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 .1
Status of Claims
Claims 24-30 and 33-46 are pending and under examination
Response to Arguments
Applicant’s arguments and amendment of claim 24, filed May 20, 2025, with respect to the rejection of claims 24, 28-30, and 45-46 under 35 U.S.C. § 102(a)(1) and/or (a)(2) as being anticipated by WO Publication No. 2018/162527 A1 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of WO 527 in view of Kaufmann.
Applicant’s arguments, filed May 20, 2025, with respect to the rejection of claims 24-26 and 28-46 under 35 U.S.C. § 102(a)(1) and/or (a)(2) as being anticipated by "Selexipag Intravenous (IV) Pulmonary Arterial Hypertension Trial ACT 293897 Jan 27 2017", have been fully considered and are persuasive. Therefore, the rejection has been withdrawn.
Applicant’s arguments, filed May 20, 2025, with respect to the rejection of claims 24-46 under 35 U.S.C. § 103 as being obvious by "Selexipag Intravenous (IV) Pulmonary Arterial Hypertension Trial ACT 293897 Jan 27 2017", have been fully considered and are persuasive. Therefore, the rejection has been withdrawn.
New 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 24-30 and 33-46 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/162527 A1 (WO 527), published Sept 13, 2018 in view of Kaufmann et al. Eur. J. Clin. Pharmacol. 2017, 73:151-60. WO 527 and Kauffmann were cited on the IDS provided by Applicant.
Independent claim 24 requires the core elements of
administering intravenous (IV) selexipag2
PNG
media_image1.png
154
320
media_image1.png
Greyscale
to a patient in need (unable to take oral selexipag) afflicted with pulmonary arterial hypertension (PAH)
wherein the IV dose to oral dose ratio is about 1.125 to 1.
Orally dosed selexipag tablets are FDA approved and marketed as UPTRAVI® by Actelion Pharmaceuticals.
In terms of claim interpretation of ““wherein the IV dose to oral dose ratio is about 1.125, ” this limitation is being interpreted as detailed in the specification, where the ratio of the intravenous dose of selexipag to the oral dose of selexipag about 1.125 to about 1, see paragraph 110 of the specification, or more simply about 1.125 : about 1.
Regarding claim 24, WO 527 describes aqueous selexipag pharmaceutical compositions with glycine, polysorbate 80 and an aqueous phosphate buffer; and lyophilized compositions of the aqueous compositions, which are reconstituted and suitable for IV administration. See abstract.
See also claims 1-4 reciting selexipag compositions, as well as claims 5-9 which are said to be lyophilized compositions appropriate for reconstitution into aqueous selexipag formulations. WO 527 teaches various embodiments of “chemically and physically stable aqueous [selexipag] formulations that can reproducibly be lyophilized to a stable cake and reconstituted to a controlled composition which is suitable for i.v. administration.” See page 3, line 34 bridging to page 4, line 2.
Regarding the patient in need of claim 24, WO 527 teaches in “certain instances the use of an oral formulation of selexipag may be inappropriate or impossible (e.g. in urgent care, or in case a patient is for some reasons unable to swallow a tablet).” See page 3, lines 9-10 of WO 527. WO 527 discloses a clinical study entitled “Safety Study of the Switch from Oral Selexipag to Intravenous Selexipag in Subjects With Stable Pulmonary Arterial Hypertension" has been posted on 15 June 2017 (https://clin icaltrials.gov/ct2/show/NCT03187678).” See page 3, lines 21-24.
While teaching the claimed subject in need (patient is unable to swallow a tablet), to be treated with IV selexipag, WO 527 does not explicitly recite the limitation wherein the IV dose to oral dose ratio is about 1.125 to 1.
However, it is known that selexipag is metabolized into a pharmaceutically active metabolite ACT-3336793. It is known that intravenous(I.V.) administration of any drug, including selexipag, avoids first-pass metabolism (via the liver). First-pass metabolism occurs for orally administered drugs, including selexipag. Per Kaufmann, first-pass (liver) metabolism converts selexipag to its pharmaceutically active metabolite ACT-333679. Kaufmann teaches, “Enzymatic hydrolysis of selexipag yields ACT-333679, the active metabolite of selexipag. It has also been shown that CYP2C8 and CYP3A4 [known liver enzymes] are involved in the [first pass] metabolism of selexipag and ACT-333679.” See page 151, column 2.
