Case 1:18-cv-00924-CFC Document 399-7 Filed 10/07/19 Page 1 of 39 PageID #: 30754
`
`648
`
`New
`o t J1,.ylam1110 ._ ____ _,
`I \.ltl
`
`Ill()( Ill \11( ,\I I N(;INI I IUM, I l ' NIMt-11 NI Al ~
`
`1)1 ~l(;N .\s; I) .\ l'f \l \ !>IS 0 1 11101 OGll Al
`
`Ill ,\("lOlt!>
`
`649
`
`' .• , nd 1; O(q ; cdl g , uh, tn11c. plot (cl\' .in,, . ., "
`<I• (cid:141) If ,,. .. 05 h
`0 .2 !,! L. /,,. o I h
`'. /.: ,
`" · , and prove h) d1rcc1 , oh1t1oll of 1hc .,hovl) equation~ th;H cl, ,Ir O for low .\ and for V ,
`D (1\ a,h1nH).
`(c ) D~tcrminc the , t:1hiht~ of ead1 slead y state to small pcrturh,ll ions.
`I) 1.:; \\·he\· fcrmcnt:11ion The fcrmcnla lion of 11 he> l.oclos,; to lawc acid hy I.,1110/,<1, 11/um lml11arn " ·'
`:,; ~-I (. a;id pl! S (> h,is h~en oh,cr1ed to Iii the modcl of Lucdeking ;1n<l Pirct [f.q (193)1 pr01 idcd
`the foll(m 111[! motlilk:111011, arc made:
`
`I. l he 111.n nnal gr1l\\lh r.1tc is /Im,- 1
`(
`
`I' .• )
`
`/I
`
`2 11. ,.
`
`0.$8 h
`
`' . />, • .,.
`
`5 ",. ;II /'• 18 ".,
`
`11,,. ,
`
`1.lh 1.1•~ •
`
`.$.1'., at /• ,lX ",.
`
`1. 1'.1r,11nc1cr, f, ,, continu,,u, krmc111:1tion :m: 7
`/I 0.2 h 1
`r O HX l! prod ucl !! , uh,t ra lc
`k,
`'iOmg l
`
`(II ) Write d1,wn the c:qu.,tion, for .,. 1 • • ,nd 1• in ~ontinu,,u, fcr me111a11on
`(/ 1) ,\ ssunung , 1c.1dy-, 1ate hch.1\ior. ,how th:11 a l a h>l,11 re1c1111011 lime of 1 'i h. lwo cqu;ol ,_tage.,
`.ire hcth:r lh:m on.:. hnl three prodm:e es,c111i.1lly no further 1111provcmc111 in the rc·duc11011 ol suh(cid:173)
`I'" 0 ).
`slr,ile lc1el. h 1hc ,amc n:,ult true for hiomas, 1 (( nnw lcr thc c. isc \ ,
`'O",., 1 .,
`1, J Keller .11111 ( oerhardl ("( 'o ntinuou, I ac11e Acid I ermenlation of Whey to Produce ,1 R11m1•
`11anl J CL'<l ',upp!cmcnl lligh 111 ( rude l'r<>ld n " Jliot,·c/1. /li,1<·11,1 . 17. '>'>7. 1'175.) note th.II when""
`is less than ~ pcrL"cnl. product 111l11h1tion is not par11cularly strong. thus ,1 rg111ng th,11 " lrom a
`, , l.1ctose. 0.2 ",. lactiL :Kid) 11111,!hl he fcr~nciuc,t
`praclkal standpoint .. ... d 1cddar d1C1.:sc whey (-l<J 0
`:Hlcqu,llcly in a ,inglc slagc fi.:rn1c111 nr. whereas collage d 1cese whey (5 X' .. l,1ch ise. 0:7' .. l;1c1u: aud)
`hcndi1 s from an addi1,onal stage.'' Illustrate the 111.1gnil11de of this henclil hy repea ling part (/,) de•
`5 I(' • . />.,
`ll.7 ",..
`sign using,.,
`(/•) I hcse :iuthor~ also poull 0111 thal addil i1>n ,,f ·"itiar woul1I red uce the amount of 1~ater
`wludt 11 1,oul<l be ne..:.;ss:,ry h> Jl'lllO VC 10 get a li.cd 111;1,s of product !lo w woul,1 sugar ,tddllton
`alli:~l a rc.1cwr desti,m , tra lcgy'?
`IJ.U, Sl:lJ!Cd fcnm:nt:llions: h~·droc:irhmL~ I.ct us suppo, :.: that you have the halch grm\lh cun c for
`1hc hi dr.>c,irhon fcrmcn,.llion dc, cnhc·d " ' vh•tdly h y M111111ra ct .11. Ill S,;c·. 8 K In l'roh. 8.11. )(1
`11
`idcn1ili.:d the pr<>h.,hlc , ontwlhng. rcsista11ccs of cad1 of the fcrm~111a111>11 ph,,,c, (>h,c r~c,t. Your
`L'Olll p ;tni· ha, decided (m your ahseucc) 10 ,,·ale up llus k rmcnl,tW'.11 hy n tanb
`111 s:.:nc,. whc~c
`11 muuh~r ol' 1,111h, numhcr ,,f dislinct o.:cll-hubhk ,subs1r,11c conhgura 11011al phases rcp,,rted 111
`I ii!. x [.\. I or c.,ch p h.isc. \\file d,,wn the co111r.11l111g rcsl'>lancds) and d " cu, , qu.111111ati1 cl) how ) 11
`11
`w,;ukl , c;olc the rcaclt>r 1olumc. po\1c1 inpuls. clc w oh1ai11 a s~al.: faclt >r ,,f 'i(K)() from lah1>ratory h>
`pn>ccss units.
