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 1-15 and 21 are pending.
Claims 16-20 were canceled.
Claim 21 is new.
Claim Objections and Rejections Withdrawn
The previous objections or rejections of claims 16-20 are moot in view of claim
cancellation.
The previous rejection of claims 1-6 and 9-15 under 35 U.S.C. 102(b) is withdrawn in view of claim amendment.
The previous rejection of claim 9 under 35 U.S.C. 102(d) is withdrawn in view of claim amendment.
The previous rejection of claims 1-4 and 7-15 under 35 U.S.C. 102(a)(1) is withdrawn in view of a translated copy of the certified copy of Korean Application No. KR 10-2019-0109256 which was filed prior to the publication of Kim YD et al. (J Cancer 2020; 11(14):4059-4072).
The previous rejection of claims 1-15 under 35 U.S.C. 103 is withdrawn in view of a translated copy of the certified copy of Korean Application No. KR 10-2019-0109256 which was filed prior to the publication of Kim YD et al. (J Cancer 2020; 11(14):4059-4072).
Claim Interpretation
Claims 1-15 and 21 claim a pharmaceutical composition comprising:
an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide, a derivative thereof or a salt thereof; and
an anti-PD-1 antibody or an anti-PD-L1 antibody,
wherein the claims 12-14, further recite process details for the composition. Recitation of process details in which the composition is administered is outside of the scope the claimed composition. Thus, the composition is claimed, not the process of administration. Therefore, the claimed composition will be examined below for claims 1-15 and 21.
Claim Rejections Maintained
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.
The rejection of claims 1-7 and 9-15 under 35 U.S.C. 103 as being unpatentable over WO 2016153839 (Pinheiro EM et al.) and Na Y-S et al. (Oncology reports 2010 1509-1514) is maintained.
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 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 did not teach: 1) a composition of the HDAC inhibitor alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide in the HDAC and PD-1 inhibitor combination composition; 2) a composition of the HDAC inhibitor alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide in the HDAC and PD-1 inhibitor pembrolizumab combination composition; 3) a composition of the HDAC inhibitor alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide in the HDAC and PD-L1 inhibitor durvalumab combination composition; 4) 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 and 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)
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;
exchange the anti-PD-1 antibody with the anti-PD-1 inhibitor pembrolizumab with a dose of 2 mg/kg every 2 or 3 weeks as taught by Pinheiro;
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.
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) Pinheiro taught using the anti-PD-1 inhibitor as pembrolizumab in the combination treatment wherein a dose of 2 mg/kg is preferred every 2 or 3 weeks; 3) Pinheiro taught using the anti-PD-L1 inhibitor MEDI4736, which is also known as durvalumab, in the combination treatment; and 4) Pinheiro taught each therapeutic agent in a combination therapy of the invention may be administered simultaneously in the same single preparation medicament.
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) 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 mg/kg every 2 or 3 weeks; 3) 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; and 4) 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.
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 (instant claim 7); and
10 mg/kg (instant claim 3) every 5 days of an anti-PD-1 antibody or the PD-L1 antibody MEDI4736, which is also known as durvalumab (instant claim 6), or 2 mg/kg every 2 or 3 weeks of the PD-1 antibody pembrolizumab (instant claim 5),
was administered to the subject, wherein the weight ratio of the composition would be 1:0.5 (instant claim 2) or 1:0.1, 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 (instant claims 11 and 13-14), 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 Pinheiro does not teach or suggest a composition comprising alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide in combination with a PD-I inhibitor. Instead, Pinheiro solely discloses the HDAC inhibitor Vorinostat with a PD-I inhibitor. In an attempt to cure this admitted deficiency of Pinheiro, the Office cites Na, asserting that it would have been obvious to a person of ordinary skill in the art (hereinafter "POSITA") to replace Pinheiro's Vorinostat with Na's CG2. However, Na does not teach or suggest using HDAC inhibitors-let alone CG2-with PD-I inhibitors. Moreover, there are no working examples in Na showing administration of CG2 with a PD-I inhibitor, nor any indication that CG2 is appropriate for such use.
A POSITA would readily recognize that CG2 is structurally distinct from Vorinostat and, therefore, would not expect it to exhibit the same biological properties. Vorinostat contains a benzene ring, a fully saturated aliphatic linker, and a primary amide group. In contrast, CG2 includes a bulky naphthalenyloxy moiety, an unsaturated octenyl chain with a double bond, and additional alkyl and substituted amino groups. These differences significantly impact polarity, size, and molecular dynamics, altering the compounds' pharmacological and biological behavior.
Furthermore, the therapeutic contexts in Pinheiro and Na are different. Pinheiro addresses cancer immunotherapy and provides working examples demonstrating anti-tumor immune responses when Vorinostat is used with a PD-I inhibitor. Its mechanism relies on immunomodulation-altering gene expression in tumor or immune cells for PD-I blockade efficacy. By contrast, Na focuses on chemotherapy sensitization in colorectal cancer, using CG2 to boost tumor cell apoptosis when combined with chemotherapeutics such as irinotecan, 5-FU, or oxaliplatin. Na describes CG2' s synergistic effect with DNA-damaging agents, not immune modulation.
