
`
`l) S”"50F"“RICA
`
`WMWWQMW: 33E SEEMS} 5%. (£93
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`  
`March 21, 2016
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`           
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`         
`OF:
`
`
`Patent and "Hademark Office
`
`  
`APPLICATION NUMBER: 13/41 7,13 7
`    
`FILING DATE: March 09, 2012
`PATENT NUMBER: 8404215
`  
`    
`ISSUE DATE: March 26, 2013
`
`
`
`Certified by
`
`7&M75 Zak
`
`Under Secretary of Commerce
`for Intellectual Property
`and Director of the United States
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 1 of 262
`
`

`

`
`
`Electronic Acknowledgement Receipt
`
`
`EFS ID:
`
`12273906
`
`Application Number:
`
`13417137
`
`International Application Number:
`
`6423
`Confirmation Number:
`
`
`Title of Invention:
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING
`DRUGS
`
`
`
`502586 Authorized User
`
`
`
`First Named Inventor/Applicant Name:
`
`Bruce SCHARSCHMIDT
`
`Customer Number:
`
`34055
`
`Filer:
`
`Patrick D. Morris/Colleen Kirchner
`
`Patrick D. Morris
`Filer Authorized By:
`
`
`Attorney Docket Number:
`
`Receipt Date:
`
`Filing Date:
`
`79532.8003.USO2
`
`09-MAR-2012
`
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`Time Stamp:
`
`
`Application Type:
`
`Utility under 35 USC111(a)
`
`Payment information:
`yes
`Submitted with Payment
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`Payment Type
`
`Deposit Account
`
`Payment was successfully received in RAM
`$1025
`
`RAM confirmation Number
`6954
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`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
`Charge any Additional Fees required under 37 C.F.R. Section 1.16 (National application filing, search, and examination fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.1 7 (Patent application and reexamination processing fees)
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 2 of 262
`
`

`

`
`
`
`
`Drawings—only black and white line drawings
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`
`
`
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`
`Charge any Additional Fees required under 37 C.F.R. Section 1.1 9 (Document supply fees)
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`Multi
`Part /.zip (ifappl.)
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`
`18577
`
`Pages
`
`1
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`Transmittal of New Application
`
`Transmittalpdf
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`lCfd23l9bc7afa29323939d99abdf96d286d
`ebge
`
`no
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`2
`
`
`Warnings:
`Information:
`
`407442
`
`38
`US_Specification.pdf
`
`
`82636226d6be4af33c5624c17l 5dd929e34
`blel4
`
`
`Multipart Description/PDF files in .zip description
`
`Document Description
`
`Specification
`
`Warnings:
`Information:
`
`28687
`
`Petition to make special based on Age/
`Heahh
`
`1PetitiontoMakeSpecial.pdf
`
`befXJQ7bIbl bl/l 299338d25ef17815b6I7b9
`111002
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`no
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`Warnings:
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`38065
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`Fee Worksheet (SBO6)
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`662566fe$00c17I8alc686d59086b363210a
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`492771
`
`Total Files Size (in bytes)
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 3 of 262
`
`

`

`
`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`Ifa new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
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`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of 262
`
`

