Doc Code: TRACK1.REQ
`Document Description: TrackOne Request
`
`PTO/AIA/424 (04-14)
`
`CERTIFICATION AND REQUESTFOR PRIORITIZED EXAMINATION
`UNDER 37 CFR 1.102(e) (Page1of 1)
`
`Scharschmidt
`
`kon Application Number(if po
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTSPRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION.
`
`forms are submitted.
`
`1. The processing fee set forth in 37 CFR 1.17(i)(1) and the prioritized examination fee set forth in
`37 CFR 1.17(c) have been filed with the request. The publication fee requirement is met
`becausethat fee, set forth in 37 CFR 1.18(d), is currently $0. The basic filing fee, search fee,
`and examination fee arefiled with the request or have been already been paid.
`| understand
`that any required excess claims fees or application size fee must be paid for the application.
`
`| understand that the application may not contain, or be amendedto contain, more than four
`independentclaims, more than thirty total claims, or any multiple dependent claims, and that
`any request for an extension of time will cause an outstanding Track | request to be dismissed.
`
`3. The applicable box is checked below:
`
`Original Application (Track One)
`
`- Prioritized Examination under § 1.102(e)(1
`
`i.
`
`(a) The application is an original nonprovisional utility application filed under 35 U.S.C. 111(a).
`This certification and request is being filed with the utility application via EFS-Web.
`
`(b) The application is an original nonprovisional plant application filed under 35 U.S.C. 111(a).
`This certification and requestis being filed with the plant application in paper.
`
`An executedinventor's oath or declaration under 37 CFR 1.63 or 37 CFR 1.64 for each
`inventor, or the application data sheet meeting the conditions specified in 37 CFR 1.53(f)(3)(i) is
`filed with the application.
`
`A requestfor continued examination has been filed with, or prior to, this form.
`If the application is a utility application, this certification and requestis being filed via EFS-Web.
`iii. The application is an original nonprovisional utility application filed under 35 U.S.C. 111(a), or is
`a national stage entry under 35 U.S.C. 371.
`iv. This certification and requestis being filed prior to the mailing of a first Office action responsive
`to the request for continued examination.
`No prior request for continued examination has been grantedprioritized examination status
`under 37 CFR 1.102(e)(2).
`
`signature/Lauren L. STEVENS/
`nate 7731-2015
`
`
`Name__Lauren L. Stevens Practitioner 36691
`
`Registration Number
`
`This form must be signed in accordance with 37 CFR 1.33. See 37 CFR 1.4(d) for signature requirements and certifications.
`Nate:
`Submit muitiple forms if more than one signature is required.*
`
`| *Total of
`
`LUPIN EX. 1022
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`Privacy Act Statement
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`The Privacy Act of 1974 (P.L. 93-579) requires that you be given certain information in connection with your
`submission of the attached form related to a patent application or patent. Accordingly, pursuant to the requirements of
`the Act, please be advised that: (1) the general authority for the collection of this information is 35 U.S.C. 2(b)(2); (2)
`furnishing of the information solicited is voluntary; and (3) the principal purpose for which the information is used by the
`U.S. Patent and Trademark Office is to process and/or examine your submission related to a patent application or
`patent.
`If you do not furnish the requested information, the U.S. Patent and Trademark Office may not be able to
`process and/or examine your submission, which may result in termination of proceedings or abandonment of the
`application or expiration of the patent.
`
`The information provided by you in this form will be subject to the following routine uses:
`
`1. The information on this form will be treated confidentially to the extent allowed under the Freedom of
`Information Act (5 U.S.C. 552) and the Privacy Act (5 U.S.C 552a). Records from this system of records may
`be disclosed to the Department of Justice to determine whether disclosure of these records is required by the
`Freedom of Information Act.
`2. Arecord from this system of records may be disclosed, as a routine use, in the course of presenting evidence
`to a court, magistrate, or administrative tribunal, including disclosures to opposing counsel in the course of
`settlement negotiations.
