DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the claims: In the reply filed 07/30/2026, Applicant amended the claim(s) to (a) cancel claims 5, 8, 11, 16, and 20, and (b) amend claims 1-3, 6, 9-10, 12, and 17-18.
Claim(s) 1-4, 6-7, 9-10, 12-13, and 17-19 are pending.
Applicant’s arguments filed 07/30/2026 have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is FINAL.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 112(a)
as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/213,863, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
As a result, claim(s) 1-4, 6-7, 9-10, and 12-13 are not entitled to the benefit of the prior-filed application, Application No. 63/213,863, for the reasons given in the rejections under 35 USC 112(a) below.
Accordingly, claim(s) 1, 17-19 are not entitled to the benefit of the prior application because species of “GSMD inhibitor” that is “a drug inhibits pore forming activity” and “. . . wherein the drug is disulfiram.”, lacks written description, e.g., cannot be found in the provisional application but can be found in the instant specification at paragraph [0012]:
“In embodiments, the GSDMD inhibitor may be a drug that inhibits GSDMD pore-forming activity. Suitable drugs include disulfiram and necrosulfonamide (NSA). The drug may be administered by any one or more of orally, parenterally, by injection, by subcutaneous injection, by intravenous injection, by intramuscular injection, transdermally, sublingually, topically, rectally, and intra- peritoneally.”
Thus, claim(s) 1-4, 6-7, 9-10, 12-13, and 17-19 have the effective filing date of the 371 filed as PCT/US22/34590 on 06/22/2022.
Priority – Response to Arguments
With respect to Applicant’s arguments about the nature of the effective filing date of the claimed invention, Applicant's arguments at page 12 of the reply filed 07/30/2026 have been fully considered but they are not persuasive.
Applicant contends that the claims directed to the “nucleotide-molecule branch” are entitled to the June 23rd, 2021, filing date of U.S. provisional application No. 63/213,863. Applicant contends that priority was denied primarily based on the breadth of the claims previously presented and that the newly amended claim 1 claims the genus “nucleotide-molecule”, and that this limitation is narrowed and is recited subject matter described in the provisional application. Applicant contends that the provisional application also identifies nucleotide-based GSDMD inhibitors, including ASOs, miRNAs, siRNAs, LNA nucleotides, guide antisense strands corresponding to GSDMD identified by Accession No. NM_024736, and that the provisional discloses targeting protein-coding regions, non-coding regions, and 3’ untranslated regions of GSDMD, and identifies aortopathies including aneurysm, dissection, and rupture.
Lastly, Applicant contends that “to the extent the Office Action relied on claim scope that encompassed undefined modalities or later-added disulfiram-specific embodiments, that rationale no longer applies to the amended nucleotide claims.
Response: In the amendments to the claims filed 07/30/2026, Applicant added the limitation of (i) “a gasdermin D (GSDMD) inhibitor that inhibits GSDMD pore-forming activity” and/or (ii) “a nucleotide molecule that reduces expression of GSDMD selected from the group consisting of an antisense oligonucleotide (ASO), an miRNA, an siRNA, a locked nucleic acid (LNA) nucleotide, a guide antisense strand, or a combination thereof.”, to independent claim 1. As stated in the Office Action mailed 06/02/2026 and reiterated above, the provisional application ‘863 lacks written description e.g., cannot be found in ‘863, for the species of GSDMD inhibitor that is “a drug inhibits pore forming activity” and “. . . wherein the drug is disulfiram.”. However, the instant specification at paragraph [0012] recites, “In embodiments, the GSDMD inhibitor may be a drug that inhibits GSDMD pore-forming activity. Suitable drugs include disulfiram and necrosulfonamide (NSA). The drug may be administered by any one or more of orally, parenterally, by injection, by subcutaneous injection, by intravenous injection, by intramuscular injection, transdermally, sublingually, topically, rectally, and intra- peritoneally.”. Accordingly, the claims do not get the priority of ‘863 is because (1) the species of “GSDMD pore-forming activity” was added as a limitation into the independent claim, and (2) despite rolling dependent claims reciting nucleotide-molecules into independent claim 1, these nucleotide-molecules still are rejected under 35 U.S.C. 112(a) for written description and enablement (see rewritten rejections below).
Accordingly, the effective filing date of claim(s) 1-4, 6-7, 9-10, 12-13, and 17-19 is the filing date of the 371 filed as PCT/US22/34590 on 06/22/2022.
Response to Arguments – Specification
The previous objection to the specification have been withdrawn in view of Applicant’s amendments filed 07/30/2026.
Claim Objections – New
Claim 12 is objected to because of the following informalities: when Applicant amended claim 12 to recite “untranslated” instead of previously recited “untranscribed”, Applicant also amended “of GSDMD gene.”, to now recite “of GSDMD mRNA.” A gene has the potential to have more than one 3’ UTR because a gene typically produces more than one isoform, however, an mRNA molecule has one 3’ UTR. Robert Weaver (Part I, Chapter 3: An Introduction to Gene Function, Section 3.1 – Translation, Molecular Biology, Fifth Edition, published by McGraw Hill, 2012, pages 1-70; mailed with the PTO 892 from 06/02/2026) teaches that a transcribed product has one 5’ UTR and one 3’ UTR (see image below; page 44 in Figure 3.20).
PNG
media_image1.png
248
344
media_image1.png
Greyscale
It would be remedial to amend claim 12 to recite “wherein the nucleotide molecule targets the 3’ untranslated region (UTR) of the GSDMD mRNA.”
Appropriate correction is required.
Response to Arguments – Claim Objections
The previous objection of claim(s) 12 and 18 has been withdrawn in view of Applicant’s amendments to the claims filed 07/30/2026.
Claim Interpretation
Claim(s) 6 and 7 recite “. . . guide antisense strand consisting/consists of about 10 to about 30 nucleotides. . . ” In light of the specification, which defines “about” in paragraph [0048] as + or - 20% in some embodiments, “about 10” will be interpreted as minimally 8, and “about 30” will be interpreted as maximally 36. Both of which as – or + 20% of 10 and 30, respectively.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This rejection was made in the Office Action mailed 06/02/2026 and has been rewritten to include the amendments filed 07/30/2026.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites the broad recitation “sequence of GSDMD”, and the claim also recites “Accession NO: NM_024736” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Response to Arguments – Claim Rejections - 35 USC § 112(b) – Indefiniteness
The previous rejection of claim 7 under 35 U.S.C 112(b) for reciting a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is maintained in view of Applicant’s arguments in the reply filed 07/30/2026.
The previous rejection of claim 7 under 35 U.S.C 112(b) for reciting the “NM_024736” a database that changes overtime has been withdrawn in view of Applicant’s arguments in the reply filed 07/30/2026.
It is of note that there were two 35 U.S.C. 112(b) rejections for claim 7 made in the Office Action mailed 06/02/2026: (1) a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim), and (2) the recitation of material that changes over time. Applicant only traversed the second rejection in the reply filed 07/30/2026.
Applicant contends that the specification expressly provides that, unless otherwise indicated or apparent, references to publicly-available databases are references to the most recent version of the database as of the filing date of the application. Applicant contends that, “thus, the accession reference in claim 7 is not open-ended or future-changing identified, but instead denotes the NM_024736 sequence as it existed on the filing date.”
Response: It is acknowledged that Applicant points to portions of the specification that explicitly provide guidance that “Unless otherwise indicated or apparent, references to publicly-available databases are references to the most recent version of the database as of the filing date of the application.”, (para [0044]). In light of this disclaimer, the 35 U.S.C . 112(b) rejection on claim 7 for the recitation of a sequence that changes over time is withdrawn.
