`Approvedfor use through 05/30/2010. OMB 0654-0032
`U.S. Patent and Trademark Office. U.S, DEPARTMENT OF COMMERCE
`lays
`8 valid OMB controt number.
`Under the Paperwork Reduction Act of 1995, no persons are required to respondto a collection of information unless it dis
`
`077350.0355
`AttomeyDocketNo.
`Chowdhury etal.
`First Inventor
`
`Title
`
`Dexmedetomidine Premix Formulation
`
`UTILITY
`PATENT APPLICATION
`TRANSMITTAL
`
`PrinvType 07/03/2012
`
`8. Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, items a.-c. are required)
`a.
`Computer Readable Form (CRF}
`b.
`Specification Sequence Listing on:
`i. Lt CD-ROM or CD-R(2 copies); or
`i. [J Paper
`« (J Statements verifying ideatity of above copies
`18. Ifa CONTINUING APPLICATION, check appropriate box, and supply the requisite information below andin the first sentence of the
`specification following the title, or in an Application Data Sheet under 37 CFR 1.76:
`CC Continuation-in-part (CIP)
`Examiner Polansky, Gregg
`19. CORRESPONDENCE ADDRESS
`
`{Only for new nonprovisional applications under 37 CFR 7.53(b))
`
`Express Mail Label No.
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerningufility patent application contents.
`
`ADDRESSTO:
`
`Commissionerfor Patents
`P.O. Box 1450
`Alexandria VA 22313-1450
`
`1.
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`2. C4 Applicant claims small entity status.
`See 37 CFR 1.27,
`39
`[Tota! Pages
`3.{¥%] Specification
`Both the claims and abstract must start on a new page
`(Forinformation on the prefered arengement, sse MPEP 608.04/a}}
`4.[-} Drawing(s) (35 U.S.C. 173)
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`5. Oath or Declaration
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`a.
`[__] Newly executed (original or copy)
`b.
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`
`12
`
`i.
`
`or continuation/divisional with Box 18 completed}
`
`}
`t
`Signed statement attached deleting inventor(s)
`name in the prior application, see 37 CFR
`1.63(d}(2) and 1.33(b).
`
`6.[¥] Application Data Sheet. See 37 CFR 1.76
`7...)
`cD-ROMor CD-R in duplicate,large table or
`puter Program (Appendix)
`Landscape Table on CD
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`ACCOMPANYING APPLICATION PARTS
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`
`Name of Assignee
`
`10. [_] 37 CFR 3.73(b) Statement
`(when there is an assignee)
`
`Powerof
`Attorney
`
`11. [_] English Translation Document(if applicable}
`
`12.
`
`Information Disclosure Statement (PTO/S8/08 or PTO-1449)
`Copies ofcitations attached
`
`43. CJ Pretiminary Amendment
`
`14, ["] Return Receipt Postcard (MPEP 503)
`(Should be soecificaily itemized)
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`15. [__] Certified Copy of Priority Document(s)
`(if foreign priority is claimed)
`
`16. Cy Nonpublication Request under 35 U.S.C. 122(b)(2)(B)(i).
`Applicant must attach form PTO/S8/35 or equivatent.
`
`Continuation
`
`CX Divisional
`
`Prior application information:
`
`17.
`
`Other: Accelerated Exam. Support and Search Docs.;
`
`IDS; Petition to Make Special Under Acc, Exam.
`
`of prior application No,:13/843,872
`
`Art Unit: 1629
`
`LYJone address associated with CustomerNumber:
`
`62965
`
`OR [| Correspondence address below
`
`}
`
`a a
`iy
`
`Signature
`Name
`
`.
`
`FegistrationNo 161,910
`Dennis M. Bissonnette
`This collection of information is required by 37 CFR 1,53(b), 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 govemed by 35 U.S.C. 122 and 37 CFR 1,11 and 1,14. This collection is estimated to take 12 minutes to
`complete, including gathering, preparing, and submitting ihe completed application form to the USPTO. Time will vary depending upon the individual case. Any
`comments on the amount of 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, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED
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`if you need assisfance in completing the form, call 1-800-PTO-9199 and select option 2.