`3. Arecord in this system of records may be disclosed, as a routine use, to a Member of Congress submitting a
`request involving an individual, to whom the record pertains, when the individual has requested assistance from
`the Member with respect to the subject matter of the record.
`4. Arecord in this system of records may be disclosed, as a routine use, to a contractor of the Agency having
`need for the information in order to perform a contract. Recipients of information shall be required to comply
`with the requirements of the Privacy Act of 1974, as amended, pursuant to 5 U.S.C. 552a(m).
`5. Arecord related to an International Application filed under the Patent Cooperation Treaty in this system of
`records may be disclosed, as a routine use, to the International Bureau of the World Intellectual Property
`Organization, pursuant to the Patent Cooperation Treaty.
`6. Arecord in this system of records may be disclosed, as a routine use, to another federal agency for purposes
`of National Security review (35 U.S.C. 181) and for review pursuant to the Atomic Energy Act (42 U.S.C.
`218(c)).
`7. Arecord from this system of records may be disclosed, as a routine use, to the Administrator, General
`Services, or his/her designee, during an inspection of records conducted by GSAaspart of that agency’s
`responsibility to recommend improvements in records management practices and programs, under authority of
`44 U.S.C. 2904 and 2906. Such disclosure shall be madein accordance with the GSA regulations governing
`inspection of records for this purpose, and any other relevant (/.e., GSA or Commerce) directive. Such
`disclosure shall not be used to make determinations about individuals.
`8. Arecord from this system of records may be disclosed, as a routine use, to the public after either publication of
`the application pursuant to 35 U.S.C. 122(b) or issuance of a patent pursuant to 35 U.S.C. 151. Further, a
`record may be disclosed, subject to the limitations of 37 CFR 1.14, as a routine use, to the public if the record
`wasfiled in an application which became abandonedor in which the proceedings were terminated and which
`application is referenced by either a published application, an application open to public inspection or an issued
`patent.
`9. Arecord 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.
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`PTO/AIA/14 (12-13)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`cat
`Application Data Sheet 37 CFR 1.76
`Application Number
`
`Title of Invention|METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`The application data sheetis part of the provisional or nonprovisional application for which it is being submitted. The following form contains the
`bibliographic data arrangedin a format specified by the United States Patent and Trademark Office as outlined in 37 CFR 1.76.
`This document may be completed electronically and submitted to the Office in electronic format using the Electronic Filing System (EFS) or the
`document may be printed and included in a paper filed application.
`
`Secrecy Order 37 CFR 5.2
`
`Oo Portionsorall of the application associated with this Application Data Sheet mayfall under a Secrecy Order pursuantto
`
`37 CFR 5.2 (Paper filers only. Applications that fall under Secrecy Order may notbefiled electronically.}
`
`Inventor Information:
`
`
`Inventor
`1
`Legal Name
`
`
`Prefix) Given Name
`Middle Name
`Family Name
`fee—*tt
`Residence Information (Select One)
`(@) US Residency
`©) NonUS Residency
`() Active US Military Service
`
`
`
`San Francisco | US State/Province Country of Residence i
`
`Mailing Addressof Inventor:
`
`45 St. Francis Boulevard
`Address 1
`
`Address 2
`
`Postal Code
`
`94127
`
`US
`
`
`
`Inventor
`Legal Name
`
`2
`
`Masoud
`
`Moknhtarani
`
`(©) Active US Military Service
`©) NonUS Residency
`Residence Information (Select One) () US Residency
`
`
`City|Walnut Creek State/Province|CA Country of Residence i|US
`
`
`
`
`Mailing Addressof Inventor:
`
`Address1
`725 Castle Rock Road
`
`Address 2
`
`
`| CA
`| State/Province
`Walnut Creek
`City
`
`
`
`Postal Code | US | 94598 | Country i
`
`All
`Inventors Must Be Listed - Additional
`Inventor Information blocks may be
`
`generated within this form by selecting the Add button. A“
`
`Correspondence Information:
`
`Enter either Customer Number or complete the CorrespondenceInformation section below.
`For further information see 37 CFR 1.33(a).
