CTNF 18/568,797 CTNF 98670 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Application Status Applicant’s amendments to the claims filed August 9, 2024 are acknowledged. Claims 37, 39, 41-43, 47-50, 53-54, 59, 62-63, 68, and 128 were amended, and claims 1-36, 40, 44, 46, 55-58, 60-61, 64-67, 69-127, and 129-158 were cancelled. Claims 37-39, 41-43, 45, 47-54, 59, 62-63, 68, and 128 are pending and under consideration hereinafter. Priority Applicant’s priority claims to Application Nos. 63/209,316, 63/304,554, and PCT/US2022/033081, are acknowledged. Claims 37-39, 41-43, 45, 47-54, 59, 62-63, 68, and 128 find support in Application No. 63/209,316. The effective filing date of the claims under examination is June 10, 2021. Drawings The drawings are objected to because of the following informalities: The view numbers for the partial views for Figs. 1D-E, and 13, are followed by "continued" instead of a capital letter such as FIG. 1A, FIG. 1B, etc. 37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” Appropriate correction is required. Specification The specification is objected to because of the following informalities: The use of terms which are trade names or marks used in commerce has been noted in this application, e.g., “GlutaMax” ([0109]), “Lipofectamine” ([0110]), and “Cytoperm” ([0134]). Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. The terms, including the exemplary terms above, should be accompanied by the generic terminology. Furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. The paragraph numbering is not ascending throughout the specification; on at least pg. 26, the paragraph numbering resets from “[0046]” to “[0018].” Appropriate correction is required. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claims 37-39, 41-43, 45, 47-54, 59, 62-63, and 68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention for the reasons that follow. MPEP 2163.II.A3.(a).(i) states the following: “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.” “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).” Species Encompassed Claims 37-39, 41-43, 45, 47-54, 59, 62-63, and 68 encompass agents “that result[] in an increase in STING activity,” wherein STING is interpreted as a “Stimulator of Interferon Genes” protein ([0004]; [0044]). The agents are further defined solely by various additional functions in the dependent claims, i.e., wherein the agent increases “STING signaling,” “decrease[s] the intracellular degradation of STING,” “results in an increase in type I interferon (IFN) expression,” “increase[s] [] production of one or more pro-inflammatory cytokines,” “enhances an immune response against a disease in a subject” wherein the disease is “cancer,” “reduces the activity of a negative regulator of STING” wherein the negative regulator is a “component of the ESCRT pathway,” “hepatocyte growth factor-regulated tyrosine kinase substrate (HGS),” “vacuolar protein sorting-associated protein 37 (VPS37A),” “a protein containing a J-domain,” “DnaJ homolog subfamily C member 13 (DNJC13).” Dependent claim 54 recites structural features of the agent, i.e., wherein the agent is “a small molecule inhibitor of the negative regulator of STING or a nucleic acid capable of reducing expression of the negative regulator of STING.” Dependent claims 59, 62-63 also recite structural features of the agent, i.e., wherein the agent is a “recombinant protein having STING activity,” or nucleic acid encoding the same, wherein the recombinant protein is a “fusion protein comprising STING and one or more additional proteins or fragments thereof,” wherein the additional protein or fragments are “one or more FYVE domains.” The claims encompass a genus of agents defined by the function of “increasing STING activity,” which are further defined solely by various additional functions. The agents encompassed by claims 37- 39, 41-43, 45, 47-53, and 68 do not have any structural limitations; the agents may be virtually any substance, e.g., small molecule, peptide, nucleic acids (e.g., aptamers), antisense agent, nuclease, recombinant protein or nucleic acid encoding the same, etc. ([0009]; [0014]-[0015]; [0022]-[0025]). The specification has not sufficiently described the structures of the small molecules, peptides, nucleic acids, antisense agents, nucleases, recombinant proteins or nucleic acids encoding the same, etc., which increase STING activity, or achieve the various additional functions in the claims, specifically, the additional therapeutic functions, and the additional regulatory functions on negative regulators of STING. Dependent claims 54, 59, and 62-63 set forth structural limitations for the agent. However, as will be further described below, these generic structure(s) also do not sufficiently