CTNF 18/249,076 CTNF 100703 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Information Disclosure Statement Thirteen information disclosure statements (IDS) submitted: Two on July 19 th , 2023; one on January 29 th , 2024; one on July 25 th , 2024; one on September 3 rd , 2024; one on October 28 th , 2024; one on November 25 th , 2024; one on March 25 th , 2025; one on April 11 th , 2025; one on April 22 nd , 2025; one on June 9 th , 2025; one on June 26 th , 2025; and one on August 14 th , 2025. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The Farkas et al. reference, cited in the IDS filed on July 19 th , 2023, has been lined through because this reference is also cited in the IDS filed on April 22 nd , 2025. Specification The use of the terms Cinryze®, Haegarda®, Barinert®, Ruconest®, etc. which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Status of the Claims Claims 43 and 46-84 are pending in this application. Claims 1-42 and 44-45 have been cancelled by applicant. 07-30-03-h AIA Claim Interpretation Claims 43, 55, 58-60, 65-67, and 69 speak to “on-demand” treatment. The specification defines “on-demand” to mean that the compound of Formula A is administered upon need of therapy in connection with one specific bradykinin-mediated angioedema attack, encompassing prophylactic administration and administration at the onset or during an angioedema attack ( page 10, lines 30 to page 11, line 15 ). Claim 77 speaks to a “mini-tablet”. The specification mentions mini-tablets can have a diameter in the range of 2 to 3 mm ( page 36, line 2 ) of about 10 mg each (see page 83, Minitab Formulation Table ). Claim Rejections - 35 USC § 112 07-30-02 AIA 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. 07-34-01 Claim 43 and 46-84 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 regards as the invention. Claims 43, 55, 58-59, 65-69, 71-73, 77, and 79 , recite the limitation, “(or a pharmaceutically acceptable salt and/or solvate thereof)”. Claim 76 recites the limitation, “(co-processed Mannitol / Maize starch)”. The inclusion of such parentheses raises the question as to which term is required by the claim because the subject matter in the parentheses is not identical in scope. Essentially, the claims use both narrow and broad limitations. A broad range of limitations, together with a narrow range of limitations that falls within the broad range of limitations in the same claim is considered indefinite, since 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 cases, it is unclear if “pharmaceutically acceptable salt and/or solvate thereof” or “co-processed Mannitol / Maize starch” are or are not included within the scope of the claims. 07-34-03 AIA The term “ slight swelling ” in claim 61 is a relative term which renders the claim indefinite. The term “ slight ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 68 recites the limitation "the BK-AEnH". There is insufficient antecedent basis for this limitation in claims 65 and 43, from which claim 68 depends . 07-35-01 AIA Claim 76 contains the trademark/trade name Pearlitol® Flash . 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 name is used to identify/describe Pearlitol® Flash and, accordingly, the identification/description is indefinite. Claims 80-81 recite the limitation "the disintegration specification". There is insufficient antecedent basis for this limitation in the claim. Claim 82-83 recite the limitation "the dissolution specification". There is insufficient antecedent basis for this limitation in the claim. Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-21-aia AIA Claim s 43, 46-47, and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 A1 – From IDS) . Regarding claims 43 and 46-47, Beaton discloses the compound of Formula A below as a plasma kallikrein inhibitor ( Abstract ) and that the compound can be administered orally in the form of tablets, syrups, or powders ( para. bridging pages 26-27 ). Beaton discloses that inhibitors of plasma kallikrein have been shown to treat hereditary angioedema (HAE) by preventing the release of bradykinin (suggesting that HAE is mediated by bradykinin and reading on treatment of bradykinin mediated angioedema) ( page 1, lines 8-10 and 33-34 ). PNG media_image1.png 397 758 media_image1.png Greyscale Therefore, regarding instant claims 43 and 46-47 , it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer an oral dose of Beaton’s compound of Formula A in the form of a tablet, gel, or syrup, for the on-demand treatment of bradykinin mediated angioedema, such as hereditary angioedema (HAE). One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Beaton’s