Atty. Docket No. 077350.0355
`U.S. Ser. No. 13/541524
`
`JN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant
`
`Roychowdhury et al.
`
`Customer No.
`
`Appln. No.
`
`13/541,524
`
`Confirmation No.
`
`Filed
`
`July 3, 2012
`
`Art Unit
`
`62965
`
`8238
`
`1629
`
`Examiner
`
`Polansky, Gregg
`
`For
`
`DEXMEDETOMJDINE PREMIX FORMULATION
`
`DECLARATION UNDER 37 C.F.R. §1.132
`
`I, Huailiang Wu, Ph.D., hereby declare the following:
`
`I.
`
`I am currently employed as a Group Leader, Global Pharma Research &
`
`Development, by HOSPIRA, INC., (hereafter "Hospira") having its principal place of
`
`business at 275 North Field Drive, Lake Forest, IL 60045. My curriculum vitae is
`
`attached as Exhibit A.
`
`2.
`
`HOSPIRA, fNC. is the sole Assignee of United States Patent Application Serial No.
`
`13/541,524 (hereafter "the '524 application") pursuant to the Assignment recorded at
`
`Reel!Frame: 0274 8010592 which was recorded with the United States Patent and
`
`Trademark Office (hereafter, "US PTO") on January 4, 2012.
`
`3.
`
`I, along with other scientists employed by, and under the direction of, Hospira,
`
`designed and conducted assays relating to a ready to use liquid pharmuceutical
`
`composition for parenteral administration to a subject, comprising dexmedetomidine
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`NY02 754427.2
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`

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`Atty. Docket No. 077350.0355
`U.S. Ser. No. l 3/54 l 524
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`or a pharmaceutically acceptable salt thereof at a concentration of about 0.005 to about
`
`50 ~Lg/mL disposed within a sealed glass container. Ready to use parenteral
`
`pharmaceutical compositions, such as the claimed dexmedetomidine composition, are
`
`manufactured to be sterile so that the compositions are safe to be administered to
`
`patients upon removal from their storage container. Sterility can be achieved, for
`
`example, by autoclaving the ready to use composition.
`
`4.
`
`A first assay (Assay 1) measured the potency of various concentrations of a ready to
`
`use dexmedetomidine composition stored in Polyvinyl chloride (PVC) bags and glass
`
`vials over a three-day period following autoclave. A second assay (Assay 2) was
`
`conducted to measure the potency of various concentrations of a ready to use
`
`dexmedetomidine composition without autoclave following storage at ambient
`
`temperature over a 24 hour period.
`
`5.
`
`As described in greater detail below, Exhibit B (describing the results of Assay l)
`
`demonstrates an unexpected maintenance of potency of I, l 0, l 5 and 50 µg/mL
`
`dexmedetomidine compositions following autoclave and storage over a three-day
`
`period in glass containers compared to storage in PVC plastic containers.
`
`6.
`
`Exhibit C (describing the results of Assay 2) demonstrates an llTiexpected maintenance
`
`of potency of I, l 0, l 5 and 50 ftg/mL dexmedetomid ine compositions when stored at
`
`ambient temperature over a 24-hour storage period without autoclave in glass
`
`containers compared to storage in PVC plastic containers.
`
`NY02:7 54427.2
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 2
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`7.
`
`For Assay l, ready to use dexmedetomidine solutions were prepared at concentrations
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`Atty. Docket No. 077350.0355
`U.S. Ser. No. 13/541524
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`of 1 µg/mL, l 0 µg/mL, 15 µg/mL and 50 µg/mL by dissolving dexmedetomidine and
`
`sodium chloride in water to achieve the target dexmedetomidine concentration and a
`
`0.9% sodium chloride concentration. The solutions were then filtered thrnugh a 0.22
`
`µm filter. A sample of the filtered solution was collected and used as the control. The
`
`filtered solution was then disposed into 100-mL PVC bags and 50-mL glass vials.
