Journal of Diabetes Science and Technology
`Volume 5, Issue 1, January 2011
`© Diabetes Technol ogy Society
`
`Injection Force of SoloSTAR'Jt Compared with Other Disposable
`Insulin Pen Devices at Constant Volume Flow Rates
`
`Thomas van der Burg, B.Sc.
`
`Abstract
`
`Background:
`Injection force is a particularly important practical aspect of therapy for patiei1ts with/ diabetes, especially
`those who have dex terity problems. This laboratory-based study compared the injection force of the SoloSTAR®
`insulin pen (SoloSTAR; sanofi-aventis) versus other available disposable pens at injection speeds based on the
`delivered volume of insulin released at the needle.
`
`Method:
`Four different prefilled disposable pens were tested: SoloSTAR containing .insuljp glargine; FlexPen® and the
`Next Generation FJexPen® (NGFP) (Novo Nordisk), both containing insulin deternir; and KwikPen® containing
`insulin lispro (Eli Lilly). All pens were investigated using the maximum dispense volume for each pen
`type [80 units (U) for SoloSTAR; 60 U for the other p ens], from the free needle tip dispensing into a beaker.
`Twenty pens of each type were fitted with the recommended needles and tested at two dose speeds (6 and
`10 U/s); each pen was tested twice.
`
`Results:
`Mean plateau injection force and maximum injection force were consistently lower with SoJoSTAR compared
`with FlexPen, NGFP, and KwikPen at both injection speeds tested. An injection speed of 10 U/s was associated
`with higher injection force compared with 6 U/s for all the pens tested (p < +.001).
`
`Conclusions:
`SoloSTAR stands out because of its low injection force, even when compared with newer insulin pen devices
`such as the KwikPen and NGFP. This may enable patients, especially those with dexterity problems, to administer
`insulin more easily and improve m anagement of their diabetes.
`
`J Dinbetes Sci Tec/1110/ 2011;5(1):150-155
`
`I 2,00 :rJ:,
`I '-3-,1 :bob
`
`Author Affiliation: sanofi-aventis D eut sc hl and GrnbH , Si te Fra nkfurt Devices/ Dev ice Industri ali sa ti on, Frankfurt, Germ any
`
`Abbreviations: (N) new ton, (NG FP) Next Generation Fl ex Pen, (U) unit
`
`Keywo rd s: flow rate, injection force, injecti on speed, insu lin pen
`
`Corresponding Author: Thom as van dcr Burg , sa nofi-avcnti s Dcutschl a nd GrnbH, Site Frank furt Devices/Device Industri alisation , lnd ustricpark
`H oec hst, D-65926 Frankfurt am Ma in, Germany; email address tl1<ll11!l, .<m11da/J11rn@;1111u/;-t1<1<'11/is.cu111
`
`150
`
`Sanofi Exhibit 2100.001
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Inj ec tion Force of SoloSTAR® Compared with Othe r Disposable Insulin Pen
`Devices a t Constant Volume Flow Rates
`
`Introduction
`
`Lie first insulin pen device was introduced in 1985.
`
`Since th en, continuing innovation has led to a steady
`improvement in
`the devices availabl e and
`they now
`account for about half of worldw ide insulin use. 1
`
`There are numerou s disposa bl e pen devices available on
`the market in the United States,2 Europe, and Japan, such
`as FlexPen® (Novo Nordisk, Bagsvaerd, Denmark), more
`recent di sposa bl e devices such as KwikPen® (Eli Lilly,
`Indi anapoli s,
`lN), and
`th e so-called Nex t Generation
`Fl ex Pen® (NGFP) (Novo Nordi sk, Bagsvaerd, Denmark).