`

`Doc code : PET.OP.AGE
`
`PTO/SBIISO (07709)
`App,on Muse through 07/31/2012 OMB 055170031
`Description : Petition to make special based on Age/Health
`US. Patent and Trademark Office, U 8. DEPARTMENT OF COMMERCE
`Under the Paperwork ReduuliuIIAulul1995, nu persuns are required to respund to a uulleuliun ul Inlurmaliun unless it contains a valid OMB control number
`
`PETITION To MAKE SPECIAL BASED ON AGE FOR ADVANCEMENT OF EXAMINATION
`UNDER 37 CFR1.102(c)(1)
`
`Application Information
`
`Application
`Number
`
`Confirmation
`Number
`
`Attorney Docket
`.
`
`79532.8003.USOZ
`
`'
`
`2012-03-09
`
`Filing
`Date
`
`'
`
`FlrSt Named
`Inventor
`
`Bruce Scharschmidt
`
`Title Of Invention
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
` M A
`
`Scharschmidt A signature of the applicant or representative is required in accordance with 37 CFR 1.33 and 10.18.
`
`n application may be made special for advancement of examination upon filing ofa petition showing that the applicant is 65
`years of age, or more. No fee is required with such a petition. See 37 CFR 1.102(c)(1 ) and MPEP 708.02 (IV).
`
`APPLICANT HEREBY PETITIONS TO MAKE SPECIAL FOR ADVANCEMENT OF EXAMINATION IN THIS APPLICATION
`
`UNDER 37 CFR 1.102(c)(1) and MPEP 708.02 (IV) ON THE BASIS OF THE APPLICANT'S AGE.
`
`A grantable petition requires one of the following items:
`(1) Statement by one named inventor in the application that he/she is 65 years of age, or more; or
`(2) Certification by a registered attorney/agent having evidence such as a birth certificate, passport, driver's license, etc.
`showing one named inventor in the application is 65 years of age, or more.
`
`Name of Inventor who is 65 years of age, or older
`
`Given Name
`
`Bruce
`
`Middle Name
`
`Family Name
`
`Suffix
`
`Please see 37 CFR 1.4(d) for the format of the signature.
`
`Select (1) or (2):
`
`O (1) I am an inventor in this application and I am 65 years of age, or more.
`
`© (2) I am an attorney or agent registered to practice before the Patent and Trademark Office, and I certify that I am in possession of
`evidence, and will retain such in the application file record, showing that the inventor listed above is 65 years of age, or more.
`
`Si nature
`9
`
`/Patrick D. Morris/
`
`Date
`(YYYY_MM_DD)
`
`2012-03-09
`
`Name
`
`Patrick D. Morris
`
`Reg'strat'on
`Number
`
`53351
`
`EFSWeb 1.0.18
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 5 of 262
`
`

`

`Doc code : PET.OP.AGE
`
`PTO/SBIISO (07709)
`Am,me Muse through 07/31/2012 OMB 0551,0031
`Description : Petition to make special based on Age/Health
`US. Patent and Trademark Office, U 8. DEPARTMENT OF COMMERCE
`Under the Paperwurk Reduullun Aul ul 1995, nu persuns are required to respund to a uulleuliun ul lnlurmaliun unless it cunlains a valid OMB uunlrul number
`
`Privacy Act Statement
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`The Privacy Act of 1974 (PL. 93-579) requires that you be given certain information in connection with your submission of
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`The information provided by you in this form will be subject to the following routine uses:
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`The information on this form will be treated confidentially to the extent allowed under the Freedom of Information
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`A record from this system of records may be disclosed, as a routine use, to a Federal, State, or local law
`enforcement agency, if the USPTO becomes aware of a violation or potential violation of law or regulation.
`
`EFSWeb 1.0.18
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 6 of 262
`
`

`

`
`
`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`Title of Invention:
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING
`DRUGS
`
`
`
`‘
`
`Bruce SCHARSCHMIDT
`First Named Inventor/Applicant Name:
`
`
`Filer:
`
`Patrick D. Morris/Colleen Kirchner
`
`Attorney Docket Number:
`
`Filed as Small Entity
`
`Utility under 35 USC 1 1 1 (a) Filing Fees
`
`79532.8003.USOZ
`
`Description
`
`
`Fee Code
`Quantity
`
`sulJ-S-rgg; in
`
`Basic Filing:
`
`Utility filing Fee(E|ectronic filing)
`4011
`1
`95
`95
`
`
`Utility Search Fee
`
`Utility Examination Fee
`
`2111
`
`2311
`
`1
`
`1
`
`310
`
`125
`
`310
`
`125
`
`Pages:
`
`Claims:
`
`
`Claims in excess of20
`
`Multiple dependent claims
`
`2202
`
`2203
`
`‘
`
`9
`
`1
`
`l
`
`‘
`
`30
`
`225
`
`270
`
`225
`
`Miscellaneous-Filing:
`
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 7 of 262
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Description | FeeCode Quantity Amount | sufiggg; in
`
`Petition:
`
`Patent-Appeals-and-lnterference:
`
`
`Post-AlIowance-ancl-Post-lssuance:
`
`Extension-of—Time:
`
`Miscellaneous:
`
`Total in USD ($)
`
`1025
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 8 of 262
`
`

