`
`Fanaa,
`
`
`
`
`y Brinker
`
`
`
`
`
`
`erankfurt ani Main, Germany
`
` rE Evans
`Nesdé Research Center, Sernpt-
`
`
`stitulion of Chemie:
`thal, Switzerland
`Knaineers, Rugby, Great Britain
`
`Gremn
`
`cal University of Munich,
`Preising- Woihensieplian,
`CGeornany
`
`
`
`Lurgi AJe
`Germany
` gory
`
`ephanopoulos
`Chusetis Institute of
`
`
`y, Cambridye MA USA
`
`
`
`BASF Akticngesclischaft,
`Ludwigshafon.
`
`
`
`Apa
`
`
`
`
`
`Yt
`Chenetall Gabe, Frankfurt am
`Main. Germany
`
`Wolfgang A. Herrmann
`
`hnieal Cniversity of Munien,
`Garehing rl ALY
`Vilneim Keim
`
`RWTH Aachen,
`4
`Lachen,
`Germany
`
`
`
`
`
`
`
`
`
`
`
`
`Chemical Industry fistitute
`
`acolory, Albuquerque, NM
`
`
` dolmsen a
`Brunswick. SJ US.4&
`
`Mitchell
`
`
`ell Laboratories,Murray Hall
`REUSA
`
`t
`
`Alia Mitsute
`
`1
`
`
`Mippon ©
`atoch Consulfing,
`Takarazuka, Japan
`
`
`
` C
`
`ation, Fokve. Japan
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 1
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 1
`
`

`

`
`
`Sixth, Completely Revised Edition
`
`Volume 10
`
`|
`
`Cyrogenic Technology
`to
`Dithiocarbamic Acid
`and Derivatives
`
`WW)WILEY-VCH
`
`
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 2
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 2
`
`

`

` DS AES
`
`
`Numerical data, descriptions of meihods or equipment,
`and other information presented in this book have
`beencarefully checked ofaccuracy. Nevertheless,
`authors and publisher do nol assume anyliability for
`misprints, faulty statements, or other kinds of errors.
`Persons intending to handle chemicals or to work
`according to informationderived from this beok are
`advised to consult the original sourcesas well as
`relevant regulations in orderto avoid possible hazards.
`
`Library of Congress Card No.: Appliedfor.
`
`British Library Cataloguing-in-Publication Data:
`A catalogue record forthis book is available fromthe
`British Library.
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`datais available in the Internet at <http://dnb.ddb.de>.
`
`
`
`ISBN 3-527-30385-5
`
`© 2003 WILEY-VCH Verlag GmbH & Ca, KGaA,
`Weinheim.
`
`Printed on acid-free paper.
`
`The paper usedcorresponds to both the U.S.standard
`ANST 2.39.48 ~ 1984
`and the European standard [ISO TC46.
`
`All rights reserved (including those of translation into
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`other means ~ nortransmittedor translated into a
`machine language without written permission from the
`publishers. Registered names, trademarks, etc. used in
`this book, even when not specifically markedas such are
`not to be considered unprotected bylaw.
`
`Cover Design: Gunther Schulz, Fussg$nheim
`Composition: Sieingraeber Satztechnik GmbH,
`Dossenheim
`Printing: Strauss Offsetdruck GmbH, Mérlenbach
`Bookbinding:Litges & Dopf Buchbinderei GmbH,
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`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 3
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 3
`
`