A person having ordinary skill in the art (PHOSITA) would recognize that, unlike orally dosed selexipag, IV administered selexipag avoids first pass liver metabolism to convert it into the active metabolite ACT-333679, as it goes directly into the circulatory system (systemic). Because of this, IV administered selexipag requires higher doses (i.e., greater than a 1:1 ratio dose compared to oral selexipag dose) in order to adjust said dose to achieve the same amounts active metabolite equivalent to an oral dose. While not expressing said 1.125 to 1 ratio, it is noted that Table 1 of Kaufmann teaches various pharmacokinetic parameters comparing IV and oral dosed selexipag, where a PHOSITA would routinely adjust an IV to oral dose ratio (such as 1.125 to 1) to achieve equivalent doses of selexipag, in terms of pharmacokinetic parameters (Cmax, tmax, AUC (ng.h/mL), and/or half-life) of measured active metabolite, ACT-333679.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference to (WO 527) treat a subject in need with IV selexipag, who is unable to take an oral dose of selexipag, and modify with the secondary reference (Kaufmann) in order to increase the IV dose vs oral dose selexipag to routinely optimize to a ratio of 1.125 : 1 The rationale to do so is it is known IV administration of drugs avoids the first pass metabolism of oral drugs prior to systemic circulation, where such first pass metabolizes selexipag into its active metabolite, ACT-333679.
The PHOSITA would have had a reasonable expectation of success because IV treatment of patients unable to be dosed orally is a well-known in the art, where it is known IV systemically administered drugs by-passing first liver metabolism would require higher doses administered compared to oral dosages, where with drugs like selexipag, the desired metabolite is pharmaceutically active.
Regarding claim 25 and the limitation where the patient receives oral dosed selexipag for at least 28 days prior to the IV administration of selexipag, a PHOSITA would routinely treat such a patient as selexipag is known to be used to treat or prevent pulmonary arterial hypertension (PAH). See WO 527 page 1, lines 18-20.
WO 527 teaches selexipag is noted to treat various chronic conditions as well. Accordingly, it would be routine for a PHOSITA to treat PAH for over 28 days with an oral dosage, as selexipag is known for its use to treat chronic conditions (WO 527 page 1, line 18 to page 2, line 19) likely requiring treatment for a period of over a month, i.e. greater than 28 days as claimed. Note where page 2 lines 25-26 disclosed selexipag to delay disease progression and reduce risk of hospitalization of PAH, both situations where PAH patients in need of treatment would require chronic selexipag oral treatment, such as periods for over 28 days. Also note, WO 527 discloses a clinical study entitled “Safety Study of the Switch from Oral Selexipag to Intravenous Selexipag in Subjects With Stable Pulmonary Arterial Hypertension" has been posted on 15 June 2017 (https://clinicaltrials.gov/ct2/show/NCT03187678).” See page 3, lines 21-24. The teaching that this clinical study involves treatment of patients stabilized with oral selexipag before switching to IV administration would be readily apparent to a PHOSITA of a chronic, long term scenario of over 28 days which would routinely be treated orally with selexipag by a PHOSITA.
Regarding claim 26 and the limitation that a patient did not receive any other prostacyclin for 28 days other than selexipag, it would be obvious for a PHOSITA to treat such a claimed subject where WO 527 teaches selexipag has approved market approval for the treatment of PAH. See page 2, lines 20-25. As selexipag is FDA approved for the treatment of PAH (delay disease progression and reduce risk of hospitalization), it would be routine for a PHOSITA to optimize treatment of a patient who has solely been treated for chronic PAH with selexipag, and no other prostacyclin or prostacyclin analog chronically, i.e. for 28 days period prior. Also note, WO 527 discloses a clinical study entitled “Safety Study of the Switch from Oral Selexipag to Intravenous Selexipag in Subjects With Stable Pulmonary Arterial Hypertension" has been posted on 15 June 2017 (https://clinicaltrials.gov/ct2/show/NCT03187678).” See page 3, lines 21-24. The fact that this clinical study involves treatment of patients stabilized with ONLY oral selexipag before switching to IV administration implies a chronic, long term scenario of over 28 days which would routinely treated orally with selexipag ONLY by a PHOSITA.
