`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`
`
`Civil Action No. 1:14-cv-01453-LPS
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`)
`)
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`
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`MEDA PHARMACEUTICALS, INC. and
`CIPLA LTD.
`
`
`Plaintiff,
`
`
`v.
`
`APOTEX, INC. and APOTEX CORP.
`
`
`Defendant.
`
`EXPERT REPORT OF RAMPRAKASH GOVINDARAJAN, PH.D.
`
`
`
`
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`PTX1664 e
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`xhibitsticker.com
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`
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`PTX1664-00001
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`1
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`CIP2030
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`1. My name is Ramprakash Govindarajan, Ph.D. As detailed in my current curriculum
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`vitae, which is attached to this declaration as Appendix A, I became Director of Preformulation
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`at the University of Iowa Pharmaceuticals in 2015. I am also a Clinical Assistant Professor at the
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`College of Pharmacy, University of Iowa.
`
`2. I obtained my Ph.D in Pharmaceutics from the University of Mumbai in 2002. After that,
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`I was a Research Associate in Pharmaceutics at the University of Minnesota until 2006. From
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`2006 to 2015, I worked in various product development roles at GlaxoSmithKline.
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`3. Throughout my career, I have had experience conducting experiments similar to the one
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`described in this report, including making pharmaceutical formulations.
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`4. I have never testified as an expert witness or prepared an expert report in connection with
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`litigation. A list of all my publications from the last 18 years is included in my curriculum vitae.
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`5. I have rendered all services in this case as an independent consultant. Apotex has
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`compensated me for these services at in the amount of $8,500. If additional testimony is
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`required of me, I will be compensated at a rate of $250/hour. My compensation does not depend
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`on the the opinions formed in this Report or the outcome of this litigation.
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`6. If called to testify, I am prepared to testify regarding the results of my experiment as
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`reported in this report and the attached documents. I am also prepared to testify about the
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`methods I used and the research I conducted in obtaining those results.
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`II.
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`
`SUMMARY OF WORK
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`7. Apotex retained me to formulate the composition in “Example III” of EP 0780127
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`(“Cramer”) (attached as Appendix B). To make the formulation, I was directed to follow any
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`instructions or guidance included in the document. To the extent the Cramer reference did not
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`PTX1664-00002
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`2
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`expressly provide information I needed to formulate, I was directed to proceed as an ordinarily
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`skilled pharmaceutical formulator would have proceeded in June 2002 after reading Cramer. I
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`was directed not to take any steps or use any equipment that was not known and readily available
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`to an ordinarily skilled pharmaceutical formulator in 2002. Cramer was the only document given
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`to me by Apotex’s counsel.
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`8. I was not told what outcome(s) to try to obtain, or what outcome would be helpful to
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`Apotex or their opponent in this litigation. I have not reviewed any patent asserted in this
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`litigation.
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`9. If I was able to make a pharmaceutical formulation as described in Example III in
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`Cramer, I was asked to make the following observations:
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`a. Observe whether Example III forms a suspension, solution, or something else.
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`i. If Example 3 does form a suspension, observe whether that suspension
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`settles.
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`1. If it settles, observe whether it is difficult to re-suspend.
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`2. If it settles, opine on whether the settling is unacceptable for a
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`pharmaceutical product.
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`b. Measure the osmolality in mOsm/kg.
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`c. Put the resulting composition in a nasal pump with a suitable actuator. Observe if
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`the composition comes out as a spray, a jet, or something else.
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`10. I was asked to record my work and the above observations/experimental results.
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`III. RESULTS AND OBSERVATIONS
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`11. The laboratory notebook entries reflecting the work I did are attached as Exhibit C.
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`PTX1664-00003
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`12. I prepared three batches of the formulation in Example III during the formulation process.
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`I conducted my final testing and made my final observations using Batch 1345-011. My
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`laboratory notebook records the steps I took to make each batch, as well as the ingredient and
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`equipment I used. I am prepared to discuss each of those steps if asked to do so, and I
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`incorporate the contents of my lab notebook to this report as if set forth herein.
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`13. I concluded that Cramer Example III is a suspension that would be acceptable as a
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`pharmaceutical product. There was some settling, but no settling or sedimentation in the product
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`that would make it pharmaceutically unacceptable.
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`14. I further concluded that the product could be delivered as a fine spray using a nasal spray
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`pump. I took two videos of the mist produced by Batch 1345-011 when actuated in a nasal pump
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`with a suitable actuator. Those videos are attached as Appendix D and Appendix E.
