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 instant application is claiming the benefit of the prior-filed United States Provisional Patent Application No. 63/203,481, filing date 07/23/2021.
Status of Application/Claims
The amendment, filed 07/30/2025 is acknowledged. Claims 5, 8-27, 31-57, 59-82, 84, 87, 89-93, 95, 97-109, and 111-140 are canceled. Claims 1, 3-4, 7, 58, and 110 have been amended. Claims 1-4, 6-7, 28-30, 58, 83, 85-86, 88, 94, 96, and 110 are currently pending.
Withdrawn Objections/Rejections
Regarding the Specification objection for trade names and/or trademark compliance issues, applicant amendment has addressed the issue. Thus, the objection is withdrawn.
Regarding the rejection for claim 32 under 35 U.S.C. 112(a) for lack of enablement: Claim 32 was canceled; Thus, the rejection for claim 32 is withdrawn.
Regarding the rejections for claims 3-4 and 110 under 35 U.S.C. 102 for lack of novelty, applicant amendment has overcome the rejections and the rejections are withdrawn. However, new grounds of rejection under U.S.C. 102 are provided below.
Regarding the rejections under 35 U.S.C. 103 for obviousness for claims 1-2, 6-8, 28-30, 32, 58, 88, and 94; claim 9; claims 83, 85, and 86; and, claim 96: Claims 8 and 9 were canceled. Applicant arguments are persuasive pertaining to the structure of Compound A and the rejections are withdrawn. However, new grounds of rejection under U.S.C. 102 and 103 are provided below.
Regarding the double patenting rejections for claims 1-4, 6-7, 28-30, 58, 83, 85-86, 88, 94, 96, and 110: Applicant arguments are persuasive pertaining to the structure of Compound A and the rejections are withdrawn. However, new grounds of rejection for non-statutory double patenting are provided below.
Response to Arguments
Applicant’s arguments filed 07/30/2025 have been fully considered and arguments concerning Compound A were persuasive and the rejections are withdrawn. Upon further consideration new rejections are made in the instant office action over newly applied art.
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, 3-4, 28-30, 58, 83, 85-86 and 110 are rejected under 35 U.S.C. 103 as being unpatentable over Zhong, et al. Cyclic di-nucleotide compounds and methods of use – WO2017161349A1, herein referred to as Zhong.
Zhong teaches cyclic di-nucleotide compounds or pharmaceutical salts thereof, mixtures, and methods of use for STING agonists, including a compound that is identical to instant “Compound A,” for medical therapy (title; abstract; p.13, [021]; p.40, [0115]; p.45, [0138]; see Zhong compound below):
[AltContent: textbox (Zhong, p.13, [021] structure:[img-media_image1.png])]
Zhong teaches that the compounds are used for methods of treatment for cancer patients (p.1, [002]; instant claims 1, 3-4, and 110), enhancing the body’s immune responses (i.e., augmenting the anti-tumor response; p.1, [002]; instant claim 3), and activation of production and infiltration of tumor-specific CD8 T cells (i.e., increasing population or function of immune cells; p.51, [0164]; instant claim 4). Zhong teaches that the STING agonists can be used in combination therapies with cytokines, including interleukin-12/IL-12 (p.48, [0149]; instant claims 1, 3-4, 58, 83, 85-86, and 110); and, in combination with at least one further therapeutic agent, which includes but is not limited to immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA-4 (p.37, [096]; p.51, [0174]; claims 57-58; instant claims 1, 28-30, 58, and 110). Additionally, Zhong teaches that the cGAMP compounds can be formulated with other components that serve as adjuvants, including cytokines; and, that cGAMP analogues are expected to function synergistically with immune checkpoint inhibitors, radiation therapies, and other anti-neoplastic agents to bring therapeutic benefits to a larger percentage of cancer patients (p.51, [0164]; p52, [0171]; p.52-53, [0177]). Zhong teaches that the STING compounds and pharmaceutically acceptable salts thereof and the other pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order, by any convenient route in separate or combined pharmaceutical compositions (p.49, [0153]); and that the routes of administration include intratumoral, intramuscular, intradermal, subcutaneous, peritoneal, intralymphatic, and intravenous (i.e., systemic) administration (p.2, [007]; p.35, [072]; p.41, [0120]; instant claims 1, 3-4, and 58).
While Zhong does not exemplify the claimed combination comprising a triple combination therapy for the methods recited in instant claims 1, 3-4, 58, and 110, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhong to arrive at the claimed methods based on the teachings of Zhong because Zhong teaches each element of the instantly claimed invention, teaches the routes of administration for the claimed invention, and teaches that each component can be conjointly administered to improve therapeutic benefit. Thus, one of ordinary skill in the art would have had a reasonable expectation of success.
Claims 2, 6-7, 88, and 94 are rejected under 35 U.S.C. 103 as being unpatentable over Zhong as applied to claim 1 above, and further in view of Dana Farber Cancer Institute. Drug delivery compositions and uses thereof – WO2018045058A1, herein referred to as Dana Farber.