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1048 — Page 1
`
`
`
`PTO/SB/M? (10-07)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S, DEPARTMENT OF COMMERCE
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`a valid CMB contro? number
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`
`Effective on 12/08/2004.
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`
`
`Fees pursuant to the Consolidated Appropriations Act, 2005 (H.R. 4818).
`FEE TRANSMITTAL
`
`
`
`
`etal.
`Chowdhury
`
`FSaminernane[ToBeAssigned|oriomnare__
`
`[To Be Assianed
`
`To Be Assigned
`
`
`
`
`
`
`TOTAL AMOUNTOF PAYMENT|(5) 1,380.00 077350.0355
`
`Complete if Known
`To Be Assigned
`
`METHOD OF PAYMENT(checkall that apply)
`
`[7] Check CJ Credit Card [Taoney Order [Tone [other (please identify):
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`
`FEE CALCULATION
`
`1. BASIC FILING, SEARCH, AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`EXAMINATION FEES
`Smali Entity
`Small Entity
`Small Entity
`
`
`
`
`
`Application Type Tree(8)Fee(S) "Fee(3)FeesPaid($}Fee ($) neeiS) Fee ($)
`380
`190
`620
`Utility
`310
`250
`125
`$1,250.00
`Design
`250
`125
`120
`60
`160
`80
`Plant
`250
`125
`380
`190
`200
`100
`
`Reissue
`
`380
`
`190
`
`620
`
`310
`
`750
`
`375
`
`250
`
`125
`
`0
`
`
`
`Provisional
`if
`2. EXCESS CLAIM FEES
`
`Fee DescriptionFee($} Fee($}
`Each claim over 20 (including Reissues)
`60
`30
`Each independent claim over 3 (including Reissues)
`250
`125
`Muttiple dependent claims
`450
`225
`Fee Paid {$)
`Eee ($)
`Total Claims
`Extra Claims
`Multiple Dependent Claims
`
`
`
`
`
`
`Z 0Fee($)- 20 or HP = 90 x 60 = Fee Paid ($)
`HP = highest numberoftotal claims paidfor, if greater than 20,
`Indep, Claims
`Extra Claims
`Fee ($)
`=
`4
`~3orHP =
`oO x 250
`HP = highest numberof independent claims paid for, if greater than 3.
`3. APPLICATION SIZE FEE
`If the specification and drawings exceed 100 sheets of paper (excluding electronically filed sequence or computer
`listings under 37 CFR 1.52(e)), the application size fee due is $310 ($155 for small entity) for each additional 50
`sheets or fraction thereof. See 35 U.S.C. 43(a)(1)(G) and 37 CFR J.16(5).TotalSheetsExtraSheets mber of iti or ionthereof Fee ($) Fee Paid {$)
`
`
`
`
`
`
`
`
`
`
`
`
`
`39 /50=_ O. {round upto awhoie number)- 100= Q x 310 = 0
`
`
`
`4, OTHER FEE(S)
`Fees
`Pai
`$130 fee {no small entity discount)
`Non-English Specification,
`Other(e.g., late filing surcharge):Petition under 37 CFR 1.17(h)
`
`0
`
`0
`
`0
`
`
`
`Fee Paid ($)
`Q
`
`
`
`7 = istration
`No.
`
`
`ReaisratonNe-64 91|Telephone 312-408-2500
`Dennis M. Bissonnette
`Date 07/03/2012
`This collection of information is required by 37 CFR 1.136. The information is required to obtain or retain a benefit by the public whichisto file (and by the
`USPTOto process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to fake 30 minutes to compfete,
`including gathering, preparing, and submitting the completed application form to the USPTO. Timewill 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, Alexandria, VA 22343-1460. DC NOT SEND FEES OR COMPLETED FORMSTO THIS
`ADDRESS. SEND TO; Commissionerfor Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
`
`
`
`$130.00
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1048 — Page 2
`
`
`
`PTO/SB/14 (11·08)
`Approved for use through 01131/2014. OMB 0651·0032
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`
`Application Data Sheet 37 CFR 1.76
`
`Attorney Docket Number
`
`077350.0355
`
`Application Number
`
`Title of Invention I
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`The application data sheet is part of the provisional or nonprovisional application for which it is being submitted. The following form contains the
`bibliographic data arranged in 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
`O Portions or all of the application associated with this Application Data Sheet may fall under a Secrecy Order pursuant to
`37 CFR 5.2 (Paper filers only. Applications that fall under Secrecy Order may not be filed electronically.)
