UNITED STTES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`STEADYMED LTD.,
`
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION
`
`Patent Owner.
`
`
`
`Case IPR Unassigned
`
`Patent No. 8,497,393
`
`____________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,497,393 UNDER 37 C.F.R. § 42.100
`
`
`
`
`
`
`
`
`Mail Stop "Patent Board"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`

`

`
`I.
`
`TABLE OF CONTENTS
`
`COMPLIANCE WITH FORMAL REQUIREMENTS .................................. 1
`A. Mandatory Notices Under 37 C.F.R. § § 42.8(b)(1)-(4) ...................... 1
`1.
`Real Party-in-Interest ................................................................. 1
`2.
`Related Matters .......................................................................... 1
`3.
`Lead And Back-Up Counsel ...................................................... 1
`4.
`Powers of Attorney and Service Information ............................ 2
`Proof of Service on the Patent Owner .................................................. 2
`B.
`Fees ....................................................................................................... 2
`C.
`II. GROUNDS FOR STANDING ........................................................................ 2
`III. STATEMENT OF PRECISE RELIEF REQUESTED.................................... 3
`IV.
`IDENTIFICATION OF CHALLENGE .......................................................... 3
`V. LEVEL OF ORDINARY SKILL IN THE ART ............................................. 4
`VI. SUMMARY OF THE '393 PATENT .............................................................. 5
`A.
`Brief Description of the '393 Patent ..................................................... 5
`B.
`Summary of the Prosecution History of the '393 Patent ...................... 7
`VII. CLAIM CONSTRUCTION ........................................................................... 10
`VIII. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST
`ONE CLAIM OF THE '393 PATENT IS UNPATENTABLE ..................... 12
`A.
`Identification of the References As Prior Art .................................... 12
`B.
`State of the Prior Art & Summary of Invalidity Arguments .............. 13
`1.
`Steps (a) – (b): The Synthesis of Treprostinil Was Well-
`Known ...................................................................................... 14
`Steps (c) & (d): Formation of a Carboxylate Salt and the
`Addition of an Acid to a Carboxylate Salt is Standard
`Chemical Purification Known in the Art ................................. 16
`IX. CLAIM-BY-CLAIM EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY .................................................................................. 22
`A. Ground 1: Detailed Explanation Under 37 C.F.R. § 42.104(b) of
`How Phares (Ex. 1005) Anticipates Claims 1-5, 7-9, 11-14 and
`16-20 Under 35 U.S.C. § 102(b) ........................................................ 22
`
`2.
`
`i
`
`

`

`B. Ground 2: Detailed Explanation Under 37 C.F.R. § 42.104(b) of
`How Claims 1-5, 7-9, 11-14 and 16-20 are Obvious under 35
`U.S.C. § 103(a) over Moriarty (Ex. 1004) with either Phares
`(Ex. 1005) or Kawakami (Exs. 1006 & 1007) ................................... 37
`C. Ground 3: Detailed Explanation Under 37 C.F.R. § 42.104(b) of
`How Claims 6, 10, 15, 21 and 22 are Obvious under 35 U.S.C.
`§ 103(a) over Moriarty (Ex. 1004) with Phares (Ex. 1005) or
`Kawakami (Exs. 1006 & 1007) and in further combination with
`Ege (Ex. 1008) .................................................................................... 53
`X. CONCLUSION .............................................................................................. 57
`
`ii
`
`