`
`The solutions from two PVC bags or two glass vials were tested for dexmedetomidine
`
`potency as the "preTS" (pre terminal sterilization) sample about 12 hours after the
`
`solutions were disposed into the PVC bags or glass vials. The remaining filled PVC
`
`bags and glass vials were autoclaved (terminal sterilization) about 12 hours after the
`
`solutions were disposed into the PVC bags or glass vials. The solutions from two
`
`PVC bags or two glass vials immediately after autoclave were tested for
`
`dexmedetomidine potency as the "T=O" samples. The autoclaved PVC bags and glass
`
`vials were stored in stability chambers under conditions of 25°C/60%RH (relative
`
`humidity) and 40°C/75%RH for up to two weeks. Samples from the PVC bags and
`
`glass vials were tested after storage times of 3 days, 1 week and 2 weeks (for PVC
`
`samples only). Testing to determine dexmedetomidine potency in the samples was
`
`conducted using HPLC.
`
`8.
`
`As shown in Exhibit B, the potency of the I µg/mL dexmedetomidine formulation
`
`decreased by 1.82% about 12 hours after being disposed in a PVC storage bag
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`Atty. Docket No. 077350.0355
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`(preTS), and by 7.81 % following autoclave (T=O) compared to control. After storage
`
`for three days in the PVC bag at 25°C and 40°C, the potency of the I ~tg/mL
`
`formulation decreased by 8.05% and 8.83%, respectively, compared to control.
`
`Similarly, the potency of the I 0, 15 and 50 µg/mL formulations disposed in PVC bags
`
`decreased by 5.84%, 5.54% and 4.32% following autoclave, respectively, compared to
`
`control, After storage for three days in PVC bags at 25°C, the potency of the three
`
`concentrations decrea;;ed by 6.24%, 6. 17% and 5.26%, respectively, compared to
`
`control. After storage for three days in PVC bags at 40°C, the potency of the lhree
`
`concentrations decreased by 6.28%, 6.62% and 5.36%, respectively, compared to
`
`control.
`
`9.
`
`As described by Exhibit B, in contrast to storing the dexmedetomidine compositions
`
`in PVC bags, when the dexmedetomidine compositions were stored in glass vials, the
`
`potency of the dexmedetomidine was maintained. When stored in glass vials, none of
`
`the four concentrations of dexmedetomidine experienced any loss in potency after
`
`disposing the formulations in glass vials or after autoclave, compared to control. After
`
`storage for three days in glass vials at 25°C, the decrease in potency of the 1, l 0, 15
`
`and 50 ~tg/mL dexmedetomidine compositions were 0%, 0%, 0.39% and 0.44%,
`
`respectively, compared to control. After storage for three days in glass vials at 40°C,
`
`the decrease in potency of the l, l 0, l 5 and 50 µg/rnL dexmedetomidine compositions
`
`were 0.42%, 0%, 0.27% and 0.5 l %, respectively, compared to control.
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 4
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`Atty. Docket No. 077350.0355
`U.S. Ser. No. 13/54 l 524
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`10.
`
`As described by Exhibit 8, storing a ready to use formulation of dexmedetomidine at
`
`concentrations recited by the claims of the' 524 application in glass containers resulted
`
`in an unexpected reduction in potency loss of the composition compared to storage in
`
`plastic PVC containers. Storing the formulations in PVC containers resulted in a
`
`decrease in dexmedetomidine potency after disposition within the containers, after
`
`autoclave, and after a three·day storage period at 25°C or 40°C. The maximum
`
`detectable loss in potency of the samples stored in PVC containers after the three·day
`
`storage period was 8.83%, whereas the glass containers showed a maximum loss of
`
`only 0.51%.
`
`l l.
`
`For Assay 2, dexmedetomidine solutions were prepared as described for Assay l at
`
`concentrations of 1, l 0, 15 and 50 µg/mL. A sample of the filtered solution was
`
`collected and used as the control. Prior to storage, the solutions from PVC bags and
`
`glass vials were tested for dcxrnedctomidine potency as the "T=O" sample. PVC bags
`
`and glass vials were stored at ambient temperature on a laboratory bench for 24 hours.
`
`Samples from the PVC bags and glass vials were tested after storage times of 12 hours
`
`and 24 hours. Testing to determine dexmedetomidine potency in the samples was
`
`conducted using HPLC.
`
`12.
