DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim to priority from Provisional Application No. 63/302,591 dated 01/25/2022 is hereby acknowledged.
Application Status
Amendments to claims filed on 11/07/2025 are hereby acknowledged. Claims 2-4 and 11-12 are cancelled. Claim 1 is currently amended. Claims 1, 5-10 are pending and under examination in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendment and is withdrawn.
Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
The following rejections from previous office action filed 05/08/2025
have been modified as necessitated by Applicant’s amendments. The prior art used has been previously cited.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1 and 5-10 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 claims contain 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. The following is a New Matter rejection necessitated by Applicant’s amendments:
Amended claim 1 recites: “[A] method of treating, or preventing, a neurodegenerative disorder in a subject in need thereof, wherein said neurodegenerative disorder is Alzheimer’s disease, the method comprising administration to the subject of a therapeutically effective dose of a selective STAT4 inhibitor”.
The common understanding of the terms “selective inhibitor” is, according to the online “Collins Dictionary” (https: //www.collinsdictionary.com), “ a molecule that binds to and inhibits the activity of a particular enzyme or group of enzymes without affecting other enzymes”.
The instant Specification does not provide a definition for the terms. However, the instant Specification provides an example of “selective inhibitor” as Berbamine.
Claim 8, depending on claim 1, also recites: “ wherein the STAT4 inhibitor is an inhibitor of STAT4 phosphorylation”. This further suggests that the “selective inhibitor” as claimed does not require specific binding to STAT4 protein, but rather to a protein that facilitates STAT4 phosphorylation. This suggests that the inhibitor can be a kinase inhibitor that acts indirectly on STAT4 phosphorylation.
Therefore, one of ordinary skills in the art would assume the Applicant’ s definition of “selective inhibitor” does not include “binding”. Applicant never stated that binding to STAT4 is the selective aspect. The required binding of STAT4 for selective inhibition is NEW MATTER.
Thus, the instant claims now recite limitations which were not disclosed in the specification as-filed, limitations that can be contradictory to dependent claims, and now change the scope of the instant disclosure as-filed. Such limitations recited in the present claims, which did not appear either in the instant specification, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C. §112.
Claims 5-10 depend from claim 1, and are therefore included in this rejection.
Written description requirement
The following rejections have been maintained and modified in view of the amendments to the claims.
Claims 1 and 5-10 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 claims contain 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states 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 applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the Invention
Claim 1 recites “[A] method of treating, or preventing, a neurodegenerative disorder in a subject in need thereof, wherein said neurodegenerative disorder is Alzheimer’s disease, the method comprising administration to the subject of a therapeutically effective dose of a selective STAT4 inhibitor”.
It is therefore expected in the instant application a disclosure of a method of treating or preventing Alzheimer’s disease using specific compositions representative of the broad genus of STAT4 inhibitors species.
It is also expected in the disclosure, a clear definition of “selective inhibitor”.
Claim 1 recites “the method comprising administration to the subject of a therapeutically effective dose of a selective STAT4 inhibitor.” Claims 5 to 9, depending all on claim 1, recite the type of required STAT4 inhibitors that would be effectively used to treat or prevent Alzheimer’s disease. The applicant claims that Alzheimer’s disease can be effectively treated or prevented with any of the STAT4 inhibitors claimed in claims 5 to 9. However, Applicant does not provide with a description, a reduction into practice with a representative of this large genus group of inhibitors species, and selective inhibitors species.
Claim 7 specifically requires a STAT4 antibody. According to the disclosure a STAT4 antibody can also be an antibody that interferes with STAT4 binding to an antigen acting in the IL-12 signaling pathway. However, there is no specific antibody described as a representative of the genus claimed.
