Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`BAUSCH HEAL TH IRELAND LIMITED,
`
`Patent Owner.
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`SUPPLEMENTAL DECLARATION OF KUNW AR SHAILUBHAI
`
`Bausch Health Ireland Exhibit 2066, Page 1 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`
`U.S. Patent No. 7,041,786
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`BAUSCH HEAL TH IRELAND LIMITED,
`
`Patent Owner.
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`SUPPLEMENTAL DECLARATION OF KUNW AR SHAILUBHAI
`
`Bausch Health Ireland Exhibit 2066, Page 1 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`I, Kun war Shailubhai, under penalty of perjury, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am of legal age and otherwise competent to make this declaration.
`
`I am the first named inventor on U.S. Patent No. 7,041,786 (Ex. 1001,
`
`"the ' 786 patent"). I have been asked to submit a declaration attesting to how the
`
`data disclosed in Table 4 in the specification of the ' 786 patent and other relevant
`
`data related to the peptides disclosed in the ' 786 patent were generated.
`
`II.
`
`EDUCATION AND WORK EXPERIENCE
`
`3.
`
`I graduated from the Maharaj a Sayajirao University of Baroda with a
`
`Ph.D. in Microbiology in 1984 and from the University of Missouri-Saint Louis
`
`with an M.B.A. in 2002.
`
`4.
`
`I am currently employed by the Pennsylvania Biotechnology Center
`
`and Baruch S. Blumberg Institute as a Senior Advisor and Professor.
`
`III. BIOLOGICAL ACTIVITY DATA IN TABLE 4 OF THE '786 PATENT
`
`5.
`
`I was involved in synthesizing and testing of guanylate cyclase ("GC-
`
`C") receptor agonists that enhance intracellular production of cyclic guanosine
`
`monophosphate ("cGMP"), including the peptides of the experimental examples
`
`reported in the ' 786 patent. As such, I have first-hand knowledge of how the
`
`peptides reported below were made and tested.
`
`1
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`U.S. Patent No. 7,041,786
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`6.
`
`I directed the synthesis and testing of the GC-C receptor agonist
`
`peptides in order to examine biological activity as disclosed in Table 4 of the ' 786
`
`patent.
`
`7.
`
`Human T84 colon carcinoma cells were obtained from the American
`
`Type Culture Collection. (Id. at 15 :27-29). Cells were grown in a 1: 1 mixture of
`
`Ham' s F-12 medium and Dulbecco 's modified Eagle' s medium ("DMEM")
`
`supplemented with 10% fetal bovine serum, 100 U penicillin/ml, and 100 µg/ml
`
`streptomycin. (Id. at 15:29-32). The cells were fed fresh medium every third day
`
`and split at a confluence of approximately 80%. (Id. at 15 :32-34).
`
`8.
`
`Peptides were custom synthesized by Multiple Peptide Systems, San
`
`Diego, Califmnia, and by Princeton Biomolecules, Langhmne, Pennsylvania. (Id.
`
`at 15 :36-38). Biological activity of the synthetic peptides was assayed. (Id. at
`
`15 :38-39). The confluent monolayers ofT84 cells in 24-well plates were washed
`
`twice with 250 µl ofDMEM containing 50 mM HEPES (pH 7.4), pre-incubated at
`
`37°C for 10 minutes with 250 µl DMEM containing 50 mM HEPES (pH 7.4) and 1
`
`mM isobutylmethylxanthine ("IBMX"), followed by incubation with peptides (0.1
`
`nM to 10 µM) for 30 minutes. (Id. at 15 :40-46). The medium was aspirated, and
`
`the reaction was tenninated by the addition of 3% perchloric acid. (Id. at 15 :46-
`
`4 7) . Following centrifugation, and neutralization with 0.1 N NaOH, the
`
`2
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`U.S. Patent No. 7,041,786
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`supe111atant was used directly for measurements of cGMP using an ELISA kit
`
`(Caymen Chemical, Ann Arbor, Michigan). (Id. at 15:47-50).
`
`9.
