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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 1
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 2
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 3
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 4
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 5
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 6
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 7
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 8
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 9
`
`
`
`Atty. Docket No. 077350.0344
`U.S, Serial No. 13/343,672
`
`composition in a glass container, Applicants submit that the claims are not obvious over the cited
`
`reference, and respectfully request that the rejection be withdrawn.
`
`IV.
`
`Conclusion
`
`In view of the above amendments and remarks,
`
`it
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`is respectfully requested that the
`
`application be reconsidered and that all pending claims be allowed and the case passed to issue. If
`
`there are any other issues remaining which the Examiner believes could be resolved through either
`
`3 Supplemental Response or in a telephone call with the undersigned, the Examiner is invited to
`
`call the undersigned at the telephone number indicated below.
`
`Applicants believe that no fee is due in connection with the filing of this paper. However,
`
`if any fees are due, or if any overpayment has been made, in connection with the filing of this
`
`response, the Commissioner is authorized to charge any such fees or credit any overpayment
`
`made, to our Deposit Account No. 02—43 77.
`
`Mack 6,20%.
`
`
`Date
`
`Respectfully submitted,
`
`BAKER BOTTS L.L.P.
`
`09/ /7497"
`
`Dennis M. Bissonnette
`
`Patent Office Reg. No. 61,910
`
`Sandra S. Lee
`
`Patent Office Reg. No. 51,932
`
`30 Rockefeller Plaza
`
`44th Floor
`
`New York, NY 10112-4498
`212-408-2500
`
`-10-
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1012 — Page 10
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 11
`
`
`
`I
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`.
`
`a-
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`o
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`"' " 15'.
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`_. q
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`-
`-.
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`W P
`
`etition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 12
`
`
`
`
`
`'in#21~038
`
`m
`r421038~
`lllllillllllllllllllll
`‘
`lllllllllllllllllllllll
`'lJm“
`’NJI'I'ZQ'.
`unuu “rm/IE: Precedex (dexmedetomidine nct Injecnon)
`(age-
`
`HFD-170
`
`APPLICANT: ABBOTT LABORATORIES
`
`"Ms"
`
`CHEMICAL & THERAPEUTIC CLA‘SS:IS
`
`
`Review Cycle: 1
`Submission DII::12~18-98
`
`.-
`
`—
`
`. Receipt Date: 1248-98
`Goal Date:12-18-99
`Action:AP
`
`Review Cycle: 3
`Submission Date:
`
`Receipt Date:
`Goal Date:
`Action:
`
`Action:
`
`. RevieWC .cles
`
`Review Cycle: 2
`Submission Date:
`
`Receipt Date:
`Goal Date:
`_
`
`Review CYele: 4
`~ Submission Date:
`
`Receipt Date:
`Goal Date:
`Action:
`
`
`
` PROJECT MANAGER! CSO :Susmita Samanta
`Phone 3 & Office Room #:301v827-7410. 93-45
`
`
`
`
`
`
`
`ABUSE LIABILITY: BeUnda A. Hayes. Ph-D.
`
`MlCROBlQLOGlST: Patricia Hughes. PILD.
`
`Volume 2 of 4
`
`Administrative volume #(s): 1
`Clinical volume #(s): 2
`CMC volume #(s): 3
`Pharmacology/1'oxicology volume #(s): 4
`
`
`
`
`
`
`W P
`
`etition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 13
`
`
`
`
`
`ODE It ACTION PACKAGE TABLE OF CONTENTS
`
`Application #21-038
`Drug Nameszrecedex (dexmedetornidine Hydrochloride injection), 2 ml. ampule/Z mI. vial, 100
`
`meg/ml.
`
`Applicant: Abbott Laboratories
`
`Chemeher. Type: 1 S
`
`C SO/PM: Susmita Samanta
`
`Phone: 301-827-7410
`
`HFD-l 70
`
`Original Application Date: December 18, 1998 Original Receipt Date: December 18, 1998
`
`CURRENTUSER FEE GOAL DATE: December 18, l999DateTableofContentsCompleted29/13/99
`
`" Sultana;
`
`'
`
`X (completed).
`NA (not applicable)-
`or Comment
`
`Tab A-l
`' Tab A-Z
`
`Action Letter(s)
`Phase 4 Commitments:
`
`Current ActionzAP " r
`
`a. Copy of applicants communication committing to Phase 4 .............
`
`b. Agency Correspondence requesting Phase 4 Commitments .............. ..
