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`DECLARATION OF DR. ARTHUR H. KIBBE, PH. D.
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`I, Dr. Arthur H. Kibbe, Ph.D., declare that:
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`1.
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`I am over 18 years of age. I have personal knowledge of the facts
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`stated in this Declaration and could testify competently to them if asked to do so.
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`Personal Background
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`2.
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`I received a Bachelors of Science in pharmacy in 1966 from Columbia
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`University. I attended graduate school at the University of Florida and received a
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`Masters of Science in pharmaceutics in 1968 and a doctorate in pharmaceutics /
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`pharmacokinetics in 1973.
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`3.
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`During my career, I worked in both the private sector and academia. I
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`was the Senior Director of Scientific and Professional Affairs for the American
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`Pharmacists Association – the national professional society of pharmacists. While
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`at
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`the American Pharmacists Association,
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`I managed
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`the Journal of
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`Pharmaceutical Science. I served as a Scientific Consultant to the House of
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`Representative’s Committee on Energy and Commerce, Subcommittee on
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`Oversight and Investigations, in its review of the generic drug industry practices
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`and the FDA’s generic drug review activities. I was a member of the FDA’s
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`Generic Drug Advisory Committee and served as Chair of a special panel
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`appointed by the FDA Commissioner to investigate Fairness in the Generic Drug
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`Approval Process. That committee issued findings which became known as the
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`“Kibbe Report.”
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`4.
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`I was Chair of the Department of Pharmaceutical Sciences at Wilkes
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`University, Nesbitt School of Pharmacy in Wilkes-Barre, Pennsylvania from 1994
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`until 2016. During my tenure at Wilkes University, I was elected President of the
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`American Pharmacists Association. I also served as the Editor-in-Chief of the
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`internationally recognized reference text, Handbook of Pharmaceutical Excipients,
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`3rd Edition. I have been a consultant to Commerce Committee of United States
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`Congress and served as the past Chair of the Governor’s Renal Disease Advisory
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`Panel and was the past Chair of the Food and Drug Administration’s Scientific
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`Advisory Committee.
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`5.
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`Previously, I was a Professor of Pharmaceutics at the University of
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`Mississippi, School of Pharmacy. While at the University of Mississippi, I
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`conducted research in the areas of formulation development, pharmacokinetics of
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`drugs of abuse (including, cocaine and amphetamine), bioequivalency evaluations
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`and impact of formulation changes on bioavailability.
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`6.
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`Between professorships, I was also the Director of Pharmaceutical
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`Development Services at the National Institutes of Health in Bethesda, Maryland.
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`During my time at the NIH, I developed delivery systems for Phase I clinical trials
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`and provided pharmacokinetics and analytical support for NIH intramural clinical
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`research programs.
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`7.
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`In 1994, I was elected a Fellow of the Academy of Pharmaceutical
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`Research and Science. Fellows have a minimum of 10 years of exemplary
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`professional experience and achievements in professional practice.
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`8. My full CV is attached as Exhibit A.
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`Background Discussion
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`9.
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`I have been retained by Flat Line Capital, LLC to provide technical
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`
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`analysis of prior art references and prepare this declaration. If I am asked to
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`provide live deposition testimony it will be at a rate of $1,000.00 an hour.
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`10.
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`In preparation for this declaration, I have reviewed U.S. Patent No.
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`9,463,183 (“the ‘183 Patent”) along with the prior art references and portions from
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`the file history of the ‘183 Patent set forth below:
`
`Exhibit
`1001
`1003
`1004
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`1005
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`1006
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`
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`Description
`U.S. Patent No. 9,463,183. (“the ‘183 Patent”)
`File History for the ‘183 Patent.
`Nahata and Morosco, “Stability of Lisinopril in Two Liquid Dosage
`Forms,” The Annals of Pharmacotherapy, (March 2004) Vol. 38, 396-399.
