Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 1 of 37 PageID #: 669
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`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`
`
`
`DEFENDANT CFT PHARMACEUTICALS LLC’S
`CLAIM CONSTRUCTION ANSWERING BRIEF
`
`
`YOUNG CONAWAY STARGATT & TAYLOR, LLP
`
`James M. Lennon (No. 4570)
`Samantha G. Wilson (No. 5816)
`Rodney Square
`1000 North King Street
`Wilmington, Delaware 19801
`(302) 571-6600
`jlennon@ycst.com
`swilson@ycst.com
`
`Attorneys for Defendant CFT Pharmaceuticals
`LLC
`
`
`OF COUNSEL:
`
`Jeffrey S. Ward
`Edward J. Pardon
`MERCHANT & GOULD, P.C.
`10 East Doty Street
`Suite 600
`Madison, WI 53703
`(608) 280-6750
`jward@merchantgould.com
`epardon@merchantgould.com
`
`Ian G. McFarland
`MERCHANT & GOULD, P.C.
`9717 Cogdill Rd.
`Suite 101
`Knoxville, TN 37932
`(865) 380-5960
`imcfarland@merchantgould.com
`
`Dated: April 30, 2015
`
`
`
`
` 
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`
`
`C.A. No. 14-cv-781-SLR
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`PFIZER INC., WYETH LLC, PFIZER
`PHARMACEUTICALS LLC, PF PRISM C.V. and
`PFIZER MANUFACTURING HOLDINGS LLC,
`
`
`Plaintiffs,
`
`v.
`
`CFT PHARMACEUTICALS LLC,
`
`
`Defendant.
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`

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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 2 of 37 PageID #: 670
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`
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`TABLE OF CONTENTS
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`Page
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`TABLE OF AUTHORITIES ......................................................................................................... iv
`INTRODUCTION .......................................................................................................................... 1 
`I. 
`The Patents ..................................................................................................................... 1 
`II. 
`Scientific Background .................................................................................................... 2 
`A.  The Manufacture and Use of Tigecycline ........................................................................2 
`B.  pH .....................................................................................................................................3 
`LEGAL STANDARDS .................................................................................................................. 5 
`ARGUMENT .................................................................................................................................. 5 
`I. 
`The ’828 Patent .............................................................................................................. 6 
`A.  “pH of the composition in a solution is” Refers to the Bulk Solution Before
`Lyophilization. ................................................................................................................6 
`1.  The specification teaches that the claimed inventions depend upon the recited
`pH range existing in the bulk solution. .........................................................................7 
`a.  The specification asserts that improved stability results from the presence of
`lactose and the recited pH in the bulk solution. .......................................................7 
`b.  Examples 1 and 3 show the recited pH range being met in the bulk solution
`and expressly distinguish the claimed compositions from tigecycline
`compositions in which the recited pH range is not met in the bulk solution. ........10 
`c.  All examples exclusively show the pH being measured or adjusted in the
`bulk solution...........................................................................................................11 
`2.  The surrounding claim language supports CFT’s construction. .................................13 
`3.  The prosecution history of a continuation patent containing the same language
`supports CFT’s interpretation because the patentee relied upon bulk solutions
`meeting the recited pH range as support for amending the claims to include the
`disputed language. ......................................................................................................14 
`4.  The claims do not make sense to persons of ordinary skill in the art if the pH
`limitation is not required to be applied to the bulk solution. ......................................15 
`a.  A person of ordinary skill in the art would understand that degradation would
`occur before lyophilization if the pH is not adjusted in the bulk solution, and
`further would not know the conditions under which to reconstitute or further
`admix and measure pH...........................................................................................15 
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`ii
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 3 of 37 PageID #: 671
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`b.  Claims should be construed to preserve their validity where possible, and
`construing the language as CFT proposes would do so. ........................................17 
`5.  CFT’s construction does not import a process claim – but even if it did, such
`importation would be proper. .....................................................................................18 
`B.  “about” Allows for a pH Within 0.05 Units of the Stated Values .................................20 
`1.  Pfizer’s proposal that “about” means “approximately” does not resolve the
`parties’ dispute. ..........................................................................................................20 
`2.  Pfizer asserted in an IPR that the same term in the same patent had essentially
`the same meaning that CFT is now proposing. ..........................................................21 
`3.  A person of ordinary skill reviewing the intrinsic record would understand that
`“about” allows for a pH within 0.05 units of the stated values. .................................22 
`The ’995 Patent ............................................................................................................ 23 
`II. 
