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. 9,604,901
`
`Issue Date: March 28, 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. 9,604,901
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`IPR2020-00770
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`VI.IV. SUMMARY OVERVIEW OF THE ’901 PATENT
`
`A.
`
`Brief Description of the ’901 Patent
`
`I understand that theThe ’901 patent is entitled “Process to Prepare Treprostinil, the Active
`
`Ingredient in Remodulin®.” The claims of the ’901 patent are product-by-process claims. These
`
`claims include one independent (claim 1) and eight dependent claims.
`
`The ’901 patent discloses an “improved process” to prepare prostacyclin derivatives such as
`
`treprostinil. (Ex. 1001, Abstract.) Claim 1 is drawn to a pharmaceutical batch comprising
`
`treprostinil or a salt thereof. (Id.,. at cols. 17-18, claim 1.)
`
`The independent claim includes limitations that the claimed composition is made by a process
`
`comprising: (a) alkylating a benzindene triol; (b) hydrolyzing the resulting product to form a solution
`
`comprising treprostinil; (c) contacting that treprostinil solution with a base to form a salt of
`
`treprostinil; (d) isolating the salt of treprostinil and; (e) optionally reacting the salt of treprostinil with
`
`an acid to form treprostinil. The claimed composition contains at least 2.9 g of treprostinil or its salt.
`
`The claim limitations of the ’901 patent are as follows:
`
`
`
`Claim Limitation
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`1[a] A pharmaceutical batch consisting of treprostinil or a salt thereof and impurities
`resulting from:
`
`1[b]
`
`(a) alkylating a benzindene triol,
`
`1[c]
`
`(b) hydrolyzing the product of step (a) to form a solution comprising treprostinil,
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`1[d]
`
`1[e]
`
`1[f]
`
`(c) contacting1 the solution comprising treprostinil from step (b) with a base to
`form a salt of treprostinil,
`
`(d) isolating the salt of treprostinil, and
`
`(e) optionally reacting the salt of treprostinil with an acid to form treprostinil, and
`
`1[g] wherein the pharmaceutical batch contains at least 2.9 g of treprostinil or its salt.
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`The pharmaceutical batch of claim 1, which has been dried under vacuum.
`
`A pharmaceutical product comprising a therapeutically effective
`
`amount of treprostinil from a pharmaceutical batch as claimed in claim 1.
`
`A pharmaceutical product comprising a therapeutically effective amount of a salt
`treprostinil from a pharmaceutical batch as claimed in claim 1.
`
`The product of claim 4, wherein the salt is the diethanolamine salt of treprostinil.
`
`A method of preparing a pharmaceutical product from a pharmaceutical batch as
`claimed in claim 1, comprising storing a pharmaceutical batch of a salt of
`treprostinil as claimed in claim 1 at ambient temperature, and preparing a
`pharmaceutical product from the pharmaceutical batch after storage.
`
`A method as claimed in claim 6, wherein the salt of treprostinil is a diethanolamine
`salt.
`
`8[a] A method of preparing a pharmaceutical batch as claimed in claim 1, comprising:
`
`8[b]
`
`(a) alkylating a benzindene triol,
`
`8[c]
`
`(b) hydrolyzing the product of step (a) to form a solution comprising treprostinil,
`
`8[d]
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`(c) contacting the solution comprising treprostinil from step (b) with a base to form
`a salt of treprostinil,
`
`8[e]
`
`(d) isolating the salt of treprostinil, and
`
`8[f]
`
`(e) optionally reacting the salt of treprostinil with an acid to form treprostinil.
`
`9
`
`A method as claimed in claim 8, wherein the salt of treprostinil is a diethanolamine
`salt.
`
`More specifically, the The ’901 patent discloses a process for the preparation of a compound
`
`of Formula I (which includes treprostinil) shown below,:
`
`
`
`1 Certificate of correction: “(c) containing the” should be –”(c) contacting the--.” (Ex. 1006
`
`at, 2.)
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`(Ex. 1001 at col. 2:7-21.), where: w = 1, 2, or 3; Y1 is trans-CH=CH-, cis-CH=CH-, -CH2(CH2)m-, or —
`
`CC—, 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-
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`R3: β-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, (C1-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 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 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: βR3, or a mixture of α-R3: β-R4 and α-R4: β-R3, wherein R3 and R4 are
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`hydrogen; and R7 is —CpH2p—CH3, wherein p is an integer from 1 to 5 inclusive (p=3). (Id. at cols.