`(“Nahata”)
`B. Beidel, J. Bohan, C. D’Ippolito, E. Thudium, A. VanWert, H. Jacobs,
`and A.H. Kibbe, “Liquid dosage forms intended for pediatric use:
`Lisinopril & Meclizine,” Department of Pharmaceutical Sciences, School
`of Pharmacy, Wilkes University, Wilkes-Barre, PA, presented at 2011
`AAPS Annual Meeting and Exposition, October 26, 2011, Washington,
`DC (“Beidel”)
`Ben Beidel, Arthur Kibbe, Adam VanWert, Harvey Jacobs, Jefferson
`Bohan, “Lisinopril as a liquid dosage form intended for pediatric use”,
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`Exhibit
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`1007
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`1008
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`1009
`1010
`
`1011
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`1012
`
`1013
`
`1014
`
`1015
`1016
`
`1017
`
`1018
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`
`
`
`Description
`Published Meeting Abstract, AAPS 2011. (“Beidel Two”).
`Minhui Ma, Antonio DiLollo, Robert Mercuri, Tony Lee, Mark Bundang,
`Elizabeth Kwong, “HPLC and LC-MS Studies of the Transesterification
`Reaction of Methylparaben with Twelve 3- to 6-Carbon Sugar Alcohols
`and Propylene Glycol and the Isomerization of the Reaction Products by
`Acyl Migration,” Journal of Chromatographic Science, J CHROMATOGR
`SCI (2002) 40 (3): 170-177.
`2011 AAPS Annual Meeting and Exposition, Preliminary Program, Oct.
`23-27, 2011, Washington, DC.
`WO 98/14196 (“Nerurkar”)
`Lloyd V Allen, Jr., “Lisinopril 1-mg/mL, Sodium Citrate, and Citric Acid
`Oral Liquid,” International Journal of Pharmaceutical Compounding,
`Vol. 10 No. 5 (September/November 2006). (“Pharma Compounding
`Sept. 2006”)
`Lloyd V Allen, Jr., “Lisinopril 1-mg/mL Oral Liquid,” International
`Journal of Pharmaceutical Compounding, Vol. 10 No. 4 (July/August
`2006). (“Pharma Compounding July 2006”)
`Chawki Boukarim, Sarah Abou Jaoudé, Rita Bahnam, Roula Barada,
`Soula Kyriacos, “Preservatives in Liquid Pharmaceutical Preparations,”
`The Journal of Applied Research, Vol. 9, No. 1&2, 2009.
`Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing
`Formulations: Liquid Products, Volume 3, Second Edition (Informa
`Healthcare USA, Inc. 2009).
`S.K. Tuse, A.R. Vadgaonkar, D.S. Musmade, V.S. Kasture, “Stress
`degradation of Lisinopril as per ICH Guidelines & Characterization,” Int’l
`Journal of Advanced Pharmaceutical Analysis, IJAP Vol. 4 Issue 2 (2014)
`(47-52).
`Lisinopril dihydrate, European Pharmacopoeia 5.0 (2005)
`Karen C. Thompson, Zhongxi Zhao, Jessica M. Mazakas, Christopher A.
`Beasley, Robert A. Reed, Cheryl L. Moser, “Characterization of an
`extemporaneous liquid formulation of lisinopril,” AM J HEALTH-SYST
`PHARM, Vol. 60 (Jan. 1, 2003). (“Thompson”).
`Beverly Glass, Alison Haywood, “Stability considerations in liquid dosage
`forms extemporaneously prepared from commercially available products,”
`J PHARM PHARMACEUT SCI, 9(3):398-426, 2006.
`Daniel C. Harris, Exploring Chemical Analysis (4th Ed.), W.H. Freeman
`and Co., New York (2009) (Chapters 8, 9, 21, 22).
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`Exhibit
`1019
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`1020
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`1022
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`1024
`
`11.
`
`Description
`Novartis AG v. Torrent Pharmaceuticals Ltd., No. 2016-1352, Slip. Op.