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`15. I also took osmolality measurements as requested. I determined that Batch 1345-011 had
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`an osmolality of 529 mOsm/kg.
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`PTX1664-00004
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`IV.
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`DECLARATION
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`I declare under penalty of perjury under the laws of the United States that the foregoing is
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`true and correct to the best of my knowledge.
`
`Date: 29 - June - 2016
`
`Signed:
`Dr. Ramprakash Govindarajan
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`PTX1664-00005
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`5
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`EXHIBIT A
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`EXHIBIT A
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`0000000000006
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`PTX1664-00006
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`6
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`Ramprakash (Ram) Govindarajan, PhD
`Iowa City, Iowa, USA
`Work: +1-319-335-6339
`E-mail: ramprakash-govindarajan@uiowa.edu
`
`PROFESSIONAL APPOINTMENTS
`
`UNIVERSITY OF IOWA, COLLEGE OF PHARMACY (2015 – PRESENT)
`(cid:120) Director, Preformulation, University of Iowa Pharmaceuticals
`(cid:120) Clinical Assistant Professor, College of Pharmacy, University of Iowa
`
`GLAXOSMITHKLINE, RESEARCH TRIANGLE PARK (2006 – 2015)
`(cid:120) Manager (2013 - 2015); Investigator (2009 – 2013); Principal Scientist (2006 – 2009)
`Served in roles of increasing responsibility in various drug product development areas
`including early developability assessment, clinical phase pharmaceutical product
`development, manufacturing process development, technical transfer and scale-up
`
`UNIVERSITY OF NORTH CAROLINA, CHAPEL HILL
`Clinical Assistant Professor (Adjunct appointment, 2007-2015)
`(cid:120) Taught topics included in course MOPH-862 to graduate students in Pharmaceutics
`(cid:120) Served on PhD dissertation committee
`
`ACADEMIC BACKGROUND
`
`Research Associate, Pharmaceutics, University of Minnesota, 2002-2006
`(cid:120)
`Ph. D. (Pharmaceutics), University of Mumbai, 1998-2002
`(cid:120)
`(cid:120) M. Pharm. Sci. (Pharmaceutics), University of Mumbai, 1995-1997
`B. Pharm. Sci., University of Mumbai, 1991-1995
`(cid:120)
`
`AFFILIATIONS
`
`(cid:120) Member of American Association of Pharmaceutical Scientists (AAPS)
`(cid:120) Scientific Reviewer for Journals – ‘Pharmaceutical Research’, ‘Journal of
`Pharmaceutical Sciences’ and ‘The Journal of Pharmacy and Pharmaceutical
`Sciences’
`
`Ram Govindarajan
`
`Page 1 of 5
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`PTX1664-00007
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`PUBLICATIONS /PRESENTATIONS
`
`Journal Articles
`1. Govindarajan, R.; Landis, M.; Hancock, B.; Gatlin, L.; Suryanarayanan, R.; Shalaev,
`E.; (2014), Surface Acidity and Solid-State Compatibility of Excipients with an Acid-
`Sensitive API: Case Study of Atorvastatin Calcium, AAPS PharmSciTech., 1-10.
`2. Chakravarty, P.; Suryanarayanan, R.; Govindarajan, R.; (2012), Phase transformation
`in thiamine hydrochloride tablets: influence on tablet microstructure, physical
`properties, and performance, J. Pharm. Sci. 101 (4), 1410-1422.
`3. Chakravarty, P.; Govindarajan, R.; Suryanarayanan, R.; (2010), Investigation of
`solution and vapor phase mediated phase transformation in thiamine hydrochloride, J.
`Pharm. Sci. 99(9), 3941-3952.
`4. Chakravarty, P.; Berendt , R.; Munson, E.; Young, V; Govindarajan, R.;
`Suryanarayanan, R.; (2009), Insights into the dehydration behavior of thiamine
`hydrochloride (vitamin B1) hydrates: Part II, J. Pharm. Sci. 99(4), 1882 - 1895.
`5. Chakravarty, P.; Berendt , R.; Munson, E.; Young, V; Govindarajan, R.;
`Suryanarayanan, R.; (2009), Insights into the dehydration behavior of thiamine
`hydrochloride (vitamin B1) hydrates: Part I, J. Pharm. Sci. 99(2), 816-827.