However, the untraversed 35 U.S.C. 112(b) rejection made in the Office Action filed 06/02/2026, based on “A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).”, is maintained. The recitation of “the sequence of GSDMD” being the broader recitation and “(Accession No: NM_024736)” being the narrower recitation. For example, regarding the broad recitation of the gene GSDMD, at the time of the filing date of the application there were already seven different versions of NM_024736, with the following number of base pairs: 1718, 1832, 1823, 3361, 1823, 1772, and 1723. The most recent version has 1723 base pairs. It is known that “the sequence of GSDMD” can be larger than 1723bp, (see versions 2-6 of NM_024736), accordingly, the broader ranger together with a narrow range has still not been remedied.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claim(s) 1-4, 6-7, 9-10, 12-13, and 17-19 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. This rejection was made in the Office action mailed 06/02/2026 and has been rewritten to address the amendment to the claims in the reply filed on 07/30/2026.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, Applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Claim(s) 1-4 are drawn to (a) a subgenus of GSDMD inhibitors that inhibit pore-forming activity. This subgenus is defined as belonging to the broad class of GSDMD inhibitors that must be capable of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, and (2) inhibiting the pore-forming activity of GSDMD; and/or (b) a subgenera “nucleotide molecules” comprising an antisense oligonucleotide (ASO), an miRNA, an siRNA, a locked nucleic acid (LNA) nucleotide, a guide antisense strand, or a combination thereof that must be capable of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, and (2) reducing expression of GSDMD.
Claim 7 is drawn to a subgenus of claim 6, which is dependent upon claim 1. Claim 7 is drawn to a guide antisense strand that consists of about 10 to about 30 nucleotides that are complementary to consecutive nucleotides of the sequence of GSDMD (Accession No: NM_024736). Claim 7 belongs to the subgenera of an antisense oligonucleotide (ASO), an miRNA, an siRNA, a locked nucleic acid (LNA) nucleotide, guide antisense strand, or a combination thereof and is defined as belonging to the broad class of GSDMD inhibitors that must be capable of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) reducing the expression of GSDMD, and/or (3) reducing the activity of GSDMD.
The rejected claims thus comprise a subgenus of “GSDMD inhibitors that inhibit pore-forming activity” and/or a subgenera “nucleotide molecules” and are defined as belonging to the broad class of GSDMD inhibitors/nucleotide molecules and as having the function of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) inhibiting the activity of GSDMD, and/or (3) reducing the expression of GSDMD.
Claim(s) 9-10, and 12 are drawn to a subgenus of “nucleotide-molecules” for treating an aortopathy in a subject identified as having or at risk of developing the aortopathy and reducing expression of GSDMD. The subgenus of claim 9 recites, “wherein the nucleotide molecule targets a protein coding region of a GSDMD mRNA.”; claim 10 recites, “. . wherein the nucleotide molecule targets a non-coding region of a GSDMD mRNA.”; and claim 12 is dependent upon claim 10 and recites, “. . . wherein the nucleotide molecule targets one or more 3' untranslated regions (UTRs) of the GSDMD mRNA.” All of which must be capable of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy and (2) reducing the expression of GSDMD.
Claim 13 is drawn to further limiting the aortopathy to “. . . [A]neurysm, a dissection, and a rupture.” The rejected claims thus comprise a subgenus of “GSDMD inhibitors that inhibit pore-forming activity” and/or a subgenera “nucleotide molecules” and are defined as belonging to the broad class of GSDMD inhibitors/nucleotide molecules and as having the function of (1) treating an aneurysm, a dissection, and/or a rupture in a subject identified as having or at risk of developing the aneurysm, a dissection, and/or a rupture, (2) inhibiting the pore forming activity of GSDMD, and/or (3) reducing the expression of GSDMD.
Claim 17 is drawn to further limiting the GSDMD inhibitor for inhibiting pore forming activity to disulfiram. The rejected claims thus comprise disulfiram and/or a subgenera “nucleotide molecules” and are defined as belonging to the broad class of GSDMD inhibitors/nucleotide molecules and as having the function of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) inhibiting the activity of GSDMD, and/or (3) reducing the expression of GSDMD.
Claim(s) 18 and 19 are drawn to further limiting the route of administration of disulfiram, i.e., by injection. The rejected claims thus comprise disulfiram administered via injection and/or a subgenera “nucleotide molecules” (administered via any route) and are defined as belonging to the broad class of GSDMD inhibitors/nucleotide molecules and as having the function of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) inhibiting the activity of GSDMD, and/or (3) reducing the expression of GSDMD.
To satisfy the written description requirement, MPEP §2163 states, in part “… a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species 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 functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
Regarding “a GSDMD Inhibitor that inhibitors pore forming activity” and “a nucleotide molecule that reduces expression of GSDMD”
The specification envisions the GSDMD inhibitor as an antisense oligonucleotide (ASO), miRNA, siRNA, locked nucleic acid (LNA) nucleotides, or a combination thereof. The GSDMD inhibitor may comprise a guide strand consisting of about 10 to about 30 nucleotides, as well as, those said nucleotides may be complementary to consecutive nucleotides of the sequence of GSDMD (Accession No: NM_024736) (see paragraph [0010]). The specification envisions expression and/or activity reduction of GSDMD may be achieved by CRISPR, ASO, miRNA, siRNA, locked nucleic acid (LNA) nucleotides, or a combination thereof (see paragraphs [0011] and [0029]). Wherein reduction of expression may be achieved by a nucleotide molecule targeting a protein coding region, a non-coding region, a promoter, or 3’ UTRS of the GSDMD gene (see paragraph [0011]). The specification envisions a drug that inhibits GSDMD pore-forming activity (see paragraph [0012]).
The specification describes disulfiram and necrosulfonamide at paragraphs [0012] and [0075]. More specifically, the specification describes the use of disulfiram in the prevention of BAPN-induced aortic aneurysm and dissection (see paragraphs [0074] to [0079]).
However, the specification does not describe any of the claimed (a) Antisense oligonucleotides, (b) miRNA, (c) siRNA, or (d) locked nucleic acid (LNA) nucleotides, in a way that is sufficient to reduce expression of GSDMD and treat a subject having or at risk of developing an aortopathy.
The specification does describe disulfiram and necrosulfonamide and their ability to reduce pore-forming activity of GSDMD.
The specification does not provide description for other GSDMD pore forming inhibitors i.e., upstream regulators or downstream feedback loops, or other means of targeting GSDMD pore forming activity through inhibitors such as shRNA, aptamers, peptide nucleic acids (PNAs), ADAR, TALENS, Zinc finger nucleases, biologics (e.g., monoclonal and polyclonal antibodies, nanobodies, antibody fragments), peptidomimetics, natural products, or any other small molecules (all structures under the genus of inhibitor) capable of inhibiting activity of GSDMD and treating a subject having or at risk of developing an aortopathy.
The specification does not provide description for the combination of a GSDMD pore-forming inhibitors AND a nucleotide molecule.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims in regard to structure and function, the examples are only representative of two GSDMD inhibitors (i.e., disulfiram and necrosulfonamide) used for (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) and (2) inhibiting the activity of GSDMD.
