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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/12/2026 has been entered.
Claim Status
Claims 5-7, 9-10, and 12-13 have been cancelled and claims 1and 26 have been amended, as requested in the amendment filed on 05/12/2026. Following the amendment, claims 1-4, 8, 11, and 14-27 are pending in the instant application.
Claims 1-4, 8, 11, and 14-27 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-4, 8, 11, and 14-27 have an effective filing date of October 9, 2019 corresponding to PRO 62/913,102.
Claim Objections - Withdrawn
Claims 1 and 26 were objected to because of the inconsistent representation of anti-STAT3-TLR9 binding conjugate. The claims have been amended such that they now consistently recite “anti-STAT3-TLR9-binding conjugate”. As such, the objection to claims 1 and 26 are withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 1-4, 8, 11, and 14-27 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement as pertained to curing and/or preventing cancer. Applicant has amended independent claim 1 to recite that “wherein said treating is alleviating or ameliorating one or more symptoms or conditions"; in view of this amendment, it is noted that the instant claims are no longer drawn to preventing cancer, but rather alleviating or ameliorating one or more symptoms or conditions associated with the cancer. As such, the rejection of claims 1-4, 8, 11, and 14-27 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1-4, 8, 11, and 14-27 were rejected under 35 U.S.C. 103 as being unpatentable over of US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”) in view of WO 2019/023525 A1 (IDS citation no. 4; herein after referred to as "Frank").
Applicant’s arguments, see Pages 6-8 of Remarks and Pages 2-4 of the Affidavit, both filed 05/12/2026, with respect to the rejections of claims 1-4, 8, 11, and 14-27 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection are made in view of , which explicitly supports the combination of STAT3, TLR9, and CTLA-4 targeting agents and CpG moieties, as is further detailed below.
Double Patenting - Withdrawn
Claims 1-4, 8, 11, and 14-27 were rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-identified U.S. Patent Nos. in view of US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”) in view of WO 2019/023525 A1 (IDS citation no. 4; herein after referred to as "Frank").
U.S. Patent No.
Brief Description of the Invention
Pertinent Claims
7951374
Method of Killing a Tumor Cell or Inhibiting Tumor Growth Comprising Contacting an Immune Cell with a STAT3 Inhibitor Conjugated to an Antibody Specific to a Surface Marker
4, 9-10
9388418
Method for Treating a Disease Comprising Administering One or More Aptamer-mRNA Conjugates
1-3, 8-9
9974854
Method for Increasing Effectiveness of Antigenic Peptide CTL Epitope Vaccine Comprising Conjugating Said Antigenic Peptide CTL Epitope to a DNA Oligomer
1-4
9976147
Compound Comprising TLR-Binding Nucleic Acid Substituent Conjugated to a STAT-Binding Nucleic Acid Substituent and Pharmaceutical Composition Thereof
1, 5-10, 18, 24
10596254
Method for Increasing Effectiveness of Antigenic Peptide CTL Epitope Vaccine Comprising Conjugating a Fusion Peptide to a DNA Oligomer
1-4
10711272
Nucleic Acid Compound Comprising CTLA-4 Aptamer Conjugated to Anti-Cancer siRNA, Pharmaceutical Composition, and Method of Treating Cancer Thereof
1, 4-5, 12-13
10829765
Method for Treating Lymphoma Comprising Administering a CpG-Containing TLR9-Binding DNA Substituent Covalently Bonded to a STAT3-Binding DNA Substituent
1, 4-5, 8-12, 15-18
10987420
A conjugated Vaccine Molecule Comprising a Fusion Peptide Covalently Attached to a DNA Oligomer
1-4
11186840
Method of Stimulating the Immune System Comprising Administering a CTLA-4 Aptamer Conjugated to a Cell Activity Modulating Nucleic Acid
1, 7, 11, 14
11912995
Nucleic Acid Compound Comprising CTLA-4 Aptamer Conjugated to STAT3 Antisense Nucleic Acid and Method of Treating Lymphoma
1-3, 11, 15
Claims 1-4, 8, 11, and 14-27 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 12-18, and 24-26 of copending Application No. 18/584,707 (herein after referred to as "reference application") in view of US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”) in view of WO 2019/023525 A1 (IDS citation no. 4; herein after referred to as "Frank").
In view of the withdrawal of the claim rejection under 35 U.S.C. 103 in view of Yu and Frank, the above-listed claim rejections under nonstatutory double patenting in view of Yu and Frank are also withdrawn. However, upon further consideration, a new ground(s) of rejection are made in view of , which explicitly supports the combination of STAT3, TLR9, and CTLA-4 targeting agents and CpG moieties, as is further detailed below.
Claim Rejections - 35 USC § 103 - New
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
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.
Claims 1-2, 8, 11, and 21-27 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”) in view of non-patent literature by Adamus and Kortylewski (Contemp. Oncol. (Pozn.), 2017, 21(1A), 56-60; herein after referred to as "Adamus").