Zhong teaches a method of treatment for cancer patients comprising conjointly administering a STING agonist of instant Compound A, an interleukin cytokine, and an immune checkpoint inhibitory PD-1, PD-L1, or CTLA-4 as applied to instant claim 1 above.
Zhong does not teach that the patient exhibits reduced recurrence of tumors following treatment (instant claims 2 and 6-7); that the interleukin is fused to a protein to form a fusion protein (instant claim 88); or, that the interleukin is fused to a protein that is not an antibody or antibody fragment (instant claim 94).
Dana Farber teaches the combined use of one or more anti-cancer therapeutic agents that activate the innate immune system and/or the adaptive immune system via drug delivery compositions and devices (p.2, paragraph 6) after breast cancer cell inoculation. In several instances, a triple combination therapy includes administration of a STING agonist, cytokine, and activator of the adaptive immune response (i.e., immune checkpoint inhibitor/ICI; see Figs.9, 17, 23, 26, 31-36, 42-43, 46-48). Dana Farber teaches the use of therapeutic compositions having a triple combination of an activator of innate immune response (i.e., a 2'3 '-cGAMP cyclic dinucleotide/CDN STING agonist), a cytokine or chemokine (i.e., an IL-15 superagonist cytokine fusion protein), and an activator of adaptive immune response (i.e., an anti-PD-1 antibody/ICI; p.127, paragraph 681; Fig.23) to treat cancer and reduce local and metastatic recurrence (Example 6, p.127, [000682]; instant claims 2 and 7). The following groups were evaluated: no treatment (sham), empty hydrogel, intraperitoneal (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), intravenous (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), local administration of the triple combination (2 '3, -cGAMP, IL-15 sa, and anti-PD-1 antibody), or device 1 (p.23, paragraph 101; p.127, paragraph 681; Fig.23; Fig.42). Dana Farber teaches that the triple combination therapy demonstrated unexpectedly high survival rates in treated mice (p.127, [000681]) and that the experiments suggest that NK cells, CD8+ T cells, and CD4+ T cells may all contribute to the antitumor effects mediated by the triple combination therapy (p.127, [000680]). Dana Farber teaches administration of a triple combination therapy wherein the STING agonist and cytokine are administered IP, IV, locally (i.e., at the site of tumor resection), or via hydrogel device drug delivery (p.30, paragraph 139; Fig.80 A-B). Further, the methods of Dana Farber describe that, in certain embodiments, implantation of the drug device may occur after tumor resection of as little as 50% or greater by weight. Thus, “local” administration of triple combination “solutions” (that are not via hydrogel device) are interpreted to include “intratumoral/IT” administration (p.114, paragraph 638; Fig.43). Dana Farber teaches that the drug delivery systems deliver one or more therapeutic agents that act on the immune system for the treatment of cancer and prevention of tumor recurrence and/or metastasis while minimizing adverse side effects (p.2, paragraph 5). Additionally, Dana Farber teaches that the compositions for treatment may include a cytokine (abstract) and that the cytokines may include IL-2, IL-7, IL-12, or IL-15 (p.56, paragraph 235). Regarding the cytokine fusion protein, IL-15sa is a fusion protein that is commercially available (eBioscience™ catalog #34-8152-82) and possesses greater biological activity than IL-15 alone and is an antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8+ T lymphocytes (p.57, [000239]. This fusion protein is a recombinant protein heterocomplex of the mouse IL-15 cytokine linked to soluble IL-15 receptor alpha chain (sushi domain) via a GS linker. Thus, the IL-15 cytokine is fused to a protein that is not an antibody or antibody fragment (instant claims 88 and 94).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the cytokine taught in the method of Zhong with the IL-15sa taught by Dana Farber. An ordinarily skilled artisan would have been motivated to use IL-15sa as the cytokine as Dana Farber teaches IL-15 as an alternative cytokine to IL-12 in combinations with STING agonists and ICI and teaches that IL-15sa possess greater biological activity than IL-15 alone. Additionally, Dana Farber teaches that IL-15sa selectively expands NK and memory CD8+ T cells, which is taught to contribute to antitumor effects. An ordinarily skilled artisan would have had a reasonable expectation of success because both Zhong and Dana Farber are teaching methods in which STING agonists are combined with cytokines and checkpoint inhibitors to treat tumors and Dana Farber demonstrates the use of a STING agonist, the IL-15sa, and an anti-PD-1 antibody.
Regarding claims 2 and 6-7, an ordinarily skilled artisan would have reasonably expected that the method would result in reduced recurrence of tumors and treatment of tumors distal to the site(s) of intratumoral administration based on the teachings of Dana Farber. For instance, Dana Farber demonstrates that local administration of a STING agonist in combination with a cytokine and anti-PD-1 antibody in breast cancer subjects prevented tumor recurrence and treated metastases that had formed in the lung prior to treatment (p.127, [000682]).