teachings that their compound of Formula A is a plasma kallikrein inhibitor that can be administered orally in the form of tablets, gels, or a syrup, and that plasma kallikrein inhibitors have therapeutic applications for the treatment of HAE. Regarding claim 77, Beaton discloses oral administration may be in the form of tablets ( page 27, line 1 ). Regarding the limitation of “mini-“ implying smaller doses of the compound of Formula A as shown in the specification (10 mg) – see claim interpretation. Beaton discloses daily dose of the crystalline form is typically between 0.1 and 10,000 mg per day, administered in single or divided doses (reading on tablets that can be of any size ranging from 0.1 mg to 10 g) ( page 26, para. 3-4 ). Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim , 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff , 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller , 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II . Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art . 07-21-aia AIA Claim s 46, 48-49, 52-57, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 A1 – From IDS); as applied to claims 43, 46-47, and 77, in view of Cicardi et. al. ( Allergy, Asthma, & Clinical Immunology, 2010, 6:14 – From IDS) . The teachings of Beaton et al. are disclosed in the 103 section above and incorporated herein. Beaton further discloses that plasma kallikrein is thought to play a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a genetic deficiency in C1 esterase inhibitor (C1-Inh) suffer from hereditary angioedema (HAE). Treatment with large protein plasma kallikrein inhibitor, ecallantide, has been shown to effectively treat HAE by preventing the release of bradykinin which causes increased vascular permeability ( page 1, lines 28-35 ). Beaton discloses that the large protein plasma kallikrein inhibitors, such as ecallantide, present risks of anaphylactic reactions, and therefore, there remains a need for compounds that selectively inhibit plasma kallikrein that do not induce anaphylaxis and are orally available ( page 4, lines 29-32 ). While Beaton et al. does not specifically teach: (i) treatment of bradykinin mediated angioedema non hereditary (BK-AEnH) (claim 48); or (ii) wherein the BK-AEnH is not caused by an inherited genetic dysfunction, fault, or mutation (claim 49); (iii) wherein the patient is aged between 2 and less than 18, or 2 and less than 12, or 70 years or older (claims 52-54); (iv) wherein treatment is administered upon recognition of a symptom of a BK-mediated angioedema attack (claim 55); (v) wherein the patient is suffering from a laryngeal attack (claim 56); (vi) wherein the symptom recognized is at least one of swelling, abdominal pain, etc. (claim 57); or (vii) wherein treatment shortens the duration of the attack (claim 63); the teachings of Cicardi et al. are relied upon for these disclosures. Cicardi teaches that, from a clinical point of view, the symptoms that characterize acquired angioedema (AAE) (reading on bradykinin-mediated angioedema non-hereditary, BK-AEnH) cannot be differentiated from those present in hereditary angioedema (HAE), due to the fact that both forms of angioedema are mediated by bradykinin episodically released by inappropriate activation of the contact-kinin system lacking its major physiologic regulator (C1-INH) and that the only significant clinical difference between HAE and BK-AEnH is the age of onset of symptoms (within the second decade of life for most subjects with HAE and after the fourth decade for subjects with AAE) ( page 1, para. 2, lines 1-9, and lines 18-20 ). Cicardi also discloses that, based on the efficacy of replacement therapy with plasma-derived C1-INH in reverting laryngeal edema in patients with HAE, the same approach has been used for AAE and no other treatments have been used extensively ( page 3, col. 2, para. 3, lines 5-12) . Cicardi discloses that, since refractoriness to plasma-derived C1-INH is due to its autoantibody-mediated rapid catabolism, the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE ( page 3, col. 2, para. 3 ). Cicardi discloses that in particular, ecallantide and icatibant have shown extremely favorable results. All treated attacks responded very rapidly either to ecallantide or icatibant, and it was suggested that either should be provided, particularly for AAE patients who have slow or no response to plasma-derived C1-INH ( page 4, col. 1, para. 1 ). Cicardi also teaches how to distinguish between hereditary or acquired angioedema: “This testing includes determination of C1q which is reduced in 70% of patients with acquired-AE (AAE) and is normal in HAE. If C1q is reduced, diagnosis of AAE can be established. If C1q is normal, autoantibodies to C1-INH can be investigated and their presence at high titer allows diagnosing AAE. If antibodies are negative, the diagnosis of AAE is assumed when complete screening of C1-INH gene gives no evidence of mutations affecting C1-INH protein” ( page 3, col. 2, para. 1 ). Therefore, regarding claims 46 and 48 , it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Beaton’s compound of Formula A for the treatment of bradykinin mediated non-hereditary angioedema (BK-AEnH) (a.k.a. acquired angioedema (AAE)). One of ordinary skill would have been motivated to do so in view of Beaton’s teachings that their compound of Formula A is a plasma kallikrein inhibitor that can be administered orally, and their disclosure that there remains a need for orally available compounds that selectively inhibit plasma kallikrein without inducing anaphylaxis. In particular, Beaton’s plasma kallikrein inhibitor provides advantages over ecallantide, such as selectively inhibiting plasma kallikrein without inducing anaphylaxis and oral availability, providing an easier, on-demand, self-administration method. One of ordinary skill would have been further motivated in view of Cicardi’s teachings that treatments of HAE are generally also effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Beaton’s disclosure that, like ecallantide, their disclosed small molecule compound is also a plasma kallikrein inhibitor suitable for HAE, and Cicardi’s disclosure that both hereditary and non-hereditary bradykinin mediated angioedemas have the same symptoms and mechanisms, differing mainly in the age of onset of symptoms. Regarding claim 49, Beaton teaches that patients who present with a genetic deficiency in C1 esterase inhibitor (C1-Inh) suffer from HAE ( page 1, lines 28-35 ). Cicardi teaches how to distinguish between hereditary or acquired angioedema: “testing includes determination of C1q, which is reduced in 70% of patients with AAE and normal in HAE. If C1q is reduced, diagnosis of AAE can be established. If C1q is normal, autoantibodies to C1-INH can be investigated and their presence at high titer allows diagnosing AAE. If antibodies are negative, the diagnosis of AAE is assumed when complete screening of C1-INH gene gives no evidence of mutations affecting C1-INH protein” ( page 3, col. 2, para. 1 ). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to treat BK-AEnH that is not caused by an inherited genetic dysfunction, fault, or mutation. One or ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Beaton’s disclosure of the plasma kallikrein inhibitor of Formula A, further in view of Cicardi’s teachings that treatments of HAE are generally also effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE. Regarding claims 52-53, Cicardi teaches the age of onset of symptoms for HAE to be within the second decade of life for most subjects ( page 1, para. 2, lines 1-9, and lines 18-20; and Table 1 ) (reading on ages between 2 and less than 18, or between 2 and less than 12). Therefore, in view of Cicardi’s teachings, one of ordinary skill would expect patients younger than twenty (within their second decade of life) suffering from an angioedema attack, to have HAE and thus be motivated to administer, with a reasonable expectation of success, Beaton’s plasma kallikrein inhibitor of Formula A, disclosed by Beaton to be effective for the treatment of HAE. Regarding claim 54, Cicardi teaches the age of onset of symptoms for AAE to be after the fourth decade of life ( page 1, para. 2, lines 1-9, and lines 18-20; and Table 1 ) (reading on patients aged 70 years or older). Therefore, in view of Cicardi’s teachings, one of ordinary skill would expect patients older than seventy (after their fourth decade of life) suffering from an angioedema attack, to have AAE and thus be motivated to administer, with a reasonable expectation of success, Beaton’s plasma kallikrein inhibitor of Formula A, further in view of Cicardi’s teachings that treatments of HAE are generally also effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE. Further regarding claims 52-54 , Applicant is reminded that the courts have stated that where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, the claimed age ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art. Regarding claims 55-57, Cicardi discloses symptoms of HAE and AAE recur at unpredictable intervals, lasting from two to five days and presenting with disfiguring, non-pitting, non-pruritic edema of the skin (face, limbs, genitals), severe abdominal pain, life threatening edema of the upper respiratory tract and edema of the oral mucosa and of the tongue ( page 1, col. 2, lines 8-16 ). Cicardi further discloses treatment of AAE should be first aimed to avoid fatalities due to angioedema and then to avoid disability caused by angioedema recurrences, and that fatalities derive from laryngeal edema (reading on a laryngeal attack, which would be expected to result in shortness of breath) ( page 3, col. 2, The treatment – section, lines 1-5 ). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to administer Beaton’s oral plasma kallikrein inhibitor (instantly claimed Formula A) to a patient showing symptoms of an angioedema attack, such as edema of the respiratory tract or laryngeal edema, which could result in shortness of breath and potentially death. One of ordinary skill would have been motivated to do so in view of Cicardi’s disclosure of the possibility of a life-threatening laryngeal edema, and their disclosure that AAE patients are sometimes partially or fully non-responsive to plasma derived C1-INH treatment ( page 4, col. 1, para. 1, lines 1-8 ), thus requiring alternative treatment options and emphasizing the need for additional treatment options. One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s disclosure of an oral plasma kallikrein inhibitor effective for the treatment of HAE; Cicardi’s teachings that treatments of HAE are generally effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE. Regarding claim 63, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP § 2103 I.C. and MPEP § 2111.04 . It is also noted that a “wherein” clause, such as that in claim 63 , must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04 . Further regarding claim 63, Cicardi discloses that reducing disability related to angioedema recurrences can be obtained by shortening attacks with an on-demand treatment with C1-INH ( page 4, col. 1, para. 2, lines 1-3 ), suggesting that treatment of an angioedema attack results in shortening the duration of the attack. Cicardi teaches that AAE patients are sometimes partially or fully non-responsive to plasma derived C1-INH treatment, thus requiring alternative treatment options ( page 4, col. 1, para. 1, lines 1-8 ). Therefore, it would it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to administer Beaton’s oral plasma kallikrein inhibitor to shorten the duration of a BK-mediated angioedema attack. One of ordinary skill would have been motivated to do so, as discussed above, in view of Cicardi’s teachings that on-demand treatment with C1-INH shortens angioedema attacks, however AAE patients are sometimes partially or fully non-responsive to C1-INH treatment, thus requiring alternative treatment options. One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s disclosure of a plasma kallikrein inhibition (instantly claimed Formula A) capable of treating HAE; further in view of Cicardi’s teachings that treatments of HAE are generally effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the teachings of the prior art references is fairly suggestive of the claimed invention . 07-21-aia AIA Claim s 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 A1 – From IDS); in view of Cicardi et. al. ( Allergy, Asthma, & Clinical Immunology, 2010, 6:14 – From IDS); as applied to claims 46, 48-49, 52-57, and 63; further in view of Scott et. al. ( Current Diabetes Reviews, 2018, 14, 327-333 – From IDS); Long et. al. ( Nanotoxicology, 2016, 10(4), 501-511 – From IDS); and Rathbun et. al. ( Oxford Medical Case Reports, 2019, 01, 11-13 – From IDS) . The teachings of Beaton and Cicardi et al. are disclosed above and incorporated herein. While Beaton in view of Cicardi et al does not specifically teach: (i) wherein the BK-AEnH is environmentally or drug induced by angiotensin converting enzyme (ACE)-induced, dipeptidyl peptidase-4 inhibitor-induced, tissue plasminogen activator (tPA)-induced, or silver nanoparticle-induced (instant claims 50-51); the teachings of Scott, Long, and Rathbun et al. are relied upon for these disclosures. Scott teaches that dipeptidyl peptidase-4 inhibitors affect degradation of kinins, bradykinin, and substance P, which can cause angioedema ( Abstract ). Rathbun teaches that ACE inhibitors are the leading cause of drug-induced (bradykinin-mediated) angioedema in the USA with 0.1-0.7% of patients taking the drug developing angioedema ( page 11 , para. 2, lines 5-10 ). Rathbun discloses that orolingual angioedema develops after treatment with rtPA in 1.3-5.1% of patients ( page 12 , col. 1, last para., lines 2-4 ). Long teaches that silver nanoparticles activated the plasma