Claim 10 recites “[T]he method of claim 1, further comprising administration of a second Alzheimer’s disease therapeutic agent.” The applicant claims here that any STAT4 inhibitor can be used alone or in combination with a second Alzheimer’s disease therapeutic agent. It is not clear whether, for treating or preventing Alzheimer’s disease, there is a need for a combination of any STAT4 inhibitor with one or two Alzheimer’s disease therapeutic agents. Applicant does not provide an example, a reduction into practice of the use of a combination drug therapy comprising a specific STAT4 inhibitor and a specific Alzheimer’s disease therapeutic agent. The limitation “a second Alzheimer’s disease therapeutic agent” encompasses a large genus of Alzheimer’s disease therapeutic agents. Applicant does not provide examples a representative number of species of this genus, nor a reduction into practice, using a second Alzheimer’s agent in combination with a selective STAT4 inhibitor to treat Alzheimer’s disease.
State of the Art
The models known in the art for a neurodegenerative disorder, especially Alzheimer’s disease are related to mutagenesis or overexpression of Beta-Amyloid gene, Tau gene, and Presenilin 1 gene. Thus, a triple mutant model for Alzheimer’s disease has been developed by Oddo et al.( Oddo, S. et al. ‘Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction’. Neuron, Vol. 39, no. 3 (July 31, 2003), pp. 409–421).
Outside of the Beta-Amyloid gene, Tau gene, and Presenilin 1 gene used for manipulations for models, there are examples of inflammatory signal pathways genes identified as relevant to Alzheimer’s disease. IL-1, IL-6 and TGF-beta1 are important in amyloidosis (senile plaques formation). See Akiyama et al. ( Akiyama, H. et al. ‘Inflammation and Alzheimer’s disease’. Neurobiology of Aging. Vol. 21.(Jan.17, 2000), pp. 383-421).
Other authors produce direct evidence of senile plaques and Alzheimer’s disease-like pathology (see Wyss-Coray, T. et al.’ Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer’s disease’. Nature, Vol. 389 (Oct.9, 1997), pp.603-606 ; see Chen, Y. et al. ‘A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: Similarities to and differences from the transgenic model (3xTg-AD mouse)’. Molecular Neurobiology, Vol. 47 (2013):711-725 ).
These publications disclose a role for inflammation or neuroinflammation in Alzheimer’s disease and neurodegenerative diseases.
As far as STAT4 is concerned, although STAT signaling is associated with inflammation, inflammatory diseases and possible neuroinflammation, i.e. prodromal symptoms of Alzheimer’s disease (Pfitzner, E. et al. ‘The role of STATs in inflammation and inflammatory diseases’. Current Pharmaceutical Design, Vol. 10, no. 23 (2004), pp. 2839-2850 ), there is no evidence that STAT4 has a direct role in the brain, especially in the brain of STAT4 knock-out mice produced by Thierfelder et al. ( Thierfelder, W.E. et al. ‘Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.’ Nature, Vol. 382 (July 11, 1996), pp. 171-174) and by Kaplan et al. (Kaplan, M.H. et al ‘Impaired IL-12 responses and enhanced development of Th 2 cells in Stat4-deficient mice.’ Nature, Vol. 382 (July 11, 1996), pp.174-177).
Thierfelder and Kaplan did produce STAT4 Knock-out mice, but did not notice specific impact of STAT4 in the brain compared to wild type.
Thierfelder et al. and Kaplan et al. found that only the IL-12 signaling pathway was affected in STAT4 knock-out mice ( Thierfelder et al. page 171, introduction section, page 174, column 1, line 6; Kaplan et al. page 174, introduction section, and page 176, second column, line 46).
As a testimony of redundancy in the STAT family signaling pathways, Thierfelder et al. disclose (page 174, column 1, line 1) “ [W]e had also anticipated effects on hematopoiesis on the basis of expression and results indicating an effect on IL-12 on erythropoiesis, but again there were no detectable effects, suggesting that expression is gratuitous in both cases”.
The main effect of STAT4 in excess seems to be peripherally, as evidence by Wirtz et al. (Wirtz, S. et al. ’Chronic Intestinal Inflammation in STAT-4 Transgenic Mice: Characterization of Disease and Adoptive Transfer by TNF- Plus IFN-γ-Producing CD4+ T Cells That Respond to Bacterial Antigens’. The Journal of Immunol. Vol. 162, no.4 (Feb. 15, 1999), pp.1884-1888).