`
`injection device
`The Lantus® SoloSTAR® d isposabl e
`(sa nofi-aventis, Pari s, France) was launched in 2007 and
`meets a combination of user needs that had not been
`previously addressed and still remain unmet by other
`d ev ices on th e market. These include ease of inj ection,
`di fferenti ation of insulin type through p en body color
`and tacti le elements, and the ability to inject up to
`80 units (U) of insulin in one injection w ith a comparatively
`short di al stroke, which is particularly useful for patients
`w ith impaired m anual dexterity. 3 The SoloSTAR pen
`was developed through a process of iterative design and
`feedback qu estionnaires involving patients, h ealthcare
`professionals, the design team, and consultants in order
`to comprehensively assess the needs of patients who use
`insulin pens. 3
`
`Injection force is a particularly important practical aspect
`of therapy for patients with type 1 or 2 diabetes, especially
`for those who ha ve dexterity problem s; these patien ts
`may have limited ability to self-inject insulin.4- 7
`
`The aim of this study, therefore, was to compare the
`injection force of th e SoloSTAR pen with three other
`commonl y avail able di sposa ble pens at two different
`injecti on speeds based on a delivered volume of insulin
`released at th e needle (consta nt volum e flow rate) w ithin
`a
`laboratory settin g. Thi s
`is
`th e first stud y directly
`evaluating the injection force of these three insulin d ev ices
`on the basis of the di spensed dose per time, using reali stic
`d ispense speeds for practical use.
`
`Methods
`
`Four different pen injection devices were tested in thi s
`in vestiga ti on: SoloSTAR
`insulin glargine pen
`(batch
`number 40U286), Flex Pen in sulin d etem ir pen (batch
`
`va n der Burg
`
`(batch
`number VH70215), NGFP insulin detemir pen
`number VH70007), and KwikPen
`insulin
`li spro pen
`(ba tch number A477063).
`
`two dose
`tested at
`type were
`Twenty pens of each
`speeds (6 and 10 U/s); each pen was tested t,,vice, with all
`doses d eli vered into a beaker. Tests we re carried out using
`the maximum di al stroke and di spensi ng the maximum
`dose volume of each pen type (80 U for the SoloSTAR;
`60 U for the comparator pens). All investigati ons were
`conducted using the manu facturers' recommended needles
`with a consistent outer diam eter of 0.25 mm based on the
`manufacturers' specifications: BD Micro-Fine 0.25 mm
`(31G) x 5 mm for SoloSTAR and KwikPen; NovoFine
`0.25 mm (31G) x 6 mm for FlexPen and NGFP.
`
`Labora tory tests were conducted using a tensile m eter
`(Zwick GmbH & Co. KG, Ulm, Germ any) and force
`cell
`[KAF-TC, Zwick GmbH & Co. KG, Ulm, Germany;
`nominal load 200 newtons (N)] under stand ard ab11ospheric
`conditions. The di stance traveled by the push button to
`deliver the appropriate dose was determined to be different
`for each of the p ens, necessitating a different push button
`speed to be chosen for th e four devices. Before evaluating
`each pen, the appropri ate needle was mounted and correct
`fitting ensured by di spensing a priming dose of 10 U.
`For each pen device, the injection force throughout the
`dose d eli very was m easured (Figure 1). The mean force
`va lue (mea n plateau injection force) was calculated and the
`maximum injection force evaluated.
`
`20
`
`-- -- ·- --- - -- - - ---- ··-- -i- -
`
`0
`
`i
`
`SliHI of
`measurement
`
`10
`
`Distance (mm)
`
`20
`
`Figure 1. Example force m easurement cu r ve. Laborn tory tests were
`ca rri ed out in order to de termine th e injection force of insulin pen
`d ev ices at maximum insulin dose and two inject ion s peeds (6 a nd
`10 U/s). Injection for ce throughout the dose delivery w as measured
`a nd mean pl atea u a nd ma ximum va lues eva lu at ed.
`
`J Diabetes Sci Tec hnol Vol 5, Issue 1, J a nuary 2011
`
`151
`
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`
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`Mylan v. Sanofi
`IPR2018-01676
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`

`Injection Force of SoloSTAR® Compared with Other Di sposable Insulin Pen
`Devices at Constant Volume Flow Rates
`
`van der Burg
`
`Stati stical analyses were carried out using Dunnett's
`test. A simultaneous test level of p < .05 was assessed with
`SoloSTA R as
`the reference group; the corresponding
`indi vidu al
`test level was p <
`.012 for each of
`the
`compared pairs. The differences in the m ea n maximum
`inj ection force and
`the mean pl ateau
`injection force
`between SoloSTAR and FlexPen, NGFP, and KwikPen
`were calculated, and th e resultant confid ence intervals
`were determin ed. The compared pair can be assum ed
`to be different (p < .012), if the confidence interval of the
`respective pair is larger than 0. Due to the suffici ent level
`of significance, no further declaration for the probability
`for the tested pairs was m ade.