`(Fed. Cir. April 12, 2017)
`Raymond C Rowe, Paul J Sheskey, Siân C Owen, Handbook of
`Pharmaceutical Excipients: Fifth Edition, Pharmaceutical Press and
`American Pharmacists Association (2006) (monographs for citric acid,
`hydrochloric acid, sodium benzoate, sodium citrate, sodium hydroxide,
`xylitol). (“Handbook of Pharmaceutical Excipients”).
`Spreadsheet of Posters, Wilkes Univ., School of Pharmacy, available at
`www.wilkes.edu/include/academics/pharmacy/poster/TestSpreadsheet.pdf
`Edward R. Garrett, “Prediction of Stability of Drugs and Pharmaceutical
`Preparations,” Journal of Pharmaceutical Sciences, Vol. 51, No. 9 (Sept.
`1962). (“Garrett”).
`
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`I understand that a patent claim is evaluated from the perspective of a
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`“person of ordinary skill in the art,” which I understand is a hypothetical person
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`considered to have the skill level and knowledge of a particular field related to an
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`alleged invention claimed in a patent. I further understand that this hypothetical
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`skilled artisan is presumed to have before him or her all of the relevant prior art.
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`The discussions in this declaration are intended to convey the state of the art and
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`the knowledge of a person of ordinary skill in the art generally prior to the earliest
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`priority date of the patent application that issued as the respective ‘183 patent.
`In view of the subject matter of the ‘183 Patent, as of the earliest
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`12.
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`possible priority date of the ‘183 Patent, a person of ordinary skill in the art
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`(“POSA”) of the ‘183 Patent would typically be a pharmaceutical formulator with
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`at least a master’s degree in pharmacy, pharmaceutics, pharmacokinetics or a
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`related discipline and at least four years of experience.
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`13. As of the priority date of the ‘183 Patent, I have been a person of
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`ordinary skill in the art as defined above.
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`Oral liquid formulations.
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`14. Long before the earliest priority date of the ‘183 Patent, it was well
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`known among POSAs that oral liquid pharmaceutical formulations had advantages
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`over tablet or capsule formulations. For instance, POSAs knew that liquid
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`formulations can be taken by newborn, pediatric or geriatric patients who have
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`difficulty swallowing. (Ex. 1016 at 69-1 (oral solutions allow “physicians to adjust
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`the dose for pediatric patients and provides easier administration for patients who
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`have difficulty swallowing tablets”); Ex. 1004 at 398-1 (liquid lisinopril
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`formulation “may improve the ease and accuracy of drug administration in infants
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`and young children”)). POSAs also knew that liquid formulations improve patient
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`compliance. (Ex. 1009 at 5 (explaining that liquid dosage forms “can improve
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`patient compliance”)).
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`15.
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`It was also well known among POSAs that oral liquid pharmaceutical
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`dosages presented unique formulation problems. (Ex. 1013 at 2-1 (“The
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`manufacture and control of oral solutions and oral suspensions presents some
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`unusual problems not common to other dosage forms.”)). In particular, POSAs
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`knew that oral liquid formulations must account for four principle issues: (i)
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`solubility; (ii) stability, (iii) microbiological quality; and (iv) taste. (See Ex. 1013
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`at 2-1 (stating that known problems for oral liquid formulations including
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`“microbiological, potency, and stability problems.”), at 4-2 (“One area that has
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`presented a number of problems is ensuring stability of oral liquid products
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`throughout their expiry period.”), at 3-2 (discussing microbiological quality issues
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`for oral liquid formulations); at 30-1 (“[A]ll of the advantages of liquid dosage
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`forms are balanced by the many problems in their formulation [including] stability
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`problems, taste masking needs, phase separations, and so forth . . . .”)).
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`Excipients for oral liquid formulations.
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`1.
