Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 1 of 100 PageID #: 30415
`Case 1:18—cv-00924-CFC Document 399-1 Filed 10/07/19 Page 1 of 100 PageID #: 30415
`
`EXHIBIT 1
`
`EXHIBIT 1
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 2 of 100 PageID #: 30416
`
`MICHAEL W. GLACKEN, Sc.D.
`
`+1.325.864.0698 (m)
`mglacken@bdo.com
`
`Senior Consultant
`
`Profile
`
`A biochemical engineer with over 27 years of experience in bioprocess manufacturing and
`strategic CMC development of biopharmaceutical products. Experienced in cell culture process
`development, rapid supply of proteins for discovery, and CMC regulatory strategy for
`recombinant proteins and monoclonal antibody products. Participated in the development of
`over 20 biological products, including the commercialization of two of these products.
`
`Experience
`
`BioProcess Technology Consultants, Inc./BDO
`Senior Consultant
`
`2014-Present
`
`Author & reviewer for CMC sections of several client BLAs
`Assisted several clients in developing process characterization and process
`validation strategies;
`Author & reviewer of PVMP, PC & PPQ protocols and PC & PPQ reports for
`several clients. Assisted in scale-down model design, PC DOE design and data
`review.
`Person-in-plant for several late stage and commercial manufacturing
`campaigns, including an ADC.
`
`Joule Unlimited Technologies, Bedford MA & Hobbs, NM
`Vice President, Development Operations, Hobbs, NM (2013-2014)
`Vice President, Bioprocessing (2011-2013)
`Sr. Director, Bioprocessing, (2010-2011)
`
`Site leader for Joule’s Demonstration facility for the outdoor R&D of
`photosynthetic processes to produce fuels. Led the experimental
`photobioreactor development program at Joule’s R&D facility in Bedford, MA
`
`Millennium Pharmaceuticals, Cambridge, MA
`Senior Director, Bioprocess Development (2009-2010)
`Director, Bioprocess Development (2006-2009)
`Associate Director, Bioprocess Development (2005-2006)
`Senior Scientist II, Bioprocess Development (2004-2005)
`Led the Bioprocess Development group responsible for the outsourcing,
`process development, process characterization and process validation of the
`Entyvio drug substance process. Team Leader for the CMC development,
`including regulatory strategy, of Vedolizumab (Entyvio). Millennium CMC
`lead for Adcetris partnership with Seattle Genetics. Responsible for the
`process development and supply of clinical trial material for numerous other
`biologics.
`
`2010-2014
`
`2004-2010
`
`BioProcess Technology Consultants, Inc.  12 Gill Street  Suite 5450  Woburn, MA  01801
`
`APPX 0001
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 3 of 100 PageID #: 30417
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Xcellerex LLC, Marlborough, MA
`Vice President, Process Development Technology and Services
`Developed high throughput tools to enable the rapid screening of the
`bioprocess design space for therapeutic proteins manufacturing.
`
`EMD Pharmaceuticals, Lexington, MA
`Manager, Cell Culture Process Development
`Led team responsible for developing a Phase III mammalian cell perfusion
`bioreactor process and successfully transferring this process to a CMO.
`
`Millennium Pharmaceuticals, Cambridge, MA
`Director, Process Development Technologies
`
`Developed high throughput tools to enable the rapid screening of the
`bioprocess design space for therapeutic proteins manufacturing.
`
`Michael W. Glacken Consulting
`Principal
`Clients served: Genentech, Immunex, Millennium, BIO, Formatech, Applied
`Process Technologies, Schering Plough, Allergan, Avigenics, Merck, Eli Lilly,
`Protein Design Labs, Dow AgroSciences, SemBioSys, Genetics Institute, BASF,
`Centocor, Genzyme, Bayer, Atlantic Biopharmaceuticals, M.I.T., Bristol Myers
`Squibb and Genzyme Transgenics
`
`Bristol Myers Squibb Pharmaceutical Research Institute, Seattle, WA
`Associate Director, Department of Bioprocess Research
`Led mammalian cell culture STR and microbial fermentor bioprocess
`development to supply protein therapeutic candidates for discovery research.
`Responsible for transferring processes to clinical manufacturing group. Led
`technology advancement for cellular protein expression in mammalian, E. coli
`and P. pastoris cell lines. Improved CTLA4Ig (Orencia) titers 20-fold for the
`clinical manufacturing group.
`
`SmithKline Beecham Pharmaceuticals, King of Prussia, PA
`Senior Investigator, Department of Bioprocess Sciences
`Developed STR process for the first large scale GMP animal cell culture
`production campaign at SB to support human clinical trials. Optimized and
`started-up large scale Prostak microfiltration unit to clarify supernatant from
`the 1000L STR. Led group responsible for GMP and research cell banking, cell
`line testing, medium development and cell line evaluation and development.
`
`Rice University, Houston, TX
`Assistant Professor of Chemical Engineering
`Supervised research thesis of five graduate students (3 M.S., 2 Ph.D.). Taught
`undergraduate Plant Design and senior lab courses, and graduate Biochemical
`Engineering course. Wrote or co-wrote three peer reviewed grants that
`received funding totaling $280,000.
`
`
`
`2003-2004
`
`2002-2003
`
`2001-2002
`
`1998-2001
`
`1993-1997
`
`1990-1993
`
`1987-1990
`
`
`
`Michael W. Glacken, Sc.D.
`
`Page 2
`
`APPX 0002
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 4 of 100 PageID #: 30418
`
`
`
`
`
`Education
`
`
`
`Massachusetts Institute of Technology, Cambridge, MA
`Sc.D., Biochemical Engineering
`
`University of Maryland, College Park, MD
`B.S., Chemical Engineering
`
`
`
`1987
`
`1976
`
`Recent
`Presentations
`
`Glacken MW and Connolly J. Managing Process Characterization and Validation on a Breakthrough
`Therapy Program. Presented at BPT-West; 2019 Mar 13; Santa Clara, CA.