`

`
`
`
`
`extra
`
`ARTHONY N. bE BeLoer, PdConsulta
`
`
`
`
`
`sala, Sweden
`
`Bs
` Ori
`
`
`
`Storage 2... ee 438
`&
`Uses oo... 0... ee. 43s
`&
`6.1. CHimical Products 000.00 0000000. 438
`6.2. General Uses
`o. 0.0000 0..0500.. 439
`
`EKconomic Aspects 2. ....0.0.0000.. 439
`7.
`o
`8
`Toxicology .. 00.0.0 .000004..
`
`References 0.0.0.0 .000..0..000.. 4a
`.
`
`chemical, and biological reports have therefore
`
`focused on this dextran. Uniess otherwise stated,
`the discussions in this article are concerned only
`with B-S12 1"). Figurel shows its structure.
`
`2. Structure, Chemical, and
`Physicochemical Properties
`
`2.1. Structure
`
`The dextran elaborated by Leuconostoc mesen-
`teroides NRRL 8-512(F} consists of
`an
`c(U—-+ 6)-Linked glucan with side chains at-
`tached to the 3-positions of the backbone giu-
`cose units. Fromperiodate and methylation anal-
`yses, the degree of branching is estimated to be
`5 %. Upon hydrolysis,
`the degree of branch-
`ing is foundto decrease slightly with decreasing
`molecular mass.
`The 'H- and '°C-NMR spectra afford com-
`pelling evidence for the main structural fea-
`tures of dextran [9]. The degree of branching
`of clinical dextrans as determined by '*C-NMR
`is 4.0-~6.0 %,
`Many details of the fine structure are unre-
`solved, in particular the length and distribution
`of the side chains. LARM and colleagues con-
`cluded that 40 %of the side chains are one
`unit long, 45 % are two units long, and there-
`maining 15 % are still longer [10]. The pre-
`ponderance of single unit branches in several
`other dextrans, Leuconostoc mesenteroides B-
`{375, B-1415, and B-/41]6, has been established
`
`introduction 2.00.00 0.0... ....0.04 435
`
`Structure, Chemical, anc
`Physicochemical Properties ©... 0... . 435
`Structure . 00 eee 435
`Physicochemical Properties .. 0... .
`. 436
`Reactivity 0.0.0.0 0.0.0.0 0000. 437
`Production o....000........... 437
`
`
`
` j
`
`2.
`
`.. 0.000.000 .0.000. 437
`3.4. Biosynthesis
`32, Production of Clinical Dextran
`..... 437
`
`L. introduction
`
`The term dextran [9004-54-0] refers to those
`polysaccharides which are composed primarily
`of | > 6 linked a-p-glucopyranose units. Many
`dextrans contain branches attached to C-2, C-3,
`or C-4. Others may also contain | — 3 linkages
`in the main chain.
`The formation ofslimes andjellies duringthe
`processing of wines and in sugar refining has
`
`ong been an undesirable complication. In the
`middie of the 19th century, reports by PASTEUR
`[lland Van Trecitem[2] implicated a bacterial
`
`mechanism. The name dextran appears to have
`been assigned ca. 1870 by SCHEIBLER |3[, who
`also established that dextran was a polymer of
`glucose. Further references to the early history
`of dextran are available [4].
`Dextrans are synthesized from sucrose by a
`large numberoforganisms. JEANES and cowork-
`ers have characterized over 96 strains of dextran-
`producing bacteria [5]. These bacteria are con-
`fmed to the family Lactobacillaceae and in par-
`ticular to the genera Lactobacillus, Leucanos-
`toc, and Streptococcus. Several members of the
`Streptococcus group are implicated in the devel-
`opment of cariogenic plaque on tooth surfaces
`iS], [7].
`Leuconostoc and Lactobacillus dextrans are
`also undesirable contaminants in the sugarrefin-
`ing industry, in which they adverscly affect the
`filterability and crystallization of sucrose [8].
`Only the slightly branched dextran from Leu-
`conostoc mesenteroides B-512(F) is of com-
`mercial interest. Most of the chemical, physico-
`
`t r
`
`
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 4
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 4
`
`