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`Preservatives
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`16. To address microbiological quality, oral liquid formulations typically
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`were known to include preservatives. (Ex. 1013 at 30-2 (“Preservatives are almost
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`always a part of liquid formulations . . . .”); Ex. 1012 at 14-2 (“Preservatives have
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`been commonly used as additives in pharmaceutical products, cosmetics, and food.
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`Liquid preparations are particularly susceptible to microbial growth because of the
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`nature of their ingredients. Such preparations are protected by the addition of
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`preservatives that prevent the alteration and degradation of the product
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`formulation.”); Ex. 1009 at 6:24-33 (discussing preservatives for oral liquid
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`formulation)).
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`17.
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`In particular, sodium benzoate was a well-known preservative for oral
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`liquid pharmaceutical formulations. (Ex. 1013 at 31-1 (identifying benzoic acid1
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`as a “prominent preservative” for oral liquid formulations); Ex. 1012 at 14-2
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`(disclosing sodium benzoate is “commonly used as [a] preservative[] in liquid
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`pharmaceutical preparations”); Ex. 1009 at 6:28-30 (identifying sodium benzoate
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`as a preferred preservative for oral liquid formulation); Ex. 1013 at 160 (disclosing
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`sodium benzoate use in numerous oral, liquid formulations); Ex. 1020 at 662
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`(“Sodium benzoate is used primarily as an antimicrobial preservative in cosmetics,
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`foods, and pharmaceuticals.”)).
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`2.
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`Sweeteners
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`18. To address taste, oral liquid formulations typically were known to
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`include sweeteners. (Ex. 1013 at 31-1 (“Because taste is of prime importance in
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`the administration of liquid products, sweetening agents ranging from sugar to
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`potassium acesulfame are widely used . . . .”); Ex. 1009 at 6:34-7:6 (discussing use
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`of sweeteners in oral liquid formulation)). (Flavor agents were also a known
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`option added to address taste.)
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`19.
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`In particular, xylitol was a well-known sweetener for oral liquid
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`pharmaceutical formulations. (Ex. 1009 at 7:1-2 (identifying xylitol as a suitable
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`sweetener); Ex. 1013 at 165 (disclosing xylitol use in numerous oral, liquid
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`formulations); Ex. 1020 at 824 (“Xylitol is used as a noncariogenic sweetening
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`1 Benzoic acid is a form of sodium benzoate. (Ex. 1020 at 662, Synonyms).
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`agent in a variety of pharmaceutical dosage forms, including tablets, syrups, and
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`coatings . . . [and] it is highly effective in enhancing the flavor of tablets and
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`syrups and masking the unpleasant or bitter flavors associated with some
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`pharmaceutical actives and excipients. . . . In liquid preparations, xylitol is used as
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`a sweetening agent . . . .”).
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`3.
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`Buffers
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`20. To address solubility and stability, oral liquid formulations typically
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`were known to include pH-adjusting buffers and surfactants. (Ex. 1013 at 30-1
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`(“A large number of pH-adjusting buffers are used in liquid products to modify the
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`solubility of drugs as well as to provide the most optimal pH for drug absorption
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`and drug stability.”); id. at 30-1 (“[M]any liquid preparations contain surfactants,
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`not only to solubilize but also to ‘wet’ the powders to allow better mixing with
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`liquid phase.”)).
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`21. Lisinopril was known to be soluble, and thus solubility was not a
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`principle concern for preparation of a liquid lisinopril formulation. (Ex. 1005,
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`Introduction (describing lisinopril as soluble at reasonable concentrations); Ex.
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`1016 at 71-2 and 71-3, Table 1 (showing complete dissolution of Prinivil
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`(lisinopril) tablets after 30 seconds); id. at 72-2 (“lisinopril has an aqueous
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`solubility almost 100 times higher than the targeted 1-mg/mL concentration in the
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`targeted pH range (4-5)”)).