set forth the structures of agents which would increase STING activity, and in case of claim 54, also reduce the activity of a negative regulator of STING. Species Disclosed in the Specification The specification describes “STING signaling” in response to dsDNA: cGAS synthesizes cGAMP, which is bound by STING, STING is trafficked from the ER to the Golgi, where it is at least palmitoylated, palmitoylated STING oligomerizes and interacts with TBK1 and IRF3 to promote expression of type I interferons, and interacts with “other transcription factors,” e.g., NF-ΚB, to promote expression of pro-inflammatory cytokines ([0044]-[0046]). The specification describes that STING may play a role in promoting cancer immunity ([0018]-[0019]), but also may “impair cancer immunity in certain contexts” ([0020]). The specification describes examples of negative regulators of STING, e.g., ESCRT complex members, including HGS and VPS37A, which the specification teaches promote STING degradation ([0048]-[0052]). The specification also describes that DNAJC13 “impedes palmitoylation of STING, preventing it from forming active oligomers” ([0056]). The specification generically describes small molecule, nucleic acid (e.g., aptamer), antisense, and peptide inhibitors of negative regulators of STING, as well as recombinant STING proteins ([0021]-[0025]). The specification describes specific agents which increase STING activity – cGAMP, c-di-GMP, c-di-AMP ([0044]), DMXAA and “cyclic dinucleotide analogs of cGAMP” ([0019]), “Intracellular DNA” and “3’3’-linked cyclic-dinucleoties (cdNs)” ([0068]). The specification describes CRISPR-Cas9-based agents which knockout several negative regulators of STING (i.e., HGS, VPS37A, UBE2N), and the agent MLN7243, each of which decrease degradation of STING, and increase STING activity in response to cGAMP stimulation ([0081]-[0082]; [0090]; [0092]; [0097]; [0139]). The specification also describes a single recombinant protein, i.e., “2XFYVE STING,” which increases STING activity ([0147]). The specification describes several other recombinant proteins, comprising STING and one or more additional domains, which do not increase STING activity ([0147]). 2XFYVE STING comprises “human STING LBD (139-376)… fused with… PI3P binding FYVE domain” ([0147]). The specification describes a single “J domain” containing protein, DNAJC13, which, when knocked out using a CRISPR-Cas9-based agent, increases STING activity in certain contexts ([0154]-[0159]). The specification describes that this effect is “independent of palmitoylation” ([0155]), which appears to contradict the earlier statement provided in [0056]. Taken together, the specification describes the following agents in the genus of agents which increase STING activity, wherein the STING activity is STING signaling: dsDNA, several, specific, small molecule activators of STING, which all share similar structural features (e.g., cGAMP, cyclic dinucleotide analogs of cGAMP, etc.), several CRISPR-Cas9-based agents (i.e., sgRNAs and Cas9) which knockout four negative regulators of STING (i.e., HGS, VPS37A, UBEN2N, and DNAJC13), and a single, specific recombinant STING protein which increases STING activity (i.e., “2XFYVE STING”). The CRISPR-Cas9-based agents also decrease intracellular degradation of STING. With the exception of the small molecule activators of STING (i.e., dsDNA, cGAMP) or analogs thereto, none of the agents described in the specification are described as increasing type I interferon (IFN) expression, or pro-inflammatory cytokine production ([0044]; [0049]). It is not evident that the CRISPR-Cas9 based agents would lead to increased type I interferon expression, given that STING signaling does not appear to be provoked directly by these agents (i.e., STING signaling was increased in response to a separate STING agonist, or was “independent of STING agonists”). There is evidenced in Barber (Barber, WO 2010/017248 A2, published 11 February 2010) and Gillooly (Gillooly et al., 2000, The EMBO Journal, Vol. 19, pgs. 4577-4588), further described in paragraphs 38-43 below, that the specific recombinant protein described in the specification would be predicted to promote type I interferon (IFN) expression. The specification also does not describe any agents which enhance immune responses against or treat a disease, e.g., cancer in a human patient. The specification describes that even direct STING agonists, e.g., DMXAA and cyclic dinucleotide analogs of cGAMP, do not consistently enhance immune responses against or treat cancer ([0018]-[0019]), and with respect to another disease, states that “spontaneous activation of STING may lead to autoimmunity” ([0047]). The specification, therefore, has not sufficiently described the structures which would