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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 overthecited
`
`reference, and respectfully request that the rejection be withdrawn.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 andthatall 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 Examineris invited to
`
`call the undersigned at the telephone numberindicated 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, 02-4377.
`
`March, (3, 2e(2-
`
`Date
`
`Respectfully submitted,
`
`BAKER BOTTSL.L.P.
`
`Ye Ve
`
`Dennis M. Bissonnette
`Patent Office Reg. No. 61,910
`
`SandraS. Lee
`Patent Office Reg. No. $1,932
`
`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
`
`
`
`°
`
`2
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`°
`
`:
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`3
`
`-,.
`
`*
`
`-
`
`-
`
`a OU,
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`—=
`
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`a
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`-
`
`—
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`.
`
`
`SEESTETT=PEDsRsnEREDresteWeaARRANFSETREELSLESEaonSAParereTUEP
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 12
`
`
`
`
`
`“42
` HFD-170
`N21038 yn #21-038
`un
`ee
`‘KU NAME: Precedex (dexmedetomidine nei myection)
`APPLICANT: ABBOTT LABORATORIES a
`
`CHEMICAL & THERAPEUTIC CLASS:1S
`
`Review C cles
`
`Review Cycler 2
`Review Cycle: 1
`Submission Date:
`Submission Date:32-18-98
`
`_|Receipt Date: 12-18-98 Receipt Date:
`Goal Date:12-18-99
`Goal Date:
`Action: AP
`
`-
`
`Action:
`
`Review Cycie; 3
`Submission Date:
`Receipt Date:
`Goat Date:
`Action:
`
`Review Cycle: 4
`-} Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`
` PROJECT MANAGER! CSO :Susmita Samanta
`Phone # & Office Room #:301-827-7410, 9B-45
`
`
`
`
`
`
`
`
`
`
`
`
`Volume 2 of 4
`
`Administrative volume #{s): 1
`Clinical volume &(s): 2
`CMCvolumeA({s): 3
`Pharmacology/Toxicology volume #(s): 4
`
`sengOAC
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 13
`
`
`
`
`
`ODE TI ACTION PACKAGE TABLE OF CONTENTS
`
`Application #21-038
`Drug Name:Precedex (dexmedetomidine Hydrochlorideinjection), 2 mL ampule/2 mL vial, 100
`meg/mL
`
`Applicant: Abbott Laboratories
`
`Chem./Ther. Type:1S
`
`CSO/PM: Susmita Samanta
`
`Phone: 301-827-7410
`
`HFD-170
`
`Original Application Date: December 18, 1998 Original Receipt Date: December 18, 1998
`
`
`CURRENT USER FEE GOAL DATE: December18, 1999DateTableofContentsCompleted:9/1 3/99
`.
`om
`X (completed),
`
`
`or Comment
`
`~ SectionA:AdministrativeInformation ~_NIA(not applicable).
`
`Tab A-1
`‘Tab A-2
`
`c. 24 our alert MemMOrandUm -vereresesesseessserserserernnersegnecsnneeensnensenes
`
`Current Action:AP oe
`
`Action Letter(s)
`Phase 4 Commitments:
`a. Copy of applicants communication committing to Phase 4 ..........00.. .
`b. Agency Correspondence requesting Phase 4 Commitments..............-
`TabA-3—.FDA revised Labels & Labeling and Reviews:
`(Separate each version/cycle with a colored sheet)
`&. Package Insert ......cesssscccssssetessesssessseevesesccnererserecaseerersanes sevens
`
`b. Immediate Container and Carton Labels ........ssssessesresreretssreeesees
`
`Tab A-4
`Tab A-5
`
`Tab A-6
`Tab A-?7
`Tab A-2
`
`Original Proposed Labeling ...-....:ssssssrssssrsssssssernsesrseasseensearsesssearsencanes
`Foreign Labeling:
`a, Foreign Marketing History...c.ccsssssccscssscerssssecenserseeeersereressegeer
`.