`6. Chatterjee, K.; Shalaev, E.Y.; Suryanarayanan, R.; Govindarajan, R. (2008),
`Correlation between chemical reactivity and the Hammett acidity function in
`amorphous solids using inversion of sucrose as a model reaction, J. Pharm. Sci.
`97(1), 274-286.
`7. Govindarajan, R.; Zinchuk, A.V.; Hancock, B.C.; Shalaev, E.Y.; Suryanarayanan, R.,
`(2006), Ionization states in the microenvironment of solid dosage forms: Effect of
`formulation variables and processing, Pharm. Res., 23(10), 2454-2468.
`8. Rani, M; Govindarajan, R.; Surana, R.; Suryanarayanan, R. (2006), Structure in
`dehydrated trehalose dihydrate - evaluation of the concept of partial crystallinity,
`Pharm. Res., 23(10), 2356-2367.
`9. Govindarajan, R.; Chatterjee, K.; Gatlin, L.; Suryanarayanan, R.; Shalaev, E.Y.
`(2006), Impact of freeze-drying on ionization of sulfonephthalein probe molecules in
`trehalose-citrate systems, J. Pharm. Sci. 95(7), 1498–1510.
`10. Zinchuk, A.V.; Hancock, B.C.; Shalaev, E.Y.; Reddy, R.D.; Govindarajan, R.;
`Novak, E. (2005), The influence of measurement conditions on the Hammett acidity
`function of solid pharmaceutical excipients. Eur. J. Pharm. Biopharm., 61(3), 158-
`170.
`11. Govindarajan, R; Nagarsenker M.S. (2005), Formulation studies and in vivo
`evaluation of a flurbiprofen – hydroxypropyl beta-cyclodextrin system, Pharm. Dev.
`Technol., 10(1), 113-122.
`12. Govindarajan, R; Nagarsenker M.S. (2004), Basic drug - enterosoluble polymer
`coevaporates: development of oral controlled release systems, Drug Dev. Ind. Pharm.,
`30(8), 847–857.
`13. Govindarajan, R; Nagarsenker M.S. (2004), Influence of preparation methodology on
`solid-state properties of an acidic drug–cyclodextrin system, J. Pharm. Pharmacol.,
`56, 725–733.
`
`Ram Govindarajan
`
`Page 2 of 5
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`PTX1664-00008
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`14. Nagarsenker, M.S; Meshram, R.N.; Ramprakash G. (2000). “Solid dispersion of
`hydroxypropyl beta-cyclodextrin and ketorolac: enhancement of in-vitro dissolution
`rates, improvement in anti-inflammatory activity and reduction in ulcerogenicity in
`rats”, J. Pharm. Pharmacol., 52 (8), 949-956.
`15. Nagarsenker, M.S.; Garad, S.D; Ramprakash G. (2000) “Design, optimization and
`evaluation of domperidone coevaporates”, J. Control. Rel., 62, 31-38.
`16. Nagarsenker, M.S.; Govindarajan, R., (1998) Solid dispersion for extended release of
`Verapamil HCl, Pharm. Pharmacol. Commun., 4 (7), 331-334.
`
`Book Chapters
`1. Govindarajan, R; Kinetic processes in Pharmaceutics, In: Pharmaceutics: Basic
`principles and applications to pharmacy practice, Ed. Dash, A; Singh, S; Tolman, J;
`(2013)
`2. Govindarajan, R; Suryanarayanan, R. (2006), Processing-induced phase
`transformations and their implications on pharmaceutical product quality, In: Hilfiker,
`Rolf (Ed.) Polymorphism: In the pharmaceutical industry, Wiley-VCH Verlag GmbH
`& Co., KGaA, Weinheim, Germany, p 333-364.
`
`Invited Talks
`1. Govindarajan, R; “Effect of water and buffer on the Hammett acidity function in
`amorphous lyophiles, Amorph-2014 Symposium, Cambridge, UK, Jul 2014
`2. Govindarajan, R “Partial crystallinity in dehydrated trehalose dihydrate: the one-state
`crystallinity”, Research Triangle Institute, Research Triangle Park, North Carolina,
`Jun 2009.
`3. Suryanarayanan, R and Govindarajan R., “Phase transformations during
`pharmaceutical processing-potential implications on product performance”, Dr.
`Reddy’s Laboratories Ltd., Nov 24, 2005, Hyderabad, India
`4. Govindarajan, R., "Evaluation of 'acidity' of Pharmaceutical solids using indicator
`probes", AAPS Pharmaceutics and Drug Delivery (PDD) conference, June 2004,
`Philadelphia, PA.
