Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LIQUIDIA TECHNOLOGIES, INC.,
`
`Petitioner
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`
`Patent Owner
`
`U.S. Patent No. 9,593,066
`
`Issue Date: March 14, 2017
`
`Title: Process to Prepare Treprostinil, the Active Ingredient in Remodulin®
`
`DECLARATION OF JEFFREY D. WINKLER, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`OF U.S. Patent No. 9,593,066
`
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`VI. IV. SUMMARY OVERVIEW OF THE ’066 PATENT
`
`A.
`
`Brief Description of the ’066 Patent
`
`I understand that the The ’066 patent is entitled “Process to Prepare Treprostinil, the Active
`
`Ingredient in Remodulin®.” The claims of the ’066 patent are product-by-process claims. These
`
`claims include two independent (claims 1 and 8) and eight dependent claims.
`
`The ’066 patent discloses an “improved process” to prepare prostacyclin derivatives such
`
`as treprostinil. (Ex. 1001, Abstract.) Claim 1 is drawn to a pharmaceutical composition comprising
`
`treprostinil or a pharmaceutically acceptable salt thereof. Claim 8 is drawn to a process of
`
`preparing the same product from claim 1, comprising the steps of alkylation of an intermediate
`
`triol and hydrolyzing to form a treprostinil or a pharmaceutically acceptable salt thereof. (Id.,
`
`claims 1 and 8.)
`
`Each of the independent claims include limitations that the claimed pharmaceutical
`
`composition/product is made by a process comprising: (a) providing a starting batch of treprostinil
`
`having one or more impurities resulting from prior alkylation and hydrolysis steps; (b) forming a
`
`treprostinil salt by adding a base; and (c) preparing a pharmaceutical composition/product
`
`comprising treprostinil or a pharmaceutically acceptable salt thereof from the isolated treprostinil
`
`salt.
`
`The claim limitations of the ’066 patent are as follows:
`
`Claim Limitation
`1 [a] A pharmaceutical composition comprising treprostinil or a pharmaceutically
`acceptable salt thereof,
`said composition prepared by a process comprising:
`1[b]
`1 [c] providing a starting batch of treprostinil having one or more impurities resulting
`from prior alkylation and hydrolysis steps,
`forming a salt of treprostinil by combining the starting batch and a base,
`
`1 [d]
`
`1
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`isolating the treprostinil salt, and
`1 [e]
`1 [f] preparing a pharmaceutical composition comprising treprostinil or a
`pharmaceutically acceptable salt thereof from the isolated treprostinil salt,
`1 [g] whereby a level of one or more impurities found in the starting batch of treprostinil
`is lower in the pharmaceutical composition, and
`1 [h] wherein said alkylation is alkylation of benzindene triol.
`2
`The pharmaceutical composition of claim 1, wherein the salt is isolated in crystalline
`form.
`The pharmaceutical composition of claim 1, wherein the base is selected from the
`group consisting of sodium, ammonia, potassium, calcium, ethanolamine,
`diethanolamine, N-methylglucamine, and choline.
`
`3
`
`4
`
`5
`
`6
`
`7
`
`The pharmaceutical composition of claim 3, wherein the base is diethanolamine.
`
`The pharmaceutical composition of claim 1, wherein the base is combined with
`treprostinil that has not been previously isolated.
`
`The pharmaceutical composition of claim 1, wherein the isolated salt is stored at
`ambient temperature.
`
`The pharmaceutical composition of claim 1, which is a pharmaceutical solution.
`
`8[a] A process of preparing a pharmaceutical product comprising treprostinil or a
`pharmaceutically acceptable salt thereof, comprising:
`8[b] Alkylating a triol intermediate of the formula:
`
`hydrolyzing the resulting compound to form treprostinil,
`8[c]
`forming a salt of treprostinil stable at ambient temperature,
`8[d]
`storing the treprostinil salt at ambient temperature, and
`8[e]
`preparing a pharmaceutical product from the treprostinil salt after storage,
`8[f]
`8[g] wherein the pharmaceutical product comprises treprostinil or a pharmaceutically
`acceptable salt thereof
`A pharmaceutical product prepared by the process of claim 8.
`The process as claimed in claim 8, wherein forming the salt of treprostinil stable at
`ambient temperature is performed by adding diethanolamine to treprostinil.