`
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`PTO/AIA/14 (12-13)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`
`Attorney Docket Number|HOR0026-201-C1US
`Application Data Sheet 37 CFR 1.76
`Application Number
`
`Title of Invention|METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`[_] An Addressis being provided for the correspondence Information of this application.
`
`Customer Number
`
`101325
`
`Email Address
`
`admin@globalpatentgroup.com
`
`Application Information:
`
`
`Title of the Invention
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`
`
`
`Application Type
`
`Nonprovisional
`
`Subject Matter
`
`Utility
`
`Total Number of Drawing Sheets {if any)
`
`3
`
`Suggested Figure for Publication (if any)
`
`Filing By Reference:
`
`Only complete this section whenfiling an application by reference under 35 U.S.C. 111(c) and 37 CFR 1.57(a). Do not complete this sectionif
`application papers including a specification and any drawings are beingfiled. Any domestic benefit or foreign priority information must be
`provided in the appropriate section(s) below(i.e., “Domestic Benefit/National Stage Information” and “Foreign Priority Information’).
`
`For the purposesofa filing date under 37 CFR 1.53(b), the description and any drawings of the present application are replaced by this
`reference to the previouslyfiled application, subject to conditions and requirements of 37 CFR 1.57(a).
`
`Application numberof the previously
`
`Filing date (YYYY-MM-DD)
`
`Intellectual Property Authority or Country i
`
`filed application
`
`Publication Information:
`
`
`
`
`
`Request Early Publication (Fee required at time of Request 37 CFR 1.219)
`
`[]
`
`Request Not to Publish. | hereby requestthat the attached application not be published under
`35U.S.C. 122(b) and certify that the invention disclosed in the attached application has not andwill not be the
`subject of an application filed in another country, or under a multilateral international agreement, that requires
`publication at eighteen months afterfiling.
`
`Representative Information:
`
`Representative information should be provided for all practitioners having a power of attorney in the application. Providing
`this information in the Application Data Sheet does not constitute a powerof attorney in the application (see 37 CFR 1.32).
`Either enter Customer Number or complete the Representative Name section below.
`If both sections are completed the customer
`Numberwill be used for the Representative Information during processing.
`
`
`
`
`Please Select One: | ©) US Patent Practitioner|() Limited Recognition (37 CFR 11.9) (#) Customer Number
`
`
`
`
`
`
`
`101325
`Customer Number
`
`
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`PTO/AIA/14 (12-13)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`Attorney Docket Number|HOR0026-201-C1US
`
`Application Data Sheet 37 CFR 1.76
`Application Number
`
`Title of Invention|METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`Domestic Benefit/National Stage Information:
`
`This section allows for the applicant to either claim benefit under 35 U.S.C. 119(e), 120, 121, or 365(c) or indicate National Stage
`entry from a PCT application. Providing this information in the application data sheet constitutes the specific reference required
`by 35 U.S.C. 119(e) or 120, and 37 CFR 1.78.
`When referring to the current application, please leave the application number blank.
`
`Prior Application Status|Pending
`
`Filing Date (YYYY-MM-DD}
`Prior Application Number
`Continuity Type
`Application Number
`
`Continuation of
`13775000
`2013-02-22
`
`
`
`
`
`Prior Application Status|Patented
`Application
`Prior Application
`Filing Date
`Issue Date
`Continuity Type
`Number (YYYY-MM-DD)—|Patent Number|tyyyy-MM-DD)Number
`
`
`13775000
`13417137
`Continuation of
`2012-03-09
`8404215
`2013-03-26
`
`Prior Application Status|Expired
`
`Filing Date (YYYY-MM-DD}
`Prior Application Number
`Continuity Type
`Application Number
`
`13417137
`Claims benefit of provisional
`61542100
`2011-09-30
`
`Prior Application Status
`
`Application Number
`
`Continuity Type
`
`Prior Application Number
`
`Filing Date (YYYY-MM-DD}
`
`13417137
`
`Claims benefit of provisional
`
`61564668
`
`2011-11-29
`
`Additional Domestic Benefit/National Stage Data may be generated within this form
`by selecting the Add button.