These results indicate that STAT4 is active in signal pathways that are involved primarily in other organs in periphery, not the brain. The role of STAT4 in the “wild-type” brain has not been sufficiently investigated.
Neuroinflammation has been characterized by leukocytes infiltration into the central nervous system, said leukocytes producing inflammatory cytokines that acts on brain tissue resident microglia and astrocytes. It is obvious to a person skilled in the art that the IL-12, JAK and STAT signaling pathways are involved in producing those inflammatory cytokines (see Yan, Z. et al. ‘Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases’. Clinical Immunology. Vol.189 (2018), pp.4-13 ; page 7, 2.1.1 section, second §).
In the brain itself, STAT4 is not well expressed, unless IL-12 is overexpressed in astrocytes in transgenic experiments. STAT4 expression is then upregulated by IL-12. See Maier, J. et al. ‘Regulation of Signal Transducer and Activator of Transcription and Suppressor of Cytokine-Signaling Gene Expression in the Brain of Mice with Astrocyte-Targeted Production of Interleukin-12 or Experimental Autoimmune Encephalomyelitis”. American Journal of Pathology, Vol. 160, no.1 (Jan, 2002), pp.272-288 ; page 275, figure 1.
Therefore, activated IL-12 signaling originates from activated macrophages and T helper cells infiltrating the brain tissue in symptomatic subjects. STAT4 expression is low to negligeable in the brain tissue of normal subjects, the said expression only rising when IL-12 is overexpressed in astrocytes (see Maier et al. page 275, first column, “Constitutive and regulated expression of STAT genes in the brain of GF-IL12 transgenic mice” section, line 9-12) .
Taken together, it is known in the art that STAT4 does not act directly itself in inflammation, furthermore in neuroinflammation; STAT4 participates in networks with other components of IL-12, JAK and STAT pathways, in the cells that infiltrate the brain during inflammation. Effects of a STAT4 inhibitor on brain tissue have not been broadly documented; effects on neuroprotection in healthy subjects or neurodegeneration have not been documented either.
Guidance from Specification
The instant application teaches a preferred embodiment and an example of reduction to practice: a mouse model that has been exposed to a high-fat diet from 8 to 24 weeks of age (¶ 14).
A person reasonably skilled in the art may associate this model with metabolic diseases and possible complications thereof. In comparison, the applicants use a STAT4 knock-out mouse, which appear to perform better in memory tests, measuring activity-dependent synaptic potentiation, than wild type, under the same feeding conditions (¶ 15 and 16).
Applicant discloses that “inhibitors of JAK and other kinases known to phosphorylate STAT4 may be administered to inhibit the activity of STAT4. Inhibitors may also include those that prevent or reduce the dimerization of STAT4 or those that reduce or interfere with IL-12 signaling. Inhibitors include, for example, Berbamine, STAT4 antisense oligonucleotides or oligodeoxynucleotide decoys to name a few.”(¶ 33, line 7).
The specification of the instant application discloses one example of selective STAT4 inhibitor, Berbamine, which is a Chinese Traditional Medicine drug, that acts on SLIM E3 ubiquitin ligase and inhibits STAT4 indirectly (Ren, Y. et al. ‘Novel Immunomodulatory Properties of Berbamine through Selective Down-Regulation of STAT4 and Action of IFN-g in Experimental Autoimmune Encephalomyelitis.’ The Journal of Immunology, Vol. 181, no. 2 (July 15, 2008), pp.1491-1498); it is also noted that SLIM is involved in STAT1 protein degradation (See Tanaka, T. et al. ‘SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling’. Immunity, Vol. 22(June, 2005), pp.729-736).