`

`
`
`Electronic Acknowledgement Receipt
`
`
`EFS ID:
`
`12273906
`
`Application Number:
`
`13417137
`
`International Application Number:
`
`6423
`Confirmation Number:
`
`
`Title of Invention:
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING
`DRUGS
`
`
`
`502586 Authorized User
`
`
`
`First Named Inventor/Applicant Name:
`
`Bruce SCHARSCHMIDT
`
`Customer Number:
`
`34055
`
`Filer:
`
`Patrick D. Morris/Colleen Kirchner
`
`Patrick D. Morris
`Filer Authorized By:
`
`
`Attorney Docket Number:
`
`Receipt Date:
`
`Filing Date:
`
`79532.8003.USO2
`
`09-MAR-2012
`
`20:28:09
`Time Stamp:
`
`
`Application Type:
`
`Utility under 35 USC111(a)
`
`Payment information:
`yes
`Submitted with Payment
`
`Payment Type
`
`Deposit Account
`
`Payment was successfully received in RAM
`$1025
`
`RAM confirmation Number
`6954
`
`Deposit Account
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
`Charge any Additional Fees required under 37 C.F.R. Section 1.16 (National application filing, search, and examination fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.1 7 (Patent application and reexamination processing fees)
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 9 of 262
`
`

`

`
`
`
`
`Drawings—only black and white line drawings
`
`
`
`
`
`
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.1 9 (Document supply fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.20 (Post Issuance fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.21 (Miscellaneous fees and charges)
`
`File Listing:
`
`Document
`
`Number
`
`
`.
`.
`File Size(Bytes)/
`Multi
`Part /.zip (ifappl.)
`Document Descnptlon m Message Digest
`
`18577
`
`Pages
`
`1
`
`Transmittal of New Application
`
`Transmittalpdf
`
`lCfd23l9bc7afa29323939d99abdf96d286d
`ebge
`
`no
`
`2
`
`
`Warnings:
`Information:
`
`407442
`
`38
`US_Specification.pdf
`
`
`82636226d6be4af33c5624c17l 5dd929e34
`blel4
`
`
`Multipart Description/PDF files in .zip description
`
`Document Description
`
`Specification
`
`Warnings:
`Information:
`
`28687
`
`Petition to make special based on Age/
`Heahh
`
`1PetitiontoMakeSpecial.pdf
`
`befXJQ7bIbl bl/l 299338d25ef17815b6I7b9
`111002
`
`no
`
`
`
`Warnings:
`Information:
`
`38065
`
`
`
`4
`
`Fee Worksheet (SBO6)
`
`fee—info.pdf
`
`662566fe$00c17I8alc686d59086b363210a
`lSLfi
`
`no
`
`Warnings:
`Information:
`
`492771
`
`Total Files Size (in bytes)
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 10 of 262
`
`

`

`
`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`Ifa new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
`1.53(b)—(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`Acknowledgement Receipt will establish the filing date of the application.
`
`National Stage of an International Application under 35 U.S.C. 371
`Ifa timely submission to enter the national stage of an international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/D0/E0/903 indicating acceptance of the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International Application Filed with the USPTO as a Receiving Office
`Ifa new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
`and ofthe International Filing Date (Form PCT/R0/105) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
`
`
`
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 11 of 262
`
`