`r
`.pp 1can t I f
`A
`f
`n orma ion:
`Annlicant 1
`Applicant Authority @Inventor I QLegal Representative under 35 U.S.C. 117
`Middle Name
`Prefix Given Name
`
`Family Name
`
`Suffix
`
`/ QParty of Interest under 35 U.S.C. 118
`
`Roychowd h ury
`Prlyanka
`Residence Information {Select One) @ US Residency 0 Non US Residency Q Active US Military Service
`I Country of Residenc~ 1 us
`State/P rovi nc e I CA
`City
`San Rafael
`JN
`
`Citizenship under 37 CFR 1.41(bi
`Mailing Address of Applicant:
`Address 1
`
`100 Marin Center Dr., Apt. 63
`
`City
`
`Address 2
`I San Rafael
`Postal Code
`
`94903
`
`/ State/Province
`I Countt1t I us
`
`I CA
`
`Annlicant 2
`Applicant Authority @Inventor I QLegal Representative under 35 U.S.C. 117
`Middle Name
`Prefix Given Name
`
`I QParty of Interest under 35 U.S.C. 118
`
`Family Name
`
`Suffix
`
`A
`Cedergren
`Robert
`Residence Information {Select One) @ US Residency 0 Non US Residency Q Active US Military Service
`I Country of Residenc~ I us
`State/Province I IL
`City
`Libertyville
`us
`
`Citizenship under 37 CFR 1.41 (b)
`Mailing Address of Applicant:
`Address 1
`
`310 Cypress Lane
`
`Address 2
`
`City
`
`I State/Province
`/ Count'1t I us
`All Inventors Must Be Listed - Additional Inventor Information blocks may be
`generated within this form by selecting the Add button.
`
`I Libertyville
`
`Postal Code
`
`60048
`
`i 1L
`
`I
`
`.Add >I
`
`Correspondence Information:
`Enter either Customer Number or complete the Correspondence Information section below.
`For further information see 37 CFR 1.33(a).
`O An Address is being provided for the correspondence Information of this application.
`
`EFS Web 2.2.3
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 3
`
`
`
`PTO/S8/14 (11-08)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
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`
`Title of Invention
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`Removes Email
`
`
` Application Data Sheet 37 CFR 1.76
`Attorney Docket Number|077350.0355
`;}F
`
`
`||
`
`
`
`
`
`
`Customer Number Email Address
`Application Information:
`
`
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`
`Attorney Docket Number! 077350.0355
`$
`Application Type
`Nonprovisional
`
`
`Subject Matter
`
`
`
`
`
`[_] 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 35 U.S.
`q C. 122(b) and certify that the invention disclosed in the attached application has not and will not be the subject of
`
`an applicationfiled in another country, or under a multilateral international agreement, that requires publication at
`
`eighteen monthsafterfiling.
`
`Title of the invention
`
`
`
`Suggested Class {if any)|
`
`514
`
`Sub Class(if any) 396
`
`Total Numberof Drawing Sheets {if any)
`Publication Information:
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`
`Suggested Figure for Publication(if any) |
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`this information in the Application Data Sheet does not constitute a powerof attorneyin the application (see 37 CFR 1.32).
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`Enter the Representative Name_sectioneither Customer Number or complete below. If both sections
`
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`are completed the Customer Number will be used for the Representative information during processing.