`

`
`EXHIBIT DESCRIPTION
`
`TABLE OF EXHIBITS
`
`ABBREVIATION
`
`1001
`
`U.S. Patent No. 8,497,393 to Batra, et al.
`
`'393 Patent
`
`1002 - 1
`
`1002 - 2
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`Prosecution History of U.S. Patent No.
`8,242,305 (excerpts)
`
`Prosecution History of U.S. Patent No.
`8,497,393
`
`U.S. Patent No. 6,765,117 to Moriarty, et al.
`
`J. Org. Chem. 2004, 1890-1902 by Moriarty,
`et al.
`
`International Publication No. WO
`2005/007081 to Phares, et al.
`
`Japanese Patent App. No. 56-122328A to
`Kawakami, et al. (Japanese)
`
`Certified English translation of Japanese
`Patent App. No. 56-122328A to Kawakami, et
`al.
`
`Ege, S. (1989). Organic Chemistry Second
`Edition (pp. 543-547)
`
`Declaration of Jeffrey D. Winkler, Ph.D.
`
`--
`
`--
`
`'117 Patent
`
`Moriarty
`
`Phares
`
`Kawakami
`
`Kawakami
`
`Ege
`
`Winkler Decl.
`
`Curriculum Vitae of Jeffrey D. Winkler, Ph.D.
`
`Affidavit of Boris Levine certifying
`Translation of Japanese Patent App. No. 56-
`122328A to Kawakami, et al.
`
`
`--
`
`--
`
`i
`
`

`

`EXHIBIT DESCRIPTION
`
`ABBREVIATION
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`Wiberg, Kenneth (1960), Laboratory
`Technique in Organic Chemistry (p. 112)
`
`U.S. Patent No. 6,441,245 to Moriarty, et al.
`
`Schoffstall, "Microscale and Miniscale
`Organic Chemistry Laboratory Experiments,"
`200-202 (2d ed.) (2004)
`
`U.S. Patent No. 3,703,544 to Morozowich, et
`al.
`U.S. Patent No. 3,888,916 to Sinkula, et al.
`
`“Getting Started in HPLC,” Section 4D:
`Precision and Accuracy, available at
`http://www.lcresources.com/resources/getstart/
`4d01.htm (accessed Sept. 29, 2015)
`
`Gilbert, “Experimental Organic Chemistry: A
`Miniscule and Microscale Approach,” 113-
`117 (5th. ed.) (2011)
`
`Wiberg
`
`'245 Patent
`
`Schoffstall
`
`'544 Patent
`
`'916 Patent
`
`--
`
`Gilbert1
`
`
`1 For ease of reference, all citations to the above references are to the bates-
`labeled page number. Petitioner utilizes the “column, line number” format,
`however, for any referenced U.S. Patents (i.e., Exhibit Nos. 1001, 1003, 1013,
`1015, and 1016).
`
`ii
`
`

`

`SteadyMed Ltd. ("Petitioner") in accordance with 35 U.S.C. §§ 311-319 and
`
`37 C.F.R. § 42.100 et seq., requests that the United States Patent and Trademark
`
`Office ("USPTO") proceed with an inter partes review of Claims 1-22 of U.S.
`
`Patent No. 8,497,393 (the '393 Patent") (Ex. 1001).
`
`I.
`
`COMPLIANCE WITH FORMAL REQUIREMENTS
`A. Mandatory Notices Under 37 C.F.R. § § 42.8(b)(1)-(4)
`1.
`Real Party-in-Interest
`SteadyMed Ltd., SteadyMed Therapeutics, Inc., and SteadyMed U.S.
`
`Holdings, Inc. are the real parties-in-interest.
`
`Related Matters
`
`2.
`Petitioner advises that to its knowledge there are no related matters to which
`
`it is a party. Petitioner further advises that the '393 Patent is subject to the
`
`following U.S. District Court litigations, currently pending in the District of New
`
`Jersey: (1) United Therapeutics Corp. v. Sandoz, Inc., Civ. No. 14-cv-05499; (2)
`
`United Therapeutics Corp. v. Teva Pharmaceuticals U.S.A., Inc., Civ. No. 14-cv-
`
`05498; and (3) United Therapeutics Corp. v. Watson Laboratories, Inc., Civ. No.
`
`15-cv-05723.
`
`Lead And Back-Up Counsel
`
`3.
`Pursuant to 37 C.F.R. § 42.8(b)(3) and 42.10(a), Petitioner provides the
`
`following designation of counsel: Lead counsel is Stuart E. Pollack (Reg. No.
`
`43,862) and backup counsel is Lisa A. Haile (Reg. No. 38,347), both at email
`
`1
`
`

