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 .
DETAILED ACTION
This Office Action is responsive to the Response to Election/Restriction filed 09/18/2025.
The Amendment filed 12/22/2022, amended claims 1, 4-5, 7-11, 28-40, 61-65 and cancelled claims 2-3, 15-37, 41-60, 62, and 66-69.
Claims 1, 4-14, 38-40, 61, and 63-65 are pending.
Priority
This application claims the following priority:
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Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: “Fig. 17B.” Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See, for example, [00257] of the specification.
Election/Restrictions
Applicant’s election without traverse of Group I, a method of use, and COVID-19 as the disease; APX-115 as the species of a compound that inhibits endothelial injury; AG-1031, as the compound that promotes endothelial regeneration and inflammation; and c) a SIRT1 inhibiting nucleic acid (a compound that promotes endothelial regeneration and vascular repair) as the species of an expressing or inhibiting nucleic acid, in the reply filed on 09/18/2025, is acknowledged.
In the course of the search, the election of species requirement for a compound that promotes endothelial regeneration and inflammation was extended to rabeprazole.
In the course of the search, the election of species requirement for a compound that inhibits endothelial injury was extended to dexamethasone.
Claims 4-6, 9-12, 14, 61, and 63-65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and subject matter, there being no allowable generic or linking claim.
Note: Claims 11-12 are withdrawn, because a)-d) in claim 11 are compounds that promote endothelial regeneration, and e) is a compound that inhibits endothelial injury and inflammation. However, none of these nucleic acids were elected as the compounds that promote endothelial regeneration, or the compound that inhibits endothelial injury and inflammation
Claims 1, 7-8, 13, and 38-40 are examined on the merits herein.
Claim Objections
Claims 1 and 8 objected to because of the following informalities:
-In claim 1, part (i), prior to “organ failure,” the phrase - -COVID-19-related- -, should be inserted.
-In claim 1, part (iii), the term “impaired” should be inserted prior to “vascular repair” in line 2, and prior to “vascular regeneration” in line 2.
-In claim 8, line 5, the term “and” prior to “Sirtuin 1,” should be deleted, and a comma should be inserted. See MPEP 2173.05(h) for guidance on proper Markush language.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1, 7, 8, 13, and 38-40 are 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.
-In claim 1, part (ii), it is not clear if the phrase “characterized by increased lung microvascular permeability,” is only describing “infection-induced organ failure,” or if this phrase is describing “sepsis, ARDS, acute inflammatory injury, and infection-induced organ failure.”
In view of compact prosecution, for the purpose of applying prior art, this phrase is interpreted as only describing “infection-induced organ failure.”
-In claim 1, part (iii), the Markush language renders the claim indefinite. A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group “consisting of” (rather than “comprising” or “including”) the alternative members (MPEP 2173.03(h)(I). Claim 1(iii) recites “one or more of vascular diseases associated with impaired endothelial regeneration, vascular repair, and vascular regeneration,” and also recites “including restenosis following percutaneous coronary intervention, peripheral vascular diseases including critical limb ischemia, in a subject in need thereof.” The phrase “one or more of” denotes a closed Markush group while the term “including” is inclusive or open-ended and does not exclude additional, unrecited elements or methods steps (MPEP 2111.03(I)).
Alternatively, it is not clear if the “including clauses” are exemplary of vascular regeneration and peripheral vascular diseases, or if the diseases recited following the “including clauses” are Markush group members.
Moreover, it is not clear if “peripheral vascular diseases” is part of the “one or more vascular diseases” or if it is part of the “including” clause that begins in line 2 of (ii).
As such, the metes and bounds of this claim are unclear.
In view of compact prosecution, for the purpose of applying prior art, (iii) is interpreted as “one or more of vascular diseases associated with impaired endothelial regeneration, impaired vascular repair, and impaired vascular regeneration.”
-In claim 7, the Markush language renders the claim indefinite. Lines 1-3 recite “wherein the compound that inhibits endothelial injury and inflammation comprises one or more compounds selected from the group consisting of. . .Resveratrol-loaded nanoparticles comprising of poly(D,L-lactic-co-glycolic acid). . .). . .” The combination of open-ended language and closed language renders the claim indefinite; the metes and bounds of the Markush group and the claim, in general, are unclear.
