filed on 02 June 2022. The effective filing date is 02 June 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 30 June 2023 are being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-20 are the original claims filed on 07 May 2023. Applicant’s response on 12 February 2026 is acknowledged. Claims 2, 4, 9, 11, 13, 17, and 20 are cancelled, claims 1, 3, 5, 10, 12, 16, and 19 are amended, and claims 21-25 are new. Claims 1, 3, 5-8, 10, 12, 14-16, 18, 19, and 21-25 are the pending and the subject of this office action.
Withdrawn Objections/Rejections
In the office action of 12 November 2025, claims 3 and 20 were rejected under 35 U.S.C. 112(b) for failing to distinctly claim the subject matter, which the inventor(s) regard as the invention. Claim 20 has been cancelled, rendering the rejection moot. Claim 3 has been amended to remove the indefinite parenthetical and as a result the 35 U.S.C. 112(b) rejection has been withdrawn.
Claims 1-20 were rejected under 35 U.S.C. 103 over Know T, el al. (2019) Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive protein in tumor cells. Sci Rep. Apr 16;9(1):6136 (HEREIN Knox) in view of US 2022/0041584 A1 (herein Piscipio) and US 2020/0283520 A1 (herein Takimoto). Claims 2, 4, 9, 13, 17, and 20 were cancelled and as a result the rejections are moot. Applicant’s arguments that the examiner has failed to meet the requirements for a prima facie obviousness rejection were not found to be compelling, as discussed below, as a result the following prior art rejections remain.
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.
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 1, 3, 6-8, 10, 12, and 14-16, 18, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Knox T. et al. (2019) Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. Sci Rep. Apr 16;9(1):6136 (herein Knox) in view of US 2022/0041584 A1 (herein referred to as Piscopio) and US 2020/0283520 A1 (herein Takimoto).
In regard to claim 1, Knox teaches the use of HDAC6 inhibitors, with a focus on Nexturastat A, a small molecule, as an immunological priming agent to improve immune check-point blockade therapies, when used in combination to treat cancer (abstract). The example provided in this disclosure is a combination of a PD/PD-L1 immune checkpoint blockade, using an anti-PD-1 antibody, and an HDAC6 inhibitor, which acts as an immunological priming agent (abstract). Knox also discloses that the combination is capable of achieving a greater anti-tumor effect, in a melanoma mouse model, than either drug alone (Figures 2a-c and 3a-c). Furthermore, it is taught that HDAC6 inhibitors, either alone or in combination with the checkpoint blocker, reduces the levels of several immunosuppressive mediators (including PD-L1 and PD-L2), and result in an increase ratio of M1 to M2 macrophages (Figure 2d-o and 3d).
Knox does not teach a method for treating cancer using a combination of HDAC6 inhibitors and blocking agents of the CD47/ SIRPα immune checkpoint signaling pathway. Takimoto and Piscipio teach this deficiency.
Takimoto teaches a method for treating ovarian cancer comprising the administration of an immune checkpoint blockade of the CD47/SIRPα signaling pathway, through the use of a pharmaceutical composition comprising an anti-CD47 antibody, Hu5F9-G4 (also known as magrolimab) ([0063] and [0052]). Takmimoto teaches that CD47 has been identified as a key molecule mediating cancer cell evasion of phagocytosis ([0005]). It is taught that CD47 is a ligand of SIRPα, which is expressed on phagocytic cells (i.e. dendritic cells and macrophages), and that, upon formation of the CD47-SIRPα complex, initiation of a signal transduction cascade results in the inhibition of phagocytosis ([0007]). Takimoto also teaches that the dysregulation of surface CD47 levels, within a diverse array of tumors, results in an immunosuppressive tumor microenvironment (i.e. the normal immune function of phagocytosis is inhibited) ([0006]).
Piscopio teaches a method of treating a cancer patient with a therapeutically effective amount of an HDAC6 inhibitor ([0007], [0039] and [0042]). Additionally, Piscopio teaches a pharmaceutical composition containing an HDAC6 inhibitor and additional therapeutic agents ([0095]). Anti-CD47 antibodies are provided as one possible example of an additional therapeutic agents ([0099]).