Claims 88, 94, and 96 is rejected under 35 U.S.C. 103 as being unpatentable over Zhong as applied to claim 1 above, and further in view of Massachusetts Institute of Technology (US20200102370A1), herein referred to as MIT.
Zhong teaches a method of treatment for cancer patients comprising conjointly administering a STING agonist of instant Compound A, an interleukin cytokine that is IL-12, and an immune checkpoint inhibitory PD-1, PD-L1, or CTLA-4 as applied to instant claim 1 above.
Zhong does not teach that the interleukin is fused to a protein to form a fusion protein (instant claim 88); that the interleukin is fused to a protein that is not an antibody or antibody fragment (instant claim 94); or, that the interleukin is fused to a collagen-binding protein, that the collagen-binding protein is lumican (instant claim 96).
MIT teaches that an immunomodulatory domain (e.g., cytokine, anti-immune receptor antibody, anti-tumor associated-antigen antibody, etc.) can be conjugated to a collagen-binding domain (instant claims 88 and 94), resulting in enhanced anti-tumor efficacy relative to the unconjugated immunomodulatory domain (p.1, column 2, paragraph 7; instant claim 96). MIT teaches that the cytokine used in treatment can be IL-12 (p.2, column 2, paragraph 26; instant claim 96). MIT also teaches that, in some embodiments, the immunomodulatory fusion protein comprises IL-12 and lumican, wherein IL-12 is operably linked to lumican, IL-12 is operably linked to lumican with albumin, or IL-12 is operably linked to the N-terminus of lumican, or IL-12 is operably linked to the C-terminus of lumican.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhong with MIT by modifying the method of Zhong by conjugating an IL-12 interleukin cytokine, as taught by Zhong and MIT, by fusing the IL-12 cytokine to collagen-binding lumican, as taught by MIT, to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by MIT, that conjugating a cytokine to a collagen-binding domain can enhance anti-tumor efficacy relative to the unconjugated form. One of ordinary skill in the art would have a reasonable expectation of success because Zhong teaches the use of IL-12 as the interleukin cytokine for treatment of cancer and MIT teaches that IL-12 can be conjugated to collagen-binding lumican to enhance anti-tumor efficacy.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US10336786
Claims 1-4, 6-7, 28-30, 58, 83, 85-86, 88, 94, 96, and 110 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, 10-11, and 15 of U.S. Patent No. 10,336,786 (herein referred to as Pat’786) in view of Zhong, Dana Farber, MIT and MR Alliance.
Pat’786 claims 1-2, 5-6, 10-11, and 15 recite compositions and methods of inducing an immune response (i.e., augmenting the anti-tumor response and increasing the population/function of immune cells) comprising administering the 2’3’-CDN STING agonist compound (Pat’786 claims 1 and 5-6).
Pat’786 does not teach a combination treatment wherein the CDN STING agonist is concurrently administered with an intratumorally administered interleukin cytokine and a systemically administered ICI that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or anti-CTLA-4 antibody; that the method increases the population or function of immune cells; that the STING agonist is instant Compound A; that the interleukin cytokine is IL-12 or an IL-12-lumican fusion protein; or, that the method reduces recurrence of tumors; that the method treats distal tumors.
Zhong teaches cyclic di-nucleotide compounds or pharmaceutical salts thereof, mixtures, and methods of use for STING agonists, including instant “Compound A,” for medical therapy (title; abstract; p.13, [022]; p.50, [0115]; p.45, [0138]). Zhong teaches that the compounds are used for methods of treatment for cancer patients (p.1, [002]; instant claims 1, 3-4, and 110), enhancing the body’s immune responses (i.e., augmenting the anti-tumor response; p.1, [002]; instant claim 3), and activation of production and infiltration of tumor-specific CD8 T cells (i.e., increasing population or function of immune cells; p.51, [0164]; instant claim 4). Zhong teaches that the STING agonists can be used in combination therapies with cytokines, including interleukin-12/IL-12 (p.48, [0149]; instant claims 1, 3-4, 58, 83, 85-86, and 110); and, in combination with at least one further therapeutic agent, which includes but is not limited to immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA-4 (p.37, [096]; p.51, [0174]; claims 57-58; instant claims 1, 28-30, 58, and 110). Zhong teaches that the STING compounds and pharmaceutically acceptable salts thereof and the other pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order, by any convenient route in separate or combined pharmaceutical compositions (p.49, [0153]); and that the routes of administration include intratumoral, intramuscular, intradermal, subcutaneous, peritoneal, intralymphatic, and intravenous (i.e., systemic) administration (p.2, [007]; p.35, [072]; p.41, [0120]; instant claims 1, 3-4, and 58).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pat’786 and Zhong by using 1) Compound A, as taught by Zhong, as the STING agonist, as taught by Pat’786, in a combination therapy (i.e., STING agonist/interleukin/ICI) that can be used to treat cancer, as taught by Zhong. One of ordinary skill in the art would have a reasonable expectation of success because Pat’786 teaches a STING agonist; Zhong teaches that “Compound A” of the instant invention can be used as the STING agonist for cancer treatment; and, Zhong teaches the use of an intratumoral STING agonist/interleukin and systemic ICI for the treatment of cancer.