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`22. With respect to stability, POSAs knew that stability was a concern for
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`oral liquid formulations. (Ex. 1013 at 2-1, 4-2 (“One area that has presented a
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`number of problems is ensuring stability of oral liquid products throughout their
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`expiry period.”)). To address stability, oral liquid formulations typically were
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`known to include pH-adjusting buffers. (Ex. 1013 at 30-1 (“A large number of
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`pH-adjusting buffers are used in liquid products to modify the solubility of drugs
`
`as well as to provide the most optimal pH for drug absorption and drug
`
`stability.”)).
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`23.
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`In particular, a citric acid/sodium citrate buffer was well known for
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`oral liquid pharmaceutical formulations. (Ex. 1020 at 185 (identifying citric acid
`
`as a buffering agent); at 675 (identifying sodium citrate as a buffering agent); Ex.
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`1018 at 205 (listing citric acid as a common buffer)).
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`Acids, bases, pH and buffer capacity.
`
`24.
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`In aqueous chemistry, the pH of a solution measures the concentration
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`of H3O+ and OH-. (Ex. 1018 at 171). An acid increases the concentration of
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`(hydronium ion) H3O+ and decreases OH-, whereas a base decreases the
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`concentration of H3O+ and increases OH-. (Ex. 1018 at 171). Hydronium ion
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`(H3O+) is a combination of water (H2O) and a proton (H+). (Id.). (When hydrogen
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`loses its electron, all that is left is a proton. (Id.)). Thus, an acid is essentially a
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`proton donor, and a base is a proton acceptor. (Id.). The products of the reaction
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`between an acid and a base are also an acid and a base (known as the conjugate
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`acid and conjugate base.) (Id. at 172).
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`25. The measurement, pH, is a measurement of the relative amounts of H+
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`and OH- in a solution. A solution is acidic if H+ is greater than OH-, and a solution
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`is basic if H+ is less than OH-. (Id. at 174). pH is a mathematical relationship: pH
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`= -log[H+]. (Id. at 173). Accordingly, pH is really defined in terms of the activity
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`of H+. (Id.). Thus, pH is related to concentration. (Id.).
`
`26. Acids and bases are classified as strong or weak depending on
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`whether they dissociate completely or partly to produce H+ and OH-. (Id. at 174-
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`75). Weak acids react with water by donating a proton to H2O. (Id. at 175). The
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`equilibrium constant, Ka, for a weak acid is called the “acid dissociation constant,”
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`and it is a measure of how weak or strong an acid is. (Id.). Accordingly, by
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`analogy to pH, the pKa is defined as the mathematical relationship: pKa = -log Ka,
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`and it is a measure of how strong or weak an acid is. (Id. at 181). Thus, the
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`stronger an acid, the smaller its pKa. (Id.).
`
`27. Buffers are added to solutions so that they resist changes in pH. (Ex.
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`1018 at 195)(“A buffered solution resists changes in pH when small amounts of
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`acids or bases are added or when it is diluted. The buffer consists of a mixture of a
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`weak acid and its conjugate base.”) Thus, a buffered solution will resist changes to
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`the solution’s pH because the respective concentrations of weak acid and weak
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`base remain relatively constant. (Id. (“If you mix A moles of a weak acid with B
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`moles of its conjugate base, the moles of acid remain close to A and the moles of
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`base remain close to B. Little reaction occurs to change either concentration.”)).
`
`28. Prior to the earliest priority date of the ‘183 Patent, POSAs knew that
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`a solution’s “buffer capacity” correspondingly improves its resistance to pH
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`change. (Ex. 1018 at 203 (“Buffer capacity measures how well a solution resists
`
`changes in pH when acid or base is added. The greater the buffer capacity, the less
`
`the pH changes.”)). POSAs also knew that “buffer capacity is maximum when pH
`
`= pKa for the buffer.” (Ex. 1018 at 203-204). “Most buffers exhibit a dependence
`
`of pKa on temperature.” (Ex. 1018 at 206).