`
`9
`10
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`The More specifically, the ’066 patent discloses a process for the preparation of a
`
`compound of Formula I (which includes treprostinil) shown below,:
`
`
`
`(Ex. 1001 at col. 2:7-21), where.) Where: w = 1, 2, or 3; Y1 is trans-CH=CH-, cis-CH=CH , —
`
`CH2(CH2)m -, or ––C≡C––; m
`
`is 1, 2, or 3; M1
`
`is α-OH: β-R5 or α-R5: β-OH
`
`or α-OR2: β-R5 or α-R5: β-OR2, wherein R5 is hydrogen or methyl, R2 is an alcohol protecting
`
`group; L1 is α-R3: β-R4, α-R4: β -R3, or a mixture of α-R3: 13-R4 and α-R4: β -R3, wherein R3 and
`
`R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and
`
`R4 is fluoro only when the other is hydrogen or fluoro; and R7 is (1) —CpH2p, CH3, wherein p is
`
`an integer from 1 to 5 inclusive, (2) phenoxy optionally substituted by one, two or three chloro,
`
`fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two
`
`substituents are other than alkyl, with the proviso that R7, is phenoxy or substituted phenoxy, only
`
`when R3 and R4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl,
`
`phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three
`
`chloro, fluoro, trifluoromethyl, (Ci-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than
`
`two substituents are other than alkyl, (4) cis-CH=CH—CH2—CH3, (5) —(CH2)2—CH(OH) —
`
`CH3, or (6) —(CH2)3—CH=C(CH3)2,; wherein —C(L1)-R7
`
`2 taken together is: (1) (C4-
`
`C7)cycloalkyl optionally substituted by 1 to 3 (C1-C5)alkyl; (2) 2-(2-furyl)ethyl; (3) 2-(3-
`
`thienyl)ethoxy; or (4) 3-thienyloxymethyl. (Id. at cols. 2:46-3:15.) Treprostinil is the specific
`
`
`
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`Formula I compound where w = 1; Y1 is—CH2(CH2)m--and m is 1; M1 is α-OH: (β-R5 or α-R5: β-
`
`OH, wherein R5 is hydrogen; L1 is α-R3: β-R4, α-R4: β-R3, or a mixture of α-R3: β-R4 and α-R4: β-R3,
`
`wherein R3 and R4 are hydrogen; and R7 is —CpH2p—CH3, wherein p is an integer from 1 to 5
`
`inclusive (p=3).
`
`The ’066 patent discloses alkylating the treprostinil precursor (benzindene triol, a.k.a.
`
`treprostinil triol) with an alkylating agent and then hydrolyzing with a base. (Id. at col. 2:7-3:17.)
`
`The ’066 patent further discloses contacting the product from the alkylation and hydrolysis steps
`
`with a base to form a salt (e.g. using the base diethanolamine to form treprostinil diethanolamine
`
`salt) of Formula Is shown below (where B is diethanolamine and where the other variables are the
`
`same as for the treprostinil-specific version of Formula I explained in the previous paragraph):1
`
`
`
`
`
`(Id. at col. 3:19-30.) The treprostinil salt can then be reacted with an acid to form the compound
`
`of Formula 1 (treprostinil-specific Formula I). (Id. at col. 3:31-33.) Formula 1 is at least 90.0%,
`
`95.0%, or 99.0% pure. (Id. at col. 9:22-23.)
`
`Formula I is a general formula, while Formula IV is specifically treprostinil. Formula IV,
`
`which is treprostinil, is disclosed to be at least 90.0%, 95.0%, or 99.0% pure. (Id. at col. 9:22-23.)
`
`
`1 Though the patent recites —C(L1)-R2, a POSA would understand this to be a typo. It should
`be “—C(L1)-R7” because the patent teaches that L1 and R7 can be taken together to form a
`“cycloalkyl,” which a POSA would understand to be a ring. (Ex. 1001 at col. 3:2.)
`
`
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`Formula IVs is the formula for a generic salt formed from treprostinil. When “B” in Formula IVs
`
`is diethanolamine, as taught at columns 9, 12, and 14 of the ’066 patent, Formula IVs is treprostinil
`
`diethanolamine salt.