`•).17 Penicillin fcrmcn t:ition l hc results st11,11 11 in l'ig. l/1'1 7. 1 ,1 cre oh1.1inc,I from .1 /',·11ici//11w1 d 1r1
`.1111111 fermcn talton r,,r pcni..:illin pro,h1et1011. l'hc ,; xpcrimcnt w ,l' run in ,1 1, cll-, 11rrc1I tc_n-lller lcd (cid:173)
`., ,,,
`h;;tdt fc rnu;ntor. acr.11..:d al O 2 VVM (gas ,·,,Jumcs per fcrmcnl ur volume per 11111111te ). I he gnm lh
`;111d prml uctinn n1cd1um c1>11t;1inc·d initially (111 grams per htcr)
`Kil I'<>, \ .fl. Na ,SO, Ol/: '.\lg( I: 0.2'i: M!,!S0, -11 10. OO'i. (iluc,>sc 10. NII,( I 2
`.
`In a,1ti11io11, gluw.,c 11a, kd c,>11li11uo11sly and Nll, 011 \1a, used for pll con1w l Hcn1.1l pcmu ll m
`'
`.
`has the r,,ll,>11111c fonn ula. ( , ,.11 ,.N, O, S.
`(al r xplait~ the pr,,lilcs f, ,r .:di m,iss. penidllin. glucose and NH, in thi, fcd-h.11ch f~r mc111a11,m.
`(/•) Nolie.: 1hat 1.:ry 1111.:, p, Ltt:dly. lhc hiosy111hcsi, of pc1milli11 Lame to a r:'.p1d halt c,·cn
`1h,1uch 1hi, orl!anism has 1hc ..:ap:1hil11 y for sy nth,;si,.ing !he 11111c, lhc a mount of pc111nlhn a,c111HU·
`l;itc,t,11 lhc po;nt oh s}n lhcs1, cc:i~e,l. ;\ s clncf 1r<1uhlc shoo1cr fo r A1111h1,1tics I 'nlnnilcd. I Ill. ~011 arc
`rc,1uc, 1cd 10 s.>h..: the 1mst,;r~ nl' why r~nicillin synthi:si, , topped.
`
`1,
`
`lt1ccllll/Cf
`
`Pa<kcd
`rnlum n ol
`unmoh1l11.cd
`I JllHf\0 ,ll. ~'lil!.C
`
`1 ~mun,,
`:,dd
`(wet , ry, 1:1ls(cid:141)
`
`1-"ii:uro, 1J1•12.1 Ca1.dy1,;d rcsolu11011 of amino a<1d, / ,.,,.,,, r. / i,.1a. /' \Ion \' / us,·. 1111d I. Sl11ba111.
`/"11: rmiJ!Of/111. 1 ol. 3 I. /'· J J ,. IW.f,.f
`
`1). 12 Optically pun: amino acids fhc pro,:,;ss d..:, d op,;d hy l'osa ,., ,ti ( .. ~ludk, on Co111inuou,
`I 111ym,; R..:,u.:rnrs 11. Prcparati,,n of DI Al'•Cd lulosc Aminoacyl,,sc ( olumn, ;111d Contmuou, Optl•
`l:tl Rcsohllion of Aw1yl-d.l.-111c.:1hiomne; · l·.11:rmolo11ic1. JI, :!25. 1%1>) GIii he rcpn:,cntc.:d , du:m.1ti•
`..-.,lly hy I 1g.. 1)1'12.1. Assumc for the momenl 1ha1 1,,,., b i11depe11den1 of pll. lhe inili,11 r.1ccn11l
`;111111w a1.:1d solulwn is acetylated hy n:.1c1ion wi1h :u.:e1ic anhydride. the I amino,1ql.1, e column
`rnerscs 1hc ao.:c1yla1ion rcacllon for t he I •,unino acid. whid, is 1hen c·r}M,1lli1cd in akohol , olution,.
`· k,,.. dc,elop .111 e\prc,~ion for the
`(<1) Assum,; 1hat lhc inillal amino .1dd com:cnlf;llinn is
`frac1ion.1l 1-amino .icid C(>n,crsion ad1ie,cd hy lhe cn,.yme .:olumn in plug. Jl,m Repc.11 induding
`axial disp.:rsh>n.
`(/,) I'll<: rawmiza1ion rcact1on m.1y he 1aken w he liN order re\'ersihk. ,o 1ha1 the ra1e "
`proportional 10 , ,. ,,. ,1-, ~ ·""'' "here,~""'' is cquilihrium I> acid level ror the ,olutmn. If 'JO perccnl or
`the I aml and 1 pen.en! of the 1> ;1e1d i, rem,>\cd in 1he we1-cryst.1l stream. along 11ith 10 pen:cn, of
`the e111cnng aqueous phase. "hat racemitation CSTR ,olumc is needed lo achicvc '15 pcr..:,;m :,p(cid:173)
`proach to cquilihrnnn'!
`(,) ·1 he cnl.}IIMlic dcacctvl.111011 ,,er releases :u.:e1ic add into the solu11011 If the pl-:'., lc.1ding 10
`cnLyme <lc:1diva11011 arc pl\ 1 S an<l pl\ :
`X. whal cnterin!,! pl I \\ot1ld gnc maximum w111 cr,10n
`' ·\/ feed n11xlurc? (,hsumc plug llow) S1,11e )·our a,s ump11011, d early.
`fi,r a 10 " \/. 10 • .\/. or IO
`1).13 l>iJ!o,stion of insoluble substrnt,-s As an eumplc of procc,~, invol~ed \\ ith dil,!c, 1ion or p.1r11u1
`,.lie suhslrales. the following unll-opcr.111un sequcnw for }cast i;r,mth <>n ne1ispr1111 ha, h~cn , ut!
`J!C.,lcd 1m:chaniL1l )!rimlinµ . .odd h~dri>lvs1s. medium ne111rali1at i1>n. a,1dition of .utd111,m.tl minor
`11111nc111., for 1cast µnmth. )Ca,1 fcrmcnlor (acrohid. vacuum liltrat1on h> ,ep;1r.1tc hqmd ln>m cell
`111,1"
`
`(11) Shc1d1 1he llow scheme .1l1111·c. mdkaling hy arr(rn·, point- of .1dd111on .md h) cirdc, e.od1
`unit operalion. lndude solid., co111eycr, and li,1uid-pump loc.1t1011s \\here needed.