`
`Tab A-3
`
`.FDA revised Labels & Labeling and Reviews:
`(Separate each version/cycle with a colored sheet)
`
`a. Package Insert ..............................................................
`
`b. Immediate Container and Carton Labels .'. ................................... ..
`
`Tab A-d
`
`Original Proposed Labeling ............................................................. ..
`
`Tab A-S
`
`Foreign Labeling:
`
`’
`
`'
`
`a. Foreign Marketing History........................................................
`
`b. Foreign Labeling and Review(s) .......... .I: .............
`
`................... ..
`
`‘
`
`Tab A~6
`Tab A-7
`
`Labeling and Nomenclature Comminee’s.Tradenarne Review ................... ..
`Summary Memoranda (e.g., Division Director, Group Leader, Office) ....... ..
`
`Tab A-E
`
`Copy of Patent Statement ..................................................................
`
`Exclusivin Checklist (and any requests for exclusivity) ........................... ..
`
`Debgment Statements ......................................................................
`
`CorrespOndences, Faxes, 8L Telecons ...................................................
`Tab A-9
`Tab A- l 0 Minutesgif Meetings:
`a. End-of-Phase II meeting ...........................................................
`
`b. Pre-NDA meeting(s) ............................................................. ..
`c. Filing meeting ...............................................................
`......
`
`d. Other meetings .................................................................... ..
`
`Tab A-l 1
`
`Advisory Committee Meeting:
`
`3. Questions Considered by the committee ..................................... ..
`
`b. Li_st of Attendees .................................................................. ..
`c. 24; hour alert memorandum ............_...........................................
`Project Management Administrative Information (optional).........................
`
`Tab A-IZ
`
`
`
`
`
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLc — Exhibit 1012 — Page 14
`
`
`
`
`
`ODE II Amen PACKAGE TABLE OF CONTENTS (continued)
`
`Application #21-038 Drug Name: Dexniedetomidine HCL
`
`W
`
`X (completed).
`N/A (n0! applicable),
`or Comment
`
`Tab 8-}
`
`Clinical Reviews and Memoranda ..................................................... ..
`
`Tab B—Z
`
`Safety Update Reviews .....................................................................
`
`Tab Bv3
`
`‘ Pediatric Page .................................................. -._. ....................... ..
`
`Tab 8-4
`
`Statistical (Clinical) Review and Memoranda ..................... .5. ................ ..
`
`Tab B-S
`
`_ Biopharmaeeutics Review and Memoranda .......................................... ..
`
`Tab 3-6
`Tab 8-7
`
`Abuse Liability Review ............................:..................................... ..
`051 Audits .................................................................................. ..
`
`Tab 843
`
`Summary of Efficacy (from the summary volume ofthejé'gplieation)
`
`.
`
`- Tab 8-9
`
`Summary of Safety (from the summary volume of the application) ................... ..
`
`
`
`SESflQILCl
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`Cl
`
`.
`
`I
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`n I
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`E
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`I
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`.
`
`I C I
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`I
`
`[CD 1:]
`
`X (completed).
`N/A (not applicable),
`or Comment
`
`Tab (3-!
`Tab 02
`
`CMC Reviews and Memoranda .........................................................
`DMF Reviews ............................................................................ ..
`
`Tab C~3
`
`EA Reviews/FONSI ..................................................................... ..
`
`Tab 04
`
`Micro Review (validation of sterilization) ........................................... ..
`
`Tab 05
`
`StatiStical Review of drug stability ................
`
`................................. ..
`
`~
`
`Tab C-6
`Tab C-7
`
`Inspection of facilities => Decision:
`Date:
`Methods Validation Information ...................................................
`
`mm;
`
`Tab 0-]
`Tab D—2
`Tab D-3
`
`I
`.
`._
`.
`'
`t
`.-= a. WWW -
`_
`Pbapnacélogyfloxicology Reviews and Memoranda ...............................
`Carcinogenicity Review (statistical) .............................
`.....................
`GAG/Executive Committee Repon .....................................................
`
`_
`
`X (completed),
`NA (not applicable).
`or Comment
`
`ADDITIONAL NOTES:
`
`'
`
`l
`
`!