`A.  “Form I tigecyline” Means a Crystalline Form with the Specified Peaks Plus or
`Minus 0.2 2 and a Hot Stage Melting Point as Set Forth in the Claims ....................23 
`B.  “A process for preparing Form I tigecycline” Means a Process that Results in
`Form I tigecycline .........................................................................................................25 
`1.  The Preamble of Claim 3 is Limiting Because it was Relied on During
`Prosecution of the Claim to Establish Patentability ...................................................26 
`2.  CFT’s proposed construction is consistent with well-established law. ......................28 
`CONCLUSION ............................................................................................................................. 29 
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`iii
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 4 of 37 PageID #: 672
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`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`AIA Eng’g Ltd. v. Magotteaux Int’l,
`657 F.3d 1264 (Fed. Cir. 2011)..................................................................................................5
`
`Andersen Corp. v. Fiber Composites, LLC,
`474 F.3d 1361 (Fed. Cir. 2007)................................................................................................18
`
`Apple, Inc. v. Motorola, Inc.,
`757 F.3d 1286 (Fed. Cir. 2014)................................................................................................14
`
`Becton, Dickinson & Co. v. Tyco Healthcare Group,
`616 F.3d 1249 (Fed. Cir. 2010)..................................................................................................5
`
`Biogen, Inc. v. Berlex Labs., Inc.,
`318 F.3d 1132 (Fed. Cir. 2003)................................................................................................13
`
`Catalina Mktg. Int’l, Inc. v. Coolsavings.com, Inc.,
`289 F.3d 801 (Fed. Cir. 2002)............................................................................................26, 27
`
`Honeywell Int’l, Inc. v. ITT Indus., Inc.,
`452 F.3d 1312 (Fed. Cir. 2006)................................................................................................13
`
`In re Cuozzo Speed Techs., LLC.,
`778 F.3d 1271 (Fed. Cir. 2015)................................................................................................21
`
`Klein v. Russell,
`86 U.S. 433 (1873) ...................................................................................................................17
`
`Markman v. Westview Instruments, Inc.,
`52 F.3d 967 (Fed. Cir. 1995), aff’d, 517 U.S. 370 (1996) .........................................................5
`
`Medeva Pharma Suisse A.G. v. Par Pharm., Inc.,
`No. 10-cv-4008, 2012 U.S. Dist. LEXIS 76348 (D.N.J. June 1, 2012) ...................................14
`
`Meds. Co. v. Teva Parenteral Meds., Inc.,
`No. 09-750-RGA, 2013 U.S. Dist. LEXIS 97265 (D. Del. July 11, 2013) .......................18, 19
`
`Microsoft Corp. v. Multi-Tech Sys., Inc.,
`357 F.3d 1340 (Fed. Cir. 2004)................................................................................................14
`
`O2 Micro Intern’l Ltd. v. Beyond Innovation Tech.,
`521 F.3d 1351 (Fed. Cir. 2008)................................................................................................20
`
`Pfizer, Inc. v. Ranbaxy Labs. Ltd.,
`457 F.3d 1284 (Fed. Cir. 2006)....................................................................................26, 28, 29
`
` 
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`iv
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`

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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 5 of 37 PageID #: 673
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`
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`Pharmastem Therapeutics, Inc. v. Viacell, Inc.,
`No. 02-cv-148-GMS, 2003 U.S. Dist. LEXIS 877 (D. Del. Jan. 13, 2003) ............................17
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005)............................................................................................5, 19
`
`Rhine v. Casio, Inc.,
`183 F.3d 1342 (Fed. Cir. 1999)..........................................................................................17, 28
`
`Schoenhaus v. Genesco, Inc.,
`440 F.3d 1354 (Fed. Cir. 2006)................................................................................................28
`
`SourceOne Global Partners, LLC v. KGK Synergize, Inc.,
`No. 08-7403, 2010 U.S. Dist. LEXIS 55015 (N.D. Ill. June 3, 2010) .........................26, 27, 28
`
`Spectrum Int’l v. Sterilite Corp.,
`164 F.3d 1372 (Fed. Cir. 1998)................................................................................................29
`
`World Class Tech. Corp. v. Ormco Corp.,
`769 F.3d 1120 (Fed. Cir. 2014)................................................................................................23
`
`STATUTES
`
`35 U.S.C. § 112(d) .........................................................................................................................26
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` 
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`v
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 6 of 37 PageID #: 674
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`INTRODUCTION
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`This Hatch-Waxman case involves two of Pfizer’s follow-on patents associated with
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`tigecycline, a tetracycline-related antibiotic that Pfizer markets under the trade name Tygacil.®
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`After obtaining patents covering the tigecycline molecule itself, Pfizer seeks to extend its
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`monopoly by patenting supposedly improved formulations and crystalline forms of tigecycline.