`
`The ’066 patent further discloses alkylating a treprostinil triol intermediate (Formula V,
`
`shown below) to form treprostinil or a pharmaceutically acceptable salt thereof:
`
`
`
`(Id. at col. 3:52-66.)
`
`The ’066 patent discloses that these process steps can be conducted at ambient temperature
`
`and the resulting treprostinil, or pharmaceutically acceptable salt thereof, can be stored at ambient
`
`temperatures. (Id. at col. 17:32-36.)
`
`
`
`. . .
`
`VIII.VI. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST ONE
`CLAIM OF THE ’066 PATENT IS INVALID UNPATENTABLE
`
`A.
`
`State of the Art & Summary of Invalidity Arguments2
`
`There are at least three strong reasonsbases for invalidation of the ’066 patent: (1) as
`
`explained in the following sections, the synthesis of the claimed compounds, including treprostinil
`
`
`2 The non-patent literature introduced in this section and cited in the petition was publicly
`available before December 17, 2007. (Ex. 1015, Declaration of Sylvia Hall-Ellis, ¶¶51-71
`(authenticating Wiberg, Schoffstall, and Ege (Exs. 1010, 1011, and 1013)).)
`
`
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`and treprostinil diethanolamine salt, was well-known in the art; (2) as detailed in Sections IX and
`
`X, the claims of the ’066 patent are product-by-process claims and the claimed process does not
`
`produce a product that is materially distinct from the product produced by the prior art, thus, the
`
`claims of the ’066 patent are invalid as anticipated and obvious; and (3) the parent patent, U.S.
`
`patent No. 8,497,393 (the “’393 patent”) was declared invalid and/or unenforceable in IPR2016-
`
`00006 under 35 U.S.C. §§ 102(b) and 103(a) and since the claim limitations of the ’066 patent are
`
`substantively similar to the invalidated ’393 patent, the ’066 patent should be similarly declared
`
`invalid. (Exs. 1004 and 1005.)
`
`I have reviewed the ’393 patent and ’393 IPR Decision. In addition, I served as an expert
`
`in the ’393 IPR for Petitioner SteadyMed and am thus familiar with the arguments and prior art
`
`contained therein. Claims 1-10 of the ’066 patent should be held invalid for similar reasons as the
`
`’393 patent because the claims of the ’066 patent are substantively similar to those of the ’393
`
`patent in that they disclose the same treprostinil and the identical treprostinil salt.
`
`For all of the reasons provided above, claims 1-10 of the ’066 patent should be held invalid,
`
`as discussed in further detail below.
`
`B. 1. The Synthesis of Treprostinil Waswas Well-Known
`
`Before December 17, 2007, synthesis for numerous prostacylcin derivatives, such as
`
`treprostinil, and intermediate compounds useful in their synthesis were well-known. (Winkler
`
`Decl., ¶ 38.) These prostacyclin derivatives and intermediates include the following general
`
`structure:
`
`
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`
`(See e.g., the ’117 patent, Ex. 1007, claim 1.)
`The For example, the ’117 patent includes the synthesis of treprostinil (which is the case in which:
`
`Z is O, n is 1, X is COOH, Y1 is CH2CH2-, M1 is an H and an OH group in the S configuration
`
`(i.e., the same stereoisomer configuration found in the structure of treprostinil (below)), L1 is α-H;
`
`β-H, and R7 is —(CH2)3-CH3 amongst its many examples. (Id; Winkler Decl., ¶ 40.) In addition,
`
`both Phares (Ex. 1008) and Moriarty (Ex. 1009) further disclose syntheses of treprostinil. For
`
`example, claim Claim 3 of the ’117 patent (Ex. 1007) discloses the structure of treprostinil
`
`below:(Id.)
`
`which is produced by a process for making 9-deoxy-PGF1-type compounds, the process
`
`comprising cyclizing the following starting compound:
`
`
`
`
`
`
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`As noted supra, the The process steps recited in claims 1 and 8 of the ’066 patent disclose
`
`the synthesis of prostacyclin derivative acids that include treprostinil acid, which is also disclosed
`
`in Moriarty (Ex. 1009) and the ’117 patent (Ex. 1007).