These results are not necessarily predictive of all “GSDMD inhibitors that inhibit pore-forming activity” and/or “a nucleotide molecule . . .selected from the group consisting of ASO, miRNA, siRNA, LNA, a guide antisense, or a combination thereof” capable of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) inhibiting pore forming activity of GSDMD, and/or (3) reducing the expression of GSDMD. Thus, it is impossible for one to extrapolate from the two examples of “GSDMD inhibitor that inhibits GSDMD pore forming activity” described herein that the of subgenus “GSDMD inhibitor that inhibits GSDMD pore forming activity” would necessarily meet the structural/functional characteristics of the rejected claims. Furthermore, it is impossible for one to extrapolate from no examples of “nucleotide molecule . . . selected from the group consisting of ASO, miRNA, siRNA, LNA, guide antisense strand, or a combination thereof.”, described herein that the of subgenus “nucleotide molecule” would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set “GSDMD inhibitors that inhibitor GSDMD pore forming activity” and/or “nucleotide molecules” capable of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) inhibiting pore-forming activity of GSDMD, and/or (3) reducing expression of GSDMD.
Broad spectrum of potential regulators of GSDMD and their implications:
Li et al (The Regulation and Modification of GSDMD Signaling in Diseases, Front Immunol, volume 13, issue 893912, pages 1-17, published June 14th, 2022; listed on the PTO 892 mailed 06/02/2026) teaches:
“At the transcription level, two functioned binding sites of NF-κB were reported in the GSDMD promoter, including 250- to 100-bp and 720- to 250-bp upstream of the initiation site (42). . . In addition, the hypermethylation of the promoter region mediated by DNMT (DNA methyltransferases) results in the reduced expression of GSDMD in NK92 cells, and enhancement of DNMT-mediated methylation-silencing of GSDMD by dimethyl fumarate (DMF) or monomethyl fumarate (MMF) was found to inhibit pyroptosis and IL-1β release (43), . . .
Moreover, recent studies have demonstrated that interferon regulatory factor 2 (IRF2) is crucial to enhance the transcription of GSDMD for the execution of pyroptosis (44). . . In conclusion, the regulation of GSDMD at the transcription level provided us a unique thought on pyroptosis suppression (Figure 1).”, (see page 2, column 2, under Transcriptional Regulation of GSDMD Expression).
Li et al further teaches, “The wide variety of diseases in which GSDMD likely mediates inflammation and its crucial role as a final bottleneck for pyroptosis suggest that GSDMD inhibition could be an extremely effective therapeutic strategy. However, interfering with the antimicrobial roles of GSDMD could lead to increased susceptibility to infection. In addition, innate immune responses are complex, and each potential therapeutic indication will need to be examined carefully in preclinical models. In a study using the monosodium urate (MSU)-induced gout model, although GSDMD was activated through the NLRP3 inflammasome, it was not needed for cell death or IL-1β release, and the GSDMD inhibitor NSA did not ameliorate disease181. Suppressing pyroptosis can activate other innate immune responses. For instance, GSDMD inhibition in a cell can activate the interferon response182. In a mouse study that modelled systemic lupus erythematosus (SLE) using injected imiquimod, the severity of SLE was unexpectedly exacerbated in Gsdmd–/– mice, leading to more severe kidney and pulmonary pathology, more autoantibodies and reduced mortality183. Type I interferons play an important driving role in many SLE models and in patients with SLE. GSDMD may have suppressed interferon induction in these mice, although a change in interferon signalling in this SLE model in Gsdmd–/– mice was not examined.
Mouse models may not always accurately mirror human disease pathogenesis, and mouse models of inflammatory diseases can be affected by small differences in experimental protocol or differences in the microbiome of mouse colonies or other poorly defined environmental or genetic differences. For example, two recent studies of dextran sodium sulfate-induced colitis found opposite results: in one study Gsdmd deficiency exacerbated colitis and enhanced cGAS–STING-mediated interferon induction184, while in another study lack of Gsdmd reduced disease severity185.
The role of GSDMD in various inflammatory diseases and potential interactions of GSDMD activation with other innate immune responses will need to be examined carefully to select disease indications and anticipate possible toxicity of GSDM-modulating compounds as they become available.”, (see page 401-402, considerations for therapeutic GSDMD inhibition).
(a/c/d/e) Antisense oligonucleotides/siRNAs/Locked Nucleic acid nucleotides (guide antisense strand included)
Ye et al (Silencing of Gasdermin D by siRNA-Loaded PEI-Chol Lipopolymers Potently Relieves Acute Gouty Arthritis through Inhibiting Pyroptosis, molecular pharmaceutics, volume 18, parges 667-678, published June 24th, 2020; listed on PTO 892 mailed 06/02/2026) discloses:
“PEI-Chol was used to transfect siRNA (GenePharma) into cells according to the manufacturer’s instructions. Sequences of siRNAs were: siGSDMD: GGU GAA CAU CGG AAA GAU UTT (sense), AAU CUU UCC GAU GUU CAC CTT (antisense).”, (see page 670, column 1, paragraph 2 – cell transfection).
Ye et al discloses a sequence of GSDMD siRNA but does not disclose the use for treating aortopathies in a subject identified with having or at risk of developing an aortopathy. Ye et al does not discloses the combination of the siRNA with an inhibitor of pore forming activity.
Regarding the efficacy of using said sequence disclosed by Ye et al, one must look to the art to establish whether this siRNA, guide antisense strand, and/or an ASO is indicative of all siRNA, guide antisense strand, and/or ASOs for reducing expression and/or activity of GSDMD for the treatment of aortopathy.
Khvorova and Watts (The chemical evolution of oligonucleotide therapies of clinical utility, nature biotechnology, volume 35, pages 238-248, published February 27th, 2017; listed on PTO 892 filed 06/02/2026) teach, “In 1978, Zamecnik and Stephenson demonstrated that an oligonucleotide that is antisense (i.e., complementary) to a viral RNA could reduce protein translation and viral replication. It is now clear that ASOs can make use of multiple mechanisms to reduce or modulate gene expression. Nonetheless, all ASOs require chemical modification to be sufficiently active in vivo.”, (see page 239, column 2, paragraph 3).
Khvorova and Watts further teach, “In many of these early programs, completely unmodified or slightly modified compounds were administered in the hope that a small but sufficient amount of oligonucleotide would be taken up by the appropriate cells and silence the target. Ultimately, most of these attempts showed limited clinical efficacy and unacceptable toxicity, primarily from induction of the innate immune response by non modified duplex RNAs. Thus, chemical modification of siRNA is absolutely necessary to achieve clinical utility.”, (see page 242, column 1, paragraph 5).
Taking into consideration that locked nucleic acid (LNA) implies at least one modification of a nucleotide, which the base sequence could be represented by the sequence disclosed in Ye et al above, Hagerdon et al (Locked Nucleic Acid: modality, diversity, and drug discovery, Drug discovery today, volume 23, issue 1, pages 101-114, published January 2018; listed on PTO 892 mailed 06/02/2026) disclose the importance of specificity in said oligonucleotide sequence that corresponds to the LNA modification.
Hagerdon et al teaches, “The higher affinity of LNAs and LNA analogs has been reported to result in hepatotoxicity [135]. By contrast, it has also been reported that hepatotoxicity was significantly reduced by using shorter version of the LNAs (from 20mer to 14mer) [135]. One should be careful to calculate any property correlations in relation to a single determinant, such as length. In other words, does a property difference result from a length change or because different compounds are being compared? For instance, it was shown that a 13mer LNA was toxic, but, by adding just one LNA nt, the corresponding 14mer was nontoxic [19]. The specific composition and the nucleotide positioning (including LNA nt) is also a determinant because LNAs with the same nucleobase sequence and with different positions of the LNA in the flanks can have different hepatotoxic profiles.”, (see page 107, column 2, paragraph 2).