`
`
`Foreign Priority Information:
`
`
`This section allows for the applicant to claim priority to a foreign application. Providing this information in the application data sheet
`constitutes the claim for priority as required by 35 U.S.C. 119(b) and 37 CFR 1.55{d). When priority is claimed to a foreign application
`that is eligible for retrieval under the priority document exchange program (PDX) ithe information will be used by the Office to
`automatically attempt retrieval pursuant to 37 CFR 1.55(h)(1) and (2). Under the PDX program, applicant bears the ultimate
`responsibility for ensuring that a copy of the foreign application is received by the Office from the participating foreign intellectual
`property office, or a certified copy of the foreign priority applicationis filed, within the time period specified in 37 CFR 1.55(g){1).
`
`
`Application Number
`
`Country i
`
`Filing Date (YYYY-MM-DD)
`
`Access Code! (if applicable)
`
`Add button.
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`Additional Foreign Priority Data may be generated within this form by selecting the
`
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`

`PTO/AIA/14 (12-13)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`
`Attorney Docket Number|HOR0026-201-C1US
`Application Data Sheet 37 CFR 1.76
`Application Number
`
`Title of Invention|METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`Statement under 37 CFR 1.55 or 1.78 for AIA (First Inventor to File) Transition
`Applications
`
`
`
`
`
`
`
`This application (1) claims priority to or the benefit of an application filed before March 16, 2013 and (2) also
`contains, or contained at any time, a claim to a claimed invention that has an effectivefiling date on or after March
`16, 2013.
`NOTE: By providing this statement under 37 CFR 1.55 or 1.78, this application, with a filing date on or after March
`
`16, 2013, will be examined underthefirst inventorto file provisions of the AIA.
`
`Authorization to Permit Access:
`
`[_] Authorization to Permit Access to the Instant Application by the Participating Offices
`
`If checked, the undersigned hereby grants the USPTO authority to provide the European Patent Office (EPO),
`the Japan Patent Office (JPO), the Korean Intellectual Property Office (KIPO), the World Intellectual Property Office (WIPO),
`and any otherintellectual property offices in which a foreign application claiming priority to the instant patent application
`is filed access to the instant patent application. See 37 CFR 1.14(c) and (h). This box should not be checkedif the applicant
`does not wish the EPO, JPO, KIPO, WIPO, or otherintellectual property office in which a foreign application claiming priority
`to the instant patent applicationis filed to have accessto the instant patent application.
`
`In accordance with 37 CFR 1.14{c), access may be provided to information concerning the date offiling this Authorization.
`
`In accordance with 37 CFR 1.14(h)(3), access will be provided to a copy of the instant patent application with respect
`to: 1) the instant patent application-as-filed; 2) any foreign application to which the instant patent application
`claims priority under 35 U.S.C. 119(a)-(d) if a copy of the foreign application that satisfies the certified copy requirementof
`37 CFR 1.55 has beenfiled in the instant patent application; and 3) any U.S. application-as-filed from which benefit is
`soughtin the instant patent application.
`
`Applicant Information:
`
`
`Providing assignmentinformation in this section does not substitute for compliance with any requirement of part 3 of Title 37 of CFR
`to have an assignment recorded by the Office.
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`PTO/AIA/14 (12-13)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`
`Attorney Docket Number|HOR0026-201-C1US
`Application Data Sheet 37 CFR 1.76
`Application Number
`
`Title of Invention|METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`1
`Applicant
`If the applicantis the inventor (or the remaining joint inventor or inventors under 37 CFR 1.45), this section should not be completed.
`The information to be providedin this section is the name and addressof the legal representative who is the applicant under 37 CFR
`1.43; or the name and address of the assignee, person to whom theinventoris under an obligation to assign the invention, or person
`who otherwise showssufficient proprietary interest in the matter who is the applicant under 37 CFR 1.46. If the applicant is an
`applicant uncer 37 CFR 1.46 (assignee, person to whom the inventoris obligated to assign, or person whootherwise showssufficient
`proprietary interest) together with one or morejoint inventors, then the joint inventor or inventors who are also the applicant should be
`identified in this section.