`
`In addition, both Phares (Ex. 1008) and Moriarty (Ex. 1009) further disclose syntheses of
`
`treprostinil. Phares discloses the synthesis of (-)-treprostinil, the enantiomer of (+)-treprostinil.
`
`
`
`(Ex. 1008(Id. at 39-40.) Phares explains that “[e]nantiomers of these compounds...can be
`
`synthesized using reagents and synthons of enantiomeric chirality of the above reagents,” thereby
`
`inherently teaching the synthesis of both enantiomeric forms of treprostinil, both (-)-treprostinil
`
`and (+)-treprostinil. (Id. at 39.) Moriarty discloses the following synthetic scheme for making
`
`treprostinil acid:
`
`(Ex. 1009 at 43, 6:.) The ’066 patent discloses the same scheme for making treprostinil
`
`acid:
`
`10
`
`1
`
`O
`
`H
`
`
`
`00%
`
`H3
`
`1
`
`C
`
`(Ex. 1001 at Examples 1 and 2.) Accordingly, the only alleged “improvement” to Moriarty in the
`
`’066 patent was the preparation of a treprostinil diethanolamine salt (from a starting batch of
`
`treprostinil or treprostinil diethanolamine salt having one or more impurities resulting from
`
`
`
`
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`alkylation and/or hydrolysis) without isolation of the treprostinil acid. This represents(Winkler
`
`Decl., ¶ 46.) These steps are nothing more than a routine, elementary organic chemistry techniques
`
`for the purification of a carboxylic acid, such as treprostinil acid. (Id.) In addition, Phares discloses
`
`methods of synthesis to produce treprostinil diethanolamine salt using the same starting material
`
`(prepared by the same chemicaland steps) as disclosed in Moriarty. (Id.)
`
`C. 2. Formation of a Carboxylate Salt from a Carboxylic Acid and the
`Addition of an Acid to a Carboxylate Salt to Regenerate the Carboxylic Acid
`is Standard Chemical Purification Known in the Art
`
`The process steps of claims 1 and 8 disclose nothing more than elementary organic
`
`chemistry techniques for purification of a carboxylic acid, such as treprostinil acid, which were
`
`well described in the prior art years before December 17, 2007. (Winkler Decl., ¶ 47.) The
`
`formation of a carboxylate salt, by the addition of a base to a neutral carboxylic acid, and the
`
`subsequent addition of a strong acid to regenerate carboxylic acid, as disclosed in claims 1 and 8
`
`are standard chemistry purification procedures — i.e., organic chemistry 101. (Id.) Indeed, similar
`
`general purification techniques were described in numerous textbooks and literature, such as basic
`
`introductory organic chemistry textbooks, well before the December 17, 2007 priority date for the
`
`’066 patent.
`
` (Id.) For example, Wiberg, an organic chemistry lab textbook provided to organic
`
`chemistry students, explicitly states:
`
`A typical example is the purification of a water-insoluble solid
`carboxylic acid by dissolving it in sodium hydroxide solution,
`filtering, precipitating the compound by the addition of acid. A
`similar procedure may be used with amines: dissolve the
`compound in acid and precipitate it with a base. These procedures
`usually work quite well in that they utilize a chemical reaction to
`aid in separation from nonacidic or nonbasic impurities.
`
`
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`(Ex. 1010 at 6; Winkler Decl., ¶ 48.) Similarly, Schoffstall (Ex. 1011), describes an experiment
`
`in which carboxylic acid is separated from neutral and basic organic compounds by conversion
`
`to a salt. Addition of an acid, such as HC1, then regenerates the carboxylic acid from the salt,
`
`which can then be filtered or extracted into an organic solvent. (Ex. 1011 at 3-40; see also
`
`Winkler Decl., ¶ 49.) More specifically, contacting a carboxylic acid of a prostacyclin derivative,
`
`such as treprostinil, with a base to form a salt, followed by the addition of a strong acid to
`
`regenerate the carboxylic acid, was a well-known chemical purification technique in the prior art.
`
`For example:(Winkler Decl., ¶ 50 (citing Kawakami, Ex. 1012 and Ege, Ex. 1013).)