`
`Glacken MW. Process characterization: It’s not a science project. Presented at BPT-West; 2017 Mar
`01; San Francisco, CA.
`
`Glacken MW. Are there drivers left for further process optimization in cell line development?
`Presented at IBC’s Sixth Annual Cell Line Development and Engineering Conference, Keynote
`address; 2010 Jun 21-23; San Francisco, CA.
`
`Glacken MW. Managing a biologics supply chain using a fully outsourced manufacturing model.
`Presented at IBC’s BioProcess International Conference; 2008 Sep 23-26; Anaheim, CA.
`
`Glacken MW. Identification of important process engineering problems requiring joint efforts of
`biologists & engineers. Presented at IBC’s BioProcess International Conference; 2005 Sep 19-22;
`Boston, MA.
`
`Glacken MW. High throughput biopharmaceutical process development. Presented at BIO
`International Convention; 2004 Jun 6-9; San Francisco, CA.
`
`Glacken MW. Plant transgenics vs. animal transgenics vs. CHO bioreactor culture: An objective
`comparison for monoclonal antibody production. Presented at IBC’s Eighth International
`Conference: Antibody Production and Downstream Processing; 2002 Feb 13-15; San Diego, CA.
`
`Full publication list is available upon request
`
`
`
`
`
`
`
`
`
`
`
`Recent
`Publications
`
`Glacken MW. Efficacious transfer of bioprocesses to CMOs: The role of process history in
`establishing clear transfer criteria. BioPharm Int. 2010 Mar;23(3): 54-9.
`
`
`
`
`
`Full publication list is available upon request
`
`
`
`
`
`
`
`
`
`Michael W. Glacken, Sc.D.
`
`Page 3
`
`APPX 0003
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 5 of 100 PageID #: 30419
`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 5 of 100 PageID #: 30419
`
`EXHIBIT 2
`
`EXHIBIT 2
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 6 of 100 PageID #: 30420
`
`I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US008574869B2
`
`c12) United States Patent
`Kao et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,574,869 B2
`Nov. 5, 2013
`
`(75)
`
`(54) PREVENTION OF DISULFIDE BOND
`REDUCTION DURING RECOMBINANT
`PRODUCTION OF POLYPEPTIDES
`Inventors: Yung-Hsiang Kao, San Mateo, CA
`(US); Michael W. Laird, San Ramon,
`CA (US); Melody Trexler Schmidt, San
`Carlos, CA (US); Rita L. Wong,
`Redwood City, CA (US); Daniel P.
`Hewitt, Sunnyvale, CA (US)
`(73) Assignee: Genentech, Inc., South San Francisco,
`CA (US)
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`(21) Appl. No.: 13/354,223
`Jan.19,2012
`(22) Filed:
`Prior Publication Data
`(65)
`
`( *) Notice:
`
`US 2013/0017598Al
`
`Jan. 17, 2013
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 12/217,745, filed on
`Jul. 8, 2008, now abandoned.
`
`(51)
`
`(60) Provisional application No. 60/948,677, filed on Jul. 9,
`2007.
`Int. Cl.
`C12P 1/00
`C12N5/02
`(52) U.S. Cl.
`USPC ............................................. 435/41; 435/325
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`(2006.01)
`(2006.01)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2004/0029229 Al *
`2004/0138424 Al
`2006/0143549 Al
`2007 /0292411 Al
`2009/0053786 Al
`
`2/2004 Reeves et al. ................ 435/69.1
`7/2004 Takeda et al.
`6/2006 Yasumoto et al.
`12/2007 Salcedo et al.
`2/2009 Kao et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`
`97/26357
`
`7 /1997
`
`OTHER PUBLICATIONS
`
`Kock et al. (Biochem Soc Trans. Apr. 2004;32(Pt 2):273-5).*
`Christiansen et al. (Biochemistry 1998, 37, 12611-12623).*
`Bobovnikova et al., "Characterization of Soluble, Disulfide Bond(cid:173)
`Stabilized Prokaryotically Expressed Human Thryotropin Receptor
`Ectodomain" Endocrinology 138(2):588-593 (1997).
`Chaderjian et al., "Effect of Copper Sulfate on Performance of a
`Serum-Free CHO Cell Culture Process and the Level of Free Thiol in
`the Recombinant Antibody Expressed" Biotechnology Progress
`21(2):550-553 (2005).
`Gromer et al., "The Thioredoxin System: From Science to Clinic"
`Medicubak Research Reviews 24(1):40-89 (Jan. 2004).
`Kao et al., "Mechanism of Antibody Reduction in Cell Culture Pro(cid:173)
`duction Processes" Biotechnology and Bioengineering 107(4):622-
`632 (Nov. 2010).
`
`Kerblat et al., "Importance of Thioredoxin in the Proteolysis of an
`Immunoglobulin Gas Antigen by Lysosomal Cys-Proteases" Immu(cid:173)
`nology 97(1):62-68 (1999).
`Li et al., "Low Level Formation of Potent Catalytic IgG Fragments
`Mediated by Disulfide Bond Instability" Molecular Immunology
`33(7-8):593-600 (1996).
`Liu et al., "Study of Tioredoxin" Journal of Northeast Agricultural
`University 34(23):219-225 (Jun. 30, 2003).
`Mun et al., "BIOT 245-Air Sparging of Harvested Cell Culture Fluid
`(HCCF) to Prevent Antibody Disulfide Bond Reduction" Abstracts of
`Papers American Chemical Society 238:245 (Aug. 2009).
`Nordberg et al., "Reactive Oxygen Species, Antioxidants, and the
`Manunalian Thioredoxin System" Free Radical Biology & Medicine
`31(11):1287-1312 (2001).