`

`Patent
`79532.8003.USO2
`
`To:
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`NEW APPLICATION TRANSMITTAL - UTILITY
`
`Sir:
`
`Transmitted herewith for filing is a utility patent application:
`
`Inventor(s):
`
`Bruce Scharschmidt
`Masoud Mokhtarani
`
`Title:
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN
`SCAVENGING DRUGS
`
`I.
`
`PAPERS ENCLOSED HEREWITH FOR FILING UNDER 37 CFR § 1.53(b):
`
`2 Page(s) of Written Description
`
`2
`
`1
`
`g
`
`Page(s) Claims
`
`Page(s) Abstract
`
`Sheets of Drawings
`
`Sheets of Sequence Listing
`ADDITIONAL PAPERS ENCLOSED IN CONNECTION WITH THIS FILING:
`
`II.
`
`K4
`
`Petition to Make Special Based on Age for Advancement of Examination
`Under 37 CFR1.102(c)(1)
`
`III.
`
`U.S. PRIORITY:
`
`The present application claims the benefit of US. Provisional Application No.
`61/564,668, filed November 29, 2011, and US. Provisional Application No.
`61/542,100, filed September 30, 2011, the disclosures of which are incorporated by
`reference herein in their entirety, including drawings.
`
`IV.
`
`FEES:
`
`K4
`IXI
`
`Applicant claims small entity status pursuant to 37 CFR § 1.27
`This application is being filed without Declaration under 37 CFR § 1.53.
`
`79532—80031’801/LEGAL23 0547561
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`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
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`V.
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`CORRESPONDENCE ADDRESS
`
`Please send all correspondence to Customer Number 34055.
`
`Patent
`79532.8003.USO2
`
`Perkins Coie LLP
`Patent — LA
`PO. Box 1208
`
`Seattle, WA 98111-1208
`
`Phone: (310) 788-9900
`Fax: (206) 332-7198
`
`Please direct all inquiries to Patrick Morris at the above customer number.
`
`
`Dated: March 9 2012
`
`Respectfully submitted,
`
`PERKINS COIE LLP
`
`By: /Patrick D. Morris/
`Patrick D, Morris
`
`Reg. No. 53,351
`
`79532—8003.L'SOl/LEGAL23 0547561
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`2
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`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
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`Attorney Ref. 79532.8003.US02
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`What is claimed is:
`
`1.
`
`A method for determining whether to increase a dosage of a nitrogen scavenging
`
`drug in a subject currently receiving the nitrogen scavenging drug, comprising:
`
`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level to determine whether to increase the dosage of a nitrogen scavenging drug,
`
`wherein the dosage needs to be increased if the fasting blood ammonia level is greater than half
`
`the upper limit of normal for blood ammonia level.
`
`2.
`
`A method for determining whether to administer a nitrogen scavenging drug to a
`
`subject having a nitrogen retention disorder comprising:
`
`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level to determine whether to administer a nitrogen scavenging drug to the subject,
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`wherein a nitrogen scavenging drug needs to be administered to the subject if the fasting blood
`
`ammonia level is greater than half the upper limit of normal for blood ammonia level.
`
`3.
`
`A method of treating a subject with a nitrogen retention disorder who has
`
`previously been administered a nitrogen scavenging drug comprising:
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`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level and administering an increased dosage of the nitrogen scavenging diu g if the
`
`fasting blood ammonia level is greater than half the upper limit of normal for blood ammonia
`
`level.
`
`4.
`
`The method of claim 1, further comprising:
`
`c) administering an increased dosage of the nitrogen scavenging drug if the need exists.
`
`5.
`
`The method of any of claims 1—3, wherein the nitrogen retention disorder is
`
`selected from the group consisting of a urea cycle disorder and hepatic encephalopathy.
`
`6.
`
`The method of any of claims 1-3, wherein the nitrogen scavenging drug is a PAA
`
`prodiug.
`
`7.
`
`The method of claim 6, wherein the PAA prodrug is selected from the group
`
`consisting of glyceryl tri—[4—phenylbutyrate] (HPN —100), phenylbutyric acid (PBA), sodium PBA
`
`(NaPBA), and a combination of two or more of HPN-100, PBA, and NaPBA.
`
`7953 278003.L’SOl/LEGAL227 14905.1
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`3 3
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`Attorney Ref. 79532.8003.US02
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`8.
`
`The method of any of claims 1—3, wherein the nitrogen scavenging drug is sodium
`
`benzoate.
`
`9.
`
`The method of claim 3 or 4, wherein administering an increased dosage of the
`
`nitrogen scavenging diu g produces a normal average daily ammonia level in the subject.
`
`10.
`
`The method of any of claims 1-3, further comprising the step of determining an
`
`upper limit of normal for blood ammonia level for the subject prior to step (b).
`
`11.
`
`The method of any of claims 1-3, wherein the upper limit of normal blood
`
`ammonia level is 35 umol/L.
`
`12.
`
`The method of claim 6, further comprising:
`
`0) measuring urinary PAGN excretion; and
`
`e) determining an effective dosage of the PAA prodrug based on a mean conversion of
