DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a U.S. National Phase Application under 37 U.S.C. §371 of International Patent Application No. PCT/US23/12263, filed February 3, 2023, which claims priority to U S Provisional Patent Application No 63/306,955, filed February 4, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/01/2024 has been considered by the examiner.
Status of Claims
Claims 20-40 are pending and under examination. Claims 1-19 are canceled.
Specification
The disclosure is objected to because of the following informalities: The specification includes laudatory language. Specifically, paragraph [0071] characterizes all-trans retinoic acid (ATRA) as a “novel therapy.” Such terminology is improper because it suggests legal conclusion regarding patentability rather than objectively describing the invention. Applicant is required to delete or amend the term “novel” to remove the laudatory characterization. Appropriate correction is required.
Claim Objections
Claims 24, 25, 31, and 32 are objected to because of the following informalities:
Claim 24 recites “heart failure and/or hypertension, and/or is more than 64 years of age.” The phrase is grammatically awkward and should be revised for clarity. Suggested language: “wherein the subject has been diagnosed with heart failure, has been diagnosed with hypertension, is more than 65 years of age, or any combination thereof.”
Claim 31 recites multiple alternative dose ranges in a single claim. Although the meaning can be understood, the claim would be clearer if each dose range were presented in separate dependent claims.
Claim 32 recites “administered at a dose of from about 1 mg/kg to about 10 mg/kg.” The phrase should be corrected to” administered at a dose from about 1 mg/kg to about 10 mg/kg” or “administered at a dose of about 1 mg/kg to about 10 mg/kg.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 26, 31-32 39, and 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.
Regarding claim 26 the phrase “administered or delivered to the atrium” is indefinite because it is unclear whether the claim requires direct administration to the atrium or merely systemic administration that results in the delivery of the retinoid acid to atrial tissue. Because substantially any systemic administration of a retinoid may ultimately expose the atrium to the retinoid, the scope of “delivered to the atrium” is unclear.
Regarding claim 39 the phrase “a conduction disease” is indefinite because the claim does not specify the type of location of the conduction disease. The specification describes significantly atrial conduction disease in the context of atrial remodeling and atrial defibrillation, but the claim broadly recites “a conduction disease,” which may encompass atrial, ventricular, atrioventricular, nodal, His-Purkinje, or other conduction disorders. Therefore, the scope of the claimed disease is unclear.
Regarding claim 40, the phrase “conduction parameter(s)” is indefinite because the claim does not identify which conduction parameter is improved. The specification describes atrial conduction-related parameters such as P wave duration and left atrial conduction velocity. However, the claim broadly recites “conduction parameter(s),” which may include atrial ventricular, AV nodal, ECG, electrophysiologic, or other parameters. The parenthetical “(s)” also renders the scope of the claim unclear because it is uncertain whether one or more parameters or all parameters are required.
Claims 31 and 32 recite dosage range using the relative term “about.” Paragraph [0028] of the specification states that the allowable variation encompassed by the term “about” depends upon the particular system under study. However, the claims do not identify the particular system or otherwise provide objective boundaries from which one of ordinary skill in the art could determine the scope of the claimed dosage ranges with reasonable certainty when construed the term “about” in light of the last statement of paragraph [0028] of the specification. Accordingly, the metes and bounds of the claimed dosage range are unclear.
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 20-10 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 treating atrial fibrillation using all-trans retinoic acid in an animal TAC model, does not reasonably provide enablement for treating and/or preventing atrial arrhythmia including atrial fibrillation and atrial tachycardia in a human subject. 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 claims broadly encompass methods of preventing and/or treating atrial arrhythmia (claim 20), treating retinoid-deficient subjects (claim 21), patient diagnosed with heart failure, hypertension, and/or over 65 year of age (claim 24), atrial fibrillation (claim 28), atrial tachycardia (claim 29), prevention or reversal of atrial remodeling (claim 35-38), prevention or treatment of conduction disease (claim 39), and improving conduction parameter(s) (claim 40), using any retinoid or pharmaceutically acceptable salt thereof. The specification, however, primarily provides data from a single murine transverse aortic constriction (TAC) model using all-trans retinoic acid (ATRA) administered under a limited experimental protocol.
Wands Factor 1- Breadth of the claims
The claims are exceptional broad.
Claim 20 encompasses both prevention and treatment of arterial arrhythmia using any retinoid and any pharmaceutically acceptable salt thereof in essentially any subject, and any route of administration. Claim 36 likewise broadly encompasses prevention or reversal of atrial remodeling in any subject and any route of administration using any retinoid or pharmaceutically acceptable salt thereof. Claims 39 and 49 extend further to any condition disease and any conduction parameter. The specification does not provide working example commensurate in scope with this breadth. In contrast, the specification provides only limited experimental data involving all-trans retinoic acid in a single pressure-overload mouse model. Given the complexity and heterogeneity of atrial fibrillation recognized in the art, one of ordinary skill in the art would not reasonably conclude these limited experiments enable the entire scope of the claimed genus without substantial additional research.
Wands Factor 2-Nature of the invention
The invention concerns treatment and/or prevention of atrial arrhythmias, atrial fibrillation, atrial tachycardia, atrial remodeling, conduction disease, and improvement of conduction parameters using retinoic acid or a pharmaceutically acceptable salt thereof.
The nature of the invention is directed to treatment and prevention of complex cardiac electrophysiology disorders. As explained by Geng et al. (Front Pharmacol. 2020 Nov 9;11, article 581837, pages 1-23) teaches atrial fibrillation is the most common sustained arrhythmia, its etiology remains incompletely understood, and despite more than two centuries of arrhythmic drugs development, a preventive or curative pharmacologic therapy has not been established. (See page 5.). Thus, the claimed invention resides in a technically complex and evolving field rather than a mature or predictable technology.