Yu teaches a novel molecule for the delivery of an active agent into cells for the treatment of cancer and other diseases including, but not limited to infectious diseases and autoimmune diseases wherein the novel molecules comprises one or more of a first moiety that directs cell or tissue specific delivery of the novel molecule linked to one or more of a second moiety that is an active agent useful for treating cancer or other diseases; the moieties can be linked together directly or they can be linked together indirectly through a linker wherein the linker is bifunctional producing a molecule of the structure A-X-B, where X is a linker, one of A and B is a moiety that is capable of delivering the molecule to cells of interest and the other one of A and B is an active agent useful for treating the cancer or other disease or the linker is a modification of, or structure present on, either moiety A or B, or both, that results in a binding between the two elements wherein the binding maybe covalent or non-covalent bonds (Paragraph 0054; emphasis added). A TLR ligand and an siRNA can be made into one molecule for delivery, immune stimulation and blocking immunosuppressive elements, such as Stat3, and/or oncogenic effects, such as caused by Stat3 (Id.). Yu teaches that cancers which can be treated with the molecules of the invention include, but are not limited to, melanoma, skin cancer, precancerous skin lesions, breast cancer, prostate cancer, lung cancer, glioma, pancreatic cancer, head and neck cancer, multiple myeloma, leukemias, and lymphomas (Paragraph 0056; emphasis added). Yu further teaches that target cells for ODN- or ORN-mediated delivery include any cell that is capable of internalizing a TLR ligand; such cells include (a) cells of the myeloid lineage including dendritic cells, macrophages and monocytes, (b) cells of the lymphoid lineage including B cells and T cells, (c) endothelial cells and (d) malignant cells being derivatives of the previously mentioned cells, e.g., multiple myeloma, B cell lymphoma and T cell lymphoma (i.e., molecules of the invention can target and treat B cell and/or T cell lymphomas) (Paragraph 0069; emphasis added). The invention of Yu describes the development of optimal Stat3 siRNAs (Dicer) with antitumor effects in vivo, and shows that Stat3siRNA linked to CpG oligonucleotide (i.e., TLR ligand) efficiently enters dendritic cells wherein targeting Stat3 drastically improves CpG-based cancer (Paragraph 0104; emphasis added); an example of the TLR ligand-siRNA chimeric construct, siRNA against Stat3 (SEQ ID NO: 3 for sense strand; SEQ ID NO: 2 for antisense strand) is linked to toll-like receptor 9 ligand, CpG oligonucleotide (ODN) (SEQ ID NO: 1) (FIG. 2a, top). Optimal sequences of both human and mouse Stat3 siRNA have been selected (FIG. 7), followed by linkage to CpG single stranded ODN (FIG. 2a, top), and other toll-like receptor ligands (FIG. 8) wherein the immune modulation induced by the toll-like receptor 9 ligand-Stat3 siRNA leads to potent antitumor effects on well -established B16 melanoma (FIGS. 3c-3e) (Paragraph 0125). Yu also teaches a method for the treatment of diseases (including, but not limited to, cancer, infectious diseases, autoimmune diseases, diseases due to excessive angiogenesis and diseases that can benefit from increased angiogenesis) which comprises using the novel molecules of the invention wherein said novel molecules are administered to patients in need of treatment using conventional pharmaceutical practices (Paragraph 0015). It is also noted that Yu demonstrated the novel molecule of the invention to be efficient and have improved antitumor effects (see for example Paragraph 0104-0105; emphasis added). Yu teaches that a suitable dosage unit of active agent moiety of the molecules of the present invention will be in the range of 0.001 to 0.25 milligrams per kilogram body weight of the recipient per day, or in the range of 0.01 to 20 micrograms per kilogram body weight per day, or in the range of 0.01 to 10 micrograms per kilogram body weight per day, or in the range of 0.10 to 5 micrograms per kilogram body weight per day, or in the range of 0.1 to 2.5 micrograms per kilogram body weight per day (Paragraph 0116; emphasis added). It is noted that the average adult weighs between 70-90 kg. As such, an average dose could range from 0.07 mg to 22.5 mg per day. Additionally, Yu teaches that a pharmacologically or therapeutically effective amount refers to that amount of a molecule of the present invention effective to produce the intended pharmacological, therapeutic or preventive result; for example, if a given clinical treatment is considered effective when there is at least a 20% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is the amount necessary to effect at least a 20% reduction in that parameter (Paragraph 0112). Furthermore, the dosage of compositions of the invention lies within a range of circulating concentrations that include the ED50 (as determined by known methods) with little or no toxicity wherein the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized; for any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays and a dose may be formulated in animal models to achieve a circulating plasma concentration range of the compound that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture wherein such information can be used to more accurately determine useful doses in humans (Paragraph 0117). The invention relates to a method for treating a disease or physiological disorder or condition in a mammal, including a human (Paragraph 0120; emphasis added). Thus, as evidenced by the reference, it is noted that doses of the anti-STAT3-TLR binding conjugates are recognized as a therapeutic variable which achieves a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of doses of the anti-STAT3-TLR binding conjugates would be seen as routine optimization. Yu teaches that compositions of the invention can be administered by any means known in the art such as by parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration; in some embodiments, the pharmaceutical compositions are administered by intravenous or intraparenteral infusion or injection (Paragraph 0115; emphasis added).
However, Yu does not teach or suggest administering the STAT3-TLR9 binding conjugates with an anti-CTLA4 antibody. This deficiency is remedied by Adamus.
