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 .
Claims 1, 3, 5, and 23-49, submitted on 2 May 2024, represent all claims currently under consideration.
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.
Priority
This application is a 371 of PCT/US2022/026833, filed 28 April 2022, PCT/US/2022/015684, filed 8 February 2022, and PCT/US/2021/030312, filed 30 April 2021. The effective filing date is 30 April 2021.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 3 April 2024 and 1 October 2024, are acknowledged and have been considered.
Claim Objections
Claims 3 and 5 are objected to because of the following informalities: The claims are missing the word “salt” in the phrase “pharmaceutically acceptable salt” in line 4 of Claim 3 and Line 5 of Claim 5. Appropriate correction is required.
Claims 24-34 are objected to because of the following informalities: The claims have the limitation of “acute hemolysis or anemia, or both” (emphasis added). The Examiner believes the bolded “or” is unnecessary. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 32-34 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. The claims are indefinite because the claims have the limitation of: “c) treating the subject for acute hemolysis or anemia, or both, if the subject shows symptoms of acute hemolysis or anemia, or both”. It is unclear where this step “c” fits in the methods of Claims 1, 3, and 5 as these claims do not have a corresponding step a or step b. It is unclear when this step should be performed.
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, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5, and 23-49 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT04000165 (ClinicalTrials.gov, Posted Online: 27 June 2019) in view of Sizemore (WO 2019/104134; Publication Date: 31 May 2019) and Agresta (WO 2016/201227; Publication Date: 15 December 2016).
Clinical Trial NCT04000165 (See IDS, 3 April 2024) discloses a clinical trial of AG-384 (mitapivat). This study was an intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Clinical Trial NCT04000165 fails to teach the use of amorphous or crystalline forms of mitapivat.
Sizemore discloses amorphous and crystalline hemisulfate salt forms of mitapivat. Also provided are pharmaceutical compositions comprising the amorphous and crystalline hemisulfate salt forms, methods of their manufacture, and uses thereof for treating conditions associated with pyruvate kinases such as pyruvate kinase deficiency (Abstract). PKR activators can be beneficial to treat pyruvate kinase deficiency, thalassemia, abetalipoproteinemia, sickle cell disease, paroxysmal nocturnal hemogloburina, anemia, and hemolytic anemia (Paragraph 0002). Provided herein are amorphous and crystalline hemisuflate forms of a compound having the formula
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(Paragraph 0005). As used herein, crystalline form A is a hemisulfate sesquihydrate of mitapivat. Crystalline form A can have Formula A or Formula B
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(Paragraph 0057). Also provided herein is an amorphous form of hemisulfate salt of a compound having the formula
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(Paragraph 0083). Paragraph 00113 discloses the administration of crystalline or amorphous forms of these compounds at doses between 2 mg and 3000 mg per day. The crystalline and amorphous forms described herein are allosteric activators of PKR and are generally useful for treating the underlying condition of PKD (Paragraph 00120).
Agresta discloses methods for using compounds which activate pyruvate kinase (Abstract). The compound used in these methods is mitapivat (referred to in this application as Compound 1) (Page 4).In some embodiments, the compound is administered orally twice daily at dosages from about 10 mg to about 1000 mg every 12 hours (Page 11). In another aspect, the present invention provides a method of evaluating a subject, the method comprising administering mitapivat and acquiring information regarding the occurrence of an adverse event to thereby evaluate the subject (Page 12-13). Lower or higher doses than those recited may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, the patient’s disposition to the disease, drug combination, the severity and course of the disease condition or symptoms, and the judgement of the treating physician. Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination may be administered. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level (Page 34).
