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
The present application is a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US2022/082197, filed October 22, 2022, and published under PCT Article 21(2) in English, which claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 63/293,874, filed December 27, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/15/2026 has been considered by the examiner.
Status of Claims
Claims 1-10 are pending and under examination.
Claim Objections
Claims 1-2 are objected to because of the following informalities: claim 1 and 2 recited “wherein the compound” utilize terminology inconsistent with the antecedent phrase “α1 A-adrenergic receptor antagonist compound” previously introduced in claim 1. While the intended antecedent basis is understood, Applicant is required to amended the claims to provide consistent terminology throughout the claims and to improve clarity. 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.
Claim 5 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.
Claim 5 recites that the stress-related disorder is selected from the group consisting of “post-traumatic stress disorder (PTSD), an anxiety disorder, and an agitation/disruptive/aggression behavior associated with dementia.”
The phrase “agitation/disruptive/aggression behavior associated with dementia” renders the metes and bounds of the claim unclear because it is not reasonably certain whether the slash notation is intended to denote agitation associated with dementia, disruptive behavior associated dementia, aggressive behavior associated with dementia combinations thereof, or some other underlined grouping of behavioral symptoms. Accordingly, one of ordinary skill in the art would not be reasonably apprised of the scope of the claimed subject matter.
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 1-10 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 the administration of RS-17053, silodosin and tamsulosin as the α1A-adrenergic receptor antagonist compounds for preventing or attenuating stress-induced special working memory impairment in an experimental stress paragdigm, does not reasonably provide enablement for treatment, prevention, cure, healing or amelioration of the claimed disorders themselves across the full scope of the claims.
Claim 1 is directed to a method of treating, ameliorating, or preventing a stress-related disorder in a subject by administering a therapeutically effective amount of a selective α1A-adrenergic receptor antagonist compound. Claim 5 further specifies that the stress-related disorder may comprise post-traumatic stress disorder (PTSD), an anxiety disorder, or agitation/disruptive/aggressive behavior associated with dementia.
The specification broadly defines prevention as encompassing prevention of disease development, prevention of further disease progression, and prevention of some or all symptoms associated with the disease or disorder. (See paragraph [0045].) The specification further broadly defines treatment as encompassing cure, handling, alleviation, relief, alteration, remedy, amelioration, improvement, or otherwise affecting the disease or disorder and/or symptoms therewith. (See paragraph [0046].) Thus, the claims encompass broad therapeutic outcomes including prevention, treatment, cure, amelioration, and symptoms control across all multiple distinct clinical disorders.
The determination of whether the disclosure enables the full scope of the claimed invention requires consideration of the factors set forth in in re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Factor 1-Breadth of the claims
The claims encompass treatment, amelioration, and prevention of broadly recited “stress-related disorders.” Claim 5 expressly encompasses PTSD, anxiety disorders, and agitation/disruptive/aggressive behavior associated with dementia. The claims further encompass administration of any selective α1A-adrenergic receptor antagonist compound that can be administered before or after the development of the disorder/disease or symptoms thereof satisfying the recited receptor selectivity limitations.
Moreover, because the specification defines treatment to include curing, and healing, and defines prevention to include prevention of the disease onset, disease progression, and symptoms, the claims encompass a wide range of therapeutic objectives extending substantially beyond the specific experimental conditions disclosed in the specification.
Factor 2- Nature of the invention
The invention pertains to treatment and/or prevention of complex neuropsychiatric disorders involving stress-response pathways, cognition, behavior, emotional regulation, and dementia-associated with behavioral disturbances.
The PTSD literature recognizes PTSD involves disruption of multiple biological systems including genetic factors, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, neurotransmitter dysregulation, and alterations in brain circuitry. Further, PTSD development is influenced by biological, psychological, and social factors.
Similarly, the agitation literature recognizes that agitation and aggression in dementia arise from multiple overlapoping causes including dementia itself, delirium, psychiatric disease, pain, fear. Environmental factors, and unmet needs.
Accordingly, the claimed subject matter pertains to complex and multifactorial disease states rather than a predictable pharmacological system.
Factor 3-State of the prior art
The prior art demonstrates that treatment of PTSD and dementia-associated agitation was not predictable at the time of filing.
