IN THE UNITED STATES PATENT AND TRADEMARK OFHCE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`U.S. Patent No. 8,497,393
`
`Case No. IPR 2016-00006
`
`SteadyMed Ltd.
`Petitioner
`
`V.
`
`United Therapeutics Corporation
`Patent Owner
`
`5*eadVMé3"3
`
`November .29, .201 6
`
`Ex. 1029; Steadylvied v. United T'nerai_Jeutics_:
`
`|DR2016—D0006
`
`

`
`'§i:“Sf":—:.:::;IIi C S
`
`1 LegcI|Concep’rs
`
`5 ObViOUSfieSS
`
`2 Key Scienfific Concepfs
`
`' Pmremnd Mommy
`
`3 Overview
`
`- Kowcnkomi cmd Moriarty
`- Dependen’rC|oIims 6, 10,21 & 22
`
`4 Anficipofion
`
`6 Claim Cons’rruc:’rion
`
`Ex.1029:SteadvMedv. Ur1itedThe~:a_:1eutic5;
`
`|PR2016—O0OO6
`
`

`
`1 Legal Concepts
`
`Ex. 1029; Stead\,rMed U. United Therapeutics;
`
`|PR2016—UUOD6
`
`

`
`
`
`We have clearly stated that
`
`"’[i]n determining validity of a
`
`product-by-process claim, the focus is on the product and not
`
`the process of making it.
`
`"That
`
`is because of the
`
`H
`
`longstanding rule that an old product is not patentable even if
`
`it is made by a new process.""
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1354 (Fed. Cir. 2016) (cites and internal quotations omitted)
`
`Ex. 1029: Stee.(i',r|\»le(! '-.4. United Tne:'a;Jeutic5:
`
`|PR2L‘I16—00OO6
`
`

`
`
`
`“If the product in a product-by-process claim is the same as or
`
`obvious
`
`from a product of
`
`the prior art,
`
`the claim is
`
`unpatentable even though the prior product was made by a
`
`different process.”
`
`in re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985)
`
`Ex.1029:Stead\r|\Iled~.«. United Therazleuticsg |PR2016—0OOO6
`
`

`
`
`
`”Purdue claimed the end product; it did not claim a particular
`
`method for creating that product,
`
`such as
`
`the use of
`
`hydrogenation after the salting step.... One need not know
`
`that the 14—hydroxy was derived from 80¢ as opposed to 8B to
`
`answer that question.”
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1353 (Fed. Cir. 2016)
`
`Ex. 1029: Stee.d';r|\»led '-.4. United T*we:'a;Jeutic5:
`
`|PR2L‘I16—0OOO6
`
`

`
`
`
`"’[T]he fact that the 14—hydroxy is derived from 80: imparts no
`
`structural or functional differences in the low-ABUK [impurity]
`
`hydrocodone API as compared to the prior art products. Thus,
`
`the court did not err in disregarding the process limitation in
`
`its obviousness determination.”
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1354 (Fed. Cir. 2016)
`
`Ex. 1029: 3T.E!d(1"y'fviE£d '-.4. United Tiwerapeuticsi
`
`|PR2L‘I16—00OO6
`
`

`
`
`
`“Cases involving the "purification" of a natural substance
`
`employ similar analysis. Our predecessor court recognized that
`
`merely purifying a naturally occurring substance does not
`
`render the substance patentable unless it results in a marked
`
`change in functionality. In re ll/Ierz, 25 CCPA 1314, 97 F.2d 599,
`
`601 (1938) (holding that there was no right to a patent on a
`
`purer version of ultramarine, but recognizing that if a claimed
`
`article is "of such purity that it differs not only in degree but in
`
`kind it may be patentable") ....”
`
`Ass'nfor Molecular Pathology v. USPTO, 689 F. 3d 1303, 1353-54 (Fed. Cir. 2012) (emphases added).
`
`Ex. 1029; Stead-,.-lvle-:1"
`
`|J'1ited T'1e"agJe;:t%Cs:
`
`|PR2L‘I;6—00DCJ6
`
`