Clinical Trial NCT04000165, Sizemore, and Agresta are considered analogous to the claimed invention as all are involved in the use of mitapivat for the treatment and management of conditions associated with pyruvate kinase. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to use the teachings of the clinical trial, Sizemore, and Agresta to arrive at the method of discontinuing the use of mitapivat. The clinical trial discloses the use of mitapivat with the effect of increasing the subject’s hemoglobin level by adapting the dosing scheme and administering 5 mg BID. Steps such as adjusting a dosage and/or discontinuing a treatment regimen if adverse effects are noted are intellectual steps that one of ordinary skill in the art (a medical professional such as a medical doctor or nurse) would usually undertake, and is part of the routine of what is performed when treating a patient with a therapeutic agent. Therefore, the modification of the method disclosed by Clinical Trial NCT04000165 to arrive at the specific method which is claimed is prima facie obvious optimization within prior art conditions or through routine experimentation (See MPEP § 2144 II (A)).
Regarding Claims 23-28, the prior art does not specifically teach a kit as claimed. However, the prior art teaches these dosages, as well as the monitoring of adverse events following administration of mitapivat. Thus, it would be obvious to one of ordinary skill in the art to combine these dosages for a tapering regimen into a kit for ease of use of the patient, which would increase patient compliance with the dosing regimen and lead to improved therapeutic outcomes.
Regarding Claims 29-40, mitapivat is useful for the treatment of pyruvate kinase deficiencies and conditions which arise from this, which includes different forms of anemia, and this is known in the prior art as taught by both Sizemore and Agresta. Thus, patients which are being treated with mitapivat are at risk of developing, or currently suffer from, acute hemolysis or anemia, and thus, should be monitored for these conditions during tapering of the treatment.
Regarding Claims 41-49, Sizemore discloses both amorphous and crystalline forms of mitapivat, as well as hemisulfate sesquihydrate salts of mitapivat. It would be obvious to utilize these forms of mitapivat as the formation of amorphous or salt forms of compounds is commonly used to improve pharmacokinetic properties of therapeutic agents. Figure 22 of Sizemore shows that orally administered hemisulfate sesquihydrate has a greater AUC compared to the crystalline free base form of mitapivat, providing a motivation and reasonable expectation of success for selecting this specific crystalline salt form.
Claims 1, 3, 5, and 23-49 are rejected under 35 U.S.C. 103 as being unpatentable over Grace (Blood, 2019; 134 (Suppl. 1):3512) in view of Sizemore (WO 2019/104134; Publication Date: 31 May 2019) and Agresta (WO 2016/201227; Publication Date: 15 December 2016).
Grace (See IDS, 4 April 2024) discloses the results of a clinical trial using mitapivat in patients with pyruvate kinase deficiency. Patients were initially randomized 1:1 to receive mitapivat 50 mg BID or 300 mg DID for a 6-month core period. Dose adjustments were allowed during the core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety improvements in Hb levels and markers of hemolysis were sustained.
Grace fails to teach the use of amorphous or crystalline forms of mitapivat.
The teachings of Sizemore and Agresta are described previously and are fully incorporated into this rejection.
Grace, Sizemore, and Agresta are considered analogous to the claimed invention as all are involved in the use of mitapivat for the treatment and management of conditions associated with pyruvate kinase. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to use the teachings of Grace, Sizemore, and Agresta to arrive at the method of discontinuing the use of mitapivat. Grace discloses the use of mitapivat with the effect of increasing the subject’s hemoglobin level by adapting the dosing scheme and administering 50 mg BID, with dosage adjustments based on safety and efficacy. Steps such as adjusting a dosage and/or discontinuing a treatment regimen if adverse effects are noted are intellectual steps that one of ordinary skill in the art (a medical professional such as a medical doctor or nurse) would usually undertake, and is part of the routine of what is performed when treating a patient with a therapeutic agent. Therefore, the modification of the method disclosed by Grace to arrive at the specific method which is claimed is prima facie obvious optimization within prior art conditions or through routine experimentation (See MPEP § 2144 II (A)).
Regarding Claims 23-28, the prior art does not specifically teach a kit as claimed. However, the prior art teaches these dosages, as well as the monitoring of adverse events following administration of mitapivat. Thus, it would be obvious to one of ordinary skill in the art to combine these dosages for a tapering regimen into a kit for ease of use of the patient, which would increase patient compliance with the dosing regimen and lead to improved therapeutic outcomes.