Dana Farber teaches the combined use of one or more anti-cancer therapeutic agents that activate the innate immune system and/or the adaptive immune system via drug delivery compositions and devices (p.2, paragraph 6) after breast cancer cell inoculation. In several instances, a triple combination therapy includes administration of a STING agonist, cytokine, and activator of the adaptive immune response (i.e., immune checkpoint inhibitor/ICI; see Figs.9, 17, 23, 26, 31-36, 42-43, 46-48). Dana Farber teaches the use of therapeutic compositions having a triple combination of an activator of innate immune response (i.e., a 2'3 '-cGAMP cyclic dinucleotide/CDN STING agonist), a cytokine or chemokine (i.e., an IL-15 superagonist cytokine fusion protein), and an activator of adaptive immune response (i.e., an anti-PD-1 antibody/ICI; p.127, paragraph 681; Fig.23) to treat cancer and reduce local and metastatic recurrence (instant claims 2 and 7). The following groups were evaluated: no treatment (sham), empty hydrogel, intraperitoneal (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), intravenous (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), local administration of the triple combination (2 '3, -cGAMP, IL-15 sa, and anti-PD-1 antibody), or device 1 (p.23, paragraph 101; p.127, paragraph 681; Fig.23; Fig.42). Dana Farber teaches administration of a triple combination therapy wherein the STING agonist and cytokine are administered IP, IV, locally (i.e., at the site of tumor resection), or via hydrogel device drug delivery (p.30, paragraph 139; Fig.80 A-B). Further, the methods of Dana Farber describe that, in certain embodiments, implantation of the drug device may occur after tumor resection of as little as 50% or greater by weight. Thus, “local” administration of triple combination “solutions” (that are not via hydrogel device) are interpreted to include “intratumoral/IT” administration (p.114, paragraph 638; Fig.43). Dana Farber teaches that the drug delivery systems deliver one or more therapeutic agents that act on the immune system for the treatment of cancer and prevention of tumor recurrence and/or metastasis while minimizing adverse side effects (p.2, paragraph 5). Additionally, Dana Farber teaches that the compositions for treatment may include a cytokine (abstract) and that the cytokines may include IL-2, IL-7, IL-12, or IL-15 (p.56, paragraph 235). Regarding the cytokine fusion protein, IL-15sa is a fusion protein that is commercially available (eBioscience™ catalog #34-8152-82). This fusion protein is a recombinant protein heterocomplex of the mouse IL-15 cytokine linked to soluble IL-15 receptor alpha chain (sushi domain) via a GS linker. Thus, the IL-15 cytokine is fused to a protein that is not an antibody or antibody fragment (instant claims 88 and 94).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pat’786 and Zhong with Dana Farber by using 1) Compound A, as taught by Zhong, as the STING agonist, as taught by Pat’786 and Dana Farber, and 2) IL-15sa, as taught by Dana Farber, as the interleukin, as taught by Zhong and Dana Farber, that is a fusion protein that does not comprise an antibody or antibody fragment, as taught by Dana Farber, to arrive at the instantly claimed invention, because Dana Farber teaches that the triple combination therapy (i.e., STING agonist/interleukin/ICI) can be used to treat cancer and reduce local and metastatic recurrence of tumors. One of ordinary skill in the art would have a reasonable expectation of success because Pat’786 teaches a STING agonist; both Zhong and Dana Farber teach the use of a STING agonist/interleukin/ICI for the treatment of cancer; Zhong teaches that “Compound A” of the instant invention can be used as the STING agonist for cancer treatment; and, Dana Farber teaches that the interleukin-fusion protein IL-15sa can be used as the interleukin for cancer treatment.
MIT teaches that an immunomodulatory domain (e.g., cytokine, anti-immune receptor antibody, anti-tumor associated-antigen antibody, etc.) can be conjugated to a collagen-binding domain, resulting in enhanced anti-tumor efficacy relative to the unconjugated immunomodulatory domain (p.1, column 2, paragraph 7; instant claim 96). MIT teaches that the cytokine used in treatment can be IL-12 (p.2, column 2, paragraph 26; instant claim 96). MIT also teaches that, in some embodiments, the immunomodulatory fusion protein comprises IL-12 and lumican, wherein IL-12 is operably linked to lumican, IL-12 is operably linked to lumican with albumin, or IL-12 is operably linked to the N-terminus of lumican, or IL-12 is operably linked to the C-terminus of lumican.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’786, Zhong and Dana Farber with MIT by modifying an IL-12 interleukin cytokine, as taught by Zhong and Dana Farber, in a combination therapy, as taught by Zhong and Dana Farber, that comprises a STING agonist, as taught by Pat’786/Zhong/Dana Farger, by fusing the IL-12 cytokine to collagen-binding lumican, as taught by MIT, to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by MIT, that conjugating a cytokine to a collagen-binding domain can enhance anti-tumor efficacy relative to the unconjugated form. One of ordinary skill in the art would have a reasonable expectation of success because both Zhong and Dana Farber teach the use of IL-12 as the interleukin cytokine for treatment of cancer, Zhong and Dana Farber teach combination therapies comprising STING agonists and interleukin cytokines, Pat’786 teaches STING agonists, and MIT teaches that IL-12 can be conjugated to collagen-binding lumican.
