PTO/SB/OS (07-07)
`Approved for use through 06/30/2010. 0MB 065141032
`US. Patent and Trademark Office. US. DEPARTMENT OF COMMERCE
`nderthc Paerwork Reduction Act a! 1995 no t - rsons are r uired to resend lo a collection at information unless it disla
`a valid OMB coni'ol number.
`0773500344
`Chowdhurv et al—
`Dexmedetomidine Premix Formulation
`
`
`
`— C
`
`ommissioner ior Patents
`P.O. Box 1450
`Alexandria VA 22313-1450
`
`ADDRESS TO:
`
`ACCOMPANYING APPLICATION PARTS
`
`9. 1:] Assignment Papers (cover sheet 8: documenl(s))
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`lIl
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`12. m lnfoEfition Disclosure Statement (PTOISBI-DB or PTO-1449)
`Copies of citations attached
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`UTILITY
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`pm” 8
`Dennis M. Bissonnette
`Attorne {Aent
`.91 O
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc - Exhibit 1008 — Page 1
`
`

`

`PTOISB/17 (10-07)
`Approved for use through 0613012010. OMS 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
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`I
`. d.
`I
`rd
`B
`I
`th p
`n er e
`aperwork Reduction Act of 1995 no persons are required to respond to a collection of information un ess 1t 1sp ays a va 1 OM contra number
`Complete if Known
`Application Number To Be Assianed
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`Herewith
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`Attorney Docket No. 077350.0344
`
`r
`
`Effective on 1210812004.
`Fees pursuant fo the Consolidated Appropriations Act, 2005 (H. R. 4818).
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`~
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`METHOD OF PAYMENT (check all that apply)
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`A1;rnlication Ty[!e ~ ~ ~ E_Q!L($)
`380
`190
`620
`310
`Utility
`250
`125
`120
`60
`250
`125
`190
`380
`380
`190
`620
`310
`250
`125
`0
`0
`
`Design
`
`Plant
`
`Reissue
`
`EXAMINATION FEES
`Small Entity
`Feem
`125
`80
`100
`375
`0
`
`.Efil1_lfil
`250
`160
`200
`750
`0
`
`Fees Paid m
`$1 250.00
`
`Provisional
`2. EXCESS CLAIM FEES
`Fee Descri12tion
`Each claim over 20 (including Reissues)
`Each independent claim over 3 (including Reissues)
`Multiple dependent claims
`fulfil
`Total Claims
`Extra Claims
`60
`x
`4
`• 20 or HP=
`0
`HP= highest number of total claims paid for, if greater than 20.
`EfilLl1l
`lndee. Claims
`Extra Claims
`=
`250
`1
`x
`-3orHP =
`0
`HP= highest number of 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 l.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. 41~)(1)(0) and 37 CFR L16(s).
`Total Sheets
`Extra Sheets
`Num er of each additional 50 or fraction thereof
`n
`39
`I 50 ~
`(round up to a whole number) x
`0
`- 100 =
`4. OTHER FEE(S)
`Non-English Specification, $130 fee (no small entity discount)
`
`Fee Paid {U
`0
`
`=
`
`Fee Paid !il
`0
`
`Small Entity
`ill.ill
`EfilUfil
`60
`30
`125
`250
`225
`450
`Multi11le De11endent Claims
`Fee Paid m
`EfilUfil
`
`f.ttill
`310
`
`=
`
`Fee Paid(§!
`0
`Fees Paid m
`
`Other (e.g., late filing surcharge): Petition under 37 CFR 1.17(hl
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`$ 130 OD
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`SUBMITIED BY
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`Signature ~ _____:_'/t----
`Name (Print!Type) Dennis M. Bissonnette
`This collection of information is required by 37 CFR 1.136. 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 30 minutes to complete,
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`ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, call 1-800-PT0-9199 and select option 2.
`
`I Registration No.
`IAttornev/Aaenn 61, 910
`
`Telephone 212-408-2500
`Date Ol/O 'f / 2o 12-
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 2
`
`