`5. Govindarajan, R., "Solid-state acidity of amorphous freeze-dried systems and surface
`acidity of solid dosage forms", Pfizer Global R&D, April 2003, Groton, CT.
`
`Conference presentations
`1. Campbell D, Patel R, Whigham T, Rhodes C, Palmer J, Bianco J, Everhart K, Farrier C, Clowes R,
`Roberts J and Govindarajan, R. Development of Fixed Dose Combinations for Extended Release of
`Metformin and Glimepiride. Poster presentation, at the American Association of Pharmaceutical
`Scientists (AAPS) Annual Meeting 2014, San Diego, CA.
`2. Chakravarty, P.; Govindarajan, R.; Suryanarayanan, Effect of in situ Phase Transformation on
`Thiamine Hydrochloride Tablets, Poster presentation, American Association of Pharmaceutical
`Scientists (AAPS) Annual Meeting 2009, Los Angeles, CA.
`3. Chakravarty, P.; Govindarajan, R.; Suryanarayanan, R. Stability and behavior of thiamine
`hydrochloride phases: role of thermodynamics, kinetics and crystal structure, Poster presentation,
`American Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2008, Atlanta, GA.
`
`Ram Govindarajan
`
`Page 3 of 5
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`PTX1664-00009
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`4. Chakravarty, P.; Govindarajan, R.; Suryanarayanan, R. Hydrate Forms of Thiamine Hydrochloride:
`Dehydration Behavior and Phase Transformation, Poster presentation, American Association of
`Pharmaceutical Scientists (AAPS) Annual Meeting 2007, San Diego CA.
`5. Govindarajan, R.; Rani, M.; Surana, R.; Suryanarayanan, R. Structure in dehydrated trehalose
`dihydrate - evaluation of the concept of partial crystallinity, Poster presentation, American Association
`of Pharmaceutical Scientists (AAPS) Annual Meeting 2006, San Antonio, TX.
`6. Chakravarty, P.; Govindarajan, R.; Suryanarayanan, R. Phase transformations in Thiamine HCl during
`simulated pharmaceutical processing, Poster presentation, American Association of Pharmaceutical
`Scientists (AAPS) Annual Meeting 2006, San Antonio, TX.
`7. Liao, X.; Govindarajan, R.; Suryanarayanan, R., Use of Atomic Force Microscopy to Detect Surface
`Crystallization, Poster presentation, American Association of Pharmaceutical Scientists (AAPS)
`Annual Meeting 2005, Nashville, TN.
`8. Govindarajan, R.; Chatterjee, K.; Gatlin, L. A.; Shalaev, E. Y.; Suryanarayanan, R., Evaluation of
`buffered amorphous lyophiles using indicator probes: use of the Hammett acidity function, Poster
`presentation, American Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2005,
`Nashville, TN.
`9. Govindarajan, R.; Gatlin, L.; Shalaev, E.Y.; Suryanarayanan, R., Effect of water content on the acidity
`and ionization states in buffered amorphous sugar lyophiles., Poster presentation, American
`Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2004, Baltimore, MD.
`10. Govindarajan, R.; Zinchuk, A.V.; Hancock, B.C.; Shalaev, E.Y.; Suryanarayanan, R., Surface acidity
`of pharmaceutical excipients: Effect of formulation variables, Poster presentation, American
`Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2004, Baltimore, MD.
`11. Rani, M; Surana, R.; Govindarajan, R.; Pyne, A.; Suryanarayanan, R., Study of enthalpic relaxation in
`ternary frozen aqueous solutions using differential scanning calorimetry, Poster presentation, American
`Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2004, Baltimore, MD.
`12. Govindarajan, R.; Shalaev, E.Y.; Gatlin, L.; Suryanarayanan, R., Effect of citrate buffer concentration
`on the degree of ionization of an indicator probe in an amorphous sugar lyophile, Poster presentation,
`July 28-31, 2004: NSF Conference on Freeze-Drying of Pharmaceuticals and Biologicals,
`Breckenridge, CO.
`13. Govindarajan, R.; Chatterjee, K.; Gatlin, L.; Shalaev, E.Y.; Suryanarayanan, R., Study of the solid-
`state acid/base relationships in amorphous freeze-dried sugar-citrate systems using colyophilized pH
`indicators and diffuse reflectance spectroscopy, Poster presentation, American Association of
`Pharmaceutical Scientists (AAPS) Annual Meeting 2003, Salt Lake City, UT.