`
`As shown in Exhibit C, when stored in PVC bags, the potency of the 1, 10, l 5 and 50
`
`~tg/mL dexmedetomidine compositions decreased by 1.48%, 1.22%, 1.06% and
`
`1.78%, respectively, compared to control following the 24-hour storage period. In
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 5
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`Atty. Docket No. 077350.0355
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`contrast, when stored in glass vials, the potency of the 1, 10, l 5 and 50 µg/mL
`
`dexmedetomidine compositions decreased by only 0%, 0.56%, 0.24% and 0%,
`
`respectively, compared to control following the 24-hour storage period.
`
`13.
`
`As described above, and as shown in Exhibits Band C, storing a ready to use
`
`formulation ofdexmedetomidine at concentrations recited by the claims of the '524
`
`application in glass containers resulted in an unexpected reduction in potency Joss of
`
`the composition compared to storage in plastic PVC containers. Specifically, storing
`
`the formulations in PVC containers resulted in a decrease in dexmedetomidine
`
`potency after disposition within the containers, after autoclave, and after a three-day
`
`storage period at 25°C or 40°C. The maximum detectable loss in potency of the
`
`samples stored in PVC containers after the three-day storage period was 8 .83%,
`
`whereas the glass containers showed a maximum loss of only 0.51%. Similarly, when
`
`the dexmedetomidine formulations were stored in glass containers and PVC bags for
`
`24 hours without autoclave, the dexmedetornidine stored in the glass vials maintained
`
`greater dexmedetomidine potency than the samples stored in PVC containers. Such a
`
`reduction in potency loss ofa dexmedetomidine composition after autoclave and
`
`storage would not have been expected when stored in a glass container, and as such, is
`
`a surprising and unexpected result of practicing the claims of the '524 application.
`
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 6
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`Atty. Docket No. 077350.0355
`U.S. Ser. No. 13/541524
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`14.
`
`I hereby declare that all statements made herein of my own knowledge are true cllld
`
`that all statements made on information and belief are believed to be true, and ,1: .. lher
`
`that these statements were made with the knowledge that willful false statemem and
`
`the like so made are punishable by fine or imprisonment, or both, under Section 1001
`
`of Title 18 of the United States Code, and that such willful statements may jeopardize
`
`the validity of the application or any patent issuing therefrom.
`
`By:
`
`Huailiang Wu
`
`)
`
`Date:
`
`Title: Group Leader, Global Pharma Research & Development, HOSPIRA,
`INC.
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`NY02:754427.2
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 7
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`

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`Atty. Docket No. 077350.0355
`U.S. Ser. No. 13/541524
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`EXHIBIT A
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`NY02:754427.2
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`8
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 8
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`

`
`Huailiang (Leon) Wu, Ph.D.
`(224) 212-5262 (O); Email: huailiang.wu@hospira.com
`
`PROFESSIONAL EXPERIENCE
`2/11 - Present: Generic, Global Pharma R&D, Hospira, Lake Forest, IL
`
`9/10 -1/11: Project Manager I (contractor), Global Formulation Sciences, Abbott, Abbott Park, IL
`./
`Investigation of root cause for unexpected bioperformance of a spray drying dispersion (SDD) tablet product
`./
`Initiation and evaluation of feasibility of developing a pediatric oral suspension ER
`./
`Improvement ofa SDD tablet product's manufacturability and scale up
`
`5/10 - 9/10: General Manger, Alpharmaca Inc., Shanghai, P.R. China
`./ Responsible for setting overall business strategy and managing daily operation for achieving company objectives
`./ Applied formulation expertise and innovation to pharmaceutical product design and development without
`infringing patents of innovators on branded products .
`./ Led and oversaw R&D activities with following specific objectives
`• Achieve bioequivalent version of branded products
`•
`Improve performance and patient compliance for extending lifecycle of branded pharmaceutical products
`• Collaborate with Big Pharma companies in China to co-develop products and to put them through SFDA
`approval process.
`
`Principal Scientist and Group leader
`5/10
`Senior Research Scientist Ill and Group leader
`10/06 - 5/10:
`8/02 - 9/06:
`Senior Research Scientist I
`8/00 - 8/02:
`Research Scientist
`Global Formulation Sciences, GPRD, Abbott Laboratories, North Chicago, IL
`./ Lead formulator for formulation design and development of multiple compounds, from early development through
`various stages of clinical studies (FIM to Phase III) .