`(/•) I n,111 any human ph)sll>h>g) te, 1. ,ke1d1 1he human food-,h!!e~tu>n pH><.:c" 111 a , 11111l.1r
`111.IIIIICf.
`(,) Hion1c, 1s 1hc stud) of n.11Ur.1l syslcms with ,Ill C)C lo\\ard dc1elopmc111 ,,f s)nlhellc ,malogs
`Di,cus, si1111briuc, ;ind dilkn.:nccs hclwccn proccs, cs (a) and (/•) I low 1111g.ht )1 >11 design a ;.c>lid,
`h,111dlit1!! scheme for p:1r1 t,l (cid:141) u,111g the "co111cycr " t)pC in p.1rl (/,)''
`'J.1.$ C't,11 maintcn:mrc; ":i,1111111 :11 sm:ill S I or some population, . a 111i111mu111 lc1cl of ,uhstr,lte 111;11
`he 11,·c•,kd to ad11.;1c a 111>11tri11al ,te:1dy , 1;1tc. ,\s an c.\amplc. con,1der the ') ',h .'lll w11h kmctk, of 1hc
`form
`
`I 11.,.. ,"
`l , A.' + '
`k ' r '
`Assumm~ lh:ll the de,ign h:1s1~ undcrly111i; l'roh. 1).10 i, 1ahd
`f11) 8how tli;il ,11 ,uhslr,ltc kvcl hdow k, /..: , '(11,,,,.
`k,) 1hc only ,1o:ady s1a1e i11 a <. SlR ,ystclll
`
`k,.'
`
`r,
`
`/lr.,H~\
`
`"
`
`'
`
`ll
`
`APPX 0334
`
`

`

`Case 1:18-cv-00924-CFC Document 399-7 Filed 10/07/19 Page 2 of 39 PageID #: 30755
`
`650
`
`3
`
`(I
`
`16
`
`14
`
`12
`£ II
`z JO
`= 0
`~
`.i
`0) 6
`
`8
`
`4
`
`2
`
`........ ,
`'
`
`'\
`\
`\
`\
`\
`\
`
`(I
`
`8 12
`
`BIOCHEMICAL ENGINEERING FUNDAMENTALS
`
`DESIGN ANO ANALYSIS OF IIIOLOGICAL RFACTORS
`
`651
`
`Z (inoculated beads----.
`per hour)
`
`- - - - - - - - - - -+ - -C e l l mass, g/L
`
`Penicillin
`
`Product
`Bead
`withdrawal
`
`, __
`'\ ' '
`---36
`
`20
`
`_________ .,,,._.,,...
`------------
`
`.,,,,orucose
`.,,...✓ /NH.1
`
`52
`
`60
`
`68
`
`76
`
`44
`Time, h
`Figure 9P17.J Time course of a batch penicillin rcrmentation.
`
`Recycle
`fluid
`
`Pump
`
`Figure 9P19.I Fluidized bed microcarricr biorcactor for tissue culture.
`
`9.18 Cyclic buu:h operations It is difficult to adminisler continuously low, controlled liquid feed rates,
`whereas the comparable periodic stepwise addition of substrate feed removal of formentor nuid is
`easier. Suppose microorganism growth is limited by a single substrate in a Monod fashion, and that
`cell growth is proportional to the time rate of substrate change. Al time "' 0, the formentation is
`begun (negligible lag). Al lime l, a volume V, is removed from the fcrmentor of liquid volume V, it is
`replaced by an identical volume of fresh feed al concentrations,.
`(11) Show that at time t (before volume removal), the substrate concentration s is given by
`
`4.0
`
`2.0
`
`[
`
`K,
`K,
`]
`[
`1 - s/s0 ]
`[ s ]
`I+ - - - - In I+ - - - --...,....,-- fn -
`(x0 / Y) + S0
`s0
`x0 /(Ys0 )
`(x0 / Y) -+ sQ
`(/,) At time I, the volume V 1 is removed, now feed is added, and the process repeal.~. Evaluate
`s 0 , •"o in tenns of s, :c, from this volume operation.
`(c) Then establish that the substrate utilization efficiency
`
`== 11.,1
`
`fl= (s, - s1)lsr =- I -
`
`1 ~ ,f, (e•<•·,,v,,,,.:i..[I - ,f,]'1 '"• - 1)- 1
`
`where ,f, = V ,IV.
`(d) As ,f, - 0, show that this efficiency becomes identical with the continuous culture result
`K,
`fl = I - - - - ' - - - (cid:173)
`s1[µ.,(V/V 1)! -
`
`I]
`
`where 1'111' 1 is the reciprocal dilution rate.
`(e) Show graphically that at sJIK, = 1.0, finite values of cf> (discrete operation) give higher /1
`values than the continuous reactor if (11,. V1/ V 1) > 4.
`9.19 Fluidized bed tissue culture It is proposed to produce tissue culture biomass continuously on
`nonporous be.ids in a fluidized bed (Fig. 9Pl9.I). The proposed fluidizing nutrient liquid moves
`
`,,~
`_,4
`
`/ ..