`
`As indicated in the following table, the peptides were custom
`
`synthesized and purified (>95% purity) using a published procedure (procedure
`
`from Klodt, et al., J Peptide Res. 50:222-230 (1997)). (Id. at 15:53-54, 18:32).
`
`Peptides were evaluated in the T84 cell-based assay for their ability to enhance
`
`intracellular levels of cGMP. (Id. at 15:55-56). The results of this test are shown
`
`in Table 4 below.
`
`TA.BLE 4
`
`Peptide agonists evaluated for biological activity
`in the T&4 cell bioassay.
`
`SEQ ID NO.*
`
`Compound Code
`
`cGMP LeveJ0
`(pmol/we-lf)
`
`1
`6
`7
`20
`14
`
`2 1
`
`SP30 1
`SP302
`SP303
`SP304
`. P306
`P310
`SP316
`
`20
`225
`195
`3 15
`0
`0
`275
`
`*SEQ ID's for SP301, SP304 and 'P316 a.re the precise amino acid
`sequences for these malogs as g iven in the text.
`**Intracellular cGMP level observed in T 84 cells follo fog treatment
`1 micromolar solution of tJ1e respective peptide agonist for 30 minutes.
`TI1e value observed for SP304 was statistically 1gnifkant with a p > 0.5.
`
`ith
`
`(Id. at 16: 1-19). I note that the p value below Table 4 contains a typographical
`
`error and should say p < 0.05. (Id. at 16:19).
`
`3
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`U.S. Patent No. 7,041,786
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`IV. DATA IN STUDY NUMBER SP-PH-001
`
`10.
`
`I directed the preparation and testing of the ability of SP-304
`
`(plecanatide) to stimulate cGMP production in T84 human colon carcinoma cells
`
`in vitro and evaluated the effects of SP-304, uroguanylin, and other peptides. (Ex.
`
`2027 at TRUL00018209).
`
`11 . SP-304, uroguanylin, and two other peptides (SP-302 and SP-303)
`
`were tested at concentrations ranging from 10-9 M to 10-5 M. (Id.) . Cell culhire
`
`supe1natants were prepared following 30-minute incubation, and cGMP levels
`
`were measured using a commercial ELISA assay. (Id.) .
`
`12. Human colon carcinoma cells T84 (ATCC Number CCL-248),
`
`provided by Dr. Lenard Forte, University of Missouri at Columbia, MO, were used
`
`in these assays. (Ex. 2027 at TRUL00018210). The cells were cultured in DMEM
`
`and Ham's F-12 medium (1:1) containing 5% fetal bovine serum and 60 µg of
`
`penicillin plus 100 µg of streptomycin per ml. (Id.) . Cells were split every 5-6
`
`days by trypsinization. (Id.). Frozen stocks of cells were stored in liquid nitrogen.
`
`(Id.) .
`
`13. The following test peptides were synthesized by BA CHEM
`
`Biosciences, Inc. (King of Prussia, PA) as the trifluoroacetic acid salt fonn:
`
`4
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`mino cid equmtt •
`
`I Tr~t Prptitlc
`
`P-301
`( uroguanylin)
`
`.\tuL
`Wd~hl
`
`1668
`
`T
`
`P-302
`
`1696
`
`SP-.303
`
`16K2
`
`SP-304
`
`1682
`
`Aan 1•1\sp2-Glu3{y•• ·Glus-leu41•Cya 1•Va1 8-Asn9•Vat 10•Ala 11 ~n ,i•Thr "·Gly •◄-cys15-L.eu 11
`L ___________ ~
`
`• Nc,le: bracket!I indicate the location of dii;ulfidc bonds
`
`(id. at TRUL00018210, TRUL00018218).
`
`14. All peptides were prepared as stock solutions at a concentration of 1
`
`mM in deionized water. (id. at TRUL00018210). For each peptide, cGMP levels
`
`were tested at concentrations ranging from 10-9 M (0.001 ~LM) to 10-5 M (10 ~LM).
`
`(id.) . Control wells contained no peptide. (id.) .
`
`15.
`
`The potency of test peptides to stimulate cGMP synthesis in T8 4 cells
`
`was assessed using a published procedure. (Ex. 2027 at TRUL000 18211 ).