`b. Foreign Labeling and Review(s) ........c:0.sssesesseeseeesseesseseveseesesneees
`Labeling and Nomenclature Committee’s Tradename Review..........-.-00:06
`Summary Memoranda(e.g., Division Director, Group Leader, Office) peseesene
`Copy of Patent Statement ........ cccccscesecsecsersescrseessessseecenesecaceeesaasasnenen
`
`Exclusivity Checklist (and any requests for exclusivity) ......ssscsecseessrserees
`Debarment Statement........sessesssrsessessverssnessesssnssersonsesvearavesensesseesness
`Tab A-9=Correspondences, Faxes, & Telecoms ...,...scscsrsssserscessersssecnsrensssseenentenes
`Tab A-10 Minutes.of Meetings:
`a. End-of-Phase HH meeting ........-s.sscsccssoscsecerscnscetssseessarsssgeacaseerae
`b. Pre-NDA meeting(s).....-.-s-ressecsssssesrersessecssnesseneecteseneseesneneree
`C. Filing meeting....csecsesererscsesesesessseesensneveeseseearensteseaene®ses
`G, Other Meetings ...ccscerssersrsrseserssssssessneetecersnssssseessepensreeansees
`Tab A-11|Advisory Committee Meeting:
`a. Questions Considered by the Committee ............-s.e-sssecsesernneesneees
`b. List of Attendees ..........scsesscessrernsssesneensnsesnssscescsnsonsnsssnveneent®
`
`Project Management Administrative Information (optional).......2:-.:-ssssee
`Tab A-12
`
`
`
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 14
`
`
`
`
`Se
`re oo
`ODEII ACTION PACKAGE TABLE OF CONTENTS(continued)
`
`Application #21-038 Drug Name: Dexmedetomidine HCL
`
`X (completed),
`
`
`or Comment
`
`SectionB:ClinicalInformation N/A (not applicable),
`
`Tab B-}
`
`Clinical Reviews and Memoranda.......scscsssessssarececserssscsereeseetssssnesess
`
`Tab B-2
`
`Safety Update Reviews ....cccceseesssssesesssscessrerssseeessesserercensnacererepetenes
`
`Tab Be3- Pediatric Page .........-scsseccsssscsseccesseeceststereseseeseeensserveseteascesssesenceusens
`
`Tab B-4
`
`Statistical (Clinical) Review and Memoranda .......ecesereeeveeneateeeaesnteees
`
`°
`
`Tab B-S_
`——_ Biopharmaceutics Review and Memoranda ........ccsssssesesresseneenserescsenenes
`Tab B-6
`Abuse Liability Review occ.eecsssessscsesessssesssersesesseaseneseesensasennerse
`Tab B-7
`DSI Audits ooo. ccceccseceseseseeesecesesseeercoseeseseceqeeseaesnensnensestsnsneaeas
`Tab B-8=Summary of Efficacy (from the summary volumeof the application) .........0s0-
`- Tab B-9
`Summary of Safety (from the summary volumeofthe application)............00000
`
`
`
`
`X (completed),
`(CMC)
`1 Controls
`facturi
`ist M
`CI
`
`SectionC:Information N/A (not applicable),
`or Comment
`
`Tab C-]
`Tab C-2
`
`CMC Reviews and Memoranda .......scssssssssssssssesessernscssesssapesesearenss
`DMF Reviews.....cssssssecssesssrerecsscersrsereseesersasssarnssvsesssssencnessueeeeesees
`
`Tab C-3
`
`EA Reviews/FONS I .......sccsressscscecssesresscesseccereserecsacersereseaenrecesearenes
`
`Tab C-4
`
`Micro Review (validation of sterilization) ..............cssscessscereneesesteeeecers
`
`
`
`TabC-5—Statistical Review of drug stability .......000Veenesseveecsesseneeanaseeenaresese .