`

`
`
` -
`
`aeoe“
`ot-
`
`:
`
`aea“a
`
`bdneendnbs dalnnratitinemnnietnnneernntamrntareabuadntinbababemnoemnseenrinbaneneernbaernmnbunnciindenbsnmuteds
`40°
`we
`we
`Moon
`
`Vignre 2. Log-log plot of intrinsic viscosity [77]
`mass-average molecular mass My for dextran B-
`
`and for a hypothetical linear dextran (b)
`
`
`
`against
`5L2 fay
`
`
`The of(1->6) linked polysaccnarides re-
`present a class of very flexible and ended
`polymers. Tabic 1] shows the relationship be
`
`ween mass-average molecular mass and the
`dius of gyration, At Ingh molecular masses,
`
`ihe molecules display increased symmetry (131,
`
`
`Table £. Molecular dimensions of dextran B-512(F1 [16]
`
`ms of gyration, am
`
`
`Molecular mass My
`
`2x 108
`5 10°
`bx 19°
`sx 194
`
`(Albumin)
`
`a8
`20
`95
`68
`3.5
`
`conformation. Several attempts have been madc
`
`At M, 2000, the solution Properties are best
`explained byatransition ren a coil to a rodlike
`to crystallize dextran, and CHanzy et al. grew
`single crystals from a dextranfraction havi
`
`19 900 and proposeda ribbon-like conformation
`f18}.
`
` yhty of Gexiranases w:
`
`
`
`roperieshas permitted W,
`
`
`
`cetheseresults pi2i.
`
` ies of the v
`ryaeEVICH
`
`Dextran B-512(F)
`is
`freely soluble in| wa-
`ier, methyl
`sulfoxide,
`formamide, cthylene
`glycol, glycerol, Nor ethylnorpholine-N-oxide,
`Some dextran
`and hexawnmethy!Iphosphoramide,
`
`
`
`n degrce of
`adopted a
`i
`cry:vstallinityand can only be brought inte s<
`
`
`tion by stro
`eating.
`The moleccular mass of hydrolyzed natural
`dextran NRRL B-312(F)is 9x 108 to 510>LO°
`13], [iS].
`IMeasurements ina variety of sol-
`
`
`
`
`s
`(c.g., 4M agueous sodium chloride and
`6M aqueous urea)
`failed to reveal any eidence
`
` t
`
`ofassociation.
`Therelationsnip between the mass-average
`
`molecular mass My, and meintrinsic
`viscosity
`is shown in Penis2 443), (16).
`tamed the viscosity deypendence
`the clinical rannee [i6)
`
`q|
`
`viscosily
`were
`Ll = iotrinsic
`§
`lecular m‘ 8.
`MM, = viscosity-avera
`
`The colloid osmotic pressure of dextran so-
`
`lutions significan
`their plasma volume
`expansion [17].
`
`and
`
`
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 5
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 5
`
`