`
`PAA prodrug to urinary PAGN of 60-75%.
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`7953 278003.L’SOl/LEGAL227 14905.1
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`Par Pharmaceutical, Inc. Ex. 1012
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`Attorney Ref. 79532.8003.US02
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`ABSTRACT
`
`The present disclosure provides methods for evaluating daily ammonia exposure based
`
`on a single fasting ammonia blood level measurement, as well as methods that utilize this
`
`technique to adjust the dosage of a nitrogen scavenging drug, determine whether to administer a
`
`nitrogen scavenging drug, and treat nitrogen retention disorders.
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`7953 278003.L’SOl/LEGAL227 14905.1
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`3 5
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`Par Pharmaceutical, Inc. Ex. 1012
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`Attorney Ref. 79532.8003.US02
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`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING
`
`DRUGS
`
`RELATED APPLICATIONS
`
`[0001] The present application claims the benefit of U.S. Provisional Application No.
`
`61/564,668, filed November 29, 2011, and U.S. Provisional Application No. 61/542,100, filed
`
`September 30, 2011, the disclosures of which are incorporated by reference herein in their
`
`entirety, including drawings.
`
`BACKGROUND
`
`[0002] Nitrogen retention disorders associated with elevated ammonia levels include urea cycle
`
`disorders (UCDs) and hepatic encephalopathy (HE).
`
`[0003] UCDs include several inherited deficiencies of enzymes or transporters necessary for
`
`the synthesis of urea from ammonia, including enzymes involved in the urea cycle. The urea
`
`cycle is depicted in Figure 1, which also illustrates how certain ammonia-scavengin g drugs act to
`
`assist in elimination of excessive ammonia. With reference to Figure l, N—acetyl glutamine
`
`synthetase (NAGS)-derived N—acetylglutamate binds to carbamyl phosphate synthetase (CPS),
`
`which activates CPS and results in the conversion of ammonia and bicarbonate to carbamyl
`
`phosphate. In turn, carbamyl phosphate reacts with omithine to produce citrulline in a reaction
`
`mediated by omithine transcarbamylase (OTC). A second molecule of waste nitrogen is
`
`incorporated into the urea cycle in the next reaction, mediated by arginosuccinate synthetase
`
`(ASS), in which citrulline is condensed with aspartic acid to form argininosuccinic acid.
`
`Argininosuccinic acid is cleaved by argininosuccinic lyase (ASL) to produce arginine and
`
`fumarate. 1n the final reaction of the urea cycle, arginase (ARG) cleaves arginine to produce
`
`omithine and urea. Of the two atoms of nitrogen incorporated into urea, one originates from free
`
`ammonia (NH4+) and the other from aspartate. UCD individuals born with no meaningful
`
`residual urea synthetic capacity typically present in the first few days of life (neonatal
`
`presentation). Individuals with residual function typically present later in childhood or even in
`
`adulthood, and symptoms may be precipitated by increased dietary protein or physiological
`
`stress (6. g., intercurrent illness).
`
`[0004] Hepatic encephalopathy (HE) refers to a spectrum of neurologic signs and symptoms
`
`believed to result from hyperammonemia, which frequently occur in subjects with cirrhosis or
`
`7953 278003.U501/LEGAL227 14905.1
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`1
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`Attorney Ref. 79532.8003.US02
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`certain other types of liver disease. Subjects with HE typically show altered mental status
`
`ranging from subtle changes to coma, features similar to subjects with UCDs.
`
`[0005] Subjects with nitrogen retention disorders whose ammonia levels and/or symptoms are
`
`not adequately controlled by dietary restriction of protein and/0r dietary supplements are
`
`generally treated with nitrogen scavenging agents such as sodium phenylbutyrate (NaPBA,
`
`approved in the United States as BUPHENYL® and in Europe as AMMONAPS®) or sodium
`
`benzoate. These are often referred to as alternate pathway drugs because they provide the body
`
`with an alternate pathway to urea for excretion of waste nitrogen (Brusilow 1980; Brusilow
`
`1991). NaPBA is a phenylacetic acid (PAA) prodrug. Another nitrogen scavenging drug
`
`currently in development for the treatment of nitrogen retention disorders is glyceryl tri-[4-
`
`phenylbutyrate](HPN-lOO), which is described in US. Patent No. 5,968,979. HPN-100, which is
`
`commonly referred to as GT4P or glycerol PBA, is a prodiug of PBA and a pre-prodiug of PAA.
`
`[0006] HPN-100 and NaPBA share the same general mechanism of action: PBA is converted
`
`to PAA Via beta oxidation, and PAA is conjugated enzymatically with glutamine to form
`
`phenylacetylglutamine (PAGN), which is excreted in the urine. The structures of PBA, FAA,
`
`and PAGN are set forth below.
`
`MK.
`
`“
`
`.-*‘
`of“
`\‘s ,x xx-
`"‘7‘
`,
`35>
`
`15
`i
`\-.
`
`\‘
`
`-
`
`\a -
`.--v,
`.-
`{jug NS
`
`[phenywiu‘iyrarta
`
`Phenyiaaeiée acid
`
`o
`“a
`M‘srffrr'N W‘s‘xwgf
`H
`
`G
`
`Pheavéaceisigmmmim
`