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`Representative Information:
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` Representative information should be provided for all practitioners having a power of attorney in the application. Providing
`
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`
`Please Select One:
`Customer Number
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`(e) Customer Number
`62965
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`©) US Patent Practitioner
`
`() Limited Recognition (37 CFR 11.9)
`
`Domestic Benefit/National Stage Information:
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`
` This section allows for the applicantto 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
`
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`35 U.S.C. 119{e) or 120, and 37 CFR 1.78(a}(2) or CFR 1.78(a)(4}, and need not otherwise be made part of the specification.
`
`
`
`
`
`
`
`Filing Date (YYYY-MM-DD)
`Application Number
`
`2012-01-04
`
`
`
`Continuity Type
`Continuation of
`
`Prior Application Number
`131343672
`
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`by selecting the Add button.
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`Foreign Priority Information:
`
`EFS Web2.2.3
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1048 — Page 4
`
`
`
`PTOISB/14 (11-08)
`Approved for use lhrough 0113112014. OMB 0651-0032
`U.S. Paten! and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under!he Paperwork Reduction Act of 1995, no persons are required to respond to a collection oflnformation unless it contains a valid OMB control number.
`
`Application Data Sheet 37 CFR 1.76
`
`Attorney Docket Number
`
`077350.0355
`
`Application Number
`
`Title of Invention
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`This section allows for the applicant to claim benefit of foreign priority and to identify any prior foreign application for which priority is
`not claimed. 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(a).
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`Country1
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`! ~emove J
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`Add button.
`Assignee Information:
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`of the CFR to have an assignment recorded in the Office.
`
`Assignee 1
`If the Assignee is an Organization check here.
`I HOSPIRA, INC.
`Mailing Address Information:
`
`Organization Name
`
`[SJ
`
`Address 1
`
`Address 2
`
`City
`Count..Y I us
`Phone Number
`
`Email Address
`
`H1-4S 275 North Field Drive
`
`Lake Forest
`
`State/Province
`
`IL
`
`Postal Code
`
`Fax Number
`
`60045
`
`Additional Assignee Data may be generated within this form by selecting the Add
`button.
`
`Signature:
`A signature of the applicant or representative is required in accordance with 37 CFR 1.33 and 10.18. Please see 37
`CFR 1.4(d) for th~ form of the sign_?ture.
`
`Date (YYYY-MM-DD) 2012-07-03
`
`Registration Number
`
`61910
`
`Signature ~ / y .---::::::::·
`I Last Name I Bissonnette
`
`First Name
`
`Dennis M.
`
`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 amount of 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, Alexandria, 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.
`
`EFS Web 2.2.3
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 5
`
`
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`077350.0355
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of and claims priority under 35 U.S.C. §120 to
`
`U.S. Application Serial No. 13/343,672 filed January 4, 2012, the contents of which are hereby
`
`incorporated by reference in its entirety.
`
`1. FIELD OF THE INVENTION
`
`[0001]
`
`The present invention relates
`
`to patient-ready, premixed formulations of
`
`dexmedetomidine, or a pharmaceutically acceptable salt thereof, that can be used, for example,
`
`in perioperative care of a patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`[0002]
`
`Racemic 4-(1-(2,3-dimethylphenyl)ethyl]-1 H-imidazole, which is known under
`
`the name medetomidine, is a selective and potent aradrenoceptor agonist. Medetomidine has
`
`been used as an antihypertensive agent and as a sedative-analgesic agent.
`
`It has further been
`
`observed that this compound also possesses anxiolytic effects and can therefore be used in the
`
`treatment of general anxiety, panic disorder and various types of withdrawal symptoms.
`
`[0003]
`
`The d-enantiomer of medetomidine,
`
`the generic name of which 1s
`
`dexmedetomidine, is described in U.S. Pat. No. 4,910,214 as an a.2-adrenoceptor agonist for
`general sedation/analgesia and the treatment of hypertension or anxiety. U.S. Pat. Nos.