Adamus teaches that initial studies on CpG ODNs demonstrated their efficacy in several preclinical tumor models, especially in hematologic malignancies, such as B cell leukemia and lymphoma; the CpG ODN triggered activation of the downstream TLR9 signaling and secretion of proinflammatory cytokines was shown to induce CD4+TH1 cells activity, thereby resulting in cytotoxic CD8+T cell responses in vivo (Page 56, The rise and the fall of CpG-based cancer immunotherapies). Discrepancies between promising preclinical results and rater unimpressive clinical outcomes at least partly resulted from different patterns of TLR9 expression in humans (selective in pDCs and B cells) and more broad in rodents (in all myeloid cells); consequently, in mice CpG ODNs monotherapy is often sufficient for induction of potent antitumor effects, but unfortunately, these effects are far less likely to occur in patients with established cancers and potently immunosuppressive tumor microenvironment (Page 57, Column 1, Second Paragraph). Continued efforts have been made to further improve immunomodulatory properties, safety and delivery of CpG ODNs; among others, protein/peptide-CpG ODNs conjugates and nanomaterial-CpG ODNs complexes have shown successful preclinical results and undergone clinical evaluations (Id.). Beyond standard therapies, recent preclinical studies identified CpG ODNs as ideal candidates for supporting ICR targeted cancer therapy; preclinical studies demonstrated (i) synergy between blocking CTLA-4 expression in order to revive T cell activity and CpG ODN-mediated activation of antigen presenting cells in melanoma mouse model and (ii) synergistic effect when CpG ODNs were combined with CTLA-4 or PD-1 antibodies in murine bladder cancer, which resulted in improved long term survival (Page 57, Column 2; emphasis added). These studies provided strong rationale for combined clinical regimens based on the stimulation using CpG ODNs and immune checkpoint inhibitors (Table 1); the ongoing clinical trial in metastatic melanoma patients focuses on the combination of a modified TLR9 agonist in proprietary 3’-3’ dimer design (IMO-2125; Idera Pharmaceutical) with CTLA4 blockade (ipilimumab) to enhance immunostimulatory properties in (Fig. 1B) and another original strategy utilizes an innovative design of TLR9 agonist the circular form (MGN1703; Mologen), which at the same time improves both immunostimulatory activity and stability of the ODN, wherein MGN1703 is currently being evaluated for therapy of advanced solid tumors in combination with anti-CTLA4 inhibitor (Page 57, Column 2 through Page 58, Column 1; see also Table 1 and Figure 1 at Page 58; emphasis added). Table 1 at Page 58 indicates that various CpG products which target TLR9/CTLA-4 and TLR9/PD-1 are indicated for melanoma and/or advanced solid tumors and CpG products which target TLR9/STAT3 are indicated for non-Hodgkin’s lymphoma (emphasis added). Adamus further teaches that STAT3 inhibition provides an opportunity for augmenting the potency of TLR9 agonists in the tumor microenvironment, wherein the proof-of-concept studies in mice demonstrated that in the absence of STAT3 signaling in hematopoietic cells, even a single intratumoral injection of CpG ODN can cause complete and long term regression of large (> 1 cm) B16 melanoma tumors; these therapeutic effects resulted from an unleashed innate and adaptive antitumor immunity without any indication of autoimmune disorders within the treatment window and these findings provided a strong rationale for combining CpG ODNs with STAT3 oligonucleotide inhibitor (CSIs) into a single molecule wherein simultaneous release of checkpoint blockade and immune stimulation leads to the gain-of-function effect amplifying therapeutic efficacy of CSIs (Page 59, Column 1, First Full Paragraph; emphasis added). Such design that STAT3 gene silencing coincides with immunostimulation of TLR9-positive tumor-associated myeloid cells, thereby generating potent gain-of-function effect; the first generation of CpG-STAT3 inhibitor (CSI-1) utilized RNA interference (RNAi) for STAT3 silencing (Figure 1D) and the CpG-STAT3siRNA conjugates are quickly internalized by TLR9-positive target cells, resulting in the downregulation of STAT3 expression and augmented TLR9 signaling wherein both CpG-STAT3siRNA effects act in concert to stimulate production of interleukin 12 (IL-12) and interferon-γ (IFN-γ), which are critical mediators of antigen-presentation and TH1 immune responses (Id.). There is a growing consensus that maximizing benefits of immunostimulatory agents for cancer therapy requires elimination of the negative influence of the tumor microenvironment; current early clinical trials explore the possibility of combining TLR agonists and also other emerging immunoadjuvants, like for example STING, together with the FDA-approved immune checkpoint inhibitors wherein the growing list of ICRs creates additional combinatorial opportunities, which can address intricacies of various types of human cancers and their immunosuppressive effects (Page 59, Column 2, First Full Paragraph). The growing arsenal of oligonucleotide strategies, including siRNA, antisense or decoy oligonucleotides, makes it possible to target central regulators of tumor immune tolerance, such as STAT3, which until now remained undruggable; combination of these gene- or protein-selective inhibitors with CpG-mediated delivery to immune cells provides a unique opportunity to overcome limitations in both oligonucleotide delivery as well as therapeutic efficacy and cancer immunotherapies addressing the complexity of cellular and molecular networks operating in the tumor microenvironment can provide new avenues for more precise and effective treatments for human malignancies (Id.).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer in a subject in need thereof comprising administering (i) an anti-STAT-TLR9-binding conjugate comprising a CpG moiety bound to an anti-STAT3 siRNA through a covalent linker and (ii) an anti-CTLA-4 antibody in a combined effective amount. One would have been motivated to combine (i) and (ii) for the treatment of cancer because both agents are independently known to treat cancer, and Adamus suggests that the combination of anti-STAT3, anti-TLR9, CpG moieties, and/or anti-CTLA-4 agents can yield synergistic anti-cancer effects. One of ordinary skill in the art would have a reasonable expectation of success because (i) anti-STAT3-TLR9-binding conjugates comprising a CpG moiety bound to an anti-STAT3 siRNA through a covalent linker are taught by Yu, and Adamus suggests that the combination of anti-STAT3, anti-TLR9, CpG moieties, and/or anti-CTLA-4 agents can yield synergistic anti-cancer effects.
Those of skill in the art recognize that the two anti-cancer agents, anti-STAT3-TLR9-binding conjugate comprising a CpG moiety covalently attached to an anti-STAT3 siRNA and anti-CTLA-4 antibodies, both known to successfully, pharmaceutically treat cancer, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat cancer and have additive and/or synergistic effects, as suggested by Adamus, through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in anti-cancer therapy, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, and are suggested as useful together and suggested to yield additive/synergistic effects by Adamus, in order to form a third composition which is to be used for the very same purpose of treating cancer.
Claims 3-4 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”) and non-patent literature by Adamus and Kortylewski (Contemp. Oncol. (Pozn.), 2017, 21(1A), 56-60; herein after referred to as "Adamus"), as applied to claims 1-2, 8, 11, and 21-27 above, and in further view of WO 2019/023525 A1 (IDS citation no. 4; herein after referred to as "Frank").