`
`2:46-3:20; Winkler Decl., ¶27.)
`
`The ’901 patent discloses alkylating benzindene triol (a.k.a. treprostinil
`
`triol) with an alkylating agent and then hydrolyzing with a base to form a solution comprising
`
`treprostinil. (Id. at cols. 10:12-12:18.) The ’901 patent further discloses contacting the solution 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
`
`above):
`
`
`
`(Id. at., 3:30-40).
`
`Formula I is a general formula, while Formula IV is specifically treprostinil. 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 ’901 patent, Formula IVs is treprostinil
`
`diethanolamine salt. The resulting salt is:
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`(Id. at cols. 9:33-45, 12:45-59, 14:35-47.) The treprostinil salt can then be isolated and reacted with
`
`
`
`an acid to form treprostinil, as shown below:
`
`
`
`
`
`
`
`(Id. at col. 14:30-15:24, Example 5.) As disclosed in one embodiment, the resulting carboxylic
`
`acid, Formula IV, is at least 90.0%, 95.0%, 99.0%, or 99.5% pure. (Id. at col. 9:49-50.)
`
`The ’901 patent further discloses alkylating a treprostinil triol intermediate (Formula V,
`
`shown below) to form treprostinil or a pharmaceutically acceptable salt thereof:
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`(Id. at col. 3:46-4:49.)
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`The ’901 patent discloses that the resulting pharmaceutical batch contains at least 2.9 g of
`
`treprostinil or its salt which has been dried under a vacuum. (Id. at., 15:8-11.) The ’901 patent does
`
`not teach storing the resulting treprostinil salt at ambient temperature; it only specifically discloses
`
`this for a “crude” salt. (Id. at col. 17:4-8.)
`
`These precipitation procedures were well-known in the art – indeed, they are no more than
`
`basic organic chemistry techniques and standard chemical purification – and they were fully
`
`disclosed in numerous prior art references, including basic organic chemistry textbooks.
`
`
`
`. . .
`
`VIII. VI. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST ONE CLAIM OF
`
`THE ’901 PATENT IS INVALIDUNPATENTABLE
`
`A. State of the Art & Summary of Invalidity Arguments3 2
`
`
`
`23 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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`There are at least three strong bases for invalidation of the ’901 patent: (1) as explained in the
`
`following sections, the synthesis of the claimed compounds, including treprostinil and treprostinil
`
`diethanolamine salt, was well-known in the art; (2) as detailed in Sections IX and X, the claims of the
`
`’901 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 ’901 patent are
`
`invalid as 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 ’901 patent are substantively similar to the invalidated ’393 patent,
`
`the ’901 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 1-9 of the ’901 patent should be held invalid for similar reasons as the
`
`’393 patent because the claims of the ’901 patent are substantively similar to those of the ’393 patent
`
`in that they disclose the same treprostinil and the identical treprostinil diethanolamine salt.
`
`For all of the reasons provided above, claims 1-9 of the ’901 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:
`
`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 ’901 patent disclose
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`the synthesis of prostacyclin derivative acids that include treprostinil acid, which is also disclosed in
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`Moriarty (Ex. 1009) and the ’117 patent (Ex. 1007). In addition, as explained in detail below, both
`
`Phares (Ex. 1008) and Moriarty (Ex. 1009) further disclose syntheses of treprostinil.Moriarty
`
`discloses the following synthetic scheme for making treprostinil acid (Ex. 1009 at 3,6).:
`
`(Ex. 1009 at 3,6.) The ’901 patent discloses the same scheme for making treprostinil ac id
`
`(Ex. 1001 at co l. 10:10-12:17, Examples 1 and 2.):
`
`
`
`
`
`(Ex. 1001 at co ls. 10:10-12:17, Examples 1 and 2.) Accordingly, the only alleged
`
`“improvement” to Moriarty in the ’901 patent was the preparation of a treprostinil diethanolamine
`
`salt (from a starting batch of treprostinil having one or more impurities likely resulting from
`
`alkylation and/or hydrolysis) without isolation of the treprostinil acid. These representsteps are
`
`nothing more than a routine, elementary organic chemistry techniques for purification of a
`
`carboxylic acid, such as treprostinil acid. In addition, Phares discloses methods of synthesis to
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`produce treprostinil diethanolamine salt using the same starting material, treprostinil carboxylic acid,
`
`and steps as disclosed in Moriarty.