As a result of the teachings of Knox it would have been prima facie obvious at the time the invention was filed to combine the teachings of Piscipio and Takimoto to treat cancers with a combination of HDAC6 inhibitors and CD47 inhibitors. As taught by Knox, Nexturastat A, either alone or in combination with the checkpoint blocker, reduces the levels of several immunosuppressive mediators and result in an increase ratio of M1 to M2 macrophages (Figure 2d-o and 3d), and when paired with an immune checkpoint therapy showed a more pronounced reduction in tumor size than with checkpoint blocker alone. This motivation can be summarized by the following quote from the abstract of Knox: “Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically “cold” tumors and subsequently improve ongoing immune check-point blockade therapies.” This statement provides a clear suggestion that HDAC6 inhibitors could be combined with immune check-point blockade therapies, beyond just PD-1/PD-L1 blockades. Piscipio’s inclusion of anti-CD47 antibodies in the list of potential therapeutic pairings for HDAC6 inhibitors suggests the combination, but clear motivation is provided by Takimoto. Takimoto teaches that tumors with elevated surface CD47 levels present an immunosuppressive tumor microenvironment (i.e. immunologically “cold” tumors), as discussed above, which provides clear motivation to combine the teaching of Knox with the CD47/SIRPα-targeted immune checkpoint blockade therapy taught by Takimoto. Furthermore, Knox provides evidence that the combination HDAC6-inhibitor-immune checkpoint blockade therapy presents a reasonable likelihood of success, as they demonstrated that HDAC6 inhibitors increase the ratio of M1 to M2 macrophages, which would help overcome the inhibition of phagocytosis present in CD47-overexpressing tumors. Thus, the teachings of Knox, Piscipio, and Takimoto all align to provide ample motivation to render the claimed invention disclosed in instant claim 1 to be prima facie obvious, to ones skilled in the art at the time of filing.
In regard to claim 3, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Knox teach the use of Nexturastat A (Knox (abstract)), as a HDAC6 inhibitor for the treatment of cancer ([0040]).
In regard to claim 6, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Piscopio teaches the use of a pharmaceutical composition comprising HDAC6 inhibitors as an anti-proliferative agent (i.e. limiting tumor growth) ([0098]).
In regard to claim 7, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Piscopio discloses a combination therapy, and teaches that the therapeutic, that is not an HDAC6 inhibitor, may be administered concurrently with, prior to, or subsequent to the HCAD6 inhibitor ([0096]).
In regard to claims 8, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Piscopio teaches multiple doses of an HDAC6 inhibitor ([0083] and [0084]). Additionally, Takimoto teaches combination therapy administered either daily, semi-weekly, weekly, once every two weeks, once a month, or annually ([00157]).
In regard to claim 10, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Piscopio teaches a direct mechanism of administration of HDAC6 inhibitors, as well as systemic mechanisms, such as oral administration ([0079]). Additionally, Takimoto teaches that the CD47 antibody may be administered systemically or locally ([0158]).
In regard to claim 12, Piscopio discloses an administered HDAC6 inhibitor dose range of between 0.001 -100 mg/kg, and the dose range per day is 0.1 mg – 2000 mg. This range encompasses the range claimed in the instant invention.
In regard to claims 14 and 15, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Takimoto teaches regular monitoring of patients undergoing the therapy to ensure safety and efficacy ([0253]).
In regard to claim 16, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Piscopio teaches a combination therapy, that can be combined with other treatments useful for treating cancer, such as hormone therapy ([0096]).
In regard to claim 18, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Piscopio discloses a combination therapy for the treatment of various cancers including breast cancer, melanoma, pancreatic cancer, ovarian cancer, lung cancer, hepatocellular cancer, among others ([0042]).
In regard to claim 23, Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1.
Takimoto teaches the use of Hu5F9-G4, also known as magrolimab, as an inhibitory anti-CD47 antibody ([0023], [0063] and [0052]).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Knox T. et al. (2019) Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. Sci Rep. Apr 16;9(1):6136 (herein Knox) , US 2022/0041584 A1 (herein referred to as Piscopio), and US 2020/0283520 A1 (herein Takimoto) in view of Shen S, et al. (2019) Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models. J Med Chem. 2019 Sep 26;62(18):8557-8577 (herein Shen).
Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim 1. The therapeutic CD47 inhibitor taught by Takimoto is Hu5F9-G4 (also known as magrolimab) ([0021]). The therapeutic HDAC6 inhibitor taught by Knox is Nexturastat A (Abstract).
Knox, Piscopio, and Takimoto do not teach SS-208 as a HDAC6 inhibitor in combination with magrolimab for the treatment of cancer. Shen teaches this deficiency.
Shen teaches the design, synthesis, and structural and biological characterization of SS-208 (Abstract). It is shown that the inhibitory potency of SS-208 is comparable to Nexturastat A and Tubastatin A in cancer cells (Results and Discussion: Inhibitory Potency of SS-208 is Comparable to NextA and Tubastatin A in Cancer Cells). In addition to possessing comparable HDAC6 inhibitory properties, SS-208 was shown to be AMES-negative, which differs from Nexturastat A and Tubastatin A. The authors show that the administration of the compound reduced melanoma tumor growth in a mouse model, and noted that these mice showed an increased M1 to M2 macrophage ratio in assayed tumors, compared to control animals (Results and Discussion: SS-208 Impairs Melanoma Tumor Growth in Immunocompetent Mice).
It would have been obvious to combine SS-208 (taught by Shen) with the method for treating cancer using a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic (taught by Knox, Piscipio, and Takimoto). As taught by Shen, the use of SS-208 as an anti-cancer therapeutic was known in the art prior to filing date of the current application. The applicant is effectively substituting one known element for another, both of which serve the same function, with predictable results. The molecule’s AMES-negative characteristics would make a clear motivation to use in the context of the claimed invention.
Claims 5, 19, and 24, are rejected under 35 U.S.C. 103 as being unpatentable over Knox T. et al. (2019) Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. Sci Rep. Apr 16;9(1):6136 (herein Knox) , US 2022/0041584 A1 (herein referred to as Piscopio), and US 2020/0283520 A1 (herein Takimoto) in view of Oronsky B, et al. (2021) RRx-001, a downregulator of the CD47- SIRPα checkpoint pathway, does not cause anemia or thrombocytopenia. Expert Opin Drug Metab Toxicol. 2021 Apr;17(4):355-357 (herein Oronsky).
Knox, Piscopio, and Takimoto teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claim. The therapeutic CD47 inhibitor taught by Takimoto is Hu5F9 G4 (5F9), and anti-CD47 antibody ([0063] and [0052]). The therapeutic HDAC6 inhibitor taught by Knox is Nexturastat A (Abstract).
Knox, Piscipio, and Takimoto do not teach the use of RRx-001 (CD47 inhibitor) and SS-208 (HDAC6 inhibitor). Oronsky and Shen teach these deficiencies.
Oronsky et al teach RRx-001, a small molecule down-regulator of CD47 and SIRP
α
(Abstract). It is also taught that RRx-001, at the time of publication, was in Phase 3 trials for treating small cell lung cancer, and was also expected to proceed to Phase 3 for the treatment of head and neck cancer (Introduction paragraph 2). RRx-001 is taught to use a unique mechanism of downregulation/inhibition, compared to anti-CD47 antibodies, which act by blocking the CD47-SIRPα interaction (Introduction paragraph 2). RRx-001 binds to red cells, activates the peroxisome proliferator-activated receptor gamma to inhibit MYC, down-regulates CD47, and activates phagocytosis (Section 2.1). The authors state that RRx-001 could be used in combination or in place of CD47 antibodies in anti-cancer treatment (Section 3).
It would have been obvious to combine RRx-001 (taught by Oronsky) with the method for treating cancer using a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic (taught by Knox, Piscipio, and Takimoto). As taught by Oronsky, the use of RRx-001 as an anti-cancer therapeutic was well-known in the art prior to filing date of the current application, moreover it was explicitly taught that the small molecule could be used as a substitute for an inhibitory anti-CD47 antibody in an anti-cancer treatment (Section 3). Knox, Piscipio, and Takimoto, teach a combination therapy in which the inhibitory anti-CD47 agent is an antibody, based on the teaching on the teachings of Oronsky the substitution of the antibody with a small molecule, RRx-001, would have been obvious to one skilled in the art. The applicant is effectively substituting one known element for another, both of which serve the same function, with predictable results. Oronsky also teaches that RRx-001 lacks the hematologic and systemic toxicity normally associated with anti-CD47 antibodies (Section 3). This provides motivation for its use in the context of the claimed invention.