`Powis et al., "Properties and Biological Activities of Thioredoxins"
`Annual Review of Pharmacology and Toxicology 41:261-295
`(2001).
`Powis et al., "Thioredoxin Redox Control of Cell Growth and Death
`and the Effects of Inhibitors" Chemico-Biologica llnteractions 111-
`112:23-34 (1998).
`Salas-Solano et al., "Optimization and Validation of a Quantitative
`Capillary Electrophoresis Sodium Dodecyl Sulfate Method for Qual(cid:173)
`ity Control and Stability Monitoring of Monoclonal Antibodies"
`Analytical Chemistry 78(18):6583-6594 (2006).
`Smith et al., "Specific Cleavage of Immunoglobulin G by Copper
`Ions" International Journal of Peptide and Protein Research
`48( 1 ):49-55 ( 1996).
`Starks et al., "Atomic-Resolution Crystal Structure of Thioredoxin
`From the Acidophilic Bacterium Acetobacter Aceti" Protein Science
`16(1):92-98 (Jan. 2007).
`Teilum et al., "Disulfide Bond Formation and Folding of Plant
`Peroxidases Expressed as Inclusion Body Protein in Escherichia coli
`Thioredoxin Reductase Negative Strains" Protein Expression and
`Purification Academic Press 15(1):77-82 (1999).
`Trexler-Schmidt et al., "Identification and Prevention of Antibody
`Disulfide Bond Reduction During Cell Culture Manufacturing"
`Biotechnology and Bioengineering 160(3):452-461 (2006).
`Urig et al., "On the Potential ofThioredoxin Reductase Inhibitors for
`Cancer Therapy" Seminars in Cancer Biology 16(6):452-465 (
`2006).
`Wipf et al., "New Inhibitors of the Thioredoxin-Thioredoxin
`Reducatase System Based on a Naphthoquinone Spiroketal Natural
`Product Lead" Bioorganic & Medicinal Chemistry Letters( 11 ):2637-
`2641 (2001).
`Zhang et al., "Free sulfhydryl in recombinant monoclonal antibod(cid:173)
`ies" Biotechnol. Prog. 18:509-513 (2002).
`Lillig, C.H. eta!. (Jan. 2007). "Thioredoxin andRelatedMolecules(cid:173)
`From Biology to Health and Disease," Antioxidants & Redox Signal(cid:173)
`ing 9(1):25-47.
`Lydersen, B.K. et al. (Nov. 1994). "Acid Precipitation ofManunalian
`Cell Fermentation Broth," Ann. NY Acad. Sci. 745:222-231.
`Roman, B. et al. (Sep. 2005). "Development ofa Robust Clarification
`Process for MAb Purification," Case Study presented at the
`BioProcess International 2005 Conference&Exhibition, Sep. 19-22,
`2005, Boston, MA, four pages particularly p. 4.
`Roush, D.J. et al. (2008). "Advances in Primary Recovery: Centrifu(cid:173)
`gation and Membrane Technology," Biotechnol. Prag. 24(3):488-
`495.
`* cited by examiner
`Primary Examiner - Suzanne M Noakes
`Jae W Lee
`Assistant Examiner -
`(74) Attorney, Agent, or Firm - Morrison & Foerster LLP
`ABSTRACT
`(57)
`Provided herein are methods for preventing the reduction of
`disulfide bonds during the recombinant production of disul(cid:173)
`fide-containing polypeptides. In particular, the invention con(cid:173)
`cerns the prevention of disulfide bond reduction during har(cid:173)
`vesting of disulfide-containing polypeptides,
`including
`antibodies, from recombinant host cell cultures.
`10 Claims, 40 Drawing Sheets
`
`APPX 0004
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 7 of 100 PageID #: 30421
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 1 of 40
`
`US 8,574,869 B2
`
`Ladder
`
`OHours
`
`1 Hours
`
`3Hours
`
`21 Hours 25Hours 29Hours
`
`[kDa]
`
`95-
`
`63-
`
`46-
`
`28-
`
`15-
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Dialysis Experiment
`FIG. 1
`
`APPX 0005
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 8 of 100 PageID #: 30422
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 2 of 40
`
`US 8,574,869 B2
`
`Ladder
`
`OHours
`
`1 Hours
`
`3Hours
`
`21 Hours 25Hours 29Hours 48Hours
`
`[kDa]
`
`150-
`
`95-
`
`63-
`
`46-
`
`28- ,,,,,,,,,,,,,,
`
`15-,
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Dialysis Experiment
`FIG. 2
`
`APPX 0006
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 9 of 100 PageID #: 30423
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 3 of 40
`
`US 8,574,869 B2
`
`900.0
`
`800.0
`
`700.0
`
`600.0
`
`500.0
`
`400.0
`
`300.0
`
`200.0
`
`100.0
`
`0.0
`
`0
`
`c
`0
`.........
`cu ,_
`c
`Q)
`0
`c
`0
`0
`
`0
`
`(1)
`(l)
`
`.....