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`CFT Pharmaceuticals, Inc. (“CFT”), filed an abbreviated new drug application seeking to market
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`a generic tigecycline product, and this case followed.
`
`I.
`
`The Patents
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`United States Patent No. 7,879,828 (“the ’828 patent”), entitled “Tigecycline
`
`Compositions and Methods of Preparation,” relates to compositions purporting to have improved
`
`stability over prior art tigecycline compositions. (JA-1460.) The patent asserts this is because the
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`claimed compositions contain a lactose excipient and possess a “pH” value in solution within a
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`specified range. According to the patent, tigecycline undergoes a known degradative process
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`called “oxidation” when exposed to higher pH values and a different known degradative process
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`called “epimerization” when exposed to lower pH values. (JA-1463–64 at 2:24 – 4:21.) The
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`patent asserts that the inventors discovered that adding lactose to tigecycline exposed to lower
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`pH environments in solution avoids oxidation and minimizes epimerization, thereby creating a
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`more stable product. (JA-1464–65 at 4:49 – 5:26.) A detailed explanation of pH is provided
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`below.
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`United States Patent No. 8,372, 995 (“the ’995 patent”), entitled “Crystalline Solid Forms
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`of Tigecycline and Methods of Preparing Same,” is a classic “polymorph” patent whose claims
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`recite a specific crystalline form of tigecycline, “Form I,” and a process for preparing Form I.
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`(JA-1.) Crystalline compounds are solids with specifically ordered arrays of molecules; different
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`arrays of the same molecule may constitute different crystalline forms. (JA-11 at 1:50–56.) In
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`1
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 7 of 37 PageID #: 675
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`contrast, a compound is said to be “amorphous” when the molecules in it are disordered. (Id. at
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`1:50–51.) Tigecycline, like many compounds, can exist in different crystalline forms or in
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`amorphous form. (Id. at 1:33–40 and 50–56.) Some crystalline forms have properties that
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`purportedly render them more advantageous for manufacturing and/or storage. (Id. at 2:21–28.)
`
`II.
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`Scientific Background
`
`A primer on two issues provides context for the disputed claim construction issues. The
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`first issue is the manufacture and use of tigecycline, and the second is the concept of pH and how
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`it is measured.
`
`A.
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`The Manufacture and Use of Tigecycline
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`Tigecycline is sold as a lyophilized (freeze-dried) powder in single use vials which are
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`reconstituted by the end user and administered intravenously. The manufacture of the finished
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`dosage product and the methods of administration employed are typical of many intravenous
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`drug products. The active pharmaceutical ingredient (“API”), tigecycline, along with other
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`excipients and sterile water for injection are added to a tank under carefully controlled
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`conditions. These conditions include a prescribed order in which the ingredients are added and
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`the careful monitoring and adjustment of factors such as temperature, pH, and oxygen levels in
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`the solution, as well as the method and timing of how the solution is mixed. The solution in the
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`tank is referred to as the “bulk solution.” Once this step is completed, the solution travels through
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`filtration lines to ensure sterility and, eventually, small specified volumes are filled into
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`individual sterile vials. The product in the vials is then lyophilized in a piece of equipment
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`called, not surprisingly, a “lyophilizer.” (See Kirsch Decl., at ¶ 13.)1
`
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`1 CFT relies on the contemporaneously filed Declaration of Lee E. Kirsch, Ph.D., (“Kirsch
`Decl.”). For the sake of brevity, citations thereto are provided at the end of several sentences of a
`paragraph, where appropriate.