`./ Led independent research activities for bioavailability improvement for insoluble molecules. Supported life cycle
`management projects and patent filing. Participated in regularly evaluation of external drug delivery technologies .
`./ Designed and developed oral formulations, including both immediate and extended release solid dosage fonn, lipid
`based systems, solid dispersion fonnulations and suspension formulation for clinical studies.
`• Developed spray drying dispersion (SDD) tablet formulations at various scales
`Defined a procedure to effectively screen and optimize SOD formulations
`Worked with a Third Party Manufacturer to manufacture SDD materials at scale of up to -4000L/batch
`Scaled up post-dried SOD tablet formulations at a scale of up to 300kg/batch
`• Defined and developed one lipid formulation for clinical study
`• Developed two controlled release formulations (either matrix tablets or multiparticulate beads)
`• Developed an oral suspension fommlation (Phase III)
`./ Led, coordinated and managed manufacturing of clinical supplies (tablets or capsules) for many clinical phase
`studies ranging from Phase I, II to III internally as well as at third party manufacturers (TPM) at scales up to
`300kg/batch
`./ Authored formulation development and/or CMC section for IND, CTA and IMPD regulatory filings
`./ Hands-on experience with manufacture of various oral fonnulations at lab and pilot plant scales
`./ Knowledgeable and experienced in biopharmaceutic and pharmacokinetic evaluations
`./ Knowledgeable and skilled in physical pharmacy (mass transport, dissolution, solubility, stability, solid state, etc)
`
`12/99 - 7/00 Postdoctoral Scientist, Exploratory Formulation, Pharmaceutical Development, Pharmacia, Ml
`../ Developed good understanding of mechanisms by which lipid-based formulations enhance oral
`absorptionJbioavailability
`•
`Investigated effect ofphysicochemical properties of formulations on permeability, absorption and
`bioavailability of insoluble model compounds in animal model.
`Evaluated effect of bile (salt), surfactants and lipids on bioavailability of the model compounds in animals
`•
`• Hands-on experience with animal studies on oral drug absorption, in situ rat intestine perfusion.
`•
`Experience in analytical chemistry and bioanalysis (HPLC, UV, fluorescence and LC/MS/MS etc)
`
`1
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 9
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`

`
`8/95 - I 1/99 Research Assistant, College of Pharmacy, University of Michigan, MI
`,/ Designed and developed topical delivery systems including microemulsion and liposomal formulations for
`hydrophilic macromolecules such as protein and DNA
`,/ Characterized DNA delivery systems and evaluated in in vivo animal models
`
`2194 - 8/95 Visiting Research Investigator II, College of Pharmacy, University of Michigan, MI
`Designed and characterized nonionic liposorne and emulsion formulations for topical delivery systems
`
`8/87 - 12/93 Assistant Researcher, Nanjing Institute of Materia Medica, Nanjing, China
`../ Designed and developed solid and parenteral formulations including analytical method development,
`pharmacokinetic evaluation and regulatory filing with SFDA
`• Amphotericin B liposomal injectable formulation (Phase II)
`•
`Famotidine powder/granule for oral suspension (commercial production approved by SFDA)
`•
`FDC ibubrofen tablet (commercial production approved by SFDA)
`•
`FeS04 CR tablets (commercial production approved by SFDA)
`• Developed Yunzhi polysaccharide injection (lyophilized)
`
`9!84 - 7/87 Research Assistant, Pharmaceutical Department, Nanjing Institute of Materia Medica, China
`,/
`Investigated feasibility of increasing efficacy and reducing toxicity of Harringtonine via liposomal iv formulations
`•
`Isolated and purified the phospholipid from the egg yolk
`•
`Evaluated impact of formulation factors and preparation methods etc on efficiency of incorporation, stability
`• Develop analytical method
`•
`Performed PK and in vivo distribution study in rat and rabbit models
`
`2/82 - 8/84 Assistant Engineer/Head of Central Research Lab/Manager
`Dongfeng Pharmaceutical Co., Lianyungang, China
`,/ Developed and manufactured allicin (garlic oil) products
`-
`Synthesized garlic oil and scaled up
`- Applied microencapsulation techniques to develop allicin (garlic oil) capsule formulation
`(commercial production approved by SFDA)
`- Developed garlic oil injection (commercial production approved by SFDA)
`,/ Developed generic products including solid dosage form and parenteral formulations
`,/ Worked with colleagues from different function areas to solve problems which might happen during production of
`various products including solid and parenteral formulations
`
`EDUCATION
`Ph.D. in Pharmaceutics, College of Pharmacy, University of Michigan, 1999
`MS. in Pharmaceutics, China Pharmaceutical University, Nanjing, China, 1987
`BS. in Pharmacy, China Pharmaceutical University, Nanjing, China, 1982
`
`PATENT APPLICATIONS
`1.
