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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`KVK-TECH, INC.
`FLAT LINE CAPITAL, LLC,
`Petitioner
`v.
`
`SILVERGATE PHARMACEUTICALS, INC.
`Patent Owner
`
`U.S. Patent No. 9,463,183
`Issue Date: Oct. 11, 2016
`Inventors: Gerald L. Mosher, David W. Miles
`
`Title: LISINOPRIL FORMULATIONS
`
`
`
`
`
`Case Number: Unassigned
`
`PETITION FOR POST GRANT REVIEW OF
`U.S. PATENT NO. 9,463,183
`UNDER TO 35 U.S.C. §§ 321 ET SEQ. AND 37 C.F.R. § 42.200 ET SEQ.
`
`
`
`iii
`
`

`

`
`
`
`
`
`
`
`
`
`Table of Contents
`I. Introduction ......................................................................................................... 1
`II. Notice of Real-Party-In-Interest ......................................................................... 3
`III. Notice of Related Matters ................................................................................. 3
`IV. Notice Under 37 C.F.R. § 42.8(b)(3) and (b)(4) ............................................... 3
`V. Payment of Filing Fee ........................................................................................ 3
`VI. Grounds for Standing ........................................................................................ 3
`VII. Statement of Precise Relief Requested ............................................................ 4
`VIII. Background ..................................................................................................... 4
`A. Lisinopril ..................................................................................................... 4
`B. Oral liquid formulations. .............................................................................. 5
`C. Excipients for oral liquid formulations. ....................................................... 6
`D. Acids, bases, pH and buffer capacity. ........................................................ 10
`E. Preparing stable oral liquid formulations. .................................................. 12
`F. Measuring stability of oral liquid formulations. ......................................... 14
`G. The ‘183 Patent .......................................................................................... 16
`G. Prosecution History of the ‘183 Patent ...................................................... 19
`H. Person of Ordinary Skill in the Art ............................................................ 27
`X. Analysis ............................................................................................................ 28
`A. GROUND 1: Claims 1-13 are unpatentable because they are not enabled
`under 35 U.S.C. § 112(a). ................................................................................ 28
`B. GROUND 2: Claims 1-13 are unpatentable because they lack adequate
`written description under 35 U.S.C. § 112(a). ................................................. 41
`C. GROUND 3: Claims 1-13 are rendered obvious under 35 U.S.C. § 103
`over Beidel in view of Nerurkar, Pharma Compounding Sept. 2006, Beidel
`Two and in further view of the understanding of the person of ordinary skill in
`the art. ............................................................................................................... 42
`XI. Conclusion ....................................................................................................... 81
`CERTIFICATE OF WORD COUNT ..................................................................... 82
`CERTIFICATE OF SERVICE ............................................................................... 83
`
`
`
`
`
`
`iv
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`
`
`

`

`
`
`
`
`Table of Authorities
`
`
`
`
`
`
`
`
`
`
`
`Cases
`
`Abbott Labs. v. Baxter Pharm. Prods.,
`471 F.3d 1363 (Fed. Cir. 2006) .............................................................. 65
`
`AK Steel Corp. v. Sollac,
`344 F.3d 1234 (Fed. Cir. 2003). .............................................................. 29, 40
`
`Apple v. Samsung,
`816 F.3d 788 (Fed. Cir. 2016) ................................................................ 79
`
`Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co.,
`598 F.3d 1336, 1355 (Fed. Cir. 2010)(en banc) ..................................... 41
`
`Automotive Tech. Int’l, Inc. v. BMW of North America, Inc.,
`501 F.3d 1274 (Fed. Cir. 2007) .............................................................. 33, 34
`
`Bristol-Myers Squibb Co. v. Teva Pharmaceuticals USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ................................................................ 75, 77
`
`Genentech, Inc. v. Novo Nordisk A/S,
`108 F.3d 1361 (Fed. Cir. 1997) .............................................................. 34
`
`Genetics Institute, LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed.Cir.2011) ................................................................ 36
`
`In re Aller,
`220 F.2d 454 (CCPA 1955) .................................................................... 56, 57
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012). ............................................................. 60
`
`In re Best,
`562 F.2d 1252 (CCPA 1977)). ................................................................ 23
`
`In re Boesch,
`617 F.2d 272 (CCPA 1980) ................................................................... 59
`
`v
`
`