`, ,,,
`
`,,,
`I •
`
`I
`
`I
`
`- 2.0 • " I
`
`10
`
`4o .__...__1._5_....,__5,_0_..._-=15
`
`h
`<M
`
`0
`
`50
`
`100
`
`150
`
`h
`(a)
`
`Figure 9Pl9.2 Production of cell number and viral titer vs. time. (11) c, (cells attached al li'."c 1)/ co
`(cells inoculated at time t = 0) vs. time (---75% 0 2 saturation; ·······S'\{. 0 : ~~turallon). _(b)
`( = virus dose yielding SO percent tissue culture infection dose per m!lhhtcr) vs. lime
`TCID
`" '
`'
`II 1
`·11·1·
`. . . I
`II
`(---13 x 10' ccllsfm111iliter initial cell concentration; -----3.S x 10 cc s, m1 1 lier mum cc
`i:on•
`ccntration). { Repri111ed from A. L. t:1111 We:cf, Mia11L·arrier C11/111res of A11i111a/ Cells, i11 " Ti.mil! C11f,
`wre · Met/mil,· um/ Applirntiom," p. 371. Awdemic Pres.I', hie, Nell' York, 1973./
`
`APPX 0335
`
`

`

`Case 1:18-cv-00924-CFC Document 399-7 Filed 10/07/19 Page 3 of 39 PageID #: 30756
`
`652
`
`BIOCHEMICAL ENGINEERING FUNDAMENTALS
`
`DESIGN AND ANALYSIS OF BIOLOGICAL REACTORS
`
`653
`
`upward, passing out of the reactor through a screen to retain beads, and then through a pump. The
`choice of beads with (Pbu d -
`1111,0 ) small allows operation at a low fluidizing volume rate and use of a
`pump which does not damage the macromolecules in the nutrient medium. For liquid fluidized
`reactors, assume that the liquid moves in plug flow while the beads are perfectly mixed and distri•
`buted throughout the reactor. Bi:ads passing over the exit funnel settle into it and are continuously
`removed ; the exit fluid being returned by a subsequent filter.
`(a) Assuming the data of Fig. 9Pl9.2 to typify cell growth kinetics on each bead withµ • 0 for
`t > 160 h [due to achievement of a complete monolayer (contact inhibition)), develop a steady state
`expression for the exit biomass concentration per bead in terms of the fluid bed void volume c, the
`feed rate of inoculated beads (Z per hour), the reactor volume V R and the appropriale growth rate
`law. The entering beads have c0 cellsibead.
`(b) Repeat (a) for the situation where the cells per entering bead have a distribution given by
`
`where A • normalizing factor
`(c) How would you design a "continuous," sterile transport system for adding new beads and
`for recovering the exit liquid volume as assumed?
`9.20 Tissue culture support inhibition It has been observed that high concentrations (cm2/cm3
`) of
`solid supports for tissue culture may be deleterious to growth because of adsorption on these surfaces
`of growth enhancing factors and scrum protein from the support medium, adsorption rendering these
`factors inaccessible (C. B. Horng and W. McLimcns, Biotech. Bioeng., 17: 713, 1975). Consider a
`well-stirred microcarrier tissue culture reactor employing nearly neutrally bouyant beads as the cell
`supports.
`(a) Assuming that the cells grow logarithmically (all nutrients present in excess) until the avail(cid:173)
`able surface area is covered (sec Figure 9PI 9.2), develop an expression for the total biomass in the
`system versus lime.
`(h) Now assume that the growth rate also depends in a Monod function fashion upon the
`concentration of a growth-enhancing factor, S,, which is not consumed. Derive the analogous result
`for biomass versus time when the growth enhancing factor S, reversibly adsorbs on the solid in an
`inactive form following a linear partition law:
`s.(I) = Ks,(adsorbed)
`
`(c) For a batch system, as.suming that growth exhaustion results from luck of further bead
`surface, show that for a finite culture time (say 6 days) there is an optimal initial loading of beads into
`the tissue culture inoculum. Develop an expression for this value.
`(J) Since the beads act in some sense as an inhibitor, it would seem logical to consider several
`stirred tanks in series rather than one tank. What problems would face the experimenter searching to
`sci up such a system?
`9.21 Penicillin-V deacylation: multiple reactions Enzymatic deacylation of penicillin•V to produce the
`desired 6-aminopenicillanic acid (Chap. 12) for production of semisynthetic penicillins involves a
`reaction network represented below:
`
`A · (pen.-V) ~ p-(6-APA) + QOH(phenoxyucctic acid)
`
`A · ~ R : - (inactive product) + H •
`..--!.L..... HS- (inactive ring cleavage product)
`K
`1
`Qo- + H •
`
`QOH ,
`
`p ·
`
`p · + H•
`
`Ki
`
`HP (stable pcnicillin-V)
`
`An optimal pH exists because protonation of p · gives stable HP, but too acidic conditions inhibit
`the reaction rate r 1•
`
`(a) Assuming r 1 given by Michaclis-Menten kinetics with noncompetitive H • inhibition, and r2
`and r3 given by simple first-order irreversible forms, write down the equations governing these three
`rates and two (assumed) equilibria.
`(h) For a steady-state CSTR system with perfect enzyme recycle, derive an expression giving the
`feed level of A · which maximizes fractional conversion to p · .
`(c) For very high conversion of an expensive starting material, use of several CSTR 's in series
`appears appropriate. Discuss tactically the ad van111ges and disadvantages attending such a series
`arrangement. Assume r2, r3 are about 2- 5 percent of the rate r 1 In the first tank.
`(L. G. Karlsen and J. Villadsen, " Optimization of a Reactor Assembly for the Production of
`6-APA from Pcnicillin-V," Bimech. Bineng., 26: 1485, 1984).
`9.22 Hollow fiber reaclor produclMty Different reactor types can yield profoundly different microbial
`densities and productivities. For eJ1amplc, P-lactamase specific production activity is less in hollow
`fiber systems than in continuous culture by a factor of five :
`Productivity
`(units E/cell-h)
`
`Reactor
`
`Shaker flask
`Hollow fiber
`
`I X 10· 10
`2 X 10· 11
`
`(a) If the biomass level in the hollow fiber reactor is (typically) 1000 times greater than in
`suspension culture, calculate the productivity of each reactor in units/(reactor volume - h), assuming
`11 shake flask biomass level of x • 109 cells/ ml.
`(b) Cell lysis in the hollow fiber, as well as protein export, accounted for some increases in P·
`lactamase release. Describe a program by which you would determine cell lysis kinetics, which could
`then be used to describe P•lactamase production by excretion and lytic release. (Sec D. S. Inloes et al,
`"Hollow Fiber Membrane Bioreactors Using Immobilized E. coll for Protein Synthesis," Biotech.
`Bioeng., 25: 2653, 1983).
`9.23 Batch produelion or non-growth associated product Batch production typically involves biomass
`production and product formation, with substrate being consumed by each process. Suppose that
`batch growth is modelled by the logistic equation, where Xmu is set by the initial value of a second
`, (not used in product formation). Then for a nongrowth associated product (e g.