Claim 1 is rendered obvious by the combination of Yu and Adamus. However, neither Yu nor Adamus explicitly teach or suggest administering the anti-STAT3-TLR9-binding conjugate (i) simultaneously or (ii) sequentially with the anti-CTLA-4 antibody, nor do they teach or suggest administration schedules. These deficiencies are remedied by Frank.
Frank teaches a method of preventing, treating, and/or managing cancer in a patient (e.g., a human patient), the method comprising administering to the patient a prophylactically effective regimen or a therapeutically effective regimen, the regimen comprising administering to the patient a compound of the invention or a composition of the invention, e.g., a combination of a STAT3 inhibitor and an immune checkpoint inhibitor, wherein the patient has been diagnosed with cancer; the amount of a compound of the invention used in the prophylactic and/or therapeutic regimens which will be effective in the prevention, treatment, and/or management of cancer can be based on the currently prescribed dosage of the compound as well as assessed by methods disclosed (Page 44). Immune checkpoint inhibitors include, but are not limited to, inhibitors of programmed death-ligand 1 (PD-L1), PD-L2, PD-1, CTLA-4, TIM-3, LAG-3, V-domain Ig suppressor of T cell activation (VISTA), T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), and B and T Lymphocyte Attenuator (BTLA; CD272) (Page 35). Frank teaches that, in some cases, STAT3 inhibitor is administered prior to administration of the immune checkpoint inhibitor (i.e., sequential administration) and in other cases the STAT3 inhibitor is administered simultaneously with
the immune checkpoint inhibitor (Page 3). Frank teaches that therapeutic regimens disclosed comprise administration of compounds of the invention or pharmaceutical compositions thereof to the patient in a single dose or in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses) wherein, in one aspect, the prophylactic and/or therapeutic regimens comprise administration of the compounds of the invention or pharmaceutical compositions thereof in multiple doses; when administered in multiple doses, the compounds or pharmaceutical compositions are administered with a frequency and in an amount sufficient to treat and/or manage the condition wherein, for example, the frequency of administration ranges from once a day up to about once every eight weeks, from about once a week up to about once every six weeks, from about once every three weeks up to about once every four weeks (Pages 62-63; emphasis added). In one embodiment, Frank teaches that the therapeutic regimen comprises administering to a patient a plurality of doses of an effective amount of a compound of the invention, wherein the plurality of doses maintains a plasma level of at least 0.1 μg/mL, at least 0.5 μg/mL, at least 1 μg/mL, at least 2 μg/mL, at least 5 μg/mL, at least 6 μg/mL, at least 10 μg/mL, at least 15 μg/mL, at least 20 μg/mL, at least 25 μg/mL, at least 50 μg/mL, at least 100 μg/mL, at least 125 μg/mL, at least 150 μg/mL, at least 175 μg/mL, at least 200 μg/mL, at least 225 μg/mL, at least 250 μg/mL, at least 275 μg/mL, at least 300 μg/mL, at least 325 μg/mL, at least 350 μg/mL, at least 375 μg/mL, or at least 400 μg/mL of the compound of the invention for at least 1 day, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 24 months or 36 months (Page 64). Frank also teaches that the amount of a compound of the invention used in the therapeutic regimens which will be effective in the treatment and/or management of cancer can be based on the currently prescribed dosage of the compound as well as assessed by methods disclosed herein and known in the art wherein the frequency and dosage will vary also according to factors specific for each patient depending on the specific compounds administered, the severity of the cancerous condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient (Page 61); the terms "effective amount" and "therapeutically effective amount" of a formulation or formulation component is meant a sufficient amount of the formulation or component, alone or in a combination, to provide the desired effect wherein the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject and ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen (Page 14). Thus, as evidenced by the reference, it is noted that doses and dosing regimen are recognized as a therapeutic variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of doses or dosing regimen (e.g., regimen length, days for administration, single dose/multiple dose administration) would be seen as routine optimization.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of treatment rendered obvious by Yu and Adamus such that the anti-STAT3-TLR9-binding conjugate is administered (i) simultaneously or (ii) sequentially with the anti-CTLA-4 antibody and wherein the doses/dosing schedule is optimized to achieve optimal therapeutic effects, as suggested by Frank. One would have been motivated to make such a modification as both simultaneous and sequential administration of a STAT3 inhibitor and an immune checkpoint inhibitor (e.g., anti-CTLA-4 antibody) are used in the art for cancer treatment, as suggested by Frank, and optimization of doses and dosing schedules is standard and routine in the art. One of ordinary skill in the art would have a reasonable expectation of success because Frank explicitly teaches that, in some cases (in certain methods of treatment), a STAT3 inhibitor is administered prior to administration of the immune checkpoint inhibitor (i.e., sequential administration) and in other cases the STAT3 inhibitor is administered simultaneously with the immune checkpoint inhibitor and that doses and dosing schedules may be determined by one of ordinary skill in the art to achieve optimal therapeutic effects; it would be expected that such modified methods would be successful in treating cancer.
Those of skill in the art recognize that the two anti-cancer agents, anti-STAT3-TLR9-binding conjugate comprising a CpG moiety covalently attached to an anti-STAT3 siRNA and anti-CTLA-4 antibodies, both known to successfully, pharmaceutically treat cancer, could have been combined by known methods, and that in a dose/dose schedule optimized combination, each agent of the composition, whether administered simultaneously or sequentially, as suggested by Frank, merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat cancer and have additive and/or synergistic effects, as suggested by Adamus, through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in anti-cancer therapy, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, and are suggested as useful together, and that in a dose/dose schedule optimized combination, each agent of the composition, whether administered simultaneously or sequentially, as suggested by Frank, and are suggested to yield additive/synergistic effects by Adamus, in order to form a third composition which is to be used for the very same purpose of treating cancer.
