`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. 0773500344
`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`reference, and respectfully request that the rejection be withdrawn.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
`
`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
`
`a 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.
`
`Mani,‘ .310‘;
`
`
`Date
`
`Respectfully submitted,
`
`BAKER BOTTS L.L.P.
`
`4,). /%,>2
`
`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 101 12-4498
`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
`
`.
`
`"'
`
`Q
`
`~"-
`
`-.5‘.
`
`_. q
`
`-v
`-.
`
`
`
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 12
`
`
`
`
`
`m
`,.,m33l_ ”m#21-038
`illllllllllllllillllill
`Illliillillllilllllillliilii
`‘H-2‘
`»M;'1-:~3a-
`umuu twuvIE: Precedex (dexmedetomidine nci 1n_]€CIl0I1)
`/3130
`
`HFD-170
`
`APPLICANT: ABBOTT LABORATORIES
`
`"W;
`
`CHEMICAL & THERAPEUTIC CLA'SS:1S
`
`
`Review Cycle: 1
`Submission DIle:12~l8-98
`
`.-
`
`—
`
`. Receipt Date: 12-18-98
`Goal Date:l2-I8-99
`Action:AP
`
`Review Cycle: 3
`Submission Date:
`
`Receipt Date:
`Goal Date:
`Action:
`
`Action:
`
`. ReviewC .c1es
`
`Review Cycle: 2
`Submission Date:
`
`Receipt Date:
`Goal Date:
`_
`
`Review Cycle: 4
`~ Submission Date:
`
`Receipt Date:
`Goal Date:
`Action:
`
`
`
` PROJECT MANAGER! CSO :Susmita Samanta
`Phone ti & Office Room fl:30l-827-7410. 9B-45
`
`
`
`
`
`
`
`ABUSE LIABILITY: BeLlnda A. Hayes. Ph.D.
`
`MICROHOLOCIST: Patricia Hughes. Pli.D.
`
`Volume 2 of 4
`
`Administrative volume #(s): 1
`Clinical volume #(s): 2
`CMC volume #(s): 3
`Pharmacologyffoxicology volume #(s): 4
`
`
`
`
`
`
`
`
`.
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 13
`
`
`
`
`
`ODE I1 ACTION PACKAGE TABLE or CONTENTS
`
`Application #21-038
`Drug Name:'Precedex (dexmedetornidine Hydrochloride injection), 2 mL ampule/2 ml. vial, 100
`
`mcg./ml.
`
`Applicant: Abbott Laboratories
`
`ChemfTher. Type: I S
`
`C SO/PM: Susmita Samanta
`
`Phone: 301-827-7410
`
`l-[FD-170
`
`Original Application Date: December 18, 1998 Original Receipt Date: December l8, 1998
`
`CURRENTUSER FEE GOAL DATE: December 18, 1999DateTableofContentsCompleted:9/13/99
`
`.
`
`-
`S.¢_cti9_n.A;
`
`.
`
`‘~
`
`__
`
`Tab A-l
`T Tab A-2
`
`Action Letter(s)
`lithase 4 Commitments:
`
`Current Action:AP " -
`
`I
`
`X (completed).
`. NA (not 3PPlicable)-
`or Comment
`
`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 .1 ................................... ..
`
`Tab A-4
`
`Original Proposed Labeling ............................................................. ..
`
`Tab A-S
`
`Foreign Labeling:
`
`’
`
`'
`
`a. Foreign Marketing History........................................................
`
`b. Foreign Labeling and Review(s) .......... .3: .............
`
`................... ..
`
`‘
`
`Tab A~6
`Tab A-7
`
`Labeling and Nomenclature Committee’s.Tradename Review ................... ..
`Summary Memoranda (e.g., Division Director, Group Leader. Office) ....... ..
`
`Tab A-8
`
`Copy of Patent Statement ..................................................................
`
`Exclusivity Checklist (and any requests for exclusivity) ........................... ..
`
`Del;_a__1_'_rr_ie_nt Statements ......................................................................
`
`Tab A-9
`Tab A- l 0
`
`Correspondences, Faxes, & Telecons ...................................................
`lv1i_t‘t_utes;t_)_fMeetings:
`3. End-of-Phase ll meeting ...........................................................
`
`b. Pre-NDA meeting(s) ..................................................... .._...... ..
`c. Filing meeting ..................................................................... ..
`
`d. Other meetings .................................................................... ..
`
`Tab A-l 1
`
`Advisory Committee Meeting:
`
`a. Questions Considered by the committee ..................................... ..