achieve the immune-related, or treatment-related functions recited in the claims. The specification also does not describe the many, possible agents which reduce the activity of a negative regulator of STING. Given the extensive network of molecules which contribute to STING activity described in the specification, the specification’s characterization of a single type of agent (i.e., CRISPR-Cas9-based agent), targeting only four negative regulators of STING does not provide sufficient description of the structures of the small molecules, peptides, nucleic acids, antisense agents, nucleases, recombinant proteins, or nucleic acid encoding the same, which inhibit one or more of the innumerable numbers of molecules up- and downstream of STING activity, and thereby, activate STING. Furthermore, the structure of one of the four negative regulators described by the specification, i.e., DNAJC13, is not well characterized ([0158]). It is not evident that the skilled artisan could identify the structures of agents which reduce the activity of DNAJC13, or the remaining, unidentified negative regulators of STING, which also may have uncharacterized structures. The specification only describes a single “J-domain” protein which is a negative regulator of STING. The specification provides no description of additional J-domain proteins, or the structures of any J-domain protein-inhibiting agents which increase activity of STING. Furthermore, the specification describes no “J-domain” proteins which facilitate palmitoylation of STING; DNAJC13 is described in the specification as either impeding, or having effects independent of palmitoylation ([0056]; [0155]). The specification does not sufficiently describe the structures of agents which are “recombinant protein[s] having STING activity.” The singular agent in the specification comprises a highly specific, truncated structure of a human STING, fused to specific intracellular localization domains. The specification provides limited guidance to determine which recombinant proteins comprising any species of STING protein or fragments thereof, when fused to any one or more additional proteins or fragments thereof, would increase STING activity ([0147]). The specification teaches that the structure and biochemistry of STING are known ([0142]). However, the specification provides evidence that the structures within STING which promote its activity are not well understood. For example, the specification states that localization of STING is crucial for its activity, but states that “the driving force of STING translocation is still highly debatable,” and teaches that “agonist-independent STING activation has also been observed in different settings,” and “mislocalization of STING protein has also been shown to activate the TBK1-IRF3 pathway” ([0142]-[0144]). Given the lack of clear structure-function relationship between STING structure and localization with STING activity, it is not evident that the skilled artisan could ascertain which STING protein or fragments thereof, when fused to any one or more additional proteins or fragments thereof, would increase STING activity. Guidance in the Prior Art The prior art was searched for further description of the agents which are insufficiently described by the specification. The prior art illustrates that STING activity intersects with many different cellular pathways, e.g., cGAS-STING, autophagy, metabolism, and inflammation, Ca 2+ homeostasis and ER stress response (Vashi and Bakhoum, Trends in Biochemical Sciences, 15 January 2021, Vol. 46, No. 6, pg. 446-460). The skilled artisan would understand that the negative regulators of STING, therefore, represent a vast number of molecules up- and downstream of STING, some of which would be structurally and functionally uncharacterized. Although means of preparing small molecules, peptides, aptamers, nucleases, antisense agents, etc., are known in the art, the structural feature(s) required of these agents would not be sufficiently described to the skilled artisan based on a generic function alone. The skilled artisan would essentially need to engage in massive screening efforts, to first, identify all of the negative regulators of STING, and then, identify agents which reduce the activity of the identified regulators. The prior art does not resolve the deficiencies of the specification with respect to the agents which activate STING by reducing the activity of a negative regulator of STING. With respect to the specific negative regulators described in the specification, the prior art describes antisense agents targeting HGS, VPS37A, and DNAJC13. See disclosures of Besemer (Besemer et al., 22 April 2020, Cellular and Molecular Life Sciences, 78:645-660), Mamińska (Mamińska et al., 