`
`
`
`"’[|]fthe process by which a product is made imparts ‘structural
`
`and functional differences’ distinguishing the claimed product
`
`from the prior art, then those differences ‘are relevant as
`
`evidence of no anticipation’ although they ‘are not explicitly
`
`part of the claim.”
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1354 (Fed. Cir. 2016) (cites and internal quotations omitted) (emphasis added)
`
`Ex. 3.U29:3l.E'.d(1"ylvlE£(l'-J. United Therapeutics:
`
`|PR2L‘I16—00OO6
`
`

`
`2 Key Scientific Concepts
`
`Ex.1D29;Stead\,rMed U. United Therapeutics; OOOOOOOOOOO O6
`
`

`
`Key Scientific Concepts
`Recrystallization
`
`Recrystallization in a Nutshell
`
`-A ->
`
`Product is not pure.
`
`(Impurities are red.)
`
`Heat up solution to
`
`dissolve impure
`
`When solution cools down,
`
`purer product “crashes out" and
`
`product.
`
`dissolved impurities get left behind.
`
`Ex. 1029; Stead\,rMed V. United Therapeutics;
`
`|PR2016—UUOD5
`
`11
`
`

`
`Recrystallization
`
`IQ
`
`How long has crystallization been
`
`around as a method of
`
`purification‘?
`
`rQF%*»Q.3.>
`
`I don°t know how long it’s been around.
`
`Before 2007‘?
`
`Oh, yes.
`
`Did you learn about it when you were in
`
`college at the unix-'ersity‘?
`
`F?
`
`Yes, I did. [...]
`
`Q:
`
`A:
`
`And when did you go to college‘?
`
`In 1968 I started. In 1968.
`
`3;
`
`=;; 3;
`
`Q:
`
`But how far back does doing that
`
`process you just described, liow far
`
`back does that go‘?
`
`T11eWit11ess: Decades.
`
`(Ex. 2058,175:19-I76:22,179:11-17)
`
`EX. 2058 (“Ruffolo Deposition Transcript) at45-46
`
`
`
`-' ” '-
`
`12
`
`

`
`Melting Point
`
`The method [of differential scanning calorimetry] can also be used as an accurate measure
`
`of the melting point and purity of the sample. In fact, the change of melting point is related
`
`to the mole fraction of impurities as given by Equation 5.2:
`
`T, = To —
`
`TERX,
`
`Fflflf
`
`(5.2)
`
`I
`
`where T5, is the sample temperature, To is the melting point of the pure compound, R is the
`
`gas constant, X,-, is the mole fraction of the impurity, F is the fraction of the solid melted, and
`
`AH, is the enthalpy of fusion of the pure compound. According to the equation, a plot of Q
`versus 1/F should give a straight line whose slope is proportional to X, (Brittain et al., 1991).
`
`Stephen R. Byrn et al., Solid-State Chemistry of Drugs, Chapter 5,
`"Thermal Methods of Analysis," Bi-901 (2d ed. 1999) (Ex. 1027, at 84.)
`
`EX. ‘I027 (“Byrn Chapter 5’) at 5
`
`
`
`

`
`Key Scienfific Concepfs
`Melting Point
`
`Figure 18
`
`Figure 21
`
`0.0l‘M0$ M. ha Q 8I—10.'a‘C
`{|L|3|HfiRIIg)
`
`O.l32WB%vR.1oIa§2fl-100 ‘G
`DBIQNJ
`
`‘I0f..|lD'O
`
`EX. 1005 (“Phares”) at 118, 121
`
`Ex. 1U29;SteadvMed u. United Therapeutics;
`
`|PR2016—UOOD6
`
`14
`
`

`
`Melting Point
`
`The method [of differential scanning calorimetry] can also be used as an accurate measure
`
`of the melting point and purity of the sample. In fact, the change of melting point is related
`
`to the mole fraction of impurities as given by Equation 5.2:
`
`T, = To —
`
`TERX,
`
`Fflflf
`
`(5.2)
`
`I
`
`where T5, is the sample temperature, To is the melting point of the pure compound, R is the
`
`gas constant, X,-, is the mole fraction of the impurity, F is the fraction of the solid melted, and
`
`AH, is the enthalpy of fusion of the pure compound. According to the equation, a plot of Q
`versus 1/F should give a straight line whose slope is proportional to X, (Brittain et al., 1991).
`
`Stephen R. Byrn et al., Solid-State Chemistry of Drugs, Chapter 5,
`"Thermal Methods of Analysis," Bi-901 (2d ed. 1999) (Ex. 1027, at 84.)
`
`EX. ‘I027 (“Byrn Chapter 5’) at 5
`
`
`
`