-In claim 7, the phrases "(e.g., Thienopyridine, NOX2ds-tat,),” “(e.g., Apocynin, Ebselen, APX-115),” “(trans-E-resveratrol),” “(e.g., Resveratrol-loaded nanoparticles comprising of poly(D,L-lactic-co-glycolic acid) (PLGA)-b-long linker poly(ethylene glycol)(e.g., PEG MW2000, 5000Da) copolymer or poly (D,L-lactic acid) (PLA)-b-PEG (e.g., PEG2000, 5000Da) copolymer, and NOX2 inhibiting nucleic acid,” render the claim indefinite because it is unclear whether these limitation(s) are part of the claimed invention or merely exemplary, and therefore not further limiting the claim. See MPEP § 2173.05(d).
In view of compact prosecution, for the purpose of applying prior art, these phrases are interpreted as exemplary and as not further limiting the claim.
-Further regarding claim 7, beginning in line 5, it is not clear where the phrase (e.g., Resveratrol-loaded nanoparticles. . .” ends since there is no closing parenthesis denoting the end of this “e.g.,” phrase.
Claim 7 is interpreted as the method of claim 1 part(i) or part (ii), wherein the compound that inhibits endothelial injury and inflammation is selected from the group consisting of dexamethasone, N-acetyl cysteine (NAC), NOX2 inhibitors, pan-NOX inhibitors, resveratrol nanoparticles and analogues thereof, and NOX2 inhibiting nucleic acid.
-In claim 8, the Markush language renders the claim indefinite. Lines 1-3 recite “wherein the compounds that promotes endothelial regeneration and vascular repair comprises one or more compounds selected from the group consisting of. . .” The combination of open-ended language and closed language renders the claim indefinite; the metes and bounds of the Markush group and the claim, in general, are unclear.
-In claim 8, the phrases "(e.g., Dacogen, INQOVI,),” “(e.g., Vidaza, ONUREG),” “(trans-E-resveratrol),” “(e.g., Selisistat and its analogues, AG-1031 and its analogues,” “(e.g., Aciphex), and (e.g., Pyridium),” renders the claim indefinite because it is unclear whether these limitation(s) are part of the claimed invention or merely exemplary, and therefore not further limiting the claim. See MPEP § 2173.05(d).
In view of compact prosecution, for the purpose of applying prior art, these phrases are interpreted as exemplary and as not further limiting the claim.
-In claim 13, the phrases "(NOX2ds-5q5),” and “(Dacogen, INQOVI, Vidaza, ONUREG),” renders the claim indefinite because it is unclear whether these limitation(s) are part of the claimed invention or merely exemplary, and therefore not further limiting the claim. See MPEP § 2173.05(d).
In view of compact prosecution, for the purpose of applying prior art, these phrases are interpreted as exemplary and as not further limiting the claim.
-Claims 8 and 13 contain the trademark/trade names “Dacogen,” “INQOVI,” “Vidaza,” “ONUREG,” “Aciphex,” and “Pyridium.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe decitabine and analogs thereof, rabeprazole, and phenazopyridine, and, accordingly, the identifications/descriptions are indefinite.
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
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.
Claims 1, 7-8, 13, and 38-40 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.
To satisfy the written description requirement, 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. See MPEP 2163.
The instant specification does not provide sufficient written description of the following:
-one or more of vascular diseases associated with impaired endothelial regeneration, vascular repair, and vascular regeneration,
-a compound that inhibits endothelial injury and inflammation,
-a compound that promotes endothelial regeneration, vascular repair, and optionally resolution of inflammation,
-a rabeprazole nanoparticle analogues,
-a decitabine analogue,
-Sirtuin1 inhibitor analogues,
-AG-1031 analogues,
-SIRT1 inhibiting nucleic acid,
-rabeprazole analogue,
-a phenazopyridine analogue,
-EGLN1 inhibiting nucleic acid,
-HIF1alpha expressing nucleic acid, and
-FOXM1 expressing nucleic acid.
The instant specification does not provide a representative number of species of the above diseases, compounds or analogues.
The instant specification provides zero examples of rabeprazole nanoparticle analogues, Sirtuin1 inhibitor analogues, AG-1031 analogues, SIRT1 inhibiting nucleic acids, rabeprazole analogues, a phenazopyridine analogues, EGLN1 inhibiting nucleic acids, HIF1alpha expressing nucleic acids, or FOXM1 expressing nucleic acids.