Claims 1-2, 8, 11, and 21-27 are rejected under 35 U.S.C. 103 as being unpatentable over:
U.S. Patent No. 9,976,147 (herein after referred to as “147”); and
U.S. Patent No. 10,829,765 (herein after referred to as “765”)
each in view of US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”) and non-patent literature by Adamus and Kortylewski (Contemp. Oncol. (Pozn.), 2017, 21(1A), 56-60; herein after referred to as "Adamus"). It is specifically noted that 765 is a continuation of 147 and therefore both patents have the same disclosure and the rejection in view of Yu and Adamus applies to each patent; the disclosure of 147 is provided below.
147 teaches a compound including a TLR-binding (e.g. endosome-associated TLR-(endosomal TLR-), TLR3-, TLR7-, TLR8-, or TLR9-binding) nucleic acid substituent conjugated to a STAT-binding substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding substituent); in embodiments the compound includes a TLR9-binding DNA substituent conjugated to a STAT-binding substituent (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding substituent) and/or in embodiments, the compound includes a TLR9-binding DNA substituent conjugated to a STAT3-binding substituent (Column 45, Lines 28-39; emphasis added). In embodiments, the STAT-binding substituent is (i) a STAT-binding nucleic acid substituent, (ii) a STAT3-binding nucleic acid substituent (e.g. STAB-binding DNA substituent), and/or a STAT3-binding DNA substituent (Column 45, Lines 59-64). In embodiments, the TLR9-binding DNA substituent includes a CpG motif (Column 49, Lines 17-18; emphasis added). In embodiments, the compound includes a linker between the TLR-binding nucleic acid (e.g., endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-binding nucleic acid) substituent and the STAT-binding DNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6- binding DNA substituent) (Column 59, Lines 14-19). Also provided is a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, of the invention (including in an aspect, embodiment, table, figure, claim, sequence listing, or example); in embodiments of the pharmaceutical compositions, the compound, or pharmaceutically acceptable salt thereof, as described herein (including in an aspect, embodiment, table, figure, claim, sequence listing, or example), is included in a therapeutically effective amount (Column 82, Lines 55-64). In embodiments, the pharmaceutical composition further includes a second agent (e.g. therapeutic agent), the second agent can be an anti-cancer agent, and the second agent (e.g. therapeutic agent) is included in a pharmaceutical composition of the invention in a therapeutically effective amount (Column 82 Lines 65-68 through Column 83, Lines 1-4). Also provided is method of treating cancer in a patient in need of the treatment, the method including administering a compound, or pharmaceutically acceptable salt thereof, of the invention (Column 83, Lines 15-20). In embodiments, the method or use includes: (i) systemic administration of the compound, (ii) parenteral administration of the compound, (iii) intravenous administration of the compound, (iv) administration directly to a tumor, and/or (v) local administration to the site of infection or cancer (Column 83, Lines 54-61). In some instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and/or multiple myeloma (Column 22, Lines 28-39; emphasis added). The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated kind of concurrent treatment, complications from the disease being treated or other health-related problems; other therapeutic
regimens or agents can be used in conjunction with the methods and compounds of the invention, and adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art (Column 27 Lines 59-67 through Column 28 Lines 1-10). The therapeutically effective amount of a compound of the invention can be initially determined from cell culture assays, and therapeutically effective amounts for use in humans can also be determined from animal models; the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards and adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan (Column 28, Lines 11-27). Dosages may be varied depending upon the requirements of the patient and the compound being employed, wherein the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time, and the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects; determination of the proper dosage for a particular situation is within the skill of the practitioner and dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated (Column 28, Lines 28-43). Thus, 147 teaches a compound comprising toll-like receptor 9 (TLR9)-binding DNA substituent conjugated to a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein the TLR9-binding DNA substituent comprises a CpG motif, a pharmaceutical composition thereof, and methods of treating cancer comprising administering said compound/pharmaceutical composition.
However, 147 does not disclose a method of treating cancer comprising administering (i) an anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker and (ii) an anti-CTLA-4 antibody in a combined effective amount, nor a pharmaceutical composition thereof comprising (i) and (ii). These deficiencies are remedied by Yu and Adamus whose teachings are provided in detail above.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case: (i) 147 discloses compounds comprising conjugates comprising a toll-like receptor 9 (TLR9)-binding DNA substituent and a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein the TLR9-binding DNA substituent further comprises a CpG motif, a pharmaceutical composition thereof, and a method of treating cancer comprising administering said compound or said pharmaceutical compositon; (ii) Yu discloses a TLR ligand-siRNA chimeric construct, wherein siRNA against Stat3 is linked to toll-like receptor 9 ligand and a CpG oligonucleotide; and (iii) Adamus teaches various oligonucleotide strategies, including siRNA, antisense or decoy oligonucleotides, making it possible to target central regulators of tumor immune tolerance, such as STAT3, and the combination of gene- or protein-selective inhibitors with CpG-mediated delivery to immune cells to provide a unique opportunity to overcome limitations in both oligonucleotide delivery as well as therapeutic efficacy and cancer immunotherapies addressing the complexity of cellular and molecular networks operating in the tumor microenvironment, wherein Adamus further suggests oligonucleotide strategies targeting STAT3 in combination with anti-CTLA4 antibodies as a possible synergistic combination, which can provide new avenues for more precise and effective treatments for human malignancies.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound/pharmaceutical composition/method of cancer treatment disclosed by 147 such that the STAT2/TLR9/CpG conjugate is an anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker, as suggested by Yu, wherein the composition further includes an anti-CTL4 antibody, as suggested by Adamus, wherein such a combination would be expected to have synergistic anti-cancer effects, as suggested by Adamus. One would have been motivated to make such a modification because the anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker is known in the art and is a re-arrangement of the components of 175 and adding an anti-CTL4 antibody would improve therapeutic efficacy and provide synergistic effects. One of ordinary skill in the art would have a reasonable expectation of success because the use of anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker and an anti-CTLA4 antibody are both known to, on their own, treat cancer and Adamus suggests that their combination could provide synergistic effects; thus the combination would be expected to treat cancer synergistically.