`
`b. List of Attendees .................................................................. ..
`e. 2{ hour alert memorandum ............_...........................................
`Project h'd_anagement Administrative information (optional).........................
`
`Tab A-I2
`
`
`
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 14
`
`
`
`X (completed).
`N/A (not applicable),
`or Comment
`
`
`
`"‘°°'“"‘°‘°‘”'
`N/A (not applicable),
`or Comment
`
`X (completed),
`NA (not applicable).
`or Comment
`
`
`
`ODE II ACTION PACKAGE Tune or Comcms (continued)
`
`Application #21-038 Drug Name: Dexinedetomidine I-ICL
`
`Seetismfiz
`
`Tab B-I
`
`Clinical Reviews and Memoranda ..................................................... ..
`
`Tab B-2
`
`Safety Update Reviews .....................................................................
`
`Tab Bv3
`
`~ Pediatric Page .................................................. ..._. ....................... ..
`
`Tab B-4
`
`Statistical (Clinical) Review and Memoranda ..................... ..'. ................ ..
`
`'
`
`Tab_ B-5
`
`_ Biopharmaeeutics Review and Memoranda .......................................... ..
`
`Tab B-6
`
`Abuse Liability Review ............................,..................................... ..
`
`Tab B-7
`
`DSI Audits .................................................................................. ..
`
`.
`
`Tab B-8
`
`Summary of Efficacy (from the summary volume ofthefépplication)
`
`- Tab B-9
`
`Summary of Safety (from the summary volume of the application) ................... ..
`
`S_e5_Li9_n_C_;_
`
`mmm
`,
`m
`
`Tab C-l
`Tab C-2
`
`CMC Reviews and Memoranda .........................................................
`DMF Reviews ............................................................................ ..
`
`Tab C-3
`
`EA Reviews/FONS} ..................................................................... ..
`
`Tab C-4
`
`Micro Review (validation of sterilization) ........................................... ..
`
`Tab C-5
`
`Statistical Review of drug stability ................
`
`................................. ..
`
`~
`
`Tab C-6
`Tab C-7
`
`inspection of facilities => Decision:
`Date:
`Methods Validation Information ...................................................
`
`i
`
`I
`
`S.ec.tinn_l2'.
`
`Tab D-l
`Tab D—2
`Tab D-3
`
`_
`.
`._
`-
`’
`_
`.-= -.5-. m -
`_
`P_i3a_t_'rnac__o.logy/Toxicology Reviews and Memoranda ...............................
`Carcinogenicity Review (statistical) .............................
`.....................
`CAC/Executive Committee Report .....................................................
`
`_
`
`ADDITlO.\'AL NOTES:
`
`
`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
`
`
`
`
`
`Midazolarn use as rescue medication during intulmion (HT)
`Stud! W97-245
`PBO
`Deicmedetomidine
`
`p-value
`
`-
`
`N-175
`
`- ~-N-I78
`
`Mean total dose (mg) ofmidazolam
`
`18.6 mg
`
`4.8 mg
`
`0.0011‘
`
`Categorized tnidazolain use
`#1 pts used
`_
`
`I08 (61%)
`43(25"/o)
`Otng
`36(20°/u)
`34 69%)‘
`0-4 mg
`34 519%!
`98 £55.42
`>4 mg
`' ANOVA model with ix and ctr. "Chi-square ( after J.Ma’s table 3.2, review, p.S)
`
`.
`<0.00l“
`
`In study W97-246, 198 patients were randomized to the placebo arm and 203 patients
`were randomized to receive dexmedetornidine by intravenous infusion at doses of 0.4
`ukg/hr (with allowed adjustment between 0.2 and 0.7 ug/kg/hr) following an initial bolus
`of 6 pg/kg IV. Patients were allowed to receive propofoi 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 (propofol) 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 W97-24$ 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 déxmedctomidine group (60%) compared to
`the placebo group (24%) maintained a Ramsay sedation score of 23 without any
`additional propofol rescue.
`
`
`Mldazolarn use as rescue medication during intubation (TIT)
`Stud! W97-246
`PBO
`Dexmedetolnidine
`.
`
`p-value
`
`.~;:_ ~._5_
`
`Mean total dose (mg) of propofol
`
`.
`
`513 mg
`
`N-=l98
`
`N-=203
`
`72 mg
`
`_
`
`<0.000l'
`
`Categorized propofol use
`# ps used
`
`122 (60%)
`47(24°/o)
`0133
`43 (21%)
`30 (15%)
`0-50 mg
`38 $1994»!