`LL
`
`+ Outside Dialysis Bag
`-0- Inside Dialysis Bag
`
`10
`
`20
`
`30
`
`40
`
`50
`
`Time (hours)
`
`Free Thiol Levels from Dialysis Experiment
`FIG. 3
`
`APPX 0007
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 10 of 100 PageID #: 30424
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 4 of 40
`
`US 8,574,869 B2
`
`Thioredoxin System
`/S
`I
`TrxR
`"-S
`
`Trx
`
`/SH
`
`'-SH
`
`NADPH+H+
`
`First Reaction in Pentose Phosphate Pathway
`
`NADPH
`
`6-Phosphogluconolactone
`
`GI ucose-6-phosphate
`
`(Mg-ADPt +H+
`
`Glucose
`
`(Mg-ADP) 2+
`
`First Reaction in Glycolysis
`
`Thioredoxin System and Other Reactions Involved in Antibody Reduction
`FIG. 4
`
`APPX 0008
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 11 of 100 PageID #: 30425
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 5 of 40
`
`US 8,574,869 B2
`
`Ladder OHours 0.5Hours 1 Hours
`
`2Hours
`
`3Hours
`
`21 Hours 23Hours
`
`[kDa]
`
`95-
`
`63-
`
`46
`
`15-
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`In Vitro Activity of Thioredoxin System
`FIG. 5
`
`APPX 0009
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 12 of 100 PageID #: 30426
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 6 of 40
`
`US 8,574,869 B2
`
`Ladder OHours O 5Hours 1 Hours
`
`2Hours
`
`3Hours
`
`21 Hours 23Hours
`
`[kDa]
`
`95- ..
`
`63-
`
`46
`
`28-
`
`15-
`
`7 -1.JliJUll! llllflJllll ! lllC M. JI 11,lllJ,JLIII ,•,Y,4~4'''~'.~4',i""' ~ .• lit JUJI Ill I I. ] !!JO •. !ll'~U-
`4. 5 -
`
`llllltMlltill:11111(lll1 n•• m=fr11w iu
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`In vitro Activity of Thioredoxin System Inhibited by Aurothioglucose
`FIG. 6
`
`APPX 0010
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 13 of 100 PageID #: 30427
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 7 of 40
`
`US 8,574,869 B2
`
`Ladder
`
`OHours 0.5Hours 1 Hours
`
`2Hours
`
`3Hours
`
`21 Hours 23Hours
`
`[kDa]
`
`150-
`
`95-
`
`63-
`
`46-
`
`28-
`
`15-
`
`7- MIIIU Ill •u11t11JJI UUJIJll(I IJJl!l~X!l!JII lllll:IIW a11a,·11
`4.5- lllilflNJ•l·ttlMlat®'l'!lid1r.m-•~i-1rn111111unr!IW
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`In vitro Activity of Thioredoxin System Inhibited by Aurothiomalate
`FIG. 7
`
`APPX 0011
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 14 of 100 PageID #: 30428
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 8 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`150-
`
`95-
`
`46-
`
`28-
`
`15-
`
`7-
`4.5-
`
`Ladder OHours 0.5Hours 1 Hours
`
`2Hours
`
`3Hours
`
`21 Hours 23Hours
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`In vitro Activity of Thioredoxin System
`FIG. 8
`
`APPX 0012
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 15 of 100 PageID #: 30429
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 9 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`Ladder OHours 0.5Hours 1 Hours
`
`2Hours
`
`3Hours
`
`21 Hours 23Hours
`
`240- - - - - - - - - - - - - - - - · - · ___
`
`ll,_Q_l,i. ........ ':It«
`
`j~ ... - - - - . . -
`
`95-
`
`63-
`
`46- · ·
`
`28- ,
`
`15-
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`In vitro Activity of Thioredoxin System Inhibited by CuSO 4
`FIG. 9
`
`APPX 0013
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 16 of 100 PageID #: 30430
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 10 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`Ladder OHours 0.5Hours 1 Hours
`
`2Hours
`
`19Hours 21 Hours 23Hours
`
`150---"'""
`
`7-·
`
`4.5- .. ·
`
`-
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Ocrelizumab Reduction
`FIG. 10
`
`APPX 0014
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 17 of 100 PageID #: 30431
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 11 of 40
`
`US 8,574,869 B2
`
`Ladder OHours 0.5Hours 1 Hours
`
`2Hours
`
`19Hours 21 Hours 23Hours
`
`[kDa]
`
`150
`
`95----
`
`46
`
`28
`
`15--,.,.--
`
`7-
`4.5-
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Inhibition of Ocrelizumab Reduction In HCCF by Aurothioglucose
`FIG. 11
`
`APPX 0015
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 18 of 100 PageID #: 30432
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 12 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`95-
`
`63-
`
`46-
`
`28-
`
`15-
`
`7-
`4.5-
`
`Ladder
`
`OHours 0.5Hours 1 Hours
`
`2Hours
`
`19Hours 21 Hours 23Hours
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Inhibition of Ocrelizumab Reduction In HCCF by Aurothiomalate
`FIG. 12
`
`APPX 0016
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 19 of 100 PageID #: 30433
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 13 of 40
`
`US 8,574,869 B2
`
`Ladder
`
`OHours
`
`1Hours
`
`2Hours
`
`4Hours
`
`19Hours 21 Hours
`
`[kDa]
`
`150-
`
`95-
`
`63-
`
`46-
`
`28-
`
`15-
`
`1-Bll111· .. r
`
`4.5- -.....-,,,...·--
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Losing Reduction Activity in HCCF
`FIG. 13
`
`APPX 0017
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 20 of 100 PageID #: 30434
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 14 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`150-
`
