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 .
DETAILED ACTION
Claims 1, 3-6, 8-15, and 21 are pending.
Claims 2 and 6-7 were canceled.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/30/2026 has been entered.
Claim Objections and Rejections Withdrawn
The previous rejections of claims 2 and 6-7 are moot in view of claim cancellation.
The previous rejection of claims 1, 3-6, 8-15, and 21 under 35 U.S.C. 103 is withdrawn in view of claim amendment.
Claim Interpretation
Claims 1, 3-6, 8-15, and 21 claim a pharmaceutical composition comprising:
(E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate; and
an anti-PD-1 antibody or an anti-PD-L1 antibody,
wherein the claims 12-15, further recite process details or results of the composition. Recitation of process details or results in which the composition is administered is outside of the scope the claimed composition. Thus, the composition is claimed, not the process of administration. Regarding claims 13-14, the claim further narrows the dependent claim because separate compositions would be required, wherein claim 14 requires only intravenous or oral formulation of the composition. Therefore, the claimed composition will be examined below for claims 1, 3-6, 8-15, and 21.
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 3-4, and 8 are 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.
Claims 3-4 and 8 recites the limitation: 1) "the dose" in line 1 of claim 3; 2) "the dose" in lines 1-2 of claim 4; and “the salt” in line 1 of claim 8; There are insufficient antecedent basis for these limitations in the claims. A dose or salt has not been previously introduced
Regarding instant claims 3-4, pharmaceutical compositions are claimed of: 1) 1 to 200 mg/kg of an anti-PD-1 antibody; or 2) 10-500 mg/kg of (E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate, but a composition in the units of “mg/kg” has an indefinite weight. Thus, the metes and bounds are indefinite of the claimed compositions.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8, 12, and 15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding instant claim 8, the claim recites the salt as (E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate, but the dependent claim already contains (E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate without another species or genus. Thus, the claim does not further narrow the claimed subject matter.
Regarding instant claim 12, a composition is claimed, but the claim recites details of administration of a dose less than or equal to a therapeutically effective dose. The administration details do not further limit the composition. Thus, claim 12 does not further narrow the composition of claim 1.
Regarding instant claim 15, a composition is claimed, but the claim recites details of the result of a method, wherein the composition is synergistic in inhibiting the growth of or killing cancer cells. The result of administration of the composition does not further limit the composition. Thus, claim 12 does not further narrow the composition of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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, 8-15, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016153839 (Pinheiro EM et al. reference of record), Na Y-S et al. (Oncology reports 2010 1509-1514 reference of record), WO 2007052938 (Lee CH et al. reference of record), Fasinu P et al. (Drug Dispos. 2011 32, 185-209 reference of record), and US 20170327582 (Bissonnette RP et al.).
Pinheiro taught a method of effectively treating a subject with colon cancer with a combination composition of 10 mg/kg anti-PD-1 antibody every 5 days and 150 mg/kg of the HDAC inhibitor Vorinostat daily, wherein the anti-tumor response was greater than either Vorinostat or anti-PD-1 single agent treatment (pages 38-39, paragraph 169-170 and Fig 8A-8B). Pinheiro taught the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to PD-1 or to PD-L1 and blocks the binding of PD-L1 to PD-1 (page 3, paragraph 11). Regarding instant claim 5, Pinheiro taught pembrolizumab is an anti-PD-1 antibody that binds human PD-1 for the treatment method (page 17, paragraph 99), wherein a dose of 2, 5, or 10 mg/kg is preferred every 2 or 3 weeks (pages 28-29, paragraph 144 and 146). Regarding instant claim 6, Pinheiro taught MEDI4736, which is also known as durvalumab, is and anti-PD-L1 antibody that binds human PD-L1 for the treatment method (pages 17-18, paragraph 100). Regarding instant claim 10, Pinheiro taught each therapeutic agent in a combination therapy of the invention may be administered simultaneously in the same medicament (page 25, paragraph 129). Regarding instant claim 12, Pinheiro taught administering a composition of 10 mg/kg of an anti-PD-1 antibody was not a fully therapeutic dose to subjects in the absence of an HDAC inhibitor as shown in the monotherapy dose of Pinheiro Fig 8A. Pinheiro further taught each therapeutic agent in a combination therapy of the invention may be administered simultaneously in the same medicament or sequentially (page 25, paragraph 129). Pinheiro taught determination of the appropriate dosage regimen may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and will depend, for example, the patient's clinical history, the type and stage of the cancer to be treated and biomarkers of response to one or more of the therapeutic agents in the combination therapy (pages 27-28, paragraph 138).