`substrate s 2
`L-glutamate from Microccocus glutamicus), we may write;
`dx/dt = µx(I - x/x,..,)
`dp/dt = nx
`ds/dt = - (dp/d1)/ Y, - (dx/dr)/ Y x
`(a) Integrate each equation to obtain x(r), p{I), s(t).
`(b) Discuss your strategy in setting Xmu ir your objective is (i) to maximize p(O) or (ii) lo
`maximize p(O)/ tis(O), where O is a fixed, end-of-fermentation time.
`(c) Under what circumstances would you choose objective (i) or (ii) in part (h)'!
`
`l
`
`REFERENCES
`
`Many or the references given for Chap. 7 contain substanti11l material on reactor design and analysis.
`Additional general presentations are available in the following lexts:
`
`I. 0. Levenspiel, Chemical Reaction Engineering, 2d ed., John Wiley & Sons, Inc., New York, 1972.
`While many other aspects of reactor design are included, this is perhaps the best single source for
`material on mixing and RTDs.
`2. J. M. Smith, Clrcmical Engineering Kinetics, 2d ed., McGraw-Hill Book Company, New York,
`1970. One of the most popular general texts in the field, made richer by many worked examples
`illustrating applications to real reactors.
`
`APPX 0336
`
`

`

`Case 1:18-cv-00924-CFC Document 399-7 Filed 10/07/19 Page 4 of 39 PageID #: 30757
`
`654
`
`1110< JII '.II( -\I I N( ,J'-JI I IUM, I l '-J(),\~11 ,-. 1-\ l ~
`
`1 J. 1. ("arhcrry, C/1<miu1/ 1111d ( a111/r1i,
`lk1111io11 /;1111i11cai1111. M.:(iraw-H1II Book ( mupany. New
`York. 1'>7<,. Rid1 in informa11on with ,p~l1,1I c1nphas1., on hclcrogcncous 1.a1;1l:,is and multipha,c
`
`Tl.!'a(..(()(S,
`
`(cid:157) C. G. Hill. Jr .. .-111 lttr1·0,lrtn11,11 to Clie1111rnl l:.1111111c,ri11q 1'111,·11,, & /fra, 1,.,. /h'.,im1. John Wiley ,I.:.
`Son,. In<.. New Yori.. 1977. l u..:1d p11:~cn1a1io11 of 111,my h>p11.~ from kinclic.~ 10 reactor cn!_!111ccr-
`111g.
`
`1 hcsc ,ourl-.:s prmiJc hroad lrc.11111c111 of many .1spc1.1, of hion:a<.lor tksign and anal}sis.
`5, II. Alkinson. Uio/011i1 c1/ /fr,1< tor., . Pion l.11ni1t:J, London. 197(cid:157).
`6 I . r f' ri,bon ,md (j_ S1cph.1nopoulo.,. •· lliolog11..tl ncac1or,." d1.1p 11 in ( l1,•111ic,1/ u,,,,, 1i1111 ,md
`Um,,.,,. b1r1i11,·,·rill,1 • . I. J ( ".irhcrr} .ind,\ V.1rma (eds.). J\.lilrccl DcHcr. lnl, New Y,,rk. 11)8~.
`\\',11! !.!""' 1h cll;xh in l11olot•1t .. 1I (SIR, .1rc c;,1n,1dcrcd in
`7. J. A. Howell. C T. Chi .• 111J l. Pa1,lm,~ky. "ffTc<.1 of W.111 Grow1h on Slalc:-l p Pn>hlc:ms and
`Dynamii; Opcr.11ing Chara<.1cn,11c~ of the lliolog11.al Aeralor.'' Biolnh Hw..:ng .. U. J5J. l'J7J .
`
`fxcd lcnl 01·cr\'iew, of time anJ lcn!_!th scale, and their 1mpor1a11cc in b1orca,tor, arc L?i,cn hv
`X N. W. I. Ko,,~n. "Model, in D1orcac·tor Design:· p. :!1 in ( 0111p111..,-
`lp1•l1, c/li11m i~ /·,•n11i111r11i11
`11
`fr, /111,./0,1,. Socic1_1 of Chemic.ii ln<lw,try. London. I 1)1!~.
`'! J. A R,1.:I,. •• f1.1a1hc111,11i1.al Modeb and lhc Dc,i!_!n ,,f ll1od1e1111c:1I Rcallors:· ,/. ( 1,. 111
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`
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`1
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`I lc111cn1ary s1ahili1y 1hcor1 and rcaclor dynam ic::,
`HI. N. It Amundson :ind R. i\ris ... An Analysis or Chcnuc.,I Reactor S1.1h1hlv and Conrrol.'" l'arb
`I III. < l;,•111. l:ll!f. Soi. 7. J :! I. 1 ')51!.
`•
`I I . (
`I'. kffrcson .md .I. fl.I '>11111h. --s1.11ionary an,t No11,ral1<>nary Mo,lel, of lla1.1crial KincliL•; 111
`\Vc!J-1\·focd I lo\\ nc.1c1orS:' C/1,w b1a. S, i. 2H· <>:!'!. 1'!71.
`I~ D. na111!.ris l111a. ,\,Ci. I rcdrid,M>n •• md II. :\1 hud1iy.1. "D~namic, nf Mieroh,al l'wpa[!ation
`f\.fodcb ( on,1dcri11g lnhihuors ;md \'ariahlc ( 'ell ( 'ompm irion. · U1otcd1
`/110, 11,1. <) I~'!. f<)(,7_
`11 S. S I.cc. A I'. faclman. and r. D. Schrocdcr. ··A I\H•-Stalc M1erohi,1l Cirm\th K1nc111. 1\lodcl.'"
`11,,,.,. lk,. •>. -1'!1. r•!7~.