Claims 3-4 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over:
U.S. Patent No. 9,976,147; or
U.S. Patent No. 10,829,765
each in view of US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”) and non-patent literature by Adamus and Kortylewski (Contemp. Oncol. (Pozn.), 2017, 21(1A), 56-60; herein after referred to as "Adamus"), as applied to claims 1-2, 8, 11, and 21-27 above, and each in further view of WO 2019/023525 A1 (IDS citation no. 4; herein after referred to as "Frank").
It is specifically noted that 765 is a continuation of 147 and therefore both patents have the same disclosure and the rejection in view of Yu, Adamus, and Frank applies to each patent.
Claim 1 is rendered obvious by the combination of 147 or 765 each in view of Yu and Adamus. However, none of the cited references explicitly teach or suggest administering the anti-STAT3-TLR9-binding conjugate (i) simultaneously or (ii) sequentially with the anti-CTLA-4 antibody, nor do they teach or suggest specific administration schedules. These deficiencies are remedied by Frank.
Frank teaches a method of preventing, treating, and/or managing cancer in a patient (e.g., a human patient), the method comprising administering to the patient a prophylactically effective regimen or a therapeutically effective regimen, the regimen comprising administering to the patient a compound of the invention or a composition of the invention, e.g., a combination of a STAT3 inhibitor and an immune checkpoint inhibitor, wherein the patient has been diagnosed with cancer; the amount of a compound of the invention used in the prophylactic and/or therapeutic regimens which will be effective in the prevention, treatment, and/or management of cancer can be based on the currently prescribed dosage of the compound as well as assessed by methods disclosed (Page 44). Immune checkpoint inhibitors include, but are not limited to, inhibitors of programmed death-ligand 1 (PD-L1), PD-L2, PD-1, CTLA-4, TIM-3, LAG-3, V-domain Ig suppressor of T cell activation (VISTA), T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), and B and T Lymphocyte Attenuator (BTLA; CD272) (Page 35). Frank teaches that, in some cases, STAT3 inhibitor is administered prior to administration of the immune checkpoint inhibitor (i.e., sequential administration) and in other cases the STAT3 inhibitor is administered simultaneously with
the immune checkpoint inhibitor (Page 3). Frank teaches that therapeutic regimens disclosed comprise administration of compounds of the invention or pharmaceutical compositions thereof to the patient in a single dose or in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses) wherein, in one aspect, the prophylactic and/or therapeutic regimens comprise administration of the compounds of the invention or pharmaceutical compositions thereof in multiple doses; when administered in multiple doses, the compounds or pharmaceutical compositions are administered with a frequency and in an amount sufficient to treat and/or manage the condition wherein, for example, the frequency of administration ranges from once a day up to about once every eight weeks, from about once a week up to about once every six weeks, from about once every three weeks up to about once every four weeks (Pages 62-63; emphasis added). In one embodiment, Frank teaches that the therapeutic regimen comprises administering to a patient a plurality of doses of an effective amount of a compound of the invention, wherein the plurality of doses maintains a plasma level of at least 0.1 μg/mL, at least 0.5 μg/mL, at least 1 μg/mL, at least 2 μg/mL, at least 5 μg/mL, at least 6 μg/mL, at least 10 μg/mL, at least 15 μg/mL, at least 20 μg/mL, at least 25 μg/mL, at least 50 μg/mL, at least 100 μg/mL, at least 125 μg/mL, at least 150 μg/mL, at least 175 μg/mL, at least 200 μg/mL, at least 225 μg/mL, at least 250 μg/mL, at least 275 μg/mL, at least 300 μg/mL, at least 325 μg/mL, at least 350 μg/mL, at least 375 μg/mL, or at least 400 μg/mL of the compound of the invention for at least 1 day, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 24 months or 36 months (Page 64). Frank also teaches that the amount of a compound of the invention used in the therapeutic regimens which will be effective in the treatment and/or management of cancer can be based on the currently prescribed dosage of the compound as well as assessed by methods disclosed herein and known in the art wherein the frequency and dosage will vary also according to factors specific for each patient depending on the specific compounds administered, the severity of the cancerous condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient (Page 61); the terms "effective amount" and "therapeutically effective amount" of a formulation or formulation component is meant a sufficient amount of the formulation or component, alone or in a combination, to provide the desired effect wherein the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject and ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen (Page 14). Thus, as evidenced by the references, it is noted that doses and dosing regimen are recognized as a therapeutic variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of doses or dosing regimen (e.g., regimen length, days for administration, single dose/multiple dose administration) would be seen as routine optimization.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of treatment rendered obvious by 147 or 765 each in view of Yu and Adamus such that the anti-STAT3-TLR9-binding conjugate is administered (i) simultaneously or (ii) sequentially with the anti-CTLA-4 antibody and wherein the doses/dosing schedule is optimized to achieve optimal therapeutic effects, as suggested by Frank. One would have been motivated to make such a modification as both simultaneous and sequential administration of a STAT3 inhibitor and an immune checkpoint inhibitor (e.g., anti-CTLA-4 antibody) are used in the art for cancer treatment, as suggested by Frank, and optimization of doses and dosing schedules is standard and routine in the art. One of ordinary skill in the art would have a reasonable expectation of success because Frank explicitly teaches that, in some cases (in certain methods of treatment), a STAT3 inhibitor is administered prior to administration of the immune checkpoint inhibitor (i.e., sequential administration) and in other cases the STAT3 inhibitor is administered simultaneously with the immune checkpoint inhibitor and that doses and dosing schedules may be determined by one of ordinary skill in the art to achieve optimal therapeutic effects; it would be expected that such modified methods would be successful in treating cancer.