The instant specification provides one species of decitabine analogue (per PubChem, Vidaza and ONUREG are synonyms, PTO-892).
The instant specification provides one species of SIRT1 inhibition nucleic acid, Sirtuin 1 siRNA ([0089] of the PGPUB 2023/0248706). And while the instant specification also teaches NOX2 siRNA as an exemplary therapeutic inhibitory nucleic acid, it does not teach NOX2siRNA as a SIRT1 inhibiting nucleic acid, a EGLN1 inhibiting nucleic acid, HIF1 alpha expressing nucleic acid, or a FOXMI expressing nucleic acid ([0089] of the PGPUB 20230248706).
The instant specification provides two examples of vascular diseases associated with impaired endothelial regeneration, vascular repair, and vascular regeneration. These diseases are a) restenosis following percutaneous coronary intervention, and b) critical limb ischemia.
Restenosis is a narrowed coronary artery that develops from scar tissue that forms under a stent in people who have undergone angioplasty (pg. 1; Cleveland Clinic, In-Stent Restenosis, PTO-892).
Critical limb ischemia is a severe stage of peripheral artery disease, in which there is significant blockages in the blood flow to arms, legs, and feet, increasing the risk of heart complications (pg. 1; Cleveland Clinic, Critical Limb Ischemia, PTO-892).
While both these diseases affect arteries, these diseases are distinct in etiology, disease progression, clinical manifestations, and physiological effects. As such, in view of the limited diseases taught by the instant specification in comparison to the vast number of diseases encompassed by “vascular diseases associated with impaired endothelial regeneration, vascular repair, and vascular regeneration,” it is impossible to determine which diseases are vascular diseases associated with impaired endothelial regeneration, vascular repair, and vascular regeneration, and which vascular diseases are not vascular diseases associated with impaired endothelial regeneration, vascular repair, and vascular regeneration.
The instant specification teaches the following compounds as “a compound that inhibits endothelial injury and inflammation”—dexamethasone, N-acetyl cysteine, NOX2 inhibitors such as thienopyridine and NOX2ds-tat, pan-NOX inhibitors such as apocynin, ebselen, APX-115, and resveratrol nanoparticles.
These compounds have distinct chemical structures. See, for example, dexamethasone, N-acetyl cysteine, and ebselen.
Dexamethasone
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N-acetyl cysteine
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Ebselen
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In view of the distinct structures of the above exemplified compounds, and in view of the specific forms required by some of the compounds, such as nanoparticles, it is impossible to determine a structure-function relationship that is critical to characterize a compound as “a compound that inhibits endothelial injury and inflammation.”
The instant specification teaches the following compounds as “a compound that promotes endothelial regeneration and vascular repair”—decitabine, Roxadustat, molidustat, vadadustat, desidustat, sirtuin inhibitors such as selisistat, AG-1031, rabeprazole, phenazopyridine, EGLN1 inhibiting nucleic acid, Sirtuin1 inhibiting nucleic acid, HIF1alpha expressing nucleic acid, and FoxM1 expressing nucleic acid.
These compounds have distinct chemical structures. See, for example, decitabine, N- rabeprazole, and roxadustat.
Decitabine
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In view of the distinct structures of the above exemplified compounds, and in view of the fact that some of these compounds are nucleic acids, it is impossible to determine a structure-function relationship that is critical to characterize a compound as “a compound that promotes endothelial regeneration and vascular repair.”
Regarding the recited analogues, Cannon (Burger’s Medicinal Chemistry and Drug Discovery, 6th ed, 2003, PTO-892) teaches that in analog design, molecular modification of the lead compound can involve one or more of bioisosteric replacement, design of rigid analogs, homologation of alkyl chains or alteration of chain branching, design of aromatic ring-position isomers, alteration of ring size, substitution of an aromatic ring for a saturated one, alteration of stereochemistry, design of geometric isomers or stereoisomers, design of fragments of the lead molecule that contain the pharmacophoric group, and alteration of interatomic distances within the pharmacophoric group or in other parts of the molecule. Cannon teaches that a combination of these strategies to the lead molecule may be advantageous. Cannon further teaches that considering the possible permutations and combinations of these changes that are possible within a single lead molecule, the number of analogs that can be designed from a lead molecule is extremely large (pg. 689).