`

`address: Steadymed-IPR@dlapiper.com. Postal and hand delivery for both is DLA
`
`Piper LLP (US), 1251 Avenue of the Americas, 27th Floor, New York, New York
`
`10020. Telephone for Dr. Pollack is (212) 335-4964; telephone for Dr. Haile is
`
`(858) 677-1456. The fax for both is (212) 335-8464.
`
`Powers of Attorney and Service Information
`
`4.
`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney accompanies this
`
`Petition. Petitioner consents to service by email at Steadymed-IPR@dlapiper.com.
`
`Proof of Service on the Patent Owner
`
`B.
`As identified in the attached Certificate of Service, a copy of this Petition in
`
`its entirety is being served to Patent Owner ("Patentee") at the address listed in the
`
`USPTO's records by overnight courier pursuant to 37 C.F.R. § 42.6.
`
`Fees
`
`C.
`A fee of $26,200 has been paid for this Petition. Twenty-two (22) claims are
`
`being reviewed. The undersigned further authorizes the United States Patent and
`
`Trademark Office, including the Patent Trial and Appeal Board to charge any
`
`additional fee that might be due or required to Deposit Account No. 07-1896.
`
`II. GROUNDS FOR STANDING
`
`In accordance with 37 C.F.R. § 42.104(a), Petitioner certifies that the '393
`
`Patent is available for inter partes review and that Petitioner is not barred or
`
`estopped from requesting an inter partes review challenging the patent claims on
`
`the grounds identified in this Petition.
`
`2
`
`

`

`III. STATEMENT OF PRECISE RELIEF REQUESTED
`In accordance with 37 C.F.R. § 42.22, Petitioner respectfully requests that
`
`Claims 1-22 of the '393 Patent be found invalid for the reasons set forth below.
`
`IV.
`
`IDENTIFICATION OF CHALLENGE
`Inter partes review is requested in view of the following references:
`
` Exhibit 1004: J. Org. Chem. 2004, 1890-1902 by Moriarty, et al.
`
`("Moriarty");
`
` Exhibit 1005: International Publication No. WO 2005/007081 to Phares, et al.
`
`("Phares");
`
` Exhibit 1006 (Japanese) and Exhibit 1007 (English): Japanese Patent App.
`
`No. 56-122328A to Kawakami, et al. ("Kawakami");
`
` Exhibit 1008: Organic Chemistry Second Edition (pp. 543-547) by Ege
`
`("Ege").
`
`Pursuant to 37 C.F.R. § 42.63(b), Exhibit 1011 contains an affidavit attesting
`
`that a professional translator and interpreter fluent in the English and Japanese
`
`languages translated Kawakami (Ex. 1006).
`
`Each of the patents and printed publications set forth below is prior art to the
`
`'393 Patent:
`
`Ground
`1
`
`Proposed Statutory Rejections for the '393 Patent
`Claims 1-5, 7-9, 11-14 and 16-20 are anticipated by Phares (Ex.
`
`3
`
`

`

`Ground
`
`Proposed Statutory Rejections for the '393 Patent
`1005) pursuant to 35 U.S.C. §102(b).
`
`2
`
`Claims 1-5, 7-9, 11-14 and 16-20 are rendered obvious by a
`
`combination of Moriarty (Ex. 1004) in view of either Phares (Ex.
`
`1005) or Kawakami (Exs. 1006 & 1007) pursuant to 35 U.S.C.
`
`§103.
`
`3
`
`Claims 6, 10, 15, 21 and 22 are rendered obvious by a
`
`combination of Moriarty (Ex. 1004) in view of either Phares (Ex.
`
`1005) or Kawakami (Exs. 1006 & 1007) and further in view of
`
`Ege (Ex. 1008) pursuant to 35 U.S.C. §103.
`
`
`Petitioner also relies on the Declaration of Jeffrey D. Winkler, Ph.D. (Ex.
`
`1009) in further support of its arguments.
`
`V. LEVEL OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the area of chemistry at the time of the alleged
`
`invention would have a master’s degree or a Ph.D. in medicinal or organic
`
`chemistry, or a closely related field. (Ex. 1009, Winkler Decl., ¶ 14). Alternatively,
`
`a person of ordinary skill would include an individual with a bachelor’s degree and
`
`at least five years of practical experience in medicinal or organic chemistry. (Id., at
`
`¶ 14).
`
`4
`
`

