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 national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2021/023292, filed 03/19/2021, which claims the priority benefit of PRO Application No. 62/992,832, filed 03/20/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/16/2022, and 12/02/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Application
Applicant's election without traverse of Group I, claims 1, 3, 5, 8-11, 13-16, 21-27 and 29, with a species election of dexrazoxane as a species of ferrous iron chelator and an agent that binds or regulates heme, deferiprone as a species of ferric iron chelator and hemopexin as a species of heme binding agent in the reply filed 12/02/2025 is acknowledged.
Claims 21 and 29 been amended. Claims 2, 4, 6-7, 12, 17-20, and 28 have been cancelled. Claims 1, 3, 5, 8-11, 13-16, 21-27 and 29 are pending and are currently under examination.
Specification
The disclosure is objected to because of the following informalities: dexrazoxane appears spelled as “dexrazonxane” in para. [0125], line 9 of the specification. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 3, 5, 8-11, 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Behrouzi (Action of iron chelator on intramyocardial hemorrhage and cardiac remodeling following acute myocardial infarction) in view of Neckar (Protective effects of dexrazoxane against acute ischaemia/reperfusion injury of rat hearts) (sic) and further in view of Tardif (Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction).
The instant claims are directed to a method of treating a subject having been diagnosed with or showing symptoms of myocardial infarction, comprising administering to the subject an effective amount of a ferrous iron chelator, an agent that binds heme, or an agent that regulates heme during the acute phase of the myocardial infarction further comprising administering colchicine, an anti-inflammatory agent to the subject in the acute phase of the MI, or after the acute phase of the MI.
Behrouzi et al. teach The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) and “[t]he purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling” (Abstract). Behrouzi teaches “Complete coronary occlusion was achieved for 90 min distal to the second diagonal branch of the left anterior descending (LAD) artery using a percutaneous balloon dilation catheter (Sprinter OTW, Medtronic, MN), followed by reperfusion. This model has been well validated to consistently create transmural infarction with MVO and hemorrhage” (pg. 3, col 1, para 1). Behrouzi also teaches DFP was fed to pigs 1–2 h before the left anterior descending (LAD) occlusion (pre-loading) and oral treatment was continued daily for 4 weeks until sacrifice (pg. 3, col 1, para 2). Behrouzi also teaches “our findings suggest that an iron chelation strategy employed early in the acute phase of I/R can mitigate hemorrhagic iron deposition and alleviate chronic adverse remodeling post-AMI” (pg. 10, col 2, para 1; pg. 11, col 1, para 1). Behrouzi discloses “Nevertheless, future preclinical studies focused on human dosing strategies, such as at reperfusion or after, are warranted to demonstrate the efficacy of DFP in a clinically translatable situation.” (pg. 13, col. 2, para. 1)
However, Behrouzi et al. fail to disclose a ferrous iron chelator or an agent that binds or regulates heme nor a disclosure of administering an anti-inflammatory agent in or after the acute phase of the MI, (cited as AMI by Behrouzi).
Neckar et al. teach intravenously administering 50-450 mg/kg dexrazoxane (DEX) as an intracellular iron chelator and that DEX in a narrow dose range can suppress arrhythmias in isolated hearts subjected to ischemia/reperfusion (I/R), while a higher dose is needed to limit myocardial infarct size in open-chest rats (Abstract).
However, Neckar et al. fail to disclose administering an anti-inflammatory agent in or after the acute phase of the MI.
Tardif et al. disclose “[w]e performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo” (abstract). Tardif also teaches “[b]ecause acute coronary syndromes are associated with higher risks of recurrent events and exacerbated inflammation, we conducted the Colchicine Cardiovascular Outcomes Trial (COLCOT) to evaluate the effects of colchicine on cardiovascular outcomes as well as its long-term safety profile in patients who had recently had a myocardial infarction.” (pg. 2498, col 1, para 2)
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to orally administer a method of treating a subject diagnosed with or showing symptoms of myocardial infarction with deferiprone as taught by Behrouzi daily over a period of 4 weeks in combination with Neckar’s disclosure of improving cardiac ischemic tolerance by administering 50-450 mg/kg of the ferrous iron chelator dexrazoxane and Tardif’s disclosure of colchicine in MI because Behrouzi teaches methods of treating these myocardial infarction patients with DFP, Tardif discloses the treatment of myocardial infarction comprising administering colchicine to the subject in or after the acute phase of the MI, and Neckar discloses DEX can suppress arrhythmias in isolated hearts subjected to I/R, and limits myocardial infarct size. MPEP 2143 and 2144.06.
A person of ordinary skill in the art would have been motivated to combine orally administering deferiprone and dexrazoxane to a human for the treatment of myocardial infarction following the teachings of Behrouzi and Neckar because, two medications recognized for the same purpose would have given a skilled artisan a reasonable expectation of success in treating myocardial infarction. Furthermore, it would have been obvious to one of ordinary skill in the art that the colchicine of Tardif could have been combined with the method of Behrouzi for treatment of myocardial infarction as evidenced by the references. See MPEP 2144.05 and 2144.06.