(b) MicroRNA
Huang et al (CN118319937A, published July 12th, 2024; Translation cited under NPL section; listed on the PTO 892 mailed 06/02/2026) discloses using miR-325-3p mimic to reduce GSDMD wildtype in Figure 2. Huang et al does not disclose the use of miR-325-3p for treating aortopathy in a subject identified as having or at risk of developing an aortopathy. Huang et al performed the studies in vitro, using mouse macrophage cell lines and HEK-293T cells (see page 3).
Regarding the efficacy of using said sequence disclosed by Huang et al, one must look to the art to establish whether this miRNA is indicative of all miRNA targeting GSDMD expression or activity for the treatment of aortopathy.
Zhang et al (The risk of miRNA Therapeutics: In a Drug Target Perspective, Drug Design, Development and Therapy, volume 15, pages 721-733, published February 22nd, 2021; listed on PTO 892 mailed 06/02/2026) teaches, “TMTME (“too many targets for miRNA effect”) is a typical and inevitable property of miRNA molecules, which is caused by incomplete complementation with the target sequence. TMTME leads to that miRNA could bind to various sequences suitable for the interaction (including protein-coding genes, lncRNA, circRNA, etc), which is different from all approved drugs (including siRNA drugs) with only a few targets… Therefore, both introduction and removal of miRNA in humans can lead to changes of a wide series of pathways and some of them are unknown, even unpredictable, probably triggering disorders of physiological function or the occurrence of additional disease.”, (Page 729, column 1, paragraph 2 to column 2, paragraph 1).
Zhang et al teaches, “Moreover, due to instability of unprotected miRNAs, delivering miRNAs required chemical modifications to avoid rapid degradation in serum, which may impair specificity of miRNAs and lead to off-target effects… Another challenge is that exogenous artificial miRNAs will trigger competition and saturation effect, a competition among exogenous and the endogenous miRNAs for the intracellular machinery, and thus affecting unexpected gene expression and leading to untoward side effects.”, (page 730, column 1, paragraph 1).
Other inhibitors that inhibit pore forming activity of GSDMD:
Schiffelers et al (Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application, Nat Commun, vol 15, issue 8266, pages 1-18, published September 26th, 2024) teaches, “Interestingly, GSDMD pore formation may also be further regulated: Efficient GSDMD pore formation relies on ROS generated by the Ragulator-Rag-mTORC1 pathway, which likely mediates the oxidative post-translational modification of GSDMD cysteine 19115,16. The same residue has recently been proposed to undergo (reversible) palmitoylation to facilitate membrane association and full activation17–19.”, (p. 2, col 1, para 1).
“To provide more insights into GSDMD pore formation in live cells, we generated nanobodies against the human GSDMD protein. Nanobodies are single domain antibodies derived from the variable domain of heavy chain-only antibodies (VHH) present in camelids21. Due to their small size, specificity, and functionality in the cytosol, they present themselves as useful tools to study target proteins in living cells22. We identified two antagonistic GSDMD nanobodies that inhibit pyroptosis and IL-1β release by blocking oligomerization of GSDMDNT”, (p. 2, col 1, para 3).
The two nanobodies of Schiffelers et al do not offset the subgenus of GSDMD inhibitor of pore-forming activity. Schiffelers et al teaches making six nanobodies, all of which contain different sequences (structure) and different levels of pore inhibition (function) (see figure 1). Schiffelers et al also teaches that ROS and palmitoylation can have an effect on pore forming activity.
Accordingly, the art does not appear to offset the deficiencies of the specification. Merely describing “GSDMD inhibitors that inhibit pore forming activity” and/or “nucleotide molecules” capable of (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) inhibiting pore forming activity of GSDMD, and/or (3) reducing the expression of GSDMD, without sufficient detail relating to the subgenus of GSDMD inhibitors and/or nucleotide molecules in (1) treating an aortopathy in a subject identified as having or at risk of developing the aortopathy, (2) inhibiting pore forming activity, and/or (3) reducing the expression of GSDMD, does not allow the skilled artesian to reasonably conclude that the Applicants were in possession of the claimed invention.
Applicant has description for administration of disulfiram alone but does not have written description for “inhibitors of pore forming activity” or “nucleotide molecules that reduces expression of GSDMD” or the combination set forth by “and/or” under 35 USC § 112(a) regarding claims 1-4, 6-7, 9-10, 12-13, and 17-19.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Written Description
The previous rejection of claim 5, 8, 11, 16, and 20 under 35 U.S.C 112(a) for written description is moot in view of Applicant’s cancellation of the claim filed 07/30/2026.
With respect to the rejection of claims 1-4, 6-7, 9-10, and 12-13 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, Applicant's arguments starting at page 9 of the reply filed 07/30/2026 have been fully considered but they are not persuasive for at least the following reasons
Applicant contends that the application as filed expressly discloses both subgenus of newly amended claim 1. Particularly, “the application states that the GSDMD inhibitor may be a drug that inhibits GSDMD pore-forming activity, and identifies suitable drugs including disulfiram and necrosulfonamide (NSA).” Applicant contends that “the GSDMD inhibitor may comprises an ASO, miRNA, siRNA, LNA nucleotide, or a combination thereof, and that reduction in expression of GSDMD may be achieved using such nucleotide molecules. . .” Applicant contends that the amended claims now excluded undefined “any reduction” genus addressed in the Office action mailed 06/02/2026 including CRISPR embodiments, physical modalities, upstream or downstream regulators, antibodies, PNAs, TALENs, zinc finger nucleases, biologics, natural products, and unspecified small molecules other than the recited GSDMD pore-forming inhibitor branch.
Applicant contends that “For the pore-forming inhibitor branch, the specification identifies representative species and describes administration of disulfiram in the therapeutic context of treating aortopathy. . . For the nucleotide- molecule branch, the application provides structural and target-based identifying characteristics for the claimed subject matter.”
Further, Applicant contends that with respect to claim 7, that the application as filed expressly identifies guide antisense strands complementary to consecutive nucleotides of GSDMD "(Accession No: NM_024736).", and that the application also explains that information associated with publicly available sequence databases is incorporated by reference and that, unless otherwise indicated or apparent, database references are to the most recent version of the database as of the filing date of the application.
Response: Regarding Applicant’s contention that “the application states that the GSDMD inhibitor may be a drug that inhibits pore-forming activity” such as disulfiram and NSA, these are two species of a broad genus of GSDMD inhibitor. Furthermore, taking into consideration that claim 1 now recites “A GSDMD inhibitor that inhibits pore-forming activity”, which narrows the previous broad genus of GSDMD inhibitor to a subgenus of inhibitors, the specification still fails to adequate describe the broad subgenus of inhibitors for inhibiting pore-forming activity. As mentioned above in the re-written 35 U.S.C. 112(a) rejection, Schiffelers et al (supra) taught that even ROS and palmitoylation regulate pore-forming activity of GSDMD. The newly amended claims do not excluded any “undefined” genus of inhibitor, for example, a complete removal of the gene would result in inhibition of pore-forming activity, an antibody or nanobody could also result in inhibition of pore-forming activity. Therefore, CRISPR embodiments, physical modalities, upstream or downstream regulators, PNAs, TALENs, zinc finger nucleases, ADAR, biologics, natural products, etc, are encompassed by the subgenus of “GSDMD inhibitor that inhibits pore-forming activity”. Moreover, with the newly amended claims, the specification lacks description for the combination of both the “pore-forming inhibitor branch” and the “nucleotide molecule branch.”, which is a limitation set forth by the “and/or” of the newly amended claim 1.