`
`5,344,840 and 5,091,402 discuss dexmedetomidine
`
`in perioperative and epidural use,
`
`respectively. For example, when used in perioperative care, dexmedetomidine can reduce the
`
`amount of anesthetic necessary to anesthetize a patient. Additionally, U.S. Pat. No. 5,304,569
`
`discusses the use of dexmedetomidine in treating glaucoma, and U.S. Pat. No. 5,712,301
`
`discusses the use of dexmedetomidine for preventing neurodegeneration caused by ethanol
`
`consumption. Furthermore, U.S. Pat. No. 6,716,867 discloses methods of sedating a patient
`
`while in an intensive care unit by administering dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, to the patient.
`
`NY02:744382.1
`
`- 1 -
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 6
`
`
`
`077350.0355
`
`[0004]
`
`Dexmedetomidine can be administered to a patient in a variety of ways. For
`
`example, U.S. Pat. Nos. 4,544,664 and 4,910,214 disclose
`
`the administration of
`
`dexmedetomidine via parenteral, intravenous, and oral routes. U.S. Pat. No. 4,670,455 describes
`
`intramuscular and intravenous administration, while U.S. Pat. Nos. 5,124,157 and 5,217,718
`
`describe a method and device for administering dexmedetomidine through the skin. Additionally,
`
`U.S. Pat. No. 5,712,301 states that dexmedetomidine can be administered transmucosally.
`
`[0005]
`
`To date, dexmedetomidine has been provided as a concentrate that must be
`
`diluted prior to administration to a patient. The requirement of a dilution step in the preparation
`
`of the dexmedetomidine formulation is associated with additional costs and inconvenience, as
`
`well as the risk of possible contamination or overdose due to human error. Thus, a
`
`dexmedetomidine formulation that avoids the expense, inconvenience, delay and risk of
`
`contamination or overdose would provide significant advantages over currently available
`
`concentrated formulations.
`
`3. SUMMARY OF THE INVENTION
`
`[0006]
`
`The present invention relates to premixed pharmaceutical compositions of
`
`dexmedetomidine, or a pharmaceutically acceptable salt thereof, that are formulated for
`
`administration to a patient, without the need to reconstitute or dilute the composition prior to
`
`administration. Thus, the compositions of the present invention are formulated as a premixed
`
`composition comprising dexmedetomidine.
`
`[0007]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition is a liquid comprising dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, at a concentration of between about 0.05 µg/mL and about 15 µg/mL.
`
`[0008]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`is a liquid comprising dexmedetomidine at a concentration of about 4 µg/mL.
`
`[0009]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`comprises dexmedetomidine mixed or dissolved in a sodium chloride saline solution.
`[0010]
`
`In certain embodiments, the premixed dexmedetomidine composition is disposed
`
`within a sealed container or vessel.
`
`[0011]
`
`In certain embodiments, the dexmedetomidine composition 1s disposed in a
`
`container or vessel and is formulated as a premixture.
`
`NY02:744382. 1
`
`- 2 -
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 7
`
`
`
`077350.0355
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`[0012]
`
`In certain embodiments, the premixed dexmedetomidine composition is disposed
`
`within a sealed container as a total volume of about 20 mL, 50 mL or I 00 mL.
`
`[0013]
`
`In
`
`certain non-limiting embodiments,
`
`the premixed dexmedetomidine
`
`composition of the present invention comprises dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, at a concentration of between about 0.05 µg/mL and about 15 µg/mL,
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`and sodium chloride at a concentration of between about 0.01 and about 2.0 weight percent.
`
`[0014]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt
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`thereof, at a concentration of about 4 µg/mL and sodium chloride at a concentration of about
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`0.90 weight percent.
`
`[0015]
`
`In certain embodiments, the compositions of the present invention are formulated
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`as a pharmaceutical composition for administration to a subject for sedation, analgesia or
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`treatment of anxiety or hypertension.
`
`[0016]
`
`The present invention also relates to the perioperative treatment of a patient to
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`reduce the response of the autonomic nervous system to stimuli during an operation by
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`administering a dexmedetomidine composition of the invention.
`
`[0017]
`
`In other non-limiting embodiments, the dexmedetomidine compositions of the
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`present invention can be administered as an anxiolytic analgesic to a patient.
`
`In certain
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`embodiments, the composition can be administered as a premedication prior to an operation with
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`or without administration of an amount of an anesthetic effective to achieve a desired level of
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`local or general anesthesia.