`

`VI. SUMMARY OF THE '393 PATENT
`A. Brief Description of the '393 Patent
`The '393 Patent is entitled "Process to Prepare Treprostinil, The Active
`
`Ingredient in Remodulin™." The claims of the '393 Patent are product-by-process
`
`claims. These claims include two independent (Claims 1 and 9) and twenty
`
`dependent claims.
`
`The '393 Patent discloses an "improved process" to prepare prostacyclin
`
`derivatives such as treprostinil. (Ex. 1001, Abstract). Claim 1 is drawn to a product
`
`comprising a compound of a genus that includes the treprostinil compound, or a
`
`pharmaceutically acceptable salt thereof. Claim 9 is identical to Claim 1 except
`
`that it is drawn to a product comprising the specific treprostinil compound, a
`
`species of the genus of Claim 1, made by the same process.
`
`Each of the independent claims includes limitations that the claimed
`
`compound is made by a process comprising three specified steps and one optional
`
`step: (a) alkylating a prostacyclin derivative (e.g., a benzindene triol precursor to
`
`treprostinil acid) to form an alkylated prostacyclin derivative (e.g., a benzindene
`
`nitrile precursor to treprostinil acid); (b) hydrolyzing the alkylated prostacyclin
`
`derivative with a base to form a prostacyclin acid (e.g., treprostinil acid); (c)
`
`contacting the prostacyclin acid (e.g., treprostinil acid) with a base to form a
`
`prostacyclin carboxylate salt (e.g., a treprostinil salt); and (d) optionally reacting
`
`5
`
`

`

`the prostacyclin carboxylate salt (e.g., a treprostinil salt) formed in step (c) with an
`
`acid to form a compound or a pharmaceutically acceptable salt of:
`
`
`
`
`
`(Ex. 1001).
`
`The alkylating and hydrolyzing steps in the synthesis of treprostinil and the
`
`other claimed compounds, as set forth in steps (a) – (b) of Claims 1 and 9, were
`
`fully disclosed in prior art to the '393 Patent, including U.S. Patent No. 6,765,117
`
`(the '117 Patent) (Ex. 1003), and in Moriarty et al., J. Org. Chem., 1890-1902
`
`(2004) (Ex. 1004, referred to as "Moriarty"), as well as other publications. Patent
`
`Owner admits that steps (a) ("alkylating") and (b) ("hydrolyzing") were in the prior
`
`art. (See Prosecution History (Ex. 1002-1), p. 109; '393 Patent, (Ex. 1001), col. 1,
`
`lines 22-28 (incorporating Moriarty (Ex. 1004), the '117 Patent (Ex. 1003), and
`
`U.S. Patent No. 6,441,245 (Ex. 1013) by reference, and col.7, lines 17-20
`
`(describing '245 Patent's process as the same as in '393 Patent)).
`
`6
`
`

`

`The '393 Patent addresses an alleged "improvement" to Moriarty through the
`
`addition of steps (c) and optionally (d), which claim a standard, basic organic
`
`chemistry purification by a precipitation technique: converting a free carboxylic
`
`acid into a salt using a weak base and then precipitating it to remove potential
`
`impurities, and then, optionally converting the salt back to the free acid. (See, e.g.,
`
`Ex. 1001, col. 17, lines 27-40) (describing the benefits of the disclosed processes
`
`as providing a "better quality" final product that removes impurities). 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. Additionally, as discussed in greater detail below and in the
`
`accompanying Declaration of Jeffrey D. Winkler (Ex. 1009), the claimed '393
`
`Patent process does not produce a product that is materially distinct from the
`
`product produced by the prior art.
`
`Summary of the Prosecution History of the '393 Patent
`
`B.
`The '393 Patent issued July 30, 2013 from application No. 13/548,446, filed
`
`July 13, 2012. Application No. 13/548,446 is a continuation of application No.
`
`12/334,731, filed on December 15, 2008, now U.S. Patent No. 8,242,305. Both
`
`patents claim priority to provisional application No. 61/014,232, filed December
`
`17, 2007.
`
`7
`
`