`

`
`
`
` Reactivity
`
`m2 oSe ct% =
`
`fete Ga}aad
`
`
`
`the reactivity of the
`As with other glucans,
`hydroxyl group at position2 toward alkylat-
`2 agents is higher than at position 3 or posi-
`4. Studies on the partial methylation of dex-
`ion
`
`wan revealed the followingrelative reactivities:
`ko 1 kat kg= 16:2: 7. Migration of the sub-
`stiinents may subject acylations to thermody-
`
`mic control. Thus, although partial acetyla-
`
`of dextran with acetic anhydride — pyridine
`in formamide as solvent gave ko > ky=kz4, the
`reactivities were virtually identical when there-
`
`action was carried out with acetic anhydride in
`aqueous alkali [19].
`
`3. Production
`
`3.1. Biosynthesis
`
`and
`The early work of BeverincK [20]
`HenRE [21] showed that dextran was clabo-
`rated by an extracellular enzyme designated
`dextransucrase (sucrose-!,6-a-D-glucan 6-a-
`
`giucosyltransferase, B.C. 2.4.1.5)
`The dextransucrases from many Leuconostoc
`and Streptococcal strains have been isolated and
`their properties studied. The purified B-512 0)
`enzyme, which binds dextran strongly, rapidly
`loses activity at 4°C and even at — 15 °C. Its ac-
`tivwy decreases by 60 %over 20 d. The enzyme
`can be stabilized by adding dextran (> 4 mg/mL)
`5if,pee
`Dextransucrase appears to be a glycoprotein
`(M@,. 64.000) with mannose being the primary
`sugar, Calcium ions appear to be essential for
`the activity of the enzyme.
`A mechanism for the biosynthesis has been
`proposed whereby the enzyme serves twofunc-
`tions [23]. It first hydrolyzes the sucrose and
`binds the glucosyl moiety, and thereafter it
`builds up the dextran chain byan insertion mech-
`anism (Fig. 3).
`he biosynthesis can be terminated by any
`one of a large number of acceptors, and ifso,
`the dextran chain is released. Examples of ac-
`ceptors are maltose, isomaltose, and methyl-a-
`b-glucoside. Dextranitself can also function as
`an acceptor[24].
`The formation of branches is also an accep-
`tor reaction in which a ring hydroxyl group on
`a dextran molecule is inserted in the growing
`dextran chain.
`
`Figure 3. Two-site mechanismfor the biosynthesis of dex-
`tran chains by dextransucrase
`G-P represents a sucrose molecule composed of glucose(G)
`and tructose (F). G--G represents a (1
`> 6) linked ghicose
`residues. The binding sites X may not pe identical.
`
`3.2. Production of Clinical Dextran
`
`In the West, naost major manufacturers of dex-
`tran employ a process based on the batchwise
`culture of Leuconostoc mesenteroides B-512(F}
`ip the presence of sucrose. The viscous culture
`fluid is precipitated in an alcohol, and the native
`dextran then is hydrolyzed and fractionated to
`the desired molecular mass range. In Japan and
`Eastern European countries, different strains of
`Leuconostoc are used, but the dextrans produced
`are of similar structure. The preparation of dex-
`tran on a laboratory scale has been described in
`letail [25], and the industrial production ofdex-
`tran has been reviewed [26-28].
`To obtain vigorous growth of the organism,
`the culture medium must contain various nutri-
`ents in addiGen to sucrose. In practice, these
`are supplied by addition of cither veast extracts,
`corn steep liquors, or malt extracts with peptone
`or tryptone broth. The pH of the medium af-
`fects both the production of dextransucrase by
`the organism and the activity and stability of the
`enzyme; Figure4 shows the pH changes. The
`influence of sucrose concentration on produc-
`tion of dextran has been reviewed [26]. A su-
`crose concentration of ca. 10 % is satisfactory; at
`higher concentrations the yield of dextran with
`My, >» 5000 decreases. The cultures are main-
`tained al a temperature of ca. 25 °C, al which
`the fermentation is complete after 24 —48 h. Pro-
`longation of the cultures for morc than 48 h may
`lead to a decrease in molecular mass ofthe dex-
`tran.
`
`The native dextran that is obtained ts then
`subjected to partial hydrolysis to form products
`of appropriate molecularsize, and fractionation
`byethanol or methanol to give clinical fractions.
`
`
`
`
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 6
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 6
`
`