`
`
`
`
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLc — Exhibit 1012 — Page 15
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 16
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 17
`
`
`
`
`
`Mldazolun use as rescue medication during intubatiou (HT)
`Stud! “197-245
`PBO
`Dennedetomidine
`
`p-value
`
`‘
`
`N=l75
`
`- ~—N-l78
`
`Mean totai dose (mg) ofmidazolam
`
`18.6 mg
`
`4.8 mg
`
`0.0011‘
`
`Categorized midazolam use
`# pts used
`_
`
`I08 (61%)
`“(25%)
`0mg
`36(2°°/u)
`34 (t9%)‘
`0-4 mg
`3‘ 519%!
`98 956%!
`>4 mg
`' ANOVA model with n: and ctr. "Chi-square ( afier JMa’s table 3.2, review, p.S)
`
`a
`<0.001“
`
`In study W97-246, 198 patients were randomized to the placebo arm and 203 patients
`were randomized to receive dexmedetomidine by intravenous infusion at doses of 0.4
`pkg/hr (with allowed adjustment between 0.2 and 0.7 ug/kg/hr) following an initial bolus
`of 6 ptng IV. Patients were allbwed to receive propofol as needed to maintain a
`Ramsay sedation score of 23. In addition, morphine sulfate could be administered as an
`analgesic as needed. The primary outcome measure for this study was the total amount of
`rescue medication (propoi‘ol) needed to maintain sedation as specified while intubated.
`There was a statistically significantly greater use of propofol in patients randomized to
`placebo than to dexmedetomidine during treatment.
`
`The same prospective primary analysis that was performed in study W97-24S um also
`performed in this Study. It can be seen from the results reported in the table below that a
`significantly greater number of patients in the déxmedetomidine group (60%) compared to
`the placebo group (24%) maintained a Rainsay sedation score of 23 without any
`additional propofol rescue.
`
`
`Miduolarn use as rescue medication during intubation (111‘)
`Study “197-246
`PBO
`Demedetolnidine
`.
`
`p-valuc
`
`.~;:_ LL
`
`Mean total dose (mg) of propofol
`
`.
`
`513 mg
`
`N=l98
`
`N=203
`
`72 mg
`
`.
`
`41.0001.
`
`Categorized propofol use
`# p5 used
`
`122 (60%)
`“(24%)
`0mg
`43 (21%)
`30 (15%)
`0-50 mg
`38 99%!
`121 361%:
`>50 mg
`' ANOVA model with rat and ctr. “Chi-square (after IMa’s table 3.5, review, p.9)
`
`<0.001”
`
`For both studies, the time to extubation was measured and analyzed, and found to be,
`based on a very conservative approach, not significantly difl‘erent between groups. For
`more detailipr. Jonathan Ma’s analysis p.10-ll should be referenced.
`In addition the
`
`NDA m-oasnmeaaomidine RC1
`
`‘
`
`Page 3 of to
`
`
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 18
`
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`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 19
`
`
`
`infusion in an appropriate animal species, either indirectly by administration to an animal
`species that does not produce these metabolites or in an animal species which produces
`the same metabolites.
`
`Dexmcdetomidine was not shown to be teratogenic in rats 'or rabbits. However fetal
`toxicity was observed in rats, evidenced by increased postimplantation losses and reduced
`number of live pups per litter. Prenatal and postnatal efl‘ects included reduced pup body
`weights during and after nursing and delayed motor development. Placental transfer of
`dexmedetomidine was observed in rats.
`
`Dexmedetomidine was not mutagenic in the'Ames test or the mouse lymphoma assay. It
`was shown to be clastogenic in both the in vitro human lymphocytes chromosomal
`aberration assay in the presence of metabolic activatior't'and in in viva mouse micronucleus
`assay. .-
`~
`
`Carcinogenicity testing was considered unnecessary due to the projected short-term use of
`this product.
`'
`
`(zlg'm’cal
`
`_
`The safety data for this NDA Was combined from two sources, ~—-
`.
`Japanese original development program, and subsequent Abbott Laboratories data from
`the more recent development. The safety datahaSe of dexmedetomidine exposure includes
`3038 subjects, of whom 1473 were ICU patients who received the drug by continuous
`intbsion. The bulk of exposure was in the range of 4.6 mykg and less than 16 hours. The
`dose and duration of exposure provide suficient experience to be able to assess the safety
`of this product for the proposed duration of up to 24 hours infusion
`
`-
`
`There was also limited exposure (78 patients) who received infirsion longer than 24 hours
`with the longest infusion lasting between 30-40 hours in 2 patients.