2016, Science Signaling, Vol. 9, Issue 411, pg. 1-14), and Yu (Yu et al., 11 February 2020, Cardiovascular Research, 117, pg. 533-546). These agents would be predicted to have the same effects as the CRISPR-Cas9-based agents described in the specification, i.e., increase STING activity, wherein the STING activity is STING signaling, and reducing STING degradation. The prior art does not describe any small molecules, peptides, aptamers, nucleases, recombinant proteins, etc., which inhibit these proteins. The prior art also does not appear to describe that inhibiting these proteins increases the activity of STING, increases type I interferon (IFN) expression, production of pro-inflammatory cytokines, or enhances an immune response against or treats a disease in a subject. Here, the prior art also fails to resolve the deficiencies of the specification with respect to the agents which activate STING, and which reduce the activity of a negative regulator of STING. Finally, the search did not uncover guidance with respect to agents which are recombinant proteins comprising STING or fragments thereof, and one or more additional proteins or fragments thereof beyond that which was described in the specification. It is evident that means to prepare fusion proteins are well known. However, knowledge of methods to prepare fusion proteins in general does not resolve the deficiencies specific to STING fusions with increased STING activity. Specifically, which residues are required for its activity, localization, etc., and the compatibility of these structures with the virtually unlimited “one or more additional proteins” or fragments thereof. Conclusion Considering the large variation in the genus of agents (i.e., any small molecule, peptide, nucleic acid, antisense agent, nuclease, recombinant protein, or nucleic acid encoding the same, etc. ), the extremely small percentage of agents described in the specification and prior art ( dsDNA, several, specific, small molecule activators of STING, which all share similar structural features (e.g., cGAMP, cyclic dinucleotide analogs of cGAMP, etc.), several CRISPR-Cas9-based agents (i.e., specific sgRNAs and Cas9) which knockout four negative regulators of STING (i.e., HGS, VPS37A, UBEN2N, and DNAJC13), and several specific antisense agents targeting the same, and a single, specific recombinant STING protein which increases STING activity (i.e., “2XFYVE STING”) ), and the lack of a reasonable structure-function relationship provided by the specification or prior art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing. Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claim 128 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim recites a method for screening for agents that modulate the activity of a Stimulator of Interferon Genes (STING) protein. This judicial exception is not integrated into a practical application and does not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow. Subject Matter Eligibility Test for Products and Processes Step 1 – Is the Claim to a Process, Machine, Manufacture, or Composition of Matter? YES Claim 128 is directed to a process, which is a statutory category. Step 2A, Prong One – Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES Claim 128 is directed to a method for screening for agents that modulate the activity of a Stimulator of Interferon Genes (STING) protein. The method recites that “a deviation in a level of STING activity in [a] first population of cells from that of [a] second population of cells is indicative that the agent is a modulator of STING.” The level of STING activity in a cell is a natural phenomenon. Accordingly, the deviation in STING activity levels in a first population of cells in response to an agent which is a STING modulator, compared to a second population of cells which does not receive the agent, is a natural phenomenon. MPEP 2106.04(b)(I) states “the law of nature and natural phenomenon exceptions reflect the Supreme Court's view that the basic tools of scientific and technological work are not patentable, because the “manifestations of laws of nature” are “part of the storehouse of knowledge,” “free to all men and reserved exclusively to none.” Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948).” Claim 128 recites a natural phenomenon, which is a judicial exception. The method also recites step (c), “comparing the level of STING activity to the level of STING activity in a second population of cells; wherein the second population of cells are not contacted with the agent.” This comparison can be performed in the human mind. MPEP 2106.04(a)(2)(III) states that “the courts consider a mental process… to be an abstract idea.” “Examples of mental processes include observations, evaluations, judgments, and opinions.” Thus, claim 128 also recites an abstract idea, which is a judicial exception. Step 2A, Prong Two – Does the Claim Recite Additional Elements that Integrate the Judicial Exception into a Practical Application? NO The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. The phrase "integration into a practical application" requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception. The claim recites several additional elements: “(a) contacting a first population of cells expressing STING with an agent,” and “(b) measuring the level of STING activity in the first population of cells.” Steps (a)-(b) amount to insignificant extra-solution activity to the judicial exception. These steps do not meaningfully limit the claim, because they amount to mere data gathering that provides information about the natural phenomena. The additional elements do not integrate the judicial exception into a practical application. See MPEP 2106.05(g). Step 2B – Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to "significantly more" than the judicial exception(s) itself. The claim as a whole is evaluated as to whether it amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05). As described above, the additional elements amount to insignificant extra-solution activity, i.e., mere data gathering that provides information about the natural phenomena. These limitations are not enough to qualify as “significantly more” than the judicial exception. See MPEP 2106.05(A). Claim Rejections - 35 USC § 102 - Barber 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15 AIA Claim s 37-38, 41-43, 45, 47, 62, 68, and 128 are rejected under 35 U.S.C. 102( a)(1) and 35 U.S.C. 102(a)(2 ) as being anticipated by Barber (Barber, WO 2010/017248 A2, published 11 February 2010) . Regarding claims 37 and 59, Barber teaches a method for modulating the activity of STING protein, comprising administering an effective amount of an agent that results in an increase in STING activity, wherein the agent is a recombinant protein having STING activity or a nucleic acid encoding the same ([00101]-[00114]; [00168]-[00172]). Regarding claim 38, the term “STING signaling” is interpreted as referring to the intracellular pathway activated by STING, i.e., TBK1, IRF3, etc. as described in paragraph [0044]. Barber teaches that the recombinant protein increases STING signaling (“All DNA vaccines function through the TBK1 pathway, activating the IFN pathway through TBK1, which is essential for the immune response,” [00130]). Regarding claim 41, Barber teaches that the agent increases type I interferon (IFN) expression (““All DNA vaccines function through the TBK1 pathway, activating the IFN pathway through TBK1, which is essential for the immune response… plasmid DNA completely fails to activate IFN in the absence of STING,” [00130]). Regarding claim 42, Barber teaches that the agent activates NF-KB (“STING was also found to activate the NF-KB pathway,” [00130]). The specification provides that STING signaling elicits the production of one or more pro-inflammatory cytokines by stimulating the activity of NF-KB. Thus, Barber’s agent, by virtue of stimulating NF-KB, is interpreted as having the claimed function. Regarding claims 43, 45, and 47, Barber teaches the agent enhances the immune response against a disease in a subject, wherein the disease is cancer (“The compounds are useful for the in vivo treatment or prevention of diseases in which STING is implicated… especially for preventing or treating diseases in which the disease pathology may be modified by modulating the immune response, e.g., cancer… whereby it is desired to increase or enhance an immune response, STING may be reconstituted, e.g., cancer,” pg. [00329]-[00330]). Barber teaches human subjects ([00334]). Regarding claim 62, Barber teaches recombinant proteins which are a fusion protein comprising STING and one or more additional proteins or fragments thereof ([00168]-[00172]). Regarding claim 68, Barber teaches a method for treating a disease in a subject comprising administering to the subject an effective amount of an agent that results in an increase in STING activity ([00329]-[00330]; pg. 117-120). Regarding claim 128, Barber teaches a method for screening for agents that modulate the activity of STING protein (“a method of identifying candidate therapeutic agents for treatment of disease”), comprising contacting a first population of cells expressing STING with an agent (“culturing an isolated cell expressing STING, administering a candidate therapeutic agent to the cultured cell”), and measuring the level of STING activity in the first population of cells and comparing the level with the level in a second population of cells which were not contacted with