What the disclosure does not teach
The subject matters claimed do not appear in specification: examples of a neurodegenerative disorder, of Alzheimer’s disease or of neuroinflammation, i.e. prodromal symptoms in subject in need of treatment or prevention, and an actual reduction to practice of the claimed invention. Applicant does not disclose any example to show relevance and/or equivalency of their model compared to other known models for Alzheimer’s disease or prodromal symptoms of neurodegenerative disorders in the literature.
For example, Wyss-Coray et al. and Chen et al. demonstrated in their models evidence of similarity to Alzheimer’s disease by providing written description with tables, figures and results of learning and memory tests. These authors also evidence neuroinflammation and neurodegeneration by presenting expression profiles, Western Blots, in situ hybridization or immunohistochemistry images.
Claim 1 recites “the method comprising administration to the subject of a therapeutically effective dose of a STAT4 inhibitor”. The disclosure did not show evidence of application of a STAT4 inhibitor and the decrease of measurable markers associated with Alzheimer’s disease or decrease in prodromal markers for prevention such as decrease of neuroinflammation nor lymphocytic, macrophagic infiltration in the preferred embodiment (high-fat diet fed mice). The disclosure does not introduce drawings, tables or figures related to the effects of a representative of the broader genus of STAT4 inhibitor species on subjects fed a high-fat diet, in vivo, ex vivo or in vitro.
The specification does not disclose a structure or a composition for said STAT4 inhibitor, nor a specific structure that would render the brain blood barrier permeable to said inhibitor. The depending claims 5 to 10 provide only limited information on the chemical structure of said inhibitor (a nucleic acid, a small molecule, an antibody, a phosphorylation inhibitor or a dimerization inhibitor). There is no chemical structure, no amino acid sequence, no nucleic acid sequence, no enumeration of residues in nucleic acid species or amino acid species, no SEQ ID No. provided, no specific antibody nor fragments or example of combination of drug to use disclosed in specification.
In view of the example of Berbamine, the applicant expands on the definition of a selective STAT4 inhibitor outside of IL-12 and JAK signaling pathways. Given the disclosure, a potent inhibitor could be any STAT family inhibitor, as well as any other protein kinase inhibitor targeting JAK2 and TYK2 signaling.
Response to Applicant’s 112(a) Arguments
Applicant's arguments filed 11/07/2025 have been fully considered but they are not persuasive.
In section 1 ( page 4 of Remarks) “The claim Rejections for lack of Written Description’, Applicant argues that “what is conventional or well known to one of ordinary skill in the art need not be disclosed in detail”. This argument has been previously argued and responded to in previous office action dated 05/08/2025.
Applicant further states “Additionally, the specification identifies at least one compound, berbamine that may be used to selectively inhibit STAT4 activity. Accordingly, the Applicant respectfully request the rejections of the claims under 35 U.S.C. §112(a) be withdrawn.”
In response, it is noted that Ren (Ren, Y. et al. ‘Novel Immunomodulatory Properties of Berbamine through Selective Down-Regulation of STAT4 and Action of IFN-g in Experimental Autoimmune Encephalomyelitis.’ The Journal of Immunology, Vol. 181, no. 2 (July 15, 2008), pp.1491-1498; previously cited) teaches that Berbamine is a selective inhibitor of STAT4. Applicant’s definition therefore does not include “binding” of STAT4 as a requirement; there is no mention of Berbamine being capable of direct binding in Ren.
Also, Farooqi (Farooqi, A.A. et al. “Regulation of cell-signaling pathways by Berbamine in different cancers”. International Journal of Molecular Sciences, Vol. 23 (2022), p: 2758) teaches different proteins that are targets for Berbamine (see Table 1 and below).
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What is noted in Farooqi’s Table 1, is that STAT4 is not listed as of 2022, as a direct target for Berbamine (used in cancer treatment). Therefore, Berbamine is neither binding directly, nor is specifically restricted to inhibiting STAT4.
As Berbamine is an example of “selective inhibitor” of STAT4, it is not clear what compounds would be encompassed by the terms “selective inhibitor of STAT4”, as Berbamine does not fit in the description of a “true” selective inhibitor according to the online Collins Dictionary’s definition.