`
`Tab C-6
`
`Inspection offacilities => Decision:
`
`Date:
`
`TabC-7=Methods Validation Information.........sssesssssssseseseesetsessesersereeseesMe
`
`X (completed),
`,
`So
`
`
`
`or Comment
`
`
`
`SectionD:Information-~=.5. Pharmacology/Toxicology - N/A(not applicable),
`
`Pharmacology/Toxicology Reviews and Memoranda ...sseprseccserereerereen
`Tab D-]
`Carcinogenicity Review (statistical) seonssnsenensseecsnsensenesseneesnenseeseseeessese
`Tab D-2
`Tab D-3
`CAC/Executive Committee Report ......ccssscrssssccsssessscerscrerceeeneraeneeaere
`
`
`7
`
`ADDITIONAL NOTES:
`
`|
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`
`
`
`Petition for Inter Partes Review of US 8,242,158
`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
`
`
`
`
`Midazolam use as rescue medication during intubation (ITT)
`Study W97-245
`PBO
`Dexmedetomidine
`
`p-value
`
`:
`
`:
`Mean total dose (mg) of midazolam
`Categorized midazolam use
`#ptsusd
`
`N=175
`18.6 mg
`
`- . -N=178
`4.8 mg
`
`108 (61%)
` 43(25%)
`Omg
`36(20%)
`34 (19%)
`0-4 mg
`34 (19%)
`98 (56%)
`>4 mg
`* ANOVA model with rx and ctr. **Chi-square ( after J.Ma’s table 3.2, review, p.5)
`
`0.0011*
`.
`<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
`ukp/hr (with allowed adjustment between 0.2 and 0.7 pg/kg/hr) followingan initial bolus
`of 6 pg/kg IV. Patients were allowed 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 measurefor this study was the total amount of
`rescue medication (propofol) needed to maintain sedation as specified while intubated.
`There wasastatistically significantly greater use of propofolin patients randomized to
`placebo than to dexmedetomidine during treatment.
`
`The same prospective primary analysis that was performed in study W97-245 was also
`performed in this study. It can be seen from the results reported in the table below that a
`significantly greater numberofpatients in the dexmedetomidine group (60%) compared to
`the placebo group (24%) maintained a Ramsay sedation score of23 without any
`additional propofol rescue.
`
`-
`-
`
`Midazolam use as rescue medication during intubation (TT)
`Study W97-246
`PBO
`Dexmedetomidine
`.
`
`p-value
`
`“ez ibe
`
`||
`
`||
`
`Mean total dose (mg) of propofol
`
`.
`
`Categorized propofol use
`# pts used
`
`N=198
`513 mg
`
`N=203
`72 mg
`
`.
`
`<0.0001*
`
`Omg
`47(24%)
`122 (60%)
`0-50mg
`30(15%)
`43 (21%)
`>$0mg
`_121 (61%
`38 (19%
`* ANOVA model with rx and ctr. **Chi-square (after J.Ma’s table 3.5, review, p.9)
`
`<0.001**
`
`a
`
`For both studies, the time to extubation was measured and analyzed, and found to be,
`based on a very conservative approach, not significantly different between groups. For
`more detail,Dr. Jonathan Ma’s analysis p.10-11 should be referenced.
`In addition the
`
`NDA#21-038Dexmedetomidine HCI
`
`Page 3 af 10
`
`
`Petition for Inter Partes Review of us 8,242,158
`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 teratogenicin rats or rabbits. Howeverfetal
`toxicity was observed in rats, evidenced by increased postimplantation losses and reduced
`numberoflive pupsper litter. Prenatal and postnatal effects 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 theAmes test or the mouse lymphomaassay.It
`was shown to be clastogenic in both the in vitro human lymphocytes chromosomal
`aberration assay in the presence ofmetabolic activatiofiand in in vivo mouse micronucleus
`
`assay.-
`
`Carcinogenicity testing was considered unnecessary due to the projected short-term use of
`this product.
`
`Clinical
`Thesafety 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 ofdexmedetomidine exposure includes
`3038 subjects, ofwhom 1473 were ICU patients who received the drug by continuous
`infusion. The bulk of exposure was in the range of4-6 mg/kg and less than 16 hours, The
`dose and duration of exposure provide sufficient experienceto be able to assess the safety
`of this product for the proposed duration ofup to 24 hoursinfusion.
`
`
`
`-
`~
`
`There was also limited exposure (78 patients) who received infusion longer than 24 hours
`with the longest infusion lasting between 30-40 hoursin 2 patients.