`

`
`
`
`
`
`
`
`
`
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) ................................................................ 75
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) ............................................................... 56, 57
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .............................................................. 65
`
`In re Klopfenstein,
`380 F.2d 1345 (Fed. Cir. 2004) ............................................................... 46
`
`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986). ............................................................. 23
`
`In re Papesch,
`315 F.2d 381 (CCPA 1963) ................................................................... 78
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003). ............................................................. 56-59, 69
`
`Ineos USA LLC v. Berry Plastics Corp.,
`783 F.3d 865 (Fed. Cir. 2015) ................................................................ 63
`
`Iron Grip Barbell Co., Inc. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) .............................................................. 78
`
`Janssen Pharmaceutica N.V., et al. v. Teva Pharmaceuticals USA, Inc.,
`583 F.3d 1317 (Fed. Cir. 2009) .............................................................. 35, 36
`
`KSR Int’l v. Teleflex Inc.,
`550 U.S. 398 (2007). ............................................................................... 64
`
`Nat'l Recovery Techs., Inc. v. Magnetic Separation Sys., Inc.,
`166 F.3d 1190 (Fed. Cir. 1999) .............................................................. 28
`
`Novartis AG v. Torrent Pharmaceuticals Ltd.,
`No. 2016-1352, Slip. Op. (Fed. Cir. April 12, 2017) ............................. 78
`
`
`vi
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`Plant Genetic Sys., N.V. v. DeKalb Genetics Corp.,
`315 F.3d 1335 (Fed. Cir. 2003). ............................................................. 35
`
`Process Control Corp. v. HydReclaim Corp.,
`190 F.3d 1350 (Fed. Cir. 1999) .............................................................. 32
`
`Sitrick v. Dreamworks, LLC,
`516 F.3d. 993 (Fed. Cir. 2008) ............................................................... 28
`
`Tex. Instruments v. Int’l Trade Comm’n,
`988 F.2d 1165 (Fed. Cir. 1993) .............................................................. 79
`
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ................................................................ 65
`
`Vas-Cath Inc. v. Mahurkar,
`935 F.2d 1555 (Fed.Cir.1991). ................................................................ 41
`
`Voter Verified, Inc. v. Premier Election Solutions, Inc.,
`698 F.3d 1374 (Fed. Cir. 2013) ............................................................... 43, 47
`
`
`
`
`
`
`
`vii
`
`

`

`
`
`
`
`
`Exhibit
`1001
`1002
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`1010
`
`1011
`
`1012
`
`1013
`
`
`
`
`
`
`
`EXHIBIT LIST
`
`Description
`U.S. Patent No. 9,463,183. (“the ‘183 Patent”)
`Declaration of Dr. Arthur Kibbe, Ph.D. (“Kibbe Decl.”)
`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”,
`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
`
`viii
`
`

`

`
`
`
`
`
`
`
`
`
`Description
`
`Exhibit
`
`1014
`
`1015
`1016
`
`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).
`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”).
`Declaration of Benjamin Beidel (“Beidel Decl.”)
`Spreadsheet of Posters, Wilkes Univ., School of Pharmacy, available at
`www.wilkes.edu/include/academics/pharmacy/poster/TestSpreadsheet.pdf
`Declaration of Jefferson Bohan (“Bohan Decl.”)
`Edward R. Garrett, “Prediction of Stability of Drugs and Pharmaceutical
`Preparations,” Journal of Pharmaceutical Sciences, Vol. 51, No. 9 (Sept.
`1962). (“Garrett”).
`1025
`Google search results for query: lisinopril liquid pediatric
`1026
`Selected pages from www.aaps.org
`1027-32 Reserved
`1032
`Andrew A. Webster, Brett A. English, Deidra J. Rose, “The Stability of
`Lisinopril as an Extemporaneous Syrup,” Int’l Journal of Pharmaceutical
`Compounding, Vol. 1, No. 5 (Sept/Oct 1997). (“Webster”).
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`1022
`
`1023
`1024
`
`
`
`ix
`
`