Given these structural and mechanistic differences, a POSIT A starting with Vorinostat in an immunotherapy context would not have a reasonable expectation that substituting CG2 would yield similar results.
Additionally, while Na reports that CG2 caused no additional toxicity when administered simultaneously with chemotherapy (Na; Abstract; FIG. 4A, body-weight panel), it also discloses that sequential administration of CG2 with 5-FU or oxaliplatin increased cytotoxicity depending on the order of dosing (Na; pages 1510-1511; FIGs. 2B-2C). This further highlights how CG2's structural differences can influence biological outcomes, including toxicity. Such sequence-dependent cytotoxicity teaches against using CG2 in an immunotherapy context, where preserving immune cell viability is desired.
Thus, the sequence-dependent cytotoxicity data in Na would further discourage a POSITA from using CG2 in PD-I immunotherapy.
Accordingly, CG2's use remains limited to chemotherapy settings, as Na's teachings address only chemotherapy sensitization and does not teach or suggest immune modulation or PD-I inhibitor combination therapy. Therefore, a POSITA would have neither motivation nor a reasonable expectation of success in substituting CG2 for Vorinostat in Pinheiro's immunotherapeutic regimen.
In response, Applicant's arguments filed 8/19/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding, Na does not teach or suggest using HDAC inhibitors-let alone CG2-with PD-I inhibitors; there are no working examples in Na showing administration of CG2 with a PD-I inhibitor, nor any indication that CG2 is appropriate for such use; the structural differences between Vorinostat and CG2; and given the structural and mechanistic differences, a POSITA starting with Vorinostat in an immunotherapy context would not have a reasonable expectation that substituting CG2 would yield similar results –
as described above, 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-8. Thus, combination treatment of cancer with an anti-PD-1 inhibitor and a HDAC inhibitor was known to be effective. Na taught a known HDAC inhibitor, CG2 with the structure
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(Fig. 1) – which is (E)-N1-(3-( dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl) octenediamide and an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide, 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, while Vorinostat and CG2 have a different structure, a person having ordinary skill in the art would recognize that both are known histone deacetylation inhibitors and are effective against cancer. It would have been obvious to exchange one effective histone deacetylation inhibitor for another with a reasonable expectation of success as outlined in the obvious rational above.
Regarding Vorinostat and CG2 structural differences significantly impact polarity, size, and molecular dynamics, altering the compounds' pharmacological and biological behavior, both are known to be effective when administered to a subject with cancer in vivo. Thus, both histone deacetylase inhibitors are known to be biologically and pharmacologically effective for cancer treatment.
Regarding the therapeutic contexts in Pinheiro and Na are different, both Vorinostat and CG2 are known to be effective histone deacetylase inhibitors for cancer treatment. The therapeutic contexts are thus the same. It would have been obvious to exchange one effective histone deacetylation inhibitor for another with a reasonable expectation of success as outlined in the obvious rational above.
Regarding Na reports that CG2 caused no additional toxicity when administered simultaneously with chemotherapy, and that sequential administration of CG2 with 5-FU or oxaliplatin increased cytotoxicity depending on the order of dosing –
Pinheiro taught combination therapy administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order (page 25, paragraph 129). Thus, histone deacetylase inhibitors in combination with an immunotherapeutic were not expected to be toxic when administered simultaneously or sequentially. While the Applicant argues that sequential administration of CG2 and chemotherapeutic combinations therapies are toxic to the subject, Na taught administration of CG2 with SN38 (irinotecan) was not significantly more toxic to the subject compared to CG2 alone and was effective at treating the cancer (Fig. 4A). Thus, sequential CG2 combinations are not toxic for all combinations. Further, chemotherapeutics are known to be more toxic than immunotherapies. Michot taught overall, immunotherapy is better tolerated than chemotherapy, wherein a study comparing the PD-1 inhibitor nivolumab with docetaxel showed a lower rate of treatment-related adverse events (Michot J-M et al. Management of toxicities related to immunotherapies. Cancerworld 5/30/2019 https://archive.cancerworld.net/e-grandround/management-of-toxicities-related-to-immunotherapies/) page 3, last paragraph). Thus, combinations with chemotherapeutics would be expected to be more toxic to the subject than immunotherapeutic combinations.
Regarding sequential administration and toxicity to cancer cells, 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), wherein the Vorinostat and anti-PD-1 were administered concurrently (page 5, paragraph 24). Pinheiro Fig 8A taught the HDAC inhibitor Vorinostat was administered concurrently, but was also administered the day before and the day after the combination composition. Thus, sequential administration of a HDAC inhibitor before and after a composition comprising an anti-PD-1 inhibitor was still effective.