`

`
`
`438
`
`Dextran
`
`Extensive studies on the acid hydrolysis and
`fractionation of native B-512(F) dextran have
`been carried out and conditions for maximal
`yields have been established [29], [30]. Follow-
`ing the partial hydrolysis,
`the clinical fraction
`can be precipitated with 39-46 % aqueous eth-
`anol under careful temperature control (25 °C).
`Membrane technology now often replaces etha-
`nol fractionation in purification operations. The
`product is then redissolved and spray dried.
`
`is now determined by size exclusion chro.
`matography. Other quality parameters are acid.
`ity/alkalinity, nitrogen impurities, residual sol-
`vents, heavy metals, sulfated ash, bacterial en-
`dotoxins, and microbial contamination.
`
`5. Storage
`
`Dextran is stable indefinitely whenstored in the
`absence of light, excessive heat, and moisture.
`Sterile solutions ofclinical dextrans with pH
`4-7 have excellent chemical stability (at least
`{0 years) when stored at 4-40 °C.
`Clinical dexiran solutions tend to form small
`amounts of flakes if kept in glass bottles and
`subjected to considerable temperature fluctua-
`tions. These flakes have been found to consist
`of dextran with the same M, as the substance in
`solution. They redissolve upon heating.
`
`6. Uses
`
`
`
`Tr 20
`16
`
`ae
`
`|
`
`og
`
`Dextran
`Cyetommemannrmnne6
`
`iWe
`2
`
`ined
`
`
`93
`6B bE Sf
`78
`ee er ompH
`So
`
`c
`324
`22 ot +tJ ge
`Time, days - Bion
`
`al
`» ibe
`ne
`a |
`3 ce 4
`
`
`
`
`
`6
`
`Sucrose
`
`Figure 4, Changes in sucrose concentration, pH, and dex-
`tran concentration during the fermentation of Leuconostoc
`mesenteroides
`
`6.1. Clinical Products
`
`3.3. Future Trends
`
`Several alternative processes have been devised
`over the years:
`
`1) Fermentation with cell-free extracts
`2) Fermentation in the presence of acceptors
`3) Continuous processes
`4) Use of immobilized dextransucrase
`
`About 40years ago, a sapplement(1 mg/mL)
`of low molecular mass dextran was found to
`yield a product dextran of lower molecular mass
`[31]. Few producers have adopted this type of
`process for clinical dextrans. One drawback is
`thai
`il requires a production facility for low
`molecular mass dextran.
`Promising results have been obtained with
`immobilized dextransucrase but only on a labo-
`ratory scale [32].
`
`4. Quality Specifications
`
`Monographs for quality specifications of dex-
`tran40, 60, and 70 substance have been pub-
`lished in the European Pharmacopoeia and for
`dextran40 and 706 in USP. The molecular size
`
`Dextran 70 (M7. ca. 70000) is marketed in most
`countries as a 6 %solution in normal saline and,
`as such, represents the plasma volume expander
`of choice. It is one of two plasma volume ex-
`panders included in the WHO list of essential
`drugs. Clinical experience supports iis use in
`the treatment of shock or impending shock as
`a result of hemorrhage, burns, or surgery. Dex-
`tran 60 has replaced dextran 70 in some parts of
`Europe.
`Dextran 40 (Mf, ca. 40000) was introduced
`in 1961 following studies ofthe erythrocyte. dis-
`aggregating and blood flow improvementprop-
`erties of lower molecular mass dextrans. It
`is
`marketed as a 10 % solution in normal saline
`or 5 % glucose which provides rapid plasma
`volume expansion and promotes microcircula-
`tory blood flow. Both products are used exten-
`sively to prevent fatal pulmonary complications
`of surgery, trauma, and shock. A 6 %solution of
`dextran 70 in a hypertonic saline solution (7.5 %
`Natl) has been shown to be exceptionally effec-
`tive as a plasma volume expander for primary
`(prehospital) resuscitation in severe trauma and
`hemorrhagic shock [33].
`In 1982, the monovalent hapten dextran | (4
`fraction of M,, ca. 1000) was launched as pro-
`phylaxis againstdextran-induced anaphylactoid
`
`
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 7
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 7
`
`