Fisher (Analog based Drug Discovery, PTO-892) teaches that the term analogue is a drug whose structure is related to that of another drug but whose chemical and biological properties may be quite different (pg. XXIII). Fisher teaches several types of analogs:
-Structural and Pharmacological analogues which have similar chemical structures, and a similar main pharmacological activity (pg. XXIII),
-Structural analogues which have a similar chemical structure but have quite different pharmacological properties (pg. XXIV), and
-Pharmacological analogues which have a similar pharmacological activity without having any discernible chemical or structural relationship (pg. XXIV).
In view of these teachings, drug analogues do not necessarily share a common structure, and if they do share a common structure, they do not necessarily share the same pharmacological activity.
Thus, it is impossible to determine a structure-function relationship between the recited compounds and their analogues that is critical to impart their function as a compound that inhibits endothelial injury and inflammation, or a compound that promotes endothelial regeneration and vascular repair.
The instant specification provides zero examples of a method of treating a disease by administering the instantly claimed compounds. Moreover, the instant specification only provides examples utilizing mice models with lung inflammation which have been administered the following compounds—decitabine, resveratrol, N-acetyl cysteine, thienopyridine, dimethyloxalylglycine, and rabeprazole (See Examples 1-10, beginning in [0112] of the specification].
Example 1 concludes that aging impairs intrinsic endothelial regeneration and vascular repair leading to persistent inflammatory lung injury following sepsis challenge and that therapeutic restoration of FoxM1 expression can reactivate vascular repair and resolution of inflammatory injury in aged mice ([0117]). Example 1 states “therapeutic activation of FoxM1 expression by delivery of FOXM1 expressing nucleic acid or pharmacological drugs may represent an effective approach to restore the endothelial barrier integrity and reverse lung edema in the prevention and treatment of COVID-19 and COVID-19 respiratory distress and multi-organ failure, sepsis, and ARDS as well as vascular disease with diminished FOXM1 expression including but not limited to restenosis and critical limb ischemia in elderly patient and adults patients” ([00163]).
Example 2 shows that rabeprazole treatment results in a recovery of vascular permeability in aged mice with endotoxemia and inflammatory injury and that rabeprazole can activate FoxM1 expression in the lung in aged mice following sepsis challenge. Example 2 also shows that phenazopyridine promotes vascular repair in aged mice. Example 2 concludes that “combination of rabeprazole or its analogue with Phenazopyridine or its analogue can be repurposed for treatment of vascular diseases associated with impaired HIF1a signaling and/or diminished FOXM1 expression including but not limited to restenosis, and critical limb ischemia” ([00217]).
Example 3, beginning in [00222], is a prophetic example that states that “EGLN1 inhibitors. . .and Egln1 inhibiting nucleic acid inducing but not limited to antisense oligo, is RNA, shRNA guide RNA are novel therapeutic agents to re-activate FoxM1-dependent vascular repair in aged subjects for treatment of COVID-19. . .and multi-organ failure” ([00223]).
Example 4, beginning in [00234] challenges aged mice with LPS and then treats it with dimethyloxalylglycine (DMOG), wherein vascular permeability and lung inflammation activity (MPO) in DMOG-treated mice was returned to the levels seen in basal mice. Roxadustat is also shown in aged mice to inhibit MPO activity and induce FoxM1 expression ([00235]).
Example 5, beginning in [0238] administering EX-527, selisistat to 20month old mice challenged with LPS. Vascular permeability in aged mice treated with EX-527 was at a basal level in contrast to control mice. Similarly, MPO activity in EX-527 treated mice also returned to basal levels and EX-527 treatment reactivated FoxM1 expression in aged mice lungs.
Example 6, beginning in [00246] teaches that aging exaggerates inflammatory lung injury.