MR Alliance teaches that systemic delivery of immunotherapies allow treatments to travel to the bloodstream to reach all parts of the body and that cancer physicians use systemic immunotherapy to treat metastatic cancer (p.1; instant claim 6).
It would have been prima facie obvious for one of ordinary sill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’786 and Zhong with MR Alliance by using the method of cancer treatment using intratumoral STING agonist/cytokine and systemic ICI administration, as taught by Pat’786 and Zhong, as a method that treats tumors distal to the site(s) of intratumoral STING agonist/cytokine administration, as taught by MR Alliance, to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by MR Alliance, that using systemic delivery of an immunotherapy allows for treatment of metastatic (i..e., distal) cancer. One of ordinary skill in the art would have a reasonable expectation of success because Pat’786 teaches a STING agonist, Zhong teaches the combination STING agonist/ICI cancer therapy, Zhong teaches that ICI immunotherapies can be delivered systemically and MR Alliance teaches that immunotherapies treat metastatic cancer.
US10519188
Claims 1-4, 6-7, 28-30, 58, 83, 85-86, 88, 94, 96, and 110 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 11-12, 16, and 19-20 of U.S. Patent No. 10,519,188 (herein referred to as Pat’188) in view of Zhong, Dana Farber, MIT and MR Alliance.
Pat’188 recites the 2’3’-CDN STING agonist compound, and also specifically “Compound A” of instant claim 9 which falls under the composition Formula Ic embodiments of Pat’188 (see structures of claims 1-6, 11-12, and 16). Pat’188 also claims a pharmaceutical composition comprising the CDN compound with one or more pharmaceutically acceptable excipients (Pat’188 claim 19) and a pharmaceutical composition comprising the CDN compound with at least one further therapeutic agent (Pat’188 claim 20). Pat’188 further recites that the claimed invention can be used in medical therapy (abstract) and specifically for the treatment of cancer (p.4, column 1, paragraph 2; p. 15-22). One skilled in the art would substitute the therapeutic agent of Pat’188 with a cytokine or ICI in order to arrive at a combination cancer therapy.
Pat’188 does not include a combination treatment wherein the CDN STING agonist is concurrently administered with an intratumorally administered interleukin cytokine and a systemically administered ICI that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or anti-CTLA-4 antibody; that the method increases the population or function of immune cells; that the STING agonist is instant Compound A; that the interleukin cytokine is IL-12 or an IL-12-lumican fusion protein; or, that the method reduces recurrence of tumors; that the method treats distal tumors.
Zhong teaches cyclic di-nucleotide compounds or pharmaceutical salts thereof, mixtures, and methods of use for STING agonists, including instant “Compound A,” for medical therapy (title; abstract; p.13, [022]; p.50, [0115]; p.45, [0138]). Zhong teaches that the compounds are used for methods of treatment for cancer patients (p.1, [002]; instant claims 1, 3-4, and 110), enhancing the body’s immune responses (i.e., augmenting the anti-tumor response; p.1, [002]; instant claim 3), and activation of production and infiltration of tumor-specific CD8 T cells (i.e., increasing population or function of immune cells; p.51, [0164]; instant claim 4). Zhong teaches that the STING agonists can be used in combination therapies with cytokines, including interleukin-12/IL-12 (p.48, [0149]; instant claims 1, 3-4, 58, 83, 85-86, and 110); and, in combination with at least one further therapeutic agent, which includes but is not limited to immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA-4 (p.37, [096]; p.51, [0174]; claims 57-58; instant claims 1, 28-30, 58, and 110). Zhong teaches that the STING compounds and pharmaceutically acceptable salts thereof and the other pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order, by any convenient route in separate or combined pharmaceutical compositions (p.49, [0153]); and that the routes of administration include intratumoral, intramuscular, intradermal, subcutaneous, peritoneal, intralymphatic, and intravenous (i.e., systemic) administration (p.2, [007]; p.35, [072]; p.41, [0120]; instant claims 1, 3-4, and 58).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pat’188 and Zhong by using 1) Compound A, as taught by Zhong, as the STING agonist, as taught by Pat’188, in a combination therapy (i.e., STING agonist/interleukin/ICI) that can be used to treat cancer, as taught by Zhong. One of ordinary skill in the art would have a reasonable expectation of success because Pat’188 teaches a STING agonist; Zhong teaches that “Compound A” of the instant invention can be used as the STING agonist for cancer treatment; and, Zhong teaches the use of an intratumoral STING agonist/interleukin and systemic ICI for the treatment of cancer.