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`2
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 8 of 37 PageID #: 676
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`During lyophilization, the product is first frozen, usually by freezing the shelves housing
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`the vials. The shelves are then heated as the lyophilizer is subjected to vacuum conditions,
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`causing the frozen water in the product to evaporate immediately without proceeding through the
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`liquid phase, a process known as “sublimation.” After one or more such steps, a dried powder or
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`cake is produced. The individual vials are then stoppered under sterile conditions. (See Kirsch
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`Decl., at ¶ 14.)
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`The advantage of lyophilization (as opposed to producing ready-to-use liquid products) is
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`typically enhanced stability. The pH of the product is ordinarily not measured or adjusted during
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`the lyophilization process. The lyophilized product in single use vials can be stored at controlled
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`temperature conditions, typically room temperature or refrigeration. (See id.)
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`In order to administer tigecycline according to the approved Tygacil label, the health care
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`provider must first reconstitute the powder in approximately 5 mL of either a 0.9% sodium
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`chloride solution, a 5% dextrose solution, or a lactated Ringers solution. (See Section 2.4 of
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`Tygacil product label, attached as Exhibit B to Kirsch Decl.) The reconstituted solution is then
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`added to a 100 mL intravenous (IV) bag which is used for infusion into the patient. No specific
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`type of infusion solution is required for the IV bag except that it be “compatible with tigecycline
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`and with any other drug(s) administered” through the IV line. The reconstituted or further diluted
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`solution must be used within 24 – 48 hours after reconstitution, depending upon the temperature
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`at which it is stored. At no time after the lyophilized powder is initially reconstituted is the pH
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`measured or adjusted. (See Kirsch Decl., at ¶¶ 16–17 & Exh. B.)
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`B.
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`pH
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`In lay terms, pH is a measure of the acidity of a solution, as determined by the
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`concentration of hydrogen ions (H+) therein. A greater concentration of hydrogen ions results in
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`a lower pH, whereas fewer hydrogen ions results in a higher pH. Values for pH are commonly
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`3
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 9 of 37 PageID #: 677
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`visualized on a scale of 1 – 14, with pH values less than 7 considered “acidic,” and pH values
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`greater than 7 considered “basic.” Pure water has a “neutral” pH of 7.0. Each change of pH
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`value represents a ten-fold change in hydrogen ion concentration. For example, a solution with a
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`pH of 6.0 has a ten-fold higher concentration of hydrogen ions than a solution with a pH of 7.0, a
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`solution with a pH of 5.0 has a hundred-fold higher concentration of hydrogen ions than a
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`solution with a pH of 7.0, and so on. (See id., at ¶ 18 & Exh. C.)
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`The pH of a solution is dependent upon many factors such as its temperature, the nature
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`of the solution itself, and the chemical compounds within it. Electrochemical forces affecting a
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`chemical compound in solution may cause some hydrogen atoms on the compound to
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`“dissociate” from the compound into the solution, thereby raising the hydrogen ion concentration
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`of the solution (and lowering its pH). Similarly, a compound may accept hydrogen ions from
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`solution, thereby lowering the hydrogen ion concentration of the solution (and raising its pH). A
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`strong acid is a compound that readily dissociates and contributes hydrogen ions to a solution,
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`and a strong base is a compound that readily accepts hydrogen ions from a solution; the addition
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`of either obviously affects the solution’s pH. Even small changes in the pH of a solution can
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`dramatically affect the environment and the chemical reactions that occur within that solution.
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`For example, for many drug substances (such as esters) their rate of degradation can be
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`proportional to the concentration of hydrogen ions in solution in specific pH regions. Thus an
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`increase in solution pH value of 0.1 in such a pH region could cause a 20% decrease in the shelf-
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`life of the drug solution. (See Kirsch Decl., at ¶¶ 19–21.) The pH of tigecycline dissolved in
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`water alone is about 7.8. (JA-1463 at 2:34–35.)