`
`[0018)
`
`In other non-limiting embodiments, the dexrnedetomidine compositions of the
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`present invention can be administered as a sedative. In certain embodiments, the composition is
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`administered preoperatively to potentiate the effect of an anesthetic, wherein administration of
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`the composition reduces the amount of anesthetic required to achieve a desired level of
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`anesthesia.
`
`[0019]
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`In certain embodiments of the present invention, the premixed dexmedetomidine
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`composition is administered parenterally as a liquid, orally, transdermally, intravenously,
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`intramuscularly, subcutaneously, or via an implantable pump.
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`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 8
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`4. DETAILED DESCRIPTION
`
`[0020]
`
`The present invention is based in part on the discovery that dexmedetomidine
`
`prepared in a premixed formulation that does not require reconstitution or dilution prior to
`
`administration to a patient, remains stable and active after prolonged storage. Such premixed
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`formulations therefore avoid the cost, inconvenience, and risk of contamination or overdose that
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`can be associated with reconstituting or diluting a concentrated dexmedetomidine formulation
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`prior to administration to a patient.
`
`[0021]
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`For clarity and not by way of limitation, this detailed description is divided into
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`the following sub-portions:
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`( 4 .1) Definitions;
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`( 4.2) Pharmaceutical formulations; and
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`(4.3) Methods of using premixed dexmedetomidine compositions.
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`4.1 Definitions
`
`[0022]
`
`The terms used in this specification generally have their ordinary meanings in the
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`art, within the context of this invention and in the specific context where each term is used.
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`Certain terms are discussed below, or elsewhere in the specification, to provide additional
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`guidance to the practitioner in describing the compositions and methods of the invention and
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`how to make and use them.
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`[0023]
`
`According to the present invention, the tenn "dexmedetomidine" as used herein
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`refers to a substantially pure, optically active dextrorotary stereoisomer of medetomidine, as the
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`free base or pharmaceutically acceptable salt.
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`In one, non-limiting embodiment,
`
`dexmedetomidine has
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`the formula (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole.
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`A
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`pharmaceutically acceptable salt of dexmedetomidine can include inorganic acids such as
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`hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
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`organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic
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`acid, malonic acid, succinic acid, maleic acid, frunaric acid, tartaric acid, citric acid, benzoic
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`acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
`
`acid, and salicylic acid. Preferably, the dexmedetomidine salt is dexmedetomidine HCI. In other
`
`non-limiting embodiments, dexmedetomidine comprises the structure depicted below in Formula
`
`I:
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`077350.0355
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`CH3
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`CH3
`
`CH;
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`Formula I
`
`N
`
`NH
`
`[0024]
`
`The terms “premix” or “premixture” as used herein refers to a pharmaceutical
`
`formulation that does not require reconstitution or dilution prior to administration to a patient.
`
`For example,
`
`in contrast
`
`to non-premixed formulations of dexmedetomidine,
`
`the premixed
`
`compositions provided herein are suitable for administration to a patient without dilution by, for
`
`example,a clinician, hospital personnel, caretaker, patient or any other individual.
`
`{0025}
`
`In certain embodiments,
`
`the compositions of the present
`
`invention can be
`
`formulated as “ready to use” compositions which refer to premixed compositions that are
`
`suitable for administration to a patient without dilution. For example, in certain embodiments,
`
`the compositions of the present invention are “ready to use” upon removing the compositions
`
`from a sealed containeror vessel.
`
`[0026]
`
`In certain embodiments,
`
`the compositions of the present
`
`invention can be
`
`formulated as a “single use dosage,” which refers to a premixed composition that is disposed
`
`within a sealed container or vessel as a one dose per container or vessel formulation.
`
`0027}
`
`According to the invention, a “subject” or “patient” is a human, a non-human
`
`mammal or a non-human animal. Although the animal subject
`
`is preferably a human,
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`the
`
`compounds and compositions of the invention have application in veterinary medicine as well,
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`e.g., for the treatment of domesticated species such as canine, feline, and various other pets; farm
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`animal species such as bovine, equine, ovine, caprine, porcine, ete.; wild animals, e.g., in the
`
`wild or in a zoological garden; and avian species, such as chickens, turkeys, quail, songbirds, etc.