Pinheiro did not teach: A) a composition of a HDAC inhibitor (E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate and PD-1 inhibitor combination composition; B) a composition of the HDAC inhibitor (E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate and PD-1 inhibitor pembrolizumab combination composition; C) a composition of (E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate and PD-L1 inhibitor durvalumab combination composition; or D) a single embodiment of combining each therapeutic agents in the combination therapy for administered simultaneously in the same single preparation medicament, but this is obvious in view of Na, Pinheiro, Lee, Fasinu, and Bissonnette.
Na taught: CG2 has the structure
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(Fig. 1), dose-dependently inhibits colon cancer cell growth (Table 1), effectively inhibits colon cancer tumor cell growth in vivo with daily administration of 20 mg/kg via injection (page 1510, left column, third paragraph and Fig. 4A), and effectively blocks histone deacetylation in vivo (Fig 5).
Lee taught an alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivative of (E)-N1-(3-( dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl) octenediamide (page 5), which is the compound of example 14 (page 48). Lee taught the alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamides may be used in the form of a pharmaceutically acceptable addition salt, wherein the salt is a phosphoric acid salt (page 7, lines 7-13 and page 11, lines 14-19).
Fasinu taught phosphate salt moieties as a conventional approach to enhance solubility properties (page 188, left column, first bullet of last paragraph).
Bissonnette taught combinations that of HDACi and PD-1 inhibitors for treating cancer (page 1, paragraph 2). Bissonnette taught pembrolizumab can be administered in the combination at an amount up to 20 mg/kg every 2 to 3 weeks (page 1, paragraph 234).
Regarding instant claims 1-7, 9-11, and 13-15, it would have been obvious for a person having ordinary skill in the art to take the method of Pinheiro of:
effectively treating a subject with colon cancer with a combination composition of 10 mg/kg anti-PD-1 antibody every 5 days and 150 mg/kg Vorinostat daily, wherein the anti-tumor response was greater than either Vorinostat or anti-PD-1 single agent treatment – and:
exchange the 150 mg/kg Vorinostat with the effective HDAC inhibitor 20 mg/kg CG2, which is (E)-N1-(3-( dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl) octenediamide of Na;
Use the HDAC inhibitor as the pharmaceutically acceptable phosphoric acid salt form of (E)-N1-(3-( dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl), which is (E)-Nl-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate in view of Lee.
exchange the anti-PD-1 antibody with the anti-PD-1 inhibitor pembrolizumab with a dose of 2, 5, or 10 mg/kg every 2 or 3 weeks as taught by Pinheiro;
use a combination of an HDAC inhibitor and anti-PD-1 inhibitor, wherein the PD-1 inhibitor is an amount up to 20 mg/kg for treating cancer in view of Bissonnette;
exchange the anti-PD-1 antibody with the anti-PD-L1 inhibitor MEDI4736, which is also known as durvalumab, as taught by Pinheiro; and
combine each of the therapeutic agents in the combination therapy for administered simultaneously in the same single preparation medicament on days wherein the subject receives both the HDAC inhibitor and the PD-1 or PD-L1 antibody as taught by Pinheiro; and
combine each of the therapeutic agents in the combination therapy for sequential administration or simultaneously administration in the same single preparation medicament wherein the subject receives both the HDAC inhibitor and the PD-1 or PD-L1 antibody as taught by Pinheiro.