`Solid Dispersions Containing An Apoptosis-Promoting Agent (Filed application in 6/10)
`2. New Pharmaceutical Formulation for ABT-072/ABT-333 (MOI submitted, 2010)
`Solid Dispersions Containing An Anti-HCV Agent (MOI submitted, 2009)
`3.
`4.
`Extended release formulation for ABT-894 (MOI submitted, 2009)
`Pharmaceutical Formulation for Feno Acid: Wu, H., Lee, D., Ju, T. and Gao, Y. (Filed application in 9/06)
`5.
`7852US02 (Dissolution criteria for Feno Acid Formulations (NFE)): Ju, T., Davila, C., Engh, E.,Gao, Y.,
`6.
`Gustavson, L., Jayaraman, S., LeBJond, D., Lee, D., Zhu, T., Wu, H. Filed in 10/06.
`Pharmaceutical Composition Having Improved Dissolution Profiles For Poorly Soluble Drugs (Provisional
`application, Case No. 7858.US.Ll. Filed 4i05), Wu, H., Lee, D., Zhang, G.
`8. Nanoemulsion Formulations (United States Patent Application, 20020 l 55084 ). Roessler, B., Baker, J .,
`Chandrasekharan, R., Weiner, N. and Wu, H.
`
`7.
`
`INVITED SPEECHES
`"NCE Based (Oral) Drug Product Development" The I '1 International Innovate and Generic Drug Research &
`I.
`
`2
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 10
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`

`
`2.
`3.
`
`4.
`5.
`
`6.
`7.
`
`Development Forum, Canton, China 20 I 0
`"Modified Release Formulation Development" College of Pharmacy, University of Michigan, Ml, 2009
`"Dissolution Enhancement For Formulations Containing Salt of Poorly Soluble Compounds" AAPS 2005 Annual
`Meeting, Nashville, TN
`"Oral Drug Absorption vs. Formulation Design" College of Pharmacy, University of Michigan, MI, 2005
`"Dissolution Enhancement For Formulations Containing Salt Of Poorly Soluble Compounds" Pharmaceutical
`Education Associates Conference: Improving Delivery of Poorly Soluble Compounds: Formulation and
`?reformulation Approaches, Philadelphia, PA, 2005
`"Principle of Oral Controlled-Release Formulation Design" College of Pharmacy, University of Michigan, Ml, 2004
`"Topical Delivery Of Hydrophilic Macromolecules With Formulations" AAPS/FIP/SFDA Joint Symposium: Drug
`Development, Clinical Research and Registration, Nanjing, China, 2004
`
`PUBLICATIONS
`1. Wu, H.et al. "Topical transfection using plasmid DNA in a water-in-oil nanoemulsion" Int. J ?harm. 221 (2001)
`23-34
`2. Wu, H. et al. "Topical transport of hydrophilic compounds using water-in-oil nanoemulsions" Int. J ?harm, 220
`(2001) 63-75
`3. Niemiec, S.M., Wu, H.L.et al. Effect ofpolyolprepolymer on the disposition ofRetinoic Acid in various strata of
`hamster ear following topical in vivo application of gel formulations: Correlation with disposition in human skin.
`Drug Delivery, 4, 33-36, 1997
`4. Hu, Z., Wu, H. et al. Topical delivery of a-interferon from liposomal systems: An in vivo study with hairless mouse.