Example 7, beginning in [00258] teaches that to gain insight into the role of NOX2 and NOX4, a CRISPR/Cas9-mediated genome editing approach to knock down their expression in aged mice was employed, and lung tissue was then collected. NOX2 and NOX4 protein expression was knocked down by NOX2 and NOX4 guide RNA. [00260] teaches that “these data. . .demonstrate that aging-dependent increase of NOX2 expression in lung ECs are responsible for the augmented inflammatory lung injury in aged mice in response to LPS challenge whereas NOX4 is protective.” [00260] then hypothesizes that specific compounds would be effective to treat COVID-19, COVID-19 sepsis, COVID-19 respiratory distress and multi-organ failure, sepsis ARDS, and multi-organ failure in elderly patients.
Example 8, beginning in [00266] teaches that NAC treatment normalizes inflammatory lung injury in aged mice to the levels similar to young mice ([00268]).
Example 9, beginning in [00271] teaches treating septic mice with resveratrol nanoparticles comprised of PLGA, PLGA-PEG600, or PLGA-PEG2000, wherein this treatment inhibiting inflammatory lung injury.
Example 10, beginning in [00273] teaches that decitabine has no effect on sepsis-induced lung injury in young adult mice. However, lung MPO activity of decitabine treated aged mice returned to basal levels. However decitabine treatment did not promote vascular repair and inflammation resolution in young adult mice ([00276]).
Thus, the instant examples provide less than ten structurally distinct species compounds, none of which are specifically described as “inhibiting endothelial injury and inflammation” or “promoting endothelial regeneration, vascular repair, and optionally resolution of inflammation.”
For these reasons, claims 1, 7, 8, 13 and 38-40 are broader than what the specification supports. The recitation of anything other than:
A method of treating
one or more of COVID-19, COVID-19 related sepsis, COVID-19-related respiratory distress and organ failure in a subject in need thereof, or
one or more of sepsis, ARDS, acute inflammatory injury, and infection-induced organ failure characterized by increased lung microvascular permeability in a subject in need thereof, or
one or more of restenosis following percutaneous coronary intervention or critical limb ischemia, in a subject in need thereof,
wherein the method comprises administering to the subject an effective amount of (a) dexamethasone, NAC, NOX2 inhibitors, pan-NOX inhibitors, and resveratrol nanoparticles, and/or (b) rabeprazole, phenazopyridine, selisistat, AG-1031, decitabine, or NOX2 siRNA,
is not sufficient for distinctly claiming the subject matter regarded as the invention.
Claim Rejections - 35 USC § 112(a)-Scope of 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.
Claims 1, 7-8, 13, and 38-40 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 COVID-19 by administering APX-115, rabeprazole, dexamethasone, and a method of treating lung inflammation in an elderly subject by administering rabeprazole, dimethyloxalylglycine, selisistat, NAC, resveratrol nanoparticles, and NOX2 siRNA, does not reasonably provide enablement for
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. 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.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
Independent claim 1 recites:
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, i.e., the treatment of one of or a combination of five specific disease and four general disease by administering one or two generically described compounds.
As such, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a clinical or an artisan with a PhD.
State of the Prior Art
WHO (World Health Organization, “Clinical Management of COVID-19,” Interim Guidance, published May 2000, IDS of 04/10/2023) teaches dexamethasone as a palliative care medicine for patients with COVID-19 (pg. 54).
WO 2021/226532 to Rogers (effectively filed May 2020, PTO-892) teaches translation blockers repurposed for COVID-19 therapy by administering an effective amount of a benzimidazole (title, abstract).
Rogers specifically teaches a method of treating a subject who has an infection with a coronavirus or a method for reducing the risk of infection, severity of infection, with a coronavirus, the method comprising administering an effective amount of a benzimidazole, wherein the benzimidazole is the benzimidazole antacid, rabeprazole (claims 6-8).
Rogers teaches the coronavirus as SARS-CoV-2 (pg. 19, claim 2).
Shin (Dorean Pharmaceutical Company AptaBio Has Been Proved Effective in Treating COVID-19 With Its Apx-115, Acrofan, published April 2000, IDS of 04/10/2023) teaches a method of treating COVID-19 with Apx-115, a NADPH oxidase (NOX) enzyme inhibitor (title, 2nd paragraph).
Thus, the prior art teaches specific species of compounds for the treatment of a specific disease.
