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 .
Claim Status
Claims 5-7, 9-10, and 12-13 have been cancelled and claim 1 has been amended, as requested in the amendment filed on August 18, 2025. 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.
Specification - Objection Withdrawn
Applicant has provided a clean version of the abstract, which is a single paragraph between 50 and 150 words in length. As such, the objection to the specification regarding the abstract is withdrawn.
Applicant has amended the specification such that any embedded hyperlinks or other forms of browser-executable code have been removed and any trade names or marks used in commerce are properly represented. As such, the objections to the specification are withdrawn.
Claim Objections - Maintained
Claims 1 and 26 stand as being objected to because of the following informalities: the claims recite an "anti-STAT3-TLR9 binding conjugate" in lines 3 and 1, respectively, but should . Appropriate correction is required.
Claim Rejections - 35 USC § 112 - Maintained
Claims 1-4, 8, 11, and 14-27 stand as rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancers in which STAT3, TLR9, and CTLA-4 are implicated , does not reasonably provide enablement for curing or preventing (emphasis added).
It is noted that Applicant has amended claim 1 to now recite “wherein said cancer is a STAT3-, TLR-9-, or CTLA4- implicated cancer. While this amendment addressed the scope of enablement rejection with regard to the treatment of any cancer, the amendment does not address the scope of enablement rejection with regard to curing or preventing cancer.
As indicated in the previous Office Action (05/19/2025), the instant specification defines “cancer”, “treating”, and “treatment” in paragraphs 0113 and 0122-0123 as presented below.
(i) All types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemias, lymphomas, carcinomas and sarcomas (Paragraph 0113; emphasis added).
(ii) Any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. (Paragraph 0122; emphasis added).
(iii) As including any approach for obtaining beneficial or desired results in a subject's condition, including clinical results wherein beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease's spread; relieve the disease's symptoms, fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things. (Paragraph 0123; emphasis added).
Thus, even as currently amended, the instant claims include preventing and/or curing cancer, the full scope of which is not enabled as described in the previous Office Action (05/19/2025). 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 maintained.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1-4, 8, 11, and 14-27 stand as rejected under 35 U.S.C. 103 as being unpatentable over of US 2014/0287987 A1 (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").
With regard to the rejection above, Applicant argues on Pages 7-10 of Remarks (08/18/2025) that Frank teaches the treatment of glioma with a combination of a small molecule STAT3 inhibitor, pyrimethamine, and a PD-1 antibody. In contrast, claim 1 as amended sets forth a combination treatment with the bifunctional conjugate of Yu, which includes (i) a TLR-binding CpG oligonucleotide as a targeting moiety, and (ii) a STAT3 siRNA as an anti-cancer agent and an anti-CTLA4 antibody; Frank's active agent and Yu's conjugates are chemically entirely different entities. Applicant argues that pyrimethamine is a small molecule, while Yu's active agent is a siRNA connected through a covalent linker with a CpG oligonucleotide; Yu's conjugates are bi-functional as they contain a CpG oligonucleotide as TLR targeting moiety in addition to the anti-STAT3 siRNA, and this targeting feature is not taught or suggested by Frank. Therefore, Applicant asserts that the STAT3 inhibitors used in Yu and Frank are not only chemically but also functionally distinct and a person of ordinary skill in the art would not be able to predict if Yu' s conjugate would be effective if combined with an anti-PD-1 antibody, much less an anti-CTLA4 antibody. Additionally, Applicant argues that Frank specifically teaches that a combination of an anti-PD-1 antibody with the STAT3 small molecule inhibitor pyrimethamine is effective in glioma treatment. While CTLA4 is mentioned as part of a laundry list of possible immune checkpoints by Frank, PD-1 and CTLA4 bind different receptors and affect independent signaling pathways; absent any teaching or suggesting by Frank that inhibition of CTLA4 would be expected to have the same effect as inhibition of PD-1 when combined with pyrimethamine during combination treatment of glioma, a person of ordinary skill in the art would not be motivated to use a CTLA4 inhibitor with a STAT3 small molecule inhibitor much less with a conjugate as taught by Yu.
With regard to the arguments above against the combination of Yu and Frank, it is noted that Applicant’s arguments have been fully considered, but are deemed not persuasive.
The following are noted:
Obviousness does not require absolute predictability, however, at least some degree of predictability is required. See MPEP 2143.02II. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
There is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004).
It is acknowledged that PD-1 and CTLA-4 are different receptors and affect independent signaling pathways, however it is noted that Frank specifically recites administering a STAT3 inhibitor before or simultaneously with an immune checkpoint inhibitor and more specifically indicates the use of a PD-1 inhibitor which comprises pembrolizumab or nivolumab, a
PD-L1 inhibitor which comprises atezolizumab, avelumab, or durvalumab, or a CTLA-4 inhibitor that is ipilimumab (see Page 3). Frank further indicates that when blocking said immune checkpoint proteins with inhibitory antibodies, for example, the “brakes” on the immune system are releases and T cells are then able to identify and kill cancer cells, and indicates that immune checkpoint inhibitors alone have shown substantial clinical responses in non-glioma cancer such as metastatic melanoma (Page 35); thus Frank indicates the selection of immune checkpoint inhibitors in order to activate the immune system, e.g., T cells, in order to improve cancer cell killing. One of ordinary skill in the art would therefore recognize that a CTLA-4 immune checkpoint inhibitor in combination with a STAT3 inhibitor would reasonably be expected to have similar results to a PD-1 immune checkpoint inhibitor with the same STAT3 inhibitor as both immune checkpoint inhibitors would be expected to activate T cells and promote tumor cell killing, despite targeting different molecules. Furthermore, Yu describes the development of optimal Stat3 siRNAs (Dicer) with antitumor effects in vivo, and shows that Stat3siRNA (i.e., STAT3 inhibitor) linked to CpG oligonucleotide (i.e., TLR ligand) efficiently enters dendritic cells wherein targeting Stat3 drastically improves CpG-based cancer (Paragraph 0104); 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). One of ordinary skill in the art would recognize the therapeutic potential of combining the STAT3-TLR9 binding conjugates of Yu (i.e., a STAT3 inhibitor) with an immune checkpoint inhibitor, as suggested by Frank, wherein synergistic effects would be expected considering the STAT3-TLR9 binding conjugates of Yu were demonstrated to be efficient and improved antitumor effects via immune modulation alone and the combination of STAT3 inhibitors with immune checkpoint inhibitors was demonstrated by Frank, wherein the addition of an immune checkpoint inhibitor would be expected to further modulate the immune system and promote cancer cell killing. Thus, the combination of Yu and Frank to arrive at the instant invention would have a reasonable expectation of success and would be expected to be predictable considering the inventions of both Yu and Frank disclose immune modulation for improved therapeutic benefits when treating cancer.