`
`z‘'\
`
`'5?‘
`
`'a/‘‘'\'
`
`-6 _:
`
`'
`
`.::<:lcmuf:<: lZ.<..:~ti<:e;:..i»li~;
`K.A:~§x’
`HLPC and Purity
`
`1-6‘
`
`~
`
`\
`
`'
`
`4‘~\'D"*-
`
`Analytical data on and Tregrostinil Diethanolamine Salt 1 1:1 3
`
`Test
`
`IR
`
`Residue on Ignition (ROI)
`Water content
`
`Melting point
`Specific rotation [o:]25539
`Organic volatile impurities
`
`Batch 1
`
`Batch 2
`
`Conforms
`
`<0.1% W/w
`0.1% W/W
`
`Con forms
`
`<0.1% W/W
`0.0% W/W
`
`105.0-106.5° C.
`+34.6°
`
`10-4.5-105.5° C.
`+35°
`
`Ethanol
`
`Ethyl acetate
`Hcptane
`
`Not detected
`
`Not detected
`
`Not detected
`<0.05% w/W
`
`<0.05 ‘/0 W/w
`<0.05 % W/W
`
`Diethanolamine
`
`Positive
`
`Positive
`
`
`
`EX. 1001, ‘393 Patent
`COH3, {L50-65
`
`Ex. 1001 (‘"393 Patent’) at9
`
`E><.1029:Stead\r|\Iled\«. UnitedThe~:a_oeutic5;
`
`|PR2U16—0OO06
`
`17
`
`

`
`Key Scientific Coracepts
`HLPC and Purity
`
`During the initial analytical method validation for the treprostinil assay, the results indicated
`
`
`that ..'=:.=..-=-t
`.
`'. '-
`.1
`':
`Our specifications of97.0-101.0% were
`centere at 99% purity or the AM. When the process for the manufacture of treprostinil was
`instituted in Silver Spiing, it was observed that the purity of the treprostinil improved to close
`
`to 100%. From a statistical stand-point, 3?-xi -:: : .- _...
`1.’
`.
`:__.-;:_..:.
`-
`in an OOS on the high side (considezing a two sigma range) when the upper limit of the
`specification is 101.0%. Scientifically.
`..
`.-.-
`.
`.
`7.
`I
`g.
`-.
`- -
`
`
`
`
`
`rin development in Silver Spring, it was observed that there were
`
`
`
`
`
`3
`
`UT Ex. 2006
`
`EX. 2006 at 3
`
`Ex.1029;SteadvMedv. Ur1itedThe:'a_oeutic5;
`
`|PR2016—O0OO6
`
`18
`
`EX. 2006 at 3
`
`Steadylvled v. United Therapeutics
`|PR2U16-00006
`
`

`
`3 Overview
`
`Ex. 1029; SteadvMed V. United Therapeutics;
`
`|PR2016—UUOD5
`
`

`
`Overview
`
`Independent Claims
`
`Claim 1
`
`(c) contacting the product of step (h) with a base 13 to form
`a salt of formula 15.
`
`Y
`
`R
`C
`C
`1- — — 1
`||
`II
`M1
`L1
`
`as)
`
`OH
`H39
`
`dH11
`
`H
`
`H
`
`O(CH2)wCOOe
`
`(d)
`reacting the salt formed in step (c) with an
`act
`to orrn the compound of formula I.
`
`
`
`
`
`What is claimed is:
`
`1. A product comprising a compound of formula I
`
`R
`Y,—c—c— 7
`II
`II
`M,
`L,
`OH
`
`H
`
`H
`
`O(CH2)..,COOH
`
`or3: wherein said
`product is prepared by a process comprising
`(a) alkylating a compound of structure II with an alkylating
`
`agent to produce a compound of formula II],
` (b) hydrolyzing the product of formula III of step (a) with
`a base,
`
` Ex. 1001 (‘"393 Paten
`
`Ex.1D29';5teadvMed v. United Therapeutics;
`
`|PR2016—UUOD5
`
`20
`
`