Applicant’s own specification, acknowledges that the α1-adrenoceptor antagonist prazosin has been used to treat PTSD and dementia-associated agitation was not predictable at the time of filing. Applicant’s own specification acknowledges that α1 adrenoceptor antagonist prazosin has been used to treat PTSD and investigated for disruptive behavior in Alzheimer’s disease. However, the specification expressly states that “prazosin does not always work” and notes varied patient responses and failed clinical trials. (spec. para. [0005].) The specification further states that another α1-adrenoreceptor antagonist, doxazosin, was considered a potential alternative but “shares similar shortcomings with prazosin, to various degrees.” Spec. para. [0006].) These admissions demonstrate that even known α1-adrenoceptor antagonists therapies exhibited inconsistent efficacy and unpredictable clinical outcomes.Further, the PTSD literature explains that significant subset of PTSD patients exhibit symptoms that are difficult to treat and often require changes in treatment modality or combined therapies.
Factors 4-Level of predictability in the art
The art was highly unpredictable.
The PTSD literature (Al Jowf et al. Int. J. Mol. Sci. 2023, 24, 523) explains that only a subset of individual exposed to traumatic stress develop PTSD and further states the mechanism underlying susceptibility and resilience remains unclear. (See first and second paragraphs of page 2.) The PTSD literature further states that the initiation and maintenance of PTSD are heterogenous and vary among individuals exposed to similar levels of trauma. (See second and third paragraphs of page 4.)
Likewise, Zoeller et al. (Depress Anxiety. 2014 February; 31(2): 97–106) expressly teaches psychiatric diagnostic categories commonly exhibit considerable symptom heterogeneity. Posttraumatic stress disorder is no exception. (See Introduction Section on page 1.) The same reference explains that PTSD shares symptoms overlap with multiple psychiatric disorders and contains heterogeneous symptom domains including fear, dysphoria, and distress. (See second paragraph of page 2.)
Kennedy et al. (JACEP Open 2020; 1:812–823) recognizes that agitation and aggression arise from heterogenous biological, psychosocial, and environment determinants. (See left column of section 4.3.)
These references collectively demonstrate substantial unpredictability regarding whether modulation of a single receptor subtype would achieve the full therapeutic scope recited in the claims.
Factor 5-Amount of direction provided
The specification provides limited direction with respect to the full claim scope. The examples primarily investigate stress-induced impairment of spatial working memory and stress-induced prefrontal cortical dysfunction following administration of selective α1A receptor antagonists.
The specification does not provide representative examples demonstrating:
(a) treatment of established PTSD;
(b) treatment of established anxiety disorders;
(c) treatment of established dementia-associated agitation/aggressive behavior.
Thus, the disclosure demonstrates modulation of a proposed biological mechanism rather than enablement of the full scope of the claimed disease-state treatment and prevention embodiments.
Factor 6-Presence or Absence of working examples
Although working examples are present, the examples do not correspond to the full scope of the claims. The examples utilize stress-induced cognitive impairment paradigms involving spatial working memory and prefrontal cortical function. Such examples constitute mechanistic or pathophysiological models rather than clinical disease-state models for PTSD, anxiety disorders, or dementia-associated agitation/aggressive. The PTSD literature itself acknowledges that animal models do not fully replicate the human condition. (See section 2.2.3. of page 5.)
Accordingly, the working examples do not demonstrate enablement for the full breadth of the claimed therapeutic methods.
Factor 7-Qunatity of experimentation necessary
Substantial experimentation would have been required. A skilled artisan would need to determine:
(1) which selective α1A antagonist are therapeutically effective;
(2) which patient populations are responsive;
(3) which dosage regimens are effective;
(4) whether treatment, prevention, cure, healing, or symptom control can be achieved;
(5) whether efficacy extends across PTSD, anxiety disorder, and dementia-associated agitation/aggressive behavior;
(6) whether efficacy extends across the heterogeneous symptom presentations associated with such disorders;
(7) whether efficacy extends to prevention embodiments where disease has not yet developed.
Such experimentation would constitute a significant research program rather than routine optimization.
Factor 8-Amount of guidance versus claim scope
The amount of guidance provided is not commensurate ins scope with the breadth of the claims.
The specification demonstrates at most, that selective α1A antagonism may reduce stress-induced impairment in a spatial working-memory paradigm. However, the claims extend to prevention, treatment, cure, healing, and amelioration of broad clinical disorders including PTSD, anxiety disorder, dementia-associated agitation/aggressive behavior.
The disclosure does not reasonably teach a skilled artisan how to achieve the full claimed therapeutic scope without undue experimentation.