As taught by Brovchenko (Brovchenko, N. et al. “Biaryl phosphates and phosphonates as selective inhibitors of the transcription factor STAT4”. Angewandte Chemie International Edition, Vol. 64 (2025), p: e202504420), it is possible to isolate and/or design STAT4 inhibitors that can bind directly and inhibit STAT4 (see title and abstract). Brovchenko teaches that it is possible to obtain small molecule inhibitors that bind and inhibit STAT4 preferentially (see Figure 3). Brovchenko therefore teaches “true” selective inhibitors of STAT4 according to the Collins Dictionary’s definition.
Therefore, the rejections of claims 1, 5-10 under 35 U.S.C. §112(a) are maintained.
The following rejections are maintained from Office Action dated 05/08/2025 with modifications necessitated by Amendments filed 11/07/2025
Claim Rejections - 35 USC § 102
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 –
(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.
The following are maintained rejections modified in view of the amendments to the claims.
Claims 1, 8 and 10 is rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Hui (Hui, Z. et al. “ The combination of acyclovir and dexamethasone protects against Alzheimer’s disease-related cognitive impairments in mice”. Psychopharmacology, Vol. 237 (2020), pp: 1851-1860; previously cited) as evidenced by Franchimont (Franchimont, D. et al. ‘Inhibition of Th1 immune response by glucocorticoids: Dexamethasone selectively inhibits IL-12-Induced STAT4 phosphorylation in T lymphocytes.’ The Journal of Immunology, Vol. 164, no. 4 (Feb 15, 2000), pp. 1768-1774; previously cited).
Regarding claims 1 and 8, claim 1 recites “the method comprising administration to the subject of a therapeutically effective dose of a selective STAT4 inhibitor”; claim 8 recites “ wherein the STAT4 inhibitor is an inhibitor of STAT4 phosphorylation”. In specification, ¶ 33, line 3, Applicant provides the definition of a STAT4 inhibitor: “[S]uch STAT4 inhibitors include small molecules that function to inhibit the activity of STAT4, including for example, those that inhibit the phosphorylation of serine and tyrosine residues said phosphorylation being demonstrated to activate STAT4 activity”.
Dexamethasone is a small molecule inhibitor that selectively inhibit IL-12-induced STAT4 phosphorylation according to Franchimont. Therefore, according to the Applicant’s disclosure, Dexamethasone is inherently a STAT4 inhibitor.
Hui also states that short-term treatment with Dexamethasone is known to inhibit Alzheimer’s disease (AD)-related neuroinflammation and prevent cognitive impairments; Hui states that prevention of cognitive impairment in offsprings of AD transgenic mice can be obtained using Dexamethasone as well (see on page 1852, left column, lines 20-25).
Regarding claim 10, Hui teaches a combination of acyclovir and dexamethasone protects against Alzheimer’s disease (AD) (see title and “[A]bstract” section). Hui teaches that big data analysis indicated that childhood herpes virus infection may be associated with the incidence of AD, suggesting that anti-herpetic drugs such as acyclovir may have preventive and suppressive effects for AD therapy (see “[A]bstract” section). Therefore, acyclovir can be considered as an Alzheimer’s disease drug. Hui also discloses protective effects of acyclovir and Dexamethasone combination on neuroinflammation, synaptic protein expression, and cognition in Aβ oligomer-treated mice (see page 1852, left column, lines 26-36).
Therefore, Hui teaches a method of preventing or treating a neurodegenerative disorder, in a subject in need thereof, especially in a subject with AD using a STAT4 inhibitor, Dexamethasone in a combination drug therapy with acyclovir.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being unpatentable over
vom Berg (vom Berg, J. et al. Nature Medicine (2012), doi: 10.1038/nm.2965).