`95
`
`63-
`
`46-
`
`28-
`
`15-
`
`Ladder
`
`1 Hours
`
`2Hours
`
`3Hours
`
`4Hours
`
`19Hours 21 Hours 23Hours
`
`pu1,,~lll!J lULll'' lltUJtU
`•n r1 u ••11111 ,11run Bl
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`The Lost Reduction Activity in HCCF Restored by Addition of NADPH
`
`FIG. 14
`
`APPX 0018
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 21 of 100 PageID #: 30435
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 15 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`Ladder OHours
`
`1 Hours
`
`2Hours
`
`3Hours
`
`4Hours
`
`19Hours 21 Hours 23Hours
`
`95-
`
`63-
`
`46-
`
`28 - ''" ····•e.•.·····"·
`
`15-7--
`
`L
`
`~~•r,-.mt·~•·~l!ll.,.11\11~~~.-i11e~tflffl ·11Jlrlf!tf1a1·· 1·1M1111r1r1r1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`The Lost Reduction Activity in HCCF Restored by Addition of Glucose-6-Phosphate
`FIG. 15
`
`APPX 0019
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 22 of 100 PageID #: 30436
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 16 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`19Hours 21 Hours
`3Hours
`2Hours
`1 Hours
`Ladder OHours
`240- ________ ......._. _____________ _
`
`150-
`
`63-
`
`46-
`
`28-
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Ocrelizumab Reduction
`FIG. 16
`
`APPX 0020
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 23 of 100 PageID #: 30437
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 17 of 40
`
`US 8,574,869 B2
`
`[kDa]
`
`150-
`
`95-
`
`63-
`
`46-
`
`15-
`
`Ladder
`
`OHours
`
`1 Hours
`
`2Hours
`
`3Hours
`
`19Hours 21 Hours
`
`···~·-·-(cid:173)
`
`••ll',R'liflllllt'. Ii ·r1N11-.•
`2
`4
`3
`
`5
`
`6
`
`L
`
`EDTA Inhibits Ocrelizumab Reduction
`FIG. 17
`
`APPX 0021
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 24 of 100 PageID #: 30438
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 18 of 40
`
`US 8,574,869 B2
`
`Ladder OHours
`
`1 Hours
`
`2Hours
`
`3Hours
`
`19Hours 21 Hours
`
`[kDa]
`
`1
`
`-
`
`95-
`
`63-
`
`46-
`
`28-
`
`15-
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`The Lost Reduction Activity in Run 8 HCCF Restored by Addition
`of Glucose-6-Phosphate but No Inhibition of Reduction by EDTA
`
`FIG. 18
`
`APPX 0022
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 25 of 100 PageID #: 30439
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 19 of 40
`
`US 8,574,869 B2
`
`..::.::::
`ro
`(l)
`CL
`(1j
`0
`..::.::::
`0
`LO
`~
`
`mo
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`0
`
`-0-20 mM EDTA
`, -A-30 mM CuS04
`I
`'-o-pH 5.5 (acetic acid)
`-+- No additions
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`HCCF Hold Time (hr)
`
`FIG. 19
`
`APPX 0023
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 26 of 100 PageID #: 30440
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 20 of 40
`
`US 8,574,869 B2
`
`100
`90
`
`80
`~ 70
`cu
`<D
`60
`0...
`m
`50
`0
`~
`0
`LO
`T'"""
`
`40
`30
`
`~ 0
`
`20
`10
`
`0
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`HCCF Hold Time (hr)
`
`FIG. 20
`
`APPX 0024
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 27 of 100 PageID #: 30441
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 21 of 40
`
`US 8,574,869 B2
`
`Light Chain
`
`45
`30
`15
`1
`DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPK
`
`90
`75
`60
`46
`LLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ
`
`105
`91
`HYTTPPTFGQGTKVEIK
`
`FIG. 21
`
`Heavy Chain
`
`45
`30
`15
`1
`EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGL
`
`90
`75
`60
`46
`EWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAED
`
`120
`105
`91
`TAVYYCSRWGGDGFYAMDYWGQGTLVTVSS
`
`FIG. 22
`
`APPX 0025
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 28 of 100 PageID #: 30442
`
`Typical Batch or Fed-Batch Culture Process
`
`Seed Train
`Multiple Passages in
`Selective Medium
`
`lnoculum Train
`Multiple Passages in
`Non-Selective Medium
`
`Production
`Non-Selective
`Production Medium
`
`~
`
`dal
`D l
`T-T-i}-f!J-!~~,~,~,-
`
`G
`
`Temperature
`Seeding density
`Culture duration
`
`d02, pH, Temperature
`Seeding densi
`Culture duration
`
`FIG. 23
`
`~
`
`____.,....
`
`Harvest
`__.,..
`
`d02, pH, Temperature
`Parameter shifts & timing
`Osmolality
`Batch feed addition
`Seeding density
`Culture duration
`
`rJJ =(cid:173)
`('D a
`
`N
`N
`0 ......
`.i;...
`0
`
`d r.,;_
`00
`tit
`-....l
`~
`00
`O',
`
`\C = N
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`z 0
`
`~
`
`~
`Ul
`N
`0 ......
`
`APPX 0026
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 29 of 100 PageID #: 30443
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 23 of 40
`
`US 8,574,869 B2
`
`0
`~
`I
`
`C)
`LO
`.,.....
`I
`
`LO
`CJ)
`I
`
`:.·.:
`
`. .
`
`i
`
`(v")
`CO
`I
`
`(0
`-st"
`I
`
`a:)
`N
`I
`
`I I
`I I
`I I
`
`LO
`.,.....
`I
`
`LO
`-tj-
`I
`
`I'-
`I
`
`(0
`
`·~
`
`_)
`
`I
`LO
`(J)
`
`I
`
`(v")
`(0
`
`I
`<.D
`-st"
`
`I
`00
`N
`
`I
`LO
`.,.....
`
`I
`I'-
`
`I
`LO
`-st"
`
`N
`l!..
`
`C)
`(v")
`
`C)
`(v")
`0
`l!..
`
`C)
`
`l!..
`
`0
`l!..
`
`a3 u
`u
`ro
`_)
`
`I
`C)
`-tj(cid:173)
`N
`
`I ,1·,
`;,. I
`I
`•· .. " '···· I
`.I'. .. ' !
`
`
`
`
`
`' . I · .• ··•· .
`
`, , .