Dana Farber teaches the combined use of one or more anti-cancer therapeutic agents that activate the innate immune system and/or the adaptive immune system via drug delivery compositions and devices (p.2, paragraph 6) after breast cancer cell inoculation. In several instances, a triple combination therapy includes administration of a STING agonist, cytokine, and activator of the adaptive immune response (i.e., immune checkpoint inhibitor/ICI; see Figs.9, 17, 23, 26, 31-36, 42-43, 46-48). Dana Farber teaches the use of therapeutic compositions having a triple combination of an activator of innate immune response (i.e., a 2'3 '-cGAMP cyclic dinucleotide/CDN STING agonist), a cytokine or chemokine (i.e., an IL-15 superagonist cytokine fusion protein), and an activator of adaptive immune response (i.e., an anti-PD-1 antibody/ICI; p.127, paragraph 681; Fig.23) to treat cancer and reduce local and metastatic recurrence (instant claims 2 and 7). The following groups were evaluated: no treatment (sham), empty hydrogel, intraperitoneal (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), intravenous (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), local administration of the triple combination (2 '3, -cGAMP, IL-15 sa, and anti-PD-1 antibody), or device 1 (p.23, paragraph 101; p.127, paragraph 681; Fig.23; Fig.42). Dana Farber teaches administration of a triple combination therapy wherein the STING agonist and cytokine are administered IP, IV, locally (i.e., at the site of tumor resection), or via hydrogel device drug delivery (p.30, paragraph 139; Fig.80 A-B). Further, the methods of Dana Farber describe that, in certain embodiments, implantation of the drug device may occur after tumor resection of as little as 50% or greater by weight. Thus, “local” administration of triple combination “solutions” (that are not via hydrogel device) are interpreted to include “intratumoral/IT” administration (p.114, paragraph 638; Fig.43). Dana Farber teaches that the drug delivery systems deliver one or more therapeutic agents that act on the immune system for the treatment of cancer and prevention of tumor recurrence and/or metastasis while minimizing adverse side effects (p.2, paragraph 5). Additionally, Dana Farber teaches that the compositions for treatment may include a cytokine (abstract) and that the cytokines may include IL-2, IL-7, IL-12, or IL-15 (p.56, paragraph 235). Regarding the cytokine fusion protein, IL-15sa is a fusion protein that is commercially available (eBioscience™ catalog #34-8152-82). This fusion protein is a recombinant protein heterocomplex of the mouse IL-15 cytokine linked to soluble IL-15 receptor alpha chain (sushi domain) via a GS linker. Thus, the IL-15 cytokine is fused to a protein that is not an antibody or antibody fragment (instant claims 88 and 94).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pat’188 and Zhong with Dana Farber by using 1) Compound A, as taught by Zhong, as the STING agonist, as taught by Pat’188 and Dana Farber, and 2) IL-15sa, as taught by Dana Farber, as the interleukin, as taught by Zhong and Dana Farber, that is a fusion protein that does not comprise an antibody or antibody fragment, as taught by Dana Farber, to arrive at the instantly claimed invention, because Dana Farber teaches that the triple combination therapy (i.e., STING agonist/interleukin/ICI) can be used to treat cancer and reduce local and metastatic recurrence of tumors. One of ordinary skill in the art would have a reasonable expectation of success because Pat’188 teaches a STING agonist; both Zhong and Dana Farber teach the use of a STING agonist/interleukin/ICI for the treatment of cancer; Zhong teaches that “Compound A” of the instant invention can be used as the STING agonist for cancer treatment; and, Dana Farber teaches that the interleukin-fusion protein IL-15sa can be used as the interleukin for cancer treatment.
MIT teaches that an immunomodulatory domain (e.g., cytokine, anti-immune receptor antibody, anti-tumor associated-antigen antibody, etc.) can be conjugated to a collagen-binding domain, resulting in enhanced anti-tumor efficacy relative to the unconjugated immunomodulatory domain (p.1, column 2, paragraph 7; instant claim 96). MIT teaches that the cytokine used in treatment can be IL-12 (p.2, column 2, paragraph 26; instant claim 96). MIT also teaches that, in some embodiments, the immunomodulatory fusion protein comprises IL-12 and lumican, wherein IL-12 is operably linked to lumican, IL-12 is operably linked to lumican with albumin, or IL-12 is operably linked to the N-terminus of lumican, or IL-12 is operably linked to the C-terminus of lumican.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’188, Zhong and Dana Farber with MIT by modifying an IL-12 interleukin cytokine, as taught by Zhong and Dana Farber, in a combination therapy, as taught by Zhong and Dana Farber, that comprises a STING agonist, as taught by Pat’188/Zhong/Dana Farger, by fusing the IL-12 cytokine to collagen-binding lumican, as taught by MIT, to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by MIT, that conjugating a cytokine to a collagen-binding domain can enhance anti-tumor efficacy relative to the unconjugated form. One of ordinary skill in the art would have a reasonable expectation of success because both Zhong and Dana Farber teach the use of IL-12 as the interleukin cytokine for treatment of cancer, Zhong and Dana Farber teach combination therapies comprising STING agonists and interleukin cytokines, Pat’188 teaches STING agonists, and MIT teaches that IL-12 can be conjugated to collagen-binding lumican.