`
`• Kawakami (Ex. 1012), entitled “Crystalline Amine Salt of Methanoprostacyclin
`
`Derivative, Manufacturing Method thereof, and Purifying Method thereof” (bolding
`
`added), is directed to the preparation and use of dicyclohexylamine (i.e., an amine base
`
`with similar reactivity to diethanolamine) to form a crystalline dicyclohexylamine salt
`
`of a methanoprostacyclin derivative, in order to purify the methanoprostacyclin.
`
`Kawakami further discloses that the dicyclohexylamine salt of a methanoprostacyclin
`
`derivative can be easily reverted to the free methanoprostacyclin derivative by
`
`conventional methods, such as treating the salt with a strong acid such as HC1 or H2SO4.
`
`(Ex. 1012 at 6.) Per Kawakami, the salt that is obtained has “fairly high purity and the
`
`purity can be further improved by recrystallization as needed with the use of an
`
`appropriate solvent.” (Id.)
`
`• Ege (Ex. 1013), an organic chemistry textbook, discloses that sodium benzoate (i.e., a
`
`carboxylate salt) can be converted back to benzoic acid (i.e., a carboxylic acid) by
`
`treatment with the acid HC1, which is prototypical of the reaction of the treprostinil
`
`
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`diethanolamine salt with a strong acid to regenerate the treprostinil carboxylic acid.
`
`(Ex. 1013 at 8.)
`
`D. 3. The Claimed Treprostinil and Treprostinil Diethanolamine Salt
`Disclosed in the ’066 Patent is Not Distinct from the Prior Art
`
`I understand that the The ’066 patent claims are product-by-process claims. It has been
`
`explained to me that theThe process limitations are not accorded any weight for determining the
`
`validity of the claims of the ’066 patent. I understand that the See e.g., Amgen Inc. v. F. Hoffman-
`
`La Roche Ltd., 580 F.3d 1340, 1369 (Fed. Cir. 2009) (“In determining validity of a product-by-
`
`process claim, the focus is on the product and not on the process of making it.”); see also MPEP ¶
`
`2113 (citing In re Thorpe, 777 F.2d 695, 698 (Fed. Cir. 1985)). The process in a product-by-process
`
`claim merits weight in reviewing the prior art only if it imparts some unique and novel property or
`
`structure in the resulting product. Such is not the case here.
`
`As discussed above and in further detail below, treprostinil and its synthesis, including the
`
`steps of alkylation and hydrolysis, isolating a treprostinil salt, the reaction of an acid with the salt
`
`to regenerate the acid and preparing treprostinil or the pharmaceutically acceptable salt (i.e.,
`
`treprostinil diethanolamine salt), was already well-known in the art. (Winkler Decl., ¶ 52.)
`
`VII.
`
`OVERVIEW OF THE GROUNDS
`
`Given the state of the art and the knowledge of a POSA as of the filing date of the priority
`
`applications that resulted in the ’066 patent, all claims of the ’066 patent are unpatentable under
`
`35 U.S.C. §§ 102(b) and 103.
`
`A.
`
`Overview ofOf Phares
`
`. . .
`
`The Phares reference is titled “Compounds and Methods for the Delivery of Prostacyclin
`
`Analogs.” (Ex. 1008.) The named inventors are Ken Phares and David Mottola. Phares was
`
`
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`published January 27, 2005 and is prior art to the ’066 patent under 35 U.S.C. § 102(b). The ’066
`
`patent seeks the benefit of provisional application No. 61/014,232, filed on December 17, 2007.
`
`For the purposes of this petition, I understand that Petitioner will use December 17, 2007 as the
`
`effective filing date of the ’066 patent.
`
`Phares describes “compounds and methods for inducing prostacyclin-like effects in a
`
`subject or a patient,” including treprostinil and derivatives thereof. (Ex. 1008 at 8.) The chemical
`
`structure of treprostinil is shown below:
`
`
`
` (Id.) Phares explains that “[t]reprostinil is a chemically stable analog of prostacyclin, and
`
`as such is a potent vasodilator and inhibitor of platelet aggregation.” (Id.)