`14. Chatterjee, K.; Govindarajan, R.; Gatlin, L.; Suryanarayanan, R.; Shalaev, E.Y., Effect of buffers on
`the acid/base properties of amorphous freeze-dried systems, Poster presentation, American Association
`of Pharmaceutical Scientists (AAPS) Annual Meeting 2003, Salt Lake City, UT.
`15. Govindarajan, R.; Chatterjee, K.; Hancock, B.C.; Shalaev, E.Y.; Suryanarayanan, R., Evaluation of the
`surface acidity of pharmaceutical excipients and formulations using pH indicators as probe molecules
`and diffuse reflectance spectroscopy, Poster presentation, American Association of Pharmaceutical
`Scientists (AAPS) Annual Meeting 2003, Salt Lake City, UT.
`16. Rani, M; Govindarajan, R.; Surana, R.; Suryanarayanan, R., Preparation, characterization and physical
`stability evaluation of the alpha-polymorph of anhydrous trehalose, Poster presentation, American
`Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2003, Salt Lake City, UT.
`17. Rani, M; Govindarajan, R.; Surana, R.; Suryanarayanan, R., Effect Of Glass Fragility On The
`Enthalpic Relaxation Measured By Differential Scanning Calorimetry, Poster presentation, American
`Association of Pharmaceutical Scientists (AAPS) Annual Meeting 2003, Salt Lake City, UT.
`18. Govindarajan, R.; Chatterjee, K.; Hancock, B.C.; Shalaev, E.Y. Suryanarayanan, R., Surface acidity of
`pharmaceutical excipients and formulations, Poster presentation, AAPS Northeast Regional Discussion
`group (NERDG) meeting 2003, Rocky Hill, CT.
`19. Govindarajan, R; Nagarsenker, MS., Effect of succinic acid on release of verapamil HCl from
`hydrophilic matrix, Poster presentation, 53rd Indian Pharmaceutical Congress, December 2001, New
`Delhi, India.
`
`Ram Govindarajan
`
`Page 4 of 5
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`PTX1664-00010
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`20. Govindarajan, R; Nagarsenker, MS., Cyclodextrin based oral delivery of flurbiprofen: effect of method
`of preparation on drug release and studies on in-vivo performance, Poster presentation, 28th Controlled
`Release Society Annual Symposium, June 2001, San Diego, California, USA.
`21. Govindarajan, R; Nagarsenker, MS., pH independent oral controlled release of verapamil HCl:
`solubilisation in the microenvironment using enterosoluble polymer or organic acid, Poster
`presentation, 28th Controlled Release Society Annual Symposium, June 2001, San Diego, California,
`USA.
`22. Govindarajan, R; Nagarsenker, MS, Development of oral controlled release systems for pH
`independent release of a weak base, Poster presentation, 3rd International Symposium on Advances in
`Technology and business potential of new drug delivery systems, October 2000, Ootacamund, India.
`23. Nagarsenker, MS.; Meshram, R.; Govindarajan, R, Solid dispersion of hydroxypropyl beta-
`cyclodextrin and ketorolac: enhancement of dissolution rates, improvement in anti-inflammatory
`activity and reduction in ulcerogenicity, Poster presentation, 10th International Cyclodextrin
`Symposium, May 2000, Ann Arbor, Michigan.
`24. Govindarajan, R; Nagarsenker, MS, Role of hydroxypropyl beta-cyclodextrin in improving dissolution
`and reducing ulcerogenicity of flurbiprofen: effect of l-tyrosine on bioavailability from coevaporate,
`Poster presentation, 10th International Cyclodextrin Symposium, May 2000, Ann Arbor, Michigan.
`25. Govindarajan, R; Nagarsenker, MS, Solid dispersion of Flurbiprofen with Hydroxypropyl beta-
`cyclodextrin, Poster presentation, 4th International symposium on innovations in pharmaceutical
`sciences and technology, February 2000, Ahmedabad, India.
`26. Govindarajan, R; Nagarsenker, MS, Verapamil HCl coevaporates using enterosoluble polymer:
`Development of oral controlled release systems, Podium presentation, 50th Indian Pharmaceutical
`Congress and the 17th Asian Congress of Pharmaceutical Sciences, December 1998, Mumbai, India.