`

`
`
`
`
`
`
`
`
`This is a petition for Post Grant Review pursuant to 35 U.S.C. §§ 321 et seq.
`
`and 37 C.F.R. §§ 42.200 et seq., of claims 1-13 of U.S. Patent No. 9,463,183 (“the
`
`‘183 Patent”). (Ex. 1001).
`
`I.
`
`
`
`Introduction
`
`Lisinopril is widely used for treatment of hypertension. Whereas lisinopril is
`
`typically administered in a solid tablet or capsule, the ‘183 Patent is directed to an
`
`oral liquid lisinopril formulation. The ‘183 Patent acknowledges that liquid lisinopril
`
`formulations existed in the art. Indeed, the claimed formulation contains excipients
`
`that were widely known for use in a liquid dosage formulation, including a sweetener
`
`(xylitol), a preservative (sodium benzoate) and a buffer (citric acid/sodium citrate).
`
`
`
`During prosecution, the Examiner asserted that the claimed formulation was
`
`prima facie obvious. In response, Applicants argued that the formulation was non-
`
`obvious because of an alleged drastically improved stability profile. But as shown in
`
`this post-grant review petition, those arguments are unavailing to sustain the ‘183
`
`Patent’s validity.
`
`First, discovery of an inherent property of an obvious formulation is not itself
`
`patentable. (See infra Sec. X.C.7, claim 1[g]). Second, Applicants relied upon
`
`stability data submitted after the filing date to show the claimed stability profile.
`
`While post-filing date evidence may be considered to rebut non-obviousness, it
`
`
`
`
`
`1
`
`

`

`
`
`
`
`
`
`
`cannot be used to cure a patent’s deficiency of enablement or written description.
`
`(See infra Sec. X.A, X.B). Third, Applicants purported unexpected stability results
`
`were not unexpected, not a difference in kind from the prior art, and not materially
`
`different than stability data existing in the prior art. (See infra Sec. X.C.8).
`
`
`
`Finally, the claims are themselves obvious because the patent’s solution was
`
`itself predictable and yielded anticipated success. It was known that an active
`
`ingredient is typically most stable at a specific pH. It was known that a liquid
`
`solution containing that active ingredient could be stabilized by buffering the solution
`
`at that pH. It was known that a solution was most stable when the buffer’s pKa was
`
`equal to the ingredient’s stable pH. It was known that citric acid/sodium citrate was a
`
`commonly used, and well-known buffer. It was known that citric acid’s pKa = 4.76
`
`was approximately equal to lisinopril’s most stable pH at 25°C. It was known that
`
`lisinopril could be formulated as a liquid for the same reasons that motivated the
`
`Applicants of the ‘183 Patent—to provide a formulation to pediatric, elderly or other
`
`patients who had difficulty swallowing. Thus, in sum, using a citric acid buffer to
`
`stabilize a liquid lisinopril formulation was predictable, motivated by the existing
`
`art and yielded anticipated success. (See infra Sec. X.C.7, claim 1[c]).
`
`Thus, Trial should be instituted, and claims 1-13 of the ‘183 Patent be
`
`cancelled.
`
`
`
`
`
`2
`
`