`
`I
`C)
`LO
`..--
`
`APPX 0027
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 30 of 100 PageID #: 30444
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 24 of 40
`
`US 8,574,869 B2
`
`-sj-
`N
`ll,
`
`LO
`ll,
`
`C0
`ll,
`
`N
`ll,
`
`0
`C0
`
`l.{")
`:=t:
`0
`ll,
`
`C)
`C0
`0
`ll,
`
`LD
`
`0
`ll,
`
`o3
`-0
`u
`rn
`_J
`
`0
`-tj-
`N
`I
`
`I
`0
`-tj-
`N
`
`0
`l.{")
`
`I
`
`'
`
`,.;
`
`1 1
`
`I
`I
`( i
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`c
`
`c
`
`I
`0
`LO
`..,....
`
`l.{")
`m
`I
`
`C0
`<.O
`I
`
`<.O
`""""
`I
`
`ro
`N
`I
`
`l.{")
`.....-
`I
`
`l.{")
`I"- -tj-
`I
`I
`
`I
`l.{")
`m
`
`I
`C0
`<.O
`
`I
`CD
`-tj-
`
`I
`co
`N
`
`I
`LO
`
`I
`I"-
`
`I
`
`l.{")
`'ST
`
`0
`
`o,
`
`ro
`
`l.{")
`
`_J
`
`lf')
`N
`
`v
`
`~
`~
`
`APPX 0028
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 31 of 100 PageID #: 30445
`
`240-
`
`150-
`
`95-
`
`63-
`
`46-
`
`28
`
`15-
`
`7-
`
`Ladder
`
`t=O
`
`5
`
`t=0:30
`
`t=0:45
`
`t=1
`
`t=1:30
`
`!=2
`
`!=5
`
`!=24
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`-240
`
`..... 11r11 ··· r · 1. · ]mr ·dlrrr t11m111mn•• m1m1mu•.111n1]urrn 1111•111111111:1111111 Ill lJll!l rn l
`
`.. . _ 150
`
`-95
`
`-63
`
`-46
`
`-28
`
`15
`
`-7
`-4.5
`
`L
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`FIG. 26
`
`z 0
`
`~
`~Ul
`N
`0 ......
`
`~
`
`rJ'1 =(cid:173)
`('D ....
`
`('D
`
`N
`Ul
`0 ......
`.i;...
`0
`
`d
`rJl.
`00
`tit
`-....l
`~
`00
`O',
`
`\C = N
`
`APPX 0029
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 32 of 100 PageID #: 30446
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 26 of 40
`
`US 8,574,869 B2
`
`C)
`~.;
`N
`I
`
`""'"
`N
`lL
`
`lD
`lL
`
`C0
`lL
`
`N
`lL
`
`C)
`(Y)
`
`~
`
`lL
`
`lL
`
`LO
`'ST
`C)
`
`lL
`
`C)
`(0
`
`ci
`lL
`
`~
`
`LO
`ci
`lL
`
`C)
`
`lL
`
`CT)
`u
`-a
`m
`_J
`
`C)
`LO
`I
`
`~
`
`~-
`;
`\,
`/
`
`'
`'
`"'
`!
`
`I
`I
`I
`I
`I
`I
`I
`I
`f
`I
`
`•
`
`'
`
`'
`
`,t
`'
`
`'
`
`'
`
`cf\'
`:I{
`
`LO
`a,
`I
`
`("')
`<.O
`I
`
`<.O
`""'"
`I
`
`co
`N
`I
`
`LO
`~ !'--
`I
`I
`
`LO
`"tj'
`
`I
`
`C)
`,--
`
`co
`
`r--
`
`(0
`
`t--
`N
`
`~
`
`LO v
`w...
`
`""'"
`
`N
`
`__I
`
`I
`
`I
`I
`~ !'--
`
`I
`LO
`-tj-
`
`I
`0
`-tj-
`('J
`
`I
`0
`lD
`
`~
`
`I
`LO
`CT)
`
`I
`(Y)
`(0
`
`I
`<O
`-tj-
`
`I
`co
`N
`
`APPX 0030
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 33 of 100 PageID #: 30447
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 27 of 40
`
`US 8,574,869 B2
`
`0
`""<!"
`N
`I
`
`0
`LO
`I
`
`~
`
`LO
`0)
`I
`
`I
`
`co
`N
`
`I I
`
`N
`J!,
`
`Lf)
`""<!"
`0
`J!,
`
`C)
`J!,
`
`C)
`
`11
`
`I
`C)
`""<!"
`N
`
`I
`0
`l("J
`~
`
`I
`LO
`0)
`
`I
`(")
`(0
`
`I
`<.D
`-tj-
`
`I
`co
`N
`
`I
`LO
`
`~
`
`I
`I"-
`
`I
`LO
`-tj-
`
`APPX 0031
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 34 of 100 PageID #: 30448
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 28 of 40
`
`US 8,57 4,869 B2
`
`LO m
`I
`
`co
`N
`I
`
`LO
`
`~
`
`I
`
`0
`LO
`
`~
`
`I I
`I
`I
`I
`I
`I
`I
`
`(';
`lL
`
`N
`lL
`
`LO
`'":'f.
`C)
`lL
`
`0
`ll..