Regarding Applicant’s contentions that “For the nucleotide- molecule branch, the application provides structural and target-based identifying characteristics for the claimed subject matter.”, then further contends that “the application also explains that information associated with publicly available sequence databases is incorporated by reference and that, unless otherwise indicated or apparent, database references are to the most recent version of the database as of the filing date of the application.”, regarding Accession No: NM_024736.
It is of note that 37 CFR 1.57 (d) and (e) recite:
(d) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. "Essential material" is material that is necessary to: (1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by 35 U.S.C. 112(a); (2) Describe the claimed invention in terms that particularly point out and distinctly claim the invention as required by 35 U.S.C. 112(b); or (3) Describe the structure, material, or acts that correspond to a claimed means or step for performing a specified function as required by 35 U.S.C. 112(f).
(e) Other material ("Nonessential material") may be incorporated by reference to U.S. patents, U.S. patent application publications, foreign patents, foreign published applications, prior and concurrently filed commonly owned U.S. applications, or non-patent publications. An incorporation by reference by hyperlink or other form of browser executable code is not permitted.
Thus, publicly available databases cannot be incorporated by reference for either essential or nonessential material.
Therefore, any structure and/or function described in the specification that depend on a sequence relating to the publicly available data set, i.e., essential mater, cannot be adequately described.
Accordingly, the rejection on 35 U.S.C. 112(a) for lack of written description is maintained for claim(s) 1-4, 6-7, 9-10, and 12-13.
Claim Rejections - 35 USC § 112(a) – Enablement
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.
Claim 7 is rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on a disclosure which is not enabling. The disclosure does not enable one of ordinary skill in the art to practice the invention without the sequence of GSDMD, which is critical or essential to the practice of the invention but not included in the claim(s). See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976). This rejection was made in the Office Action mailed 06/02/2026 and has been rewritten to include the amendments filed 07/30/2026.
For the purpose of this rejection, claim 7 is being interpreted as requiring NM_024736, see the rejection under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
The omitted subject matter, i.e., a sequence of GSDMD, is essential subject matter for the invention. This particular feature has been considered essential by the Application but is not reflected in the claim which is rejected. Applicant envisions a guide antisense strand that consists of about 10 to about 30 nucleotides that are complementary to the sequence of GSDMD and provides an accession number to retrieve said sequence, i.e., No: NM_024736. Essential material cannot be incorporated by reference to an electronic database. Moreover, NM_024736’s sequence has been changed seven times since 2003, and has the ability to change at any given time moving forward which would not enable a person of ordinary skill in the art to make/use the invention as it stands.
Thus, claim 7 is rejected under 35 USC § 112(a) for lack of enablement.
Claim(s) 1-4, 6-7, 9-10, 12-13, and 17-19 are 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
A method of treating an aortopathy, the method comprising:
identifying a subject having or at risk of developing the aortopathy; and
administering to said subject an effect amount of a gasdermin D (GSDMD) pore-forming activity inhibitor;
wherein said inhibitor is disulfiram.,
does not reasonably provide enablement for any/all GSDMD inhibitors that inhibit pore-forming activity, any/all ASOs, miRNAs, siRNAs, LNAs, guide antisense strands, or a combination thereof that reduce expression of GSDMD, and/or a combination of any/all GSDMD inhibitors that inhibit pore-forming activity and those of the nucleotide-molecules previously listed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This rejection was made in the Office Action mailed 06/02/2026 and has been rewritten to include the amendments filed 07/30/2026.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
Claim 1 is drawn to a method for treating an aortopathy, comprising: identifying a subject having or at risk of developing the aortopathy; and administering to the subject (i) a gasdermin D (GSDMD) inhibitor that inhibits pore-forming activity, and/or (ii) a nucleotide molecule that reduces expression of GSDMD selected from the group consisting of antisense oligonucleotide (ASO), an miRNA, an siRNA, a locked nucleic acid (LNA) nucleotide, a guide antisense strand, or a combination thereof. The nature of the invention is complex in that inhibiting pore-forming activity of GSDMD and/or reducing expression of GSDMD must result in a treating an aortopathy or a subject at risk of developing one.
Claim(s) 6-7 are drawn to further limiting an antisense guide strand. Claim 6 limits claim 1 to a guide antisense strand consisting of about 10 to about 30 nucleotides. Claim 7 limits claim 6 to the guide antisense strand consists of about 10 to about 30 nucleotides that are complementary to consecutive nucleotides of the sequence of GSDMD (Accession No: NM_024736). The nature of the invention is complex in that claim 1 embodies any/all ASOs, miRNA, siRNA, LNA, guide antisense strand, or a combination thereof targeting directly GSDMD or indirectly targeting regulators of GSDMD, all of which must be capable of treating aortopathy in a subject. The nature of the invention is complex in that claim 6 embodies anywhere between 8 and 36 nucleotides of a guide antisense strand targeting directly GSDMD or indirectly regulators of GSDMD, all of which must be capable of treating aortopathy in a subject. The nature of the invention is complex in that claim 7 embodies anywhere between 8 and 36 nucleotides of a guide antisense strand targeting directly GSDMD, however the sequence of GSDMD is indefinite due to the improper incorporation by reference thus it is complex in that one would not know where the boundaries begin and end with designing a guide antisense strand complementary to GSDMD which must be capable of treating aortopathy in a subject.
Claim(s) 9-10 and 12 are drawn to further limiting claim 1 and the reduction of expression of GSDMD through targeting either the protein coding region of the GSDMD mRNA (claim 9), targeting the non-coding region of the GSDMD mRNA (claim 10), and targeting one or more 3’ untranslated regions of the GSDMD region (claim 12). The nature of the invention is complex in that claim(s) 9-10, and 12 target the GSDMD mRNA with an unknown length of nucleotides or modifications for the reduction of GSDMD gene expression and must be capable of treating aortopathy in a subject.
Claim 13 further limits the type of aortopathy. The nature of the invention is complex in that the reduction of expression and/or inhibition of pore-forming activity of GSDMD must be capable of treating aneurysm, a dissection, and a rupture.
Claim 17 further limits pore-forming activity inhibitor to disulfiram. The nature of the invention is complex in that disulfiram must be capable of inhibiting pore-forming activity and treating aortopathy in combination with a nucleotide molecule that reduces expression of GSDMD.
Claim(s) 18 and 19 further limit the route of administration of disulfiram, i.e., by injection. The nature of the invention is complex in that disulfiram by injection must be capable of inhibiting pore-forming activity and treating aortopathy in combination with a nucleotide molecule (administering via any route) that reduces expression of GSDMD.
Breadth of the claims:
The broadest reasonable interpretation of claim 1 is that it encompasses a method for treating any/all aortopathies, comprising: identifying a subject having or at risk of developing the any/all aortopathies; and administering to the subject (i) any/all gasdermin D (GSDMD) inhibitors that inhibit pore-forming activity, and/or (ii)any/all nucleotide molecules that reduce expression of GSDMD selected from the group consisting of antisense oligonucleotides (ASO), miRNAs, siRNAs, locked nucleic acid (LNA) nucleotides, guide antisense strands, or a combination thereof.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples:
Looking the specification on “treatment/treating”, “GSDMD inhibitors that inhibit pore-forming activity”, “nucleotide molecules”, combinations of the two, and working examples.
The specification discloses that “treating” or “treatment” refer to the medical management of a subject with the intent to cure, ameliorate, reduce, or prevent an aortopathy, see paragraph [0033].