`

`
`
`
`
`
`
`
`II. Notice of Real-Party-In-Interest
`
`
`
`The real-parties-in-interest for this Petition are KVK-Tech, Inc. and Flat
`
`Line Capital, LLC. No other entity or person has authority to direct or control
`
`Petitioner’s actions or decisions relating to this petition.
`
`III. Notice of Related Matters
`
`
`Petitioner is not aware of any potentially related matters. This petition
`
`contains arguments regarding the unpatentability of the ‘183 Patent not previously
`
`presented to the United States Patent and Trademark Office.
`
`IV. Notice Under 37 C.F.R. § 42.8(b)(3) and (b)(4)
`
`
`Lead Counsel
`Zachary D. Silbersher
`Kroub, Silbersher & Kolmykov PLLC
`305 Broadway 7th Fl.
`New York, NY 10007
`Tel: (212) 323-7442
`zsilbersher@kskiplaw.com
`(Reg. No. 62,090)
`
`Backup Counsel
`Gaston Kroub
`Kroub, Silbersher & Kolmykov PLLC
`305 Broadway 7th Fl.
`New York, NY 10007
`Tel: (212) 323-7442
`gkroub@kskiplaw.com
`(Reg. No. 51,903)
`
`Pursuant to 37 C.F.R. § 42.10(b), Powers of Attorney have been filed with
`
`this Petition. Petitioner consents to electronic service by email at:
`
`zsilbersher@kskiplaw.com, gkroub@kskiplaw.com, info@kskiplaw.com.
`
`V.
`
`
`
`Payment of Filing Fee
`
`A fee set forth in 37 C.F.R. § 42.15(a) accompanies this petition.
`
`
`
`VI. Grounds for Standing
`
`
`
`3
`
`

`

`
`
`
`
`
`
`
`
`
`
`Petitioner hereby certifies that the patent for which review is sought is
`
`
`
`available for post grant review and that the Petitioner is not barred or estopped
`
`from requesting a post grant review challenging the patent claims on the grounds
`
`identified in the petition.
`
`VII. Statement of Precise Relief Requested
`
`Petitioner respectfully requests that Claims 1-13 of the ‘183 Patent be
`
`
`
`cancelled based upon the following grounds of unpatentability:
`
`GROUND 1: Claims 1-13 are unpatentable because they are not enabled
`
`under 35 U.S.C. § 112(a).
`
`GROUND 2: Claims 1-13 are unpatentable because they lack adequate
`
`written description under 35 U.S.C. § 112(a).
`
`GROUND 3: Claims 1-13 are unpatentable under 35 U.S.C. § 103 as
`
`obvious in view of Beidel, Nerurkar, Pharma Compounding Sept. 2006, Beidel
`
`Two and the understanding of the person of skill in the art.
`
`VIII. Background
`
`A. Lisinopril
`
`
`
`High blood pressure, or hypertension, can be a substantial risk factor for
`
`numerous diseases, including coronary heart disease, myocardial disease,
`
`congestive heart failure, stroke and kidney failure. (Ex. 1001 at 1:5-13).
`
`
`
`
`
`4
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`

`

`
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`
`
`
`Hypertension falls into two classes: primary hypertension, for which there is no
`
`known cause, and secondary hypertension, which can be caused by surgical or
`
`drug interventions or other abnormalities in the renal, cardiovascular or endocrine
`
`system. (Id. at 1:13-20).
`
`As of the earliest priority date of the ‘183 Patent, several known
`
`antihypertensive drugs were available falling into numerous therapeutic classes.
`
`(Id. at 1:20-30). One antihypertensive class of drugs includes angiotensin-
`
`converting enzyme (ACE). (Id. at 1:28-30). Lisinopril is a drug belonging to the
`
`ACE inhibitor class. (Id. at 1:33-35; Ex. 1014 at 47-1). As of the filing of the ‘183
`
`Patent application, orally-administered commercially available drugs containing
`
`lisinopril were available, including Prinivil®. (Id. at 1:52-55).
`
`
`
`B. Oral liquid formulations.
`
`Long before the earliest priority date of the ‘183 Patent, it was well known
`
`among POSAs that oral liquid pharmaceutical formulations had advantages over
`
`tablet or capsule formulations. For instance, POSAs knew that liquid formulations
`
`can be taken by newborn, pediatric or geriatric patients who have difficulty
`
`swallowing. (Ex. 1002 ¶14, citing Ex. 1016 at 69-1 (oral solutions allow
`
`“physicians to adjust the dose for pediatric patients and provides easier
`
`administration for patients who have difficulty swallowing tablets”); Ex. 1004 at
`
`
`
`
`
`5
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`