Regarding claim 1, vom Berg teaches a method of treating Alzheimer’s disease-like pathology and cognitive decline (see title and abstract) in a specific Alzheimer’s disease mouse model APPPS1. Vom Berg teaches administering intracerebroventricularly a specific antibody against IL-12 subunit p40 to APPPS1 mice and their littermate and shows reduction of Alzheimer’s disease like pathology (see page 5, left column), e.g. the reduction in Aβ plaques (see figure 4c). The APPPS1 mice also show improvement compared to non-treated control in behavior, in Barnes maze test (see Figure 5).
Vom Berg is silent on a specific selective STAT4 inhibitor, however, according to Applicant’ s disclosure, an antibody against a protein within the IL12 signaling can be used and is considered a STAT4 inhibitor. The Specification states:
“[00040] In an embodiment, antibody molecules that bind to STAT4 may also be used
inhibit the activity of STAT4 in Alzheimer's disease subjects. "Antibody molecule" as used herein is intended to include intact antibodies, such as polyclonal antibodies or monoclonal antibodies (mAbs), as well as proteolytic fragments thereof such as the Fab or F(ab')2 fragments, chimeric antibodies, nanobodies, recombinant and engineered antibodies, single-chain antibodies and fragments thereof, as well as other molecules having at least one STAT4 antigen-binding site. Antibody molecules that also inhibit JAK and other kinases known to phosphorylate STAT4 may be administered to inhibit the activity of STAT4. Inhibitors also include antibodies may function to prevent or reduce the dimerization of STAT4 or those that reduce or interfere with IL-12 signaling.”
Response to Applicant’s 102 Arguments (sections 2 and 3)
Applicant’s arguments with respect to rejections under 35 U.S.C. 102 of claims 1, 8 and 10 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments against the references in both rejections under 35 §U.S.C 102(a)(1), stating that the references do not teach “selective STAT4 inhibitor”, Applicant stated in Section 1, that Berbamine is a selective STAT4 inhibitor. Berbamine does not bind directly to STAT4 according to current knowledge. Berbamine is not limited/specific to STAT4 protein, according to Farooqi’s Table 1. Berbamine is listed in this table, as a JAK inhibitor.
Applicant discloses that “inhibitors of JAK and other kinases known to phosphorylate STAT4 may be administered to inhibit the activity of STAT4. Inhibitors may also include those that prevent or reduce the dimerization of STAT4 or those that reduce or interfere with IL-12 signaling. Inhibitors include, for example, Berbamine, STAT4 antisense oligonucleotides or oligodeoxynucleotide decoys to name a few.”(¶ 33, line 7).
Therefore, Examiner interprets the definition of a “selective inhibitor” according to Specification as an inhibitor that inhibit directly or indirectly STAT4 activity, as stated in Specification ([0040]). A selective inhibitor can be a compound that does not bind STAT4 directly and is an inhibitor of IL-12 signaling, such as JAK inhibitors.
Applicant also argues. stating on pages 6 and 7, that “Accordingly, the usefulness of dexamethasone for treatment of Alzhiemer's disease could be attributed to one of many of cellular pathways that may be impacted by dexamethasone and would not necessarily be attributable to dexamethasone's inhibition of IL-12-induced STAT4 phosphorylation. Additionally, in regard to claim 10, Hui discloses "whether acyclovir and DXMT combination could protect against AD-related cognitive impairments are largely unknown." (Page 1852, left column, lines 31-33.)”, and “ The usefulness of an IL-12 inhibition for treatment of Alzhiemer's disease could be attributed to one of many of cellular pathways that may be impacted by IL-12 inhibition and would not necessarily be attributable to STAT4 inhibition”.
In response, Table 1 of Farooqi teaches that Berbamine acts through different target proteins, e.g., STAT3, CaMKII, and JAK2.Therefore, Berbamine may act through different pathways to eventually also inhibit STAT4. Berbamine is a JAK2 inhibitor, according to Farooqi’s Table 1; yet it is also a selective inhibitor of STAT4, according to Ren, and as disclosed by Applicant. Berbamine’s mechanisms of action is also largely unknown.
The rejections are maintained.
