06/25/2009 15: 29 FAX 2_062330644 __ _
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`AMGEN
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`RECEIVED
`CENTRAL FAX CENTER
`JUN 2 5 2009
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`14! 021
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`Doclcet No.: A-1012-US-NP
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`IN THE UNITED' STATES PATENT ·AN·o TRADEMARK Of!F1C'E
`
`Applic;ant: Grace C. CHU
`
`~erial No.: 1'1'(437,6Q2
`
`May 18.2006
`
`Filed:
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`For:
`
`Grou,p Art Unit
`No.:
`
`1644
`
`Examiner: Yunsoo Kim
`
`COMPOSITIONS AND METHODS FOR INCREASING
`THE STABILITY OF ANTtBODIES
`
`Docket No.: A-10·1~-US-NP
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`1.
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`2.
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`3.
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`1 4.
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`DECLARATION· OF GRACE C. CHU. Ph.D. UNDER "57 C.F.R. § 1.132
`I receive'd a Ph.D. in Biophysics. and Bioe11gineerlng from Case Westem Reserve
`University ir:~,2000. I joined ArngeA:as a Scientist in 2002. I worked at Amgen untJ12008,
`ach~ving the rank of Product Qua:rity Director by the time I left.
`I am now wo.rl<ing at A TR
`lntemaHonaJ as a Quality Control Director. I am nol being compensated for my time to
`make this declaration. I own 197 shares of Amgen··stock. My Curriculum Vitae is attached
`as Exhioit A.
`I have reviewed U-S· Application No. 11/437,602. 1 am familiar with·the data In this .
`application, and I performed lhe experiments disclosed in this application.
`Antibodies •. like other proteins. have hidividual properties. Therefore. I would not
`necessarily expe<:.:t different antibodies, or even· ctffferent isoforms of the same· antibody. to
`be similarly stable ill any particular formulation. Thus, I would n<!lt expect that a formulation
`that is optirrJal forr8tabilizing a particular antibody or isoform thereof to neaJSsarily also be
`optimal for:a different antibody or isoform. ln'fact,.data in U.S. Application No. 11/437,602
`show. that different,purified isoforms of an antibody do exhibit different.stabilities when
`compared to each other and to mixtures of isoforms in a variety of forrnutations.
`Specification, EXamples 2 and 4. Figures 4-B, 24, and 25.
`Before I perfonned the·.set of experiments described in Example 2 of U.S. Appficatiort No.
`11/437,602,. the.resulfs of which are shown In Figures 4A-4E, I did not know whether one
`of the pHs tested would yield J1'19Te intact monorners llian o1hers and, if so, 'What pH that
`would be. These.data indicate· !hat more monomers are retained at pH 6than at pH 4, ·5,
`
`PAGE 21/38 * RCVD AT 6/25/2009 6:27:45 PM ~astern Oa~ight Time)~ SVR:USPTO.fFXRF·5/5 ~ ONIS:2738300 ~ C$10:2062330644 ~DURATION (mm-ss):OB-12
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`Ex. 2019-0001
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`06/25/2009 15: 30 FAX 2062330<..0:6--"-44...___
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`AMGEN
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`141022
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`Docket No.:· A-101'2-US-NP
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`5.
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`6.
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`7, or 6 upon storage. for three months at 37 "C·. I had no basis for predicting I his outcome
`before U1e experiment was·performed. Thus, it was an unexpected result
`.At the tin:te 1 did.' the experimentS descn'bed ih Examples 1, 2, and 4, !·was unaware of
`ather experiments. in "WhiCh !he. stability of various individual isoforms af a given· protein, or
`various mixtures. of such isdforms, had been rom pared for stability. The experiments
`desc®ed in Examples. 2 and 4 and~sl:lown in Figures 4A-4E, 24, and 25 show 'that
`mixtures of isofbrms,. especially:mixtures containing at least 1hree lsoforms, are ,generally
`more.stable than indiVidual isoforms or mixtures with less 'than· three isoforms. Of the fO\Ir
`differenl combinatiens of'two isoforms tested, one had stabiflty comparable to mixtures of
`lhree·or more isoforms, but the other three-mixtures containing two isoforms were less
`stable. ·specification, Figures 24 and 25 and Example 4. Sing\e isoforms were uniformly
`less stable thqi!T combinations of two or more i!i0!¢rms. Specification, F~gureS' 24 and 25
`and Example 4. These· results further confirm other results in Uie appllcafian showing that
`different iSoforms have different .stabilities. These results, especialiy the stabilizing effects
`of. mixing iSoforms, were1dompletely une~ted to ine.