`

`During prosecution, the Examiner rejected the pending claims (substantially
`
`identical to issued Claims 1-22 of the '393 Patent) under 35 U.S.C. §102(b) as
`
`being anticipated by Moriarty (Ex. 1004; see also Ex. 1002-2, p. 295, 1/3/2013
`
`Office Action; pp. 327-329, 5/15/2013 Office Action). As noted above, Moriarty
`
`discloses the synthesis for treprostinil, which involves, inter alia, the isolation of
`
`treprostinil prior to the formation of treprostinil salt. The Examiner stated that
`
`Moriarty discloses a compound having the same structure of the claimed product
`
`disclosed in the '393 Patent. (Ex. 1002-2, p. 295, 1/3/2013 Office Action; pp. 327-
`
`329, 5/15/2013 Office Action). The Examiner further stated that the claims are
`
`product-by-process claims, and since the product disclosed in the prior art is the
`
`same as the claimed product, the "patentability of the product does not depend on
`
`the method of its production." (Id.).
`
`In response, Patent Owner submitted arguments and a Declaration under 37
`
`C.F.R. §1.132 by Dr. David Walsh, one of the inventors, and Executive Vice
`
`President of Chemical Research and Development at United Therapeutics
`
`Corporation
`
`(the "Walsh Declaration")
`
`(Ex. 1002, pp. 346-350, Walsh
`
`Declaration). The Walsh Declaration provides data from "representative
`
`Certificates of Analysis" with impurity profiles for treprostinil free acid prepared
`
`according to the process of Moriarty (Ex. 1004), and treprostinil diethanolamine
`
`and treprostinil free acid prepared according to the process of the '393 Patent. (Id.).
`
`8
`
`

`

`Relying on the Walsh Declaration, Patent Owner differentiated its synthesis of
`
`treprostinil by emphasizing that its product (treprostinil) was different than the
`
`product of Moriarty (Ex. 1002-2, pp. 343-344, 6/5/2013 Remarks; pp. 346-350,
`
`Walsh Declaration) because: (1) the product of Moriarty is "physically different"
`
`than the instant claims, as a "base addition salt is formed in situ with treprostinil
`
`that has not been previously isolated"; and (2) the product of Moriarty contained
`
`more impurities:
`
`"In the response filed February 8, 2013, Applicants submitted that the
`product of Moriarty 2004 is physically different from the product of
`claims 1 and 10, in which a base addition salt is formed in situ with
`treprostinil that has not been previously isolated. Specifically,
`Applicants noted that when a batch of treprostinil acid made by the
`type of process disclosed in Moriarty 2004 was analyzed by the
`applicants, it was found to contain small amounts of 4 different
`impurities (benzindene triol, treprostinil methyl ester, and 2 different
`stereoisomers of treprostinil) […] Applicants explained that this
`physical difference in the product resulted directly from the steps
`recited in claims 1 and 10, in which a salt is formed in situ without
`previously isolating treprostinil."
`
`(Ex. 1002-2, pp. 343-344). The Walsh Declaration demonstrated a
`
`treprostinil purity of 99.8%, above both Claim 2 and Claim 10's 99.5% purity level
`
`and Moriarty's 99.7% purity level, and according to Dr. Walsh, Moriarty's purity is
`
`really 99.4%, and not 99.7% as Moriarty reported. (Ex. 1002-2, pp. 347). These
`
`9
`
`