`
`Overview
`
`Independent Claims
`
`Claim 9
`
`9. A product comprising a compound having formula IV
`
`(IV)
`
`
`
`
`
`
`
`(c) contacting the product of step (h) with a base B to form
`a salt of formula IV,, and
`
`HO
`
`(IVE)
`
`(d)—reacting the salt formed in step (c) with an
`acid to form the compound of formula IV.
`
`
`
`
`
`m~ wherein the
`product is prepared by the process comprising
`(a) alkylating a compound of formula V with an alkylating
`agent to produce a compound of formula VI,
`
`
`(b)hyd1-olyzing the product of formula VI of step (a) with
`a base,
`
`
`Therapeutics;
`
`|PR2016-D0006
`
`21
`
`

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`Prior Art: Moriarty
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`EX. 1004 (‘Moriarty’) at 1'3
`
`Ex. 1U29;Steacl\,rMed v. United Therapeutics;
`
`|PR2016—UODD6
`
`22
`
`

`
`Overview
`
`Prior Art: Moriarty
`
`10%
`
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`
`EX. 1004 (“Mon'an‘y’j at 1'3
`
`Ex. 1029; Stead\,rMed V. United Therapeutics;
`
`|PR2016—UODD6
`
`23
`
`

`
`Overview
`
`Prior Art: Phares
`
`(C) contécting the product ofstep (b) with a base B such as
`diethanoiamjne to for a salt of the following structure,
`and
`
`H0
`
`
`
`.uIII IIOH
`
`
`
`ea NH;(CH;CH;0HIj;
`
`(cl) reacting the salt from step (b) with an acid such as HC1
`to form the compound of formula IV.
`In one embodiment, the purity ofcompound of formula IV
`is at least 90.0%, 95.0%, 99.0%, 99.5%.
`
`
`
`EX. 1005 (“Phares”) at 99 {Claim 49),‘ EX. 1001 at 6 {‘393 Patent) coI.8. ff. 47-68.
`
`Ex. 1D29;SteadvMed V. United Therapeutics; |PR2D16—UOU06
`
`24
`
`

`
`Phares and Melting Point
`
`The method [of differential scanning calorimetry] can also be used as an accurate measure
`
`of the melting point and purity of the sample. In fact, the change of melting point is related
`
`to the mole fraction of impurities as given by Equation 5.2:
`
`TS=T0—
`
`TERX,
`FA]-If
`
`(52)
`
`I
`
`where T5, is the sample temperature, To is the melting point of the pure compound, R is the
`
`gas constant, X,-, is the mole fraction of the impurity, F is the fraction of the solid melted, and
`
`5H,: is the enthalpy of fusion of the pure compound. According to the equation, a plot of Q
`versus 1/F should give a straight line whose slope is proportional to X, (Brittain et al., 1991).
`
`Stephen R. Byrn er a!., Solid-State Chemistry of Drugs, Chapter 5,
`"Thermal Methods of Analysis," 81-901 (2d ed. 1999) (Ex. 1027, at 84.)
`
`EX. ‘I027 (“Byrn Chapter 5’) at 5.
`
`
`
`

`
`Overview
`
`Prior Art: Phares
`
`EX. 1005
`
`
`
`-elm-In~a=-t—a.~..l.-am.»-..--van-vr::LnuI\:n.-..a.-u
`as-..".EI’.".}'.'.'»IT.;‘..'I;'?$...........
`‘damn-In-axw-1;
`
`The thelmal data for-are shown in Figure 21. The DSC thermogram
`
`(Sample ID 1557-17-01) shows a single enclotherma
`
`weight loss up to 100 °C.
`
`At this stage,i
`it-i—hIa “'5.
`"'"“'"“"'”"'”‘"°""‘”"''”"
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`- There is no need of recrystallization. If it is less than 104°
`‘M
`C., it is recrystallized in EtOH—EtOAc to increase the melting
`point.
`
`Data on Tregrostinil Diethanolamine Salt Hz] 1 WE. of
`
`Batch
`N0-
`
`Benzin dene Triol
`(3)
`
`Wt. offi-eprostinil _
`Dietha.noIa.mine
`Yield -
`Salt (H) (3)
`(°/0) _
`
`1
`2
`
`1 2 50
`1250
`
`1 640
`152 8
`
`88.00 _
`82.00‘ —
`
`EX. 1005 (“Phares”) at 91; EX. 1001 at 8 (‘393 Patent) coI.12. II. 43-68.
`
`Ex. 1D29;SteadvMed V. United Therapeutics; |PR2016—UOUU6
`
`26
`
`