`
`Preparing stable oral liquid formulations.
`
`29. Several factors can affect the stability of the API in a dosage
`
`form. They include hydrolysis (degradation due to the affects of water), oxidation
`
`(the impact of oxidation on the API) and photo degradation (the impact of light on
`
`the API). Dr. Garret, in his review article, which was published in 1962, described
`
`studies that can be carried out to determine the optimum conditions for storage of
`
`the API. (Ex. 1024). FIG. 4 demonstrates the relationship between pH and
`
`stability, generally, because each compound will have a different pH curve. (See
`
`Ex. 1024 at 818, FIG. 4). Temperature is another factor which can speed or slow
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`the degradation. As a rule of thumb each increase of 10 degrees C will double the
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`rate of degradation. In the case of lisinopril determining the optimum pH at which
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`to set the solution is easy to determine. The real goal is to formulate the solution to
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`the pH at which the active ingredient is most stable. That involves two well-
`
`known steps. First, you determine the pH at which the active ingredient is most
`
`stable. Second, knowing that pH, you find a buffer whose buffer capacity is
`
`highest at that pH. With respect to the first step, persons of skill knew that, for a
`
`given active ingredient, you can conduct stability tests at different pHs, and
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`eventually you will find the pH at which the ingredient is most stable for a given
`
`temperature. For instance, in Beidel, we stability-tested three solutions with
`
`varying pH values (4.2, 5.2 and 5.75). (Ex. 1005, Methods). With respect to the
`
`second step, persons of ordinary skill were well aware that “buffer capacity is
`
`maximum when pH = pKa for the buffer.” (Ex. 1018 at 203). Thus, once you
`
`determine the pH at which the ingredient is most stable, and then identify a buffer
`
`solution with a pKa that is close to that pH, then you prepare a stable liquid
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`formulation through routine experimentation.
`
`Measuring stability of oral liquid formulations.
`
`30. To measure the stability of an oral liquid formulation for a
`
`given period of time, you begin by mixing the formulation, storing it for the
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`pre-determined period of time, under the specified conditions (such as
`
`temperature), and then measuring the amount of active ingredient that is still
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`present. The way to do that is to separate out each component in the
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`formulation. The components are separated out in order to make sure the
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`other components do not interfere with measurement of the active
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`ingredient. (See e.g., Ex. 1004 at 397-1 (“The HPLC method was proven to
`
`be stability indicating to ensure that the degradation products did not
`
`interfere with the measurement of lisinopril in suspensions.”)).
`
`31. The components can be separated out through chromatography
`
`or HPLC (high performance liquid chromatography). The ‘183 Patent
`
`identifies HPLC as a known method to assess stability. (Ex. 1001 at 15:7-8).
`
`32. Chromatography is a process for separating components from
`
`one another by forcing a formulation through a column that retains some
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`components longer than others. (Ex. 1018 at 459). Because different
`
`components are adsorbed differently, they each move through the column at
`
`different speeds. (Id. at 459-60). A chromatogram shows detector response
`
`as a function of time in chromatography separation, where each peak, which
`
`is a function of its retention time, corresponds to a different component. (Id.
`
`at 461-62). HPLC is a form of chromatography that uses high pressure to
`
`force eluent through a column packed with micrometer-size particles that
`
`sharpen resolution of the peaks. (Id. at 492-93).
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`33. Accordingly, the HPLC method permits stability assessment of
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`liquid lisinopril formulations through direct measurement of the active
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`ingredient. (See Ex. 1004 at 397-1 (“The HPLC method was proven to be
`
`stability indicating to ensure that the degradation products did not interfere
`
`with the measurement of lisinopril in suspensions.”); id. at 397-2 (“the
`
`quantification of lisinopril was not influenced by degradation products”)).