Predictability in the Art
Dong (Current COVID-19 treatments: Rapid review of the literature, PTO-892) teaches that there is no single therapy effective against COVID-19. Dong teaches that a combination of therapies administered at different stages of infection may provide some benefit (pg. 1, abstract). Dong teaches remdesivir, convalescent plasma, hydroxychloroquine/chloroquine, lopinavir, ritonavir, ribavirin, interferon, corticosteroids, and monoclonal and polyclonal antibodies, as active agents that have been studied to treat COVID-19. However, none of these treatments were shown to be effective, and many were discontinued or had adverse effects (Table 2, beginning on pg. 5).
Gauer (Sepsis: Diagnosis and Management, AAFP, published 2020, PTO-892) teaches that sepsis is the leading cause of death among adults in intensive care units. While medical advances over the past decade have significantly improved survival, mortality rates remain between 20% and 36% (pg. 401, 1st paragraph).
Gauer teaches that despite scientific advances over the past 20 years, the management of sepsis remains largely unchanged The main difference is the concept of bundles, which are multiple interventions that should be completed within a specified time frame (pg. 410, “Overall Approach”). Treatments included fluid resuscitation, antimicrobial therapy, vasopressor therapy, and other interventions (pgs. 412-415).
Thus, Dong and Gauer teach that the art of treating diseases, such as instantly claimed COVID-19 and sepsis, is unpredictable, and further teaches that both diseases are treated by administering a combination of treatments, and not a single pharmacological agent.
Working Examples
The instant specification provides zero examples of a method of treating a disease by administering the instantly claimed compounds. Moreover, the instant specification only exemplifies methods of treating CLP or LPS mice or Foxm1 transgenic mice by administering the following compounds—decitabine, resveratrol, N-acetyl cysteine, thienopyridine, dimethyloxalylglycine, and rabeprazole (See Examples 1-10, beginning in [0112] of the specification].
Example 1, concludes that aging impairs intrinsic endothelial regeneration and vascular repair leading to persistent inflammatory lung injury following sepsis challenge and that therapeutic restoration of FoxM1 expression can reactivate vascular repair and resolution of inflammatory injury in aged mice ([0117]). Example 1 states “therapeutic activation of FoxM1 expression by delivery of FOXM1 expressing nucleic acid or pharmacological drugs may represent an effective approach to restore the endothelial barrier integrity and reverse lung edema in the prevention and treatment of COVID-19 and COVID-19 respiratory distress and multi-organ failure, sepsis, and ARDS as well as vascular disease with diminished FOXM1 expression including but not limited to restenosis and critical limb ischemia in elderly patient and adults patients” ([00163]).
Example 2 shows that rabeprazole treatment results in a recovery of vascular permeability in aged mice with endotoxemia and inflammatory injury and that rabeprazole can activate FoxM1 expression in the lung in aged mice following sepsis challenge. Example 2 also shows that phenazopyridine promotes vascular repair in aged mice. Example 2 concludes that “combination of rabeprazole or its analogue with Phenazopyridine or its analogue can be repurposed for treatment of vascular diseases associated with impaired HIF1a signaling and/or diminished FOXM1 expression including but not limited to restenosis, and critical limb ischemia” ([00217]).
Example 3, beginning in [00222], is a prophetic example that states that “EGLN1 inhibitors. . .and Egln1 inhibiting nucleic acid inducing but not limited to antisense oligo, is RNA, shRNA guide RNA are novel therapeutic agents to re-activate FoxM1-dependent vascular repair in aged subjects for treatment of COVID-19. . .and multi-organ failure” ([00223]).
Example 4, beginning in [00234] challenges aged mice with LPS and then treats it with dimethyloxalylglycine (DMOG), wherein vascular permeability and lung inflammation activity (MPO) in DMOG-treated mice was returned to the levels seen in basal mice. Roxadustat is also shown in aged mice to inhibit MPO activity and induce FoxM1 expression ([00235]).
Example 5, beginning in [0238] administering EX-527, selisistat to 20month old mice challenged with LPS. Vascular permeability in aged mice treated with EX-527 was at a basal level in contrast to control mice. Similarly, MPO activity in EX-527 treated mice also returned to basal levels and EX-527 treatment reactivated FoxM1 expression in aged mice lungs.
Example 6, beginning in [00246] teaches that aging exaggerates inflammatory lung injury.