`

`
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`
`
`
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`398-1 (liquid lisinopril formulation “may improve the ease and accuracy of drug
`
`administration in infants and young children”)). POSAs also knew that liquid
`
`formulations improve patient compliance. (Ex. 1002 ¶14, citing Ex. 1009 at 5
`
`(explaining that liquid dosage forms “can improve patient compliance”)).
`
`
`
`It was also well known among POSAs that oral liquid pharmaceutical
`
`dosages presented unique formulation problems. (Ex. 1002 ¶15 citing Ex. 1013 at
`
`2-1 (“The manufacture and control of oral solutions and oral suspensions presents
`
`some unusual problems not common to other dosage forms.”)). In particular,
`
`POSAs knew that oral liquid formulations must account for four principle issues:
`
`(i) solubility; (ii) stability, (iii) microbiological quality; and (iv) taste. (See Ex.
`
`1002 ¶15 citing Ex. 1013 at 2-1 (stating that known problems for oral liquid
`
`formulations including “microbiological, potency, and stability problems.”), at 4-2
`
`(“One area that has presented a number of problems is ensuring stability of oral
`
`liquid products throughout their expiry period.”), at 3-2 (discussing
`
`microbiological quality issues for oral liquid formulations); at 30-1 (“[A]ll of the
`
`advantages of liquid dosage forms are balanced by the many problems in their
`
`formulation [including] stability problems, taste masking needs, phase separations,
`
`and so forth . . . .”)).
`
`C.
`
`Excipients for oral liquid formulations.
`
`6
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`

`

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`
`
`1. Preservatives
`
`
`
`To address microbiological quality, oral liquid formulations typically were
`
`known to include preservatives. (Ex. 1002 ¶16 citing Ex. 1013 at 30-2
`
`(“Preservatives are almost always a part of liquid formulations . . . .”); Ex. 1012 at
`
`14-2 (“Preservatives have been commonly used as additives in pharmaceutical
`
`products, cosmetics, and food. Liquid preparations are particularly susceptible to
`
`microbial growth because of the nature of their ingredients. Such preparations are
`
`protected by the addition of preservatives that prevent the alteration and
`
`degradation of the product formulation.”); Ex. 1009 at 6:24-33 (discussing
`
`preservatives for oral liquid formulation)).
`
`In particular, sodium benzoate was a well-known preservative for oral liquid
`
`pharmaceutical formulations. (Ex. 1002 ¶17, citing Ex. 1013 at 31-1 (identifying
`
`benzoic acid as a “prominent preservative” for oral liquid formulations; (Benzoic
`
`acid is a form of sodium benzoate. (Ex. 1020 at 662, Synonyms)); Ex. 1012 at 14-
`
`2 (disclosing sodium benzoate is “commonly used as [a] preservative[] in liquid
`
`pharmaceutical preparations”); Ex. 1009 at 6:28-30 (identifying sodium benzoate
`
`as a preferred preservative for oral liquid formulation); Ex. 1013 at 160 (disclosing
`
`sodium benzoate use in numerous oral, liquid formulations); Ex. 1020 at 662
`
`
`
`
`
`7
`
`