`
`Confluent monolayers ofT84 cells in 24-well plates were washed twice with 250
`
`~Ll of DMEM and containing 50 mM N-(2-hydroxyethyl)piperazine-N'-(2-
`
`ethanesulfonic acid) ("HEPES") (pH 7.4) and pre-incubated at 37°C for 10 minutes
`
`with 250 ~Ll of DMEM containing 50 mM HEPES (pH 7.4) and 1 mM IBMX.
`
`(id.) . The test peptides were then incubated for 30 min. (id.) . The medium was
`
`then aspirated and the reaction was te1111inated by the addition of 3°/o perchlmic
`
`5
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`acid. (Id.). Following centrifugation and the addition ofNaOH (0.1 N) to
`
`neutralize the pH, intracellular cGMP levels were detennined in lysates using a
`
`cGMP ELISA kit (Cat No. 581021 , Cayman Chemical, Ann Arbor, MI.). (Id.) .
`
`Samples were run in duplicate incubations and each sample was run as duplicates
`
`in ELISA test. (Id.) .
`
`16. As illustrated by Table 1 and Figure 1 below, the results of this study
`
`demonstrated that SP-304 stimulated cGMP production in T84 colon carcinoma
`
`cells in a concentration-related manner, with an ECso of 1.1 x 10-7 M (185 ng/mL).
`
`(Ex. 2027 at TRUL0001822-TRUL00018224). Uroguanylin showed an ECso of
`
`2.3 x 10-7, SP-302 showed an ECso of 3.5 x 10-7, and SP-303 showed an ECso of2.4
`
`6
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`Table I.
`Effects of SP-304~ llroguanylin, and Other Test Peptides in the T84 cGJ\,IP
`Stimulation Bioassa}'
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`Case IPR2022-00722
`U.S. Patent No. 7,041,786
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`Tc~f \fatcrial
`
`SP-301
`(uroguanylin)
`
`SP-302
`
`I
`
`• P-30
`
`SP-304
`
`Concentration
`cGMP Levels
`(pmol/wcll) *
`:\·lohu-
`n~j mL
`0
`0
`0
`10·~ ~1
`0
`1.668
`10" M
`16.668
`12
`10 '\1
`166.8
`82
`10-nM
`205
`1668
`Jff· M
`254
`16680
`0
`0
`0
`IO"M
`0
`1.696
`10·• 1'1
`8
`16.96
`10 M
`169.6
`62
`JO"' \1
`1696
`185
`1o·· M
`248
`16960
`0
`0
`0
`lff' M
`1.682
`0
`10" \1
`16.82
`12
`10· ' ).1
`168.2
`82
`IO~M
`1682
`195
`254
`IO'M
`16820
`0
`0
`0
`10- 1'1
`1.682
`0
`10" M
`16.82
`17
`10 ' \ 1
`168.2
`149
`.no
`10•n \1
`1682
`Jff· M
`16820
`315
`"' cGMP le -el !> in T84 cells alter a 30-m.lnute incubation.
`"'* EC50 ; median effective concentr~tion (required to induce a 50% effect)
`
`-
`
`-
`
`-
`
`I
`
`- -
`
`I
`
`I
`
`I
`
`- -
`
`EC~ 0
`
`\lolnr
`
`ng/ml ,
`
`+O~-M
`2.JxHr',1
`
`~
`383.6
`
`W-6-M
`J.S vrn •h,1
`
`l@e
`~93.6
`
`.w-l, , r
`2.4 HI 7 , f
`
`~
`403.7
`
`+0..'.l-.\4
`1. txHr7M
`
`~
`185.0
`
`(Ex. 2027 at TRUL000l 8222).
`
`7
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`350 ·
`
`--·• ·- SP 303
`
`flgure 1: Dose-Response ror P-304. Uroguanylin (l1roG). and Orher Test Peprides in the
`T84 Cell t<;MP Stimulafion Bioassa~
`..... UG
`-300 - ··- SP-304
`-•~ SP-302
`'ii
`3: 250 •
`"'
`0 200 ·
`E
`S 150·
`~
`~ 100 •
`
`"' ~ so-
`o+
`-10
`
`I
`4 ~}'
`-7
`--8
`Log Peptide [M]
`
`"
`
`-9
`
`,E
`
`(Ex. 2027 at TRUL000l 8223).