`
`C)
`
`lL
`
`I
`0
`~
`N
`
`I
`C)
`LO
`
`I
`LO
`O"l
`
`I
`0')
`CO
`
`I
`(CJ
`"1"
`
`I
`CO
`N
`
`I
`LO
`~
`
`APPX 0032
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 35 of 100 PageID #: 30449
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 29 of 40
`
`US 8,574,869 B2
`
`LO
`0)
`I
`
`co
`N
`I
`
`~
`
`LO
`I
`
`I'-
`I
`
`LO
`""'1'"
`I
`
`(D
`
`I
`
`I
`I
`I
`I'
`r I
`I
`I
`I
`I
`I
`
`I
`0
`'Sj(cid:173)
`N
`
`I
`0
`LO
`
`I
`LO
`0)
`
`I
`C0
`<.O
`
`I
`(D
`'St
`
`I
`co
`N
`
`APPX 0033
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 36 of 100 PageID #: 30450
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 30 of 40
`
`US 8,574,869 B2
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`LO
`0)
`I
`
`co
`(0
`(")
`(0 ~ N
`I
`I
`I
`
`l()
`~ r---
`I
`I
`
`LO
`~
`I
`
`0
`
`co
`
`r
`i
`I
`
`;:\'
`l
`
`'
`l
`~ !:
`
`l()
`
`.....J
`
`I
`I
`
`'Wt f:+ I i
`
`'
`
`I
`LO
`0)
`
`I
`
`(")
`(0
`
`I
`(0
`~
`
`I
`co
`N
`
`I
`LO
`
`~
`
`I
`I
`r--- ~
`'SJ"
`
`,.........
`('("')
`
`. u
`
`~
`~
`
`0
`l()
`
`I
`
`'
`
`'
`
`'
`
`I
`I
`0
`LO
`
`~
`N
`!_I.,
`
`LO
`l!.
`
`(")
`
`lL
`
`N
`lL
`
`0
`(Y)
`
`~
`
`,.n
`ci
`lL
`
`0
`lL
`
`©
`-0
`-0
`co
`
`_J
`
`ro
`0
`.::£
`
`I
`0
`'SJ"
`N
`
`APPX 0034
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 37 of 100 PageID #: 30451
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 31 of 40
`
`US 8,574,869 B2
`
`0
`~
`N
`I
`
`~
`N
`lL
`
`LO
`lL
`
`(Y)
`
`lL
`
`N 11,
`
`.,--
`lL
`
`0
`(Y)
`C)
`
`lL
`
`~
`
`ITT
`ci
`)_I,
`
`0 lL
`
`0
`LO
`I
`
`~
`
`,'
`
`': I
`I '
`' I
`I
`I
`I ,
`I
`I
`I
`
`LO m
`I
`
`(Y)
`(0
`I
`
`(D
`"Ct
`I
`
`co
`N
`I
`
`LO
`.,-
`I
`
`I'-
`I
`
`'
`
`" ~
`
`LO
`"Ct
`
`I I 0
`I 0)
`I co
`I I'-
`I <D
`
`LO
`
`_J
`
`N
`("1")
`
`d
`~
`~
`
`'
`
`I
`0
`~
`
`I
`0
`LO
`
`~
`
`I
`LO
`0)
`
`I
`(Y)
`<D
`
`I
`<D
`~
`
`I
`co
`N
`
`I
`LO
`
`~
`
`APPX 0035
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 38 of 100 PageID #: 30452
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 32 of 40
`
`US 8,574,869 B2
`
`'Sj"
`N
`11.,
`
`LO
`11.,
`
`(<)
`11.,
`
`N
`11.,
`
`.,--
`11.,
`
`LO
`.,--
`
`C)
`11.,
`
`C)
`11.,
`
`C)
`LO
`.,--
`I
`
`.
`'
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`.
`
`..
`
`LO
`0)
`I
`
`C0
`c.o
`I
`
`(0
`sq-
`I
`
`co
`N
`I
`
`LO
`.,--
`I
`
`LO
`sq-
`I
`
`I"-
`I
`
`rri
`rri .
`0
`[:.I...
`
`-
`
`li:
`?
`l "<:!"
`t
`
`("")
`
`N
`
`II f'
`
`0
`:0
`;.·
`
`'
`
`.,--
`
`I
`0
`'St
`N
`
`I
`0
`LO
`.,-
`
`I
`Lf)
`0)
`
`I
`
`(")
`(D
`
`I
`(D
`"<:!"
`
`I
`CX)
`N
`
`I
`LO
`.,--
`
`I
`!"--
`
`I
`
`LI)
`~
`
`_J
`
`APPX 0036
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 39 of 100 PageID #: 30453
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 33 of 40
`
`US 8,574,869 B2
`
`C.::)
`"'1'
`("J
`
`I
`C)
`'SI"
`N
`
`N
`l_l_,
`
`C)
`('0
`
`C) J!,
`
`C)
`
`l~
`
`C)
`LD
`
`I I
`I
`I
`I
`I
`I
`I
`I
`I
`I I li! I '£
`
`I
`C)
`LO
`
`LO
`0)
`I
`
`<:0
`(D
`I
`
`CD
`'SI"
`I
`
`00
`N
`I
`
`~
`
`LD
`I
`
`LD
`I'- 'tj(cid:173)
`I
`I
`
`I
`LO
`0)
`
`I
`<:')
`(D
`
`I
`(0
`"SI"
`
`I
`co
`N
`
`I
`LO
`
`I
`I
`r-- ~
`'S:]'"
`
`APPX 0037
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 40 of 100 PageID #: 30454
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 34 of 40
`
`US 8,574,869 B2
`
`0
`"""'"
`N
`I
`
`""Cf'
`N
`l!.,
`
`LO
`l!.,
`
`<:")
`l!.,
`
`N
`l!.,
`
`Cl
`(Y)
`.,,.--
`l!.,
`
`~
`
`l!.,
`
`lD
`"'1:
`0
`l!.,
`
`Cl
`<:")
`
`C)
`l!.,
`
`l{)
`
`a3
`u
`"D ro
`
`_J
`
`Cl
`LO
`I
`
`; '
`
`I
`I
`I
`I
`I
`I
`I
`' I
`:
`I
`I
`
`'
`
`'
`
`LO
`0)
`I
`
`(Y)
`
`c.o
`I
`
`(D
`-tj-
`I
`
`co
`N
`I
`
`~
`
`LO
`I
`
`,......
`I
`
`L.C::
`-tj-
`I
`
`D
`
`~
`
`0)
`
`lD
`
`N
`
`_J
`
`t.n
`("f')
`
`u
`
`i,.,..,i
`~
`
`I
`
`I
`,......