`·1. II. 'otmt!, D. I . Bruley. :uid II. R. llunga}. Ill ... •\ Dyna111ic Mathc111a11ctl l\lodcl of th"
`( hcmo,1a1: · 1/101.-, /1. /Jio, 11,1 . 12· 7(cid:157) 7, 1'!70
`
`I(cid:157)
`
`Nonidc.11 mixini,t 111 rc.1ctor,
`J'\ S Nagar.1. ·\livin,1
`/'ri11,1pl,·., 11111/ •lpplin11io11,·. Wiley. New Yori... 1•P ,
`I(,_ R Shinn;1r -- 1k~1,lcncc I nnc ,111d Conlall ·1 imc D1,1rih1uion, 111 ( hc1111, .1I ncaclor lk, t[!n ·•
`111
`( l1t 1111"1/ l<u1<11011 1111d l<«ic to,· /·11a111,·,•ri1111. J. J. Carberry and A \'arm.t (cd,). l\l.1rcel Dd kcr.
`Im •. '-.!e11 YorL l'!K'\
`17 .I V1llcrn1.111\. "\11\mg in Chemic.ii Rcaclors.'' p. 11:i in< /rt'111iu 1/ /{,·c1t1i,,11 /·11,1111t·,r111,1 l'l,11,1ri
`(icort:,1ki, (cd~ I. A111criL;111 Chc1nic1I SoL1c:ly. \Va,h1111!1on. f).( .
`/.,·,·11,n .... J Wei and (
`l'!ll l
`II! 1\1 ( h.irlcs. ·· 1 nhnic.11 hpeLt, nf rhc llhs·ut.1gic;.1I Prop,r1i..:, ol Microh1al ( ulturc,."' p. I in
`Id, ,111,,, 111 /110, /Jc111i"1/ /·1111111,·,·rmy. vol Ii, I . K. <,ho,:.: . .-\. I i~dH.:r :011,l '.: lllal..chrout!h icd, >.
`·
`Sprin!?er-Vcrl.1!?, Nc11 , ..r~. I •nx.
`J'I J Hrv,rnt. ·· 1 he ( h.1raLkri1.a1i11n ,,r \li.,inf in I crn1c111crs: · p.101 in
`111 /J;.,, /,, mi, al
`lr/1,111, n
`/"11,1m, ·,·m1 1. 101. ' · J K. < rh,,~c. ·\ J icdHcr. I\: Hlakchrou!_!h (ed,.). Sprint!er \-crlal!. r-..:11 , orl...
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`/c11,1 .\, i . JH 201 ~- l'!ll.l.
`ll1orcac1nrs. ( l1,·111
`
`No111Jc;al rc,i<:tor model,
`llr.11111. ·· I he I fkc1 of lnco111plctc l\lrnn!! 011 1hc ·\n.1IJsh ,,r 1hc St;11ic.:
`:?2 ( - G Sind.ur ;111d D I
`lkh.ni,,r ,,r ( ,,11r11u1<>11, Culture,." llio1t·cl1. /Ji,w1111 .. 12: IOOI. 1970.
`
`Ill Sl< ,N ·\"-1> -\ N,\ I \ ~I', 01
`
`11101 IJ(ill ,II Il l ,\( TOlt\
`
`655
`
`:J. K. G, dmcnd. A. I ied11cr. and I Widmer. ··oxy[!:.:n fransfor in .1 Loop Rc,1•1<•r for Vi.,wu,
`Non-Nc1110111an llio,}·,t..:111,."' .I. l· <'rt11<·m J.-c/1110/ .• 61: (cid:157) •!I. 1')81.
`
`\I i.\lnl!•h1orc;11.tio11 in1cr:1ct 1<1n,
`I V,1r<l,1r. ··J>rohlcrn, of "-lass anJ l\l omcnlum f ran,for in L.a r~c I crmcntcr< ' 1•ron°.>' /lio, l1<·111 ..
`2(cid:157)
`IH :I. 1'181
`:!5. I . I 'J•111·,i. L rend. M \ lu,i'l~O\i1. and l Scidicrr. "DcpcnJc111.:c of l!clc.1s:: of ';udcolldc.,
`from rungi on I crmenwr 1 urhinc Spc:.:d.- /Ji1•1,·,·/r. 1Ji,w11a . 22· :!17. 1980.
`2'1. J. (. ,an Smhd.1111 anJ B. l\lc11.. '" lnllucm:c or [nginccring Variahlcs upon lhe Morphol1•!!~ of
`I ilamcnlou, 1\1,,hb." /Ji,111•1 Ir. /Jio,•11!1. 23· 11 1. I'll!! .
`27 D . I ( . \V,illt! a nd I!. C. J. I cwkcs: ·· f ITe<.1 of ( )p,rating an,t Gc,,mc;tnc l',1ramc;1cr, 011 the
`Bcha\lor of N:,n-Nc1\lon1,111. Mycdial A1111hiolic l'cr111c•n1:11ion.s.'' /l<Td. /ri,I -Hi, r,,/,iol. Ill 1'1.
`1'!77
`JK F. V;int.,r .rnd 1\1. [) lilly. ·· flkLl of Cyding Dis,oh·cd (hygl.!n Co1Kcnlralio11, on Prod111.1
`rorm,llion III l'.:nicillin I .:rmcnlation< · b11-,.,.,.,111 .I. ·l l'/'f. Mi, 1·,1/(cid:141) /11/. /Ji11r,·, /1110/ . 1-l 20J. I '!82.
`
`I he ,1a ndard rcfcrcm:e for u11stl.!;1dy•slalc ht:;11 1.nnd11c11,,n in S<>lids
`:!'I I I. S ( .tr,l:111 and .I ( · hq?c.:r. < 1111r/11< 11011 11/ ll,·111 in Solid,. :!tl ed .• ( larcndon l'r.:•;s. ( hford.
`1')5'!.
`
`I h:al-lrcatmcnl dc,i!!II 101· food proc.:c,•,in[!
`10 S I . ( h.mu. /11c• /- 1111dm11.-111ah o/ l- 11,,,/ h1,1i11,·,·,-i1111. :Od c,t .. A l'i l'uhli, lun!! Co . Inc· .. \V.:,1pnr1.
`( 'onn . J•)1 I.
`
`I ,1rn111lauon. ch. tra1.tcnz.111on . . ind apphc:lliou of i111111ohili1.cd <.:ell hioc.:;llaly, h arc 111d 111kd in ncr,
`1-1 and I~ , ,r ( fl.Ip . ./ < >1 her m:.:ful source,, indudc the following
`, I K VcnL1h11hra111:11uan (ed.). -- 1n11nohih1.cd /1.·I icrohi:11 ( "ells··. ,\( ·s Symposium "icri~s IOh. :\mcri
`Lall ( hcnuc:11 !-.ocicly. Washington. D .t'. 1'179.
`1: I I! . .I.id ,llld .1. r. /ajii: . ... , he l111n1nhili1;11ion or Who!,; Cells."· p. I !5 in :l,fr,111, , ., i11 /liod1c 1111•
`, al I.11,1ill11·ri11,1. 101 ). I'. K . Ghmc. A. I icchlcr. anti N. lll al..chrc•u[!h (eds). Spnn1!er-\'crla[:. :-.Jcw
`, or!.. 1•)77
`11 K . (ihc\\ Oll\o and D. I. C. \Vanl!. --conlining /1.lycclia l (irnw lh I<• l'orou, !\licrohc,ub. ,\ N,11·d
`J"cdm1quc· ,·o •\l rc·r the l\forphol;•!!~ ,,f Non N.:w lonian !\ls,eli.11 ( ullurc,:· /li,,1,, Ir
`/110, 11,1 . 25
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`f(cid:141) r,1d11c~1on 111 Jap:111. ( ·u11lirn11111~ Alcohol l'wd11c1io11 with l111111ohili1c,I l\ li,rc1h1al ( ell<' 11111.
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`1) (
`( 0111i1111011, l' ro,111<.ri,111 ,,r 1\kt.tholitc,.· /:ur . .I
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`\kc hank.11 A1!Hati,,n)." 0 p.
`I iecht<.'r an,I !\. ll!a~chroo~h (.:d,. ). Spnnt:..: r Vcrlat! N.;w Y,,rk. 1'17'
`17 I, :-.d1u!icrl. ··< h.1racteriza1i,1n and l'crfo rnianc·c of Sint:lc· and !\.111111,rat:c To\\c:r Rc.1c1,,r, \\i lh
`p. •n in 1,/, 1111«'' i11
`/110,-/1.-,11ic',,I b:,111w, ritt!f. 22. A.
`l >utcr I 11,1p for ( \;II l\las,, f(cid:141) rod11c111111
`I ll'ch1c1 ktU. Springer-\'crla!?. ,c11 \ ork. 1118! .
`1K .-\ h 11.11. 11
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`( unt111uu11, I crmeutor. /Ji,,,.,, 1, IJin, 1111 •• 11
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`l'rc•lop ct .ti
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`,10. I
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`l'crform.111cc I csr:;:· lliot,·, Ir. /11u, 11,1 .. 11
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`12 -lM. l<i"'O
`
`N
`
`APPX 0337
`
`

`

`Case 1:18-cv-00924-CFC Document 399-7 Filed 10/07/19 Page 5 of 39 PageID #: 30758
`
`656
`
`1110( Ill ~11( -\I l·M;!NI I ltlN(; I l Nl>A!\tl :-IALS
`
`DI ~1nN ,\NI) ,\N ,\1 ,s1\ 01 11101 O(il( ,\I
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`IU •\( IOIIS
`
`657
`
`-II R Ci ,'\ull cl al. ·•Biol,>!,!ic,1 ,md Biochcmic.11 ,\,pc<.h or I m\er I crmc111a1ion:· .I. /11.,r /fr,•um11.
`75 260. 1%9
`I . Smnh. •· I O\\cr-J crmcnl.uu,n S)-slcn1s .tnd ·1 heir Applkations:·
`.I~ H N (,rccushidds ;111d I
`C 11,111. I 1111. I 011,/.. May 1971. p. 18:>.
`
`I h1id111.·d•hcd ; mt tn<.kk•h~d rc,11.tor,
`-11. ( D Swlt. · Fluid,zcd-lkd Bion:actors 11,m!,! .1 I locrnla11ng S1r.1in or /._1111011w1111, 1110/,i/h rnr
`flhanol l'ro,ludiou:· . !111111/, \ r -lnrd .\, r . -U.l -I-IX. (1)81.
`-1-1. r. I la,d1cl. 1'-1 . Fam1uc~ .• md l\ Renken . .. Lum Vcrh.1hc11 \an I lii,sigke11,-W1rhcbd1id1tcn mil
`rinh:nilcn:· ( hem. /1111- • lu /1. 5-1 ~-1. 198.2.
`-1, J c; van 1k Vu,sc an,! .I ,\. \Vcs.-.clmgh. •· Multiphase Hc.1ch(cid:141) r,." p. 5(,1 in -lth lntcrnational_·c,th
`ruropcan Symposium 011 ( hcmical Rcacuon r nginccring. \ol. :."!. l)f'Cllf M ti. /),-111,d,,· <h·sdl
`"/1,1/1 fur ( hm1h,lres ·l1•1•m·,rr. 110.-11. c.V. I r.111kr11n. 197(,.
`-1(, J. llnffa111I and J. rng,,s,cr . .. ( itrit: A1.id l'roduc11on rrom Glu,mc. II. Growth and r~uetion
`Kinc111., 111 a ·1 rid,k-rto\\ I ern1c111nr." /1101,·d,. /liou111. 21 :?091 ( 197'>1
`
`I "t:rrncntation 1c1.hnoloyy
`II J. Peppler and D. l'crlm;,n (eds). -\Ii, 1·01>it1I In 11110/0111· • .:!d cd .• rnb. I ,1ml II. Academic Press.
`-17
`In,. Nc1\ \ 1>rk. l'J79. An unusually m:h <.ollcclron of rc11c\\ ,lrlldc, on proLcs,c,. technology.
`pn1,h11.1s. and markets.