`Drug Delivery, 2, 94-97, l 995
`5. Wu, H. et al. Pharmacokinetics of harringtonine liposomes in rabbits. Acta Pharmacologica Sinica, 15, 84-6, 1994
`6. Wu, H. et al. Distribution of harringtonine in positively and negatively charged liposomes in rat tissues Acta
`Pharmacologica Sinica, 14, 176-8, 1993
`7. Wu, H. et al. Quantitation of liposomally entrapped and free harringtonine in tissues ofrat by HPLC. Zhongguo
`Yaoke Daxue Xuebao, 20, 77-81, 1989
`Ze, Q. and Wu, H. Industrial production of Allicin microcapsule. J. Chinese Traditional Medicine, (I): 7-9, 1984.
`
`8.
`
`5.
`
`4.
`
`ABSTRACTS AND PRESENT A TIO NS
`I. Wu, H. et al. Formulation Design to Improve Bioavailability and Reduce Biovariability of the Salt of a Poorly Soluble
`Base Compound, AAPS 2009 Annual Meeting, Los Angeles, CA
`2. Wu, H. et al. Understanding Dissolution Behavior of the Salt of a Poorly Soluble Acid Compound In Dual Ph
`Media. AAPS 2005 Annual Meeting, Nashville, TN
`3. Wu, H.et al. Effect of Polymers on Dissolution of the Salt of a Poorly Soluble Acid Compound In Dual Ph Media.
`AAPS 2005 Annual Meeting, Nashville, TN
`Sever, N., Ibrahim, R., Sharma, S., Schmidt, C., Wu, H. Hiestand Indices Predict Tablet Compression Behavior,
`AAPS PharmSci, 5(4),2003
`Zhang, G., Cao, Y., Gao, Y., Han, J. and Wu, H. In Situ Precipitation of Weak Acid In Aqueous Meda:
`Considerations Beyond Salt Selection, AAPS PharmSci, 4(4),2002
`6. Wu, H. et al. Dissolution Testing Using Multi-Medium In The Development Of Formulations For An Acidic Salt
`Compound, AAPS PharmSci, 4(4)2002)
`7. Wu, H. et al. Influence of Bile Salt Micelles And Mixed Micelles on the Absorption of PNU-96988 in the Rat
`Small Intestine, AAPS Annual Meeting, Indianapolis, 2000
`8. Wu, H. et al. Evaluation of Water-in-Oil DNA Microemulsions as Topical Vehicles for Skin Transfection. AAPS
`Annual Meeting, New Orleans, LA, 1999.
`9. Wu, H. et al Topical Delivery of Expression Plasmid DNA and Transfection In Vivo Using A Novel Nonionic
`Microemulsion System, American Society of Gene Therapy national meeting, Washington, D.C, 1999
`10. Wu, H. et al. A Simple Method to Estimate the Contribution of the Transfollicular Pathway to Transport of
`Minoxidil into and Across Skin from Various Vehicles. AAPS Annual Meeting, San Francisco, CA, 1998.
`11. Wu, H.et al. Topical Delivery ofTranexamic Acid from Nonionic Liposomal and Emulsion Formulations ?harm.
`Res, I4: S-314, 1997
`12. Wu, H.et al. Deposition of Taxol from Nonionic Liposomal Systems: An Jn Vitro-In Vivo Study Using Hairless
`Mouse Skin. ?harm. Res., 1 J:S-187, 1994.
`13. Hu, Z., Niemiec, S.M., Wu, H. et al. Topical Delivery of Alpha-Interferon from Nonionic Liposomal
`Formulations Pharm. Res, l l:S-I86,1994
`14. Wu, H. et al. Pharmacokinetics ofHarringtonine Liposomes in Rabbits. Chemical Abstracts, 120:24, 1994
`
`3
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 11
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`

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`15. Wu, H. et al. Distribution of Harringtonine in Positively and Negatively Charged Liposomes in Rat Tissues.
`Chemical Abstracts, 118:417, 1993
`16. Wu, H. et al. Quantitation of Liposome Encapsulated Harringtonine and Haringtonine in Tissues of Rat by HPLC.
`Chemical Abstracts, 112:6, 1990.