`
`4 Anticipation
`
`Ex. 1029; Stead\,rMed V. United Therapeutics;
`
`|PR2016—UUOD5
`
`

`
`Anticipation
`Independent Claims
`
`Claim 9
`
`9. A product comprising a compound having formula IV
`
`(IV)
`
`
`
`
`
`
`
`(c) contacting the product of step (h) with a base B to form
`a salt of formula IV,, and
`
`HO
`
`(IVE)
`
`(d)—reacting the salt formed in step (c) with an
`acid to form the compound of formula IV.
`
`
`
`
`
`m~ wherein the
`product is prepared by the process comprising
`(a) alkylating a compound of formula V with an alkylating
`agent to produce a compound of formula VI,
`
`
`(b)hyd1-olyzing the product of formula VI of step (a) with
`a base,
`
`
`Therapeutics;
`
`|PR2016-D0006
`
`28
`
`

`
`Anficipdrion
`Prior Art: Phares
`
`(C) contécting the product ofstep (b) with a base B such as
`diethanoiamjne to for a salt of the following structure,
`and
`
`H0
`
`
`
`.uIII IIOH
`
`
`
`ea NH;(CH;CH;0HIj;
`
`(cl) reacting the salt from step (b) with an acid such as HC1
`to form the compound of formula IV.
`In one embodiment, the purity ofcompound of formula IV
`is at least 90.0%, 95.0%, 99.0%, 99.5%.
`
`
`
`EX. 1005 (“Phares”) at 99 {Claim 49),‘ EX. 1001 at 6 {‘393 Patent) coI.8. ff. 47-68.
`
`Ex. 1D29;SteadvMed V. United Therapeutics; |PR2D16—UOU06
`
`29
`
`

`
`‘393 Patent/Phares Melting Points
`
`Ex. 1001: '393 Patent
`
`Example 3
`
`Batch 1: 104.3-106.3 “C
`
`Batch 3: 104.7-106.6 “C
`
`
`
`Ex. 1005: Pha res
`
`“The DSC thermogram
`(Sample ID 1557-17-01)
`shows a single endotherm
`at 107’ QC that is consistent
`
`wuznoa-'.I-IM'IJIlllllllI1I:LIIICllI|JII
`
`
`
`
`
`-'-\-...'.'.-..’-I"2"’-\}'
`
`_
`with a melting event (as
`Exam '94
`*4 determined by hotstage microscopy)?’
`Batch 1: 105.0-106.5 00
`Ex. 1005 at91
`
`Batch 2: 1045-1055 0c
`
`Figure 21: “107.06 0C”
`
`EX_m5m21
`
`EX. 1001 at 8-9 ["393 Patent) COH2-13,‘ Ex. 1005 (“Phares’) at 91, 121
`
`Ex. f10.19;SteadyMed United Tnesagjeutics: IPR2016-00005
`
`30
`
`

`
`Anticipation
`Prior Art: Phares
`
`IX. CONCLUSION
`
`88.
`
`In summaly, no matter how Form B is made, Form B has a single,
`
`defined melting point, and since the Phares Reference (Ex. 1005) discloses the
`
`same Form B crystal form as the '393 Patent (Ex. 1001), but a higher melting point
`
`than most of the '393 Patent examples, Phares necessarily discloses a salt of at least
`
`equal purity to the salt in the '393 Patent, if not higher.
`
`
` '5 "REPLY
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`
`EX. 1022 (“Rogers Declaration’? at 40
`
`Ex. 1U29;Stead\,rMed v. United Therapeutics;
`
`|PR201t':—UODD6
`
`31
`
`WET
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`
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`
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`
`