`
`injection force
`that the
`Pre! iminary studi es revea led
`of insulin d ev ices w ith the ne edl e attached is mainly
`determin ed by th e following factors: friction between
`the mechanical parts of the mechanism; friction between
`the bung and the glass partiti on of the cartridge; fluid
`friction of the liquid (insulin); and tissue pressure. Because
`tissue pressure is difficult to measure or simulate with
`high consistency, all tests were performed by dispensing
`into a beaker. Preliminary studies also showed that the
`fluid friction of th e ex pelled insulin is mainly affected
`by changes in flow rates. Therefore, only comparisons at
`equal volume flow rates were pursued in this study.
`
`Theoretical considerations were made to determine the
`depend ence of fluid friction on the volume flow rate.
`Using basic fluid dynamics theory, one can demonstrate
`that the fluid friction of the insu lin being expelled causes
`an accessory pressure inside the cartridge that increases
`the force required by the user to disp ense the dose.
`The additional pressure can be calculated using the formula
`in Equation (1), which is deri ved from the Bernoulli
`equation8 by adding terms for th e press ure reduction
`caused by fluid
`friction 9 and cross-section changes. 8
`In Equation (1), p represents the density of the fluid,
`d,m•,II,• th e inner di ameter_ of the needl e,
`l,, 1•1,,11,. the total
`V the volume flow rate; a and
`length of the needl e,
`l;2 are empiri c coefficients main ly caused by crossover
`at the needl e tip, s1 is an empiri c coefficient for the
`crossover of the fluid between cartridge and needle, and
`A is the coeffi cient of friction for th e need le (depending
`on viscosity, flm,v rate, roughness of the needle, and
`need le diam eter).
`
`As p, d,,,,,11,, l,,,.cdlc, a, Si, l; 1, and A are rou ghly constant
`for one needle/device combination at the used flow rate
`area, th ey can be expressed as the constant coefficient
`B, resulting in th e simplified formula in Equation (2),
`where th e accessory pressure insid e the cartridge only
`depends on the volume flow rate of the insulin .
`
`t:,.p = B · V2
`
`(2)
`
`This formula was used to verify the theoretical approach
`by calculating the increase of th e injection force at
`10 U/s compared w ith 6 U/s for SoloSTAR w ith BO
`0.25 mm (31G) x 5 mm needles. Subject to A, an increase
`in the range of 2.8-4.4 N could be ex pected becau se of
`the higher volume flow rate.
`
`Results
`
`The mean plateau injection force at the maximum doses
`with the pens (SO U for SoloSTAR versus 60 U for the
`comparator pens) was significantly higher w ith FlexPen,
`NGFP, and Kw ikPen compared with SoloSTAR at both
`injection speeds tested (Figures 2A and 3A). The difference
`in mean plateau injection force compared w ith SoloSTAR
`for the various pens was 95, 51, and 43% with FlexPen,
`NGFP, and KwikPen, respectively, at 6 U/s, and 87, 47,
`and 37%, respectively, at 10 U/s (Table 1). An injection
`speed of 10 U/s was associated with high er injection
`force compared with 6 U/s in all the pens (p < .001).
`
`the ma ximum
`In line with the mean plateau force,
`injection force was also significantly higher with Fl exPen,
`NGFP, and KwikPen compared with SoloSTAR at both
`injection speeds tested (Figures 2B and 3B). The difference
`in maximum injection force compared w ith SoloSTAR
`for the various pens was 70, 26, and 29% with FlexPen,
`NGFP, and Kw ikPen, respecti vely, at 6 U/s, and 65, 31,
`and 30%, respectively, at 10 U/s (Table 1).
`
`FlexPen showed the highest injection forces of all tested
`devices. Although KwikPen and NGFP showed comparable
`maximum forces,
`the mean plateau force of KwikPen
`was calculated
`to be significantl y lower th an th at of
`NGFP (p < .012).