`

`
`
`
`
`
`an aston-
`
`ommonly adied io infusion and
`
`
`Several microcarriers
`
`ons, for example, in connect
`ni brans-
`
`dextran substituted W
`
`
`;. A dextran sulfate of M,, 7€
`0 and sulfur
`
`
`tient of116%Te WasStesied chinal aS an anti-
`fe8 Cytodex)
`
`
`in rage-c-cepeniden
`
`
`
`
`ed, it caused toxic
`: production
`
`ate with M, ap-
`:
`WX.8009 with in vitro antiviral properties has
`
`=i tested in patients with HIVinfection. The
`‘ ultss were not encouraging[35]. A dieethylami-
`
`noethyl derivative of oye (My ca. 500 000)
`
`
`
`seen foundto beeffectivein reducing serum
`
`usec"widely for
`anemic©pigletsaand‘henans,
`
`1 1977, a cross-linked Gextran in bead form
`Debrisan) was introduced as awound-cleansing
`gent for secreting and infected woundsin par-
`
`
`
`7. Economic Aspects
`
`Exact figures for the annual world production aré
`
`not available butihe size of magnitude would b
`somewnat in excess of SOO C.
`The major producer of dextran is Amersham
`Pharmacia Biotech (Uppsala, Sweden): other
`producers are Meito (lapan), Polfa (Poland)
`Pharmacosmas (Denmark). The maior produc~
`ers of clinical dextran solutions are: Abbott
`(United States), Baxter-Traveno! (Unites States
`and Europe),), Polfa (Poland), Infusia (Czech Re-
`public), Otsuka and Green Cross (Japan),
`FR.
`Braun(Germany) and Pharmalink (Sweden).
`
`8. Toxicology
`
`‘The infusion of chnical dextran solutions in hu-
`mans is now approved by the regulatory au-
`Unorities in most countries. No adverse effects
`are to be expected, provided the recommended
`doses are observed. However, a low incidence
`of dextran-induced anaphylactoid reactions has
`been reported. The risk ofthis type of reactio
`has been virtually eliminated bythe preinjection
`of 20mL of a 15 % dextran 1 (4, ca. 1000) so-
`lution [40].
`Dextran B-512(F) given orally is degraded
`by bacteria m the gut and the products produce a
`rapid increase in bloodsugar and liver glycogen.
`Dextran administered intravenously is degraded
`in the liver to carbon dioxide and water.
`Dextrans arc not permitted as food additives
`mthe United States and Western Furope [41],
`[42], but
`they are considered safe as compo-
`nents of food packing materiais. Dextrans may
`be used as additives in pharmaceutical and cos-
`metic formulations providedthat the necessary
`safety documentation is presented.
`
`€.2, General Us
`
`
`
`Portied dextran fractions are currently used in
`the cosmetic and photographic industries. A
`
`apprehensive bibliography covering dextran
`
`erature and patentsis available [36]. Dextran
` Ta
`ciions find application for partitioning sub-
`cellular particles in two-phase polymer systems
`
`as cryoprotective agents.
`.
`Sephadex gels, prepared by emulsion poly-
`merization of dextran, have occupied a demi-
`nant place among gel filtration media for many
`years. Sephadex G-25 is used on an industrial
`scale for desalting operations during the purifi-
`cation of biopolymers of medical
`importance,
`g., insulin.Manyofthe ion exchangers derived
`n Sephadex are also used commerciallyfor
`separations [37].
`Dextran fractions have been used extensively
`for preparing conjugates with biologically active
`substances, c.g., drugs, enzymes, and hormones
`
`(38). Conjugation prolongs the lifetime of the
`active componentin vivo, increases its stability,
`and facilitates the tarecting of the active com-
`ponent. Many dertvatives of dextran have been
`described and numerous patents have appeared.
`However, few haveattained significant commer-
`cial interest. Dextran sulfate (M7, ca. 500 000;
`sulfur content 18 %) and diethylaminocthyl dex-
`
`
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 8
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 8
`
`