This is obvious because: 1) CG2 is an HDAC inhibitor that dose-dependently inhibits colon cancer cell growth, effectively inhibits colon cancer tumor cell growth in vivo with daily administration of 20 mg/kg, and effectively blocks histone deacetylation in vivo; 2) Lee taught the alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamides may be used in the form of a pharmaceutically acceptable addition salt, wherein the salt is a phosphoric acid salt; 3) Pinheiro taught using the anti-PD-1 inhibitor as pembrolizumab in the combination treatment wherein a dose of 2, 5, or 10 mg/kg mg/kg is preferred every 2 or 3 weeks; 4) Bissonnette taught pembrolizumab can be administered in combination with an HDAC inhibitor for cancer treatment at an amount up to 20 mg/kg every 2 to 3 weeks; 5) Pinheiro taught using the anti-PD-L1 inhibitor MEDI4736, which is also known as durvalumab, in the combination treatment; 6) Pinheiro taught each therapeutic agent in a combination therapy of the invention may be administered simultaneously in the same single preparation medicament; and 7) Pinheiro taught each therapeutic agent in a combination therapy of the invention may be administered sequentially or simultaneously in the same single preparation medicament. Sequential or simultaneous single medicament administration would require separate formulations because sequential administration would have at least one less component.
There is a reasonable expectation of success because: 1) CG2 is an HDAC inhibitor that dose-dependently inhibits colon cancer cell growth, effectively inhibits colon cancer tumor cell growth in vivo with daily administration of 20 mg/kg, and effectively blocks histone deacetylation in vivo; 2) the phosphoric salt was taught to be pharmaceutically acceptable by Lee and Fasinu taught phosphate salt moieties as a conventional approach to enhance solubility properties. Thus, the composition of an HDAC inhibitor as a phosphate salt form and an anti-PD-1 or anti-PD-L1 would still be expected to effectively inhibit cancer growth; 3) pembrolizumab binds human PD-1 to block the same protein and would be effective in humans in combination therapy with the HDAC inhibitor and 2, 5, or 10 mg/kg every 2 or 3 weeks; 4) usage of PD-1 antibody inhibitors such as pembrolizumab in combination with HDAC inhibitors are thought to be effective at dosages of 20 mg/kg and Pinheiro taught determination of the appropriate dosage regimen may be made by the clinician. Thus, treatment of dosages of 2, 5, 10 or 20 mg/kg of PD-1 antibody inhibitors are within the range for a clinician to use; 5) MEDI4736, which is also known as durvalumab, binds human PD-L1 and would inhibit the PD-1 signaling pathway and would be effective in humans in combination therapy with the HDAC inhibitor; 6) combining the HDAC inhibitor and PD-1 or PD-L1 antibody inhibitor in the same composition would allow the subjects to only have a single administration of the composition on days wherein the agents are both administered and CG2 and the anti-PD-1 antibody are both injectable; and 7) sequential administration of the HDAC inhibitor and the PD-1 antibody inhibitor in separate formulations was present in the effective method of Pinheiro wherein a HDAC inhibitor was administered daily without a PD-1 antibody inhibitor the day before and the day. Further, sequential administration would have at least one less component in the formulation with a separate dosage.
This would produce a method of treating a subject with colon cancer wherein a combination composition of:
An HDAC inhibitor of 20 mg/kg (instant claim 4) CG2 daily, which is (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl) octenediamide phosphate (instant claim 8); and
2, 5, 10, or 20 mg/kg (instant claim 3) every 2 or 3 weeks of an anti-PD-1 antibody pembrolizumab (instant claim 5) or the PD-L1 antibody MEDI4736, which is also known as durvalumab (instant claim 6),
was administered to the subject, wherein the weight ratio of the composition of the HDAC inhibitor to the PD-1 antibody would be 1:0.1, 1:0.25, 1/0.5, or 1:1, wherein the composition would naturally be synergistic (instant claim 15), wherein the CG-745 (also known as CG-2) was administered before the anti-PD-1 antibody, which would require a separate composition and formulation in a separate dosage form (instant claims 11, 13-14 and 21), and wherein on days wherein the CG2 and anti-PD-1 or anti-PD-L1 antibody where administered on the same day the composition was administered simultaneously in the same single preparation medicament (instant claims 9-10) (instant claim 1).