`
`I
`C)
`'tj'
`N
`
`I
`0
`lD
`
`~
`
`I
`LO
`Cl)
`
`I
`c.o
`
`<:')
`
`I
`(D
`-s:r
`
`I
`co
`N
`
`I
`LO
`.,,.--
`
`APPX 0038
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 41 of 100 PageID #: 30455
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 35 of 40
`
`US 8,574,869 B2
`
`lD
`m
`I
`
`C0
`(D
`I
`
`(D
`'tj-
`I
`
`00
`N
`I
`
`lO
`~ !'--
`I
`I
`
`~
`'tj-
`I
`
`0
`
`0)
`
`\0
`LO ~
`
`. v
`
`~
`~
`
`i'
`
`r
`
`/
`'.f
`
`N
`
`I! I I:
`I
`I
`'. I
`I
`I
`I
`I
`I ~
`
`ii
`}'.
`ti;
`
`,
`
`,
`
`;
`
`0
`lO
`I
`
`• •
`
`0
`'tj-
`N
`I
`
`lO
`1l
`
`C0
`1l
`
`~
`
`1l
`
`~
`
`1l
`
`LO
`
`I
`0
`'tj-
`N
`
`I
`0
`lO
`
`I
`LO
`0)
`
`I
`<:')
`CD
`
`I
`<-0
`'tj-
`
`I
`co
`N
`
`I
`L.()
`
`I _J
`
`I
`!'--
`
`I
`lO
`'tj-
`
`APPX 0039
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 42 of 100 PageID #: 30456
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 36 of 40
`
`US 8,574,869 B2
`
`0
`"St
`N
`I
`
`0
`LO
`-<--
`I
`
`lO
`0)
`I
`
`'
`
`'
`
`'
`'
`
`:
`
`',
`'t
`
`:,
`
`j
`
`~
`
`;
`
`(
`
`]
`
`',
`
`'
`
`'s:t
`N
`J!.,
`
`LO
`l',
`
`(0
`l',
`
`(",J
`l',
`
`C)
`";:;
`'<'"
`l',
`
`LO
`cl':
`C)
`l',
`
`LO
`ci
`l',
`
`0
`l',
`
`a5
`'"O
`'"O m
`
`_J
`
`ro
`0
`.:=,
`
`I
`0
`"'T
`N
`
`<'0
`(D
`I
`
`(D
`'s:t
`I
`
`I
`
`00
`N
`I
`
`LO
`~ I'-
`I
`I
`
`C)
`-c-
`
`(D
`
`r-
`LO ~ .
`0
`~
`~
`
`I
`I
`~ I
`I
`'i I
`I
`' I
`I
`I
`I
`
`_J
`
`I
`LO
`0)
`
`I
`
`<:')
`(D
`
`I
`(£)
`"'T
`
`I
`00
`N
`
`I
`LO
`,.,--
`
`I
`I'-
`
`I
`LO
`"SI'
`
`I
`C)
`lO
`r -
`
`APPX 0040
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 43 of 100 PageID #: 30457
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 37 of 40
`
`US 8,574,869 B2
`
`LO
`CT)
`I
`
`(")
`(0
`I
`
`(0
`-s:t
`I
`
`co
`N
`I
`
`L{)
`.......
`I
`
`0
`'St
`N
`I
`
`0
`LO
`
`~
`
`I I
`~ •
`11·
`I
`I
`I
`I
`I
`I
`I
`I
`
`I
`0
`~
`
`I
`C)
`LO
`
`~
`
`I
`LO
`Ol
`
`I
`("')
`CD
`
`I
`CD
`-s:t
`
`I
`CO
`N
`
`I
`LO
`~
`
`Iii)~
`' t? ·~ I I
`
`APPX 0041
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 44 of 100 PageID #: 30458
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 38 of 40
`
`US 8,574,869 B2
`
`LO
`0)
`I
`
`(")
`(D
`I
`
`(0
`'st
`I
`
`ro
`N
`I
`
`.,.....
`LO
`I
`
`0
`'ST
`N
`I
`
`N
`N
`lL
`
`0
`CC)
`0
`j_l_,
`
`LO
`
`0
`j_l_,
`
`C)
`j_l_,
`
`0
`LD
`
`r,,
`'
`: ,;
`
`I I
`I
`.
`•••• I
`\ i I
`I
`I
`I
`I
`I
`I
`
`LO
`
`N
`
`.....J
`
`I
`0
`~
`('.J
`
`I
`0
`LO
`
`I
`
`l[)
`0)
`
`I
`
`(")
`(D
`
`I
`(D
`"CT
`
`I
`ro
`N
`
`I
`lO
`~-
`
`I
`f'-
`
`I
`lO
`'st
`
`APPX 0042
`
`

`

`Case 1:18-cv-00924-CFC Document 399-1 Filed 10/07/19 Page 45 of 100 PageID #: 30459
`
`U.S. Patent
`
`Nov. 5, 2013
`
`Sheet 39 of 40
`
`US 8,574,869 B2
`
`.r,,,,
`oy
`°c~y
`
`0,?, ov
`Py
`
`0,?,
`ov
`cy
`
`{)
`
`0,?,
`oy
`.('\,'
`
`0,;i
`Oy
`ov
`
`..\;,,,?,
`ov
`o~v
`
`..\;,,,?,
`oy
`,6, y
`..c-,,, ov
`c'y
`
`0,?, oy
`<;,,
`s-0, ov
`ov
`
`./:9
`
`:V,a i?;
`
`C)
`""1-
`N
`I
`
`C)
`lO
`I
`
`~
`
`lD
`a:,
`I
`
`(")
`(.D
`I
`
`(.D
`""1-