`
`Prior Art: Phares
`
`Dr. Williams declared identical polymorphs might have different melting points, depending
`
`on how they were made.
`
`THE WITNESS: Yeah. 80 I'm not a polymorph expert.
`
`Ex. 2059 (Wfllfains Dep.) 158.17-18
`
`Q. Do you consider yourself an expert on crystal forms of
`organic molecules?
`
`A. No.
`
`EX. 2059 (Williams Dep.) ’i56.'25—i57.'2
`
`Ex. 2059 (“Williams Deposition Transcript’? at 156-58
`
`Ex. 102$"; Stead-,.-l.»le-:13
`
`I_J".itE'd T'1e'a:)e_;t::5‘
`
`l3'R2L‘I’_=Eu-FJOIJCJEI
`
`32
`
`

`
`Prior Art: Phares
`
`Dr. Williams relied on “Adhiyaman reference” (Ex. 2030), which he initially believed showed
`
`different melting points for same crystal form.
`
`Q. Okay. So each of these is really a different crystal form of
`the same drug; is that fair?
`
`A.
`
`I think that's fair.”
`
`Ex. 2059 (l/l/iiiiams Dep.) 180517-20.
`
`EX. 2059 (“Wi.-‘Hams Deposition Transcript’) at 180
`
`Ex. 102$";Stead-,-lylé:-:f I_J-niteciT'Ve'a:)e_;t::5‘
`
`It-R2cu;=3.-0-3-Joe
`
`33
`
`

`
`Arriicipcxtiora
`Process can be Different
`
`
`
`"If the product in a product—by—process claim is the
`
`same as or obvious from a product of the prior art,
`
`the claim is unpatentable even though the prior
`
`product was made by a different process.”
`
`in re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985)
`
`Ex.1029;SteadvMedv. United The.:'a_oeutics;
`
`|PR2016—O0OO6
`
`34
`
`

`
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`
`
`
`”Purdue claimed the end product; it did not claim a
`
`particular method for creating that product, such as
`
`the use of hydrogenation after the salting step....
`
`One need not know that
`
`the 14—hydroxy was
`
`derived from 80¢ as opposed to 88 to answer that
`
`question.”
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1353 (Fed. Cir. 2016)
`
`Ex.1029:Stead\r|\Iled~.«. United TherarJeutics;
`
`|PR2016—0OOO6
`
`35
`
`

`
`AflTiCipC]TiOh
`Prior Art: Phares
`
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`
`EX. 1005 (“Phares”) at 42
`
`Ex. 1U29;Stead\,rMed v. United Therapeutics;
`
`|PR2016—{}DUD6
`
`

`
`An’ri<:ipoI’rion
`Prior Art: Phares
`
`R9
`
` /\/\/\/
`
`‘\
`
`.5.
`OT!-[P
`
`g 11- H
`
`OCH3
`
`Q R= TBDMS
`
`Q.
`
`Okay.
`
`So what we see here is there's an
`
`alkylating step (a) and hydrolyzing step (b) on
`
`page 42 of the Phares reference.
`
`A.
`
`Yes.
`
`Ex. 2059 (Williams Dep.) 190: 16-19
`
`Ex. 1005 (“Phares’3 at 42; Ex. 2059 (VI/mfams Deposition Transcript) at 190.
`
`Ex. 1D29;SteadyMed V. United Therapeutics; 1932015-some
`
`

`
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`
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`Prior Art: Phares
`
`UNITE: srnrlamfnfinan ll1:m.EH.uu: arm!
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`
`55.
`
`Second, Phares also details the same Claim 1 and 9 steps (a) or (b) as
`
`were used to make treprostinil in the ‘£17 Patent and Moriarty reference, but
`
`applies them to make (-)-treprostinil, the enantiomer of (+)- treprostinil (Ex. 1005,
`
`p. 42). The '393 Patent and prosecution history admits using these steps (a) and (b)
`
`in the prior art.
`
`(‘393 Patent, (Ex. 1001), col. 1,
`
`lines 22-28 (incorporating
`
`Moriarty (Ex. 1004), tl1e ‘I17 Patent (Ex. 1003), and U.S. Patent No. 6,441,245
`
`(Ex. 1013) by reference, and coI.7, lines 17-20 (describing '245 Patent's process as
`
`the same as in the '393 Patent); See also Ex. 1002-1, p. 109).
`
`Ex. 1009 {Winkier Ded.) fi 55 at 21
`
`
`fl$__;':jd'-;:m‘:,;°:°{:;‘_*:f-,";Pj_'_~‘*"'='“’
`
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`
`
`EX. 1009 (“VI/inkler Decl”) at 21.
`
`Ex. 1U29;Siead\,rMed u. United Therapeutics;
`
`|PR2016—UOOD6
`
`33
`
`