`121 §6I°/62
`>50 in;
`' ANOVA model with rat and ctr. “Chi-square (after I.Ma’s table 3.5, review, p.9)
`
`<0.00l“
`
`For both studies, the time to extubation was measured and analyzed, and found to be,
`based on a very conservative approach, not significantly difierent between groups. For
`more detail,_‘_Dr. Jonathan Ma's analysis p.10-ll should be referenced.
`In addition the
`
`NDA #21-03'8-Dexzmedetnmidine Hcl
`
`’
`
`Page 3 of to
`
`
`Petition for Inter Partes Review of U$ 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.
`
`Dexmedetomidine was not shown to be teratogenic in rats or rabbits. However fetal
`toxicity was observed in rats, evidenced by incre_ase_d 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.
`-
`
`Dexmedetornidine 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 activation'_and in in viva mouse rnicronucleus
`assay. .-
`V
`
`Carcinogenicity testing was considered unnecessary due to the projected short-term use of
`this product.
`v
`
`gzlgnical
`
`_
`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 database of deiuriedetontidirte exposure includes
`3038 subjects, of whom 1473 were ICU patients who received the drug by continuous
`infiision. 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 innrsion 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 pliieélio-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 #21-038-Dennedetornidine HCI
`
`‘
`
`Past 5 of 10
`
`Petition for Inter Partes Review of US 8,242,1 58
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 20
`
`
`
`Adverse Event
`
`— .
`
`- -
`
`Summary of Treatment-Emergent Adverse Events Occuning in >l°/. ofbexrnedctomidinc patients in
`Phase mm Continuous Infusion ICU Sedation Studies’
`Placebo
`Randomized dexrnedetomidine
`N=319
`(N=-387)
`16 (6%)
`84 (22%)‘
`Hypoteruion
`24 (6%)
`47 01%)"
`Hypertension
`6(2%)
`20 (5%)‘
`Bradycardia
`4 (1%).
`13 (3%)
`Mouth Dry
`20 (5%)
`16 (4%)
`V
`..
`_
`Nausea
`‘Statistically significant difference between modernized dexmedetornidine and placebo patients ps0.05
`Data scum: 2.2.5.5
`
`-’
`
`.
`
`Abnormal laboratory findings, which might have been -anticipated from the preclinical
`studies, such as elevated Ll-"Is and glycosur-la, were not home 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.
`‘
`
`Abuse Porenfigl
`~
`.
`Dexmedetomidine might be expected, based on its clinical pharmacological efiects 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
`dexmedetornidine 1.0 ug/kg/dose >saline and equivalent to saline at 0.0625 pg/kydose.
`At a dose of 0.25 pg/kg/dose dexmedetomidine produced reinforcing behavior comparable
`to pentazocine (CW); Dexmedetomidine also has been shown to attenuate morphine
`withdravial,‘ suggestive but not conclusive evidence for dependence liability. A mild
`withdrawal syndrome has been described in rodents afier 7 days of treatment.
`
`Extensive receptor binding studies using standard radioligands were presented in the
`NDA, demonstrating very high amnity for the a-adrenergic receptors and moderate
`afl-lnity for the serotonergic receptors. Binding at the opiate receptors was negligible.
`Comparative binding to relevant controlled substances was not provided.
`
`’
`
`'
`
`’ Afler Sponsor’s Table 2] ISS 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 clonidinc to suppress withdrawal
`symptoms rather than for its psychotropic efiects.
`
`NDA aztazsncunaaemmaaine no
`
`-
`
`Pageé arm
`
`.
`
`.
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 21
`
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`Petition for Inter Partes Review of US 8,242,158
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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
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`have significant problems.
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`'
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`_
`Commentts:
`There is adequate evidence to support the eficacy and safety of dexmedetomidine 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. _
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`Additional datashould be obtained for safe use at the extremes of age—pediatric dosing,
`pharmacokinetics and safety should be obtained. Geriatric phannacodynamic/safety data
`in the vmyflderly >75 years should also be generated-or existing data analyzed.
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`Once metabolic profile is better established with multiple dosing, its safety should be
`evaluated in patients with renal failure.
`-
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`Surveillance for possible diversion and abuse can be done through the existing mechanisms
`such as Medwatch, SAMHSA's DAWN database, and DEA reports.
`'
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`Phase 4 Commitmenm
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`The focus of the dexrnedetornidine development plan was short-term ICU sedation in
`adults. It is quite clear that this product will not have use limited to this population, and
`therefore the following phase