`
`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 that involve salt formation and carboxylic acid
`
`regeneration (claim elements 1[c]-1[e]) disclose nothing more than elementary organic chemistry
`
`techniques for purification of a carboxylic acid, such as treprostinil acid, well described in the prior
`
`art years before December 17, 2007. 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. (Winkler Decl., ¶47.)
`
`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 ’901 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, and 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 HCl, then regenerates the carboxylic acid from the salt, which can
`
`then be filtered or extracted into an organic solvent. (Ex. 1011 at, 3-4; Winkler Decl., ¶48.)
`
`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,(See Winkler Decl., ¶49 (citing Kawakami (Ex. 1012), entitled “Crystalline Amine Salt of
`
`Methanoprostacyclin Derivative, Manufacturing Method thereof,) and Purifying Method thereof”,
`
`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 HCl 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 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 HCl,
`
`which is prototypical of the reaction of the treprostinil diethanolamine salt with an acid to
`
`regenerate treprostinil carboxylic acid).). (Ex. 1013 at 8.)
`
`D. 3. The Claimed Treprostinil and Treprostinil Diethanolamine Salt Disclosed in the
`
`’901 Patent is Not Distinct from the Prior Art
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`I understand that theThe ’901 patent claims are product-by-process claims. It has been
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`explained to me that theThe process limitations are not accorded any weight for determining the
`
`validity of the claims of the ’901 patent. I understand that theSee 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 thereof
`
`(i.e., treprostinil diethanolamine salt), werewas already well-known in the art.
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`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 ’901 patent, all claims of the ’901 patent are unpatentable under 35
`
`U.S.C. §§ 102(b) and 103.
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`. . .
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`
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`IX. GROUND 1: CLAIMS 1-9 ARE PHARES RENDEREDS OBVIOUS UNDER 35 U.S.C. § 103(A) OVER
`
`PHARES THE CLAIMS OF THE ’901 PATENT
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`
`
`Nothing inventive is claimed by the ’901 patent. Every product and process of the claimed
`
`invention was known in the prior art. As described detailed in the sections detail below, claims 1-9
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`of the ’901 patent are rendered obvious by Phares.
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`A. Overview ofOf Phares
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`The Phares reference is titled “Compounds and Methods for Delivery of Prostacyclin
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`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 ’901 patent under 35 U.S.C. § 102(b). The ’901
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`patent seeks the benefit of provisional application No. 61/014,232, filed on December 17, 2007. For
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`the purposes of this petition, I understand that Petitioner will use December 17, 2007 as the effective
`
`filing date of the ’901 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, 8.2).)3The
`
`chemical structure of treprostinil is shown below:
`
`
`
`(Id.) Phares exp la ins t hat “[t ]repro st inil is a chemica lly st able ana lo g o f 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
`
`
`
`23 For Phares, the page numbers I cite refer to the numbers at the bottom center of each page,
`with the first two pages (coverpage/abstract) unnumbered.
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`invention disclosed in Phares is “Form B of treprostinil diethanolamine.” (Id.) The structure of
`
`treprostinil diethanolamine salt described by Phares is reproduced below:
`
`
`
`(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
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`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 (+)-
`
`treprostinil 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: “(l) i.
`
`ClCH2CN, 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 (l) coverts the precursor into treprostinil.
`
`(Winkler Decl., ¶60.)
`
`The invention of Phares further “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., ¶61.)
`
`B.
`
`Phares Discloses Each Limitation of Claims 1–9
`
`As described in detail below, claims 1-9 of the ’901 patent are rendered obvious by
`
`Phares.
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`B. 1. Independent Claim 1
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`a.
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`Phares discloses claim element 1[a]
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`1[a] A pharmaceutical batch consisting of treprostinil or a salt thereof and impurities
`resulting from:
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`Phares inherently discloses the same synthesis of treprostinil as set forth in independent
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`claim 1 of the ’901 patent. Phares describes “compounds and methods for inducing prostacyclin-
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`like effects in a subject or a patient,” including treprostinil and derivatives thereof. (Ex. 1008, 8.)
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`The chemical structure of treprostinil disclosed in Phares is shown below:
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`(Id.) This is the same treprostinil disclosed in the ’901 patent:
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`
`
`
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`where:
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`• w = 1;
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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 are
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`hydrogen;
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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. 2:7-
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`3:20; Winkler Decl., ¶64.)
