Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 1 of 749 PageID #:
`5275
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`Plaintiffs and Counter Defendants,
`
`v.
`
`CELLTRION, INC., CELLTRION,
`HEALTHCARE CO., LTD., TEVA
`PHARMACEUTICALS USA, INC., and
`TEVA PHARMACEUTICALS
`INTERNATIONAL GMBH,
`
`C.A. No. 18-95-CFC
`(CONSOLIDATED)
`
`GENENTECH, INC., CITY OF HOPE, and )
`HOFFMANN LA ROCHE INC.,
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`Defendants and Counterclaim Plaintiffs. )
`)
`GENENTECH, INC. and CITY OF HOPE, )
`)
`Plaintiffs and Counterclaim Defendants, )
`)
`)
`)
`)
`)
`)
`)
`GENENTECH, INC. and CITY OF HOPE, )
`)
`)
`)
`)
`)
`)
`)
`)
`)
`JOINT CLAIM CONSTRUCTION CHART
`APPENDIX C VOLUME 10B
`
`v.
`
`AMGEN INC.,
`
`Defendant and Counterclaim Plaintiff.
`
`Plaintiffs,
`
`v.
`
`SAMSUNG BIOEPIS CO., LTD,
`
`Defendant.
`
`C.A. No. 18-924-CFC
`
`C.A. No. 18-1363-CFC
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 2 of 749 PageID #:
`5276
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________________________
`
`HOSPIRA, INC.
`Petitioner
`
`v.
`
`GENENTECH, INC.
`Patent Owner
`___________________________________
`
`U.S. Patent No. 7,807,799
`Issue Date: October 5, 2010
`Title: REDUCING PROTEIN A LEACHING DURING
`PROTEIN A AFFINITY CHROMATOGRAPHY
`___________________________________
`
`Inter Partes Review No. Unassigned
`___________________________________
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,807,799
`UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42
`
`
`
`
`
`
`JA00003714
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 3 of 749 PageID #:
`5277
`
`
`
`Table of Contents
`
`V. 
`
`OVERVIEW .................................................................................................... 1 
`I. 
`II.  MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................... 4 
`A. 
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ............................ 4 
`B. 
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ..................................... 4 
`C. 
`Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) .................. 5 
`D. 
`Service Information Under 37 C.F.R. § 42.8(b)(4) ............................... 5 
`III.  GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a) ..................... 5 
`IV.  STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22) ................................................. 6 
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ................... 6 
`The Challenged Claims and Grounds (37 C.F.R. §§
`A. 
`42.104(b)(1) and (2)) ............................................................................. 6 
`The ’799 Patent ..................................................................................... 7 
`1. 
`The Specification ........................................................................ 8 
`2. 
`The Claims ................................................................................ 10 
`Summary of the Prosecution Histories ................................................ 11 
`1. 
`The ’704 Patent Prosecution History ........................................ 11 
`2. 
`The ’799 Prosecution History ................................................... 14 
`3. 
`The EP ’940 Prosecution History ............................................. 15 
`Claim Construction (37 C.F.R. § 42.104(b)(3)) .................................. 17 
`1. 
`Claim 1 ...................................................................................... 17 
`Claims 2 and 3 ........................................................................... 20 
`2. 
`Claims 5 to 9 ............................................................................. 21 
`3. 
`
`B. 
`
`C. 
`
`D. 
`
`JA00003715
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 4 of 749 PageID #:
`5278
`
`
`
`Claims 10 and 11....................................................................... 21 
`4. 
`VI.  LEVEL OF ORDINARY SKILL IN THE ART ........................................... 22 
`VII.  TECHNICAL BACKGROUND AND THE PRIOR ART ........................... 22 
`A.  WO ’389 (Ex. 1003) ............................................................................ 24 
`B.  Van Sommeren (Ex. 1004) .................................................................. 24 
`C. 
`Balint (Ex. 1005) ................................................................................. 25 
`D. 