`
`
`©) Legal Representative under 35 U.S.C. 117
`
`©)
`
`Joint Inventor
`
`
`
`OQ Person to whom theinventoris obligated to assign. Person who showssufficient proprietary interest QO
`
`
`
`
`
`If applicant is the legal representative, indicate the authority to file the patent application, the inventor is:
`
`
`
`Nameof the Deceased or Legally Incapacitated Inventor :
`
`If the Applicant is an Organization check here.
`Organization Name
`Horizon Therapeutics, Inc.
`
`Mailing Address Information:
`Address 1
`520 Lake Cook Road
`
`
`Address 2
`
`City
`
`Suite 520
`
`Deerfield
`
`State/Province
`
`IL
`
`Email Address
`
`Add
`Additional Applicant Data may be generated within this form by selecting the Add button.
`
`
`AssigneeInformation including Non-Applicant Assignee Information:
`
`
`Providing assignment information in this section does not subsitute for compliance with any requirementof part 3 of Title 37 of CFR to
`have an assignment recorded by the Office.
`
`
`
`Assignee 1
`
`Complete this section if assignee information, including non-applicant assignee information, is desired to be included on the patent
`application publication . An assignee-applicant identified in the "Applicant Information" section will appear on the patent application
`publication as an applicant. For an assignee-applicant, complete this section only if identification as an assigneeis also desired on the
`patent application publication.
`
`
`
`If the Assignee or Non-Applicant Assignee is an Organization check here.
`
`LC]
`
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`PTO/AIA/14 (12-13)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`
`Attorney Docket Number|HOR0026-201-C1US
`Application Data Sheet 37 CFR 1.76
`Application Number
`
`Title of Invention|METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
`
`Prefix
`
`
`
`Given Name
`
`Middle Name
`
`Family Name
`
`Email Address
`
`Mailing Address Information For Assignee including Non-Applicant Assignee:
`
`Address 1
`
`
`Address 2
`
`
`
`Phone Number
`
`Fax Number
`
`Additional Assignee or Non-Applicant Assignee Data may be generated within this form by
`selecting the Add button.
`
`
`Add
`
`Signature:
`NOTE: This form must be signed in accordance with 37 CFR 1.33. See 37 CFR 1.4 for signature requirements and
`certifications
`
`
`
`Signature
`
`|/Lauren L. STEVENS/
`
`Date (YYYY-MM-DD)|
`
`2015-07-31
`
`
`
`
`First Name|Lauren Last Name|Stevens Registration Number|36691
`
`
`
`Additional Signature may be generated within this form by selecting the Add button. Add
`
`This collection of information is required by 37 CFR 1.76. The information is required to obtain or retain a benefit by the public which
`is to file (and by the USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This
`collection is estimated to take 23 minutes to complete, including gathering, preparing, and submitting the completed application data
`sheet form to the USPTO. Time will vary depending upon the individual case. Any comments on the amountof time you require to
`complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and
`Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexancria, VA 22313-1450. DO NOT SEND FEES OR
`COMPLETED FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
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`Privacy Act Statement
`
`
`
`The Privacy Act of 1974 (P.L. 93-579) requires that you be given certain information in connection with your submission of the attached form related to
`a patent application or patent. Accordingly, pursuant to the requirements of the Act, please be advised that:
`(1) the general authority for the collection
`of this information is 35 U.S.C. 2(b)(2}; (2) furnishing of the information solicited is voluntary; and (3) the principal purpose for which the information is
`used by the U.S. Patent and Trademark Office is to process and/or examine your submission related to a patent application or patent.
`If you do not
`furnish the requested information, the U.S. Patent and Trademark Office may not be able to process and/or examine your submission, which may
`result in termination of proceedings or abandonmentof the application or expiration of the patent.
`
`The information provided by you in this form will be subject to the following routine uses:
`
`1.