kallikrein-kinin system, causing the release of bradykinin ( Abstract, lines 9-11 ). With regards to BK-AEnH attacks triggered by other drugs or environmental factors, such as dipeptidyl peptidase-4, ACE, tPA, or silver nanoparticles as recited in claims 50-51 , it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to administer Beaton’s oral dosage (instantly claimed as Formula A) to treat an angioedema attack triggered by exposure to drugs or environmental factors known in the art to disrupt or interfere with the degradation of kinins or bradykinin (such as dipeptidyl peptidase-4 inhibitors, ACE inhibitors, or tPA) or known to activate the plasma kallikrein-kinin system (such as silver nanoparticles). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in view: (i) Beaton’s plasma kallikrein inhibitor of Formula A, known to treat HAE; (ii) Cicardi’s teachings that treatments of HAE are generally effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE; (iii) Scott’s disclosure that that dipeptidyl peptidase-4 inhibitors affect degradation of kinins, bradykinin, and substance P, which can cause angioedema, (iv) Rathbun’s disclosures that ACE inhibitors are the leading cause of drug-induced (bradykinin-mediated) angioedema in the USA and that orolingual angioedema develops after treatment with rtPA in 1.3-5.1% of patients, and (v) Long’s disclosure that silver nanoparticles activated the plasma kallikrein-kinin system, causing the release of bradykinin. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention . 07-21-aia AIA Claim s 58-62 and 64-67 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 A1 – From IDS); in view of Cicardi et. al. ( Allergy, Asthma, & Clinical Immunology, 2010, 6:14 – From IDS); as applied to claims 46, 48-49, 52-57, and 63; further in view of Magerl et al. ( Clinical and Experimental Dermatology , 2014, 39, 298-303 – From IDS) . The teachings of Beaton and Cicardi et al. are disclosed above and incorporated herein. While Beaton in view of Cicardi does not specifically teach: (i) treatment administration on-demand within 1 hour of the symptom of a bradykinin-mediated angioedema attack (claim 58); (ii) treatment administration within 30, 20, 10, or 5 minutes of the symptom of a bradykinin-mediated angioedema attack (claim 59); (iii) treatment administration in the prodromal phase of a of a bradykinin-mediated angioedema attack (claim 60); (iv) wherein the symptom recognized is at least one of slight swelling, abdominal pain, or reddening of the skin (claim 61) or erythema marginatum (claim 62); (v) wherein treatment prevents the bradykinin mediated angioedema from progressing to the swelling stage (claim 64); or (vi) wherein treatment is administered prophylactically to reduce the likelihood or prevent a bradykinin mediated angioedema attack, or wherein the attack might be anticipated (claims 65-67); the teachings of Magerl et al. are relied upon for these disclosures. Magerl discloses the prodromal symptoms of hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency, and the value of their recognition in predicting the onset of an attack of angioedema, diagnosing the condition, and aiding in the management of C1-HAE ( abstract ). Reduced C1-INH activity results in increased activation of plasma kallikrein-kinin system proteases, resulting in raised bradykinin levels ( page 298, col. 2, para. 2 ). The onset of angioedema in C1-HAE may occur in variable degrees of severity. Because of its significant morbidity and mortality of 15-30% due to untreated or insufficiently treated laryngeal edema and subsequent asphyxiation, all patients need to carry emergency therapies, and some require long-term prophylaxis ( page 299, col. 1, para. 2 ). Magerl teaches that numerous reports about prodromal signs and symptoms of C1-HAE attacks have been reported, and that prodromes develop minutes to hours before the onset of the actual angioedema episode ( page 299, col. 1, para. 3-4 ) with some patients experiencing the first prodromal symptom less than an hour before the HAE attack ( Figure 4 on page 300 ), and that prodromes could be used as an indication for treatment in some patients, as early treatment is more effective ( para. bridging 301-302 ). Known symptoms include skin rashes, erythema marginatum, paraesthesia, tingling, stinging, fatigue, muscle aches, and malaise ( page 301, col. 2, para. 2; Box - What’s already known about this topic? page 302 ). Regarding claims 58-60 and 64 , it would it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to administer Beaton’s oral plasma kallikrein inhibitor as soon as possible (within 1 hour, or within 30, 20, 10, or 