`
`Ram Govindarajan
`
`Page 5 of 5
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`PTX1664-00011
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`EXHIBIT B
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`EXHIBIT B
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`PTX1664-00012
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`12
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`Enropiisches
`Patentamt
`
`European
`Patent Office
`
`Offi :e eumpéen
`dcs brevets
`
`
`[Publication
`Title
`|EP0780127 (A1)
`A nasal spray containing a steroid an...
`
`
`
`Espacenet my patents list on 24-07-2015 09:55
`
`1
`
`item in my patents list
`
`Displaying selected publications
`
`APOTEX_AZFL 0052951
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`PTX1664-00013
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`13
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`
`EUROPEAN PATENT APPLICATION
`
`(43) Date 0* Publlcatlon
`25.06199? Bulletin 1997126
`
`[21) Application number: 963038511
`
`{22) Date or tiring: 05.12.1995
`
`[84) Designated Contracting States.
`AT BE CH DE DK ES FI FFI GB GR IE IT LI LU NI.
`PT SE
`
`[72) Inventor: Cramer, Ronald Dean
`Cincinnati. Ohio 45215 (US)
`
`{30) Priority: 19.12.1995 US 5?4791
`
`[71) Applicant: THE PROCTER 8: GAMBLE COMPANY
`Cincinnati. Ohio 45202 (us)
`
`[74) Representative Woof, Victoria
`Procter & Gamble Pharmaceuticals Ltd..
`Patent Department.
`Lovell House,
`Lovett Flood
`Slalnas, Mlddlossx TWIB 3A2 (65}
`
`(54)
`
`A nasal spray containing a steroid and a antihistamine
`
`The present invention relates to nmral nasal
`(5?)
`spray compositions comprising a solo and ofloctlvo
`
`amount of a glucoconicosleroid and an antihistamine
`possessing leukotriono inhibiting properties.
`
`EP0780127A1
`
`Prlnlsd try sou-2r! TKCI aMil-.5 [FFi
`
`APOTEX_AZFL 0052952
`
`PTX1664-00014
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`14
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`

`EP 0 780 12? Al
`
`Description
`
`TECHNICAL FIELD
`
`The present invention relates to novel nasal spray compositions comprising a sale and etlective amount ol 3
`giucocorticosteroid and an antihistamine
`
`BACKGROUND OF THElNVENTI ON
`
`Allergic disorders remain a leading cause of both acute and chronic illnesses the world over These illnesses are
`oiten times present in the forth of acute or chronic rhinoconjunctivitis. The symptoms oi allergic rhinoconjunctivitis arc
`reddening of the eyes. ocular secretions. nasal congestion, ocular and palatial irritation. sneezing and hypersecretion
`These symptoms occur tollowing exposure to allergens. The most common allergens are grass andior tree pollene.
`hence allergic rhinoconjunclivitis is most common during the spring and summer months.
`The symptoms cl allergic rhinoconjunctivitis are believed to be due primarin to the stimulation or Hvt receptors by
`histamine. loliowed by reflexive activation oi parasympathetic nerves causing increases in nasal secretion and ob—
`struction. Histamine is initiallyr released irom the tissue mastcells upon sensitization oi the mast cells This sensitization
`results when airborne alirgens combine with specilic igE antibodies attached to mast cell membranes.
`Antihistamines andior decongestants have traditionally been the drugs oi circles in treating allergic rhincconiuric—
`tivitis. Other forms of therapy include the use ot crorriolyn sodium, hypertonic salt solutions or irni'nuriotherapy.
`in addition. Hagen et at. US. Patent 4 76'? 612. discloses nasal corticosteroidthcrapy as art elfective means oi
`treating allergic rhinoconjunct'rvitis; and is herein incorporated by relerence Ii’t its entirety. Notwithstanding the many
`disclosures in the area oi allergic rhinoconjunctivitis. there Is still a need tor additional formulations which provide
`improved symptomatic reliel wnh increased user acceptance and compliance.
`The present inventor has found that by combining a nasal corticosteroid with a leukotriene inhibiting antihistamine.
`improved intranasal compositions result, providing improved reiiet oi symptoms generally associated with either sea-
`canal or perennial allergic rhinoconjunctivilis
`it is. therefore, an obiect of the present invention to provide pharmaceutical compositions having improved stlec—
`titreness in the treatment or symptoms generain associated with either seasonal or perennial allergic rhinoconjunctlvitis
`A further object of the present invention is to provide a safe and eitoctive method for treating th symptoms of
`seasonal or perennial allergic rhinoconjunciivitls.