`
`Starting Material Irrelevant
`
`”Purdue claimed the end product; it did not claim a
`
` the use of hydrogenation after the salting step....
`
`particular method for creating that product, such as
`
`One need not know that
`
`the 14—hydroxy was
`
`derived from 80¢ as opposed to 88 to answer that
`
`question.”
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1353 (Fed. Cir. 2016}
`
`Ex.1O29:Stead';r|\Iled'-.4. United TherarJeutics;
`
`|PR2016—0OOO6
`
`39
`
`

`
`Impurity Profile Irrelevant
`
`
`
`“'[T]he fact that the 14—hydroxy is derived from 8a
`
`imparts no structural or functional differences in the
`
`low-ABUK [impurity] hydrocodone API as compared
`
`to the prior art products. Thus, the court did not err
`
`in
`
`disregarding
`
`the
`
`process
`
`limitation
`
`in
`
`its
`
`obviousness determination.”
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1354 (Fed. Cir. 2016}
`
`Ex. 1029: Stee.d';r|\Iled '-.4. United The:'arJeutic5:
`
`|PR2L”I16—0OOO6
`
`40
`
`

`
`A.rflricipC:‘i‘i0ra
`Impurity Profiles Not Different
`
`at 5
`Ex
`(Prior Art 12/23/2003)
`
` TESTIREFERENCE
`
`RESULTS‘ SPECIFICATIONS
`
`
`
`Chromatographic Purity (E-IPLC}
`NB 1, LDR 63 — 72
`
`H
`No! more than 0.5%
`H
`Nut more than 0.5%
` No! more than 0.2%
`
`Not more than 1.0%
`3 A590
`
` Not more than 0.2%
`
`«Not more than 0.6%
`Treprostinil Ethyl Ester
`
`Not more than 1.5%
`750W93
`
`75lW93
`Nflt l'I10i'C than
`
`Not more than 0.1 /1: AU(. each
`Umdennfied
`
`
`
`
`stinil as the free acid
`
`accord'n in claims I
`
`10
`
`Ex. 1004: Moriarty
`
`Ex. 1001:
`
`‘393 Patent
`
`.
`
`(Walsh Declaration)
`
`impurities (H?LC]
`
`
`Tr rostinil fieth E Ester
`Not more than 0.20% jar.
`impurities (J-IPLC]
`_
`rumnmunuesa W T
`Impurities (HFLCJ
`.
`new waved substances-I
`“‘°* ”“°""‘ "“’" 3*‘’°”’° “
`
`Ex. 1002 at 249
`
`Ex. 2036 {“Phares’9 at 5; Ex. 1002 at 249 (‘393 Patent Prosecution)
`
`Ex.1O29:Stead~,I|\»1edv. Un1teciThera$3eutic5;
`
`|PR2016-00006
`
`41
`
`

`
`Anficipolfion
`Impurity Profiles Meaningless
`
`
`
`
`Reslilts from HPLC Assa
`Results from HPLC Assa
`
`
`
` Average =
`
`Standard Deviation =
`
`
`
` 997i05% m
`
`EX- 1021 at 5
`
`Ex. 1U29;Stead\,rMed v. United Therapeutics;
`
`|PR2016—UODD6
`
`42
`
`Ex. 1021 at 5 (Moriarty, average of-45 samples)
`
`..,..,..
`
`.
`
`..m...
`
`