`
`The deaths and serious adverse events reported were not unexpected for the ICU
`population understudy in this NDAeither in quality or in quantity.
`
`In the placebo-controlled infusion studies in Phase 2-3, the only commonly reported
`adverse events observed in more than !% ofpatients treated with dexmedetomidine and
`occurring with a frequency more than 2-fold that ofthe placebo were predictably
`hypotension (22%) , hypertension (12%) , and bradycardia (5%).
`
`NDA#21-038Dexmedetomidine HCl
`
`;
`
`Page 5 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 20
`
`
`
`Adverse Event
`
`LLTLLETD
`Summary of Treatment-Emergent Adverse Events Occurring in >1% of Dexmedetomidine patients in
`Phase I/II Continuous Infusion ICU Sedation Studies?
`Randomized dexmedetomidine
`Placebo
`(N=387)
`N=379
`Hypotension
`84 (22%)* - .--
`16 (4%)
`Hypertension
`47 (12%)*
`24 (6%)
`Bradycardia
`20 (5%)*
`6(2%)
`Mouth Dry
`13 (3%)
`4 (1%).
`Nausea
`16 (4%)
`20 (5%)
`*Statistically significant difference between randomized dexmedetomidine and placebo patients ps0.05
`Data source 2.2.5.5
`
`-
`
`Abnormal laboratory findings, which might have beenanticipated from thepreclinical
`studies, such as elevated LFTs and glycosuria, were not boreoutin laboratory testing.
`
`There are no safety data in pediatric patients. The sponsorwill 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 ofthe 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
`neededin the veryelderly patients based on anticipated PD differences associated with
`sedative agents.
`
`Abuse Potential
`~
`.
`Dexmedetomidine might be expected, based onits clinical pharmacological effects 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
`deamedetomidine 1.0 g/kg/dose >saline and equivalent to saline at 0.0625 pg/ke/dose.
`At a dose of0.25 jsg/ke/dose dexmedetomidine produced reinforcing behavior comparable
`to pentazocine (CIV). Dexmedetomidine also has been shown to attenuate morphine
`withdrawal’ suggestive but not conclusive evidence for dependence liability. A mild
`withdrawalsyndrome has been described in rodents after 7 days oftreatment.
`Extensive receptor binding studies using standard radioligands were presented in the
`NDA, demonstrating very high affinity for the a-adrenergic receptors and-moderate
`affinity for the serotonergic receptors. Binding at the opiate receptors was negligible.
`Comparative binding to relevant controlled substances was not provided.
`
`? After Sponsor’s Table 2] ISS 8/10-239-65
`* Clonidineis not currently controlled in the CSA. There have been reports of abuse with
`clonidine, mostly ofreports of opiate addicts using clonidine to suppress withdrawal
`symptoms rather than for its psychotropic effects.
`
`NDA #21]-038Dexmedetomidine HCI
`
`‘
`
`Page 6 of 10
`
`ETTTTTLeaaRTEPETaAaTTCLAL
`
`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
`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
`havesignificant problems.
`~
`
`_
`Comments:
`There is adequate evidence to support the efficacy and safety of dexmedetomidine to
`approveit for ICU sedation by continuousinfusion for 24 hours. It is anticipated that
`there will be increasing demand for more prolongeduseof this product onceit is
`approved. In addition to collecting additional safety data on prolonged use, there should
`be a better characterization ofthe activity, toxicity and fate of the metabolites. _
`Additional datashould be obtained for safe use at the extremes ofage—pediatric dosing,
`pharmacokinetics and safety should be obtained. Geriatric pharmacodynamic/safety data
`in the veryelderly >75 years should also be generated-or existing data analyzed.
`Oncethe metabolic profile is better established with multiple dosing, its safety should be
`
`evaluated in patients with renal failure.
`
`Surveillance for possible diversion and abuse can be done through theexisting Mechaniens
`such as Medwatch, SAMHSA's DAWN database, and DEAreports.
`
`Phase 4 Commitments
`The focus ofthe dexmedetomidine development plan was short-term ICU sedation
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