Factor 3-State of the prior art
The prior art demonstrates that retinoids were not recognized as established therapies for atrial arrhythmias. Instead, McGully (Cleveland State University, Undergraduate Posters, 2018) merely proposes retinoic acid as a research tool to promote atrial-and ventricular-like cardiomyocytes for atrial fibrillation research. (See Abstract.) It does not demonstrate successful treatment or prevention of atrial arrhythmias in patients.
Likewise, Leaf et al. (US5,576,349) evaluates ATRA in murine pressure-overload models (see Examples) and does not establish clinical efficacy across the broad scope claimed.
The state of the art further demonstrates successful treatment of atrial fibrillation remains difficult. Geng reviews numerous antiarrhythmic drug classes and conclude that although many pharmacologic agents have been developed, no therapy provides a preventive or curative solution for atrial fibrillation, and available treatments primarily provide rhythm or ate control whole being associated with significant limitations and adverse effects. (See Table 4, 5, 6; page 6, last paragraph of left col.; and first paragraph of the left col.; page 5.)
Factor 4-level of predictability
The art is highly unpredictable. Tereshchenko et al. (Heart Rhythm. 2025 Feb 26;22(8): e492–e499) explains that electrophysiologic surrogate endpoints (including atrial fibrillation burden and ECG parameters) do not necessarily predict clinical benefit and may overestimate treatment effects. (See page 2; first paragraph of page 3.) Thus, improvement of fibrosis, improvement of conduction velocity, improvement of ECG findings, and improvement of inducibility, cannot reasonably be extrapolated to successful treatment or prevention of atrial arrhythmias throughout the entire scope of the claims.
Geng explains that atrial fibrillation is a heterogenous and progressive disease involving multiply underlying mechanisms and that modern therapeutic strategies continue to evolve because no single pharmacologic approach has proven broadly effective. (See right column of page 5.) Rather than supporting predictability, the prior art demonstrates that therapeutic success depends on numerous patient-and disease-specific variables. (See right column of page 10)
Wands Factor 5- Amount of guidance
The specification provides limited guidance. It describes administration of ATRA to TAC-banded mice and reports reduced fibrosis, normalized P-wave duration, improved atrial conductivity velocity, and reduced inducibility. However, the specification provides little guidance regarding other retinoids, other pharmaceutically acceptable salts, atrial tachycardia, conduction disease, conduction disorders unrelated to pressure overload, elderly human patients, hypertensive patients, and prevention in otherwise asymptomatic individuals.
Wands Factor 6- Presence of working examples
Working examples are limited. The examples concern only ATRA, murine TAC models, relative short treatment duration. No working examples are provided for atrial tachycardia, human atrial fibrillation, elder subjects, hypertensive patients, conductive disease, conduction parameter improvement independent of TAC, and other retinoic acids.
Wands Factor 7- Quantity of experimentation
Substantial experimentation would be required. A person of ordinary skill in the art need to determine, without meaningful guidance:
which retinoid is effective;
which dose is effective;
which patient population respond;
whether efficacy extends beyond TAC-induced modeling;
whether treatment prevents atrial fibrillation;
whether treatment prevents atrial tachycardia;
whether treatment improves conduction disease generally; and
whether surrogate improvements translate into meaningful clinical outcomes.
Such work would require extensive animal studies followed by human clinical
investigation.
Wands Factor 8-Relative skill in the art
Although a person of ordinary skill in the art would possess substantial expertise in
cardiovascular pharmacology and electrophysiology, such skill cannot substitute for the absence of an enabling disclosure where the claims encompass broad therapeutic methods in an unpredict able art.
Additional evidentiary support
Atrial tachycardia (claim 29), Banderowicz et al. (Forum Dermatologicum 2024, vol. 10, No. 1, 10-17) reports that systemic retinoic acid treatment has been associated with atrial tachycardia adverse effects. (See last paragraph of the left col. Page 14.) Thus, the prior art raises questions regarding whether systemic administration of retinoic acid would successfully treat atrial tachycardia across the full scope of the claim. The specification provides no working example demonstrating treatment of atrial tachycardia.
Prevention embodiment
Isakadze et al. (J Atr Fibrillation. 2018 Oct 31;11(3):2051) explains that prevention of atrial fibrillation remains an unresolved clinical challenge and that currently available evidence does not establish reliable prevention across the broad patient population. (See Abstract; left col. First para. Page 5.) Accordingly, the specification’s single murine TAC model does not reasonably enable the broad prevention method recited in claims 20 and 35.
Treatment embodiment
Tereshchenko et al. explains that surrogate electrophysiologic endpoints-including arrhythmia burden and ECG parameters-do not necessarily predict true clinical benefit and may overestimate treatment effects. Accordingly, the specification’s reliance upon impartments in surrogate endpoints such as P-wave duration, conduction velocity, fibrosis, and inducibility does not reasonably enable treatment of atrial arrhythmia throughout the full scope of the claims.
Conclusion
In view of the exceptional broad claim scope, the highly unpredictable nature of cardiac electrophysiology, the limited murine working examples, the absence of example across the claimed patient population and disease states, the lack of guidance for retinoids other than ATRA, the uncertainty surrounding prevention of atrial arrhythmia, and the recognition in the prior art that surrogate electrophysiologic endpoints do not necessarily establish clinical efficacy, one of ordinary skill in the art would be required to engage in undue experimentation to practice the full scope of claims 20-40. Therefore, the specification does not comply with the enablement requirement of 35 U.S.C 102(a).
Conclusion
Claims 20-40 are not allowed.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628
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