Regarding instant claim 12, the Pinheiro composition of 10 mg/kg of an anti-PD-1 antibody was not a fully therapeutic dose to subjects in the absence of an HDAC inhibitor as shown in the monotherapy dose of Pinheiro Fig 8A. Thus, the above combination CG2 and anti-PD-1 antibody composition meets the claim limitations of instant claim 12.
Response to Arguments
Applicant argues amended claim 1 recites, in part, "[a] pharmaceutical composition for treating or preventing cancer comprising (E)-N1-(3-( dimethylamino )propyl)-NB-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate; and an anti-PD-1 antibody or an anti-PD-L1 antibody; wherein the weight ratio of the (E)-N 1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate to the anti-PD-1 antibody or the anti-PD-L 1 antibody is 1:1 to 1:5” ( emphasis added). Neither Pinheiro nor Na, alone or in combination, discloses this claimed composition. Pinheiro does not disclose (E)-N 1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate, and Na does not disclose its use in combination with an anti-PD-1 antibody or an anti-PD-L 1 antibody, much less at the claimed 1 :1 to 1 :5 weight ratio.
In response, Applicant's arguments filed 3/30/2026 have been fully considered but they are not persuasive. The updated rejection is above. Importantly, the claim states that the ratio of the (E)-N1-(3-( dimethylamino )propyl)-NB-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate (CG-745); to an anti-PD-1 antibody or an anti-PD-L1 antibody is (1:1) to (1:5). The ratio claimed does not overlap with the effective composition tested in the instant disclosure, wherein Fig. 1 treats subjects with 20 mg/kg CG-745 and 5 mg/kg anti-PD-1 antibody. This would be a ratio of (4:1) not (1:4). Compositions of CG-745 and an anti-PD-1 antibody have not been shown to be effective within the range claimed, but the 1:1 ratio is obvious as detailed above. Thus, the claimed subject matter does not encompass the surprising results of instant Fig. 1.
Applicant argues the Office's proposed modification improperly reconstructs Pinheiro's Vorinostat based immunotherapy combination using a chemotherapy-sensitization context.
Applicant argues MPEP § 2143.01 (VI) recognizes that a proposed modification does not support a prima facie case of obviousness if it would change the principle of operation of the reference being modified or render it unsatisfactory for its intended purpose.
That principle applies here because Pinheiro's disclosed operating rationale is a Vorinostat-based checkpoint-blockade regimen. Pinheiro reports that administering Vorinostat together with an anti-PD-1 regimen produces anti-tumor activity, and Pinheiro's examples show regressions only in a subset of animals. Pinheiro, p. 25, ,i 129; pp. 38-39, ,i,i 169-170; Figs. 8A-8B. Pinheiro is therefore tied to a specific immunotherapy combination involving Vorinostat, not to a generic proposition that any HDAC inhibitor can be substituted into the regimen with the same result.
The Office's proposed modification therefore reconstructs Pinheiro's Vorinostat-based immunotherapy combination into a different therapeutic concept imported from a chemotherapy sensitization reference. This distinction is technically meaningful because Pinheiro is directed to immune-mediated anti-tumor activity in the context of PD-1 checkpoint blockade, where the relevant question is whether the HDAC inhibitor will modulate the immune microenvironment in a manner that supports anti- tumor immunity. Na, by contrast, is directed to chemotherapy-mediated tumor cell cytotoxicity, where the relevant question is whether CG2 sensitizes tumor cells to cytotoxic agents such as irinotecan, 5-FU, or oxaliplatin. Na, pp. 1509-1514. Thus, the two references do not merely disclose different partner agents; they operate toward different technical objectives through different biological mechanisms.