`

`PTOISB/14 (11-08)
`Approved for use through 01/3112014. OMB 0651-0032
`U.S. Pa\ent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under !he Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`Application Data Sheet 37 CFR 1. 76
`
`Attorney Docket Number
`
`077350.0344
`
`Application Number
`
`Title of Invention I DEXMEDETOMlDINE PREMIX FORMULATION
`
`The applicatlon 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 submitled to the Office in electronic format using the Electronic Fillng System (EFS) or the
`document may be printed and included in a paper filed application.
`
`Secrecy Order 37 CFR 5.2
`D 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 flied electronically.)
`r
`,pp 1can t I t
`f
`n orma ion:
`A
`Aoolicant 1
`Applicant Authority @Inventor I QLegal Representative under 35 U.S.C. 117
`Prefix Given Name
`Middle Name
`
`I QParty of Interest under 35 U.S.C. 118
`Family Name
`Suffix
`
`Roychowdhury
`Priyanka
`0 Non US Residency Q Active US Military Service
`Residence Information (Select One) (!) US Residency
`I Country of ResidencJ I us
`City
`State/Province I CA
`San Rafael
`IN
`
`Citizenship under 37 CFR 1.41(b)
`Mailing Address of Applicant:
`Address 1
`
`100 Marin Center Dr., Apt. 63
`
`Address 2
`I San Rafael
`Postal Code
`
`City
`
`94903
`
`I State/Province
`I Counti1i I US
`
`I CA
`
`Armlicant 2
`Applicant Authority (!)Inventor I QLegal Representative under 35 U.S.C. 117
`Prefix Given Name
`Middle Name
`
`I QParty of Interest under 35 U.S.C. 118
`Suffix
`Family Name
`
`A
`Robert
`Cedergren
`Residence Information (Select One) (!) US Residency 0 Non US Residency 0 Active US Military Service
`I Country of ResidencJ I us
`State/Province I IL
`City
`Libertyville
`us
`
`Citizenship under 37 CFR 1.41(bl
`Mailing Address of Applicant:
`Address 1
`
`310 Cypress Lane
`
`Address 2
`
`I Libertyville
`
`City
`
`Postal Code
`
`60048
`
`/ State/Province
`I Countr~ I US
`
`/ 1L
`
`All Inventors Must Be Listed - Additional Inventor Information blocks may be
`generated within this form by selecting the Add button.
`
`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).
`D An Address is being provided for the correspondence Information of this application.
`
`EFS Web 2.2.3
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 3
`
`

`

`PTOISB/14 (11-08)
`Approved for use through 0113112014. 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.
`
`Application Data Sheet 37 CFR 1.76
`
`Attorney Docket Number
`
`077350.0344
`
`Application Number
`
`Title of Invention
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`Customer Number
`
`62965
`
`Email Address
`
`Application Information:
`
`I I Adct E:inai1 ·· ..
`
`!Rern6vet:ma11 j
`
`Title of the Invention
`
`Attorney Docket Number 077350.0344
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`I Small Entity Status Claimed D
`
`Application Type
`
`Nonprovisional
`
`Subject Matter
`
`Suggested Class (if any) 514
`
`Suggested Technology Center (if any)
`
`I Sub Class (if any)I 396
`
`j Suggested Figure for Publication (if any) /
`
`Total Number of Drawing Sheets (if any)
`Publication Information:
`D Request Early Publication (Fee required at time of Request 37 CFR 1.219)
`Request Not to Publish. I hereby request that the attached application not be published under 35 U.S.
`C. 122(b) and certify that the invention disclosed in the attached application has not and will not be the subject of
`an application filed in another country, or under a multilateral international agreement, that requires publication at
`eighteen months after filing.
`
`D
`
`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 power of attorney in the application (see 37 CFR 1.32).
`section
`If
`the Representative Name
`below.
`both
`complete
`Enter either Customer Number or
`are completed the Customer Number will be used for the Representative Information during processing.
`
`sections
`
`Please Select One:
`
`(!) Customer Number
`
`Customer Number
`
`62965
`
`I Q US Patent Practitioner 10 Limited Recognition (37 CFR 11.9)
`
`Prior Application Status Pending
`
`Domestic Benefit/National Stage Information:
`This section al!ows 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(a)(2) or CFR 1.78(a)(4), and need not otherwise be made part of the specification.
`I Remove I
`Filing Date (YYYY-MM-DD)
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`Application Number
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`Prior Application Number
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`non provisional of
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`Additional Domestic Benefit/National Stage Data may be generated within this form
`by selecting the Add button.
`
`Foreign Priority Information:
`
`EFS Web 2.2.3
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 4
`
`

`

`PTOISB/14 (11-08)
`Approved for use through 0113112014. 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 1! contains a valid OMB control number.
`
`Application Data Sheet 37 CFR 1.76
`Title of Invention I DEXMEDETOMIDINE PREMIX FORMULATION
`
`Application Number
`
`Attorney Docket Number
`
`077350.0344
`
`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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`of the CFR to have an assignment recorded in the Office.
`
`Assianee 1
`If the Assignee is an Organization check here.
`I HOSPIRA, INC.
`Mailing Address Information:
`
`Organization Name
`
`[SJ
`
`Address 1
`
`Address 2
`
`City
`Count..;) I us
`Phone Number
`
`Email Address
`
`Hi-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 the form of the signat~r-
`
`Signature ~ ~/
`I Last Name I Bissonnette
`
`First Name
`
`Dennis M.
`
`Date (YYYY-MM-00) 2 op,~ 01- oy
`61910
`
`Registration Number
`
`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 US PTO 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 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 5
`
`