Regarding Claims 29-40, mitapivat is useful for the treatment of pyruvate kinase deficiencies and conditions which arise from this, which includes different forms of anemia, and this is known in the prior art as taught by both Sizemore and Agresta. Thus, patients which are being treated with mitapivat are at risk of developing, or currently suffer from, acute hemolysis or anemia, and thus, should be monitored for these conditions during tapering of the treatment.
Regarding Claims 41-49, Sizemore discloses both amorphous and crystalline forms of mitapivat, as well as hemisulfate sesquihydrate salts of mitapivat. It would be obvious to utilize these forms of mitapivat as the formation of amorphous or salt forms of compounds is commonly used to improve pharmacokinetic properties of therapeutic agents. Figure 22 of Sizemore shows that orally administered hemisulfate sesquihydrate has a greater AUC compared to the crystalline free base form of mitapivat, providing a motivation and reasonable expectation of success for selecting this specific crystalline salt form.
Claims 1, 3, 5, and 23-49 are rejected under 35 U.S.C. 103 as being unpatentable over van Beers (Blood, 2019; 134 (Suppl. 1):4791) in view of Sizemore (WO 2019/104134; Publication Date: 31 May 2019) and Agresta (WO 2016/201227; Publication Date: 15 December 2016).
Van Beers (See IDS, 3 April 2024) performed a study of the use of mitapivat in adults with pyruvate kinase deficiency. This study evaluated the efficacy and safety of mitapivat. Adults with PK deficiency who are not regularly transfused were randomized in a 1:1 ratio to mitapivat (orally administered, BID) or matched placebo. The study consists of a screening period of up to 42 days, a 12-week dose optimization period, and a 12-week fixed dose period. During the dose optimization period, mitapivat or matched placebo is titrated up to each subject’s individually optimized dose, with an initial dose of 5 mg BID for all subjects and 2 sequential dose increases (from 5 to 20 mg BID and from 20 to 50 mg BID) depending on safety and Hb changes.
Van Beers fails to teach the use of amorphous or crystalline forms of mitapivat.
The teachings of Sizemore and Agresta are described previously and are fully incorporated into this rejection.
Van Beers, Sizemore, and Agresta are considered analogous to the claimed invention as all are involved in the use of mitapivat for the treatment and management of conditions associated with pyruvate kinase. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to use the teachings of Van Beers, Sizemore, and Agresta to arrive at the method of discontinuing the use of mitapivat. Van Beers discloses the use of mitapivat with the effect of increasing the subject’s hemoglobin level by adapting the dosing scheme and administering from 5 to 50 mg of mitapivat BID, with dosage adjustments based on safety and efficacy. Steps such as adjusting a dosage and/or discontinuing a treatment regimen if adverse effects are noted are intellectual steps that one of ordinary skill in the art (a medical professional such as a medical doctor or nurse) would usually undertake, and is part of the routine of what is performed when treating a patient with a therapeutic agent. Therefore, the modification of the method disclosed by Van Beers to arrive at the specific method which is claimed is prima facie obvious optimization within prior art conditions or through routine experimentation (See MPEP § 2144 II (A)).
Regarding Claims 23-28, the prior art does not specifically teach a kit as claimed. However, the prior art teaches these dosages, as well as the monitoring of adverse events following administration of mitapivat. Thus, it would be obvious to one of ordinary skill in the art to combine these dosages for a tapering regimen into a kit for ease of use of the patient, which would increase patient compliance with the dosing regimen and lead to improved therapeutic outcomes.
Regarding Claims 29-40, mitapivat is useful for the treatment of pyruvate kinase deficiencies and conditions which arise from this, which includes different forms of anemia, and this is known in the prior art as taught by both Sizemore and Agresta. Thus, patients which are being treated with mitapivat are at risk of developing, or currently suffer from, acute hemolysis or anemia, and thus, should be monitored for these conditions during tapering of the treatment.