Those of skill in the art recognize that the two anti-cancer agents, anti-STAT3-TLR9-binding conjugate comprising a CpG moiety covalently attached to an anti-STAT3 siRNA and anti-CTLA-4 antibodies, both known to successfully, pharmaceutically treat cancer, could have been combined by known methods, and that in a dose/dose schedule optimized combination, each agent of the composition, whether administered simultaneously or sequentially, as suggested by Frank, merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat cancer and have additive and/or synergistic effects, as suggested by Adamus, through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in anti-cancer therapy, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, and are suggested as useful together, and that in a dose/dose schedule optimized combination, each agent of the composition, whether administered simultaneously or sequentially, as suggested by Frank, and are suggested to yield additive/synergistic effects by Adamus, in order to form a third composition which is to be used for the very same purpose of treating cancer.
Double Patenting - New
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.
Claims 1-4, 8, 11, and 14-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-10, 18, 24 of U.S. Patent No. 9,976,147 (herein after referred to as “147”) in view of US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”), non-patent literature by Adamus and Kortylewski (Contemp. Oncol. (Pozn.), 2017, 21(1A), 56-60; herein after referred to as "Adamus") and WO 2019/023525 A1 (IDS citation no. 4; herein after referred to as "Frank").
Claims 1-4, 8, 11, and 14-27 are rendered obvious by the combined teachings of the prior
art above as discussed in the 103 section, the 103s being incorporated here. The addition of the
patented claims above over related subject matter only further supports this obviousness.
Claim 1 of 147 is drawn to a compound comprising a toll-like receptor (TLR)-binding nucleic acid substituent conjugated to a signal transducer and activator of transcription (STAT)-binding nucleic acid substituent, wherein said STAT-binding nucleic acid substituent is capable of binding to a STAT transcription factor. Claim 5 of 147 is drawn to a compound comprising a toll-like receptor 9 (TLR9)-binding DNA substituent conjugated to a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein said STAT3-binding nucleic acid substituent is capable of binding to a STAT3 transcription factor. Claims 6-7 of 147 further modify claim 1 wherein, respectively: (i) the TLR9-binding DNA substituent comprises a CpG motif and (ii) the TLR9-binding DNA substituent comprises a Class A CpG DNA sequence, a Class B CpG DNA sequence or a Class C CpG DNA sequence. Claims 8-10 of 147 further modify claim 7 wherein, respectively: (i) the TLR9-binding DNA substituent is a Class A CpG DNA sequence, (ii) the TLR9-binding DNA substituent is a Class B CpG DNA sequence, and (iii) the TLR9-binding DNA substituent is a Class C CpG DNA sequence. Claim 18 of 147 further modifies claim 5, wherein the compound of claim 5 further comprises a linker between the TLR9-binding DNA substituent and the STAT3-binding DNA substituent. Claim 24 of 147 is drawn to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1. Thus, 147 claims a toll-like receptor 9 (TLR9)-binding DNA substituent conjugated to a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein the TLR9-binding DNA substituent comprises a CpG motif, and a pharmaceutical composition thereof.
However, 147 does not claim a method of treating cancer comprising administering (i) an anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker and (ii) an anti-CTLA-4 antibody in a combined effective amount, wherein administration of (i) and (ii) is simultaneous or sequential, nor a pharmaceutical composition thereof comprising (i) and (ii). These deficiencies are remedied by Yu, Adamus, and Frank whose teachings are provided in detail above.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case: (i) 147 claims conjugates comprising a toll-like receptor 9 (TLR9)-binding DNA substituent and a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein the TLR9-binding DNA substituent further comprises a CpG motif, and a pharmaceutical composition thereof; (ii) Yu discloses a TLR ligand-siRNA chimeric construct, wherein siRNA against Stat3 is linked to toll-like receptor 9 ligand and a CpG oligonucleotide; (iii) Adamus teaches various oligonucleotide strategies, including siRNA, antisense or decoy oligonucleotides, making it possible to target central regulators of tumor immune tolerance, such as STAT3, and the combination of gene- or protein-selective inhibitors with CpG-mediated delivery to immune cells to provide a unique opportunity to overcome limitations in both oligonucleotide delivery as well as therapeutic efficacy and cancer immunotherapies addressing the complexity of cellular and molecular networks operating in the tumor microenvironment, wherein Adamus further suggests oligonucleotide strategies targeting STAT3 in combination with anti-CTLA4 antibodies as a possible synergistic combination, which can provide new avenues for more precise and effective treatments for human malignancies; and (iv) Frank teaches cancer treatments wherein a STAT3 inhibitor is administered prior to administration of an immune checkpoint inhibitor (i.e., sequential administration) and in other cases the STAT3 inhibitor is administered simultaneously with the immune checkpoint inhibitor, wherein the immune checkpoint inhibitor can include an anti-CTLA4 antibody.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound/pharmaceutical composition claimed by 147 such that the STAT2/TLR9/CpG conjugate is an anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker, as suggested by Yu, wherein the composition further includes an anti-CTL4 antibody, as suggested by Adamus, wherein said composition could be administered to treat cancer, as suggested by the Yu, Adamus, and Frank, and wherein said administration occurs simultaneously or sequentially, as suggested by Frank, and wherein such a combination would be expected to have synergistic anti-cancer effects, as suggested by Adamus. One would have been motivated to make such a modification because the anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker is known in the art and is a re-arrangement of the components of 175, adding an anti-CTL4 antibody would improve therapeutic efficacy and provide synergistic effects, and the administration of combination therapies comprising STAT3 inhibitors and immune checkpoint inhibitors are also known in the art. One of ordinary skill in the art would have a reasonable expectation of success because the use of anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker and an anti-CTLA4 antibody are both known to, on their own, treat cancer and Adamus suggests that their combination could provide synergistic effects; thus the combination would be expected to treat cancer synergistically.