The specification discloses that “inhibiting” or “inhibition” does not refer to the ability to completely inactive all target biological activity in all cases. The specification further discloses, “[T]he skilled artisan will understand that the term "inhibiting" refers to decreasing biological activity of a target, such as a GSDMD, such as can occur, for example, when a nucleotide limits the expression of the target gene, when a ligand binding site of the target protein is blocked, or when a non-native complex with the target is formed. Such decrease in biological activity can be determined relative to a control, wherein an inhibitor is not administered and/or placed in contact with the target. For example, in some embodiments, a decrease in activity relative to a control can be about a 1,2,3,4,5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% decrease. The term "inhibitor" refers to a compound of composition that reduces the expression of and/or decreases the biological activity of a target, such as a GSDMD.”, (see paragraph [0034]).
The specification discloses types of inhibitors of GSDMD, such as “In embodiments, the GSDMD inhibitor comprises an antisense oligonucleotide (ASO), miRNA, siRNA, locked nucleic acid (LNA) nucleotides, or a combination thereof. The GSDMD inhibitor may comprise a guide antisense strand consisting of about 10 to about 30 nucleotides. The guide antisense strand may consist of about 10 to about 30 nucleotides that are complementary to consecutive nucleotides of the sequence of GSDMD (Accession No: NM_024736). . . In embodiments, reduction in expression of and/or activity of GSDMD may be achieved using CRISPR, ASO, miRNA, siRNA, locked nucleic acid (LNA) nucleotides, or a combination thereof. . . . In embodiments, the GSDMD inhibitor may be a drug that inhibits GSDMD pore-forming activity. Suitable drugs include disulfiram and necrosulfonamide (NSA).”, (see paragraphs [0010] to [0012]).
The working examples provided are of the following:
Figure 1A-D demonstrate that Gsdmd knockout mice are protected against AngII-induced aortic rupture.
Figures 2-4 demonstrate six of 13 Gsdmd knockout mice died of descending aortic rupture by necropsy, but no Gsdmd knockout mouse died of aortic rupture. All when administered BAPN, an aortic-rupture inducing agent, at 4 weeks of age.
Applicant summarizes in [0073] that GSDMD deficiency (as represented by the Gsdmd knockout mice) prevented aortic rupture in mice infused with AngII or orally administered BAPN, but had not effects on aortic dilation.
Figure 5 demonstrates that administering disulfiram to wildtype mice prevent BAPN-induced death.
The working examples demonstrate that deficiency of GSDMD could protect against aortic rupture in mouse models (i.e., AngII infusion and BAPN oral administration). The working examples lack demonstrating the reduction of GSDMD expression via antisense oligonucleotides (ASOs), miRNA, siRNA, locked nucleic acids, CRISPR, or a combination thereof. The working examples of figure 1-4 demonstrate what occurs when a mouse already deficient in GSDMD is subjected in a stress that would typically induce aortic dissection, instead of reducing GSDMD expression or activity after said stressor has occurred. The specification/working examples demonstrate one GSDMD inhibitor, disulfiram, in wild-type mice for the treatment of aortopathy.
Predictability and state of the art:
Looking to the predictability in the art for using a constitutive Gsdmd knockout mouse model and “reducing” expression and/or activity of GSDMD, Li et al (supra) discloses:
“In a study using the monosodium urate (MSU)-induced gout model, although GSDMD was activated through the NLRP3 inflammasome, it was not needed for cell death or IL-1β release, and the GSDMD inhibitor NSA did not ameliorate disease181. Suppressing pyroptosis can activate other innate immune responses. For instance, GSDMD inhibition in a cell can activate the interferon response182. In a mouse study that modelled systemic lupus erythematosus (SLE) using injected imiquimod, the severity of SLE was unexpectedly exacerbated in Gsdmd–/– mice, leading to more severe kidney and pulmonary pathology, more autoantibodies and reduced mortality183. Type I interferons play an important driving role in many SLE models and in patients with SLE. GSDMD may have suppressed interferon induction in these mice, although a change in interferon signalling in this SLE model in Gsdmd–/– mice was not examined. . . Mouse models may not always accurately mirror human disease pathogenesis, and mouse models of inflammatory diseases can be affected by small differences in experimental protocol or differences in the microbiome of mouse colonies or other poorly defined environmental or genetic differences. For example, two recent studies of dextran sodium sulfate-induced colitis found opposite results: in one study Gsdmd deficiency exacerbated colitis and enhanced cGAS–STING-mediated interferon induction184, while in another study lack of Gsdmd reduced disease severity185.”, (see page 401-402, considerations for therapeutic GSDMD inhibition).
A GSDMD inhibitor could be direct or indirect. Looking to the art for predictability of inhibitors, Li et al further discloses three other regulators of GSDMD expression:
“At the transcription level, two functioned binding sites of NF-κB were reported in the GSDMD promoter, including 250- to 100-bp and 720- to 250-bp upstream of the initiation site (42). . . In addition, the hypermethylation of the promoter region mediated by DNMT (DNA methyltransferases) results in the reduced expression of GSDMD in NK92 cells, and enhancement of DNMT-mediated methylation-silencing of GSDMD by dimethyl fumarate (DMF) or monomethyl fumarate (MMF) was found to inhibit pyroptosis and IL-1β release (43), . . . .
Moreover, recent studies have demonstrated that interferon regulatory factor 2 (IRF2) is crucial to enhance the transcription of GSDMD for the execution of pyroptosis (44). . . In conclusion, the regulation of GSDMD at the transcription level provided us a unique thought on pyroptosis suppression (Figure 1).”, (see page 2, column 2, under Transcriptional Regulation of GSDMD Expression).
Looking to the art for ASOs, miRNAs, siRNAs, LNAs, and guide antisense strand guidance for therapeutics:
Antisense oligonucleotides/siRNAs/Locked Nucleic acid nucleotides/guide antisense strand
Khvorova and Watts (supra) teach, “It is now clear that ASOs can make use of multiple mechanisms to reduce or modulate gene expression. Nonetheless, all ASOs require chemical modification to be sufficiently active in vivo.”, (see page 239, column 2, paragraph 3).
Khvorova and Watts further teach, “In many of these early programs, completely unmodified or slightly modified compounds were administered in the hope that a small but sufficient amount of oligonucleotide would be taken up by the appropriate cells and silence the target. Ultimately, most of these attempts showed limited clinical efficacy and unacceptable toxicity, primarily from induction of the innate immune response by non modified duplex RNAs. Thus, chemical modification of siRNA is absolutely necessary to achieve clinical utility.”, (see page 242, column 1, paragraph 5).
Hagerdon et al (supra) disclose the importance of specificity in said oligonucleotide sequence that corresponds to the LNA modification: “The higher affinity of LNAs and LNA analogs has been reported to result in hepatotoxicity [135]. By contrast, it has also been reported that hepatotoxicity was significantly reduced by using shorter version of the LNAs (from 20mer to 14mer) [135]. One should be careful to calculate any property correlations in relation to a single determinant, such as length. In other words, does a property difference result from a length change or because different compounds are being compared? For instance, it was shown that a 13mer LNA was toxic, but, by adding just one LNA nt, the corresponding 14mer was nontoxic [19]. The specific composition and the nucleotide positioning (including LNA nt) is also a determinant because LNAs with the same nucleobase sequence and with different positions of the LNA in the flanks can have different hepatotoxic profiles.”, (see page 107, column 2, paragraph 2).