A person of ordinary skill in the art (hereinafter "POSITA") therefore would not have been motivated to rely on Na to cure the deficiencies of Pinheiro, much less conclude that results disclosed for CG2 in Na's chemotherapy-sensitization context would transfer to Pinheiro's checkpoint-immunotherapy context merely because both regimens involve an HDAC inhibitor.
Applicant argues a POSITA would be dissuaded from substituting Na's CG2, disclosed in a chemotherapy-sensitization context, into Pinheiro's immunotherapy regime. The Office acknowledges that Pinheiro does not disclose Applicant's claimed HDAC inhibitor and instead relies on Vorinostat in combination with an anti-PD-1 regimen. Final Office Action, p. 5. The Office attempts to cure that deficiency with Na's CG2, asserting that it would have been obvious to substitute CG2 for Vorinostat because both are HDAC inhibitors and CG2 inhibits colon cancer tumor growth and blocks histone deacetylation in vivo. Final Office Action, pp. 5-9. A POSITA, however, would not have looked to Na as reasonably pertinent to the therapeutic context addressed by Pinheiro. Pinheiro is directed to checkpoint-blockade immunotherapy and discloses that Vorinostat may be used with an anti-PD-1 regimen to improve anti-tumor response relative to either monotherapy. Pinheiro, pp. 38-39, ,i,i 169-170; Fig. 8A-8B. Na, by contrast, is directed to chemotherapy sensitization, studying CG2 in combination with lrinotecan, 5-FU, and Oxaliplatin. Na, pp. 1509-1514. Na does not evaluate anti-PD-1 or anti-PD-L 1 combinations, does not address immune-mediated anti-tumor activity, and does not suggest that CG2 is suitable for checkpoint-blockade therapy.
Applicant argues even if the scope of analogous art is broad, it is not without limit, and the Office's position that the therapeutic contexts of Pinheiro and Na are "the same" because both Vorinostat and CG2 are anti-cancer HDAC inhibitors defines the context at too high a level of generality. The relevant question is whether Na would have led a POSITA to expect that CG2, disclosed in a chemotherapy-sensitization context, could be substituted for Pinheiro's Vorinostat in a checkpoint-blockade immunotherapy regimen with a reasonable expectation of success. It would not. Na is directed to chemotherapy sensitization, not checkpoint immunotherapy, and it teaches that combinations containing CG2 are both partner-dependent and regimen-dependent: the combination with irinotecan was beneficial, the combination with 5-FU was not meaningfully better than the single agents, and the combination with oxaliplatin showed no additive anti-tumor effect and significant weight loss. Na, pp. 1510, 1514; Kim Decl. ,¶ ¶ 9-10. These results would have dissuaded a POSITA from using CG2 as a substitute for Vorinostat in Pinheiro's immunotherapy regimen because Na affirmatively shows that CG2 was not a universally suitable combination partner and that its use could lead to no added benefit, or even an undesirable toxicity profile, depending on the partner therapy. A POSITA therefore would have been dissuaded from adopting the Office's proposed substitution of CG2 for Vorinostat in Pinheiro's immunotherapy regimen.
Applicant argues the Kim Declaration explains that it was generally known before the filing of the '356 Application that pan-HDAC inhibitors can have contrasting effects on the immune system, including effects that suppress anti-cancer immunity rather than enhance it, and therefore would not have been treated by a POSITA as equivalent substitutes in a checkpoint-blockade regimen. Kim Decl. , ¶6. The Kim Declaration further explains, with reference to Kim et al. (Ex. B to Kim Decl.), that pan-HDAC inhibitors can have "contrasting therapeutic effects" in the immune system, including inhibition of Th 1 and Th 17 development and expansion of Treg cells, and that "not all HDAC is are positively associated with anti-cancer immunity" and can "compromise host defense" in animal models. Kim Decl. , ¶6. In addition, Kim et al. (Ex. B to Kim Decl.) reports that CG-745 has an approximately 10-fold lower IC50 than Vorinostat, Entinostat, and Resminostat, confirming that HDAC inhibitors are not interchangeable and may differ materially in anti-cancer efficacy. Kim Decl. , ¶7.