`
`PROFESSIONAL ACTIVITIES
`A member of2001 and 2002 AAPS New Investigator Grant in Oral Lipid·based Drug Delivery Systems Selection
`Committee
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 12
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`;\tty. Docket No. 077350.0355
`U.S. Ser. No. 13/541524
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`EXHIBITB
`
`NY02·754427.2
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`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 13
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`

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`Exhibit B
`Storage in PVC Bags
`
`Exhibit B
`Storage in Glass Vials
`
`Time
`
`Initial
`
`3 days
`
`1wk
`
`Sample
`1 ua/ml-control
`1uq/mL-preTS
`1ug/ml-T"'O
`1 Ouq/m L-control
`1 Ouqlm L-ore TS
`10uo/ml-T=O
`15uq/m L-con!rol
`15uq/m L-ore TS
`15ug/ml-T"'0
`50ua/ml-conlrol
`50ua/m L-pre TS
`50ug/mL-T=O
`1ualmL-46C
`1uglml-25C
`1 Oualml-40C
`1 Oualml-25C
`15ualm L-40C
`15ualml-25C
`50uaim L-4DC
`50uglmL-25C
`1ua/ml-40C
`1ua/mL-25C
`1 Oualml-4DC
`1 Dualml-25C
`15ualml-40C
`15uq/ml-25C
`50uq/ml-40C
`50uq/ml-25C
`
`i.;oncentratio n
`(ug/ml)
`1.0323
`1.0392
`1.0357
`10 1482
`10 1855
`10.1771
`15.2373
`15.2542
`15.2453
`5t 1483
`51 2673
`513839
`1.0280
`1.0330
`10.1550
`10.1526
`15 1969
`15.1782
`50.8883
`50.9256
`1 0252
`1.0214
`10.0452
`10.0631
`15 1969
`15.1782
`50.7608
`50.9493
`
`Potency(%) of
`control
`100.00
`100.67
`100.33
`101.14
`101.51
`101.43
`101.48
`101.59
`101.53
`102.53
`102.77
`103.00
`99 58
`100 07
`100.07
`100.04
`99.73
`9961
`99.49
`99.56
`99.31
`98.94
`98.98
`99.16
`99.73
`99.61
`99.24
`99.61
`
`Potency(%) of TO
`NIA
`NIA
`100
`NIA
`N/A
`100
`NIA
`N/A
`100
`NIA
`NIA
`100
`9926
`99.74
`99.78
`99.76
`99.68
`99.56
`99 04
`99.11
`98.99
`98 62
`98.70
`98.88
`99.68
`99.56
`98.79
`9915
`
`Time
`
`Initial
`
`3 days
`
`1 wk
`
`2wk
`
`Sample
`1 uaim.L-control
`1 uqlm L-pre TS
`1uq/ml-T=O
`1 Our:i/ml-control
`10ualml-preTS
`10ua/ml-T=O
`i 5uqlm L-control
`1 5ualm L-pre TS
`1 Sualm L-T =O
`SDuq/mL-control
`5Dualml-oreTS
`50ua/mL-T=O
`1ualml-40C
`1ualml-25C
`1 DuQ/mL-40C
`1 Oua/ml-25C
`1 5uq/m L -40C
`15uq/ml-25C
`5Duq/m L-40C
`50uq/ml-25C
`1uqlml-40C
`1uqlml-25C
`1 Ouq/m L-4DC
`1 Oug/m L-25C
`15ua/mL-40C
`1 Sui:ilm L-25C
`50uglml-40C
`50ualml-25C
`1ualml-40C
`1uglml-25C
`1 Oualml-40C
`1 Oug/ml-25C
`15uaimL-40C
`15ua/ml-25C
`50uqlmL-40C
`50uqlmL-25C
`
`i.;oncentrati on
`(uglml)
`1.0176
`0 9991
`0.9381
`10.0337
`9.9222
`94481
`15.0155
`14.9035
`14.1842
`49.8850
`497035
`47.7288
`0.9277
`0.9356
`9.4037
`9.4078
`14.0222
`14.0887
`47.2099
`47.2603
`0.9433
`0.9444
`9.4544
`9.5342
`14.2671
`14.2785
`47 9910
`48.1394
`0.9380
`0.9481
`94631
`9.5210
`14.1631
`14 2959
`47 5557
`48 2287
`
`Potency ('lo) of Potency (%) of
`control
`TO
`NIA
`100.00
`NIA
`98.18
`92.19
`100.00
`NIA
`100.00
`NIA
`98.89
`94.16
`100.00
`NiA
`100 00
`NIA
`99.25
`94.46
`100.00
`NIA
`100.00
`NIA
`99.64
`95.68
`100.00
`91.17
`98.89
`91.95
`99.73
`93 72
`99.53
`93.76
`99.57
`93.38
`98.86
`93.83
`99.33
`98.91
`94.64
`94.74
`99 02
`92.70
`100.55
`92.81
`100.67
`100 07
`94.23
`100 91
`95.02
`95.02
`100.58
`95.09
`100.66
`96.20
`100.55
`96.50
`10086
`92.18
`99.99
`93.17
`101.06
`..