Therefore, the teachings of Na for sequence-dependent cytotoxicity of cancer cells treated with combination chemotherapeutics and an HDAC inhibitor does not: 1) teach against using CG2 in an immunotherapy context in a subject with cancer; 2) discourage a person having ordinary skill in the art from using CG2 in PD-I immunotherapy; or 3) limit CG2's use to chemotherapy settings. The obvious rational above discusses why it would be obvious with a reasonable expectation of success to 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;
exchange the anti-PD-1 antibody with the anti-PD-1 inhibitor pembrolizumab with a dose of 2 mg/kg every 2 or 3 weeks as taught by Pinheiro;
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.
The rejection of claims 1-15 under 35 U.S.C. 103 as being unpatentable over WO 2016153839 (Pinheiro EM et al.) and Na Y-S et al. (Oncology reports 2010 1509-1514) as applied to claims 1-7 and 9-15 above, and further in view of WO 2007052938 (Lee CH et al) and Fasinu P et al. (Drug Dispos. 2011 32, 185-209) is maintained.
Pinheiro and Na are described above.
Pinheiro is silent to the HDAC inhibitor as the salt of (E)-N1-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate, but this is obvious in view of Lee and Fasinu.
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).
Regarding instant claim 8, it would have been obvious for a person having ordinary skill in the art to take the method of Pinheiro and Na above – and:
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 as taught by Lee.
This is obvious because: 1) 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.
There is a reasonable expectation of success because: 1) the 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.
Response to Arguments
Applicant argues Fasinu is a pharmacokinetic reference that reviews absorption, distribution, metabolism, and excretion (ADME) properties of various compounds, including HDAC inhibitors. Fasinu does not address combination therapy with PD-I inhibitors, nor does it provide any teaching or suggestion to substitute alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamides for Vorinostat in a therapeutic context involving PD-I blockade.
Accordingly, Lee and Fasinu do not teach or suggest combining alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamides with PD-I inhibitors or using them in an immunomodulatory role. A POSITA would not be motivated to use alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamides in Pinheiro's immunotherapeutic setting or have a reasonable expectation of success.
In response, Applicant's arguments filed 8/19/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
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). Thus, Lee taught the phosphoric acid salt as an acceptable form of (E)-N1-(3-( dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl) octenediamide.
Fasinu taught phosphate salt moieties as a conventional approach to enhance solubility properties (page 188, left column, first bullet of last paragraph). Thus, phosphate salts are known to be conventional.
As described above, it would have been obvious for a person having ordinary skill in the art to take the method of Pinheiro and Na above – and:
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 as taught by Lee.
This is obvious because: 1) 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.
There is a reasonable expectation of success because: 1) the 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. Thus, the prior art taught phosphate salt moieties as a conventional approach to enhance solubility properties and (E)-Nl-(3-(dimethylamino)propyl)N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate was expected to be an effective salt form.
New Claim Rejections of New Claims
Claims 1-7, 9-15, and 21 under 35 U.S.C. 103 are rejected as being unpatentable over WO 2016153839 (Pinheiro EM et al.) and Na Y-S et al. (Oncology reports 2010 1509-1514) as applied to claims 1-7 and 9-20 above.
Pinheiro and Na are described above.
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 did not teach a single embodiment of combining each therapeutic agent in the combination therapy for administration of simultaneously in the same single preparation medicament or sequentially, but this is obvious in view of Na and Pinheiro.
Regarding instant claim 21, 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;
exchange the anti-PD-1 antibody with the anti-PD-1 inhibitor pembrolizumab with a dose of 2 mg/kg every 2 or 3 weeks as taught by Pinheiro;
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 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) Pinheiro taught using the anti-PD-1 inhibitor as pembrolizumab in the combination treatment wherein a dose of 2 mg/kg is preferred every 2 or 3 weeks; 3) Pinheiro taught using the anti-PD-L1 inhibitor MEDI4736, which is also known as durvalumab, in the combination treatment; and 4) 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) 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 mg/kg every 2 or 3 weeks; 3) 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; 4a) 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 4b) 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.
The method produced by the combination of Pinheiro and Na 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 (instant claim 7); and
10 mg/kg (instant claim 3) every 5 days of an anti-PD-1 antibody or the PD-L1 antibody MEDI4736, which is also known as durvalumab (instant claim 6), or 2 mg/kg every 2 or 3 weeks of the PD-1 antibody pembrolizumab (instant claim 5),
was administered to the subject, wherein the weight ratio of the composition would be 1:0.5 or 1:0.1, wherein the composition would naturally be synergistic, wherein the CG2 was administered before the anti-PD-1 antibody, which would require a separate composition and formulation in a separate dosage form (instant claim 21) or simultaneous administration wherein CG2 and anti-PD-1 or anti-PD-L1 antibody where formulated together and administered in the same single preparation medicament.
Response to Arguments
Claim 21 is new. The rejection is above.
Conclusion
Claims 1-15 and 21 are rejected.
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.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643