the agent (“correlating STING expression and/or function in the presence or absence of a candidate therapeutic agent as compared to control cells”), wherein a deviation in the level of STING activity between the populations indicates the agent is a modulator of STING (“wherein a drug is identified based on desirable therapeutic outcomes. For example, a drug which modulates expression of STING; a drug which modulates interferon production; association of STING with various molecules; modulation of pathways; ~2-microglobulin expression and the like; thereby, identifying candidate therapeutic agents that regulates STING expression and/or function,” [00282]). Claim Rejections - 35 USC § 102 - Besemer 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-15 AIA Claim s 37-39, 48, 51, and 53-54 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Besemer (Besemer et al., 22 April 2020, Cellular and Molecular Life Sciences, 78:645-660) . The phrase “that results in an increase in STING activity” in claim 37 is interpreted as encompassing agents which directly increase STING activity, and those which facilitate increased STING activity in response to an agonist (e.g., each of the CRISPR-Cas9-based agents targeting HGS, VPS37A, and DNAJC13 described in the specification which increase STING activity in cells administered a STING agonist). Regarding claims 37, 39, 48, 51, and 53-54, Besemer teaches a method of administering a nucleic acid capable of reducing expression of the J domain-containing protein, DNAJC13, to human cells (“ DNAJC13 siRNA,” Figs. 1-3; Cell culture, pg. 647; “Due to the presence of the central DNAJ domain, DNAJC13 binds HSC70,” pg. 646, left col.). Besemer is silent as to whether DNAJC13 is a negative regulator of STING activity, or whether reducing the expression of DNAJC13 results in a decrease in the intracellular degradation of STING, and an increase in STING activity. However, as evidenced by the specification, DNAJC13 is a negative regulator of STING activity, wherein reducing the expression of DNAJC13 results in an decrease in the intracellular degradation of STING, and an increase in STING activity as interpreted herein ([0154]-[0159]). Thus, as evidenced by the specification, Besemer’s method inherently meets the limitations of instant claims 37, 39, 48, 51, and 53-54. Regarding claim 38, based on the specification, an increase in STING activity is sufficient to increase STING signaling ([0044]). Thus, Besemer’s method is interpreted as inherently meeting the limitations of instant claim 38. Examiner notes that claim 52 is not included in this rejection, because as described above in paragraph 11, the specification teaches that DNAJC13 impedes or functions independent of palmitoylation of STING ([0056]; [00155]). The specification does not describe any J-domain containing proteins which facilitate STING palmitoylation. Claim Rejections - 35 USC § 102 - Mamińska 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-15 AIA Claim s 37-39, 48-50, and 54 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Mamińska (Mamińska et al., 2016, Science Signaling, Vol. 9, Issue 411, pg. 1-14) . As stated above, the phrase “that results in an increase in STING activity” in claim 37 is interpreted as encompassing agents which directly increase STING activity, and those which facilitate increased STING activity in response to an agonist (e.g., each of the CRISPR-Cas9-based agents targeting HGS, VPS37A, and DNAJC13 described in the specification which increase STING activity in cells administered a STING agonist). Regarding claims 37, 39, 48-50, and 54, Mamińska teaches a method of administering a nucleic acid capable of reducing expression of the ESCRT pathway component, VPS37A, to human cells (“Silencing of VPS37A … by RNAi in either one of the libraries also resulted in activation of the pathway,” pg. 2, right col.; Fig. 1; “Vps37A are subunits of the ESCRT-I complex,” pg. 3, left col.). Mamińska is silent as to whether VPS37A is a negative regulator of STING activity, or whether reducing the expression of VPS37A results in a decrease in the intracellular degradation of STING, and an increase in STING activity. However, as evidenced by the specification, VPS37A is a negative regulator of STING activity, wherein reducing the expression of VPS37A results in an decrease in the intracellular degradation of STING, and an increase in STING activity as interpreted herein ([0048]-[0052]). Thus, as evidenced by the specification, Mamińska’s method inherently meets the limitations of instant claims 37, 39, 48-50, and 54. Regarding claim 38, based on the specification, an increase in STING activity is sufficient to increase STING signaling ([0044]). Thus, Mamińska’s method is interpreted as inherently