`

`
`
`
`
`
`
`
`(“Sodium benzoate is used primarily as an antimicrobial preservative in cosmetics,
`
`foods, and pharmaceuticals.”)).
`
`
`
`2.
`
`Sweeteners
`
`To address taste, oral liquid formulations typically were known to include
`
`sweeteners. (Ex. 1002 ¶18 citing Ex. 1013 at 31-1 (“Because taste is of prime
`
`importance in the administration of liquid products, sweetening agents ranging
`
`from sugar to potassium acesulfame are widely used . . . .”); Ex. 1009 at 6:34-7:6
`
`(discussing use of sweeteners in oral liquid formulation)). (Flavor agents were also
`
`a known option added to address taste. Ex. 1002 ¶18)).
`
`In particular, xylitol was a well-known sweetener for oral liquid
`
`pharmaceutical formulations. (Ex. 1002 ¶19 citing Ex. 1009 at 7:1-2 (identifying
`
`xylitol as a suitable sweetener); Ex. 1013 at 165 (disclosing xylitol use in
`
`numerous oral, liquid formulations); Ex. 1020 at 824 (“Xylitol is used as a
`
`noncariogenic sweetening agent in a variety of pharmaceutical dosage forms,
`
`including tablets, syrups, and coatings . . . [and] it is highly effective in enhancing
`
`the flavor of tablets and syrups and masking the unpleasant or bitter flavors
`
`associated with some pharmaceutical actives and excipients. . . . In liquid
`
`preparations, xylitol is used as a sweetening agent . . . .”).
`
`
`
`
`
`8
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`