Regarding claim 27 and the monitoring of blood pressure in the subject (less 90 mmHg), Kaufmann teaches the safety measure of measuring blood pressure (BP) during the IV administration of selexipag. See page 153, column 1. A PHOSITA would routinely monitor for low blood pressure (systolic BP less than 90mmHg), during the administration of IV selexipag as part of a basic safety protocol taught by Kaufmann.
Claims 28-30 recite the limitation wherein the subject in need is administered in ranges about 200 μg to about 1000 or 1600 μg twice daily; or about 1200 μg to about 1600 μg twice daily. Regarding claims 28-30, WO 527 teaches a reconstituted pharmaceutical composition (IV) wherein the dose of selexipag is about 4.5 μg/ml, 9 μg/ml, 13.5 10 μg/ml, 18 μg/ml, 22.5 μg/ml, 27 μg/ml, 31.5 μg/ml, or 36 μg/ml. See claim 17. A PHOSITA, knowing the concentration of selexipag as taught by WO 527 would routinely adjust volumes of such a reconstituted pharmaceutical composition so as to arrive at the claimed selexipag dose.
Regarding claim 33 and where the patient resumes the same oral dose before the IV dose administration, WO 527 teaches in “certain instances the use of an oral formulation of selexipag may be inappropriate or impossible (e.g. in urgent care, or in case a patient is for some reasons unable to swallow a tablet).” See page 3, lines 9-10 of WO 527. It would be routine for a PHOSITA to optimize the oral dose of selexipag for the PAH patient to the same dose prior to the IV administration.
Regarding claim 34 and a selexipag treatment regimen, where a first treatment period comprises oral administration, a second period comprises IV administration and a third period comprises resumption of the same oral dose prior to IV, a PHOSITA would routinely optimize such a treatment regimen of claim 34 as detailed above in the rejection of claim 33. It would be obvious to do so as, WO 527 teaches a scenario where a patient already orally dosed selexipag, is in need of IV administration (as they can’t take the oral dose) and administered afterwards the same oral dose of selexipag as prior to the IV selexipag, once the patient is able to resume oral dosing.
Regarding claims 35-37 and the limitations of the following pharmacokinetic (PK) parameters where selexipag plasma-concentration time is about two times greater in periods in the second period than the first period; where ACT-333679 plasma-concentration time curve is comparable in the first and second period; and where time to reach max plasma concentration at steady state of selexipag and ACT-333679 is comparable in the first and second period, it is noted that Kaufmann teaches the need to have higher doses of IV selexipag, and consequently higher plasma concentration time curves versus orally dosed selexipag, due to the avoidance of first pass metabolism into active metabolite by IV selexipag.
Therefore, a PHOSITA would routinely adjust doses to achieve higher plasma concentration time curves with IV selexipag during the second period as per claim 35, so as to achieve a similar therapeutic effect as orally dosed selexipag. Note that Table 1 of Kaufmann teaches pharmacokinetic parameters of selexipag and ACT-333679 after IV and oral dosing of selexipag so as to provide a PHOSITA the requisite information to optimize dosing A PHOSITA would adjust IV dosing to achieve a desired increased plasma-concentration time curve greater than with oral dosing so as to compensate for the lack of first pass metabolism into active metabolite as with oral selexipag dosing.
Further, with regard to claims 36-37, as the goal to achieve similar pharmacokinetics of the active metabolite, ACT-333679, whether the dose is oral or IV, in the patient in need, it would be routine for a PHOSITA to do so to reach comparable plasma-concentration time curves between a first oral administration time period and a second IV administration time period.