Applicant further argues that even if, arguendo, a person having ordinary skill in the art would follow the Examiner's logic, which they would not, and modify the method of Yu by adding an anti-CTLA4 antibody, they would not be able to predict whether this modification would result in effective treatment. It was Applicants who discovered the surprising therapeutic effect of an anti-STAT3-TLR9 binding conjugate in combination with anti-CTLA4 antibody and the Examiner is using impermissible hindsight. Applicant argues that based on the conventional meaning in the biological arts, a person having ordinary skill in the art would understand that synergy or a synergistic amount is a measured effect of two compounds administered in combination where the measured effect is greater than the sum of the individual effects of each of the compounds; based on that conventional meaning Frank fails to teach or suggest a synergistic effect of pyrimethamine in combination with an anti PD-1 antibody. Applicant further argues that Figure 7 of Frank depicts a photographic image of bioluminescence
in mice bearing glioblastoma cells after treatment with an anti-PD-l antibody alone, the small
molecule STAT3 inhibitor pyrimethamine or a combination thereof; referring to Figure 7,
Frank claims at page 34, second paragraph, that the combination of a STAT3 inhibitor and an
inhibitor of the immune checkpoint PD-1 leads to synergistic therapeutic effects, however
Frank fails to provide any quantitative analysis that would support the effect of the treatment
with pyrimethamine, and the anti-PD-1 antibody is indeed synergistic and not merely additive. It
appears that in Figure 7, the anti-PD-l antibody treatment alone or the treatment with pyrimethamine alone each result in one out of four animals being free of glioma cells. Among
the group of mice treated with a combination of the antibody and pyrimethamine, two out of four
animals are cancer free, which suggests an additive rather than a synergistic effect. For at least
these reasons Applicant argues that Frank fails to teach or suggest synergistic effects of the STAT3 small inhibitor compound and the anti-PD-1 antibody.
With regard to the above arguments regarding Frank and synergistic effects, it is noted that Applicant’s arguments have been fully considered but are deemed not persuasive.
With regard to impermissible hindsight, it is noted that “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). The rejection of record only takes into account the disclosures of the cited prior art references which would have been within the level of ordinary skill in the art at the time the claimed invention was filed. Furthermore, regarding the arguments against Frank and the observed synergistic effects, the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). It is noted that Applicant is arguing synergistic effects solely based on one presented Figure, i.e., Figure 7. First, it is noted that Frank does not define “synergistic” in any special way, and as such the term takes on the regular meaning as would be understood by one having ordinary skill in the art, i.e., the definition provided by Applicant, which is further supported on Page 66 of Frank (see last paragraph). The argument that Frank does not teach synergistic effects are solely based on Figure 7. It is specifically noted that the disclosure of Frank describes the results of enhanced (i.e., synergistic) effects of immune checkpoint inhibitor with STAT3 inhibitors using the data presented in Figure 3 and Figure 7 (see Page 72). Applicant argues that the anti-PD-l antibody treatment alone or the treatment with pyrimethamine alone each result in one out of four animals being free of glioma cells, and among the group of mice treated with a combination of the antibody and pyrimethamine, two out of four animals are cancer free, which suggests an additive rather than a synergistic effect. This is not persuasive as the number of animals being cancer free is not the only factor to be considered; the level of bioluminescence overall within a given treatment group is more comprehensive and more indicative of improved efficacy and synergistic effects, which is more clearly depicted in/supported by Frank Figure 3. At day 26 of the study, the bioluminescence of the combination anti-PD-1/pyrimethamine is approximately 5,000%, whereas each of the pyrimethamine alone and anti-PD-1 alone conditions have a bioluminescence of roughly 23,000% and all animals in the control group died prior to day 26. Taking this data together as disclosed by Frank, one of ordinary skill in the art would take the teachings of Frank to indicate synergistic effects.
In view of the above, the rejection of claims 1-4, 8, 11, and 14-27 under 35 U.S.C. 103 as being unpatentable over of US 2014/0287987 A1 (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") is deemed proper and is maintained.
Double Patenting - Maintained
Claims 1-4, 8, 11, and 14-27 stand as 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 (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 stand as 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 (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").
It is noted that no arguments regarding the above-listed double patenting rejections were presented, as Applicant has requested the rejections be held in abeyance until allowable subject matter is found. As such, in view of the maintained art rejections under 35 U.S.C. 103, the double patenting rejections above are also maintained.
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.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642