`
`Phares further discloses that “[a] preferred embodiment of the present invention is the
`
`diethanolamine salt of treprostinil.” (Id. at 9.) A particularly preferred embodiment of the invention
`
`disclosed in Phares is “Formform B of treprostinil diethanolamine.” (Id.) The structure of
`
`treprostinil diethanolamine salt described by Phares is reproduced below:
`
`
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`(Id. at 96, claim 49.) Phares discloses two crystalline forms of treprostinil diethanolamine
`
`salt, Form A and Form B. (Id. at 85-89.) The crystalline Form B “appears to be the most
`
`thermodynamically stable form” with “full conversion to Form B at ambient, 15 °C, and 30 °C
`
`after 7 days, 11 days, and 1 day, respectively.” (Id. at 89.)
`
`Phares further discloses the synthesis of (-)-treprostinil, the enantiomer of treprostinil. (Id.
`
`at 39-40.) Phares explains that “[e]nantiomers of these compounds...can be synthesized using
`
`reagents and synthons of enantiomeric chirality of the above reagents,” thereby inherently teaching
`
`the synthesis of both enantiomeric forms of treprostinil, both (-)-treprostinil and (+)-treprostinil.
`
`(Id. at 39.) In particular, Phares teaches that “the enantiomer of the commercial drug (+)-
`
`treprostinilTreprostinil was synthesized using the stereoselective intramolecular Pauson Khand
`
`reaction as a key step and Mitsunobu inversion of the side-chain hydroxyl group.” (Id. at 40.)
`
`Phares discloses the following reaction procedure for the synthesis of 2, the enantiomer of
`
`treprostinil, from the benzindene triol 11 (outlined in the red-dotted square below):
`
`
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`
`(Id.)
`
` The reaction procedure for the conversion of 11b to 2 is disclosed in Phares as: “(1) i.
`
`C1CH2CN, K2CO3. ii, KOH, CH3OH, reflux. 83% (2 steps).” (Id.) Steps (i) to (k) shown above
`
`result in treprostinil triol (the precursor for treprostinil), and step (1) coverts the precursor into
`
`treprostinil.
`
`The invention of Phares “also “provides for compositions which may be prepared by
`
`mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts
`
`thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, to treat
`
`or ameliorate a variety of disorders related vasoconstriction and/or platelet aggregation.” (Id. at
`
`48.) Thus, the pharmaceutical acceptability of the compounds is clearly disclosed in Phares.
`
`(Winkler Decl., ¶ 62.)
`
`B.
`
`Ground 1: Phares Renders Obvious Claims 1-7 of the ’066 Patent under 35
`U.S.C. § 103
`
`As described in detail below, claims 1-7 of the ’066 patent are rendered obvious by Phares.
`
`1.
`
`Independent Claim 1
`
`a.
`
`Phares discloses claim element 1[a]
`
`
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`1 [a] A pharmaceutical composition comprising treprostinil or a
`pharmaceutically acceptable salt thereof, said composition
`prepared by a process comprising:
`Phares inherently discloses the same synthesis of treprostinil as set forth in independent
`
`claims 1 and 8 of the ’066 patent.
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` Phares describes “compounds and methods for inducing prostacyclin-like effects in a
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`subject or a patient,” including treprostinil and derivatives thereof. (Ex. 1008 at 8.) The chemical
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`structure of treprostinil disclosed in Phares is shown below:
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`(Id.) This is the same treprostinil disclosed in the ’066 patent:
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`
`
`
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`where:
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`
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`• Where w = 1;
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`•
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`•
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`•
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` Y1 is—CH2(CH2)m- and m is 1;
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` M1 is α-OH: β-R5 or α-R5: β-OH, wherein R5 is hydrogen;
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` L1 is α-R3: β-R4, α-R4: β-R3, or a mixture of α-R3: β-R4 and α-R4: β-R3, wherein R3 and R4
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`are hydrogen;
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`
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` and R7 is —CpH2p—CH3, wherein p is an integer from 1 to 5 inclusive (p=3). (Ex. 1001 at col.
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`2:7-3:15; Winkler Decl., 63-65.)
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`Phares
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`further discloses
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`the
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`identical, pharmaceutically acceptable
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`treprostinil
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`diethanolamine salt as the ’066 patent. (Ex. 1008 at 96, claim 49; Winkler Decl., ¶ 66; Ex. 1005 at
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`47.) The structure of treprostinil diethanolamine salt disclosed by Phares (left) is reproduced below
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`in a side-by-side comparison with the treprostinil diethanolamine salt disclosed in the ’066 patent
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`(right):
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`
`
`(Phares)
`
`
`
`(’066 patent)
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`(Ex. 1008 at 96, claim 49; Ex. 1001 at col. 9:5-20, col. 12:8-23, Examples 3 and 5.) Other than a
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`change in formatting, one can easily see that these two structures from Phares and the ’066 patent
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`are identical. (Winkler Decl., ¶ 66.)