Claims 21 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Knox T. et al. (2019) Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. Sci Rep. Apr 16;9(1):6136 (herein Knox) , US 2022/0041584 A1 (herein referred to as Piscopio), US 2020/0283520 A1 (herein Takimoto), and Oronsky B, et al. (2021) RRx-001, a downregulator of the CD47- SIRPα checkpoint pathway, does not cause anemia or thrombocytopenia. Expert Opin Drug Metab Toxicol. 2021 Apr;17(4):355-357 (herein Oronsky) in view of Shen S, et al. (2019) Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models. J Med Chem. 2019 Sep 26;62(18):8557-8577 (herein Shen).
Knox, Piscopio, Takimoto, and Oronsky teach a method for treating cancer comprising administering to a subject a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic, as discussed above for the 35 U.S.C. 103 rejection of claims 19 and 24. The therapeutic CD47 inhibitor taught by Oronsky is RRx-001, a small molecule (Abstract). The therapeutic HDAC6 inhibitor taught by Knox is Nexturastat A (Abstract).
Knox, Piscopio, Takimoto, and Oronsky do not teach SS-208 as a HDAC6 inhibitor in combination with a RRx-001 for the treatment of cancer. Shen teaches this deficiency.
Shen teaches the design, synthesis, and structural and biological characterization of SS-208 (Abstract). It is shown that the inhibitory potency of SS-208 is comparable to Nexturastat A and Tubastatin A in cancer cells (Results and Discussion: Inhibitory Potency of SS-208 is Comparable to NextA and Tubastatin A in Cancer Cells). In addition to possessing comparable HDAC6 inhibitory properties, SS-208 was shown to be AMES-negative, which differs from Nexturastat A and Tubastatin A. The authors show that the administration of the compound reduced melanoma tumor growth in a mouse model, and noted that these mice showed an increased M1 to M2 macrophage ratio in assayed tumors, compared to control animals (Results and Discussion: SS-208 Impairs Melanoma Tumor Growth in Immunocompetent Mice).
It would have been obvious to combine SS-208 (taught by Shen) with the method for treating cancer using a HDAC6 inhibitor therapeutic and a CD47 inhibitor therapeutic (taught by Knox, Piscipio, Takimoto, and Oronsky). As taught by Shen, the use of SS-208 as an anti-cancer therapeutic was known in the art prior to filing date of the current application. The applicant is effectively substituting one known element for another, both of which serve the same function, with predictable results. The molecule’s AMES-negative characteristics would make a clear motivation to use in the context of the claimed invention.
Response to Arguments
Applicant’s arguments filed in the response of 12 February 2026 have been fully considered in so far as they apply to the rejections of the instant application, but were not persuasive.
With regards to the rejections under 35 U.S.C. 103, the applicant argues that the analysis fails to establish grounds for a prima facie finding of obviousness. The applicant argues that there would have been no motivation for one skilled in the art to combine the examiner’s referenced art in such a way to arrive at the instant invention.
In regard to Knox, the applicant argues that the referenced art only refers to the PD-1/PD-L1 pathway, and implies that the authors did not intend for their teachings to extend beyond the limits of the PD-1/PD-L1 pathway. In the initial office action, filed on 12 November 2025, the examiner cited the following quotation: “Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically “cold” tumors and subsequently improve ongoing immune check-point blockade therapies.” A person skilled in the art would interpret this statement to extend to immunologically “cold” tumors, and not immunologically “cold” tumors that have elevated PD-1/PD-L1 levels. There are many cancers with immunologically “cold” tumors, that may or may not have elevated PD-1 levels, as evident by the teachings of Takimoto.
In regard to the teachings of Takimoto, the applicant argues that there is connection between the combination HDA6i and PD-1/PD-L1 blockade therapy. Takimoto teaches that tumors with elevated surface CD47 levels have immunosuppressive tumor microenvironments (i.e. immunologically “cold”), due to inhibited phagocytosis within macrophage and dendritic cell populations within the tumor microenvironment. This is the motivation for combining the teachings of Knox with Takimoto, as discussed in the 35 U.S.C. 103 rejections of the current office action and in the office action of 12 November 2025.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/ Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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