Example 7, beginning in [00258] teaches that to gain insight into the role of NOX2 and NOX4, a CRISPR/Cas9-mediated genome editing approach to knock down their expression in aged mice was employed, and lung tissue was then collected. NOX2 and NOX4 protein expression was knocked down by NOX2 and NOX4 guide RNA. [00260] teaches that “these data. . .demonstrate that aging-dependent increase of NOX2 expression in lung ECs are responsible for the augmented inflammatory lung injury in aged mice in response to LPS challenge whereas NOX4 is protective.” [00260] then hypothesizes that specific compounds would be effective to treat COVID-19, COVID-19 sepsis, COVID-19 respiratory distress and multi-organ failure, sepsis ARDS, and multi-organ failure in elderly patients.
Example 8, beginning in [00266] teaches that NAC treatment normalizes inflammatory lung injury in aged mice to the levels similar to young mice ([00268]).
Example 9, beginning in [00271] teaches treating septic mice with resveratrol nanoparticles comprised of PLGA, PLGA-PEG600, or PLGA-PEG2000, wherein this treatment inhibiting inflammatory lung injury.
Example 10, beginning in [00273] teaches that decitabine has no effect on sepsis-induced lung injury in young adult mice. However, lung MPO activity of decitabine treated aged mice returned to basal levels. However decitabine treatment did not promote vascular repair and inflammation resolution in young adult mice ([00276]).
Thus, the instant examples provide less than ten structurally distinct species, none of which are specifically described as “inhibiting endothelial injury and inflammation” or “promoting endothelial regeneration, vascular repair, and optionally resolution of inflammation” for the treatment of mice characterized by lung inflammation
Direction and Guidance
In view of the unpredictability in the art, the great breadth of the claims, and the lack of working examples, the specification does not provide sufficient direction or guidance to enable an ordinary skilled artisan to use the instant invention as claimed.
Quantity of Experimentation
In view of the great number of diseases and compounds claimed, and combinations thereof, the amount of experimentation required would be astronomical. This amount of experimentation is undue and amounts to invention, not development.
As such, while being enabled for a method of treating COVID-19 by administering APX-115, rabeprazole, dexamethasone, and a method of treating lung inflammation in an elderly subject by administering rabeprazole, dimethyloxalylglycine, selisistat, NAC, resveratrol nanoparticles, and NOX2 siRNA, the instant specification does not reasonably provide enablement for
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Claim Rejections - 35 USC § 102
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 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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 7, and 38-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WHO (World Health Organization, “Clinical Management of COVID-19,” Interim Guidance, published May 2000, IDS of 04/10/2023).
Regarding claims 1 and 7, WHO teaches dexamethasone as a palliative care medicine for patients with COVID-19 (pg. 54).
Regarding claims 38-39, WHO teaches the palliative care for COVID-19 for adults and pediatric patients and their families (pg. 46), and teaches the care for humans in Table A3.1 (pg. 54).
Claims 1, 8, 13 and 38-39 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2021/226532 to Rogers (effectively filed May 2020, PTO-892).
Rogers teaches translation blockers repurposed for COVID-19 therapy by administering an effective amount of a benzimidazole (title, abstract).
Rogers specifically teaches a method of treating a subject who has an infection with a coronavirus or a method for reducing the risk of infection, severity of infection, with a coronavirus, the method comprising administering an effective amount of a benzimidazole, wherein the benzimidazole is the benzimidazole antacid, rabeprazole (claims 6-8).
Rogers teaches the coronavirus as SARS-CoV-2 (pg. 19, claim 2), wherein Rogers states “The methods can be used to treat subjects who have, or have been diagnosed with, infection with SARS-CoV-2 (i.e., COVID-19),” (pg. 6, lines 27-30).
Regarding claims 38-39, while Rogers does not explicitly name the subject as a human, the subject is a human. See pg. 1, lines 20-25, wherein the compounds are taught as FDA pre-approved and novel drugs. See pg. 1 that discusses the widespread infection of SARS-CoV-2 causing the COVID-19 pandemic “challenging healthcare an economic systems worldwide,” and that there is no successful treatment, and see pg. 2 which teaches the inventive drugs as reducing infectivity and can thus be used to treat infections, as well as reduce the risk of infection, with SARS-CoV-2, in treating subjects. As such, these limitations are met.
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 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable WHO (World Health Organization, “Clinical Management of COVID-19,” Interim Guidance, published May 2000, IDS of 04/10/2023).