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`The measurement of pH in laboratory solutions and industrial applications is fairly
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`straightforward. Digital instruments commonly measure pH values to the nearest hundredth of a
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`4
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 10 of 37 PageID #: 678
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`pH unit, and pH values are commonly reported to the nearest tenth of a pH unit. (See id., at ¶ 22
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`& Exh. D.)
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`LEGAL STANDARDS
`
`Claim construction is an issue of law that is performed by the Court. Markman v.
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`Westview Instruments, Inc., 52 F.3d 967, 979 (Fed. Cir. 1995), aff’d, 517 U.S. 370 (1996). A
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`claim is construed by examining the language of the claims themselves, the patent specification,
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`the prosecution history, and any relevant extrinsic evidence. See, e.g., Phillips v. AWH Corp.,
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`415 F.3d 1303, 1314 (Fed. Cir. 2005); Markman, 52 F.3d at 979. Ultimately, claim terms should
`
`be construed based on how persons skilled in the art would understand them when the patent
`
`application was filed. Phillips, 415 F.3d at 1313.
`
`The primary tool for claim construction analysis is the patent’s specification, which
`
`explains the invention and defines the claim terms. Becton, Dickinson & Co. v. Tyco Healthcare
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`Group, 616 F.3d 1249, 1255 (Fed. Cir. 2010) (the specification “is the single best guide to the
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`meaning of a disputed term”) (internal citations omitted); Phillips, 415 F.3d at 1315. The
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`prosecution history can also reveal whether there are any express limitations made regarding the
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`scope and meaning of the claims. Phillips, 415 F.3d at 1317. Extrinsic evidence such as expert
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`and inventor testimony, dictionaries, and treatises may also be useful in determining the “true
`
`meaning of the language employed in the patent.” AIA Eng’g Ltd. v. Magotteaux Int’l, 657 F.3d
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`1264, 1273 (Fed. Cir. 2011) (internal citations and quotations omitted).
`
`ARGUMENT
`
`CFT’s proposed constructions reflect how one of ordinary skill in the art would
`
`understand the claims in light of the intrinsic evidence. In contrast, Pfizer’s proposed
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`constructions ignore the teachings in the specification and seek to have the claims interpreted in
`
`isolation and divorced from the context of the patent. The Court should reject Pfizer’s arguments
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`5
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 11 of 37 PageID #: 679
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`and accept CFT’s proposals. CFT’s proposed claim constructions assign meaning to the disputed
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`claim terms consistent with the teachings in the specification and based on how one of ordinary
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`skill in the art would actually understand them.
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`I.
`
`The ’828 Patent
`
`The parties disagree about two claim terms in the ’828 patent, both of which relate to
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`claim limitations directed to the pH of the claimed compositions.2
`
`A.
`
`“pH of the composition in a solution is” Refers to the Bulk
`Solution Before Lyophilization.
`
`
`Term To Be Construed
`
`“pH of the composition
`in a solution is”
`
`(claims 1, 4, 5, 10-12,
`14-17)
`
`Pfizer’s Proposed
`Construction
`“the pH of the composition,
`when the composition is in a
`solution”
`
`CFT’s Preliminary Proposed
`Construction
`“the pH of the composition,
`when the composition is in the
`bulk solution and before
`lyophilization, is”
`
`
`
`The parties dispute whether the claimed pH range of the composition in a solution must
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`apply to the bulk solution. CFT’s proposal is correct for several reasons. First, the specification
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`teaches that the claimed inventions depend upon the recited pH range existing in the bulk
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`solution. Second, the claim language itself supports CFT’s construction. Third, prosecution
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`history of a continuation patent containing the same language supports CFT’s interpretation.
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`Fourth, the claims would not make sense if the pH limitation is not required to be applied to the
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`bulk solution. (See Kirsch Decl., at ¶ 25.) Finally, contrary to Pfizer’s assertions, CFT’s proposal
`
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`2 Representative claim 1 recites:
`A composition comprising tigecycline, lactose, and an acid selected from hydrochloric
`acid and gentisic acid, wherein the molar ratio of tigecycline to lactose is between about
`1:0.2 and about 1:5 and the pH of the composition in a solution is between about 3.0 and
`about 7.0.