Regarding Claims 41-49, Sizemore discloses both amorphous and crystalline forms of mitapivat, as well as hemisulfate sesquihydrate salts of mitapivat. It would be obvious to utilize these forms of mitapivat as the formation of amorphous or salt forms of compounds is commonly used to improve pharmacokinetic properties of therapeutic agents. Figure 22 of Sizemore shows that orally administered hemisulfate sesquihydrate has a greater AUC compared to the crystalline free base form of mitapivat, providing a motivation and reasonable expectation of success for selecting this specific crystalline salt form.
Claims 1, 3, 5, and 23-49 are rejected under 35 U.S.C. 103 as being unpatentable over Xu (Blood, 2020; 136 (Suppl. 1):21-22) in view of Sizemore (WO 2019/104134; Publication Date: 31 May 2019) and Agresta (WO 2016/201227; Publication Date: 15 December 2016).
Xu (See IDS, 3 April 2024) performed a clinical study of mitapivat in subjects with sickle cell disease. Subjects received either 3 or 4 ascending dose levels of mitapivat (5 mg BID, 20 mg BID, 50 mg BID, 100 mg BID) for 2 weeks duration each, followed by a 12-15 day drug taper. The initial six subjects escalated to a maximum dose of 50 mg BID, and the subsequent 2 subjects escalated up to a 100 mg BID dose following a protocol amendment. Only 1 serious adverse event was attributed to mitapivat, a vaso-occlusive crisis during drug taper, after which the protocol was amended to increase the length of taper from 9 to 12 days for the 50 mg BID dose and 15 days for the 100 mg BID dose. No VOCs have occurred during core period or on the prolonged drug taper.
Xu fails to teach the use of amorphous or crystalline forms of mitapivat.
The teachings of Sizemore and Agresta are described previously and are fully incorporated into this rejection.
Xu, Sizemore, and Agresta are considered analogous to the claimed invention as all are involved in the use of mitapivat for the treatment and management of conditions associated with pyruvate kinase. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to use the teachings of Xu, Sizemore, and Agresta to arrive at the method of discontinuing the use of mitapivat. Xu discloses the use of mitapivat with the effect of increasing the subject’s hemoglobin level by adapting the dosing scheme and administering from 5 to 100 mg of mitapivat BID, with a tapering period of 12-15 days following this treatment. Steps such as adjusting a dosage and/or discontinuing a treatment regimen if adverse effects are noted are intellectual steps that one of ordinary skill in the art (a medical professional such as a medical doctor or nurse) would usually undertake, and is part of the routine of what is performed when treating a patient with a therapeutic agent. Therefore, the modification of the method disclosed by Xu to arrive at the specific method which is claimed is prima facie obvious optimization within prior art conditions or through routine experimentation (See MPEP § 2144 II (A)).
Regarding Claims 23-28, the prior art does not specifically teach a kit as claimed. However, the prior art teaches these dosages, as well as the monitoring of adverse events following administration of mitapivat. Thus, it would be obvious to one of ordinary skill in the art to combine these dosages for a tapering regimen into a kit for ease of use of the patient, which would increase patient compliance with the dosing regimen and lead to improved therapeutic outcomes.
Regarding Claims 29-40, mitapivat is useful for the treatment of pyruvate kinase deficiencies and conditions which arise from this, which includes different forms of anemia, and this is known in the prior art as taught by both Sizemore and Agresta. Thus, patients which are being treated with mitapivat are at risk of developing, or currently suffer from, acute hemolysis or anemia, and thus, should be monitored for these conditions during tapering of the treatment.
Regarding Claims 41-49, Sizemore discloses both amorphous and crystalline forms of mitapivat, as well as hemisulfate sesquihydrate salts of mitapivat. It would be obvious to utilize these forms of mitapivat as the formation of amorphous or salt forms of compounds is commonly used to improve pharmacokinetic properties of therapeutic agents. Figure 22 of Sizemore shows that orally administered hemisulfate sesquihydrate has a greater AUC compared to the crystalline free base form of mitapivat, providing a motivation and reasonable expectation of success for selecting this specific crystalline salt form.
Conclusion
Claims 1, 3, 5 and 23-49 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625