`These objects and other objects will become more apparent from the detailed description that foilolrirs.
`
`
`
`SUMMARY OF THE [MENTION
`
`The present invention relates to pharmaceutical compositions tor nasal administration comprising:
`
`a] a sale and effective amount ola glucooorticoid selected irorn the groupeonsrsting oi beolomethasone. flunisolide.
`triamcinoloner lititioasona. mometasone, budesonide, pharmaceuticain acceptable salts theraol and mixtures
`thereot.
`b] a sale and eiieciive amount oi a leukolriene inhibiting antihistamine selected from the group constsling oi celi-
`rittine. ioratedins. ezslastine‘ phermaceuttcatly acceptable salts thersot. optically active racemates thereof and
`mixtures thereol; and
`c.) an intranasat carrier.
`
`The intranasal carrier of the present invention is preferably aqueous.
`The present invention also relate toa method tor the treatment of symptoms associated with seasonal or perennial
`allergic rhinoconiunctivitiscomprising the admin retratron oi a sale and effective amount oi the intranasai pharmaceutical
`compositions ol'the present invention. By 'symptoms of seasonai or perennial allergic rhinoconjunctivitis‘ or “symptoms
`associated with seasonal or perennial allergic rhinoconiunctivitis “ is meant ocular and palatial irritation. ocular secre-
`tions. reddening of the eyes. sneezing. mucoid hypersecretion. nasal congestion and itching
`By "sale and efieciiveamount.‘ as used herein. is an amount that is efiective to mitigate andfor treat thesymptoms
`for which the active ingredient is indicated in a human without undue adverse side ellects commensurate with a rea-
`sonable riskibenelil ratio.
`By ‘Ieukotiienc inhibiting antihistamine. "as used herein. is meant an antihistamine effective in inhibiting or reducing
`in vivo the biosynthesis oi andior cellular release oi leukotrienes or otherwise modutat ing mammalian teukotriene levels
`The pH oi the compositions is preferably from about 4.5 to about 9. more preferably from about 6 to about 7'.
`All percentages and ratios herein are by weight unless otherwise specified. Additionally, all measurements are
`
`APOTEX_AZFL 0052953
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`PTX1664-00015
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`15
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`EP 0 730 12? AI
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`made at 25°C unless otherwise specified
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The compositions of the present invention contain the essential components as well as various optional compo-
`nents as indicated below.
`More specifically. the compositions oithe instant invention are tor nasal administration and contain atherapeuticaliy
`attentive amount of the herein described pharmaceutical agents They are preterabiy provided as isotonic aqueous
`solutions. suspensions or viscous compositions which may be buttered to a selected pH.
`
`Essential ingredients
`
`Glucocorticoid Agents
`
`
`
`The combination oi any oi the above described antihistamines and glucocorticciids can be conveniently adminis-
`tered naselly to warm—blooded animals to elicit the desired therapeutic response by lormulatlng it into a nasal dosage
`torm. together with a nontoxic pharmaceulically-accepleble nasal carrier Suttable nontoxic pharmaceutically—accept-
`able nasal carriers are known to those skilled In the an and are also fully disclosed in Remington's Phanneceutical
`Sciences. 1?Ih edition. 1985 Obviously. the choice oi suitable carrier terms will depend on the exact nature at the
`particular nasal dosage form required. e.g., whether the drugts} is to be lorrnulated into a nasal solution [tor use as
`drops or as a spray). a nasal suspension. a nasal ointment. a nasal gel or another nasal l'orn'i. Preferred nasal dosage
`forms are solutions. suspensions and gels. which normally contain sodium chloride in a major amount oi water (prel-
`erebly purified Water} In addition to the antihistamine and giucocortiooid Minor amounts oi other ingredients such as
`pl-i ediusters {e 9.. an acid such as HUI]. emulsifiers or dispersing agents. butteran agents. preservatives. Wetting
`agents and letting agents is. g.. methyloe Iluiosel may also be present. Most preferably. the nasal composition ls isotonic.