Claim Rejections - 35 USC § 103
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 following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 non-obviousness.
Claim 5 is rejected under 35 U.S.C. § 103 as being unpatentable over Hui (Hui, Z. et al. Psychopharmacology, Vol. 237 (2020), pp: 1851-1860) in view of Franchimont (Franchimont, D. et al. ‘Inhibition of Th1 immune response by glucocorticoids: Dexamethasone selectively inhibits IL-12-Induced STAT4 phosphorylation in T lymphocytes.’ The Journal of Immunology, Vol. 164, no. 4 (Feb 15, 2000), pp. 1768-1774; previously cited) as applied to claim 1 above and in further view of Xue (Xue, Y-L. et al. Inflammation, Vol. 42 (2019), pp: 1179-1189).
Regarding claim 5, the rejection of claim 1 is discussed above. It is noted that claim 1 is anticipated by Hui as evidenced by Franchimont. However, Hui and Franchimont do not teach an inhibitory nucleic acid that binds directly to a STAT4 nucleic acid.
However, one with ordinary skills in the art would have considered the teachings of Xue, since Xue’s teachings pertain to inflammation involving STAT4; STAT4 is well-known in the art as the major transcription factor that mediates IL-12 signal pathway genes and important mediators of inflammation cytokines and chemokines genes. Xue uses STAT4 inhibitory nucleic acids as a therapeutic perspective for a condition that involved inflammation and cell apoptosis, autoimmune myocarditis (see title and “[A]bstract” section).
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Applying the KSR standard of obviousness to Hui, Franchimont and Xue, it is concluded that the combination of the references represents a combination of known elements which yield the predictable result. At the time of invention, a practitioner could have combined the teachings of Hui and Franchimont of using Dexamethasone, an inhibitor of the IL-12 signaling, for its therapeutic use against neuroinflammation (Hui teaches that Dexamethasone effectively inhibits AD-related neuroinflammation (see abstract)), knowing the indirect impact on STAT4 according to Franchimont, with the teachings of Xue of using a direct inhibitor and using an inhibitory nucleic acid designed to target and bind STAT4 directly. As a result, the predictable result of substituting Dexamethasone for a STAT4 inhibitory nucleic acid as a drug to treat neuroinflammation in AD would be achieved. Such a combination is merely a "predictable use of prior art elements according to their established functions." KSR Int’l 7, 127 S. Ct. at 1740.
Claims 6 and 9 are rejected under 35 U.S.C. § 103 as being unpatentable over Hui (Hui, Z. et al. Psychopharmacology, Vol. 237 (2020), pp: 1851-1860) in view of Franchimont (Franchimont, D. et al. ‘Inhibition of Th1 immune response by glucocorticoids: Dexamethasone selectively inhibits IL-12-Induced STAT4 phosphorylation in T lymphocytes.’ The Journal of Immunology, Vol. 164, no. 4 (Feb 15, 2000), pp. 1768-1774; previously cited) as applied to claim 1 above and in further view of Yao (Yao, B.B. et al. Archives of Biochemistry and Biophysics, Vol. 368 (1999), pp: 147-155).
The rejection of claim 1 is discussed above. It is noted that claim 1 is anticipated by Hui as evidenced by Franchimont. However, Hui and Franchimont do not teach a small molecule that binds to STAT4 directly nor a STAT4 inhibitor that is an inhibitor of STAT4 dimerization.
Regarding claim 6, Yao teaches a small molecule that binds directly to STAT4. Yao teaches that STAT4 has a direct interaction with IL-12 receptor to further the signal transduction by IL-12 (see abstract section). Yao teaches a phosphopeptide Y800-PO4 derived from IL-12 receptor that is capable of strongly binding STAT4 (see page 149, left column, “[R]esults” section, lines 20-23 ; and figure 1). Yao teaches that this phosphopeptide is capable of blocking IL-12-induced activation of STAT4, therefore, blocking the phosphorylation of STAT4 by binding directly to STAT4 (see Figures 5 and 6).