Conclusion
When the Wands factors are considered collectively, including the substantial breadth of the claims, the complexity and unpredictability of PTSD, dementia-associated agitation/aggression, Applicant’s own admissions regarding failed and inconsistent α1-adrenoreceptor antagonist therapies (spec. paras. [0005]-[0006]), the limited mechanistic examples provided, the absence of representative disease-state treatment and prevention examples, and the substantial experimentation required to practice the full scope of the claims, the specification fails to enable the full scope of claims 1-10 without undue experimentation.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al. (EP0799618 A2) in view of McElligott et al. (Neuropsychopharmacology (2008)33,2313–2323), and Ford et al. (Mol Pharmacol. 1996 Feb;49(2):209-15).
Thompson teaches a method for treating or preventing a cancer in a mammal which comprises administering to said mammal an amount of a drug, comprising an α1-adrenoreceptor antagonist or pharmaceutically acceptable acid addition salt thereof, effective for treating or preventing the cancer. (See Abstract.) Thompson teaches the α1-adrenoreceptor antagonist is selected from the group comprising alfuzosin, indoramin, terazosin, bunazosin, doxazosin and its 6'- and 7'- hydoxy metabolites, prazosin, tamsulosin, abanoquil, Recordati 15/2739, RS-17053 and SL 89.0591. (See claim 2.) Thompson additionally teaches the active compounds are most desirably administered in doses ranging from about 0.01 to about 2.0 mg/kg per day for the prevention or the treatment of cancer in a patient via oral, parenteral. (See paragraph [0015].)
Thompson however, does not expressly teach treatment, amelioration, or prevention of a stress-related disorder, in this case anxiety disorder.
McElligott teaches α1-adrenergic receptors are involved in stress-responsive neural circuitry and anxiety-related behaviors and explains that α1-adrenegic receptors within bed nucleus of the stria terminalis (BNST) are implicated in modulation of anxiety responses and that blocking the α1-adrenegic receptors decrease anxiety responses concurrent with reduction in activation of hypothalamic-pituitary-adrenal axis. (See Abstract.) Moreover, McElligott teaches that noradrenergic signaling in the BNST is implicated in anxieity, depression, stress-induced relapse behavior, and affective disorders. (See Abstract and right column of page 2313.) McElligott states that clinical data have highlighted α1-adrenegic receptors as therapeutic target for anxiety disorders and discuss the efficacy of α1-adrenegic receptors antagonists in patient suffering from post-traumatic stress disorder (PTSD). (See left column of page 2322.)
Ford teaches that RS-17053 is a selective α1-adrenoreceptor antagonist that exhibits high affinity for α1A-adrenoreceptors, with pKi values of approximately 9.1-9.9, and demonstrates approximately 30-100-fold selectivity over α1B- and α1D adrenoreceptors subtypes. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize the α1-adrenoreceptor antagonist taught by Thompson, particularly the expressly identified compound RS-17053, for treatment, amelioration, or prevention of stress-related disorders, in this case anxiety disorder as taught by McElligott because McElligott teaches α1-adrenergic receptor signaling contributes to stress-related and anxiety-related behavioral responses and further teaches that α1-adrenoreceptor antagonism reduces such responses and represents a therapeutic target for affective disorders.
One of ordinary skill in the art would have been motivated to select RS-17053 from the finite list of α1-adrenoreceptor antagonists taught by Thompson because Ford teaches that RS-17053 possesses a highly selective α1A receptor profile and would therefore have been expected to provide the therapeutic benefits associated with α1-adrenergic antagonism while preferentially targeting the α1A- receptor subtype.
One would have had a reasonable expectation of success because all three references are directed to modulation of the same adrenergic signaling pathway, McElligott teaches α1-adrenergic receptors are involved in stress and anxiety responses, Thompson teaches therapeutic administration of α1-adrenoreceptor antagonists, and Ford teaches that RS=17053 is a highly selective α1A antagonist.
With regard to claim 4, McElligott teaches that α1-adrenergic receptor signaling mediates stress-responsive neural pathways and contributes to stress-induced behavioral and neurological responses. Because McElligott teaches therapeutic modulation of stress-related neural circuitry through α1-adrenergic receptor antagonism, treatment of stress-induced preftrontal cortical dysfunction would have been obvious application of the same mechanism.
With respect to claim 8, Thompson teaches dosage regimens that overlap the presently claimed dosage limitation. It is well established that discovery of an optimum value within a known range is ordinarily obvious absent evidence of criticality or unexpected results.
With respect to claim 10, Thomson expressly contemplates administration of human patients by its teaching of patient. Therefore, claim 10 would have been obvious.
Conclusion
Claims 1-10 are not allowed.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628
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