`Potier (Ex. 1006) ................................................................................. 26 
`E. 
`The ’526 Patent (Ex. 1007) ................................................................. 26 
`VIII.  STATEMENT OF THE REASONS FOR THE RELIEF
`REQUESTED (37 C.F.R. §§ 42.104(b)(4) and (5)) ...................................... 28 
`A.  Ground 1: WO ’389 Anticipates Claims 1 and 5 ................................ 28 
`B.  Ground 2: Van Sommeren Anticipates Claims 1, 2, and 5 ................ 33 
`C.  Ground 3: WO ’389 Renders Claims 1 and 5 Obvious ....................... 37 
`D.  Ground 4: WO ’389, Balint and Potier Render Claims 1 to 3
`and 5 Obvious ...................................................................................... 40 
`Ground 5: WO ’389 and the ’526 Patent Render Claims 2, 3
`and 6 to 11 Obvious ............................................................................ 44 
`Ground 6: Claims 2, 3 and 6 to 11 Would Have Been Obvious
`Over WO ’389, and Further in View of Balint, Potier, and
`the ’526 Patent ..................................................................................... 49 
`G.  Ground 7: Van Sommeren Renders Claims 1, 2, and 5 Obvious ...... 51 
`H.  Ground 8: Van Sommeren and the ’526 Patent Render Claims 3
`and 6 to 11 Obvious ............................................................................ 53 
`IX.  NO SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ....... 57 
`X. 
`CONCLUSION .............................................................................................. 58 
`
`E. 
`
`F. 
`
`JA00003716
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 5 of 749 PageID #:
`5279
`
`
`
`TABLE OF AUTHORITIES
`
`
`
`Cases
`Andersen Corp. v. Fiber Composites, LLC,
`474 F.3d 1361 (Fed. Cir. 2007) ..................................................................... 19
`
`Page (s)
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ............................................................... 38, 39
`
`Atofina v. Great Lakes Chem. Corp.,
`411 F.3d 991 (Fed. Cir. 2006) ....................................................................... 30
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) ............................................................... 30, 36
`
`In re Cruciferous Sprout Litig.,
`301 F.3d 1343 (Fed. Cir. 2002) ............................................................... 29, 35
`
`Epos Techs. Ltd. v. Pegasus Techs. Ltd.,
`766 F.3d 1338 (Fed. Cir. 2014) ..................................................................... 19
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ........................................................................................... 37
`
`Ineos USA LLC v. Berry Plastics Corp.,
`783 F.3d 865 (Fed. Cir. 2015) ................................................................. 30, 36
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ..................................................................... 58
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)................................................................................. 22, 38
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) ..................................................................... 57
`
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) ............................................................... 57, 58
`
`Ormco Corp. v. Align Tech., Inc.,
`498 F.3d 1307 (Fed. Cir. 2007) ..................................................................... 19
`
`-i
`
`JA00003717
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 6 of 749 PageID #:
`5280
`
`
`
`Pall Corp. v. Micron Separations, Inc.,
`66 F.3d 1211 (Fed. Cir. 1995) ....................................................................... 19
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ............................................................... 30, 38
`
`Southwall Techs., Inc. v. Cardinal IG Co.,
`54 F.3d 1570 (Fed. Cir. 1995) ....................................................................... 18
`
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ....................................................................... 30
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ..................................................................... 57
`
`
`
`-i
`
`JA00003718
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 7 of 749 PageID #:
`5281
`
`
`
`List of Exhibits
`
`(Filed Pursuant to 37 C.F.R. § 42.6)
`
`Description
`
`Hospira Exhibit
`Number
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`U.S. Patent No. 7,807,799 to Fahrner et al.
`
`Declaration of Todd M. Przybycien, Ph.D.
`
`International Publication No. WO 95/22389 to Shadle et al.
`
`A.P.G. van Sommeren et al., Effects of Temperature, Flow
`Rate and Composition of Binding Buffer on Adsorption of
`Mouse Monoclonal IgG1 Antibodies to Protein A Sepharose 4
`Fast Flow, 22 PREPARATIVE BIOCHEMISTRY 135 (1992)
`
`J.P. Balint, Jr. & F.R. Jones, Evidence for Proteolytic
`Cleavage of Covalently Bound Protein A from a Silica Based
`Extracorporeal Immunoadsorbent and Lack of Relationship to
`Treatment Effects. 16 TRANSFUS. SCI. 85 (1995)
`
`P. Potier et al., Temperature-dependent changes in proteolytic
`activities and protein composition in the psychrotropic
`bacterium Arthrobacter globiformis S155. 136 J. GEN.
`MICROBIOL. 283 (1990)
`
`U.S. Patent No. 6,127,526 to G.S. Blank
`
`U.S. Patent No. 7,485,704 to Fahrner et al.
`
`European Patent No. EP 1 648 940 B1 to Fahrner et al.
`
`Excerpts from the Prosecution File History of U.S. Patent No.
`7,485,704
`
`Excerpts from the Prosecution File History of U.S. Patent No.
`7,807,799
`
`Excerpts from the Prosecution File History of European Patent
`No. EP 1 648 940 B1
`
`-
`
`JA00003719
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 8 of 749 PageID #:
`5282
`
`
`
`1013
`
`Hjelm et al., Protein A from Staphylococcus Aureus. Its
`Isolation by Affinity Chromatography and Its Use As An
`Immunoadsorbent for Isolation of Immunoglobulins, 28 FEBS
`LETT. 73 (1972)
`
`JA00003720
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 9 of 749 PageID #:
`5283
`
`
`
`Hospira, Inc. requests inter partes review (“IPR”) under 35 U.S.C. §§ 311-
`
`319 and 37 C.F.R. § 42 et seq. of claims 1 to 3 and 5 to 11 of U.S. Patent No.
`
`7,807,799 (the “’799 Patent”) to Fahrner et al., titled “Reducing Protein A
`
`Leaching During Protein A Affinity Chromatography” (Exhibit 1001).1
`
`Pursuant to 37 C.F.R. § 42.15, the Petition Fee of $23,000 is being paid
`
`concurrently with the filing of this Petition. The undersigned representative of
`
`Petitioner hereby authorizes the Patent Office to charge any additional fees or
`
`credit any overpayment to deposit account 232405.
`
`I.
`
`OVERVIEW
`
`Claims 1 to 3 and 5 to 11 of the ’799 Patent (the “Challenged Claims”) are
`
`invalid over the prior art cited in this Petition and should not have been issued.
`
`The Challenged Claims merely recite a well-known method of purifying proteins
`
`using protein A chromatography. Because Petitioner is, at a minimum, reasonably
`
`likely to prevail in demonstrating invalidity, this Petition should be granted and
`
`trial instituted on all of the Challenged Claims.
`
`This Petition and the Declaration of Dr. Przybycien (Ex. 1002, the
`
`“Przybycien Decl.”) explain that every element of the Challenged Claims was
`
`disclosed in the prior art, and also that the claimed subject matter would have been
`
`obvious to those of ordinary skill in the art. The ’799 Patent as a whole is directed
`
`
`1
`“Exhibit” shall hereinafter be referenced as “Ex.”
`
`-
`
`JA00003721
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 10 of 749 PageID #:
`5284
`
`
`
`to methods for reducing leaching of protein A during protein A affinity
`
`chromatography by reducing temperature or pH, or by adding protease inhibitors.
`
`Well before the earliest priority date of the ’799 Patent, protein A affinity
`
`chromatography was widely used to purify proteins having a CH2/CH3 region. The
`
`Challenged Claims require the step of conducting protein A chromatography “at a
`
`temperature in the range from about 10° C to about 18° C.” The Challenged
`
`Claims are anticipated and/or or rendered obvious by the prior art under Grounds 1
`
`through 8 as set forth below.
`
`It was known in the prior art to conduct protein A chromatography at
`
`ambient temperature, as well as at temperatures below ambient temperature.
`
`International Publication No. WO 95/22389 to Shadle et al. (“WO ’389,” Ex.
`
`1003) as well as A.P.G. van Sommeren et al., Effects of Temperature, Flow Rate
`
`and Composition of Binding Buffer on Adsorption of Mouse Monoclonal IgG1
`
`Antibodies to Protein A Sepharose 4 Fast Flow, 22 PREPARATIVE BIOCHEMISTRY
`
`135 (1992) (“van Sommeren,” Ex. 1004) each disclose purifying an antibody using
`
`protein A affinity chromatography at temperature ranges overlapping with the
`
`claimed range of “about 10° C to about 18° C.” As set forth in detail below, the
`
`temperature range of “about 10° C to about 18° C” is not critical to the operability
`
`of the claimed invention. In other words, performing protein A chromatography at
`
`the claimed range does not produce unexpected results when compared to the
`
`-
`
`JA00003722
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 11 of 749 PageID #:
`5285
`
`
`
`temperature ranges disclosed in the prior art. Accordingly, the claims are
`
`anticipated and/or rendered obvious by WO ’389 and van Sommeren.
`
`Protein A chromatography is used to purify a protein of interest from other
`
`proteins produced in a cell. During protein A affinity chromatography, protein A
`
`that has been immobilized on a column is used to capture proteins that have a
`
`CH2/CH3 region. The captured proteins are separated from the other cellular
`
`proteins, which do not have a CH2/CH3 region, and therefore can be washed away.
`
`However, purifying proteins using this type of column chromatography can also
`
`cause some of the immobilized protein A to leach from the column. The alleged
`
`invention of the ’799 Patent is based on the idea that protein A leaching is caused
`
`by protease activity. Protease activity can be reduced by lowering the temperature
`
`of the composition comprising the proteins, or by adding protease inhibitors to this
`
`composition. By extension, reducing temperature and adding protease inhibitors
`
`also must reduce protein A leaching.
`
`However, the inventors of the ’799 Patent did not invent the idea of reducing
`
`protein A leaching by reducing protease activity. As explained in this Petition, it
`
`was well-known in the art that protease activity could cause protein A leaching. It
`
`was also known that protease inhibitors and lower temperatures could inhibit
`
`protease activity during protein A chromatography. The temperature activation of
`
`proteolysis is not fundamentally different in the range of “about 10° C to about 18°
`
`-
`
`JA00003723
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 12 of 749 PageID #:
`5286
`
`
`
`C” versus other temperature ranges. That is, a relative temperature reduction at
`
`any temperature at which chromatography is practicable, such as 3° C or 30° C,
`
`will lead to a reduction in protein A leaching. Protein A chromatography need not
`
`be practiced at the claimed range in order to achieve reductions in protein A
`
`leaching. Because the Challenged Claims recite conducting a known process at
`
`known parameters using known components, they are invalid under §§ 102 and
`
`103 as set forth in detail below, and should be cancelled.
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`Hospira, Inc. (“Hospira” or “Petitioner”) is the real party-in-interest for
`
`Petitioner. Out of an abundance of caution, and as a result of ongoing integration
`
`and reorganization activities, Petitioner identifies Pfizer Inc. as a real party-in-
`
`interest who, going forward, may have control or an interest in the outcome of this
`
`proceeding. No other parties exercised or could have exercised control over this
`
`Petition; no other parties funded or directed this Petition. See Trial Practice Guide,
`
`77 Fed. Reg. 48759-60.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`There are no judicial or administrative matters that would affect, or be
`
`affected by, a decision in the proceeding.
`
`-
`
`JA00003724
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 13 of 749 PageID #:
`5287
`
`
`
`There are no child applications claiming benefit of U.S. Application No.
`
`12/269,752 (the “’752 Application”), which issued as the ’799 Patent, listed in the
`
`Patent Application Information Retrieval System.
`
`C. Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`Pursuant to 37 C.F.R. §§ 42.8(b)(3) and 42.10(a), Petitioner designates the
`
`following counsel:
`
`
`
`
`
`Lead Counsel
`
`Thomas J. Meloro (Reg. No. 33,538)
`Willkie Farr & Gallagher LLP
`787 Seventh Avenue
`New York, New York 10019-6099
`
`Telephone: (212) 728-8428
`Facsimile: (212) 728-8111
`tmeloro@willkie.com
`
`Back-Up Counsel
`
`Michael W. Johnson (Reg. No. 63,731)
`Willkie Farr & Gallagher LLP
`787 Seventh Avenue
`New York, New York 10019-6099
`
`Telephone: (212) 728-8137
`Facsimile: (212) 728-8111
`mjohnson1@willkie.com
`
`Service Information Under 37 C.F.R. § 42.8(b)(4)
`
`
`D.
`Please address all correspondence to lead counsel at the contact information
`
`above. Hospira consents to service by electronic mail at tmeloro@willkie.com and
`
`mjohnson1@willkie.com. A Power of Attorney is being filed concurrently
`
`herewith under 37 C.F.R. § 41.10(b).
`
`III. GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a)
`Petitioner certifies that the ’799 Patent is available for IPR, and that
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’799
`
`Patent on the grounds set forth herein.
`
`-
`
`JA00003725
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 14 of 749 PageID #:
`5288
`
`
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22)
`
`Petitioner requests inter partes review and cancellation of claims 1 to 3 and
`
`5 to 11 of the ’799 Patent under 35 U.S.C. § 102 and/or § 103, as set forth herein.
`
`Petitioner’s detailed statement of the reasons for the relief requested is provided in
`
`Section VIII below.
`
`V.
`
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`Inter partes review of claims 1 to 3 and 5 to 11 of the ’799 Patent is
`
`requested. Per 37 C.F.R. § 42.6(c), copies of the references are filed herewith. In
`
`support of the proposed grounds for invalidity, this Petition is accompanied by the
`
`Declaration of Todd M. Przybycien, Ph.D. (Ex. 1002), which explains the ’799
`
`Patent, its prosecution history and the teachings of the cited prior art.
`
`A. The Challenged Claims and Grounds (37 C.F.R. §§ 42.104(b)(1)
`and (2))
`
`Pursuant to 37 C.F.R. §§ 42.104(b)(1) and (2), the following grounds are
`
`offered as reasons for cancelling the Challenged Claims of the ’799 Patent:
`
`Ground
`
`Reference(s)
`
`Statutory Basis
`
`WO ’389 (Ex. 1003)
`
`§ 102(b)
`
`Challenged
`Claims
`1 and 5
`
`1
`
`2
`
`3
`
`van Sommeren (Ex. 1004)
`
`§ 102(b)
`
`1, 2 and 5
`
`WO ’389 (Ex. 1003)
`
`§ 103(a)
`
`1 and 5
`
`JA00003726
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 15 of 749 PageID #:
`5289
`
`
`
`Ground
`
`Reference(s)
`
`Statutory Basis
`
`§ 103(a)
`
`Challenged
`Claims
`1 to 3 and 5
`
`§ 103(a)
`
`2, 3 and 6 to 11
`
`§ 103(a)
`
`2, 3 and 6 to 11
`
`WO ’389 (Ex. 1003), Balint
`(Ex. 1005) & Potier (Ex.
`1006)
`
`WO ’389 (Ex. 1003) &
`the ’526 Patent (Ex. 1007)
`
`WO ’389 (Ex. 1003), Balint
`(Ex. 1005), Potier (Ex. 1006)
`& the ’526 Patent (Ex. 1007)
`
`4
`
`5
`
`6
`
`7
`
`8
`
`
`
`van Sommeren (Ex. 1004)
`
`§ 103(a)
`
`1, 2 and 5
`
`van Sommeren (Ex. 1004) &
`the ’526 Patent (Ex. 1007)
`
`§ 103(a)
`
`3 and 6 to 11
`
`The ’799 Patent
`
`B.
`The ’799 Patent issued on October 5, 2010 from the Application No.
`
`12/269,752 (the “’752 Application”), which was filed on November 12, 2008.
`
`The ’752 Application was filed as a continuation of U.S. Application No.
`
`10/877,532 (the “’532 Application”), now issued as U.S. Patent No. 7,485,704 (the
`
`“’704 Patent,” Ex. 1008). The ’532 Application claimed priority to Provisional
`
`Application No. 60/490,500 (the “500 Provisional”), which was filed on July 28,
`
`2003. International Application No. PCT/US04/20480 and European Patent No.
`
`EP1648940 (“EP ’940,” Ex. 1009), among other foreign counterparts, also claim
`
`priority to the ’500 Provisional.
`
`-
`
`JA00003727
`
`

`

`Case 1:18-cv-01363-CFC Document 48-12 Filed 12/11/18 Page 16 of 749 PageID #:
`5290
`
`
`
`The inventors listed for each of these applications and patents are Robert L.
`
`Fahrner, Amy Laverdiere, Paul J. McDonald, and Rhona M. O’Leary. The ’799
`
`Patent, ’704 Patent and EP ’940 appear to be assigned to Genentech, Inc. The
`
`assignment by the inventors to Genentech, Inc. is located at reel/frame
`
`015216/0197 of the U.S. Patent & Trademark Office’s patent assignment database.
`
`No assignment has been recorded for the ’799 Patent.
`
`The Specification
`
`1.
`According to the ’799 Patent, the invention concerns a method for reducing
`
`leaching of protein A during protein A affinity chromatography. (Ex. 1001, 1:17-
`
`18.) The disclosed method includes reducing the temperature of a composition
`
`comprising the protein subjected to protein A affinity chromatography to below
`
`room temperature, such as “about 3° C. to about 20° C., e.g. from about 10° C. to
`
`about 18° C.” (Id. at 18:4-9.) In another aspect, the alleged invention includes
`
`adding protease inhibitor(s) and/or lowering the pH of the composition in
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`combination with the above-mentioned temperature reduction. (Id. at 18:17-21.)
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`The specification acknowledged the relationship between protease activity and
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`protein A leaching in the following way:
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`“Protease activity” refers to the enzymatic activity of one
`or more proteases. Such activity may be measured
`indirectly by measuring leaching of protein A, for
`instance. The activity may be reduced by reducing
`temperature of a composition comprising the protease(s),
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`JA00003728
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`and/or by adding one or more protease inhibitors to the
`composition etc.
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`(Id. at 5:1-6.) The ’799 Patent does not provide any explanation or data showing
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`how or why protease activity may be measured indirectly by measuring leaching of
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`protein A. That is of no matter, however, because the relationship between
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`protease activity and protein A leaching was known in the prior art and is not
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`inventive subject matter.
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`Most of the specification is devoted to modes of carrying out protein A
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`chromatography, including prior art techniques for generating proteins that have a
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`CH2/CH3 region (id. at 7:48-17:28), and prior art methods for measuring protein A
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`leaching (id. at 17:50-18:3). The specification explicitly discloses that protein A
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`chromatography was a widely used tool for purifying antibodies, and that it
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`efficiently separates them from host cell proteins, DNA, and other small
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`molecules. (Id. at 20:7-9.)
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`The specification includes two experimental examples. Example 1 is titled
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`“Temperature Reduction for Reducing Protein [A] Leaching During Protein [A]
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`Affinity Chromatography” (id. at 20:3-4), and Example 2 is titled “Protease
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`Inhibitors for Reducing Protein [A] Leaching During Protein [A] Affinity
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`Chromatography” (id. at 24:54-55). The materials utilized in these examples,
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`including the target proteins (id. at 20:19-31), chromatography columns (id. at
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`21:56-57) and protease inhibitors (id. at 25:22-52, Table 5), were all well-known
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`and commercially available before the date of the alleged invention. After testing
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`the target proteins at a range of temperatures, the Patentee plotted the results in
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`Figures 1 to 3, and superimposed exponential trend-lines, asserting that “[t]his type
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`of non-linear correlation would be consistent with temperature-activated
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`proteolytic cleavage.” (Id. at 22:1-3.)
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`The Patentee concluded that, by controlling temperature of the harvested cell
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`culture fluid (“HCCF”) that was subjected to protein A chromatography, the level
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`of protein A in the protein A pool could be controlled, or reduced. (Id. at 24:36-
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`37.) For example, trastuzumab HCCF at pilot scale was chilled to 15±3° C, and
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`protein A leaching was controlled to less than or equal to 10 ng/mg. (Id. at 24:43-
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`45.) All of the experimental data shown in the ’799 Patent relates to a mass ratio
`
`of protein A to the purified antibody, or protein A in parts per million. (See, e.g.,
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`id. at 2-3 and 7, Figs. 1-3, 8 and 9.) Nothing in the disclosure established the
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`absolute amount of target protein purified during the experimental examples, or the
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`nature of the relationship between protein purification and temperature, or any
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`other parameter.
`
`The Claims
`
`2.
`The ’799 Patent concludes with 12 claims directed to methods of purifying a
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`protein comprising a CH2/CH3 region. Claims 1 and 12 are independent, and
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`claims 2 through 11 ultimately depend from claim 1, which provides:
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`A method of purifying a protein which comprises a
`CH2/CH3 region, comprising subjecting a composition
`comprising said protein to protein A affinity
`chromatography at a temperature in the range from about
`10 ° C. to about 18 ° C.
`
`The further limitations of claims 2 and 3 relate to exposing the composition to a
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`protease inhibitor. Dependent claim 5 recites that the protein to be purified is an
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`antibody, and claims 6 through 9 recite further limitations regarding the claimed
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`antibody. Claim 10 depends from claim 1, and recites that the protein is an
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`immunoadhesin. Claim 11 further limits the immunoadhesin of claim 10 to a TNF
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`receptor immunoadhesin.
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`C.
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`Summary of the Prosecution Histories
`1.
`The original 19 claims of the ’532 Application were directed to methods of
`
`The ’704 Patent Prosecution History
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`reducing leaching of protein A during protein A affinity chromatography. Claims
`
`1, 12 and 13 were independent, and claim 1 provided the following:
`
`A method of purifying a protein which comprises a
`CH2/CH3 region, comprising reducing the temperature of
`a composition comprising the protein and one or more
`impurities subjected to protein A affinity
`chromatography in the range from about 3°C to about
`20°C, wherein protein A leaching is reduced.
`
`(Ex. 1010, ’704 Patent File History at 38.) Claim 12 recited the additional steps of
`
`measuring leached protein A in the composition, and, if protein A leaching was
`
`detected, reducing the temperature of the composition. (Id. at 39.)
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`JA00003731
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` On October 6, 2006, the Examiner issued a Non-Final Office Action
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`rejecting all 19 claims of the ’532 Application as being either anticipated or
`
`obvious based on prior art. Horenstein et al., Design and scaleup of downstream
`
`processing of monoclonal antibodies for cancer therapy: from research to clinical
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`proof of principle, 275 JOURNAL OF IMMUNOLOGICAL METHODS, 99 (2003)
`
`(“Horenstein”) disclosed performing the protein A liquid chromatography at room
`
`temperature, about 22° C. The Examiner stated that this teaching met the claim
`
`limitation of “about 3°C to about 20°C.” (Id. at 50.)
`
`On January 4, 2007, the Applicant amended several claims in response to the
`
`rejections, including removing one instance of the word “about” so that amended
`
`claims 1, 12, 13 and 17 recited performing the chromatography “in the range from
`
`about 3°C to 20°C.” (Id. at 55.) The Applicant argued that this amendment set 20°
`
`C as the upper limit of the temperature range for conducting protein A affinity
`
`chromatography, thereby ostensibly avoiding the teachings of Horenstein. (Id. at
`
`59.)
`
`However, the Examiner found this characterization of the temperature range,
`
`as well as the Applicant’s other arguments, to be unpersuasive, and issued a Final
`
`Rejection on March 20, 2007. (Id. at 63-72.) There, the Examiner pointed out that
`
`there was no basis in the specification for the range of “about 3°C to 20°C”
`
`defining an upper cutoff of 20°C. (Id. at 65.) The Examiner also rejected the
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`claims under 35 U.S.C. § 102(e) as being anticipated by U.S. Patent No. 6,927,044
`
`to Stahl et al. (“Stahl”). (Id. at 68.) Stahl was cited for teaching purifying fusion
`
`polypeptides having CH2/CH3 regions using protein A chromatography at 4° C.
`
`Stahl also disclosed the use of protease inhibitors, including
`
`ethylenediaminetetraacetic acid (“EDTA”), with protein A chromatography.
`
`In response to this rejection, on June 14, 2007, the Applicant amended the
`
`temperature ranges to recite “about 3°C to about 18°C.” (Id. at 74-75.) The
`
`Applicant argued that Horenstein was not anticipatory because it disclosed
`
`performing protein A chromatography at 22° C, which was not within the scope of
`
`the pending claims. (Id. at 79.) The Applicant also amended claim 1 to include
`
`additional recovering and measuring steps, similar to claim 12. (Id. at 74.) The
`
`Applicant asserted that the additional steps patentably distinguished the claimed
`
`method from Stahl. (Id. at 80.)
`
`Following two more rejections on December 26, 2007 and July 14, 2008, the
`
`amended claims presented on November 12, 2008 were allowed. Claim 1 of
`
`the ’704 Patent provides:
`
`1. A method of purifying a protein which comprises a
`CH2/CH3 region comprising:
`a. subjecting a composition comprising said protein to
`protein A affinity chromatography to provide a
`recovered composition and measuring leached
`protein A in said recovered composition; and
`b. if greater than about 20 ng protein A per mg of said
`protein is measured in said recovered composition,
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`JA00003733
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`then performing subsequent purification of
`compositions comprising said protein by protein A
`affinity chromatography at a temperature in the
`range from about 3° C. to about 18° C., such that
`protein A leaching is reduced.
`
`(Ex. 1008, ’704 Patent at 35:45-59.) This claim recites subjecting a composition
`
`comprising a protein to protein A chromatography and measuring the leached
`
`protein A. If more than 20 ng/mg of protein A is measured, under the claims of
`
`the ’704 patent, the practitioner must perform a subsequent purification on other
`
`compositions at a reduced temperature in order to reduce the protein A leaching.
`
`(See Ex. 1010, ’704 Patent File History at 77-78.)
`
`The ’799 Prosecution History
`
`2.
`The ’752 Application was filed on November 12, 2008. Original claims 1
`
`through 19 were cancelled, and new claims 20 to 33 were added in a preliminary
`
`amendment. New claim 20 recited:
`
`A method of purifying a protein which comprises
`CH2/CH3 region, comprising subjecting a composition
`comprising said protein to protein A affinity
`chromatography at a temperature in the range from about
`10 °C to about 18 °C, such that protein A leaching is
`reduced.
`
`(Ex. 1011, ’799 Patent File History at 4.)
`
`The Examiner only issued one rejection during the prosecution of the ’752
`
`Application. On October 9, 2009, she provisionally rejected the claims for double
`
`pat