Regarding claim 9, Hui teaches Dexamethasone as a drug used to treat and prevent Alzheimer’s disease. Dexamethasone selectively inhibits IL-12-induced STAT4 phosphorylation as evidenced by Franchimont, therefore, Dexamethasone is inherently a STAT4 inhibitor. Hui and Franchimont do not teach STAT4 dimerization and the effect of Dexamethasone on STAT4 dimerization.
However, Yao teaches that tyrosine phosphorylation of STAT4 is required for its subsequent dimerization and activation (see page 154, right column, lines 40-47).
Therefore, Hui, in view of Yao, teaches a method wherein the STAT4 inhibitor is an inhibitor of STAT4 dimerization.
One with ordinary skills in the art would have considered the teachings of Yao, since both Franchimont and Yao teachings are about the IL-12 signal pathway. Yao teaches about the mechanistic behind the signal pathway involving IL-12, IL-12 receptor and STAT4.
It would have been obvious to one with ordinary skills in the art, before the effective filing date, to have substituted Dexamethasone taught by Hui as evidenced by Franchimont with the phosphopeptide Y800-PO4 taught by Yao. One with ordinary skills in the art, motivated in a direct binding for a direct effect on STAT4 would have considered all peptide fragments from receptor known to bind directly to STAT4. It would have been the substitution of a small molecule inhibitor with another one, both having the same function. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Claim 7 is rejected under 35 U.S.C. §103 as being unpatentable over
vom Berg (vom Berg, J. et al. Nature Medicine (2012), doi: 10.1038/nm.2965), as applied to claim 1 above and in further view of Naeger (Naeger, L.K. et al. The Journal of Biological Chemistry, Vol. 274 (1999), pp: 1875-1878).
The rejection of claim 1 is described above. It is noted that claim 1 is anticipated by vom Berg.
Vom Berg does not teach a specific STAT4 inhibitor that is a STAT4 antibody. However, Naeger teaches that there is a direct relationship between IL12, its receptors and STAT4. Naeger teaches that transfecting IL12 receptor β1 and β2 subunits is sufficient for STAT4 activation specifically (not STAT1, not STAT3; see abstract, lines 10-13). Naeger teaches that IL12 is a heterodimeric cytokine (p40 + p35) that binds to the receptor comprising IL-12Rβ1 and IL-12Rβ2 (see page 1875, left column, lines 16-23; right column, line 1). Naeger further teaches that IL12-Rβ2 binds STAT4, identifying specific binding site and a phosphopeptide SFDpYMPHVL corresponding to this site.
Naeger teaches the use of a specific antibody against STAT4 blocks the interaction of IL12-Rβ2 receptor with STAT4 (see page 1876, Figure 1):
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STAT4 is recognized as the main inflammatory transcription factor responsible for the IL12 cascade of regulation of cytokines and chemokines genes during inflammation. Neuroinflammation is known to be a result of Aβ plaque accumulation and a prodromal symptom in Alzheimer’s disease.
It would be obvious to one with ordinary skills in the art, before the effective filing date, to have combined the teachings of vom Berg and Naeger. One with ordinary skills in the art could have performed the substitution of an anti- IL-12 p40 antibody taught by vom Berg, with a STAT4 antibody taught by Naeger, an antibody that blocks the binding of STAT4 to IL12 receptor. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success and arrived at the claim invention.
Response to Applicant’s 103 Arguments (sections 5 and 6)
Applicant's arguments filed 11/07/2025 against rejections under 35 U.S.C. §103 have been fully considered but they are not persuasive.
In response, amending claim 1 to include the term “selective” does not change the interpretation of the scope of the invention according to the Specification in view of the example provided, i.e. Berbamine. When limiting the scope of the invention to traditionally recognized definition of the terms “selective inhibitor”, the claim would enter NEW MATTER, in the fact that Applicant never stated that the compound should selectively bind STAT4 protein. The selectivity suggested by the disclosure does not include “binding”.
And in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636