MicroRNA
Zhang et al (supra) teaches, “TMTME (“too many targets for miRNA effect”) is a typical and inevitable property of miRNA molecules, which is caused by incomplete complementation with the target sequence. TMTME leads to that miRNA could bind to various sequences suitable for the interaction (including protein-coding genes, lncRNA, circRNA, etc), which is different from all approved drugs (including siRNA drugs) with only a few targets… Therefore, both introduction and removal of miRNA in humans can lead to changes of a wide series of pathways and some of them are unknown, even unpredictable, probably triggering disorders of physiological function or the occurrence of additional disease.”, (Page 729, column 1, paragraph 2 to column 2, paragraph 1).
Zhang et al teaches, “Moreover, due to instability of unprotected miRNAs, delivering miRNAs required chemical modifications to avoid rapid degradation in serum, which may impair specificity of miRNAs and lead to off-target effects… Another challenge is that exogenous artificial miRNAs will trigger competition and saturation effect, a competition among exogenous and the endogenous miRNAs for the intracellular machinery, and thus affecting unexpected gene expression and leading to untoward side effects.”, (page 730, column 1, paragraph 1).
Thus, without guidance of the specification and working examples for (1) length and modifications of ASOs, siRNAs, and LNAs; (2) miRNA modifications and complete complementarity to said miRNA’s respective target; (3) the combination of both a pore-forming activity inhibitor and a nucleotide molecule; and (4) which indirect regulator is also a target to decrease expression of GSDMD, one of skill in the art would not be enabled to use the invention commensurate in scope with these claims. The art is not predictable regarding (a) an inhibitor for inhibiting the pore forming activity of GSDMD, (b) a nucleotide molecule for reducing expression of GSDMD, and (c) the combination of the two, for the treatment of aortopathy in a subject identified as having or at risk of developing an aortopathy.
Amount of experimentation necessary:
The quantity needed to carry out the scope of the invention is large. (1) one would need to test a broad subgenus of “GSDMD inhibitors for inhibiting pore-forming activity” included but not limited to testing a broad spectra of direct inhibitors such as shRNA, peptide nucleic acids (PNAs), aptamers, ADAR, TALENS, Zinc finger nucleases, biologics (e.g., monoclonal and polyclonal antibodies, nanobodies, antibody fragments), peptidomimetics, natural products, or any other small molecule. (2) one would need to test the broad subgenera of ASO, miRNA, siRNA, LNA, and guide antisense strand capable of reducing expression of GSDMD via means of directly and indirectly targeting GSDMD with and without modifications to ensure in vivo efficacy. (4) once a set of inhibitors representative of the broad genus of GSDMD inhibitors that inhibit pore-forming activity (1) and nucleotide molecules that reduce expression of GSDMD (2) has been identified, one would need to test each inhibitor in an art-accepted model of aortopathy to see if said inhibitor is capable of treating aortopathy, namely those recited in claim 13. Once molecules were identified in (1) and (2), one would need to test them in combination in an art accepted model that covers the broad genus of aortopathy, namely those in claim 13. This type of experimentation is not routine in the art and would require a large amount of inventive effort. Further considering any positive results (e.g., the successful treatment of aortopathy with the broad genus of (a) GSDMD inhibitor that inhibits pore-forming activity and/or (b) a nucleotide that reduces GSDMD expression) would amount to a significant advancement in the state of the art, additional experimentation required is considered undue.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claim(s) 1-4, 6-7, 9-10, 12-13, and 17-19 are not considered to be fully enabled, but are scoped, by the instant disclosure.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Enablement
The previous rejection of claim 5, 8, 11, 16, and 20 under 35 U.S.C 112(a) for enablement is moot in view of Applicant’s cancellation of the claim filed 07/30/2026.
With respect to the rejection of claims 1-4, 6-7, 9-10, and 12-13 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement, Applicant's arguments starting at page 10 of the reply filed 07/30/2026 have been fully considered but they are not persuasive for at least the following reasons:
Applicant contends that amended claim 1 is materially narrower than what was formerly recited and that the claims no longer present the open-ended breadth of which the prior Office Action’s undue experimentation analysis is based. Applicant contends that the specification expressly identifies drugs that inhibit GSDMD pore-forming activity, names disulfiram and necrosulfonamide (NSA), and provides a therapeutic example in which administration of disulfiram is used in an aortopathy model. These disclosures, together with the ordinary skill in the art regarding formulation and administration of known drugs, enable this branch of the claims.
Applicant contends that regarding “nucleotide molecule branch”, the ordinarily skilled artesian could design and use nucleotide-based inhibitors of the invention without undue experimentation. Applicant contends that Accession No. NM_024736 is information associated with publicly available sequence databases and is incorporated by reference, with database references referring to the most recent version of the database as of the filing date of the application unless otherwise indicated or apparent and that the target sequence for designing guide antisense strands was available to a person of ordinary skill in the art as of the filing date, and claim 7 does not require undue experimentation merely because the target sequence is identified by accession number.
Response: Regarding Applicant’s contention that amended claim 1 is materially narrower than what was previously presented, Examiner agrees that it is narrower than “reducing”, however “inhibitor that inhibits pore forming activity” is not specific for only for disulfiram (the enabled scope). Also, the amended independent claim now recites “and/or” regarding “inhibitor that inhibits pore-forming activity” and/or “nucleotide molecules to reduce GSDMD expression”, i.e., a combination, and that is also not enabled by the specification (see rewritten rejection above).
Regarding Applicant’s contention that one of skill in the art could look to the specification to make/use the “nucleotide molecule branch”, Applicant is reminded that publicly available databases, as well as essentially material, cannot be incorporated by reference (see above 35 U.S.C. 112(a) Written Description rejection for reference to 37 CFR 1.57). Thus, one of skill could not look to the specification to make or use the claimed invention. Further, it is not routine to optimize LNA’s, Hagerdon et al (supra) teaches the importance of specificity in said oligonucleotide sequence that corresponds to the LNA modification: “The higher affinity of LNAs and LNA analogs has been reported to result in hepatotoxicity [135]. By contrast, it has also been reported that hepatotoxicity was significantly reduced by using shorter version of the LNAs (from 20mer to 14mer) [135]. One should be careful to calculate any property correlations in relation to a single determinant, such as length. In other words, does a property difference result from a length change or because different compounds are being compared? For instance, it was shown that a 13mer LNA was toxic, but, by adding just one LNA nt, the corresponding 14mer was nontoxic [19]. The specific composition and the nucleotide positioning (including LNA nt) is also a determinant because LNAs with the same nucleobase sequence and with different positions of the LNA in the flanks can have different hepatotoxic profiles.”, (see page 107, column 2, paragraph 2).
Accordingly, the rejection on 35 U.S.C. 112(a) for Enablement is maintained for claim(s) 1-4, 6-7, 9-10, and 12-13.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-2, 4, 13 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (WO 2020/006229 A1; published January 2nd, 2020; listed on PTO 892 mailed 06/02/2026) in view of Napiorkowska-Baran et al (Treatment of Ruptured Infected Abdominal Aortic Aneurysm Caused by Samonella spp.: A Case Report, Infect Dis Ther, Vol 10, pages 1799-1805, published July 12, 2021; listed on PTO 892 mailed 06/02/2026). This rejection was made in the Office Action mailed 06/02/2026 and has been rewritten to include the amendments filed 07/30/2026.
Regarding claim(s) 1, 2, 4, 13, and 17-19, Wu et al teaches chemical compounds useful in inhibiting gasdermin pore formation in a cell, inhibiting inflammasome-mediated death of a cell (pyroptosis); inhibiting cytokine secretion from a cell, inhibiting an inflammatory caspase in a cell, and/or covalently reacting with a cysteine of a gasdermin protein in a cell. These compounds are also useful in treating or preventing diseases or conditions in which inflammasome activation is implicated in pathogenesis. One example of such disease or condition is sepsis (see abstract, and Figures 81-83).