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`The PharesThis salt is made by the same process steps as claim 1 of the ’066 patent: (a) by
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`forming a salt of treprostinil by combining the starting batch of treprostinil acid and a base and;
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`(b) isolating the treprostinil salt. (Ex. 1001, claim 1; Ex. 1008 at 22.) The isolated salt is then used
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`
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`to prepare a pharmaceutical composition comprising treprostinil or a pharmaceutically acceptable
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`salt thereof. (Ex. 1001, claim 1; Ex. 1008 at 58.)
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` This shows that Phares necessarily discloses the same process steps to make a
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`pharmaceutically acceptable salt thereof disclosed in claim 1— treprostinil diethanolamine salt —
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`claimed in the ’066 patent, and thus inherently anticipates claim 1 of the ’066 patent. (Winkler
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`Decl., ¶¶ 67-68.) I point to further Further support for anticipation of each process element of claim
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`1 is provided in the following sections Sections IX.B.1.(b)-(g).
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`b.
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`Phares discloses claim element 1[b]
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`1 [b]
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`providing a starting batch of treprostinil having one or more impurities
`resulting from prior alkylation and hydrolysis steps,
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`As discussed above in Section IX.B.1.a, Phares discloses the
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`It is my opinion that theidentical treprostinil and pharmaceutically acceptable treprostinil
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`diethanolamine salt as the ’066 patent. (Winkler Decl., ¶¶ 63-68.) The remaining process claim
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`elements do nothing to impart structural or functional differences in the claimed treprostinil or
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`pharmaceutically acceptable salt thereof, and thus, do not patentably limit the claimed
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`pharmaceutical composition.
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` (Id., ¶ 70.) Even so, Phares discloses each of the remaining process claim elements.
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`Pharesfurther discloses providing a starting batch of treprostinil having one or more impurities
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`resulting from alkylation and hydrolysis steps.
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`TheFirst, the claim language does not disclose the percentage of “impurity” required in the
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`starting batch of treprostinil and simply states “having one or more impurities.” (Ex. 1001, claim
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`1.) The ’066 patent discloses that in one embodiment the “purity of compound of formula IV is at
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`least 90.0%, 95.0%, 99.0% or 99.5%,” where the formula IV is treprostinil. (Id. at col. 9:22-23.)
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`This disclosure shows that the purity of treprostinil may be as low as 90.0%. (Winkler Decl., ¶ 73.)
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`Phares discloses two crystalline forms of treprostinil diethanolamine salt, Form A and Form B.
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`(Ex. 1008 at 85-89.) Form A has an endotherm at 103 °C, and Form B has an endotherm at 107
`
`°C.; Winkler Decl., ¶ 74.) (Ex. 1008 at 87.) A form exhibiting a higher endotherm temperature is
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`inherently compatible with a higher purity. Thus, the higher melting point of Form B is consistent
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`and compatible with a higher degree of purity in Form B in comparison with Form A based on
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`these endotherm temperatures. (Winkler Decl., ¶ 74.) Further, Form A is utilized as the starting
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`material for formation of Form B. (Ex. 1008 at 87Id., ¶ 75.) A POSA would understand that
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`through this transformation, similar to that described in the ’066 patent, one is typically removes
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`removing impurities. (Id.) This is consistent with As such, Form A should be being more pure than
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`the starting batch, and Form B being more pure than Form A. (Id.)
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`SecondIn addition to the above, Phares discloses the same steps of alkylating and
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`hydrolyzing to make the treprostinil disclosed in the ’066 patent. (Winkler Decl., ¶ 76.) Phares
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`discloses the synthesis of (-)-treprostinil, the enantiomer of (+)-treprostinil. (Ex. 1008 at 39-40.)