WHO is applied to claims 1, 7, and 38-39 as discussed above and incorporated herein.
While WHO teaches a method of treating COVID-19 by administering dexamethasone, it differs from that of instant claim 40 in that it does not teach the subject as at least 60 years old.
WHO teaches that known risk factors for rapid deterioration, severe disease, and/or increased mortality is older age, greater than 60 years old (pg. 13), and that older age has been reported as a risk factor for increased mortality in those affected by COVID-19. WHO teaches that older people be screened for COVID-19 at the first point of access to the health system, be recognized promptly if they are suspected to have COVID-19 and treated appropriately according to established COVID-19 care pathways, and that this should occur in all settings where older people may seek care (pg. 45, pg. 50).
WHO further teaches that over 20% of adults over 60 years have pre-existing mental or neurological conditions for which they may already be taking medications before infection and that a clinician must consider how these medications may affect such a patient’s COVID-19 symptoms (pg. 45).
WHO teaches that older people who experience COVID-19 are more likely to experience pronounced functional decline and require coordinated rehabilitation care after acute hospitalization, and teaches that chronic infections must be diagnosed and treated appropriately in older people (pg. 46).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select a subject at least 60 years old as the patient in the methods of WHO, to arrive at instant claim 40. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-WHO teaches that an age greater than 60 is a known risk factor for rapid deterioration, severe disease, and/or increased mortality in patients with COVID-19.
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at an effective method of treating COVID-19 in a patient population known as at risk for severe disease, rapid deterioration, and increased mortality.
Claims 1, 7, 13, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Shin (Dorean Pharmaceutical Company AptaBio Has Been Proved Effective in Treating COVID-19 With Its Apx-115, Acrofan, published April 2000, IDS of 04/10/2023).
Shin teaches a method of treating COVID-19 with Apx-115, a NADPH oxidase (NOX) enzyme inhibitor (title, 2nd paragraph).
Shin teaches that through cell experiments, APX-115, has been proved effective in treating COVID-19 (2nd paragraph). In the process of virus penetration, APX-115 hinders the enzyme NOX2 in the endosome and inhibits reactive oxygen species, thereby preventing viral migration the endosome and inhibits reactive oxygen species, thereby preventing viral migration through the endosome and infecting cell (3rd and 4th paragraphs).
Regarding claims 1 and 38, while Shin teaches a method of treating COVID-19 with Apx-115, it does not explicitly teach administering APX-115 to a subject.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select human patients as subjects treated for COVID-19 with APX-115, to arrive at instant claim 1 and 38. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because Shin teaches APX-115 for COVID-19 patients as planning to undergo phase 2 clinical trials.
As such, an ordinary skilled artisan would reasonable expect that administering APX-115 to a human subject would treat COVID-19.
Claims 1, 8, 13, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over Blanc (Interest of proton pump inhibitors in reducing the occurrence of COVID-19: a case-control study, Preprints, published May 2020, PTO-892).
Blanc teaches proton pump inhibitors (PPIs) as reducing the occurrence of COVID-19 and as a preventive treatment of COVID-19 in elderly patients (title, abstract). Blanc teaches proton pump inhibitors as lowering the risk of development of COVID-19 infection (conclusion). Taking PPIs is associated with a 2.3 fold reduction in the risk of COVID-19 (lines 188-189).
Blanc teaches rabeprazole as a proton pump inhibitors (lines 161-168).
Regarding claims 1, 8, and 13, while Blanc teaches PPIs, such as rabeprazole, as lowering the risk in developing COVID-19, Blanc does not teach a method of treating COVID-19 by administering rabeprazole.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, select administration of rabeprazole to patients with COVID-19, to arrive at instant claims 1, 8 and 13. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Blanc teaches PPIs such as rabeprazole as being associated with a 2.3 fold reduction in the risk of COVID-19.
As such, an ordinary skilled artisan would have been motivated to make such a selection to predictably arrive at a therapeutically effective method of treating COVID-19.
Regarding claims 8 and 13, Blanc teaches rabeprazole.
Regarding claims 38-40, Blanc teaches its patients as elderly and as people over 60 years of age (lines 9-11, 12, 15-16, 29-32, 54-62, 70-74, 161-170, 188-211).
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622