`
`V.
`
`DAT A IN STUDY NUl\lBER SP-PH-004
`
`A.
`
`Uroguanylin and SP-304 Topoisomeric Properties
`
`17.
`
`I directed the preparation and testing of topoisome1ic confo1111ations
`
`of SP-304 (plecanatide) and uroguanylin monitored by HPLC analysis and further
`
`evaluated by NMR to characte1ize their three-dimensional structures. (Ex. 2028 at
`
`TRUL000 l 8269).
`
`18.
`
`Sample SP-304 ( 10 ~LM) and uroguanylin ( 10 ~LM) were incubated for
`
`16 hours at 37°C in a pH 3.0 solution comp1ised of25 mM sodium acetate, 150
`
`mM NaCl, and then analyzed by HPLC. (id.) .
`
`19.
`
`Peptide solutions were subjected to reverse phase chromatography on
`
`an HPLC system attached with a VYDAC C 18 column using a 20-40% gradient of
`
`8
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`solvent A (0.1 °/o TFA in water) and solvent B (0.1 % TFA in Acetonitiile ). The
`
`column flow rate was adjusted to 1 ml/min. Under these conditions, the
`
`biologically active and inactive fractions were eluted at 21.4 and 23.7 minutes,
`
`respectively. (Ex. 2028 at TRUL000l 8268).
`
`20. As shown in Figure 1 below, after the 16-hour incubation,
`
`uroguanylin showed two major peaks and two minor peaks. (Ex. 2028 at
`
`TRUL000l 8269). In contrast, SP-304 showed only a single peak. (id.) .
`
`Figure I: HPLC Chromatographs of UroguanJlin and SP-304 Following JG-Hour
`h1cubatio11s at pH 3.0 in Aqueous ~kdia at 37°C
`
`rroG
`
`Active
`fraction
`
`+- Inactive
`fraction
`
`.. ... . ~ " ... ~
`
`..
`
`.....
`
`(id.).
`
`B.
`
`pH Dependency of cGl\lP Stimulation by SP-304, Uroguanylin,
`SP-302, and SP-303
`
`21.
`
`I directed the preparation and testing of SP-304, uroguanylin, and two
`
`other peptides (SP-302 and SP-303) in T84 cells to deten11ine if cGMP stimulation
`
`9
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`U.S. Patent No. 7,041,786
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`by 0.1 µM concentrations was affected by the pH of culture medium. (Ex. 2028 at
`
`TRUL00018269). I tested a range of pH values (pH 5.5-7.0). (Id.) .
`
`22. Human colon carcinoma T84 cells (ATCC Number CCL-248),
`
`provided by Dr. Lenard Forte, University of Missouri at Columbia, MO, were used
`
`in these assays. (Ex. 2028 at TRUL00018267). The cells were cultured in DMEM
`
`and Ham's F-12 medium (1 :1) containing 5% fetal bovine serum and 60 µg of
`
`penicillin plus 100 µg of streptomycin per ml. (Id.). Cells were split every 5-6
`
`days by trypsinization. (Id.) . Frozen stocks of cells were stored in liquid nitrogen.
`
`(Id.) .
`
`23. Confluent monolayers of cultured T84 colon carcinoma cells were
`
`washed and pre-incubated with Hanks Balanced Salt Solution containing IBMX at
`
`pH 5.5, 6.0, 6.5, or 7.0 for 10 minutes, and were then incubated with test peptides
`
`(uroguanylin, SP-302, SP-303, or SP-304) for 30 minutes at a concentration of 0.1
`
`µMat pH 5.5, 6.0, 6.5, or 7.0, respectively. (Ex. 2028 at TRUL000l 8277; see
`
`infra Section V. C ( discussing procedure)). The reactions were then tenninated,
`
`cells were lysed, and the resulting lysates were assayed for intracellular cGMP
`
`content using ELISA. (Id.) .