`

`DEXMEDETOMIDINE PREMIX FORMULATION
`
`077350.0344
`
`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]-lH-imidazole, which is known under
`
`the name medetomidine, is a selective and potent a 2-adrenoceptor 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
`
`rs
`
`dexmedetomidine, is described in U.S. Pat. No. 4,910,214 as an a2-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.
`
`[0004}
`
`Dexmedetornidine 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
`
`dexmedetornidine 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
`
`NY02:732410.1
`
`~ 1 -
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 6
`
`

`

`077350.0344
`
`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 ts disposed m a
`
`container or vessel and is formulated as a premixture.
`
`[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 100 mL.
`
`[0013]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition of the present invention comprises dexmedetomidine, or a pharmaceutically
`
`NY02:732410.1
`
`- 2 -
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 7
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`077350.0344
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`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]
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`In other non-limiting embodiments, the premixed dexmedetomidine composition
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`of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt
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`thereof, at a concentration of about 4 ~tg/mL and sodium chloride at a concentration of about
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`0.90 weight percent.
`
`(0015]
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`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.
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`[0016]
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`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]
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`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
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`In certain
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`embodiments, the composition can be administered as a prcmedication 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.
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`[0018]
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`In other non-limiting embodiments, the dexmedetomidine 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.
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`[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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`4. DETAILED DESCRIPTION
`
`(0020}
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`The present invention is based in part on the discovery that dexmedetomidine
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`prepared in a premixed formulation that does not require reconstitution or dilution prior to
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`administration to a patient, remains stable and active after prolonged storage. Such premixed
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 8
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`077350.0344
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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.
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`[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
`
`(00221
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`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]
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`According to the present invention, the term "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,
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`dexmedetomidine has
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`the formula (S)-4-[l-(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, fumaric acid, tartaric acid, citric acid, benzoic
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`acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
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`acid, and salicylic acid. Preferably, the dexmedetomidine salt is dexmedetomidine HCL In other
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`non-limiting embodiments, dexmedetomidine comprises the structure depicted below in Formula
`
`I:
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`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 9
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`077350.0344
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`CH3
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`Formula]
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`N
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`NH
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`[0024]
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`The terms “premix” or “premixture” as used herein refers to a pharmaceutical
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`formulation that does not require reconstitution or dilution prior to administration to a patient.
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`For example,
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`in contrast to non—premixed formulations of dexmedetomidine,
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`the premixed
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`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]
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`In certain embodiments,
`
`the compositions of the present
`
`invention can be
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`formulated as “ready to use” compositions which refer to premixed compositions that are
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`suitable for administration to a patient without dilution. For example, in certain embodiments,
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`the compositions of the present invention are “ready to use” upon removing the compositions
`
`from a sealed container or vessel.
`
`[0026]
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`In certain embodiments,
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`the compositions of the present
`
`invention can be
`
`formulated as a “single use dosage,” which refers to a premixed composition that is disposed
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`within a sealed container or vessel as a one dose per container or vessel formulation.
`
`[0027]
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`According to the invention, a “subject” or “patient” is a human, a non-human
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`mammal or a non-human animal. Although the animal subject
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`is preferably a human,
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`the
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`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, etc; wild animals, e.g., in the
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`wild or in a zoological garden; and avian species, such as chickens, turkeys, quail, songbirds, etc.
`
`[0028]
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`The term “purified” as used herein refers to material that has been isolated under
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`conditions that reduce or eliminate the presence of unrelated materials,
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`i.e., contaminants,
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`including native materials from which the material
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`is obtained. As used herein,
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`the term
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`“substantially free” is used operationally, in the context of analytical testing of the material.
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`Preferably, purified material substantially free of contaminants is at
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`least 95% pure; more
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`Amneal Pharmaceuticals LLc — Exhibit 1008 — Page 10
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`077350.0344
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`preferably, at least 97% pure, and more preferably still at least 99% pure. Purity can be
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`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
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`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
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`are physiologically tolerable and do not typically produce untoward reactions when administered
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`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
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`other generally recognized pharmacopeia for use in animals, and more particularly in humans.
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`The term "carrier" refers to a diluent, adjuvant, excipient, dispersing agent or vehicle with which
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`the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water
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`and oils. For example, water, aqueous solutions, saline solutions, aqueous dextrose or glycerol
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`solutions can be employed as carriers, particularly for
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`injectable solutions. Suitable
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`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
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`or more pharmaceutically acceptable carriers or excipients. A "pharmaceutically acceptable"
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`carrier or excipient, as used herein, means approved by a regulatory agency of the Federal or a
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`state government, or as listed in the U.S. Pharmacopoeia or other generally recognized
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`pharmacopoeia for use in mammals, and more particularly in humans.
`
`[0031]
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`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
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`administered in accordance with a particular dosage regimen. A "dose" is an amount of an agent
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`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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`NY02:7324 l 0.1
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1008 – Page 11
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`077350.0344
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`[0032]
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`The
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`terms
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`"therapeutically effective dose,"
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`"effective amount,"
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`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 wiH depend on
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`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
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`determined according to standard good medical practice by those of skill in the art.
`
`[0034]
`
`In other non-limi