`l further declare lhat .all statements.made herein·of my own knowledge are troe, that all
`statements made en infol:matloh· and belief are befiaYed to be true, and that these
`statements ·were made with the kncwledge·that willful falSe statements and the like so
`made are punishable by fine or~imprisonment. or botJ:r (18 U.S.C. § 1001), and may
`jeopardize the validity or the application or any patent issuing theJ~n-
`
`
`
`oated: 'l .. :SJ~ 'J:Q!tl ---!:~;_,.__--:----. :-:-----=--C_. -~---...:=----­
`
`Grace C. Chu
`
`2
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`PAGE 22138 * RCVD AT 6/25/2009 6:27:45 PM ~astern Da~ight Timej ~ SVR:USPTO·EFXRF·5/5 1 DNIS:2738300 1 CSID:2062330644 1 DURATION (mm-ss):08-12
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`Ex. 2019-0002
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`06/25/2009 15:30 FAX 2062330644
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`--~A.t"GEN
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`~023
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`Exhibit A
`
`GRACE C. CHU, PHD
`(H) 805,499,2321 • (C:) 805,300,0374 • BIOGC¢2@YAHOO.COM
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`)o Highly motivated, resourceful, and innovative Biotechnology PTofessi~nal with over 1~ years in cG~ product quality
`and operations, protein fQrmulation and <:ommercialization, and ana)ytJcal method and Jrt.Strumentanon development
`}> Proven success in leading and managing cross-functional groups to achieve corporate objectives
`}> Effective interfaces with executive management, ext~al business partners, and scientific peers
`> Expedjtious proficiency in authorin,g technical publicatiQns, patent applicatiortS, and regulatory filings
`.
`,
`~ Global work experience in U.S., Puerto Rico, and Japan; Familiar with Cantonese, Japanese, French., Span1sh, and Latm
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`2009- Present
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`ATR IN1'ERNATIONALJNC. CAi\WUI.l.O,CA.
`QUALITY CONTROL DIRECTOR
`Oversee Quality Control business and technology for the Symyx Biologics Contract Research Development and
`Manufacturing Organization (CRO/CMO); Current responsibilities include:
`CJ Developing and executing a cost-effective strategy to establish a new Quality Control (QC) Laboratory to perform
`contract cGMP lot release and stability testing, under an accelerated six.-month timeline and capital budget of $300K
`CJ Managing QC business development and organization to increase overall Contract Manufacturing annual gross
`revenue by more than 30%, and improve cross-functional efficiency between Development and Manufacturing
`CJ Leading Symyx Analytical Development and Quality staff on efficient q_ualification/validation of analytical methods,
`ensuring cGMP compliance and successful transfer to and from external clients
`CJ Providing technical guidance and mentorshlp to Symyx CRO project leaders on resolving development issues
`effectively, and achieving project timelines and deliverables
`Identifying current trends and issues, and facilitating interfaces between small- to medhnn-sized biopharma!chemical
`businesses, as a member of the American Chemical Society Industry Member Business Advisory Panel
`AMGEN MANUFACTURING LTD. JUNCOS, PUERTO Rico
`PRODUCT QUALITY DIRECTOR
`Directed Quality strategies and business activities for two $4-Billion marketed products, Neupogen (fllgrastim) and Neulasta
`(PEGylated f.Llgrastim), as the Global Product Quality Leader; Led a 40+ member team from Quality, Process Development,
`Manufacturing, and Regulatory Affairs to support all Neupogen and Neulasta drug substance and drug product quality
`i.rtitiatives
`CJ
`Identified operation units that impacted product quality by firill.!T\"! mode and effects analyses (FMEA); Coliaborated
`with PhD-scientists and associates from Process Development and Manufactwing to improve processes, and
`implemented i.rt-process controls (IPCs) to monitor effectiveness of process capabilities
`Q Designed and ovBTSaw cGMP stability studies that met regulatory requirements on demonstrating comparability of
`drug substance and drug producr before and after proposed process and fill/finish changes; Collaborated with
`Regulatory Affairs to prepare wmldwide regulatory filings, the approval of which harmonized specifications across
`multiple regions (e.g. US, Europe, Australia, and Canada)
`CJ Led investigations by QC to determine root causes, and corrective and preventive actions (CAPAs) for OOS and OOT,
`that minimized disruptions to cGJ\.1P lot releases and cGMP stability studies
`CJ Oversaw monthly Global Product Complaint investigations related to lack of efficacy, contamination, and alleged
`counterfeit; Achieved resolutions that ensured patient safety and prevented product recalls
`CJ Managed qualification ofuew drug s11bstance and dmg product reference standards, under an accelerated rimeline of
`less than seven months, ensuring continuous reference standard supply and cG.MP compliance
`CJ Recognized as the Subject Mauer Expert for Neupogen and Neulasta product quality and Annual Product Reviews,
`during regulatory inspections
`AMGEN :(Nc. THOUSAND OAKS, CA
`SI!NIOR 5CIENTISTISCIENT15T, PROTI!IN FORMULATION, R&D
`Developed formulations for monoclonal antibodies, and supported life cycle mlUlagement of marketed products (e.g.