`
`Discussion
`
`(1)
`
`Among the four di sposable insulin pen dev ices compared
`in this study, the SoloSTAR pen had the lowest injection
`force irrespecti ve of the injection speed tested. The di spense
`force of all pens rose when dispensing the dose at higher
`
`J Di abetes Sci Technol Vo l 5, Iss ue 1, January 2011
`
`152
`
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`Mylan v. Sanofi
`IPR2018-01676
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`

`Injection Force of SoloSTAR® Compared with Other Disposa ble Ins ulin Pen
`Devices at Constant Volume Flow Rates
`
`van der Burg
`
`remained
`for SoloSTAR
`force
`injection
`speed, but
`significantly lm,ver than those of the other pens. This
`difference was observed for both mean plateau force and
`ma ximum force.
`
`The empi rical increase of the injection force at 10 U/s
`compared with 6 U/s for SoloSTAR was 3.7 N for the
`m ean plateau force, which corresponds to the theoretical
`expectation with a calc ul ated increase in th e range of
`
`A
`
`20
`
`18
`
`16
`
`14
`
`-
`z 12
`... 10
`(l)
`u
`0
`u..
`8
`
`6
`
`4
`
`2
`
`0
`
`Injection speed:
`II 10 U/s ■ 6 U/s
`
`B
`
`24
`
`22
`
`20
`
`18
`
`-
`16
`z 14
`... 12
`10
`
`QJ
`u
`0
`u..
`
`8
`
`6
`
`4
`
`2
`
`0
`
`FlexPen KwikPen NGFP SoloSTAR
`(80 U)
`(60 U)
`(60 U)
`(60 U)
`
`FlexPen KwikPen NGFP SoloSTAR
`(60 U)
`(60 U)
`(60 U)
`(80 U)
`
`Figure 2. Compari son of mean pl ateau injec tion force (A) and m ax imum injection forc e (B) at two injection speeds for each pen and dose tested.
`Mean plateau and ma ximum inject ion forces of the va ri ous insul in pen devices were measured at ma ximum insulin dose for each p en (80 U fo r
`SoloSTAR; 60 U fo r the other pens and at two injection speeds (6 and 10 U/s) fo r each pen. Twenty pens of each ty pe of device were tested twice
`for each dose and speed combin ation, and average valu es calcu lated. *p < .001 co mpared to comparator pen s at the sa me injection speed.
`
`Table 1.
`Injection Force with Various Disposable Insulin Pen Types, Doses, and Injection Speed Combinations
`
`Dose (U)
`
`Injection
`speed (U/s)
`
`Button speed
`(mm/s)
`
`Mean plateau
`injection force
`± S08 (N)
`
`Min-Max values
`(n)
`
`Maximum
`injection force
`± SDa (N)
`
`Min- Max values
`(n)
`
`SoloSTAR
`
`80
`
`80
`
`6
`
`10
`
`2.6
`
`4.3
`
`6.43 ± 0.59
`
`5.22-7.60
`
`9.30 ± 1.71
`
`6.17-14.68
`
`10.10 ± 0.84
`
`8 .72-12.15
`
`10.24-17.93
`
`FlexPen
`
`NGFP
`
`KwikPen
`
`60
`
`60
`
`60
`
`60
`
`60
`
`60
`
`a SD = s ta nda rd deviation
`
`13.10 ± 1.90
`
`6
`
`10
`
`6
`
`10
`
`6
`
`10
`
`3.3
`
`5.5
`
`3.3
`
`5.5
`
`2.8
`
`4.7
`
`12.51 ± 0.96
`
`10.72-1 4.30
`
`15.79 ± 1.41
`
`13.07-19.57
`
`18.91 ± 1.24
`
`16.05-20.91
`
`21.64 ± 1.52
`
`18.46-23.72
`
`9.72 ± 0.72
`
`8.44-11.87
`
`11.71 ± 0.83
`
`10.32- 13.75
`
`14.79 ± 1.50
`
`12.10-18.92
`
`17.13 ± 2.17
`
`13.76-25.30
`
`9.1 7 ± 1.54
`
`6.54-1 2. 50
`
`11.95 ± 2.52
`
`6.67- 16.58
`
`13.82 ± 1.31
`
`11.32-16.35
`
`16.99 ± 2.40
`
`13.13-22.51
`
`J Diabetes Sci Tec hno l Vol 5, Iss ue 1, January 2011
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`

`Injection Force of SoloSTAR® Compared with Othe r Di sposable Insu lin Pen
`Devices a t Constant Volume Flow Rates
`
`2.8-4.4 N. Therefore, the results of this study confirm the
`th eore ti cal approa ch that th e volume flow rate provides
`th e main influence on th e inj ection force for a sp eci fic
`pen /n eedl e combin ati on.
