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 .
Current Status of 18/288,888
Claims 1, 3, 5, 24, and 29-34 have undergone amendments. Thus, Claims 1, 3, 5, and 23-49, submitted on 18 June 2026, 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.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 18 June 2026, is acknowledged and has been considered.
Response to Arguments
The objection to Claim 3 and 5 is withdrawn. Applicant has added the word “salt” to the phrase “pharmaceutically acceptable salt”.
The objection to Claims 24-34 is withdrawn. Applicant has amended the phrase to recite “acute hemolysis, anemia, or both” to correct the informality.
The 35 U.S.C. § 112(b) rejection of Claims 32-34 is withdrawn. Applicant has removed the “step c)”, obviating the indefiniteness.
The 35 U.S.C. § 103 rejection of Claims 1, 3, 5, and 23-49 over Clinical Trial NCT0400165 in view of Sizemore and Agresta is withdrawn. Applicant has amended the claims to recite a method of minimizing the risk of acute hemolysis, which is not taught, suggested, nor is there any motivation provided for, in the clinical trial, Sizemore, or Agresta.
The 35 U.S.C. § 103 rejection of Claims 1, 3, 5, and 23-49 over Grace in view of Sizemore and Agresta is withdrawn. Applicant has amended the claim to recite a method of minimizing risk of acute hemolysis, which was not disclosed in the prior claim set. However, a rejection is made over Grace in view of Sizemore and Agresta as a result of these amendments (See response to amendments, below).
The 35 U.S.C. § 103 rejection of Claims 1, 3, 5, and 23-49 over van Beers in view of Sizemore and Agresta is withdrawn. Applicant has amended the claims to recite a method of minimizing the risk of acute hemolysis, which is not taught, suggested, nor is there any motivation provided for, by van Beers, Sizemore, or Agresta.
The 35 U.S.C. § 103 rejection of Claims 1, 3, 5, and 23-49 over Xu in view of Sizemore and Agresta is withdrawn. Applicant has amended the claims to recite a method of minimizing the risk of acute hemolysis, which is not taught, suggested, nor is there any motivation provided for, by Xu, Sizemore, or Agresta.
Response to Amendment
The 35 U.S.C. § 103 rejection of Claims 1, 3, 5 and 23-49 over Grace in view of Sizemore and Agresta is now modified to reference the minimization of acute hemolysis which was disclosed in the Grace New England Journal of Medicine article due to the newly added amendments which were not found in the prior claim set. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
Response to Amendment
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 Grace (N Engl J Med, 391; 10, 2019), Sizemore (WO 2019/104134; Publication Date: 31 May 2019) and Agresta (WO 2016/201227; Publication Date: 15 December 2016).
Determining the Scope and Contents of the Prior Art:
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 does not disclose the minimization of the risk of acute hemolysis.
Grace (See IDS, 4 April 2024) provides an overview of an uncontrolled phase 2 study of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were assigned to either 50 mg or 300 mg of mitapivat twice daily for 24 weeks. Dose decreases were allowed for adverse events thought to be related to mitapivat or if the hemoglobin level exceeded the midpoint of the normal range (>15.0 g per deciliter in men and >13.5 g per deciliter in women). Early in the trial, two patients had acute hemolysis after the abrupt discontinuation of the 300-mg dose of mitapivat following a rapid increase in the hemoglobin level. An additional seven patients for whom dose reduction was necessary because of a robust hemoglobin response underwent dose tapering, according to a protocol amendment, without acute hemolysis (Page 935, Dose Selection).
Grace 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
PNG
media_image1.png
169
489
media_image1.png
Greyscale
(Paragraph 0005). As used herein, crystalline form A is a hemisulfate sesquihydrate of mitapivat. Crystalline form A can have Formula A or Formula B
PNG
media_image2.png
317
674
media_image2.png
Greyscale
(Paragraph 0057). Also provided herein is an amorphous form of hemisulfate salt of a compound having the formula
PNG
media_image3.png
156
471
media_image3.png
Greyscale
(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).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The prior art does not specifically disclose a method for reducing the risk of acute hemolysis in a subject discontinuing treatment of mitapivat.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have medical training, with further expertise in the treatment of hematological disorders using pharmacological agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Grace, 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, Grace, Sizemore, and Agresta to arrive at the method of reducing the risk of acute hemolysis in patients being treated with mitapivat by tapering the dosages which are used. 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. The second Grace study then demonstrates that there is a risk of acute hemolysis following the abrupt cessation of treatment with mitapivat, and that a dose reduction and help to mitigate the risk of this hemolysis. 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.
Conclusion
Claims 1, 3, 5, and 23-49 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
Prosecution Insights