`
`Antlcipoilora
`Key Scientific Concepts: HPLC and Purity
`
`
`
`
`EX. 2006 61' 3
`
`Ex.1029;SteadvMedv. Ur1itedTlie:'a_neutics;
`
`|PR2016—O0OO6
`
`43
`
`EX. 2006 at 3
`
`Steadylvled v. United Therapeutics
`|PR2016-00006
`
`During the initial analytical method validation for the treprostinil assay, the results indicated
`.,‘,':|
`'
`.’
`I- _.‘-_|
`\
`I
`1|
`-
`.
`-- __~_...,_
`
`that ..'=:-=._-=.:
`.
`'. --
`..
`..
`.
`Our specifications of97.0-101.0% were
`centere at 99% purity or the AM. When the process for the manufacture of treprostinil was
`instituted in Silver Spiing, it was observed that the purity of the treprostinil improved to close
`
`to 100%. From a statistical stand-point, 3?-xi -:: : .- _...
`1.’
`.
`:__.-;:_..:.
`-
`in an OOS on the high side (considering a two sigma range) when the upper limit of the
`specification is 101.0%. Scientifically,
`‘-
`”
`'
`-
`'-
`"
`r-
`'-
`' "
`
`
`
`rin development in Silver Spring, it was observed that there were
`
`
`
`3
`
`UT Ex. 2006
`
`

`
`No Functional Differences
`
`
`
`""[|]fthe process by which a product is made imparts
`
`‘structural and functional differences’ distinguishing
`
`the claimed product from the prior art, then those
`
`differences
`
`‘are
`
`relevant
`
`as
`
`evidence
`
`of
`
`no
`
`anticipation’ although they ‘are not explicitly part of
`
`the claim.”
`
`Purdue Pharma LP. v. Epic Pharma, LLC, 811 F.3d 1345, 1354 (Fed. Cir. 2016}
`
`(cites and internal quotations omitted) (emphasis added}
`
`Ex. 3.U29:3T.E'.d(1"ylvlE£(l'-.#. United Tiwerapeuticsi
`
`|PR2L‘I16—00OO6
`
`44
`
`

`
`Andricipoiion
`No Functional Differences
`
`m':|'_::TM':'
`pH,D
`
`Q. Do any of the —— as far as you know, any of these particular impurities have
`deleterious biological consequences?
`
`THE WITNESS: I'm not a clinician, so I don't know.
`
`BY MR. POLLACK:
`
`Q. You don't know?
`
`A-
`
`' donrt k“°W-
`
`Ex. 2059(Wi!!icrms Dep.) 47:4-13
`
`ROBERT R_
`RUFFOLDI
`PH.D
`
`Q. Do you know if any of these listed chromatographic impurities have any adverse
`effects In humans?
`BY MR. POLLACK:
`
`Q. And if so, what are they?
`
`I don't know. What i can tell you is that if you review the FDA label,
`THE WITNESS:
`there are a host of adverse effects produced or observed in patients who are taking
`tT‘3F3T05ti“”-
`Ex. 2058 (Ruffoib Dep.) 257:22-253:9
`
`Ex. 2059 {Williams Dep. at 47; Ex. 2058 {Ruffofo Dep.) at 66
`
`Ex. 1029; Steadv|’\.'led'-J. United Therapeutics:
`
`|PR2016—O0006
`
`45
`
`

`
`Anticipation
`No Functional Differences
`
`u... .
`
`ROBERT R. RUFFGLD, PH.D
`
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`I
`avvitzuxralimwnutuaawsuwuo
`
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`5
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`
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`
`Enlarge:
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`ht
`
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`imnsmmw ammo
`w.mgm.nr:2unos
`
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`
`in mm: lmwo. In nu .
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`
`
`
`Q. Okay. And i make another batch of treprostinil APl and I measure its HPLC
`
`analysis and it's 98.5 percent. Could that batch move on in the process?
`
`THE WiTNESS: Yes, with that current level spec, that could move on.
`
`Ex. 2058 (Ruffo.-‘o Dep.) 160: 1 7-24
`
`Q.
`
`is there a difference between the approved Moriarty treprostinil product
`
`that was shown clinically that's different from the '393 product?
`
`THE WiTNESS: Not —— not to my knowledge.
`
`Ex. 2058 (Ruffolo Dep.) 315:5-23
`
`Ex. 2058 (Ruffolo Dep.) at 41, 80
`
`Ex.1EJ29;SteadvMed v. United Therapeutics;
`
`|PR2016—UOOO6
`
`46
`
`

`
`Conclusions
`
`1. No structural differences
`
`2.