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`Phares further discloses the identical, pharmaceutically acceptable treprostinil
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`diethanolamine salt as the ’901 patent. (Ex. 1008 at, 96, claim 49; Winkler Decl., ¶65; 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 ’901 patent
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`(right):
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`(Phares)
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`(’901 patent)
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`(Ex. 1008 at, 96, claim 49; Ex. 1001 at col. 9:32-48, col. 12:45-59, 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 ’901 patent
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`are identical. (Winkler Decl., ¶65.)
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`The PharesThis salt is made by the result of the same process steps asdescribed in claim 1
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`of the ’901 patent: (a) by forming a salt of treprostinil by combining the starting batchsolution of
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`treprostinil acid and a base and; (b) isolating the treprostinil salt. (Ex. 1001, claim 1; Ex. 1008 at,
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`22.) The isolated salt is then used to prepare a pharmaceutical batch comprising treprostinil or a
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`salt thereof. (Ex. 1001, claim 1; Ex. 1008 at, 58.)
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`The claim language of the ’901 patent does not disclose the percentage of “impurity”
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`required in the starting solution of treprostinil and simply states “and impurities.” (Ex. 1001, claim
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`1.) The ’901 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. 9:49-50.) This
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`disclosure shows that the impurity of treprostinil may be as low as 90.0%. (Winkler Decl., ¶67.)
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`Phares discloses two crystalline forms of treprostinil diethanolamine salt, Form A and Form
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`B. (Ex. 1008 at, 85-89; Winkler Decl., ¶68.) Form A has an endotherm at, 103 °C and Form B has
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`an endotherm at, 107 °C. (Ex. 1008 at, 87, 88.) A form exhibiting a higher endotherm temperature
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`is inherently compatible with a higher purity. Thus, theThe higher melting point of Form B is
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`consistent and compatible with a higher degree of purity in Form B in comparison with Form A
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`based on these endotherm temperatures. (Winkler Decl., ¶68.) Further, Form A is utilized as the
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`starting material for the formation of Form B. (Ex. 1008 at, 87; Winkler Decl., ¶69.) A POSA would
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`understand that through this transformation, similar to that described in the ’901 patent, one is
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`typically removing impurities. (Id.) As such, Form A should be more pure than the starting batch
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`and Form B more pure than Form A. (Id.) The starting batch treprostinil or salt thereof contains
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`impurities that would most likely result from the steps of alkylation and hydrolysis as described in
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`further detail below.
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`This shows that Phares thus necessarily discloses and/or renders obvious the same process
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`steps to make treprostinil and a salt thereof disclosed in claim 1 of the ’901 patent (treprostinil
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`diethanolamine salt). (Winkler Decl., ¶71.) This treprostinil or salt thereof contains impurities
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`resulting from the steps of alkylation and hydrolysis as described in further detail below. I point to
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`further Further support for the obviousness of each process element of claim 1 is also provided in the
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`following sections.Sections XI.B.1.(b)-(g).
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`It is my opinion that the remaining process claim elements do nothing to impart structural or
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`functional differences in the claimed treprostinil or salt thereof, and thus, do not patentably limit the
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`claimed pharmaceutical composition.
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`Even so, Phares renders obvious each of the remaining process claim elements.
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`2. b. Phares discloses claim elements 1[b] and 1[c]
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`1[b]
`1[c]
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`(a) alkylating a benzindene triol,
`(b) hydrolyzing the product of step (a) to form a solution comprising treprostinil,
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`As I explained discussed above in Section IX.B.1.a, Phares discloses the identical
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`treprostinil and pharmaceutically acceptable treprostinil diethanolamine salt as the ’901 patent.
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`(Winkler Decl., ¶74.) The remaining process claim elements do nothing to impart structural or
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`functional differences in the claimed treprostinil or salt thereof, and thus, do not patentably limit the
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`claimed pharmaceutical composition. (Id., ¶72.) Even so, Phares further discloses providing a
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`starting solution of treprostinil having one or more impurities that would most likely resultresulting
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`from the alkylation and hydrolysis steps.
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`Specifically, Example 1 of the ’901 patent describes the alkylation of benzindene triol. (Ex.