`

`alleged purity differences were intended to rebut the Examiner's statement that
`
`"[o]n page 1902 [of Moriarty] … [i]n the second column 99.7 pure compound 7
`
`[treprostinil] is disclosed thereby meeting the purity limitations of claims 2 and
`
`11." (Ex. 1002-2, pp. 327-328). In fact, these purity differences are illusory, and
`
`reflect differences in unclaimed process conditions and the precision of the HPLC
`
`instrument measuring impurities, and cannot confer patentability.
`
`VII. CLAIM CONSTRUCTION
`A claim subject to inter partes review receives the "broadest reasonable
`
`construction in light of the specification of the patent in which it appears." 42
`
`C.F.R. § 42.100(b). This means that the words of the claim are given their plain
`
`meaning from the perspective of one of ordinary skill in the art unless that meaning
`
`is inconsistent with the specification. In re Zletz, 893 F.2d 319, 321 (Fed. Cir.
`
`1989). Indeed, there is a "heavy presumption" that a claim term carries its ordinary
`
`and customary meaning. CCS Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359,
`
`1366 (Fed. Cir. 2002). Here, each claim term carries its ordinary and customary
`
`meaning, with the exception of the following terms that should be construed:
`
`"Product": "Product" appears in each independent Claim 1 and 9, and in
`
`dependent Claim 22. The broadest reasonable interpretation of "product" is
`
`"chemical composition." Both claims use the transition "comprising" ("a product
`
`comprising…" and "a process comprising…"), which is expressly defined in the
`
`10
`
`

`

`'393 Patent specification: "The expression 'comprising' means 'including but not
`
`limited to.' Thus, other non-mentioned substances, additives, carriers, or steps may
`
`be present." (Ex. 1001, col. 4, lines 23-24). "Product," is therefore properly defined
`
`as a "chemical composition," which includes the treprostinil compound along with
`
`other substances (including impurities). A composition connotes more than one
`
`element or ingredient; it is a chemical composition because treprostinil is a
`
`chemical and a composition containing treprostinil is a chemical composition. For
`
`these reasons, "product" should be construed as "a chemical composition."
`
`"A product comprising a compound of formula I/IV or a pharmaceutically
`
`acceptable salt thereof" (Claims 1 & 9): This term appears in each independent
`
`claim, Claims 1 and 9. The broadest reasonable interpretation is "a chemical
`
`composition that includes, but is not limited to, a compound of Formula I, or a
`
`pharmaceutically acceptable salt thereof, and that may also include other non-
`
`mentioned substances (including impurities), additives, or carriers, without
`
`limitation as to the types or relative amounts thereof." Petitioner's proposed
`
`construction incorporates Patent Owner’s definition of "comprising" in the '393
`
`Patent specification (Ex. 1001, col. 4, lines 23-25). For example, isolating
`
`treprostinil during the process is included in the claims, since it is an additional
`
`process step allowed by the transitional phrase "comprising."
`
`11
`
`

`

`"A process comprising" and "the process comprising" (Claims 1 & 9):
`
`These terms appear in each independent claim, Claims 1 & 9. The broadest
`
`reasonable interpretation is "a process that includes, but is not limited to, the
`
`recited process steps, and may include, without limitation, any other non-recited
`
`steps." This construction is supported by Patent Owner's definition of "comprising"
`
`as meaning "including but not limited to" and that "other non-mentioned…steps
`
`may be present." (Ex. 1001, col. 4, lines 23-25). The term "comprising" dictates
`
`that while the claimed process must include the recited steps it is not otherwise
`
`limited and can include any other non-recited steps.
`
`Because the claim construction standard in this proceeding differs from that
`
`used in U.S. district court litigations, Petitioner expressly reserves the right to
`
`assert different claim construction positions under the standard applicable in
`
`district court for any term of the '393 Patent in any district court litigations, should
`
`Petitioner become a party to any future litigation involving the '393 Patent.
`
`VIII. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST ONE
`CLAIM OF THE '393 PATENT IS UNPATENTABLE
`A.
`Moriarty was published in 2004 in the Journal of Organic Chemistry,
`
`Identification of the References As Prior Art
`
`Volume 69, No. 6. (Ex. 1004). Moriarty is prior art to the '393 Patent under 35
`
`U.S.C. §103, as a publication under § 102(b).
`
`12
`
`