`
`24. The results of the study are shown in Figure 2 below.
`
`10
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`Figurt> 2: Effocl of 30 I\Unult> Incubations of 0.1 µM Concent.-alions of SP-304.
`Uroguanylin, SP-302 and SP-303 on cGMP Production at Various Physiological pH Values
`in T84 Ct>lls
`
`45 .
`40 .
`35 -
`30 ·
`25 ·
`20 ·
`15 ·
`10 ·
`5 .
`0 -
`
`pH
`a 5.5
`■ 6.0
`a e.s
`D 7.0
`
`-c-
`
`1 0
`
`E
`.0..
`
`C.
`~
`l9
`tJ
`
`hoG
`
`Test Peptides
`
`(Ex. 2028 at TRUL00018270). The raw data reported in Figure 2 are presented in
`
`Table 2 below.
`
`Table 2: Raw Data (pH s~nsitivily assays)
`
`Teit Pc1Hidc
`
`Concentration
`
`cG~tP Le,·els (~mol/wtll) *
`J!H 6.11
`J!H 6.!li
`
`)IH. 7.0
`
`'.!I. 72
`
`18.18
`
`17.94
`
`13.62
`
`l1roguar1ylin
`
`SJ>-304
`
`SP-302
`
`SP-303
`
`(1. 1 µ:\-1
`( 1.67 µ~ml)
`0.1 µM
`( I .68 ~8'.ml l
`0.1 µM
`(l.67µf~ntll
`,i..'1
`0.1
`(l.68 µ~mL)
`• cGMP levels in T~4 cells after a 30-111inu1e incubation at 3 7"C'.
`
`24.6
`
`24.9
`
`14.80
`
`li.46
`
`2l.36
`
`43 .8
`
`lSJ,
`
`22 .26
`
`24.fi
`
`36.68
`
`22.Q~
`
`28.14
`
`(Ex. 2028 at TRUL00018273).
`
`C.
`
`Thennostability of SP-304, Uroguanylin, SP-302, and SP-303
`
`25.
`
`I directed the preparation and testing ofSP-304, uroguanylin, SP-302,
`
`and SP-303 to stimulate cGMP after incubation at 95°C for various lengths of time
`
`11
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`to compare their thennostability to high temperature. (Ex. 2028 at
`
`TRUL000l 8270).
`
`26. Human colon carcinoma T84 cells (ATCC Number CCL-248),
`
`provided by Dr. Lenard Forte, University of Missouri at Columbia, MO, were used
`
`in these assays. (Ex. 2028 at TRUL00018267). The cells were cultured in DMEM
`
`and Ham's F-12 medium (1 :1) containing 5% fetal bovine serum and 60 µg of
`
`penicillin plus 100 µg of streptomycin per ml. (Id.). Cells were split every 5-6
`
`days by trypsinization. (Id.) . Frozen stocks of cells were stored in liquid nitrogen.
`
`(Id.) .
`
`27. Peptides for analysis were prepared as 1 mM stock solutions in
`
`deionized water. (Ex. 2028 at TRUL00018277). The potency oftest peptides to
`
`stimulate cGMP synthesis in T84 cells was assessed using a published procedure
`
`(procedure from Shailubhai, K., et al., Uroguanylin treatment suppresses polyps
`
`formation in APCmin/+ mouse and induces apoptosis in human colon
`
`adenocarcinoma cells by a cGMP dependent mechanism, Cancer Res. 60:5151-
`
`5157 (2000)). (Id.) . Confluent monolayers of T84 cells in 24-well plates were
`
`washed twice with 250 µl ofDMEM containing 50 mM HEPES (pH 7.4) and pre(cid:173)
`
`incubated at 37°C for 10 minutes with 250 µl ofDMEM containing 50 mM
`
`HEPES (pH 7.4) and 1 mM IBMX. (Id.) . Monolayers ofT84 cells were then
`
`incubated with 250 µl of a solution ofDMEM, 40 mM HEPES (pH 7.4) plus
`
`12
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`peptide for 30 minutes. (Id.) . Control cells were incubated in the above solution
`
`minus peptide. (Id.) . After 30 minutes, the medium was aspirated and the reaction
`
`was terminated by the addition of 3% perchloric acid to cells. (Id.) . Following
`
`centrifugation and the addition ofNaOH (0.1 N) to neutralize the pH, cell lysates
`
`were made and intracellular cGMP levels measured using a cGMP ELISA kit (Cat.