MR Alliance teaches that systemic delivery of immunotherapies allow treatments to travel to the bloodstream to reach all parts of the body and that cancer physicians use systemic immunotherapy to treat metastatic cancer (p.1; instant claim 6).
It would have been prima facie obvious for one of ordinary sill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’188 and Zhong with MR Alliance by using the method of cancer treatment using intratumoral STING agonist/cytokine and systemic ICI administration, as taught by Pat’188 and Zhong, as a method that treats tumors distal to the site(s) of intratumoral STING agonist/cytokine administration, as taught by MR Alliance, to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by MR Alliance, that using systemic delivery of an immunotherapy allows for treatment of metastatic (i..e., distal) cancer. One of ordinary skill in the art would have a reasonable expectation of success because Pat’188 teaches a STING agonist, Zhong teaches the combination STING agonist/ICI cancer therapy, Zhong teaches that ICI immunotherapies can be delivered systemically and MR Alliance teaches that immunotherapies treat metastatic cancer.
US10508129
Claims 1-4, 6-7, 28-30, 58, 83, 85-86, 88, 94, 96, and 110 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, and 7 of U.S. Patent No. 10,508,129 (herein referred to as Pat’129) in view of Zhong, Dana Farber, MIT and MR Alliance.
Pat’129 claims 1-3, and 7 recite a pharmaceutical formulation comprising administration of the CDN compound of the instant application that can be used in the treatment of cancer (Pat’129 p.26, column 48, paragraph 2).
Pat’129 does not include a combination treatment wherein the CDN STING agonist is concurrently administered with an intratumorally administered interleukin cytokine and a systemically administered ICI that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or anti-CTLA-4 antibody; that the method increases the population or function of immune cells; that the STING agonist is instant Compound A; that the interleukin cytokine is IL-12 or an IL-12-lumican fusion protein; or, that the method reduces recurrence of tumors; that the method treats distal tumors.
Zhong teaches cyclic di-nucleotide compounds or pharmaceutical salts thereof, mixtures, and methods of use for STING agonists, including instant “Compound A,” for medical therapy (title; abstract; p.13, [022]; p.50, [0115]; p.45, [0138]). Zhong teaches that the compounds are used for methods of treatment for cancer patients (p.1, [002]; instant claims 1, 3-4, and 110), enhancing the body’s immune responses (i.e., augmenting the anti-tumor response; p.1, [002]; instant claim 3), and activation of production and infiltration of tumor-specific CD8 T cells (i.e., increasing population or function of immune cells; p.51, [0164]; instant claim 4). Zhong teaches that the STING agonists can be used in combination therapies with cytokines, including interleukin-12/IL-12 (p.48, [0149]; instant claims 1, 3-4, 58, 83, 85-86, and 110); and, in combination with at least one further therapeutic agent, which includes but is not limited to immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA-4 (p.37, [096]; p.51, [0174]; claims 57-58; instant claims 1, 28-30, 58, and 110). Zhong teaches that the STING compounds and pharmaceutically acceptable salts thereof and the other pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order, by any convenient route in separate or combined pharmaceutical compositions (p.49, [0153]); and that the routes of administration include intratumoral, intramuscular, intradermal, subcutaneous, peritoneal, intralymphatic, and intravenous (i.e., systemic) administration (p.2, [007]; p.35, [072]; p.41, [0120]; instant claims 1, 3-4, and 58).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pat’129 and Zhong by using 1) Compound A, as taught by Zhong, as the STING agonist, as taught by Pat’129, in a combination therapy (i.e., STING agonist/interleukin/ICI) that can be used to treat cancer, as taught by Zhong. One of ordinary skill in the art would have a reasonable expectation of success because Pat’129 teaches a STING agonist; Zhong teaches that “Compound A” of the instant invention can be used as the STING agonist for cancer treatment; and, Zhong teaches the use of an intratumoral STING agonist/interleukin and systemic ICI for the treatment of cancer.