`•Ill. I.. r. ( .1,1da. Jr .. /11rl11s1d,1/ \/rr1·ol>io/"'11· John Wiley & Son,. Inc . New Y,,rk. 1%8. A good
`,1u;1htati,c rc11cw ,,f producis. pro..-cs,cs. and technique, m the rcrmenlatwn indu,lr}, induding
`palc111s ,1111t c<.<>n,,mics. :S..umcrous pho1ogr.1phic 1llt1Stralio11, grl'c a good 1mprc,sion or in<lus1rial
`pra<.tll"C.
`-I'). I (. \Vcbh. /Ji11d1,·111inr/ b1,111:, ,·1·11111. I>. V,111 Nostrand Company. Ll<l. l.on<lon, 196-1. lksi<les
`disc11,s1111r some mkn•hial prud11c1, and c11uip111c11t-1ksig11 con,i1kratio11,, thi, rclcrcncc is dts•
`tingm,hcd hy ind11,11m of sc,·cral othcr imporwnl ,uhJctts. c !! . c·olloitl,. e11mls1ons. rc<lm poten(cid:173)
`tials. d1cmiL:1I d1,111kL1i1>n. dehydration. radi;nion. and v;1cdnc rnanufo<.turc
`50. K. Sdttigcrl. '"Ne\\ lliorca<.lors for ,\crohu; Processes:· Im. Clr.•111. /:11(1. 22: 591. l'Jl!2.
`
`<,~ r. 1\1. S1.,111crnood. ,\. J Sd1lahad1. W. J. l'vkAkcr. and M. It. Hillcm.111 "SLalc- Ll p of(. luck Ccll
`- Grm\lh on l\1iuoc,rricr~ in rcrmcntcrs for Vacdnc Prod mrion:· .l1t111d.\ r\ r .·lead. Sd .. -'l.l
`11:?. 1981
`63. R J . Wlntc. I . Klein. J. ,\. Chen. and It M. S1rosh;1ne. ··Large-Scale l'roduclion of Human
`Interferons:· m -t11111ur/ R,•,,,,,1, 011 hm1t•m,uim1 l'ro«':." ·,. vol. -1. G. T. T~ao (ed.) . .\1.adcmic
`l'r..-,.\, I 980
`
`Pl.mt Lell 1.ulturc
`<,-1 H r . S1rcct (c<l.). T,nue ( 11/111n and />lm,1 S, rm,, •• Academic l'n:,s. London, 197-1.
`<,5. ,\. fic<.hlcr (ed.). t,/, ,111,,, i11 /Jiorlwm, al b1ai11,•,•ri11r1. rnb. I 6. Ill. Springer-Verlag. Bcrhn. 1980
`(,(1 G Wibon, ··( onlmuous ( ulturc or Planl Cells Usmg the ( hc111ostat Prin,1plc." p I in .·ldr,111, ,·s
`111 /liod1.:111i«1I I:.11q111«·rill!/, vol. 16. A. 1-tedttcr (cd ). Sprmgcr• Vcrlag. Ne\\ Yorf... 1980.
`(,7. M. L. Shuler. O. P. Sah,1i. and G . A. lfalhhy. " [ntrappcd Plant ('ell Tissue ( u!lurcs:· .Imm/,
`,v. f .·1«11/. Sci .. 413- 373. 1983.
`68. P. llrodcliu~. "Produ1.tio11 of lhochemicals wtlh lmmoh1h1.c<l Plant Cells Possihiliue, .m<l Proh(cid:173)
`lcm<' •1111111/., ,'l;.r . !<111/. Sd . . lJJ: .1HJ. 19!!].
`<,')_ M. r . Curtin. ·• I larv~,tmg Prolitahk l'rodu<.t~ from l'lanl Ttssuc Culture." /lw ·1 cdmol()(/_L I:
`6-l'J. !981.
`
`51
`
`q
`
`Animal .:ell cultmc
`51. J. r..-<lcr and W. It l<>lh:;rl. ··nrc l..argc-S..-.1Jc Cult1v;i1ion of Mammali.111 Cclls.'' Sd,·1111/i, .-l111,rr-
`< WI. 2-1!1: 31,. I 1)81
`.
`~::>. W. IC I olhcn. R. ·\. Sd1oc11rcld. ( '. l cwis. and J . 1 ·cdcr. " l.argc-Scalc M.11111nalian Cell ( ulturc:
`Dcsign and l ',c or an [c,,nomic";tl Ba1d1 Suspcn,ion Sy,lcrn." /Jio,,., /r /Jio, 11,1. 2-' 1671. l'l!!2
`·\ I i.:.:hlcr. ··Jlalch and ( 011ti1111011s Cultmc of Microbial. l'la111 and Anun:il Cdls:· r -153 in
`/J,.,rn l111oloa1·. vol I. II -J. Rehm and C,. Recd tc<l,. >. Verl.1g ( hc1111c. Wcrnhcim l'JH :?.
`II \V D. l.:;,1i11gcr and \\/. Sdtdrcr. ··swtus and D<!1·clopmcnh or ,\111im;II Ccll I cdurnlogy u,ing
`S11spc11,i,1n ( ullurc lcd1111q11cs:· .·lt1<1 llior.-,/1110/oyi,-11, 2· .1. I'll!:?.
`~~- 1\1. W. (ila, ~cn. IC J . I lc1Sdtak.:r. and .-\. J. Srn,kcy. " l.argc•,calc l'roduclion of i\fammahan
`< db an<l I h,1r l'n,duc1s· f nginccring l'rin1.·1plc, and Barrier, lo S1.alc-11p .. -t1111,1h \. l
`.-k11d.
`S,i. -' U· .155. I')'\ 1
`'i<>. I' I . Kru,c. Jr .111d M h.
`l'i-css. I 11..-.. I '171
`'i7 I. S. Johns,>n .111d <, B llotlcr. --;-.1c1ah1•li1cs from ,\nimal and Plant ( cll Culture." Jdr . ;\li<r,,.
`/>iol. 15· ~15. 1971
`IC .-\1.ton ;111<1 J D I )IHI (cd, ). ( di ( 11/1111·,· 11111/ it., .-l1•1•l1u111011. Academic Prc,.,. New York. rein.
`'ill
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