`94 31
`100.16
`94 89
`100.77
`99 85
`94.32
`95.21
`100.79
`95.33
`99.64
`96.68
`101.05
`
`Note
`Control: Formulations before filling into PVC bags and glass vials;
`Pre TS: Formulations filled in PVC bags and glass vials without autoclave;
`TO: Formulations fi lied in PVC bags and glass vials immediately after autoclave
`Variability of the analytical method is not greater than 2%
`
`NY02:754596 1
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 14
`
`

`
`Atty. Docket No. 077350.0355
`U.S. Ser. No. 13/541524
`
`EXHIBIT C
`
`NY02 754427.2
`
`10
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 15
`
`

`
`Exhibit C
`
`PVC bags
`
`Time
`
`Initial
`
`12h
`
`24h
`
`Sample
`1 ug/ml-contro!
`1 ug/ml-T"'O
`1 Ou g/ml-contro I
`10ug/ml-T"'0
`15ugirn l-contro!
`15uq/ml-T"'O
`50ug/ml-control
`50uq/ml-T=O
`1 ug/ml
`10ug/rnl
`15ug/ml
`50u(!/ml
`1ug/ml
`1 Oug/rnl
`15u9/ml
`50ug/rnl
`
`Concentration
`(ug/ml)
`1.0274
`1.0326
`10.2784
`10.2380
`15.1541
`15.1725
`50.7557
`50.5099
`1.0157
`10.1602
`15.0347
`50.0469
`1 0122
`10 1532
`14.9934
`49 8515
`
`Potency(%) of Potency(%) of
`TO
`control
`N/A
`100 00
`100.00
`100.51
`N/A
`100.00
`100.00
`99.61
`N/A
`100.00
`100.12
`100.00
`N/A
`100.00
`99.52
`100.00
`98.86
`98.36
`99.24
`98.85
`99.21
`99.09
`98.60
`99 08
`98.02
`98.52
`98.78
`99.17
`98.82
`98.94
`98.22
`98.70
`
`Glass vials
`
`Time
`
`Initial
`
`12h
`
`24h
`
`Sample
`1 ug/m L-co ntrol
`1 uq/mL-T:oO
`1 Oug/ml-control
`1 Oug/ml-T=O
`1 Sug/ml-control
`15u(!/ml-T=O
`50 ug/m L-control
`50uo/ml-T=O
`1 ug/mL
`1Dug/ml
`15ug/ml
`50uq/ml
`fog/ml
`10ug/ml
`15ug/ml
`50u(!/ml
`
`Concentration
`(ug/ml)
`1.0274
`1.0337
`10.2784
`10.2390
`15.1541
`15.1478
`50.7557
`50.5308
`1.0405
`10.2327
`15.1351
`50.7833
`1.0374
`10.2204
`15.1177
`50.8899
`
`Potency (%) of
`control
`100.00
`100.61
`100.00
`99.62
`100 00
`99.96
`100.00
`9956
`101.28
`99.56
`99.87
`100.05
`100 97
`99.44
`99 76
`100.26
`
`Potency(%) of
`TO
`N/A
`100.00
`N/A
`100.00
`N/A
`10000
`NIA
`100.00
`100.66
`99.94
`99.92
`10050
`100.36
`99.82
`99.80
`100. 71
`
`Note:
`Control: Formulations before filling into PVC bags and glass vials;
`
`NY02 754596 1
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1057 – Page 16