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`1001 at col. 10:10-67.) This alkylation reaction is shown below:
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`(Id.) Benzindene triol is the fused three ring core wherein the three hydroxyl groups (-OH) are not all
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`located on the core. (Winkler Decl., ¶77.) In this example, the hydroxyl group indicated with the red
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`square is being alkylated using ClCH2CN in the presence of K2CO3, Bu4NBr and acetone. (Id.)
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`Phares discloses an alkylation reaction identical in nature to the ’901 patent alkylation
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`reaction: (l) i. ClCH2CN, K2CO3. (Ex. 1008 at, 39-40.) In particular, in step (l) the starting
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`treprostinil precursor compound, the benzindene triol, is the enantiomer of the treprostinil precursor
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`being alkylated in the ’901 patent (11b indicates that “R” can be “H”). (Winkler Decl., ¶78.) Phares
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`discloses the synthesis of (-)-treprostinil, the enantiomer of (+)-treprostinil and explains that
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`“[e]nantiomers of these compounds...can be synthesized using reagents and synthons of
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`enantiomeric chirality of the above reagents,” thereby inherently teaching the synthesis of both
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`enantiomeric forms of treprostinil, both (-)-treprostinil and (+)-treprostinil.” (Id., ¶79; Ex. 1008, 39-
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`40.) The reaction from Phares is shown below for comparison:.)
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`(Ex. 1008, 39-40Id., -OH group (where R=H) being alkylated indicated with red square.)
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`Phares teaches a A POSA towould understand that one could selectively alkylate the phenolic –OH
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`group on the fused three-ring core of Compound 11b as (where R=H) indicated in the red box.
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`(IdWinkler Decl., ¶81.)
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`Further, it was not a novel step at the time of the invention to alkylate an –OH group on the
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`benzene of a fused ring system. The references contained in Phares, in addition to the above clear
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`disclosures in Phares itself, teach such alkylation. For exampleIn addition, Phares cites to U.S.
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`Patent No. 4,306,075 for routes in which compounds disclosed in Phares can be modified, includes
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`the step of selectively alkylating a benzindene triol. (Ex. 1008 at, 9; Ex. 1014, the “’075 patent.”)
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`Chart P of the ’075 patent provides a synthetic scheme where the –-OH of a benzindene triol, as
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`referred to in the ’901 patent, is alkylated. (Ex. 1014 at col. 90.) While the ’075 patent does not
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`disclose the same synthesis reaction, this reference supports the proposition that it was not a novel
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`step at the time of the invention to alkylate an –OH group on the benzene of a fused ring system
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`and that a POSA could arrive at the treprostinil compound disclosed in the ’901 patent by reading
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`the disclosures and references contained in Phares. (Winkler Decl., ¶82.) This includes the step of
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`selectively alkylating a benzindene triol. (Id.)
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`Thus, Phares discloses alkylation of a benzindene triol that can be used to prepare
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`treprostinil.
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`3. Phares discloses claim element 1[c]
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`As I explained above, Phares discloses the identical treprostinil and pharmaceutically
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`acceptable treprostinil diethanolamine salt as the ’901 patent.
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`Phares further discloses hydrolyzing the product from the alkylation reaction (discussedstep
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`(a) above) to form the enantiomeric treprostinil starting material. (Winkler Decl., ¶85.) The
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`hydrolyzing procedure is disclosed in Phares as: “ii, KOH, CH3OH, reflux. 83%.” (Ex. 1008 at, 40
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`(boldingemphasis added).) Phares further explains that “[e]nantiomers of these compounds...can be
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`synthesized using reagents and synthons of enantiomeric chirality of the above reagents,” thereby
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`inherently teaching this hydrolysis step for treprostinil as well. (Id at, 39-40). A comparison
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`between the treprostinil starting material disclosed in the ’901 patent (left) and Phares (right) are
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`produced below for a side-by-side comparison:
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`
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`(’901 patent)
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`(Phares)
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`(Ex. 1001 at col. 11:1-12:17, Example 2; Ex. 1008 at, 8.)
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`Claim 1 of the ’901 patent simply teaches that one can perform the alkylation and hydrolysis
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`steps, i.e., making the nitrile and then hydrolyzing to make the treprostinil carboxylic acid (salt
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`precursor). (Ex. 1001, claim 1.) Phares teaches that the treprostinil carboxylic acid is in a solution.
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`(Ex. 1008 at, 22, 40.) Treatment of Compound 11b with KOH, CH3OH