Wu et al teaches, “In some instances, the compounds of the present disclosure are useful in treating or preventing a cardiovascular disease. Examples of such diseases include stroke, heart failure, . . . , aortic aneurysms, peripheral artery disease, thromboembolic disease, coronary artery disease, myocardial infarction and venous thrombosis.”, (see page 31, lines 22 to 27).
Figure 83 measures survival rates after challenge of lipopolysaccharide (LPS) utilizing disulfiram or vehicle in four different mouse genotypes: (a) wild-type, (b) Casp1-/-, (c) Casp11-/, (d) Gsdmd-/-.
More specifically, Wu et al discloses, “To investigate the in vivo effect of disulfiram, the LPS-induced sepsis was examined in C57BL/6 mice. Mice were treated with vehicle or disulfiram intraperitoneally before challenge with LPS using a drug dose (50 mg/kg) that was equivalent, after allometric scaling to account for body surface area, to 284 mg/day in humans, which is within the 125-500 mg/day dose range clinically approved to treat alcohol dependence. Whereas the lowest concentration of LPS (15 mg/kg) killed 3 of 8 control mice after 9-6 hours, all the disulfiram-treated mice survived (p = 0.045).”, (page 76, line 30-33 to page 77, lines 1-3).
Further, Wu et al teaches, “Disulfiram inhibition of GSDMD pore formation in mouse and human cells complements its activity in blocking inflammasome priming and caspase activity to suppress pyroptosis and inflammatory cytokine release triggered by both canonical and non-canonical pathways. The simultaneous targeting of three steps in the inflammasome pathway means that disulfiram, especially when given with Cu(II) to stabilize its intermediate, is an especially potent inhibitor of inflammation. . . . Its relatively weaker activity in inhibiting priming and caspases may have allowed disulfiram to be non-toxic to humans while more potent NF-kB inhibitors such as Bay 11-7082 and caspase inhibitors have both been associated with toxicity. Additionally, the non-canonical inflammasome does not require priming and in disease situations, priming of the relevant immune and epithelial cells may have already occurred by the time signs and symptoms of inflammation are clinically recognized, suggesting that inhibiting GSDMD to stop the most downstream step in pyroptosis and inflammatory mediator release will be especially useful. Finally, the relative selectivity of disulfiram is supported by the lack of activity against GSDMD of a number of other covalent Cys-reactive compounds, including the highly reactive DMF.”, (see page 78 lines, 17-33 to page 79, lines 1-2).
Wu et al does not teach identifying a subject having or at risk of developing the aortopathy.
Regarding claim 1 and 13, Napiorkowska-Baran et al teaches, “Despite significant advances in diagnostic methods, sepsis is still a current medical problem, and its complications contribute to increased mortality among different age groups. The incidence of sepsis worldwide is up to 535 cases per 100,000 person-years [1, 2]. Sepsis complications include meningitis, osteomyelitis, and endovascular changes, e.g., an aneurysm, as in the case described below.”, (see page 1800, column 1, paragraph 1).
Napiorkowska-Baran et al further teaches, “The abdominal ultrasound examination is characterised by 95% sensitivity and nearly 100% specificity in the diagnosis of this disease [12]. The lack of visualisation of the aneurysm in the ultrasound examination of the described patient (performed on admission to hospital) confirms that the aneurysm arose in the course of the infection.”, (see 1803, column 1, paragraph 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Wu et al, i.e., using disulfiram to treat diseases or conditions in which inflammasome activations is implicated in pathogenesis, such as sepsis, with the teachings of Napiorkowska-Baran et al, i.e., sepsis complications include the development of an aneurysm, to arrive at the predictable results of treating subjects identified as at risk of developing an aortopathy (e.g., an aneurysm) when presenting with sepsis. One would find a reasonable expectation of success in treating a subject identified with sepsis, whose complications could include an aneurysm (e.g., at risk) as taught by Napiorkowska-Baran et al, with a GSDMD pore-forming activity inhibitor such as disulfiram, as taught by Wu et al.
Accordingly, claim(s) 1-2, 4, 13, and 17-19, are rejected for being unpatentable over Wu et al in view of Napiorkowska-Baran et al.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claim 16 and 20 under 35 U.S.C 103 for Anticipation is moot in view of Applicant’s cancellation of the claim filed 07/30/2026.
With respect to the rejection of claims 1-2, 4, 13, and 17-19 under 35 U.S.C. 103 for being unpatentable over Wu et al (supra) in view of Napiorkowska-Baran et al (supra), Applicant's arguments starting at page 13 of the reply filed 07/30/2026 have been fully considered but they are not persuasive for at least the following reasons:
Applicant contends that Napiorkowska-Baran et al was published after the provisional application and that it does not apply as prior art.
Further, Applicant argues that the references individually do not teach the newly amended claims. Applicant argues impermissible hindsight and that Napiorkowska-Baran treats the aneurysm as an infectious complication requiring prompt diagnosis, antibiotics, and surgical/endovascular intervention. It does not identify GSDMD-mediated pore formation as a therapeutic target in aortopathy, does not connect gasdermin inhibition to prevention or treatment of aneurysm, dissection, or rupture, and does not suggest that a subject with or at risk of an aortopathy should be treated by reducing GSDMD expression or inhibiting GSDMD pore-forming activity. Applicant further contends that the amended claims also are not directed merely to treating sepsis.
Applicant further contends that the results described in the present application were unexpected and that at the time of the invention, GSDMD and pyroptosis had not been recognized as causal mediators of aortic rupture, and the field was focused on other mechanisms contributing to vascular inflammation, aneurysm formation, and disease progression. The specification shows that GSDMD inhibition had little or no effect on aneurysm formation yet prevented aortic rupture. This selective protective effect against rupture, rather than aneurysm formation, would not have been predicted from the cited art or from the prior understanding of GSDMD as a mediator of inflammatory signaling.
Lastly, Applicant contends that the nucleotide-molecule branch is even further removed from the asserted combination and that neither Wu nor Napiorkowska-Baran teaches or suggests administering an ASO, miRNA, siRNA, LNA nucleotide, guide antisense strand, or combination thereof to reduce expression of GSDMD for treating an aortopathy.
Response: Applicant’s priority is that of the PCT application, PCT/US22/34590 filed 06/22/2026 (see response to arguments involving the priority above), thus such argument regarding priority is moot.
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).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant’s contention that Napiorkowska-Baran treats the aneurysm as an infectious complication requiring prompt diagnosis, antibiotics, and surgical/endovascular intervention does not negate the fact that such infection is a risk factor for the development of an aortopathy. Further, Applicant’s contention that the amended claims are not directed merely to treating sepsis is an incorrect determination in that “risk of developing” is a broad, and Napiorkowska-baran describes sepsis as a risk factor for an aortopathy.
Lastly, Wu et al in view of Napiorkowska-Baran et al need not teach a nucleotide molecule since that is an optional embodiment of newly amended independent claim 1 as set forth by the “and/or”.
Accordingly, the rejection on 35 U.S.C. 103 for being unpatentable over Wu et al in view of Napiorkowska-Baran et al is maintained for claim(s) 1-2, 4, 13, and 17-19.
Conclusion
No claims 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEXUS M TATGE whose telephone number is (571)272-0061. The examiner can normally be reached Monday-Friday: 8:30am to 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