`
`The information on this form will be treated confidentially to the extent allowed under the Freedom ofInformation Act (5 U.S.C. 552)
`and the Privacy Act (5 U.S.C. 552a). Records from this system of records may be disclosed to the Departmentof Justice to determine
`whether the Freedom of Information Act requires disclosure of these records.
`
`A record from this system of records may be disclosed, as a routine use, in the course of presenting evidence te a court, magistrate, or
`administrative tribunal, including disclosures to opposing counsel in the course of settlement negctiations.
`
`A recordin this system of records may be disclosed, as a routine use, to a Memberof Congress submitting a request involving an
`individual, to whom the record pertains, whenthe individual has requested assistance from the Memberwith respect to the subject matter of
`the record.
`
`A recordin this system of records may be disclosed, as a routine use, to a contractor of the Agency having need for the information in
`order to perform a contract. Recipients of information shall be required to comply with the requirements of the Privacy Act of 1974, as
`amended, pursuant to 5 U.S.C. 552a(m).
`
`A record related to an International Application filed under the Patent Cooperation Treaty in this system of records maybe disclosed,
`as a routine use, to the International Bureau of the World Intellectual Property Organization, pursuant to the Patent Cooperation Treaty.
`
`A recordin this system of records may be disclosed, as a routine use, to another federal agency for purposes of National Security
`review (35 U.S.C. 181) and for review pursuant to the Atomic Energy Act (42 U.S.C. 218(c)).
`
`A record from this system of records may be disclosed, as a routine use, to the Administrator, General Services, or his/her designee,
`during an inspection of records conducted by GSA aspart of that agency's responsibility to recommend improvementsin records
`managementpractices and programs, under authority of 44 U.S.C. 2904 and 2906. Such disclosure shall be made in accordance with the
`GSA regulations governing inspection of records for this purpose, and any otherrelevant (i.e., GSA or Commerce)directive. Such
`disclosure shall not be used to make determinations aboutindividuals.
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`A record from this system of records may be disclosed, as a routine use, to the public after either publication of the application pursuan
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`Attorney Ref. HOR0026-201C1-US
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`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING
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`DRUGS
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`RELATED APPLICATIONS
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`[0001] The present application is a divisional of U.S. Patent Application No. 13/417,137, filed
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`March 9, 2012 and now pending, which claimsthe benefit of U.S. Provisional Application No.
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`61/564,668, filed November 29, 2011, and U.S. Provisional Application No. 61/542,100, filed
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`September30, 2011, the disclosures of which are incorporated by reference herein in their
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`entirety, including drawings.
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`BACKGROUND
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`[0002] Nitrogen retention disorders associated with elevated ammonialevels include urea cycle
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`disorders (UCDs) and hepatic encephalopathy (HE).
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`[0003] UCDsinclude several inherited deficiencies of enzymes or transporters necessary for
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`the synthesis of urea from ammonia, including enzymes involved in the urea cycle. The urea
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`cycle is depicted in Figure 1, which also illustrates how certain ammonia-scavenging drugs act to
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`assist in elimination of excessive ammonia. With reference to Figure 1, N-acetyl glutamine
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`synthetase (NAGS)-derived N-acetylglutamate binds to carbamyl phosphate synthetase (CPS),
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`which activates CPS and results in the conversion of ammonia and bicarbonate to carbamyl
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`phosphate.
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`In turn, carbamyl phosphate reacts with ornithine to producecitrulline in a reaction
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`mediated by ornithine transcarbamylase (OTC). A second molecule of waste nitrogen is
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`incorporated into the urea cycle in the next reaction, mediated by arginosuccinate synthetase
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`(ASS), in which citrulline is condensed with aspartic acid to form argininosuccinic acid.
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`Argininosuccinic acid is cleaved by argininosuccinic lyase (ASL) to produce arginine and
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`fumarate. In the final reaction of the urea cycle, arginase (ARG)cleaves arginine to produce
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`ornithine and urea. Of the two atoms of nitrogen incorporated into urea, one originates from free
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`ammonia (NHq*) and the other from aspartate. UCD individuals born with no meaningful
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`residual urea synthetic capacity typically present in the first few days of life (neonatal
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`presentation). Individuals with residual function typically present later in childhood or even in
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`adulthood, and symptoms maybeprecipitated by increased dietary protein or physiological
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`stress (e.g., intercurrent illness).