`
`The deaths and serious adverse events reported Were not unexpected for the ICU
`population under study in this NDA either in quality or in quantity.
`
`in the pliaébo-controlled infusion studies in Phase 2-3, the only commonly reported
`adverse events observed in more than 1% of patients treated with dexmedetomidine and
`occurring with a frequency more than 2-fold that of the placebo were predictably
`hypotension (22%) , hypertension (12%) , and bradycardia (5%).
`
`NDA fill-OSS-Dennedetomidine KC]
`
`‘
`
`Page 5 of 10
`
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 20
`
`
`
`
`
`Abuse Parenfigl
`~
`.
`Dexmedetomidine might be expected, based on its clinical pharmacological efi‘ects and its
`similarity to Clonidine , to have some abuse liability. Indeed animal studies indicate that
`there are some reinforcing properties. Reinforcing behavior in primates was elicited by
`demedetornidine 1.0 ug/kg/dose >saline and equivalent to saline at 0.0625 ug/kydose.
`At a dose of 0.25 tig/lrg/dose dexmedetomidine produced reinforcing behavior comparable
`to pentazocine (CW); Dexmedetomidine also has been shown to attenuate morphine
`withde suggestive but not conclusive evidence for dependence liability. A mild
`withdrawal syndrome has been described in rodents tiller 7 days of treatment.
`
`Abnormal laboratory findings, which might have been. anticipated from the preclinical
`studies, such as elevated LFI‘s and glycosm-ia, were not borne out in laboratory testing.
`
`There are no safety data in pediatric patients. The sponsor will be required to study this
`product in children from birth to 16 years of age as a Phase 4 commitment.
`
`Approximately 500 patients over 65 years of age have been studied in this NDA. An
`additional analysis ofpatients over 75 years has been requested of the Sponsor with
`comparison of adverse events by age, separating the elderly by >65 to 75 and >75 years of
`age. This will be undertaken in an effort to assess whether dosage adjustment may be
`needed in the very elderly patients based on anticipated PD differences associated with
`sedative agents.
`‘
`
`Extensive receptor binding studies using standard radioligands were presented in the
`NDA, demonstrating very high amnity for the a-adrenergic receptors and moderate
`aflinity for the serotOnergie receptors. Binding at the opiate receptors was negligible.
`Comparative binding to relevant controlled substances was not provided.
`
`V
`
`'
`
`2 After Sponsor’s Table 2] 155 8/l0-239-65
`3 Clonidine is not currently controlled in the CSA. There have been reports of abuse with
`clonidine, mostly of reports of opiate addicts using clonidine to suppress withdrawal
`symptoms tether than for its psychotropic efiects.
`
`NDA fill-Oilincmaddomidine RC1
`
`‘
`
`Page 6 of 10
`
`W P
`
`etition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 21
`
`Adverse Event
`
`Summary of TreatmentoEmergent Adverse Events Occum‘ng in >l% ofDexmedetomidine patients in
`Phase mm Continuous Infusion ICU Sedation Studies’
`Placebo
`Randomized demedetomidine
`N=379
`(N=387)
`16 (4%)
`84 (22%? — .
`Hypotemion
`24 (6%)
`47 (12%)'
`Hypertension
`60%)
`20 (5%)°
`Bradycardia
`4 (1%).
`13 (3%)
`Month Dry
`20 (5%)
`16 (4%)
`r
`.1
`_
`Nausea
`'Statistically significant difference between randomized deannedetornidine and placebo patients ps0.05
`Data source 2.2.5.5
`
`-’
`
`- -
`
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 22
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 23
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`that the data on which the conclusions and recommendations for this NDA will be based
`
`have significant problems.
`
`'
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`_
`Comments:
`There is adequate evidence to support the eficacy and safety of dexrnedetomidine to
`approve it for ICU sedation by continuous infusion for 24 hours. It is anticipated that
`there will be increasing demand for more prolonged use of this product once it is
`approved. In addition to collecting additional safety data on prolonged use, there should
`be a better characterization of the activity, toxicity and fate of the metabolites. _
`
`Additional dataIIshould be obtained for safe use at the extremes of age—pediatric dosing,
`pharmacokinetics and safety should be obtained. Geriatric phannacodynamic/safety data
`in the veryElderly >75 years should also be generated'dr existing data analyzed.
`
`Once metabolic profile is better established with multiple dosing, its safety should be
`evaluated in patients with renal failure.
`-
`
`Surveillance for
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