`
`The fi ndings from thi s study are in line w ith previously
`published laboratory-based studies in which the SoloSTAR
`pen had an improved injection force compared w ith the
`FlexPen device. 3
`
`The findings of thi s stud y disagree with the results of
`one study by Rissl er and colleagues 10 and one study by
`Asaku ra and colleagues,11 which suggested that the NGFP
`h ad a lower inj ecti on forc e compared with SoloSTAR.
`To und erstand the rel eva nce of these conflicting data, it is
`importa nt to recall that constant volume flow rates (U/s)
`were used in our study, whereas the other two studies
`used different injection button speeds (mm/s). The latter
`m eth odology m ea ns th at, even at equal inj ection button
`sp eeds, the insulin flow in terms of U/s is not the same
`between
`th e p en system s. Owing to
`the differences
`between the mechanisms of the pens, the volume of insulin
`expelled per second for SoloSTAR is 27.5% larger than
`that for Fl exPen and NGFP. Elucidating the differences in
`the volume flow ra tes, di sp ensi ng th e same volume of
`insulin w ith SoloSTAR requires a 22% smaller push(cid:173)
`button
`travel and
`inj ection
`tim e (not accounting for
`differences in the holding time). This shorter push-button
`travel as the result of th e s horter dial stroke extension
`is likely to be preferable for patients with impaired
`dexterity3- 7•I 2 as well as unimpaired patients. I3•14
`
`An observational, survey-based clinical study by Carter
`and colleagues reported hi gh levels of acceptance of the
`SoloSTAR device among patients both with and without
`manu al or dexterity impairm ent.I3 Participants found
`SoloSTAR easy to use and th at using the p en had a
`posi ti ve impact on th e managem ent of their diabetes,
`such as
`increasing confidence and helping overcome
`their reluctance to use insulin. I3 In a study by Haak and
`colleagues where ]6% of patients had dexterity problems
`and 19% vis ual
`impairment, more p ati ents preferred
`the effort required to inject a 40 U dose with SoloSTAR
`versus FlexPen. 14 The fi ndings of these studi es may relate
`to the lower injecti on force characteristics of SoloSTAR
`versus the FlexPen device as demonstrated by Clarke and
`Spollett. 3 Hm,vever, both of these studies demonstrated
`th e usa bility and acceptance of SoloSTAR
`in
`these
`popu lations; they di d not report the impact of injection
`forc e on th e outcomes. Therefore, prospective studi es
`are needed to ex tend
`th ese findin gs in patients with
`and without dexterity problems, and investigate whether
`
`A
`
`FlexPen, 6 Uls
`
`FlexPen, 10 Uls
`
`NGFP, 6 Uls
`
`NGFP, 10 Uls
`
`KwikPen, 6 Uls
`
`KwikPen, 10 U/s
`
`B
`
`FlexPen, 6 UIS
`
`FlexPen, 10 U/s
`
`NGFP, 6 Uls
`
`NGFP, 10 Uls
`
`KwikPen. 6 Uls
`
`KwikPen, 10 U/s
`
`van de r Burg
`
`······ •
`
`Difference in mean plateau injection force versus SoloSTAR (N, limits)
`
`f--♦ --;
`
`10
`
`10
`
`Difference in maximum injection force versus SoloSTAR (N, limits)
`
`Figure 3. Interva l of differe nces in m ean plateau inj ecti on forc e (A)
`a nd ma ximum injection forc e (B) betwee n SoloSTAR a nd the variou s
`compara tors at maxim um d oses tested . Mean pl a teau a nd maxim um
`injection forces of the va rious insu lin pen devices were measu red at
`ma xi mum insulin dose for each pen (80 U for SoloSTAR; 60 U for
`the oth er pens) and at two injection s peed s (6 and 10 U/s) for each
`pen. The average va lues for 20 pens tested twice each were calculated,
`a nd hence the difference be twe en th e average fo rces for SoloSTAR
`and each of the co mparator p ens as well as th e limi ts (calculated
`wi th Dunnet t's test for the di fference between the respecti ve group
`m ea n and SoloSTAR at 80 U). The d ifferences in t he m ea n m aximum
`injection force and the mea n plateau injection force between SoloSTAR
`and FlexPen, NGFP, and Kwi k Pen were calculated w ith the resulta nt
`confidence intervals shown in Figures 3A and B. Only if O is w ithin
`th e confiden ce interva l of the respective pair do es the tes ted d evice
`show no sig ni ficant difference to SoloSTA R. If O is not w ithin the
`confidence interval, the compared pair ca n be assu med to be different
`w ith a probabilit y of at leas t 98.8%. Du e to the su fficient level of
`significance (p < .01 2), no further decl arati on for the probability for the
`tested pairs seems to be of va lu e.