Dana Farber teaches the combined use of one or more anti-cancer therapeutic agents that activate the innate immune system and/or the adaptive immune system via drug delivery compositions and devices (p.2, paragraph 6) after breast cancer cell inoculation. In several instances, a triple combination therapy includes administration of a STING agonist, cytokine, and activator of the adaptive immune response (i.e., immune checkpoint inhibitor/ICI; see Figs.9, 17, 23, 26, 31-36, 42-43, 46-48). Dana Farber teaches the use of therapeutic compositions having a triple combination of an activator of innate immune response (i.e., a 2'3 '-cGAMP cyclic dinucleotide/CDN STING agonist), a cytokine or chemokine (i.e., an IL-15 superagonist cytokine fusion protein), and an activator of adaptive immune response (i.e., an anti-PD-1 antibody/ICI; p.127, paragraph 681; Fig.23) to treat cancer and reduce local and metastatic recurrence (instant claims 2 and 7). The following groups were evaluated: no treatment (sham), empty hydrogel, intraperitoneal (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), intravenous (i.e., systemic) injection of the triple combination (2'3 '-cGAMP, IL-15sa, and anti-PD-1 antibody), local administration of the triple combination (2 '3, -cGAMP, IL-15 sa, and anti-PD-1 antibody), or device 1 (p.23, paragraph 101; p.127, paragraph 681; Fig.23; Fig.42). Dana Farber teaches administration of a triple combination therapy wherein the STING agonist and cytokine are administered IP, IV, locally (i.e., at the site of tumor resection), or via hydrogel device drug delivery (p.30, paragraph 139; Fig.80 A-B). Further, the methods of Dana Farber describe that, in certain embodiments, implantation of the drug device may occur after tumor resection of as little as 50% or greater by weight. Thus, “local” administration of triple combination “solutions” (that are not via hydrogel device) are interpreted to include “intratumoral/IT” administration (p.114, paragraph 638; Fig.43). Dana Farber teaches that the drug delivery systems deliver one or more therapeutic agents that act on the immune system for the treatment of cancer and prevention of tumor recurrence and/or metastasis while minimizing adverse side effects (p.2, paragraph 5). Additionally, Dana Farber teaches that the compositions for treatment may include a cytokine (abstract) and that the cytokines may include IL-2, IL-7, IL-12, or IL-15 (p.56, paragraph 235). Regarding the cytokine fusion protein, IL-15sa is a fusion protein that is commercially available (eBioscience™ catalog #34-8152-82). This fusion protein is a recombinant protein heterocomplex of the mouse IL-15 cytokine linked to soluble IL-15 receptor alpha chain (sushi domain) via a GS linker. Thus, the IL-15 cytokine is fused to a protein that is not an antibody or antibody fragment (instant claims 88 and 94).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pat’129 and Zhong with Dana Farber by using 1) Compound A, as taught by Zhong, as the STING agonist, as taught by Pat’129 and Dana Farber, and 2) IL-15sa, as taught by Dana Farber, as the interleukin, as taught by Zhong and Dana Farber, that is a fusion protein that does not comprise an antibody or antibody fragment, as taught by Dana Farber, to arrive at the instantly claimed invention, because Dana Farber teaches that the triple combination therapy (i.e., STING agonist/interleukin/ICI) can be used to treat cancer and reduce local and metastatic recurrence of tumors. One of ordinary skill in the art would have a reasonable expectation of success because Pat’129 teaches a STING agonist; both Zhong and Dana Farber teach the use of a STING agonist/interleukin/ICI for the treatment of cancer; Zhong teaches that “Compound A” of the instant invention can be used as the STING agonist for cancer treatment; and, Dana Farber teaches that the interleukin-fusion protein IL-15sa can be used as the interleukin for cancer treatment.
MIT teaches that an immunomodulatory domain (e.g., cytokine, anti-immune receptor antibody, anti-tumor associated-antigen antibody, etc.) can be conjugated to a collagen-binding domain, resulting in enhanced anti-tumor efficacy relative to the unconjugated immunomodulatory domain (p.1, column 2, paragraph 7; instant claim 96). MIT teaches that the cytokine used in treatment can be IL-12 (p.2, column 2, paragraph 26; instant claim 96). MIT also teaches that, in some embodiments, the immunomodulatory fusion protein comprises IL-12 and lumican, wherein IL-12 is operably linked to lumican, IL-12 is operably linked to lumican with albumin, or IL-12 is operably linked to the N-terminus of lumican, or IL-12 is operably linked to the C-terminus of lumican.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’129, Zhong and Dana Farber with MIT by modifying an IL-12 interleukin cytokine, as taught by Zhong and Dana Farber, in a combination therapy, as taught by Zhong and Dana Farber, that comprises a STING agonist, as taught by Pat’129/Zhong/Dana Farger, by fusing the IL-12 cytokine to collagen-binding lumican, as taught by MIT, to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by MIT, that conjugating a cytokine to a collagen-binding domain can enhance anti-tumor efficacy relative to the unconjugated form. One of ordinary skill in the art would have a reasonable expectation of success because both Zhong and Dana Farber teach the use of IL-12 as the interleukin cytokine for treatment of cancer, Zhong and Dana Farber teach combination therapies comprising STING agonists and interleukin cytokines, Pat’129 teaches STING agonists, and MIT teaches that IL-12 can be conjugated to collagen-binding lumican.
MR Alliance teaches that systemic delivery of immunotherapies allow treatments to travel to the bloodstream to reach all parts of the body and that cancer physicians use systemic immunotherapy to treat metastatic cancer (p.1; instant claim 6).
It would have been prima facie obvious for one of ordinary sill in the art before the effective filing date of the cl