`

`Phares was published January 27, 2005. (Ex. 1005). Phares is prior art to the
`
`'393 Patent under 35 U.S.C. §§102(b) and 103.
`
`Kawakami was published September 25, 1981 to Kawakami, et al. (Exs.
`
`1006 & 1007). Kawakami is prior art to the '393 Patent under 35 U.S.C. §103, as a
`
`publication under § 102(b).
`
`Ege was published in 1989 in Organic Chemistry, Second Edition, at pages
`
`543-547. (Ex. 1008). Ege is prior art to the '393 Patent under 35 U.S.C. §103, as a
`
`publication under § 102(b).
`
`State of the Prior Art & Summary of Invalidity Arguments
`
`B.
`There are three separate – and strong – bases for invalidation of the '393
`
`Patent: (1) the synthesis of the claimed compounds including treprostinil and
`
`treprostinil diethanolamine salt was well-known in the art; (2) the '393 Patent’s
`
`only alleged "improvement" over the prior art involves nothing more than basic
`
`organic chemistry 101 – standard chemical purification through salt formation and
`
`precipitation, and this salt formation and purification step was carried out on
`
`treprostinil in the prior art; and (3) since the claims of the '393 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, the claims of the
`
`'393 Patent are invalid as anticipated and obvious. Accordingly, all claims of the
`
`'393 Patent should be held invalid, as discussed in further detail below.
`
`13
`
`

`

`1.
`
`
`
`Steps (a)) – (b): Thee Synthesiis of Treprrostinil Waas Well-
`
`
`
`
`
`
`
`Known
`
`
`
`BBefore Deccember 17,
`
`
`
`
`
`2007, synntheses for
`
`numerous
`
`lin derivat
`prostacycl
`ives,
`
`
`
`
`
`
`
`
`
`such ass treprostinnil, and inntermediatee compounnds useful
`
`
`
`
`
`in their ssyntheses wwere
`
`
`
`
`
`well-knnown. Theese prostaacyclin derivatives
`
`
`
`
`
`
`
`:
`followinng general structures
`
`
`
`
`
`
`
`(see e.gg., the '1177 Patent, EEx. 1003, CClaim 1).
`
`
`
`
`
`
`
`and
`
`
`
`inteermediatess
`
`
`
`include
`
`the
`
`
`
`
`
`For exampple, the '1
`
`17 Patent
`
`(Ex.
`
`
`
`1003) inncludes thee synthesiss of treprosstinil (whicch is the caase in whicch, Z is O,, n is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1, X is
`
`
`
`
`
`
`
`
`
`
`
`ation S configuraup in the Sa OH grous a H and aCOOH, YY1 is CH2CCH2-, M1 is
`
`
`
`
`
`
`
`(i.e., thhe same sttereoisomeer configurration founnd in the
`
`
`
`
`
`
`
`
`
`
`
`-H; -H, an(below))), L1 is - nd R7 is ––(CH2)3-CHH3) among
`
`
`
`
`
`
`
`
`
`structure
`
`
`
`of treprosstinil
`
`
`
`es. In st its manyy example
`
`
`
`
`
`additionn, both MMoriarty (EEx. 1004)) and Phaares (Ex.
`
`
`
`
`
`
`
`1005) fuurther discclose
`
`
`
`3 of the
`
`
`
`'117 Pateent (Ex. 1
`
`003)
`
`
`
`
`
`
`
`syntheses of trepprostinil. FFor example, Claim
`
`
`
`
`
`
`
`
`
`disclosees the struccture of treprostinil (bbelow),
`
`
`
`
`
`
`
`14
`
`

`

`
`
`which iis produced by a proocess for mmaking 9--deoxy-PGGF1-type coompounds
`
`
`
`
`
`
`
`, the
`
`
`
`
`
`
`
`
`
`
`
`process comprisinng cyclizingg the followwing startiing compoound:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`AAs noted abbove, stepss (a) – (b)
`
`
`
`of Claims
`
`
`
`1 and 9 off the '393 PPatent discclose
`
`
`
`
`
`
`
`the syntthesis of prrostacyclinn derivativee acids thaat include ttreprostinill acid, whicch is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`also disclosed in MMoriarty (EEx. 1004)
`
`
`
`
`
`
`
`and the '1117 Patent ((Ex. 1003)). For exammple,
`
`
`
`
`
`
`
` and p. 3
`Moriartty (Ex. 10004) at p. 6
`
`
`
`
`
`
`
`making treprostinil acid:
`
`
`
`
`
`discloses tthe followiing syntheetic schemee for
`
`
`
`
`
`
`
`
`
`15
`
`