`
`34. You cannot adequately measure the stability of an oral
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`formulation simply by measuring one or two degradants, and without
`
`measuring the active ingredient. Measuring only one or two degradants
`
`ignores additional degradants that are likely to appear during the storage
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`period. For instance, for lisinopril, persons of skill in the art knew there
`
`were multiple degradants other than just the ones measured in the ‘183
`
`Patent, including diketopiperazine and hydrolysate. (See Ex. 1014 at 49-51
`
`(describing “[f]orced degradation studies were carried out for Lisinopril”
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`and showing numerous degradation products); Ex. 1015 at 1923 (listing
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`numerous lisinopril dihydrate impurities)). Furthermore, active ingredients
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`degrade into multiple degradants, and in the case of lisinopril, into serial
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`degradants. (See e.g., Ex. 1015 at 51).
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`GROUNDS 1 AND 2
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`35.
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`In the ‘183 Patent’s specification, Example F describes seven solution
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`formulations (F1 to F7) that were tested for stability at 19-23° C. (Ex. 1001 at
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`34:40-56). Among those formulations, only F7 arguably satisfies all required
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`limitations of claim 1.2 Specifically, F1 through F6 has more than twice the
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`amount of citric acid recited in claim 1, F3 and F5 do not include xylitol, F1-F6 do
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`not include sodium citrate, and F4, F5 and F6 do not include sodium benzoate. (Id.
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`at 35:1-20). During prosecution, Applicants stated that Formulations F1 and F7
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`were each “within the instant claims.” (Ex. 1003 p. 168). Even if both
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`Formulations F1 and F7 are within the claims, neither is sufficient disclosure to
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`meet the enablement requirement for at least three reasons.
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`36. Example F did not adequately test for stability as defined in the
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`specification. That definition requires testing for the amount of remaining
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`lisinopril compared to the “initial lisinopril amount” at the end of a given storage
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`period. (Ex. 1001 at 15:1-7).
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`37. But Example F did not test for that. Instead, Example F tested only
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`for two degradants, lisinopril diketopiperazine and lisinopril hydrolysate. (Ex.
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`1001 at 35:20-55; see also Ex. 1003 p. 183 ¶16 (describing stability of F1 and F7
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`2 During prosecution, Patent Owner stated that formulation F1 contains ~1.44
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`mg/mL of sodium citrate anhydrous “formed in situ.” (Ex. 1003 p. 183). That
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`explanation, however, does not appear in the specification of the ‘183 Patent—i.e.,
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`the patent’s disclosure as of the filing date.
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`based on the “increase in lisinopril diketopiperazine and lisinopril hydrolysate
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`formation”)).
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`38. This is insufficient. First, and most importantly, Applicants did not
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`assess the initial lisinopril amount prior to storage and subsequent analysis. (See
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`Ex. 1001 at 34:44-56). Without doing so, they could not adequately assess the loss
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`of lisinopril during the given storage period. POSAs knew that lisinopril possessed
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`degradants in addition to lisinopril diketopiperazine and lisinopril hydrolysate.
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`(Ex. 1014 at 49-51 (describing “[f]orced degradation studies were carried out for
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`Lisinopril” and showing numerous degradation products); Ex. 1015 at 1923 (listing
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`numerous lisinopril dihydrate impurities)). POSAs also knew that lisinopril
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`degrades into serial degradants, where the original degradant further degrades to an
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`another degradant. (See e.g., Ex. 1015 at 51).
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`39.
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`In fact, Applicants’ method of assessing lisinopril content contradicts
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`long-term stability assessments of lisinopril liquid formulations previously known
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`in the art. For instance, Thompson individually assessed the percentage of initial
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`concentration remaining after a given storage period for both lisinopril as well as
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`diketopiperazine, methylparaben and propylparaben. (Ex. 1016 at 72, Table 4).3
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`3 Thompson acknowledges that sodium benzoate is a known preservative used in
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`oral liquid formulations. (Ex. 1016 at 69-2). Thompson also discloses, “[v]ehicles
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`Similarly, Nahata also directly assessed the percentage of initial lisinopril
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`concentration remaining. (Ex. 1004 at 398, Table 4).
