Glyceryl phenylbutyrate - USA

IPR decision (Oct 05, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-01767	07/13/2017	01/30/2018	Par Pharma	9,254,278	Terminated-Settled
IPR2017-01768	07/13/2017	01/30/2018	Par Pharma	9,095,559	Terminated-Settled
IPR2017-01769	07/13/2017	01/30/2018	Par Pharma	9,326,966	Terminated-Settled

On US’278 patent, Lupin filed IPR (IPR2017-01159) on 03/27/2017 which was terminated because of settlement on 07/26/2018.

On US’559 patent, Lupin filed IPR (IPR2016-00829) on 04/01/2016 & final written decision (unpatentable) issued by PTAB on 09/26/2017.

On US’966 patent, Lupin filed IPR (IPR2017-01160) on 03/27/2017 which was terminated because of settlement on 07/26/2018.

On US 9,254,278 (Horizon Therapeutics, Inc.; Exp: Mar 9, 2032)

1. A method of treating a subject with a urea cycle disorder, the method comprising: administering to the subject in need thereof glyceryl tri-[4-phenylbutyrate] in an amount sufficient to produce a fasting plasma ammonia level that is less than half the upper limit of normal for plasma ammonia level.

4. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level, and wherein the method further comprises restricting the subject's dietary protein intake.

8. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level, and wherein the method further comprises monitoring the subject's ammonia levels if the glyceryl tri-[4-phenylbutyrate] is not being adequately digested by the subject's pancreatic lipases.

12. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of sodium phenylbutyrate and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; (c) administering an initial dosage of glyceryl tri-[4-phenylbutyrate], wherein the initial dosage is determined by the amount of the initial dosage of sodium phenylbutyrate, and (d) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage of glyceryl tri-[4-phenylbutyrate] if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

US 9,095,559 (Horizon Therapeutics, Inc.; Exp: Mar 9, 2032)

1. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

2. A method of treating a subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

3. A method of administering glyceryl tri-[4-phenylbutyrate] to a subject having a urea cycle disorder, the method comprising: (a) measuring a first fasting plasma ammonia level for the subject; (b) comparing the first fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an initial dosage of glyceryl tri-[4-phenylbutyrate] to the subject if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level and less than the upper limit of normal for plasma ammonia level.

US 9,326,966 (Horizon Therapeutics, Inc.; Exp: Mar 9, 2032)

1. A method of treating a subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level, wherein the upper limit of normal for plasma ammonia level is in the range of 26-64 .mu.mol/L.

6. A method of treating a pediatric subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the pediatric subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

9. A method of treating an adult subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the adult subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

12. A method of treating a patient having a urea cycle disorder comprising: (a) administering an initial effective dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100) to the patient, wherein the initial effective dosage is calculated based on body surface area of the patient; (b) measuring the patient's urinary PAGN and/or fasting plasma ammonia level to determine whether to change the dosage of the glyceryl tri-[4-phenylbutyrate] (HPN-100); and (c) administering a subsequent effective dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100) to the patient that is either the same as the initial effective dosage or is an increased dosage, wherein said increased dosage, if any, is calculated based on the patient's urinary PAGN and/or fasting plasma ammonia level.