Pinheiro's disclosure of concurrent or sequential dosing of Vorinostat fails to establish that a different HDAC inhibitor species would be expected to behave the same way in that regimen. Pinheiro discloses only a Vorinostat-based checkpoint regimen. Accordingly, it would not have been obvious for a POSITA to substitute CG2 for Vorinostat with a reasonable expectation of success. To the contrary, Na would have discouraged the proposed substitution on its own terms, and a POSITA would not have
expected that substituting CG2 into Pinheiro's immunotherapeutic regimen would preserve, let alone improve upon, Pinheiro's reported result. For at least this additional reason.
In response, Applicant's arguments filed 3/30/2026 have been fully considered but they are not persuasive. The obvious rational is above regarding the amended claims. Pinheiro taught a method of effectively treating a subject with cancer with a combination composition of 10 mg/kg anti-PD-1 antibody every 5 days and 150 mg/kg of the HDAC inhibitor Vorinostat daily, wherein the anti-tumor response was greater than either Vorinostat or anti-PD-1 single agent treatment, wherein the treatment resulted in a complete response for some of the subjects (pages 38-39, paragraph 169-170 and Fig 8A-8B and Fig. 9A-9B). Thus, combination of an HDAC inhibitor and a PD-1 inhibitor would be expected to be an effective treatment in view of Pinheiro. Na taught: CG2 has the structure
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(Fig. 1), dose-dependently inhibits colon cancer cell growth (Table 1), effectively inhibits colon cancer tumor cell growth in vivo with daily administration of 20 mg/kg via injection (page 1510, left column, third paragraph and Fig. 4A), and effectively blocks histone deacetylation in vivo (Fig 5). Thus, CG2 is known to effectively block HDAC in tumors in vivo and have anti-cancer activity as a single agent. It is not outside of the skill of a person having ordinary skill in the art to exchange one tumor effective HDAC inhibitor for another in a combination. Thus, as detailed in the obvious rational above, it would be obvious with a reasonable expectation of success to exchange one cancer effective HDAC inhibitor for another in the HDAC + anti-PD-1 antibody inhibitor composition. CG-745 is the phosphate salt form of CG2 and is obvious as detailed above.
Regarding the Kim Decl., the Kim Decl.,¶ 5 states the comparative in vivo data disclosed in the '356 Application (e.g., Experimental Example 1) evaluates CG-745 in combination with an anti-PD-1 antibody in a Hepa1-6 syngeneic tumor model, using 20 mg/kg CG-745 in repeated treatment cycles and 5 mg/kg anti-PD--1 antibody administered together with CG-745 on the fifth day of the first cycle. The ratio claimed does not overlap with the effective composition tested in the instant disclosure, wherein Fig. 1 treats subjects with 20 mg/kg CG-745 and 5 mg/kg anti-PD-1 antibody. This would be a ratio of (4:1) not (1:4). The instant disclosure and the Kim Decl. have not described surprising results of compositions of CG-745 and an anti-PD-1 antibody are effective within the range claimed. Additionally, while a composition comprising a combination of CG-745 and an anti-PD-1 antibody is surprisingly effective based on the surprising results achieved in instant Fig. 1, the scope of the claim is not commensurate with the surprising results. Only combination with an anti-PD-1 antibody has been shown to be effective. MPEP 716.02(d) requires that unexpected results are commensurate in scope with the claimed invention. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.
Applicant argues the remaining dependent claims depend from claim 1 and thus include all features of claim 1. As such, these dependent claims are allowable at least for the reasons discussed above for claim 1 and further in view of each dependent claim's patentable combination of features.
In response, Applicant's arguments filed 3/30/2026 have been fully considered but they are not persuasive. Regarding the dependent claims the updated rejection is above.
Conclusion
Claims 1, 3-6, 8-15, and 21 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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