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`40.
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`In fact, as explained above, HPLC is used to separate a formulation’s
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`components so that the active ingredient can be directly measured independent of
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`the degradants. (See supra ¶¶30-34; Ex. 1004 at 397-1 and 397-2). Nahata
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`explained that “[t]he HPLC method [which was used] was proven to be stability
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`preserved with sodium benzoate increased the risk of adverse events for pediatric
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`patients and were not considered for use in this suspension.” (Id. at 69-2 to 69-3).
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`For the purpose of assessing the validity of the ‘183 Patent, this disclosure does not
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`constitute a teaching away from any claimed elements of the ‘183 Patent. The
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`claims of the ‘183 Patent are not limited to use for pediatric purposes. In fact, the
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`patent teaches the claimed formulations are advantageous over solid dosage forms
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`because they can also treat elderly patients or improve patient compliance. (Ex.
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`1001 at 4:24-29). Even if the claims were limited to pediatric use, (which they are
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`not), to the extent that Thompson teaches away from the ‘183 Patent by disclosing
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`that sodium benzoate increases the risk of adverse events for pediatric patients, that
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`would also be true of the claims of the ‘183 Patent, because they expressly recite
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`sodium benzoate as an ingredient. In that case, the ‘183 Patent claims are
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`inoperable, not useful.
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`indicating to ensure that the degradation products did not interfere with the
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`measurement of lisinopril in suspensions.” (Id. at 397-1). Nahata established the
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`stability-indicating nature of the method by subjecting the formulations to forced
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`degradation, and then showing “that the quantification of lisinopril was not
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`influenced by degradation products.” (Id. at 397-2).
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`41. Put another way, whereas Thompson and Nahata actually directly
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`measured lisinopril content to determine stability, the inventors of the ‘183 Patent
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`measured something entirely different, namely two degradants. As explained
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`above (¶30-34), measuring only select degradants alone, and not measuring the
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`active ingredient, is insufficient to assess the stability of a formulation over a given
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`period of time.
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`42. Accordingly, Applicants method of assessing the purported essential
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`feature of their patent, namely the amount of lisinopril compared to the initial
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`amount after a given storage period, was plainly insufficient to assess stability over
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`12 months or any other period of time. Given this, the ‘183 Patent is not enabled
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`for what it claims, namely, “wherein the formulation is stable at about 25±5° C. for
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`at least 12 months.”
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`43. During prosecution, Applicants submitted new data purporting to
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`measure lisinopril content. Specifically, the Mosher Decl. provided “additional
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`data” directly measuring lisinopril content for both Formulations F1 and F7. That
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`data was not previously disclosed in the specification (id. p. 167), but constituted
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`new, different data. For instance, whereas the specification (Table F-2) disclosed
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`measurements of degradant content (diketopiperazine and hydrolysate) during the
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`storage periods (see Ex. 1001 Table F-2, 35:20-55), the new data for F1 and F7
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`disclosed direct measurements of lisinopril content during the storage periods.
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`(Compare Ex. 1001 Table F-2, 35:20-55 with Ex. 1003 p. 184).
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`44.
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`Importantly, this new data (measuring lisinopril content directly)
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`cannot be derived from the degradant content data disclosed in the patent
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`application—rather it is completely new data. (Id.). For instance, the data in the
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`patent application (Table F-2) measured Formulations F1 and F7 at 19-23°C,
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`whereas the new data measured Formulations F1 and F7 at 25°C. (Id.). Further,
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`the data in the patent application (Table F-2) discloses total degradant content of
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`F7 at 26 weeks to be 1.2%, whereas the new data discloses the lisinopril content
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`for the same point in time to be 101.3%. (Id.). These two percentages are not
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`compatible. Nor did Dr. Mosher’s new data disclose any standard