`(JA-1469 at 14:36–40.)
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`6
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 12 of 37 PageID #: 680
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`does not import a claim limitation from the specification – rather, it merely describes a property
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`of the claimed inventions. Even if the Court were to consider CFT’s proposal a process
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`limitation, however, it would properly be imported from the specification here.
`
`1.
`
`The specification teaches that the claimed inventions depend upon the
`recited pH range existing in the bulk solution.
`
`A thorough review of the specification demonstrates that the claimed inventions depend
`
`upon the recited pH range existing in the bulk solution. The specification asserts that improved
`
`stability results from the presence of lactose and the recited pH range in the bulk solution.
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`Further, the examples distinguish compositions of the invention from those that are not
`
`compositions of the invention. For the former, the pH is measured or adjusted in the bulk
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`solution, whereas, for the latter, the pH is never measured or adjusted. Indeed, all the pH
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`measurements or adjustments shown in the examples were performed in the bulk solution.
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`a.
`
`The specification asserts that improved stability results from the
`presence of lactose and the recited pH in the bulk solution.
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`The specification begins by explaining that the present invention relates to “improved
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`tigecycline compositions and methods for making such compositions” that achieve improved
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`stability over prior art tigecycline compositions “when dissolved, lyophilized, reconstituted,
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`and/or diluted than compositions of tigecycline not made according to the invention.” (JA-1463
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`at 1:7–21.) But the latter three states are dependent upon the first one, because a compound
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`cannot be reconstituted or further diluted without first having been dissolved in bulk solution and
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`lyophilized. As discussed below, the only method of making the claimed tigecycline
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`compositions described in the patent involves one in which the pH meets the recited limitations
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`during initial dissolution – i.e., in the bulk solution. (See Kirsch Decl., at ¶ 26.)
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`The specification then explains that tigecycline is manufactured as a lyophilized powder
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`prepared by compounding and freeze-drying. (JA-1463 at 1:54–62.) The specification further
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`7
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/15 Page 13 of 37 PageID #: 681
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`explains that to administer the product, the lyophilized cake is first reconstituted and then further
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`diluted for IV administration (the latter process being referred to as admixing). (Id. at 1:66 –
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`2:10.) The specification explains that prior art tigecycline compositions degrade during each of
`
`these phases, including while it sits on the shelf in the lyophilized state. (JA-1463–64 at 2:9–16
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`and 3:23–31.) The specification then describes prior art manufacturing processes in order to
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`contrast them with the current invention. (JA-1464 at 3:46 – 4:48.) (See Kirsch Decl., at ¶ 27.)
`
`Turning to the current invention, the specification explains that the invention offers
`
`advantages over the prior art by reducing oxidation:
`
`By lyophilizing an aqueous solution containing tigecycline and a suitable
`carbohydrate at an acidic pH, we have prepared tigecycline compositions
`that are more stable against both oxidative degradation and epimerization
`than existing compositions. Because the pH is acidic, oxidative degradation
`has been minimized.
`
`(JA-1464 at 4:51–57) (emphasis added.) Clearly, the specification attributes the avoidance of
`
`undesirable oxidation to the pH at which the aqueous solution is lyophilized. A person of
`
`ordinary skill in the art would understand that this refers to the pH of the bulk solution because a
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`solid composition such as a lyophilized cake is not ordinarily considered to have a “pH” – rather,
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`the concept refers to hydrogen ion activity in solution. Thus, a person of ordinary skill would
`
`understand the pH at which a solution is lyophilized to refer to the pH of the solution
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`immediately before lyophilization, i.e., the pH of the bulk solution. (See Kirsch Decl., at ¶¶ 28–
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`29.)
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`Minimizing oxidative degradation with an acidic pH in the bulk solution (along with the
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`presence of an appropriate carbohydrate) translates into improved stability of the composition in
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`lyophilized and reconstituted forms:
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`Compositions of the invention are more stable in the lyophilized state than
`the existing compositions …. Such compositions are also expected to
`possess reconstitution and admixture stability times greater than that of the
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`existing compositions.