`

`vy. Carbotyar CLA. Witham, 3.
`
`
` n. Chem. boc. 76 (1964)
`
`2
`
` 2
`
`MO
`
` . Walker:
` PRY
`470 -a7,
`
`Manners (ed):)
`
` timore i
`vol. 46, Univ,
`3G, M.7fief, G. Bruber, .
`
`pp. 75-110.
`
`a(1959
`
`&. PA. Inkerman in M.S, Lopez, €. MM. Madraze
`{eds.): Proceedings X VECCongress,
`tonal §*eeteny f
`Sugar Cane
`
`hnologists, WG13]aulive Committee of
`
`oT, Metro Manila 1980, po. 2411-2427.
`>. Gagnaire, M. Vignon, Makromol, Chem.
`178 (1977) 2321-2333.
`1G. ©. Larm, B.
`I
`dbeerg, S. Syensson,
`ry
`EL Weivel
`20 (1971) 39-48.
`ume
`Hi. Autson, H.
`Weige
`,
`bed
`«
`_
`Biochem. J. 8(1.963) 555-562.
`12. c.taylor, NW. Cheetham, Gud.
`aC
`;
`om
`
`
`_%
`.
`
`E37 (985)
`3.
`(3.
`Gellman, N.W Toa
`1
`p
`g
`Polym. Sei.
`al, J,
`°
`.
`
`
`
`4
`
`tA. Stormo
`
`Oe
`oe
`a
`9, Suppl. 29 (1957).
`3
`4
`Be ant\ 9RaA
`oe
`35. ©. Flexner ct al., Antimicrob. A
` 2550.
`
`
`emother., 35 (991) 2544—
`
`ae
`.
`hae:
`Bibhioer
`ay
`Aiags
`Dextran £presenMEMise.
`36,
`Publication no. 1355, U.S. Depart
`a
`Agriculture, Washington 1978.
`
`
`Mi. Curlin
`J.
`
`Proteins, Phar
`Uppsala 198
`38. L. Molteni in HL Bundgaard,A u. Ka
`
`
`oe ws
`yp ae
`me elak
`Kofod (eds.
`
`. Granath, J Colloid Sci. 13 (1958)
`\S ‘.
`
`
`
`OD howe Os
`a9
`Munksg
`
`Copenhagen 1982, pp. 2
`
`a>
`2. A. Rogovin, A.D. Virnik, K.P Khomiakey,
`. Gruber: Blutersaiz
`
` j nger Verlag,
`
`
`nactal,
`£ Macromol. Sei. Ch
`18. 6suizard, H. Chanzy, A. Sarko,
`erlin 1968, p. 68.
`2) $69 493,
`39. A.N. de Belder in R.L. Whistler (ed.):
`Macromolecules 17 (1984) 1G0- 107,
`
`
` 19. ALN. de Belder, B. Norrman, Carbaln Res.
`
` industrial Gums: Polysaccharides and Their
`
`
`8 (1968) L-6
`,
`Derive ives, Grd ed.Academic Press, 1993.
`wa
`“jerinck, Akad. Wetensch.
`40, AOW. Richter, H.1. Hedin, Pumunol. Today 3
`
`a
`(FORD)
`139.138
`Amsterdam Proc. Sect, Sc. 12 C910) 635.
`(1982) 132-138.
`
`4], M. Glicksman in M. Glicksman (ed.j: food
`2i, ELF. Hehre, Science (Was
`hington, B.C, 1883)
`i
`colloids,
`val.
`1Wate Press, Boca
`
`83 (1941) 237-238,
`137,
`22, M. Kobayashi, K. Matsuda, Biochem. Biophys.
`I
`
`
`tea.
`en
`AD
`Fed Revist
`Acta 644 (1980) 46-62.
`“2. Fed. Regist. 42
`-> Glucose and Glucose-Containing Syrups
`Dextrose
`Diacetone Alcohol
`-> Acetone
`Diacyl Peroxides
`-> Perexy Compounds, Organic
`
`.
`
`4,
`‘A
`
`37.
`
`
`
`Raton, Florida,
`
`
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1037 - Page 9
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1037 - Page 9
`
`