meeting the limitations of instant claim 38. Notice to Joint Inventors 07-20-02-aia AIA 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. Claim Rejections - 35 USC § 103 – Barber in view of Gillooly 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-21-aia AIA Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Barber (Barber, WO 2010/017248 A2, published 11 February 2010) as applied to claims 37-38, 41-43, 45, 47, 62, 68, and 128, in view of Gillooly (Gillooly et al., 2000, The EMBO Journal, Vol. 19, pgs. 4577-4588) . The teachings of Barber are described above and applied as to claims 37-38, 41-43, 45, 47, 62, 68, and 128 therein. Barber teaches that in response to intracellular DNA, STING traffics to endosomal compartments, predominantly in early endosomes (as assessed by co-localization with the marker EEA1), which results in the induction of type I IFN ([00407]-[00408]). Barber teaches that this pathway is disrupted in cancer cells, and suggests that because “reconstitution of STING” can induce type I IFN, its expression in cancer cells “would thus be useful… perhaps to kill cancer but not normal cells” ([0085]; [00130]). Barber also teaches recombinant proteins comprising STING fused to a second domain, wherein the second domain comprises a sequence facilitating intracellular targeting (“Nucleic acids encoding for STING peptides are set forth in SEQ ID NOS: 1 and 2… Modified peptides which retain the activity of the peptides of the invention are encompassed within the scope of the invention… transport thru tissues or cell membranes,” [00144]-[00151]; “In a preferred embodiment, one or more STING nucleic acids, proteins or peptides can be linked or fused to another moiety… intracellular targeting moiety,” [00168]; “linked or fused to a second domain,” pg. 115-116). Barber does not teach a recombinant fusion protein comprising STING and one or more FYVE domains. However, Gillooly teaches a “probe” consisting of two PI(3)P-binding FYVE domains (“2XFYVE”), which when fused to a second domain, facilitates localization of the resulting fusion protein to early endosomes (“The localization of 2XFYVE was then compared.. myc- or GFP-tagged 2XFYVE co-localized extensively with endogenous EEA1… a well-characterized marker of early endosomes,” pg. 4578, right col.; “early endosomes… showed specific labelling with the 2XFYVE probe,” pg. 4581, left col.). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have prepared the recombinant STING protein taught by Barber, with the 2XFYVE probe of Gillooly. It would have amounted to preparing a known recombinant protein, with two domains suitable for fusion, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in preparing the STING-2XFYVE recombinant fusion protein because as evidenced by at least Barber and Gillooly, means to prepare recombinant fusion proteins were well known in the art, and because both STING and 2XFYVE are suitable domains for fusion (see myc- and GFP-2XFYVE fusions of Gillooly, and HA-STING fusion of Barber, [0011]). As stated above, Barber teaches that activated STING primarily localizes to early endosomes, which results in the induction of type I IFN. Barber also suggests reconstituting STING as a therapeutic approach for cancer. The skilled artisan would have been motivated to prepare the aforementioned recombinant protein because they would have recognized that Gillooly’s 2XFYVE domain would localize reconstituted STING to an intracellular compartment which results in type I IFN production, and therefore, would have facilitated its therapeutic effects. Conclusion No claims are allowed. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JENNA L PERSONS/Examiner, Art Unit 1637 /Soren Harward/Primary Examiner, TC 1600 Application/Control Number: 18/568,797 Page 2 Art Unit: 1637 Application/Control Number: 18/568,797 Page 3 Art Unit: 1637 Application/Control Number: 18/568,797 Page 4 Art Unit: 1637 Application/Control Number: 18/568,797 Page 5 Art Unit: 1637 Application/Control Number: 18/568,797 Page 6 Art Unit: 1637 Application/Control Number: 18/568,797 Page 7 Art Unit: 1637 Application/Control Number: 18/568,797 Page 8 Art Unit: 1637 Application/Control Number: 18/568,797 Page 9 Art Unit: 1637 Application/Control Number: 18/568,797 Page 10 Art Unit: 1637 Application/Control Number: 18/568,797 Page 11 Art Unit: 1637 Application/Control Number: 18/568,797 Page 12 Art Unit: 1637 Application/Control Number: 18/568,797 Page 13 Art Unit: 1637 Application/Control Number: 18/568,797 Page 14 Art Unit: 1637 Application/Control Number: 18/568,797 Page 15 Art Unit: 1637 Application/Control Number: 18/568,797 Page 18 Art Unit: 1637 Application/Control Number: 18/568,797 Page 19 Art Unit: 1637
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