`Neupogen and Nc:ulasta); Awarded four Amgen Bravo! Awards, in recognition of exceptional work and exceeding corporate
`objectives in Product Strategy, Operations, and Process Development for clinical and commercial products
`D Supervised a team of three that developed formulations for Phase I to Phase 3 monoclonal antibodies, and analytical
`methods which were used to monitor short· and long-tenn protein stability; Recommended first-in-human (FIH) lUld
`cpmmercial formulations to Global Clinieal Development, Operations, and Process Teams
`CJ Authored CMC sections ofiND applications, the approval of which permitted the launch ofFlH clinical trials
`i
`
`CJ
`
`2007 - 2008
`
`2002 - 2007
`
`PAGE 23/38 a RCVD AT 6/25/2009 6:27:45 PM ~astern Da~ight Time) R SVR:USPTO·EFXRF·5/5 R DNIS:2738300 ~ CSID:2062330644 ~DURATION (mm-ss):08·12
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`Ex. 2019-0003
`
`

`
`06/25/2009 15:30 FAX 2062330~64~4~---
`
`AMGEN
`
`Grace c. Chu, PhD
`(h) 805.499.2321 • (c) 805.300.0374
`
`~024
`
`Pagu 2
`
`a Mitigated risks of critical single-sourced excipients and primary containers (e.g. pre-filled syringes) by comparing
`stlbilit)' of the product prepared with materials :from alternative suppliers; Awarded the Amgen Excellence and
`Service Award for successfully exceeding Corporate Quality goals and ensuring patient safety
`0 Distinguished product quality of Amgen trademarked product, Neupogen, against filgrastiro biosirrJiars from Asia and
`Europe, protecting the Ncupogen brand and Amgen intellectual property
`0 Reinforced company intellectual property on monoclonal antibodies by authoring patent applications on novel
`metho'ds and compositions that increased antibody stability, and received the Amgen Pharmace'lltic.r Dept. Research
`Innovation Award far New Methods to iderrt:i:fy degradants in monoclonal antibodies; Fostered external scientific
`exchanges through jou:rn.nl publications and oral presentations at international scientific conferences
`0 Led the Pharmaceutics Analytical Core Expertise (PACE) Spectroscopy Group, which supported users on
`spectroscopy instruments for protein and peptide characterization!!; Managed its expansion across sites (from Amgen
`Thousand Ollks to Amgen W~J.Shington), and increased membership from 5 to 24+ aTJd capit'al equipments from 7 to
`24+ in 4 years; A warded the Amgen Spat Stock Award by Phannaceutics executive management for leading this
`PACE Spectroscopy Group and its expansion
`
`2001 - 2002
`
`THERMO F1NNIGAN (NOW THERMO SCIENTIFIC) SA.l'l JO~E, CA.
`SCII!NTIST 1 RESEARCH & ENGINEERING DIVISIOt-1
`Developed mass spectrometers for life science applications
`Supported the new proteomics business unit by developing novel ftont-end technology for MALDI-ion r.rap mass
`0
`spectrometers
`OKAZA.Kl NATIONAL RESEARCH INSTITUTES OK/V..AKI,JAPAN
`RESEARCH FI!LLOW1 INSTITUTE FOR MOLECULAR SC:II!NCIII.
`Elucidated the stnlcti.ITe ofhemeproteins by spectroscopy, and fostered scientific and cultural exchange in Japan
`0 Awarded the Research E:x:perience Fellowship for Yormg Foreign Researchers (I of23 granted) by the National
`Science Foi.Uldarion and Japanese Ministry of Education, Science, Sports, and Culture; Stutlied HmuO-hcme complex
`and its CO and oxygen ligand coordination by r~onance Raman and IR. spectroscopy, and x-ray crystallography
`HEWLETI-PACKA.RD LABORATORIES (NOW AGILENT TECiiNOLOGmS) PAID ALTo, CA
`1995 9 1996
`TECHNICAL STAFF, BIOSCIENCE DIVISION
`Evaluated photosensitive labeling of oligonucleotides for development of a fluorescence-b~ed nucleic acid bioanalyzer
`D Characterized surface derivarization chemistry on silica by fluorescence spectroscopy, and the impact of fluorescence
`quenching at solid-liquid it1terfaces-on quantifYing chemically derivatized substrates
`
`1999
`
`PhD, Biophysics and Bioengineering • Case Western Reserve University • Cleveland, OH.
`MS, Engineering Physics • Carnell University • fthaca, NY.
`BA, Physics and Latin • University of California at Berkeley
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`Decision Making
`Developing and Delivering Effective Messaees
`Guiding Your Career
`Perfonnance Coacning
`Personal Skills for Managing Change
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`PAGE 24138' RCVD AT 6/25/2009 6:27:45 PM ~astern Da~ight TimeJ 1 SVR:USPTO·EFXRF·5/5 1 DNIS:273830D * CSID:2062330644 'DURATION (mm-ss):08·12
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`Ex. 2019-0004