`[0007] The clinical benefit of NaPBA and HPN-lOO with regard to nitrogen retention disorders
`
`derives from the ability of PAGN to effectively replace urea as a vehicle for waste nitrogen
`
`excretion and/or to reduce the need for urea synthesis (Brusilow 1991; Brusilow 1993). Because
`
`7953 278003.L’SOl/LEGAL227 14905.1
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`Attorney Ref. 79532.8003.US02
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`each glutamine contains two molecules of nitrogen, the body rids itself of two waste nitrogen
`
`atoms for every molecule of PAGN excreted in the urine. Therefore, two equivalents of nitrogen
`
`are removed for each mole of PAA converted to PAGN. PAGN represents the predominant
`
`terminal metabolite, and one that is stoichiometrically related to waste nitrogen removal, a
`
`measure of efficacy in the case of nitrogen retention states. The difference between HPN-100
`
`and N aPBA with respect to metabolism is that HPN —100 is a triglyceride and requires digestion,
`
`presumably by pancreatic lipases, to release PBA (McGuire 2010).
`
`[0008]
`
`In contrast to NaPBA or HPN—lOO, sodium benzoate acts when benzoic acid is
`
`combined enzymatically with glycine to form hippuric acid. For each molecule of hippuric acid
`
`excreted in the urine, the body rids itself of one waste nitrogen atom.
`
`[0009] Methods of determining an effective dosage of PAA prodrugs such as NaPBA or HPN-
`
`100 for a subject in need of treatment for a nitrogen retention disorder are described in
`
`WOO9/1134460 and W010/025303. Daily ammonia levels, however, may vary greatly in a
`
`subject. This can lead to overestimation by the physician of the average daily ammonia levels,
`
`which may result in overtreatment. Thus, there is a need in the art for improved methods for
`
`PAA prodrug dose determination and adjustment based on ammonia levels in subjects with
`
`nitrogen retention disorders such as UCDs or HE.
`
`W
`
`[0010] Provided herein in certain embodiments are methods for determining whether to
`
`increase a dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder by
`
`measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the
`
`upper limit of normal (ULN) for blood ammonia, where a fasting blood ammonia level that is
`
`greater than half the ULN for blood ammonia indicates that the dosage needs to be increased. In
`
`certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments,
`
`the nitrogen scavenging drug is HPN—lOO, PBA, NaPBA, sodium benzoate, or any combination
`
`thereof (i.e., any combination of two or more of HPN—lOO, PBA, NaPBA). In certain
`
`embodiments, the ULN is around 35 umol/L or 59 rig/mL.
`
`In certain embodiments, the methods
`
`include an additional step of administering an increased dosage of the nitrogen scavenging drug
`
`if the need exists, and in certain of these embodiments administration of the nitrogen scavenging
`
`drug produces a normal average daily ammonia level in the subject. In certain embodiments
`
`wherein a determination is made to administer an increased dosage of nitrogen scavenging drug
`
`7953 278003L'SOI/LEGAL227 14905.1
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`3
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`Par Pharmaceutical, Inc. Ex. 1012
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`Page 19 of 262
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`Attorney Ref. 79532.8003.US02
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`and wherein the nitrogen scavenging drug is a PAA prodrug, the methods include an additional
`
`step of measuring urinary PAGN excretion and determining an effective dosage of the PAA
`
`prodrug based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%.
`
`[0011] Provided herein in certain embodiments are methods for determining Whether to
`
`administer a nitrogen scavenging drug to a subject with a nitrogen retention disorder by
`
`measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the
`
`ULN for blood ammonia, where a fasting blood ammonia level that is greater than half the ULN
`
`for blood ammonia indicates that the nitrogen scavenging drug needs to be administered. In
`
`certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments,
`
`the nitrogen scavenging drug is HPN—lOO, PBA, NaPBA, sodium benzoate, or any combination
`
`thereof (i.e., any combination of two or more of HPN—lOO, PBA, NaPBA). In certain
`
`embodiments, the ULN is around 35 umol/L or 59 ug/mL.
`
`In certain embodiments, the methods
`
`include an additional step of administering a nitrogen scavenging drug if the need exists, and in
`
`certain of these embodiments administration of the nitrogen scavenging drug produces a normal
`
`average daily ammonia level in the subject. In certain embodiments wherein a determination is
`
`made to administer a nitrogen scavenging drug and wherein the nitrogen scavenging drug is a
`
`PAA prodrug, the methods further include a step of determining an effective initial dosage of the
`
`PAA prodrug by determining a target urinary PAGN output based on a target nitrogen output and
`
`calculating an effective initial dosage that results in the target urinary PAGN output based on a
`
`mean conversion of PAA prodru g to urinary PAGN of 60-75%. In certain embodiments, the
`
`methods include a step of administerin