`

`
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`
`
`
`
`
`
`3.
`
`Buffers
`
`
`
`To address solubility and stability, oral liquid formulations typically were
`
`known to include pH-adjusting buffers and surfactants. (Ex. 1002 ¶20 citing Ex.
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`1013 at 30-1 (“A large number of pH-adjusting buffers are used in liquid products
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`to modify the solubility of drugs as well as to provide the most optimal pH for drug
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`absorption and drug stability.”); id. at 30-1 (“[M]any liquid preparations contain
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`surfactants, not only to solubilize but also to ‘wet’ the powders to allow better
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`mixing with liquid phase.”)).
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`Lisinopril was known to be soluble, and thus solubility was not a principle
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`concern for preparation of a liquid lisinopril formulation. (Ex. 1002 ¶21 citing Ex.
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`1005, Introduction (describing lisinopril as soluble at reasonable concentrations);
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`Ex. 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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`With respect to stability, POSAs knew that stability was a concern for oral
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`liquid formulations. (Ex. 1002 ¶22 citing Ex. 1013 at 2-1, 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.”)). To address stability, oral liquid formulations
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`typically were known to include pH-adjusting buffers. (Ex. 1002 ¶22 citing Ex.
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`1013 at 30-1 (“A large number of pH-adjusting buffers are used in liquid products
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`to modify the solubility of drugs as well as to provide the most optimal pH for drug
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`absorption and drug stability.”)).
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`In particular, a citric acid/sodium citrate buffer was well known for oral
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`liquid pharmaceutical formulations. (Ex. 1002 ¶23 citing Ex. 1020 at 185
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`(identifying citric acid as a buffering agent); at 675 (identifying sodium citrate as a
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`buffering agent); Ex. 1018 at 205 (listing citric acid as a common buffer)).
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`D. Acids, bases, pH and buffer capacity.
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`In aqueous chemistry, the pH of a solution measures the concentration of
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`H3O+ and OH-. (Ex. 1002 ¶24 citing Ex. 1018 at 171). An acid increases the
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`concentration of (hydronium ion) H3O+ and decreases OH-, whereas a base
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`decreases the concentration of H3O+ and increases OH-. (Ex. 1018 at 171).
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`Hydronium ion (H3O+) is a combination of water (H2O) and a proton (H+). (Id.).
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`(When hydrogen loses its electron, all that is left is a proton. (Id.)). Thus, an acid
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`is essentially a proton donor, and a base is a proton acceptor. (Id.). The products
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`of the reaction between an acid and a base are also an acid and a base (known as
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`the conjugate acid and conjugate base.) (Id. at 172).
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`The measurement, pH, is a measurement of the relative amounts of H+ and
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`OH- in a solution. A solution is acidic if H+ is greater than OH-, and a solution is
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`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 of
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`H+. (Id.). Thus, pH is related to concentration. (Id.). (Ex. 1002 ¶25).
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`Acids and bases are classified as strong or weak depending on whether they
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`dissociate completely or partly to produce H+ and OH-. (Id. at 174-75). Weak
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`acids react with water by donating a proton to H2O. (Id. at 175). The equilibrium
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`constant, Ka, for a weak acid is called the “acid dissociation constant,” and it is a
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`measure of how weak or strong an acid is. (Id.). Accordingly, by analogy to pH,
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`the pKa is defined as the mathematical relationship: pKa = -log Ka, and it is a
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`measure of how strong or weak an acid is. (Id. at 181). Thus, the stronger an acid,
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`the smaller its pKa. (Id.). (Ex. 1002 ¶26).
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`Buffers are added to solutions so that they resist changes in pH. (Ex. 1018 at
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`195)(“A buffered solution resists changes in pH when small amounts of acids or
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`bases are added or when it is diluted. The buffer consists of a mixture of a weak
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`acid and its conjugate base.”)). Thus, a buffered solution will resist changes to the
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`solution’s pH because the respective concentrations of weak acid and weak base
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`remain relatively constant. (Id. (“If you mix A moles of a weak acid with B moles
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`of its conjugate base, the moles of acid remain close to A and the moles of base
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`remain close to B. Little reaction occurs to change either concentration.”)). (Ex.
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`1002 ¶27).
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`Prior to the earliest priority date of the ‘183 Patent, POSAs knew that a
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`solution’s “buffer capacity” correspondingly improves its resistance to pH change.
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`(Ex. 1002 ¶28, citing Ex. 1018 at 203 (“Buffer capacity measures how well a
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`solution resists changes in pH when acid or base is added. The greater the buffer
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`capacity, the less the pH changes.”)). POSAs also knew that “buffer capacity is
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`maximum when pH = pKa for the buffer.” (Ex. 1002 ¶28, citing Ex. 1018 at 203-
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`204). “Most buffers exhibit a dependence of pKa on temperature.” (Ex. 1002 ¶28,
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`citing Ex. 1018 at 206).
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`E.
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`Preparing stable oral liquid formulations.
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`Petitioner’s expert, Dr. Arthur Kibbe, herein testifies that, as of 2015—the
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`earliest priority date of the ’183 Patent—POSAs were well-aware how to optimize
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`the stability of an oral liquid formulation. Dr. Kibbe explains:
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`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
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`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 the
`degradation. As a rule of thumb each increase of 10 degrees C will
`double the rate of degradation. In the case of lisinopril determining
`the optimum pH at which to set the solution is critical but easy to
`determine.
`The real goal is to formulate the solution to 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 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 formulation through
`routine experimentation.
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`(Ex. 1002 ¶29).
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`F. Measuring stability of oral liquid formulations.
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`Dr. Kibbe also testifies that, as of 2015, POSAs were also well-aware how to
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`measure the stability of an oral liquid formulation. Dr. Kibbe explains:
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`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
`pre-determined period of time, under the specified conditions (such as
`temperature), and then measuring the amount of active ingredient that
`is still present. The way to do that is to separate out each component
`in the formulation. The components are separated out in order to
`make sure the other components do not interfere with measurement of
`the active 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.”)).
`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).
`Chromatography is a process for separating components from
`one another by forcing a formulation through a column that retains
`some components longer than others. (Ex. 1018 at 459). Because
`different components are adsorbed differently, they each move
`through the