Claims 1-4, 8, 11, and 14-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 4-5, 8-12, 15-18 of U.S. Patent No. 10.829,765 (herein after referred to as “765”) in view of US 2014/0287987 A1 (06/25/2024 IDS citation no. 1; herein after referred to as “Yu”), non-patent literature by Adamus and Kortylewski (Contemp. Oncol. (Pozn.), 2017, 21(1A), 56-60; herein after referred to as "Adamus"), and WO 2019/023525 A1 (IDS citation no. 4; herein after referred to as "Frank").
Claims 1-4, 8, 11, and 14-27 are rendered obvious by the combined teachings of the prior
art above as discussed in the 103 section, the 103s being incorporated here. The addition of the
patented claims above over related subject matter only further supports this obviousness.
Claim 1 of 765 is drawn to a method of treating lymphoma, leukemia, or prostate cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound which comprises SEQ ID NO:23 covalently bonded to SEQ ID NO:12. Claim 4 of 765 is drawn to the method of claim 1, for treating lymphoma. Claims 5 and 8 of 765 are drawn to the method of claim 4 wherein, respectively: (i) the lymphoma is a non-Hodgkin’s lymphoma and (ii) the lymphoma is B cell lymphoma. Claims 9-11 of 765 further modify the method of claim 1 wherein, respectively, the method comprises: (i) systemically administering the compound to the patient, (ii) intravenously administering the compound to the patient, and (iii) intratumorally administering the compound to the patient. Claim 12 of 765 is drawn to a method of treating lymphoma, leukemia, or prostate cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound which comprises a toll-like receptor (TLR)-binding nucleic acid substituent conjugated to a signal transducer and activator of transcription (STAT)-binding nucleic acid substituent, wherein the STAT-binding nucleic acid substituent is capable of binding to a STAT transcription factor. Claim 15 of 765 modifies the method of claim 12, wherein the method is for treating lymphoma. Claim 16 of 765 further modifies the method of claim 15, wherein the lymphoma is non-Hodgkin’s lymphoma. Claim 17 of 765 further modifies the method of claim 16, wherein the TLR9-binding DNA substituent comprises a Class A CpG DNA sequence, a Class B CpG DNA sequence, or a Class C CpG DNA sequence. Claim 18 of 765 further modifies the method of claim 12 wherein the toll-like receptor (TLR)-binding nucleic acid substituent is a toll-like receptor 9 (TLR9)-binding DNA substituent; and wherein the activator of transcription (STAT)-binding nucleic acid substituent is a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent. Thus, 765 claims a method of treating cancer (e.g., lymphoma) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound which comprises a toll-like receptor (TLR)-binding nucleic acid substituent conjugated to a signal transducer and activator of transcription (STAT)-binding nucleic acid substituent, wherein the STAT-binding nucleic acid substituent is capable of binding to a STAT transcription factor and wherein the TLR9-binding DNA substituent comprises a CpG DNA sequence.
However, 765 does not claim a method of treating cancer comprising administering (i) an anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker and (ii) an anti-CTLA-4 antibody in a combined effective amount, wherein administration of (i) and (ii) is simultaneous or sequential, nor a pharmaceutical composition thereof comprising (i) and (ii). These deficiencies are remedied by Yu, Adamus, and Frank whose teachings are provided in detail above.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case: (i) 765 claims methods of treating cancer (e.g., lymphoma) comprising administering conjugates comprising a toll-like receptor 9 (TLR9)-binding DNA substituent and a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein the TLR9-binding DNA substituent further comprises a CpG motif; (ii) Yu discloses a TLR ligand-siRNA chimeric construct, wherein siRNA against Stat3 is linked to toll-like receptor 9 ligand and a CpG oligonucleotide; (iii) Adamus teaches various oligonucleotide strategies, including siRNA, antisense or decoy oligonucleotides, making it possible to target central regulators of tumor immune tolerance, such as STAT3, and the combination of gene- or protein-selective inhibitors with CpG-mediated delivery to immune cells to provide a unique opportunity to overcome limitations in both oligonucleotide delivery as well as therapeutic efficacy and cancer immunotherapies addressing the complexity of cellular and molecular networks operating in the tumor microenvironment, wherein Adamus further suggests oligonucleotide strategies targeting STAT3 in combination with anti-CTLA4 antibodies as a possible synergistic combination, which can provide new avenues for more precise and effective treatments for human malignancies; and (iv) Frank teaches cancer treatments wherein a STAT3 inhibitor is administered prior to administration of an immune checkpoint inhibitor (i.e., sequential administration) and in other cases the STAT3 inhibitor is administered simultaneously with the immune checkpoint inhibitor, wherein the immune checkpoint inhibitor can include an anti-CTLA4 antibody.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method claimed by 765 such that the STAT2/TLR9/CpG conjugate is an anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker, as suggested by Yu, wherein the composition further includes an anti-CTL4 antibody, as suggested by Adamus, wherein said combination could be administered simultaneously or sequentially, as suggested by Frank, and wherein such a combination would be expected to have synergistic anti-cancer effects, as suggested by Adamus. One would have been motivated to make such a modification because the anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker is known in the art and is a re-arrangement of the conjugate components of 765, adding an anti-CTL4 antibody would improve therapeutic efficacy and provide synergistic effects, and the administration of combination therapies comprising STAT3 inhibitors and immune checkpoint inhibitors are also known in the art. One of ordinary skill in the art would have a reasonable expectation of success because the use of anti-STAT3-TLR9-binding conjugate comprising a CpG moiety bound to STAT3 siRNA through a covalent linker and an anti-CTLA4 antibody are both known to, on their own, treat cancer and Adamus suggests that their combination could provide synergistic effects; thus the combination would be expected to treat cancer synergistically.
Conclusion
Claims 1-4, 8, 11, and 14-27 are pending. Claims 1-4, 8, 11, and 14-27 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
Prosecution Insights