5 minutes) upon recognition of a symptom of an angioedema attack either during the prodromal phase or the swelling stage of the attack. One of ordinary skill would have been motivated to do so in view of Magel’s teachings that prodromes could be used as an indication for treatment in some patients, as early treatment is more effective. One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s disclosure of an oral plasma kallikrein inhibitor, effective for the treatment of HAE; Cicardi’s teachings that treatments of HAE are generally effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE; and Magerl’s disclosure of common symptoms and prodromes for HAE. Regarding claims 61 and 62, Magerl discloses skin rashes and erythema marginatum (reading on reddening of the skin) as symptoms of HAE. Regarding claims 65-67, Cicardi discloses that C1-INH has had controversial results when used for prophylaxis, and that C1-INH should be reserved for on-demand treatment, not for prophylaxis ( page 4, col. 2, last 3 lines ). Magerl discloses that, due of its significant morbidity and mortality of 15-30% of untreated or insufficiently treated laryngeal edema and subsequent asphyxiation, all patients (at risk) need to carry emergency therapies, and some require long-term prophylaxis ( page 299, col. 1, para. 2 ). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Beaton’s oral plasma kallikrein inhibitor to prophylactically reduce the likelihood of a bradykinin mediated angioedema attack, or to prevent a bradykinin mediated angioedema attack when one is anticipated. One of ordinary skill would have been motivated to do so in view of Cicardi’s disclosure that C1-INH therapies should be reserved for on-demand treatment and not for prophylactic prevention, emphasizing the need for alternative treatment options with lower risk of anaphylaxis. One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s disclosure of their plasma kallikrein inhibitor, effective for the treatment of HAE; Magerl’s disclosures on the morbidity and mortality of untreated or undertreated laryngeal edema, which could benefit from long-term prophylaxis in patients with high risk; further in view of Magerl’s disclosure of the prodromes of an angioedema attack, which would allow for recognition of an attack prior to onset. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention . 07-21-aia AIA Claim 68 is rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 A1 – From IDS); in view of Cicardi et. al. ( Allergy, Asthma, & Clinical Immunology, 2010, 6:14 – From IDS); and Magerl et al. ( Clinical and Experimental Dermatology , 2014, 39, 298-303 – From IDS); as applied to claims 58-62 and 64-67; further in view of Rathbun et. al. ( Oxford Medical Case Reports, 2019, 01, 11-13 – From IDS) . The teachings of Beaton, Cicardi, and Magerl et al. are disclosed above and incorporated herein. While Beaton in view of Cicardi and Magerl do not specifically teach BK-AEnH that is tPA-induced, wherein the patient is also being administered tPA, and wherein Formula A is administered prior to, during, or after administration of tPA; the teachings of Rathbun et al. are relied upon for these disclosures. Rathbun teaches that orolingual angioedema develops after treatment with rtPA in 1.3-5.1% of patients ( page 12 , col. 1, last para., lines 2-4 ) and that, while most cases of angioedema are mild and self-limiting, there is a risk of rapidly progressing edema that could lead to asphyxia ( page 12, col. 1, last 2 lines and col. 2 first 2 lines ). Rathbun discloses angioedema following rtPA infusion is BK-mediated ( page 12, col. 2, para. 2 ) and that treatment with icatibant, ecallantide may be helpful in rtPA associated angioedema ( page 12, col. 2, para. 3, lines 3-8 ). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Beaton’s plasma kallikrein inhibitor to a subject undergoing treatment with tPA, if orolingual angioedema develops after or during tPA administration. One of ordinary skill in the art would be motivated to do so in view of Beaton’s disclosure that ecallantide sometimes results in anaphylaxis, making it a less-than-ideal treatment option; Magerl’s disclosures on the morbidity and mortality of untreated or undertreated laryngeal edema, which could benefit from long-term prophylaxis in patients with high risk; and Rathbun’s disclosure that angioedema caused by bradykinin, after administration of tPA, does not respond to antihistamines, corticosteroids, or epinephrine ( page 12, col. 2, para. 2 ). One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s disclosure of their oral plasma kallikrein inhibitor (instantly claimed formula A), taught to be effective for the treatment of HAE; and Cicardi’s teachings that treatments of HAE are generally effective for AAE, and that the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention . 07-21-aia AIA Claim s 69-70 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 A1 – From IDS); in view of Cicardi et. al. ( Allergy, Asthma, & Clinical Immunology, 2010, 6:14 – From IDS); in view of Magerl et al. ( Clinical and Experimental Dermatology , 2014, 39, 298-303 – From IDS); as applied to claims 58-62 and 64-67; further in view of Magerl et. al. (Magerl 2017) ( Immunol. Allergy. Clin. N. Am. , 37, 2017, 571-584 – From IDS) . The teachings of Beaton, Cicardi, and Magerl et al. are disclosed above and incorporated herein. While Beaton in view of Cicardi, further in view of Magerl et al. does not specifically teach: (i) on-demand treatment of a bradykinin-mediated angioedema attack anticipated or induced by physical traumata and/ or stress (claim 69) or by the physical traumata and/ or mental stress associated with a dental procedure (claim 70); the teachings of Magerl 2017 et al. are relied upon for these disclosures. Magerl 2017 teaches that short-term prophylactic strategies are used in HAE-C1-INH to prevent attacks during medical or surgical procedures, and that similar attacks can be triggered by mechanical trauma, including dental procedures (reading on physical traumata and/or stress) ( page 578, paragraph 2) . With regards to on-demand administration of treatment prior to an anticipated physical traumata and/or stress, wherein the physical traumata or stress may be associated with a dental procedure, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to prophylactically administer Beaton’s oral plasma kallikrein inhibitor (instantly claimed Formula A) prior to an upcoming dental procedure, or prior to being subjected to any physical traumata or stress, which may be associated with a dental procedure. One of ordinary skill in the art would have been motivated to do so in order to reduce the risk of a BK-mediated angioedema attack during a dental procedure in a patient population afflicted with HAE or AAE, in order to further improve the patient’s quality of life. One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s oral plasma kallikrein inhibitor, which poses a safer prophylactic alternative to ecantallide, which has been associated with anaphylaxis; further in view of Magerl 2017’s guidance that short-term prophylactic strategies are used in HAE patients to prevent attacks during dental procedures. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention . 07-21-aia AIA Claim s 71-76, 78-79, and 80-84 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 A1 – From IDS); as applied to claims 43, 46-47, and 77; in view of Dey et al. ( J. Nat. Sci. Biol. Med., 2010, 1, 2-5); and Kohr et al. (US 2015/0283067 A1) . The teachings of Beaton et al. are disclosed above and incorporated herein. Beaton discloses oral administration may be in the form of tablets ( page 27, line 1 ). Beaton further discloses oral formulations include semi-solid (including dispersed systems) such as tablets, and fast dispersing dosage forms, films, etc. ( page 27, para. 3 ). While Beaton et al. does not specifically disclose: (i) a dispersible tablet or orodispersible tablet (claims 71-73); (ii) wherein the orodispersible tablet comprises microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium , camphor, sodium saccharin, and magnesium stearate (claim 74); (iii) wherein the tablet comprises polyvinyl polypyrrolidone or crospovidone (claims 75 and 84); (iv) co-processed Mannitol, maize starch, sucralose, and sodium stearyl fumarate (claim 76); (v) an orodispersible film (claim 79); (vi) a disintegration specification of >80% in less than about 10 min or 1 min (claims 80-81); or (vii) dissolution specifications of >80% in less than 45 min or 5 min (claims 82-83); the teachings of Dey and Kohr et al. are relied upon for these disclosures. Dey discloses orodispersible tablets are gaining importance among novel oral drug-delivery systems as they have improved patient compliance. Dey discloses this type of drug delivery helps administration with populations where swallowing may be a matter of trouble ( abstract ). Kohr discloses an orodispersible film composition ( abstract ). Kohr discloses orodispersible films allow for fast release of active pharmaceutical ingredient and cannot be spit out, allowing for increased administration compliance in patients. Kohr teaches the thickness and size of the orodispersible films may be adapted to achieve the desired time for dissolution ( [0010], last 3 lines ). Regarding claim 79, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to formulate an orodispersible dosage film of Beaton’s plasma kallikrein inhibitor (instantly claimed Formula A). One of ordinary skill in the art would have been motivated to do so in view of Kohr’s teachings that orodispersible films improve patient compliance and allow for fast release of active ingredients. One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s disclosure of their oral formulations of Formula A, which may be in the form of fast dispersing dosage forms, such as films. Regarding claims 71-73, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to formulate an orodispersible dosage form of Beaton’s plasma kallikrein inhibitor (instantly claimed Formula A). One of ordinary skill in the art would have been motivated to do so in view of Day’s teachings that orodispersible tablets improve patient compliance and simplify administration for subjects who may have difficulty swallowing. One of ordinary skill would have had a reasonable expectation of success in view of Beaton’s disclosure of their oral formulations of Formula A, which may be in the form of semi-solid (dispersed systems) such as tablets, and fast dispersing dosage forms. Regarding claim 74 and 78, Dey discloses important disintegrants used in the preparation of orodispersible tablets are croscarmellose sodium and microcrystalline cellulose ( page 3, Compacting Methods – section ). Regarding claim 75 and 84, Dey discloses important disintegrants used in the preparation of orodispersible tablets include crospovidone (polyvinyl polypyrrolidone) ( page 3, Compacting Methods – section ). Regarding claim 76, Dey discloses important materials used in the preparation of orodispersible tablets, such as mannitol (as a bulk agent) and a starch disintegrant (such as sodium starch glycolate) ( page 3, Spray-drying Method – section ). Regarding claims 80-81, Dey discloses orodispersible tablets are solid dosage forms which disintegrate in the mouth within a minute in the presence of saliva ( abstract, lines 4-5 ) and generally less than 1 min, and the actual disintegration time that a patient can experience ranges from 5 to 30 seconds ( page 6, last para. ). Regarding claims 82-83, Dey discloses that dissolution of orodispersible tablets is “very fast” (reading on less than about 5 min and less than about 45 min). While Dey does not specifically report an average dissolution time, Dey discloses a USP procedure for dissolution tests, allowing one of ordinary skill to troubleshoot their formulations to achieve the desired dissolution ( page 7, Dissolution test – section). Furthermore, Kohr teaches the thickness and size of the orodispersible forms may be adapted to achieve the desired time for dissolution ( [0010], last 3 lines ). Therefore, one of ordinary skill would have had a reasonable expectation of success in designing an orodispersible tablet that can dissolve > 80% is less than 45 min or less than 5 min. A person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007). Further regarding claims 80-83, and the instantly claimed disintegration and dissolution specifications, Applicant is reminded the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, the claimed time ranges of disintegration and dissolution merely represent an obvious variant and/or routine optimization of the values of the cited prior art. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention . Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. 08-36 AIA Claim s 43, 46-49, 52-57, 63, and 77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-7, 23, 30-32, and 34 of U.S. Patent No. 11,234,939 B2 (US ‘939) – From IDS; in view of Cicardi et. al. ( Allergy, Asthma, & Clinical Immunology, 2010, 6:14 – From IDS) . Regarding instant claims 43, 46-48, US ‘939 claims a method of treating a disease or condition mediated by plasma kallikrein (reading on HAE and BK-AEnH) comprising administration of an oral solid form of the instantly claimed compound of Formula A ( US ‘939 claim 30 ). Further regarding claims 46-47, US ‘939 specifically mentions treatment of HAE ( US ‘939 claims 31-32 and 34 ). Regarding claim 77, US ‘939 discloses oral administration may be in the form of tablets ( US ‘939 claim 23 ). Regarding the limitation of “mini-“ implying smaller doses of the compound of Formula A as shown in the specification (10 mg) – see claim interpretation. US ‘939 discloses the amount of Formula A in each tablet is typically between 0.1 and 1000 mg ( US ‘939 claim 2 ). Applicant is reminded that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed r