`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In the Inter Partes Review of:
`
`Trial Number: To Be Assigned
`
`
`
`U.S. Patent No. 6,407,213
`
`Filed: November 17, 1993
`
`Issued: June 18, 2002
`
`Inventor(s): Paul J. Carter; Leonard G. Presta
`
`Assignee: Genentech, Inc.
`
`
`
`
`
`
`
`
`
`
`
`Title: METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`Panel: To Be Assigned
`
`Mail Stop Inter Partes Review
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`
`DECLARATION OF KAREN YOUNKINS
`
`
`
`1
`
`PFIZER EX. 1184
`Page 1
`
`

`

`
`
`DECLARATION OF KAREN YOUNKINS
`I, Karen Younkins, declare under penalty of perjury as follows:
`
`1.
`
`2.
`
`I am an Associate of the law firm Kirkland & Ellis LLP.
`
`I make this Declaration in support of the petition for inter partes
`
`review of U.S. Patent No. 6,407,213 before the United States Patent and
`
`Trademark Office. I make this Declaration of my own personal knowledge.
`
`3.
`
`The following Protein Data Bank (PDB) entries were accessed at the
`
`PDB webpage http://www.rcsb.org.
`
`4.
`
`Exhibit 1003F is a true and correct copy of the PDB entry for PDB ID
`
`2HFL.
`
`5.
`
`Exhibit 1184A is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=2HFL, accessed April 25,
`
`2017. Exhibit 1184A is a report showing that entry 2HFL was first deposited in the
`
`PDB August 17, 1987 and released October 16, 1987.
`
`6.
`
`Exhibit 1003G is a true and correct copy of the PDB entry for PDB ID
`
`1FB4.
`
`7.
`
`Exhibit 1184B is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=1FB4, accessed April 25,
`
`2017. Exhibit 1184B is a report showing that entry 1FB4 was first deposited in the
`
`PDB May 9, 1983 and released July 28, 1983.
`
`
`
`2
`
`PFIZER EX. 1184
`Page 2
`
`

`

`
`
`8.
`
`Exhibit 1003H is a true and correct copy of the PDB entry for PDB ID
`
`3FAB.
`
`9.
`
`Exhibit 1184C is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=3FAB, accessed April
`
`25, 2017. Exhibit 1184C is a report showing that entry 3FAB was first deposited
`
`September 29, 1981 and released December 8, 1981.
`
`10. Exhibit 1003I is a true and correct copy of the PDB entry for PDB ID
`
`2FBJ.
`
`11. Exhibit 1184D is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=2FBJ , accessed May 4,
`
`2017. Exhibit 1184D is a report showing that entry 2FBJ was first deposited
`
`August 18, 1989 and released July 15, 1990.
`
`12. Exhibit 1003J is a true and correct copy of the PDB entry for PDB ID
`
`1MCP.
`
`13. Exhibit 1184E is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=1MCP , accessed May 4,
`
`2017. Exhibit 1184E is a report showing that entry 1MCP was first deposited July
`
`9, 1984 and released January 2, 1985.
`
`14. Exhibit 1003K is a true and correct copy of the PDB entry for PDB ID
`
`4FAB.
`
`
`
`3
`
`PFIZER EX. 1184
`Page 3
`
`

`

`
`
`15. Exhibit 1184F is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=4FAB , accessed May 4,
`
`2017. Exhibit 1184F is a report showing that entry 4FAB was first deposited April
`
`10, 1989 and released July 15, 1990.
`
`16. Exhibit 1003L is a true and correct copy of the PDB entry for PDB ID
`
`3HFM.
`
`17. Exhibit 1184G is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=3HFM , accessed May 4,
`
`2017. Exhibit 1184G is a report showing that entry 3HFM was first deposited
`
`August 11, 1988 and released July 12, 1989.
`
`18. Exhibit 1003M is a true and correct copy of the PDB entry for PDB
`
`ID 1REI.
`
`19. Exhibit 1184H is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=1REI , accessed May 4,
`
`2017. Exhibit 1184H is a report showing that entry 1REI was first deposited March
`
`17, 1976 and released May 19, 1976.
`
`20. Exhibit 1003N is a true and correct copy of the PDB entry for PDB ID
`
`2RHE.
`
`21. Exhibit 1184I is a true and correct copy of the PDB webpage
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=2RHE , accessed May 4,
`
`
`
`4
`
`PFIZER EX. 1184
`Page 4
`
`

`

`
`
`2017. Exhibit 1184I is a report showing that entry 2RHE was first deposited June
`
`13, 1983 and released September 15, 1983.
`
`22.
`
`I declare under penalty of perjury under the laws of the United States
`
`of America that all statements made herein of my own knowledge are true and that
`
`all statements made on information and belief are believed to be true; and further
`
`that these statements were made with the knowledge that willful false statements
`
`and the like so made are punishable by fine or imprisonment, or both, under
`
`Section 1001 of the Title 18 of the United States Code.
`
`Executed on March 24, 2017 in Los Angeles, California.
`
` / Karen Younkins /
`Karen Younkins
`
`
`
`5
`
`PFIZER EX. 1184
`Page 5
`
`

`

`Exhibit A
`
`Exhibit A
`
`PFIZER EX. 1 184
`
`Page 6
`
`
`
`
`
`
`
`PFIZER EX. 1184
`Page 6
`
`

`

`RCSB PDB - Obsolete Entry Report
`
`RCSB PDB
`
`Deposit
`
`Search
`
`Visualize
`
`Analyze
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`Download
`
`Learn
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`More
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`An Information Portal to
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`   
`
`THREE-DIMENSIONAL STRUCTURE OF AN ANTIBODY-ANTIGEN COMPLEX
`
`Obsolete Structure Summary Page
`
`2HFL
`
`
`
`
`
` Display Files
` Download Files
` Share this Page
`
`
`
`2HFL was obsoleted on 1995-07-31 and superseded by 3HFL
`
`Image of 2HFL
`
`1972-01-01
`
`2017-04-25
`
`Archive of Obsolete PDB Structures
`
`2HFL
`3HFL
`1YQV
`
`Note: Mouse over colored bars for date info, mouse over PDB IDs for file download or Structure Explorer link.
`
`
`Title
`
`Authors
`
`2HFL
`THREE-DIMENSIONAL STRUCTURE
`OF AN ANTIBODY-ANTIGEN
`COMPLEX
`Sheriff, S., Davies, D.R.
`
`Textual Comparison
`3HFL
`THE REFINED STRUCTURE OF THE MONOCLONAL ANTIBODY
`HY(SLASH)HEL-5 WITH ITS ANTIGEN HEN EGG WHITE
`LYSOZYME
`Cohen, G.H., Sheriff, S., Davies, D.R.
`
`
`
`1YQV
`The crystal structure of the antibody Fab
`HyHEL5 complex with lysozyme at 1.7A
`resolution
`Cohen, G.H., Silverton, E.W., Padlan, E.A.,
`Dyda, F., Wibbenmeyer, J.A., Wilson, R.C.,
`Davies, D.R.
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=2HFL&evtc=Suggest&evta=PDBID&evtl=autosearch_SearchBar_querySuggest[4/25/2017 9:34:15 AM]
`
`PFIZER EX. 1184
`Page 7
`
`

`

`RCSB PDB - Obsolete Entry Report
`Residues per chain
`Number of Atoms
`Non-polymer entities
`Source
`
`B: 213, A: 212, C: 129
`4227
`PCA
`Polymer 1: n/a, Polymer 2: n/a,
`Polymer 3: n/a
`X-RAY DIFFRACTION
`54.79 74.82 78.95
`90.00 101.82 90.00
`
`Exp. Method
`Unit cell
` Length [Å]: a b c
` Angle: alpha beta gamma
`Space Group
`P 2
`1
`Resolution
`n/a
`R-value
`n/a
`Deposited
`1987-08-17
`Released
`1987-10-16
`Obsoleted
`1995-07-31
`Replaced by
`3HFL
`Replaces
`
`Details
`n/a
`Note: Mouse over table elements for additional info
`
`B: 215, A: 212, C: 129
`4251
`PCA
`Polymer 1: n/a, Polymer 2: n/a, Polymer 3: n/a
`
`X-RAY DIFFRACTION
`54.79 74.82 78.95
`90.00 101.82 90.00
`
`P 2
`1
`2.65
`0.196 (obs.)
`1995-05-02
`1995-07-31
`2005-04-26
`1YQV
`2HFL
`n/a
`
`B: 215, A: 211, C: 129
`4273
`none
`Polymer 1: Mus musculus, Polymer 2: Mus
`musculus, Polymer 3: Gallus gallus
`X-RAY DIFFRACTION
`54.46 74.26 78.26
`90.00 101.65 90.00
`
`P 2
`1
`1.70
`0.195 (work)
`2005-02-02
`2005-04-26
`
`
`3HFL
`
`
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`RCSB PDB is a member of the
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`
`
`The RCSB PDB is funded by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=2HFL&evtc=Suggest&evta=PDBID&evtl=autosearch_SearchBar_querySuggest[4/25/2017 9:34:15 AM]
`
`PFIZER EX. 1184
`Page 8
`
`

`

`PFIZER EX. 1 184
`
`Page 9
`
`
`Exhibit B
`
`Exhibit B
`
`
`
`
`
`PFIZER EX. 1184
`Page 9
`
`

`

`RCSB PDB - Obsolete Entry Report
`
`RCSB PDB
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`Deposit
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`   
`
`THE THREE-DIMENSIONAL STRUCTURE OF ANTIBODIES
`
`Obsolete Structure Summary Page
`
`1FB4
`
`
`
`
`
` Display Files
` Download Files
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`
`1FB4 was obsoleted on 1989-07-12 and superseded by 2FB4
`
`Image of 1FB4
`
`1972-01-01
`
`2017-04-25
`
`Archive of Obsolete PDB Structures
`
`1FB4
`2FB4
`
`Note: Mouse over colored bars for date info, mouse over PDB IDs for file download or Structure Explorer link.
`
`Textual Comparison
`
`
`
`
`Title
`
`Authors
`Residues per chain
`Number of Atoms
`
`1FB4
`THE THREE-DIMENSIONAL
`STRUCTURE OF ANTIBODIES
`Marquart, M., Huber, R.
`B: 229, A: 216
`3317
`
`2FB4
`DIR PRIMAERSTRUKTUR DES KRISTALLISIERBAREN MONOKLONALEN IMMUNOGLOBULINS IGG1 KOL. II.
`AMINOSAEURESEQUENZ DER L-KETTE, LAMBDA-TYP, SUBGRUPPE I (GERMAN)
`Marquart, M., Huber, R.
`B: 229, A: 216
`3312
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=1FB4[4/25/2017 9:41:28 AM]
`
`PFIZER EX. 1184
`Page 10
`
`

`

`none
`Polymer 1: n/a, Polymer 2: n/a
`X-RAY DIFFRACTION
`78.30 138.90 40.00
`90.00 90.00 90.00
`
`RCSB PDB - Obsolete Entry Report
`Non-polymer entities
`Source
`Exp. Method
`Unit cell
` Length [Å]: a b c
` Angle: alpha beta gamma
`Space Group
`P 2 2 2
`1 1 1
`Resolution
`n/a
`R-value
`n/a
`Deposited
`1983-05-09
`Released
`1983-07-28
`Obsoleted
`1989-07-12
`Replaced by
`2FB4
`Replaces
`
`Details
`n/a
`Note: Mouse over table elements for additional info
`
`none
`Polymer 1: Homo sapiens, Polymer 2: Homo sapiens
`X-RAY DIFFRACTION
`78.30 138.90 40.00
`90.00 90.00 90.00
`
`P 2 2 2
`1 1 1
`1.90
`0.189 (work)
`1989-04-18
`1989-07-12
`
`
`1FB4
`
`
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`The RCSB PDB is funded by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=1FB4[4/25/2017 9:41:28 AM]
`
`PFIZER EX. 1184
`Page 11
`
`

`

`PFIZER EX. 1 184
`
`Page 12
`
`
`Exhibit C
`
`Exhibit C
`
`
`
`
`
`PFIZER EX. 1184
`Page 12
`
`

`

`RCSB PDB - Obsolete Entry Report
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`RCSB PDB
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`   
`
`PRELIMINARY REFINEMENT AND STRUCTURAL ANALYSIS OF THE FAB
`FRAGMENT FROM HUMAN IMMUNOGLOBULIN NEW AT 2.0 ANGSTROMS
`RESOLUTION
`
`Obsolete Structure Summary Page
`
`3FAB
`
`
`
`
`
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`
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`
`3FAB was obsoleted on 1994-01-31 and superseded by 7FAB
`
`Image of 3FAB
`
`1972-01-01
`
`2017-04-25
`
`Archive of Obsolete PDB Structures
`
`1FAB
`2FAB
`3FAB
`7FAB
`
`Note: Mouse over colored bars for date info, mouse over PDB IDs for file download or Structure Explorer link.
`
`
`Title
`
`1FAB
`PRELIMINARY REFINEMENT AND
`STRUCTURAL ANALYSIS OF THE FAB
`FRAGMENT FROM HUMAN
`IMMUNOGLOBULIN NEW AT 2.0
`
`Textual Comparison
`2FAB
`PRELIMINARY REFINEMENT AND
`STRUCTURAL ANALYSIS OF THE FAB
`FRAGMENT FROM HUMAN
`IMMUNOGLOBULIN NEW AT 2.0
`
`3FAB
`PRELIMINARY REFINEMENT AND
`STRUCTURAL ANALYSIS OF THE FAB
`FRAGMENT FROM HUMAN
`IMMUNOGLOBULIN NEW AT 2.0
`
`7FAB
`CRYSTAL STRUCTURE OF
`HUMAN IMMUNOGLOBULIN
`FRAGMENT FAB NEW
`REFINED AT 2.0
`
`
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=3FAB[4/25/2017 9:43:34 AM]
`
`PFIZER EX. 1184
`Page 13
`
`

`

`RCSB PDB - Obsolete Entry Report
`
`Authors
`
`Residues per chain
`Number of Atoms
`Non-polymer entities
`Source
`
`ANGSTROMS RESOLUTION
`Poljak, R.J., Amzel, L.M., Chen, B.L.,
`Phizackerley, R.P., Saul, F.
`B: 220, A: 208
`3187
`PCA
`Polymer 1: n/a, Polymer 2: n/a
`
`ANGSTROMS RESOLUTION
`Poljak, R.J., Amzel, L.M., Chen, B.L.,
`Phizackerley, R.P., Saul, F.
`B: 220, A: 208
`3184
`PCA
`Polymer 1: n/a, Polymer 2: n/a
`
`ANGSTROMS RESOLUTION
`Poljak, R.J., Amzel, L.M., Chen, B.L.,
`Phizackerley, R.P., Saul, F.
`B: 220, A: 208
`3189
`PCA
`Polymer 1: n/a, Polymer 2: n/a
`
`X-RAY DIFFRACTION
`111.43 56.68 90.30
`90.00 116.46 90.00
`
`Exp. Method
`Unit cell
` Length [Å]: a b c
` Angle: alpha beta gamma
`Space Group
`C 2
`Resolution
`n/a
`R-value
`n/a
`Deposited
`1976-08-27
`Released
`n/a
`Obsoleted
`1979-07-10
`Replaced by
`2FAB
`Replaces
`
`Details
`n/a
`Note: Mouse over table elements for additional info
`
`X-RAY DIFFRACTION
`111.43 56.68 90.30
`90.00 116.46 90.00
`
`X-RAY DIFFRACTION
`111.43 56.68 90.30
`90.00 116.46 90.00
`
`C 2
`n/a
`n/a
`1979-06-07
`n/a
`1981-12-08
`3FAB
`1FAB
`n/a
`
`C 2
`n/a
`n/a
`1981-09-29
`1981-12-08
`1994-01-31
`7FAB
`2FAB
`n/a
`
`ANGSTROMS RESOLUTION
`Saul, F., Poljak, R.J.
`
`B: 217, A: 208
`3084
`none
`Polymer 1: Homo sapiens,
`Polymer 2: Homo sapiens
`X-RAY DIFFRACTION
`111.43 56.68 90.30
`90.00 116.46 90.00
`
`C 2
`2.00
`0.169 (obs.)
`1991-11-20
`1994-01-31
`
`
`3FAB
`
`
`About
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`RCSB Partners Nucleic Acid Database Structural Biology Knowledgebase
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`RCSB PDB (citation) is managed by two members of the
`Research Collaboratory for Structural Bioinformatics:
`Rutgers and UCSD/SDSC
`
`RCSB PDB is a member of the
`
`
`
`The RCSB PDB is funded by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
`
`http://www.rcsb.org/pdb/explore/obsolete.do?obsoleteId=3FAB[4/25/2017 9:43:34 AM]
`
`PFIZER EX. 1184
`Page 14
`
`

`

`PFIZER EX. 1 184
`
`Page 15
`
`
`Exhibit D
`
`Exhibit D
`
`
`
`
`
`PFIZER EX. 1184
`Page 15
`
`

`

`RCSB PDB - 2FBJ: REFINED CRYSTAL STRUCTURE OF THE GALACTAN-BINDING IMMUNOGLOBULIN FAB J539 AT 1.95-ANG...
`
`Page 1 of 3
`
`An Information Portal to
`129745 Biological
`Macromolecular Structures
`
`Biological Assembly 1 
`
`2FBJ
`
`REFINED CRYSTAL STRUCTURE OF THE GALACTAN-BINDING IMMUNOGLOBULIN FAB
`J539 AT 1.95-ANGSTROMS RESOLUTION
`DOI: 10.2210/pdb2fbj/pdb Entry 2FBJ supersedes 1FBJ
`
`Classification: IMMUNOGLOBULIN
`Deposited: 1989-08-18 Released: 1990-07-15
`Deposition author(s): Bhat, T.N., Padlan, E.A., Davies, D.R.
`Organism: Mus musculus
`Mutation(s): 18
`
`Structural Biology Knowledgebase: 2FBJ (>14 annotations)
`
`wwPDB Validation
`
`(cid:423) 3D Report Full Report
`
`Experimental Data Snapshot
`
`Method: X-RAY DIFFRACTION
`Resolution: 1.95 Å
`R-Value Observed: 0.194
`
`Literature
`
`Macromolecule Content
`
`• Unique protein chains: 2
`
`Refined Crystal Structure of the Galactan-Binding Immunoglobulin Fab J539 at 1.95-
`Angstroms Resolution
`Bhat, T.N., Padlan, E.A., Davies, D.R.
`
`To Be Published
`
`Macromolecules
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=2FBJ
`
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 16
`
`

`

`RCSB PDB - 2FBJ: REFINED CRYSTAL STRUCTURE OF THE GALACTAN-BINDING IMMUNOGLOBULIN FAB J539 AT 1.95-ANG...
`Classification: IMMUNOGLOBULIN
`
`Page 2 of 3
`
`Length
`
`213
`
`Organism
`
`Mus musculus
`
`Details
`
`Mutation: L2I, M11T, S12A, P15L, ΔR32, ΔF33, A41T, L45P, D49E,
`T50I, P55S, S75N, S76T, S84I, F86Y, H88Q, ΔS93, S91T
`
`220
`
`Mus musculus
`
`Gene Name(s):
`
`Gene Name(s):
`
`Total Structure Weight: 48292.41
`
`
`
`Macromolecule Entities
`
`Molecule
`
`Chains
`
`L
`
`H
`
`IGA-KAPPA J539 FAB
`(LIGHT CHAIN)
`
`IGA-KAPPA J539 FAB
`(HEAVY CHAIN)
`
`
`
`Small Molecules
`
`Ligands
`
`3 Unique
`
`Chains
`
`Name / Formula / InChI Key
`
`
`
`& Interactions2D Diagram
`
`3D Interactions
`
`H
`
`H
`
`H
`
`N-ACETYL-D-GLUCOSAMINE
`C H N O
`8
`15
`6
`OVRNDRQMDRJTHS-FMDGEEDCSA-N
`
`ALPHA-L-FUCOSE
`C H O
`6
`12
`5
`SHZGCJCMOBCMKK-SXUWKVJYSA-N
`
`ZINC ION
`Zn
`PTFCDOFLOPIGGS-UHFFFAOYSA-N
`
`Ligand Explorer
`
`NGL
`
`Binding Pocket (JSmol)
`
`Electron Density (JSmol)
`
`Ligand Explorer
`
`NGL
`
`Binding Pocket (JSmol)
`
`Ligand Explorer
`
`NGL
`
`Binding Pocket (JSmol)
`
`ID
`
`NAG
`
`FUC
`
`ZN
`
`
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=2FBJ
`
`
`
`
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 17
`
`

`

`RCSB PDB - 2FBJ: REFINED CRYSTAL STRUCTURE OF THE GALACTAN-BINDING IMMUNOGLOBULIN FAB J539 AT 1.95-ANG...
`
`Page 3 of 3
`
`Experimental Data & Validation
`
`Experimental Data
`Method: X-RAY DIFFRACTION
`Resolution: 1.95 Å
`R-Value Observed: 0.194
`Space Group: P 2 2 2
`1
`1
`1
`
`Unit Cell:
`
`Length (Å)
`
`a = 54.02
`
`b = 74.29
`
`c = 131.35
`
`Angle (°)
`
`α = 90.00
`
`β = 90.00
`
`γ = 90.00
`
`
`
`Entry History
`
`Deposition Data
`Deposited Date: 1989-08-18
`Released Date: 1990-07-15
`Deposition author(s): Bhat, T.N., Padlan, E.A., Davies, D.R.
`Previous versions: 1FBJ
`
`
`
`Structure Validation
`View Full Validation Report or Ramachandran Plots
`
`
`
`
`
`Revision History
`• 2013-09-11
`Type: Source and taxonomy | Details: --
`• 2011-07-13
`Type: Version format compliance | Details: compliance with PDB Exchange Dictionary
`V4
`• 2011-07-13
`Type: Non-polymer description | Details: chemical name/synonym update
`
`The RCSB PDB is funded by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=2FBJ
`
`
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 18
`
`

`

`PFIZER EX. 1 184
`
`Page 19
`
`
`Exhibit E
`
`Exhibit E
`
`
`
`
`
`PFIZER EX. 1184
`Page 19
`
`

`

`RCSB PDB - 1MCP: PHOSPHOCHOLINE BINDING IMMUNOGLOBULIN FAB MC/PC603. AN X-RAY DIFFRACTION STUDY AT 2.7...
`
`Page 1 of 3
`
`An Information Portal to
`129745 Biological
`Macromolecular Structures
`
`Biological Assembly 1 
`
`1MCP
`
`PHOSPHOCHOLINE BINDING IMMUNOGLOBULIN FAB MC/PC603. AN X-RAY
`DIFFRACTION STUDY AT 2.7 ANGSTROMS
`DOI: 10.2210/pdb1mcp/pdb
`
`Classification: IMMUNOGLOBULIN
`Deposited: 1984-07-09 Released: 1985-01-02
`Deposition author(s): Satow, Y., Cohen, G.H., Padlan, E.A., Davies, D.R.
`Organism: Mus musculus
`Mutation(s): 1
`
`Structural Biology Knowledgebase: 1MCP (>14 annotations)
`
`wwPDB Validation
`
`(cid:423) 3D Report Full Report
`
`Experimental Data Snapshot
`
`Method: X-RAY DIFFRACTION
`Resolution: 2.7 Å
`R-Value Work: 0.225
`
`Literature
`
`Macromolecule Content
`
`• Unique protein chains: 2
`
`Phosphocholine binding immunoglobulin Fab McPC603. An X-ray diffraction study at 2.7 A.
`Satow, Y., Cohen, G.H., Padlan, E.A., Davies, D.R.
`
`(1986) J.Mol.Biol. 190: 593-604
`
`PubMed: 3097327
`
`PubMed Abstract:
`The crystal structure of the Fab of McPC603, a phosphocholine-binding mouse myeloma protein, has been refined at
`2.7 A resolution by a combination of restrained least-squares refinement and molecular modeling. The overall
`structure remains as previously reported, with an elbow bend angle between the variable and constant modules of
`133 degrees. Some adjustments have been made in the structure of the loops as a result of the refinement. The
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=1MCP
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 20
`
`

`

`RCSB PDB - 1MCP: PHOSPHOCHOLINE BINDING IMMUNOGLOBULIN FAB MC/PC603. AN X-RAY DIFFRACTION STUDY AT 2.7...
`hypervariable loops are all visible in the electron density map with the exception of three residues in the first
`hypervariable loop of the light chain. A sulfate ion occupies the site of binding of the phosphate moiety of
`phosphocholine.
`
`Page 2 of 3
`
`Keywords:
`Amino Acid Sequence, Binding Sites, Antibody, Choline, Hydrogen Bonding, Immunoglobulin Fab
`Fragments, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Phosphorylcholine, Protein
`Conformation, X-Ray Diffraction
`
`Macromolecules
`
`Classification: IMMUNOGLOBULIN
`
`Total Structure Weight: 48529.22
`
`
`
`Macromolecule Entities
`
`Molecule
`
`Chains
`
`Length
`
`Organism
`
`Details
`
`IGA-KAPPA MCPC603 FAB
`(LIGHT CHAIN)
`
`IGA-KAPPA MCPC603 FAB
`(HEAVY CHAIN)
`
`L
`
`H
`
`220
`
`222
`
`Mus musculus
`
`Mutation: L112I
`
`Mus musculus
`
`Gene Name(s):
`
`
`
`Small Molecules
`
`Ligands
`
`1 Unique
`
`ID
`
`SO4
`
`Chains
`
`Name / Formula / InChI Key
`
`
`
`& Interactions2D Diagram
`
`3D Interactions
`
`H
`
`SULFATE ION
`O S
`4
`QAOWNCQODCNURD-UHFFFAOYSA-L
`
`Ligand Explorer
`
`NGL
`
`Binding Pocket (JSmol)
`
`Electron Density (JSmol)
`
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=1MCP
`
`
`
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 21
`
`

`

`RCSB PDB - 1MCP: PHOSPHOCHOLINE BINDING IMMUNOGLOBULIN FAB MC/PC603. AN X-RAY DIFFRACTION STUDY AT 2.7...
`
`Page 3 of 3
`
`Experimental Data & Validation
`
`Experimental Data
`Method: X-RAY DIFFRACTION
`Resolution: 2.7 Å
`R-Value Observed:
`Space Group: P 63
`
`
`
`Entry History
`
`Structure Validation
`View Full Validation Report or Ramachandran Plots
`
`Unit Cell:
`
`Length (Å)
`
`a = 162.53
`
`b = 162.53
`
`c = 60.72
`
`Angle (°)
`
`α = 90.00
`
`β = 90.00
`
`γ = 120.00
`
`
`
`Deposition Data
`Deposited Date: 1984-07-09
`Released Date: 1985-01-02
`Deposition author(s): Satow, Y., Cohen, G.H., Padlan, E.A., Davies, D.R.
`
`
`
`
`
`Revision History
`• 2011-07-13
`Type: Flag nonstandard coordinate frame | Details: Tagged nonstandard coordinate
`frame
`• 2011-07-13
`Type: Version format compliance | Details: compliance with PDB Exchange Dictionary
`V4
`
`
`
`The RCSB PDB is funded by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=1MCP
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 22
`
`

`

`PFIZER EX. 1 184
`
`Page 23
`
`
`Exhibit F
`
`Exhibit F
`
`
`
`
`
`PFIZER EX. 1184
`Page 23
`
`

`

`RCSB PDB - 4FAB: THREE-DIMENSIONAL STRUCTURE OF A FLUORESCEIN-FAB COMPLEX CRYSTALLIZED IN 2-METHYL-2,...
`
`Page 1 of 4
`
`An Information Portal to
`129745 Biological
`Macromolecular Structures
`
`Biological Assembly 1 
`
`4FAB
`
`THREE-DIMENSIONAL STRUCTURE OF A FLUORESCEIN-FAB COMPLEX CRYSTALLIZED
`IN 2-METHYL-2,4-PENTANEDIOL
`DOI: 10.2210/pdb4fab/pdb
`
`Classification: IMMUNOGLOBULIN
`Deposited: 1989-04-10 Released: 1990-07-15
`Deposition author(s): Herron, J.N., He, X., Mason, M.L., Vossjunior, E.W., Edmundson, A.B.
`Organism: Mus musculus
`Mutation(s): 12
`
`Structural Biology Knowledgebase: 4FAB (>12 annotations)
`
`wwPDB Validation
`
`(cid:423) 3D Report Full Report
`
`Experimental Data Snapshot
`
`Method: X-RAY DIFFRACTION
`Resolution: 2.7 Å
`R-Value Observed: 0.215
`
`Literature
`
`Macromolecule Content
`
`• Unique protein chains: 2
`
`Three-dimensional structure of a fluorescein-Fab complex crystallized in
`2-methyl-2,4-pentanediol.
`Herron, J.N., He, X.M., Mason, M.L., Voss Jr., E.W., Edmundson, A.B.
`
`(1989) Proteins 5: 271-280
`
`PubMed: 2508085
`DOI: 10.1002/prot.340050404
`
`PubMed Abstract:
`The crystal structure of a fluorescein-Fab (4-4-20) complex was determined at 2.7 A resolution by molecular
`replacement methods. The starting model was the refined 2.7 A structure of unliganded Fab from an autoantibody
`(BV04-01) with specificity for single-stranded DNA. In the 4-4-20 complex fluorescein fits tightly into a relatively deep
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=4FAB
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 24
`
`

`

`RCSB PDB - 4FAB: THREE-DIMENSIONAL STRUCTURE OF A FLUORESCEIN-FAB COMPLEX CRYSTALLIZED IN 2-METHYL-2,...
`slot formed by a network of tryptophan and tyrosine side chains. The planar xanthonyl ring of the hapten is
`accommodated at the bottom of the slot while the phenylcarboxyl group interfaces with solvent. Tyrosine 37 (light
`chain) and tryptophan 33 (heavy chain) flank the xanthonyl group and tryptophan 101 (light chain) provides the floor
`of the combining site. Tyrosine 103 (heavy chain) is situated near the phenyl ring of the hapten and tyrosine 102
`(heavy chain) forms part of the boundary of the slot. Histidine 31 and arginine 39 of the light chain are located in
`positions adjacent to the two enolic groups at opposite ends of the xanthonyl ring, and thus account for neutralization
`of one of two negative charges in the haptenic dianion. Formation of an enol-arginine ion pair in a region of low
`dielectric constant may account for an incremental increase in affinity of 2-3 orders of magnitude in the 4-4-20
`molecule relative to other members of an idiotypic family of monoclonal antifluorescyl antibodies. The phenyl carboxyl
`group of fluorescein appears to be hydrogen bonded to the phenolic hydroxyl group of tyrosine 37 of the light chain. A
`molecule of 2-methyl-2,4-pentanediol (MPD), trapped in the interface of the variable domains just below the
`fluorescein binding site, may be partly responsible for the decrease in affinity for the hapten in MPD.
`
`Page 2 of 4
`
`Keywords:
`Antibodies, Monoclonal, Computer Graphics, Crystallization, Fluorescein, Fluoresceins, Glycols,
`Immunoglobulin Fab Fragments, Immunoglobulin G, Immunoglobulin Heavy Chains, Immunoglobulin Light
`Chains, Models, Molecular, Protein Conformation, X-Ray Diffraction
`
`Organizational Affiliation:
`Department of Biology, University of Utah, Salt Lake City 84112.
`
`Macromolecules
`
`Classification: IMMUNOGLOBULIN
`
`Total Structure Weight: 48303.08
`
`
`
`Macromolecule Entities
`
`Molecule
`
`Chains
`
`IGG2A-KAPPA 4-4-20 FAB
`(LIGHT CHAIN)
`
`IGG2A-KAPPA 4-4-20 FAB
`(HEAVY CHAIN)
`
`L
`
`H
`
`
`
`Small Molecules
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=4FAB
`
`Length
`
`219
`
`Organism
`
`Mus musculus
`
`Details
`
`Mutation: I2V, S7T, V29L, N33Q, E39R, F41Y, L51V, Y92F, F94S,
`A96S, S97T, G217N
`
`216
`
`Mus musculus
`
`Gene Name(s): Igh-1a
`
`
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 25
`
`

`

`RCSB PDB - 4FAB: THREE-DIMENSIONAL STRUCTURE OF A FLUORESCEIN-FAB COMPLEX CRYSTALLIZED IN 2-METHYL-2,...
`
`Page 3 of 4
`
`Ligands
`
`2 Unique
`
`ID
`
`FDS
`
`MPD
`
`Chains
`
`Name / Formula / InChI Key
`
`
`
`& Interactions2D Diagram
`
`3D Interactions
`
`H
`
`H
`
`FLUORESCIN
`C H O
`20
`14
`5
`MURGITYSBWUQTI-UHFFFAOYSA-N
`
`(4S)-2-METHYL-2,4-PENTANEDIOL
`C H O
`6
`14
`2
`SVTBMSDMJJWYQN-YFKPBYRVSA-N
`
`Ligand Explorer
`
`NGL
`
`Binding Pocket (JSmol)
`
`Ligand Explorer
`
`NGL
`
`Binding Pocket (JSmol)
`
`External Ligand Annotations
`
`Binding Affinity (Sequence Identity %)
`
`N/A in BindingDB
`N/A in BindingMoad
`Kd: 8.8 nM PDBbind
`
`ID
`
`FDS
`
`
`
`Experimental Data & Validation
`
`Experimental Data
`Method: X-RAY DIFFRACTION
`Resolution: 2.7 Å
`R-Value Observed: 0.215
`Space Group: P 1
`
`Unit Cell:
`
`Length (Å)
`
`a = 58.30
`
`b = 43.90
`
`c = 42.50
`
`Angle (°)
`
`α = 82.10
`
`β = 87.30
`
`γ = 84.60
`
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=4FAB
`
`Structure Validation
`View Full Validation Report or Ramachandran Plots
`
`
`
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 26
`
`

`

`RCSB PDB - 4FAB: THREE-DIMENSIONAL STRUCTURE OF A FLUORESCEIN-FAB COMPLEX CRYSTALLIZED IN 2-METHYL-2,...
`
`Page 4 of 4
`
`Entry History
`
`Deposition Data
`Deposited Date: 1989-04-10
`Released Date: 1990-07-15
`Deposition author(s): Herron, J.N., He, X., Mason, M.L., Vossjunior, E.W., Edmundson,
`A.B.
`
`
`
`
`Revision History
`• 2011-07-13
`Type: Version format compliance | Details: compliance with PDB Exchange Dictionary
`V4
`
`
`
`The RCSB PDB is funded by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=4FAB
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 27
`
`

`

`
`
`Exhibit G
`
`Exhibit G
`
`
`
`PFIZER EX. 1 184
`
`Page 28
`
`PFIZER EX. 1184
`Page 28
`
`

`

`RCSB PDB - 3HFM: STRUCTURE OF AN ANTIBODY-ANTIGEN COMPLEX. CRYSTAL STRUCTURE OF THE HY/HEL-10 FAB-LYS...
`
`Page 1 of 3
`
`An Information Portal to
`129745 Biological
`Macromolecular Structures
`
`Biological Assembly 1 
`
`3HFM
`
`STRUCTURE OF AN ANTIBODY-ANTIGEN COMPLEX. CRYSTAL STRUCTURE OF THE
`HY/HEL-10 FAB-LYSOZYME COMPLEX
`DOI: 10.2210/pdb3hfm/pdb
`
`Classification: COMPLEX(ANTIBODY-ANTIGEN)
`Deposited: 1988-08-11 Released: 1989-07-12
`Deposition author(s): Padlan, E.A., Davies, D.R.
`Organism: Mus musculus | Gallus gallus
`
`Structural Biology Knowledgebase: 3HFM (>23 annotations)
`
`wwPDB Validation
`
`(cid:423) 3D Report Full Report
`
`Experimental Data Snapshot
`
`Method: X-RAY DIFFRACTION
`Resolution: 3.0 Å
`R-Value Observed: 0.246
`
`Literature
`
`Macromolecule Content
`
`• Unique protein chains: 3
`
`Structure of an antibody-antigen complex: crystal structure of the HyHEL-10 Fab-lysozyme
`complex.
`Padlan, E.A., Silverton, E.W., Sheriff, S., Cohen, G.H., Smith-Gill, S.J., Davies, D.R.
`
`(1989) Proc.Natl.Acad.Sci.USA 86: 5938-5942
`
`PubMed: 2762305
`PubMedCentral: PMC297746
`
`PubMed Abstract:
`The crystal structure of the complex of the anti-lysozyme HyHEL-10 Fab and hen egg white lysozyme has been
`determined to a nominal resolution of 3.0 A. The antigenic determinant (epitope) on the lysozyme is discontinuous,
`consisting of residues from four different regions of the linear sequence. It consists of the exposed residues of an
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=3HFM
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 29
`
`

`

`Page 2 of 3
`RCSB PDB - 3HFM: STRUCTURE OF AN ANTIBODY-ANTIGEN COMPLEX. CRYSTAL STRUCTURE OF THE HY/HEL-10 FAB-LYS...
`alpha-helix together with surrounding amino acids. The epitope crosses the active-site cleft and includes a tryptophan
`located within this cleft. The combining site of the antibody is mostly flat with a protuberance made up of two
`tyrosines that penetrate the cleft. All six complementarity-determining regions of the Fab contribute at least one
`residue to the binding; one residue from the framework is also in contact with the lysozyme. The contacting residues
`on the antibody contain a disproportionate number of aromatic side chains. The antibody-antigen contact mainly
`involves hydrogen bonds and van der Waals interactions; there is one ion-pair interaction but it is weak.
`
`Keywords:
`Antibodies, Monoclonal, Antigen-Antibody Complex, Computer Simulation, Crystallization, Immunoglobulin
`Fab Fragments, Immunoglobulin G, Models, Molecular, Muramidase, Protein Conformation, X-Ray Diffraction
`
`Organizational Affiliation:
`Laboratory of Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD 20892.
`
`Macromolecules
`
`Classification: COMPLEX(ANTIBODY-ANTIGEN)
`
`Total Structure Weight: 61207.29
`
`
`
`Macromolecule Entities
`
`Molecule
`
`Chains
`
`Length
`
`Organism
`
`Details
`
`214
`
`215
`
`129
`
`Mus musculus
`
`Mus musculus
`
`Gallus gallus
`
`EC#: 3.2.1.17 IUBMB
`
`LYZ Gene View
`
`HYHEL-10 IGG1 FAB (LIGHT
`CHAIN)
`
`L
`
`HYHEL-10 IGG1 FAB
`(HEAVY CHAIN)
`
`HEN EGG WHITE
`LYSOZYME
`
`H
`
`Y
`
`
`
`Experimental Data & Validation
`
`Experimental Data
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=3HFM
`
`Structure Validation
`
`
`
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 30
`
`

`

`RCSB PDB - 3HFM: STRUCTURE OF AN ANTIBODY-ANTIGEN COMPLEX. CRYSTAL STRUCTURE OF THE HY/HEL-10 FAB-LYS...
`Method: X-RAY DIFFRACTION
`Unit Cell:
`View Full Validation Report or Ramachandran Plots
`Resolution: 3.0 Å
`R-Value Observed: 0.246
`Space Group: P 2 2 2
`1
`1
`1
`
`Length (Å)
`
`a = 57.47
`
`Angle (°)
`
`α = 90.00
`
`Page 3 of 3
`
`
`
`b = 118.73
`
`c = 137.68
`
`β = 90.00
`
`γ = 90.00
`
`
`
`Entry History
`
`Deposition Data
`Deposited Date: 1988-08-11
`Released Date: 1989-07-12
`Deposition author(s): Padlan, E.A., Davies, D.R.
`
`
`
`
`
`Revision History
`• 2011-07-13
`Type: Version format compliance | Details: compliance with PDB Exchange Dictionary
`V4
`
`
`
`The RCSB PDB is funded by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
`
`http://www.rcsb.org/pdb/explore/explore.do?structureId=3HFM
`
`5/4/2017
`
`PFIZER EX. 1184
`Page 31
`
`

`

`
`
`Exhibit H
`
`Exhibit H
`
`
`
`PFIZER EX. 1 184
`
`Page 32
`
`PFIZER EX. 1184
`Page 32
`
`

`

`RCSB PDB - 1REI: THE MOLECULAR STRUCTURE OF A DIMER COMPOSED OF THE VARIABLE PORTIONS OF THE BENCE-JO...
`
`Page 1 of 3
`
`An Information Portal to
`129745 Biological
`Macromolecular Structures
`
`Biological Assembly 1 
`
`1REI
`
`THE MOLECULAR STRUCTURE OF A DIMER COMPOSED OF THE VARIABLE PORTIONS
`OF THE BENCE-JONES PROTEIN REI REFINED AT 2.0 ANGSTROMS RESOLUTION
`DOI: 10.2210/pdb1rei/pdb
`
`Classification: IMMUNOGLOBULIN(PART)SEQUESTERS ANTIGENS
`Deposited: 1976-03-17 Released: 1976-05-19
`Deposition author(s): Epp, O., Lattman, E.E., Colman, P., Fehlhammer, H., Bode, W., Schiffer, M., Huber, R., Palm,
`W.
`Organism: Homo sapiens
`
`Structural Biology Knowledgebase: 1REI (>16 annotations)
`
`wwPDB Validation
`
`(cid:423) 3D Report Full Report
`
`Experimental Data Snapshot
`
`Method: X-RAY DIFFRACTION
`Resolution: 2.0 Å
`R-Value Work:
`
`Literature
`
`Macromolecule Content
`
`• Unique protein chains: 1
`
`The molecular structure of a dimer composed of the variable portions of the Bence-Jones
`protein REI refined at 2.0-A resolution.
`Epp, O., Lattman, E.E., Schiffer, M., Huber, R., Palm, W.
`
`(1975) Biochemistry 14: 4943-4952
`
`P