`
`the low injection force of ava il able insulin pens is an
`important fac tor in their use of insulin and ultim ately
`di abetes m anagement.
`
`In order to m ax imi ze clinical releva nce, we evaluated
`each pen together with the m anufacturer's recommended
`needle in order to emulate rea l-world use. While needl e
`outer diam eters were consistent, potenti al va riations of
`th e inner di a meter of needles within the manufacturers'
`specifications may have contributed to differences observed
`between th e pens. It must also be ack nowledged th at
`
`J Diabetes Sci Tec hnol Vol 5, Issue 1, J anuary 20 11
`
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`
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`

`Injection Force of SoloSTAR® Compared with Other Dis posable Insulin Pen
`Devices at Constant Volume Flow Rate s
`
`the study was performed in a simulated, laboratory
`environment, with doses delivered into a beaker rath er
`than inj ected into tissue. Therefore, the data m ay not fully
`reflect patients' perceptions of the forces encou ntered in
`everyday use of the devices because the injection force
`may be affected by th e different properti es of the ti ss ue
`being injected into and the indi vidual characteristics of
`the injection. Further investigations using m ore than the
`two different dispense speeds tested in thi s stud y might
`also be worthwhile to verify the influence of the volume
`flow rate. Additionally, the impact of injection force and
`injection speed on patients' perceptions of the pain of
`injection should be evaluated because there are limited
`d ata at present. A rapid speed of injection may be
`preferable to patients but may be achieved at the expense of
`increased inj ection force and increased patient di scomfort.
`
`Conclusions
`
`The results of this study confirm the theoretical approach
`that the injection force for a specific pen/needle combination
`is mainly influenced by the volum e flow rate. Therefore,
`it can be said that comparisons of injection forces at fixed
`button speeds are misleading and that the m ethodology
`used in our study provides a more realistic picture of
`the perform ance characteristics of the pens tested.
`
`The mean plateau injection force as well as the maximum
`injection force was significantly lower w ith SoloSTAR
`compared with FlexPen, NGFP, and KwikPen at both
`injection speeds tested. The lower injection force need ed
`w ith SoloSTAR versus the comparator pens may have a
`posi tive impact on the management of diabetes, particul arl y
`in patients who have dexterity issues.
`
`Even compared with newer insulin pen devices such as
`KwikPen and NGFP, SoloSTAR stands out du e to its low
`inj ection force as well as the possibility to inject up to
`80 U of insulin in one injection w ith a comparati vely
`short extension of the dial stroke.
`
`van der Burg
`
`Acknowledgments:
`
`Editorial support was provided by the Global Publications group of
`sa no fi-avcntis.
`
`Di sclos ure:
`
`Thomas van der Burg is a n employee of sanofi-aventis.
`
`References:
`
`1. IMS Health. IMS Midas™ June 2006, Quarterl y insulin sales volume
`in units. 2006.
`
`2. Selam JL. Evolution of diabetes insulin delivery dev ices. J Di abetes
`Sci Tec hnol. 2010;4(3)505-13.
`
`3. Clarke A, Spollett G Dose accuracy and injection force dynamics
`of a novel d isposable insu lin pen. Expert Opin Drug Deliv.
`2007;4 (2): 165-74.
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`J Diabetes Sci Technol Vol 5, Issue 1, January 2011
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`155
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`www.iournalofdst.o rg
`
`Sanofi Exhibit 2100.006
`Mylan v. Sanofi
`IPR2018-01676
`
`