`

`And the '393 Patent (Ex. 1001) at cols. 9-10 discloses the same synthetic
`
`scheme for making treprostinil acid:
`
`
`
`Accordingly, the only alleged "improvement" to Moriarty in the '393 Patent
`
`was the addition of step (c) and optionally step (d) of Claims 1 and 9.
`
`2.
`
`Steps (c) & (d): 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
`
`Steps (c) and (d) of Claims 1 and 9 disclose nothing more than basic 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 weak base to a neutral carboxylic acid, and
`
`the subsequent addition of a strong acid to regenerate carboxylic acid, as disclosed
`
`in steps (c) and (d), is standard chemistry purification – i.e., organic chemistry 101.
`
`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 '393 Patent. For example,
`
`16
`
`

`

`Wiberg (Ex. 1012), an organic chemistry lab textbook (Ex. 1012) 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.
`
`(Ex. 1012, p. 6; see also Ex. 1009, Winkler Decl., ¶ 42). Similarly,
`
`Schoffstall (Ex. 1013), 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,
`
`which can then be filtered or extracted into an organic solvent. (Ex. 1013,
`
`pp. 3-40; see also Winkler Decl., ¶ 42). As the '393 Patent claims do not
`
`require isolation (or non-isolation) of the claimed treprostinil prior to
`
`formation of the treprostinil diethanolamine salt, general purification
`
`procedures, as disclosed in basic organic chemistry textbooks like Wiberg or
`
`Schoffstall, accordingly fall within the '393 Patent claims. See also (Ex.
`
`1002-2, p. 343, 2/8/2013 Remarks ("…the steps recited in claims 1 and 10,
`
`in which a salt is formed in situ without previously isolating treprostinil").
`
`17
`
`

`

`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:
`
` Kawakami (Ex. 1007), 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., a base)
`
`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 (Ex. 1007, p. 6), such
`
`as treating the salt with a strong acid such as HCl or H2SO4. 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.).
`
` Phares (Ex. 1005), entitled "Compounds and Methods for Delivery of
`
`Prostacyclin Analogs," discloses
`
`that
`
`the preparation of
`
`treprostinil
`
`diethanolamine includes the step of adding and dissolving diethanolamine (i.e.,
`
`a base) to treprostinil that is dissolved in a 1:1 molar ratio mixture of ethanol:
`
`18
`
`

`

`water. (Ex. 1005, p. 24, bottom para.). This treprostinil diethanolamine can be
`
`further precipitated and purified to form the purer and more stable crystal form
`
`called "Form B." (Ex. 1005, pp. 85-93).
`
` Ege (Ex. 1008), 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. (Ex. 1008, p. 8).
`
`3.
`
`The Claimed Treprostinil and Treprostinil Diethanolamine Salt is Not
`
`Distinct from the Prior Art
`
`As noted above and as recognized by the Patent Office during prosecution,
`
`the '393 Patent claims are product-by-process claims. The process limitations are
`
`not accorded any weight for determining the validity of the claims of the '393
`
`Patent. 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 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 noted during prosecution, Patent Owner differentiated its synthesis of
`
`treprostinil from Moriarty (Ex. 1004) by emphasizing that its product (treprostinil)
`
`contained less impurities than the product of Moriarty. Accordingly, there are three
`
`19
`
`

`

`reasons why the claimed treprostinil is not distinct from the same compound in the
`
`prior art:
`
`(1) First, during prosecution, Patent Owner provided a declaration claiming
`
`to show that its purification method achieved 99.8% purity (Ex. 1002-2, p. 348)
`
`despite the admission in the '393 Patent itself that: "In one embodiment, the purity
`
`of compound of formula IV is at least 90.0%, 95.0%, 99.0%, 99.5%," ('393 Patent,
`
`Ex. 1001, col. 8, lines 66-67)2 where the compound of Formula IV is treprostinil.
`
`This admission shows that the purity of treprostinil may be as low as 90.0%, and
`
`Patent Owner's suggestion that 99.8% is achieved or that greater than 99.5% is
`
`always achieved is based on a particular set of process steps that are not claimed
`
`and which must h