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`[0004] Hepatic encephalopathy (HE)refers to a spectrum of neurologic signs and symptoms
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`believed to result from hyperammonemia, which frequently occur in subjects with cirrhosis or
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`certain other types of liver disease. Subjects with HE typically show altered mental status
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`ranging from subtle changes to coma, features similar to subjects with UCDs.
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`[0005] Subjects with nitrogen retention disorders whose ammonia levels and/or symptomsare
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`not adequately controlled by dietary restriction of protein and/or dietary supplements are
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`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
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`benzoate. These are often referred to as alternate pathway drugs because they provide the body
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`with an alternate pathway to urea for excretion of waste nitrogen (Brusilow 1980; Brusilow
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`1991). NaPBAis a phenylacetic acid (PAA) prodrug. Another nitrogen scavenging drug
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`currently in developmentfor the treatment of nitrogen retention disorders is glyceryl tri-[4-
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`phenylbutyrate](HPN-100), which is described in U.S. Patent No. 5,968,979. HPN-100, which is
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`commonlyreferred to as GT4P or glycerol PBA,is a prodrug of PBA and a pre-prodrug of PAA.
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`[0006] HPN-100 and NaPBA share the same general mechanism of action: PBA is converted
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`to PAAvia beta oxidation, and PAA is conjugated enzymatically with glutamine to form
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`phenylacetylglutamine (PAGN), which is excreted in the urine. The structures of PBA, PAA,
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`and PAGNareset forth below.
`
`hu
`we Na— Ae eit
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`“
`LAS Ns
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`phenyibulyrate
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`Phemlaoetic acid
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`ny a
`_—
`8g A id
`RO. wi
`1 “Ni Ne
`Na
`Ss
`oH
`es
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`Dheeyfacetylatutaming
`Prenyisoetligitamins
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`[0007] The clinical benefit of NaPBA and HPN-100 with regard to nitrogen retention disorders
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`derives from the ability of PAGN to effectively replace urea as a vehicle for waste nitrogen
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`excretion and/or to reduce the need for urea synthesis (Brusilow 1991; Brusilow 1993). Because
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`each glutamine contains two molecules of nitrogen, the bodyridsitself of two waste nitrogen
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`atoms for every molecule of PAGN excreted in the urine. Therefore, two equivalents of nitrogen
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`are removed for each mole of PAA converted to PAGN. PAGNrepresents the predominant
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`terminal metabolite, and one that is stoichiometrically related to waste nitrogen removal, a
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`measure of efficacy in the case of nitrogen retention states. The difference between HPN-100
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`and NaPBA with respect to metabolism is that HPN-100 is a triglyceride and requires digestion,
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`presumably by pancreatic lipases, to release PBA (McGuire 2010).
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`[0008]
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`In contrast to NaPBA or HPN-100, sodium benzoate acts when benzoic acid is
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`combined enzymatically with glycine to form hippuric acid. For each molecule of hippuric acid
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`excreted in the urine, the body rids itself of one waste nitrogen atom.
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`[0009] Methods of determining an effective dosage of PAA prodrugs such as NaPBA or HPN-
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`100 for a subject in need of treatment for a nitrogen retention disorder are described in
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`WO009/1134460 and WO10/025303. Daily ammonia levels, however, may vary greatly in a
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`subject. This can lead to overestimation by the physician of the average daily ammonialevels,
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`which may result in overtreatment. Thus, there is a need in the art for improved methodsfor
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`PAAprodrug dose determination and adjustment based on ammonia levels in subjects with
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`nitrogen retention disorders such as UCDsor HE.
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`SUMMARY
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`[0010] Provided herein in certain embodiments are methods for determining whetherto
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`increase a dosageof a nitrogen scavenging drug in a subject with a nitrogen retention disorder by
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`measuring a fasting blood ammonia level and comparing the fasting bloo