`i a ,
`it has the same osmotic pressure as blood and Iaorimal fluid
`Preterebly the composition is applied to the nasal mucosa via topical application of a safe and attentive amount
`oi the composition to treat nasal symptoms. The amount of the antihistamine and glucocorlicold combination and
`lreouency oi topical application to the nasal mucosa may vary. depending upon personal or medical needs but it is
`suggested, as an example. that topical application range from about once per day to about tour times daily. prelerably
`thrice daily. most preferably once daily. As a practical matter the selected therapeutic compoSitions will normally be
`prepared in unit dosage terms or actuations to contain therapeutically eitective amounts oi the selected antihistamine
`and glucocorticoid combination. in specific instances fractions oi those dosage units or multiple dosage units Will be
`employed. Typically. dosage units may be prepared to deliver from about 0.5 mcg to about 100 mcg ol the glucocoiticoid
`
`Agents Within this class have potent glucoconicoid activny and week mineralocorticoid activity. Glucoconicoid
`agents most uselul to the present invention include those selected irom the group conststing oi beclomethasone.
`tlunieollds. triemoinolone. fluticaaone. mometeeone. budeeonlds. pharmace utically acceptable salts the reol and mix-
`tures lhereol.
`When used in the composttlons oi the present invention. the glucocor‘ticotd component is prelerably present at a
`concentration oi irorrt aboutflDOt‘ii: to about 0.2%, more preferably lrom about 0.01% to about 0.1%
`
`Leukotriene Inhibiting. Antihistaminic Agents
`
`Antihistamines useiul to the present invention are histamine H-t receptor antagonists which also reduce mamma-
`lian leukolriene levels. Such H-t receptor antihistamines may be selected irom among the following groups oi antihis-
`tamines: piperezines. phenothiazlnes, plperioines
`Examples of uselul leukotriene inhibiting antihistamines include cetirizme. loratadine. azelastine and the like. op-
`tically active racemates thereoi. phannaceutically acceptable salts thereol and mixtures thereof. When Used in the
`compositions ot the present invention. Ihe antihistamine component is preferably present at a concentration oi irom
`about 0.01% to about 4.0%. more preferably lrorn about 0.01% to about ‘i%.
`
`Pharmaceulloatiy-Acceptablo Aguoous Nasal Carrier.
`
`One other essential component of the present invention to a phannaoouticelIii-acceptable intranasal carrier. Pro-
`lerred for use herein are aqueous saline solution carriers. These solutions which generally contain sodium chloride as
`the salt are lully described in Remington‘s Pharmaceutical Sciences. 1?th edition [1985] p 335. wl'iich is herein incor-
`porated by releience. The salt is present in the solution at a level oi about 0.01 94; to about 2%. preferably from about
`0.5% to about 1 0%
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`APOTEX_AZFL 0052954
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`PTX1664-00016
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`EP 0 780127 AI
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`
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`Optional Ingredients useful In the present Invention include decongestants. Decongestants useful to the present
`invention may be selected from among the class of sympathomimetlc agents: examples of which include pseudoephe-
`drina. desoxyephedrine. propylheiradrlne phenylpropanolamina. Iylometatrollne. phenylephr‘me.
`tetrahydromlina.
`naphazollne. oxymetazoiine tramazoline and pharmaceuticthl acceptable salts thereoi. Also useful as decongestants
`are the 5-(2-imidazoiinylaminolbenzlmedazole compounds Mixtures oi these decongestants can also be used.
`When used in the compositions oi the present invention. the sympathomimctic agents may be incorporated at
`concentrations preferably. of from about 0 01% to about 0.5%, more preferably troi'n about 0 05% to abou1 0.1%.
`The compositions of the present invention may also contain antrallergics. Suitable anilellergics include, but are
`not limitedto, crorriolyn. ketotiten N-allyI-(dichloro-B. 4-banzyli-2-rnelhyiamino-2-propanol-1. AP-EBQ (Pharmaprojecls
`No. 3055~under investigation by Ariad Pharmaceuticals). Andolast. cxatemide and pham'iaceuticallyeccoptable salts
`thereof. Mixtures of these antiailergics may also be used.
`Similarly, mucolytics such as acetylcysteine and antioholinsrgics such as ipratropium bromide may also be used
`in the compositions of the present invention.
`also oi optional use in the compositions oi the present invention are nonopiete analgesics such as cxaproziri. The
`inlranasal use oi oxaprozin is described in Namil-ti el al.. Studies on improvement oi pharmaceutical preparations
`prescribed in hospitals. VI. oxaprozin nasal spray. Drug Design and Delivery 1988;21pp. Sit-321. herein incorporated
`by referencs Further examples of preferred nonopiale analgesics include. but are not limited lo. acetaminophen. ace-
`tylsalicylicacid. flauproien. elodol