Note that Table 1 of Kaufmann teaches pharmacokinetic parameters of selexipag and ACT-333679 after IV and oral dosing of selexipag so as to provide a PHOSITA the requisite information to optimize dosing so as to arrive at equivalent times to maximum plasma concentration and area under plasma concentration time curves between oral and IV administered dosing in the first and second time periods claimed.
Regarding claim 38 and administration of oral doses twice daily, once before mid-day and once after mid-day, based on the Figure 1 time and concentration curves and the half-life times disclosed by Table 1, a PHOSITA would note that ACT-333679 metabolite when administered orally has a half-life of 11.0 hours and selexipag has half-life of 0.9 hour, which would guide a PHOSITA to administer oral selexipag twice a day as per a combined about 12 hour half-life of both selexipag and metabolite in a subject.
Regarding claim 40 and the limitation of about an 80-90 minute infusion time, Kaufmann teaches that 200 mcg of selexipag was infused over 80 minutes. See Table 1, page 155.
Regarding claims 39 and 41-42 and the limitations of three IV infusion doses, where two are administered once before mid-day and once after mid-day, it would obvious for a PHOSITA to do so as the administration of 3 doses a day based on the Figure 1 time and concentration curves and Table 1 of Kaufmann disclosing the a) linear and b) semilogarithmic scale of both selexipag and ACT-333679 plasma concentrations versus time in a subject.
PNG
media_image2.png
606
776
media_image2.png
Greyscale
Based on Figure 1 and the half-life times disclosed by Table 1, a PHOSITA would note that ACT-333679 metabolite when administered via IV, has a measured half-life in a subject of 9.3 hours and selexipag has a half-life of 0.84 hours, where the PHOSITA would administer IV twice within a within a day, once before mid-day and once after mid-day, followed by a third dose administered the next day after the second infusion. Based on total combined selexipag and ACT-333679 total time half-life time, a PHOSITA would have a rationale to administer a first pre-midday dose, followed by a later second post-midday dose, where a third dose would be likely be administered the next day, after an evening of sleep, as required by claims 39 and 41-42.
Regarding claim 43, it would be obvious for a PHOSITA to resume orally dosed selexipag to a patient, after the third dose of an IV selexipag dosing, as the noted by WO 527, such a patient would have been stabilized by oral selexipag to treat PAH. See page 3, lines 21-24 noting the “Safety Study of the Switch from Oral Selexipag to Intravenous Selexipag in Subjects With Stable Pulmonary Arterial Hypertension.”
Regarding claim 44 and IV dose of selexipag comprises about 225 μg to about 1800 μg twice daily, WO 527 teaches a reconstituted pharmaceutical composition (IV) wherein the dose of selexipag is about 4.5 μg/ml, 9 μg/ml, 13.5 10 μg/ml, 18 μg/ml, 22.5 μg/ml, 27 μg/ml, 31.5 μg/ml, or 36 μg/ml. See claim 17. A PHOSITA, knowing the concentration of selexipag as taught by WO 527 would routinely adjust volumes of such a reconstituted pharmaceutical composition so as to arrive at the claimed selexipag dose.
Regarding claim 45 and the oral dose tablet limitation, WO 527 teaches the oral form that a patient is unable to swallow is tablet. See page 3 lines 9-11.
Regarding claim 46 and the limitation that the patient is temporarily unable to take oral medication due a hospitalization, WO 527 teaches a patient where oral formulations of selexipag are inappropriate or impossible, e.g. in urgent care. See page 3, lines 9-10. The limitation of hospitalization is interpreted to include urgent care such as emergency room care in a hospital setting.
Conclusion
No claims are allowed.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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, Adam C. Milligan can be reached at (571) 270-7674. 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.
/WILLIAM Y LEE/
Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 This application claims earliest priority to 62/860,121, filed June 11, 2019.
2 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide
Selexipag from Actelion Pharmaceuticals LTD.
NS-304
ACT-293987
3 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino )butoxy)acetic acid
MRE-269