`(JA-1464 at 4:60–65) (emphasis added). The specification’s linkage of lyophilized compositions
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`(“such compositions”) to subsequently reconstituted and admixed solutions confirms that the
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`increased stability of those solutions is a consequence of lyophilizing an acidic bulk solution
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`containing a suitable carbohydrate. (See Kirsch Decl., at ¶ 30.)
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`The specification then describes four embodiments of the invention. The specification
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`first states that the compositions of the invention “include solutions, such as those prepared prior
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`to lyophilization, containing tigecycline, a suitable carbohydrate, and an acid or buffer.” (JA-
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`1465 at 5:27–29.) This refers to bulk solutions. The patent goes on to state that compositions of
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`the invention “further include lyophilized powders or cakes containing tigecycline, a suitable
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`carbohydrate, and an acid or buffer.” (Id. at 5:32–34.) Finally, in referring to reconstituted
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`solutions and admixtures, the patent then states that:
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`Compositions of the invention also include solutions made from the
`lyophilized powder or cake by, for example, reconstitution with saline or
`other pharmaceutically acceptable diluents. Compositions of the invention
`further include solutions resulting from diluting those reconstituted
`solutions with pharmaceutically acceptable diluents for use in intravenous
`bags.
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`(Id. at 5:41–46.) (emphases added.) The patent thus makes clear that in order for these
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`reconstituted solutions and admixtures to be compositions of the invention, they must first have
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`been derived from the lyophilized powder – which itself had to have been derived from a bulk
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`solution meeting the required pH limitations. In that regard, Pfizer’s citation to this portion of the
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`specification in its brief (see D.I. 39 at 10-11) to suggest that reconstituted solutions and
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`admixtures can be compositions of the invention irrespective of the bulk solution’s pH is
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`erroneous. (See Kirsch Decl., at ¶ 31.)
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`Consistently, the only procedure described in the patent for making the claimed
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`compositions involves one in which the pH of the bulk solution meets the recited limitation. The
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`specification explains that the bulk solution is formed by dissolving tigecycline in water and that
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`the “pH of the solution is subsequently lowered by addition of an acid or buffer” (as well as a
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`suitable carbohydrate). (JA-1465 at 6:10–16.) Only “[a]fter the pH of the solution is adjusted to
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`be acidic,” is the solution lyophilized to dryness. (Id. at 6:16–18.) Likewise, when the
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`specification introduces the specified pH ranges included in the claims, it explicitly instructs that
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`the pH adjustment is made to the bulk solution:
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`[W]hen preparing tigecycline solutions of the invention for lyophilization,
`one adds sufficient acid or buffer to the aqueous solution containing
`tigecycline to obtain a pH from about 3.0 and about 7.0 including from
`about 4.0 to about 5.0 and from about 4.2 to about 4.8.
`(Id. at col. 6:31–35) (emphasis added.) These discussions uniformly teach that the pH of the bulk
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`solution is adjusted to be acidic prior to lyophilization. Thus, the stability of the lyophilized cake
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`as well as the stability of any of the subsequent solutions of the invention is dependent upon the
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`presence of the recited pH limitation in the bulk solution. (See Kirsch Decl., at ¶ 32.)
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`b.
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`Examples 1 and 3 show the recited pH range being met in the bulk
`solution and expressly distinguish the claimed compositions from
`tigecycline compositions in which the recited pH range is not met
`in the bulk solution.
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`The specification concludes with six examples purportedly detailing several experiments
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`“where tigecycline was dissolved with a carbohydrate in aqueous acidic solution, lyophilized,
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`and analyzed for degradation.” (JA-1465 at 6:65–67). The examples measure stability in
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`lyophilized compositions, reconstituted solutions, and admixtures. In doing so, Examples 1 and 3
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`distinguish samples in which the bulk solution had the recited pH, which they refer to as
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`compositions of the invention, from those in which the bulk solution did not have the recited pH,
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`which are not compositions of the invention. (See Kirsch Decl., at ¶ 33.)
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`In Example 1, the pH of each composition of the invention was adjusted prior to
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`Case 1:14-cv-00781-SLR Document 51 Filed 04/30/1