Claims 21-27 and 29 is rejected under 35 U.S.C. 103 as being unpatentable over Spino (US 2014/0314676 A1).
In addition to the disclosures above, the instant claims are directed to a method for reducing myocardial infarct size, and/or inhibiting expansion of the myocardial infarct size, in a subject with ST-elevation myocardial infarction in need thereof, comprises administering a composition comprising an effective amount of a ferrous iron chelator, an agent that binds or regulates heme, or a combination thereof, during the acute phase or within 3 days of the onset of myocardial infarction;
measuring a blood level of troponin or cardiac troponin of the subject before and after coronary re-vascularization or reperfusion therapy, or at two or more time points after the coronary re-vascularization or the reperfusion therapy; and
administering a treatment or not administering a treatment to the subject to control hemorrhage from the cardiac chamber of the subject, when the blood level of troponin or cardiac troponin rises within 30 minutes to 12 hours following the coronary re-vascularization or the reperfusion therapy, which is at least 3 times higher compared to the level in the subject before the coronary re-vascularization or the reperfusion therapy
Spino et al. teach “methods of treating or ameliorating myocardial ischemia, an acute coronary event, and a myocardial reperfusion injury comprising administering a therapeutically effective amount of deferiprone or a pharmaceutically acceptable salt thereof to a patient in need thereof and for reducing the risk for myocardial reperfusion injury as well as promoting the beneficial remodeling of cardiac tissue in a patient (Abstract). Spino teaches deferiprone can be administered intravenously, yielding rapid cardiac protection, or administered orally for convenient chronic administration [0017]. Spino discloses “[a]nother aspect of the invention is directed to a method for reducing the risk for intramyocardial hemorrhage or damage resulting therefrom, cardiac edema, or reperfusion arrhythmias, comprising administering a therapeutically effective amount of deferiprone or a pharmaceutically acceptable salt thereof to a patient at risk of intramyocardial hemorrhage, cardiac edema, or reperfusion arrhythmias after Suffering a myocardial infarction” [0029]. Spino also discloses “By “subject” or “individual” or “animal” or "patient’ or “mammal. is meant any subject, particularly a mammalian Subject, for whom diagnosis, prognosis, or therapy is desired. In certain embodiments, the patient is a human” [0074]. Spino teaches a patient at risk for intramyocardial hemorrhage or the damage resulting therefrom is diagnosed with or determined to have one or more risk indicators of: (i) ST-segment elevation myocardial infarction (STEMI), e.g., determined by ECG; (ii) an increase in one or more markers for myocardial damage, e.g., increased creatine kinase and/or troponin levels (e.g., cardiac troponin I and T), e.g., determined by a troponin test; [0094]. Spino discloses “Patients with hemorrhagic infarcts appear to be at high risk, with poor long-term outcomes” [0104]. Spino also teaches a method of treating or limiting reperfusion injury and promoting the beneficial remodeling of cardiac tissue following myocardial ischemia, an acute coronary event and wherein the method comprises administering a therapeutically effective amount of deferiprone to a patient for a first period of time prior to and/or during which the patient is undergoing the revascularization procedure and for a second period of time after the patient has completed the revascularization procedure. [0111]. Spino teaches that iron chelation may be beneficial in acute coronary syndromes and that early treatment can limit ischemia-reperfusion injury and also reduce infarct size [0141]. Spino discloses ” In addition, blood samples are drawn at various times post-infarction for evaluating oxidative status and inflammatory response” [0146]. Spino discloses “DFP was able to penetrate the infarct Zone and was also effective in neutralizing hemorrhagic byproducts. Elimination of hemorrhage resulted in faster resolution of edema and normal ventricular volumes, representing a beneficial remodeling process” [0152]
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer the compound of deferiprone in a composition to a human subject in a method for reducing or in habiting expansion of myocardial infarct size because Spino discloses a method for reducing or inhibiting myocardial infarct size, and/or inhibiting expansion of the myocardial infarct size, in a human subject in need thereof by measuring a blood level of troponin or cardiac troponin of the subject before and after or at two or more time points after coronary re-vascularization or reperfusion therapy and a subject with ST-elevation myocardial infarction and is in need of or having had a reperfusion therapy or at risk of developing intramyocardial hemorrhage and administering an effective amount of a ferric iron chelator to the subject in the chronic phase of the myocardial infarction or after 3 days from the onset of symptoms of the myocardial infarction.
A person of ordinary skill in the art would have been motivated to administer the compound of deferiprone in a composition to a human subject in a method for reducing or inhibiting expansion of myocardial infarct size, ST-elevation, at risk of developing intramyocardial hemorrhage, in need of or having had a reperfusion therapy and measure the level of blood troponin as disclosed by Spino because deferiprone was disclosed as a compound capable of binding and regulating heme and a ferrous iron chelator, while one of ordinary skill in the art would have further optimized using routine experimentation, to identify the exact value for the blood level of troponin for diagnostic purposes. See MPEP 2144.05
Conclusion
All claims are rejected, no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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