`
`No. 581021, Cayman Chemical, Ann Arbor, MI.). (Id.) . All incubations were
`
`performed in duplicate. Cell lysates subjected to ELISA detenninations were also
`
`perfonned in duplicate. (Id.) .
`
`28.
`
`Test peptides (uroguanylin, SP-302, SP-303, or SP-304) were
`
`dissolved in phosphate buffered saline solution (pH 7.4) at a concentration of
`
`0.1 µMand were incubated at 95°C for times ranging from 0-90 minutes. (Ex.
`
`2028 at TRUL000l 8268). After the incubation, the peptide solutions were rapidly
`
`cooled to 4 °C and then assayed for stimulation of cGMP production in T84 cells
`
`using the standard cGMP T84 cell assay. (Id.). This involved taking confluent
`
`monolayers of cultured T84 colon carcinoma cells, washed and pre-incubated with
`
`DMEM and IBMX for 10 minutes, and then incubating them for 30 minutes with
`
`the test peptides (1 µM) obtained from the earlier 95°C incubations. (Id.) . The
`
`reactions were terminated, cells were lysed, and the resulting lysates were assayed
`
`for intracellular cGMP levels using ELISA. (Id.) .
`
`29.
`
`Figure 3 below shows the results from the study.
`
`13
`
`Bausch Health Ireland Exhibit 2066, Page 14 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
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`
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`Figure 3: The1·mostability of SP-304, U1·og11anylin. SP-302 and SP-303 Folloll·ing Heat
`Treatment at 95°C in T84 Ct'lls as a Function or Tim"
`
`100 .
`
`,!l
`Ill,)
`> Ill,)
`H 90
`~
`C, ...,
`
`.
`
`0
`~ -
`
`80
`
`-
`
`70
`
`-1- rnG·
`-e- SP !>01
`--+- SP-30.\
`-&- SP :\O,t
`
`0
`
`15
`
`30
`
`45
`
`60
`
`90
`
`Time (min)
`
`(Ex. 2028 at TRUL000 18271 ). The raw data for Figure 3 are presented in Table 3
`
`below.
`
`Table 3: Raw Data (fhermtJstabilitJ assaJs)
`
`T ei.t Pe1)tide J Concentration
`
`Uroguanylin
`
`SP-304
`
`O.J µ\t
`( 1.67 u.iz/mL)
`0 .1 µ\t
`
`II
`
`21.72
`
`J5min
`
`20.92
`
`20.44
`
`21.12
`
`cCMP Lc,·clr. (J!mttl/wcm •
`Jllmin
`4, min
`
`61t min
`
`90 min
`
`21 .68
`
`2(1.64
`
`20.88
`
`18.76
`
`18.96
`
`21.4
`
`20.8
`
`21.88
`
`116.ll~ml} --- (
`
`SP 302
`
`SP-303
`
`0 .1 µ\t
`(l .67 µg/mL)
`0.1 p.\t
`( 1.68 µJr/ml)
`• c<.iMP levels in T84 cells alter heat treatment at95"C for the indicated times. Sample..'- at different times of
`treatment were withdrawn and as..~ayed for their ability to stimulate cGMP sy nthe~is.
`
`2J.16
`
`20.44
`
`2 1.64
`
`20.0
`
`21.12
`
`20.56
`
`20.32
`
`20.68
`
`20.36
`
`20.36
`
`20.34
`
`19.8
`
`(Ex. 2028 at TRUL00018273).
`
`14
`
`Bausch Health Ireland Exhibit 2066, Page 15 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`VI. DATA DISCLOSED IN TABLE 4 OF THE '786 PATENT, STUDY NO.