`
`[0028]
`
`The term “purified” as used herein refers to material that has been isolated under
`
`conditions that reduce or eliminate the presence of unrelated materials,
`
`i.e., contaminants,
`
`including native materials from which the material
`
`is obtained. As used herein,
`
`the term
`
`“substantially free” is used operationally, in the context of analytical testing of the material.
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`077350.0355
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`Preferably, purified material substantially free of contaminants is at least 95% pure; more
`
`preferably, at least 97% pure, and more preferably still at least 99% pure. Purity can be
`
`evaluated, for example, by chromatography or any other methods known in the art. In a specific
`
`embodiment, purified means that the level of contaminants is below a level acceptable to
`
`regulatory authorities for safe administration to a human or non-human animal.
`
`[0029]
`
`The term "pharmaceutically acceptable," when used in connection with the
`
`pharmaceutical compositions of the invention, refers to molecular entities and compositions that
`
`are physiologically tolerable and do not typically produce untoward reactions when administered
`
`to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved
`
`by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or
`
`other generally recognized pharmacopeia for use in animals, and more particularly in humans.
`
`The term "carrier" refers to a diluent, adjuvant, excipient, dispersing agent or vehicle with which
`
`the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water
`
`and oils. For example, water, aqueous solutions, saline solutions, aqueous dextrose or glycerol
`
`solutions can be employed as carriers, particularly for
`
`injectable solutions. Suitable
`
`pharmaceutical carriers are described in, for example, "Remington's Pharmaceutical Sciences"
`
`by Philip P. Gerbino, 21st Edition (or previous editions).
`
`[0030]
`
`The term "pharmaceutical composition" as used in accordance with the present
`
`invention relates to compositions that can be formulated in any conventional manner using one
`
`or more pharmaceutically acceptable carriers or excipients. A "pharmaceutically acceptable"
`
`carrier or excipient, as used herein, means approved by a regulatory agency of the Federal or a
`
`state government, or as listed in the U.S. Pharmacopoeia or other generally recognized
`
`pharmacopoeia for use in mammals, and more particularly in humans.
`
`[0031]
`
`The term "dosage" is intended to encompass a formulation expressed in terms of
`
`µg/kg/day, µg/kg/hr, mg/kg/day or mg/kg/hr. The dosage is the amount of an ingredient
`
`administered in accordance with a particular dosage regimen. A "dose" is an amount of an agent
`
`administered to a mammal in a unit volume or mass, e.g., an absolute unit dose expressed in mg
`
`or µg of the agent. The dose depends on the concentration of the agent in the formulation, e.g.,
`
`in moles per liter (M), mass per volume (m/v), or mass per mass (m/m). The two terms are
`
`closely related, as a particular dosage results from the regimen of administration of a dose or
`
`doses of the formulation. The particular meaning in any case will be apparent from context.
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`NY02:744382.1
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`077350.0355
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`{0032]
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`The
`
`terms
`
`"therapeutically effective dose,"
`
`"effective
`
`amount," and
`
`"therapeutically effective amount" refer to an amount sufficient to produce the desired effect.
`
`(0033]
`
`In some non-limiting embodiments, a "therapeutically effective dose" means an
`
`amount sufficient to reduce by at least about 15%, preferably by at least 50%, more preferably by
`
`at least 90%, and most preferably prevent, a clinically significant deficit in the activity, function
`
`and response of the host. Alternatively, a therapeutically effective amount is sufficient to cause
`
`an improvement in a clinically significant condition in the host. These parameters will depend on
`
`the severity of the condition being treated, other actions, such as diet modification, that are
`
`implemented, the weight, age, and sex of the subject, and other criteria, which can be readily
`
`determined according to standard good medical practice by those of skill in the art.
`
`[0034]
`
`In other non-limiting embodiments a therapeutic resp