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`Phares explains that enantiomers of these compounds (including (-)-treprostinil) “can be
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`synthesized using reagents and synthons of enantiomeric chirality of the above reagents,” referring
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`to the reaction scheme where “the enantiomer of the commercial drug (+)-treprostinilTreprostinil
`
`was synthesized using the stereoselective intramolecular Pauson Khand reaction as a key step and
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`Mitsunobu inversion of the side-chain hydroxyl group.” (Id. at 40.) In this way,A POSA would
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`therefore understand that Phares inherently teachingdiscloses the synthesis of both enantiomeric
`
`forms of treprostinil, both (-)-treprostinil and (+)-treprostinil. (Id.) Phares illustrates the following
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`synthesis reaction:
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`
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`(Id.) The reaction procedure for alkylation to treprostinil is disclosed in Phares (i.e., the conversion
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`of Compound 1 lb to the intermediate nitrile product (not shown) in the above reaction scheme)
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`as: (1) i. C1CH2CN, K2CO3.” (Id.)
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`Phares details the exact same alkylation and hydrolyzing steps (detailed as “step (1)”): (1)
`
`i. C1CH2CN, K2CO3. ii. KOH, CH3OH, reflux. 83% (2 steps). (Id.; Winkler Decl., ¶ 77.)
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`Chloroacetonitrile (C1CH2CN) was known in the art at the time of the invention to play an
`
`important role in alkylation reactions, and potassium hydroxide in methanol (KOH, CH3OH) was
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`known to play an important role in hydrolysis.
`
` (Winkler Decl., ¶ 78.) Further, in view of the immediate steps prior to conversion to the
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`salt and/or crystallization being those of alkylation and hydrolysis, a POSA would understand that
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`at least one impurity in the substrate for salt formation and/or crystallization would most likely
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`result from these intermediate steps. (Id.,¶ 79.)
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`Therefore, in my opinion, based on the identical starting materials and chemical steps in
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`Phares and the ’066 Patent, a POSA would expect to observe the same impurity profiles in each.
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`In both cases, a POSA would understand these impurities to most likely result from either the prior
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`alkylation and/or hydrolysis steps. Phares therefore renders obvious providing a starting batch of
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`treprostinil having one or more impurities resulting from prior alkylation and hydrolysis steps.
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`c.
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`Phares discloses claim element l[c]
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`1 [c]
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`forming a salt of treprostinil by combining the starting batch and a base,
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`
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`As I explaineddiscussed above in Section IX.B.1.a, Phares discloses the identical
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`treprostinil and pharmaceutically acceptable treprostinil diethanolamine salt as the ’066 patent.
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`(Winkler Decl., ¶¶ 63-68, 81.)
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`Phares further discloses combining a starting batch and a base. (Ex. 1008 at 22.) In
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`particular, page 22 of Phares further teaches dissolving treprostinil acid in a 1:1 molar ratio mixture
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`of ethanol: water and treating the resulting solution with diethanolamine (i.e., a base). (Id.)
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`d.
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`Phares discloses claim element l[d]
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`1 [d]
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`isolating the treprostinil salt, and
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`As I explained above, Phares discloses isolating the identical pharmaceutically acceptable
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`treprostinil diethanolamine salt as the ’066 patent.
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` (Winkler Decl., ¶¶ 63-68, 83.) Phares alsofurther discloses isolating crystalline forms of
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`treprostinil diethanolamine salt — Form A and Form B. (Ex. 1008 at 83-89.)
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`It is routine that upon Upon completion of a reaction, the product is isolated. (Winkler
`
`Decl., ¶ 85.) The isolation steps needed following conversion of Form A to Form B are routine
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`and understood by a sophomore organic chemistry student. (Id.)
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`e.
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`Phares renders obvious claim element l[e]
`
`1 [e]
`
`
`
`preparing a pharmaceutical composition comprising treprostinil or a
`pharmaceutically acceptable salt thereof from the isolated treprostinil salt,
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`The invention of Phares “provides for compositions which may be prepared by mixing one
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`or more compounds of the instant invention, or pharmaceutically acceptable salts thereof, with
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`pharmaceutically acceptable carriers, excipients, binders, diluents or the like, to treat or ameliorate
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`a variety of disorders related vasoconstriction and/or platelet aggregation.” (Ex. 1008 at 48.) Thus,
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`the pharmaceutical acceptability of the compounds is clearl