`SP-PH-001, AND STUDY NO. SP-PH-004
`
`30. Based on my involvement with the synthesis and testing of GC-C
`
`receptor agonist peptides in order to examine their isomerization, biological
`
`activity, and heat stability as disclosed in Table 4 of the ' 786 patent, Study No. SP(cid:173)
`
`PH-001, and Study No. SP-PH-004, I have first-hand knowledge of how these test
`
`data disclosed were generated.
`
`31 .
`
`I hereby certify that each of the records for Study No. SP-PH-001 and
`
`Study No. SP-PH-004 (i.e., Ex. 2027 and Ex. 2028):
`
`(A) were made or obtained at or near the time of occurrence of the matters
`
`set forth in the records, by, or from information transmitted by, a person
`
`with personal knowledge of those matters;
`
`(B) were kept in the course of regularly conducted business activity;
`
`(C) were created or obtained as a regular business practice; and
`
`(D) are the types of infonnation created, obtained, and used in the ordinary
`
`course of business.
`
`32. Exhibit 2027 (Study No. SP-PH-001) is a document that I directed to
`
`be prepared and that I approved while at Synergy Phannaceuticals, Inc., entitled
`
`"SP-304: Stimulation of Intracellular cGMP Synthesis in T84 Cells." The date of
`
`the Final Report is Febniary 15, 2008, the date of the Final Report Amendment
`
`15
`
`Bausch Health Ireland Exhibit 2066, Page 16 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
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`
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`Number 1 is June 25, 2015, and the date of the Final Report Amendment Number 2
`
`is September 17, 2015 .
`
`33. Exhibit 2028 (Study No. SP-PH-004) is a document that I directed to
`
`be prepared and that I approved while at Synergy Phannaceuticals, Inc., entitled
`
`"Studies on SP-304 Thermostability, pH Dependency and Topoisomeric Stability."
`
`The date of the Final Report is February 15, 2008, and the date of the Final Report
`
`Amendment Number 1 is July 15, 2015.
`
`34.
`
`I hereby certify that the documents marked as Exhibits 2027 and 2028
`
`are true and correct copies of the records for Study No. SP-PH-001 and Study No.
`
`SP-PH-004.
`
`VII. LETTER DATED MARCH
`PENNINGTON, PH.D.
`
`31,
`
`2004, FROM MICHAEL
`
`35. Exhibit 2040 is a letter dated March 31, 2004, that I received from
`
`Michael Pennington, Ph.D., who was with BACHEM Bioscience Inc.
`
`36.
`
`I hereby certify that the document marked as Exhibit 2040 is a true
`
`and correct copy of the letter.
`
`37.
`
`I hereby certify that the letter (Ex. 2040):
`
`(A) was made or obtained at or near the time of occurrence of the matters set
`
`forth in the records, by, or from information transmitted by, a person with
`
`personal knowledge of those matters;
`
`16
`
`Bausch Health Ireland Exhibit 2066, Page 1 7 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`(B) was kept in the course of regularly conducted business activity;
`
`(C) was created or obtained as a regular business practice; and
`
`(D) is the type of infonnation created, obtained, and used in the ordinary
`
`course of business.
`
`3 8.
`
`In signing this declaration, I understand that the declaration will be
`
`filed as evidence in a contested case before the Patent Trial and Appeal Board of
`
`the United States Patent and Trademark Office. I acknowledge that I may be
`
`subject to cross-examination in this case and that cross-examination will take place
`
`within the United States. If cross-examination is required of me, I will appear for
`
`cross-examination within the United States during the time allotted for cross-
`
`examination.
`
`39.
`
`I declare that all statements made herein ofmy knowledge are true,
`
`and that all statements made on information and belief are believed to be true, and
`
`that these statements were made with knowledge that willful false statements and
`
`the like so made are punishable by fine or imprisonment, or both, under Section
`
`1001 of the Title 18 of the United States Code.
`
`17
`
`Bausch Health Ireland Exhibit 2066, Page 18 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`Kunwar Shailubhai
`
`18
`
`Bausch Health Ireland Exhibit 2066, Page 19 of 19
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`
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