Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`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®
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. Patent No. 9,604,901
`
`

`

`Table of Contents
`
`
`
`I.
`
`MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(A)(1) ....................... 1
`A.
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ........................... 1
`B.
`Related Matters Under 37 C.F.R. § 42.8(b)(2) .................................... 1
`C.
`Lead and Back-Up Counsel under 37 C.F.R. § 42.8(b)(3) .................. 1
`D.
`Service Information .............................................................................. 1
`E.
`Power of Attorney ................................................................................ 2
`PAYMENT OF FEES - 37 C.F.R. § 42.103 .................................................. 2
`II.
`III. REQUIREMENTS FOR INTER PARTES REVIEW UNDER 37
`C.F.R. §§ 42.104 AND 42.108 ....................................................................... 2
`A. Grounds for Standing Under 37 C.F.R. § 42.104(a) ............................ 2
`B.
`Identification of Challenge Under 37 C.F.R. § 42.104(b) and
`Statement of Precise Relief Requested ................................................ 2
`Threshold Requirement for Inter Partes Review 37 C.F.R. §
`42.108(c) ............................................................................................... 3
`Considerations under 35 U.S.C. § 325(d) ............................................ 3
`D.
`IV. SUMMARY OF THE ’901 PATENT ............................................................ 8
`A.
`Brief Description of the ’901 Patent .................................................... 8
`B.
`Summary of the Prosecution History of the ’901 Patent ................... 13
`CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) ................. 18
`V.
`VI. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST
`ONE CLAIM OF THE ’901 PATENT IS UNPATENTABLE ................... 19
`A.
`State of the Art & Summary of Invalidity Arguments ....................... 19
`1.
`The Synthesis of Treprostinil was Well-Known ..................... 20
`
`C.
`
`
`
`i
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`

`

`2.
`
`3.
`
`Table of Contents
`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 .................................................. 22
`The Claimed Treprostinil and Treprostinil
`Diethanolamine Salt Disclosed in the ’901 Patent is Not
`Distinct from the Prior Art ....................................................... 24
`VII. OVERVIEW OF THE GROUNDS .............................................................. 25
`VIII. PERSON OF ORDINARY SKILL IN THE ART & STATE OF THE
`ART .............................................................................................................. 25
`IX. GROUND 1: CLAIMS 1-9 ARE RENDERED OBVIOUS UNDER
`35 U.S.C. § 103(A) OVER PHARES ........................................................... 26
`A. Overview Of Phares ........................................................................... 26
`B.
`Phares Discloses Each Limitation of Claims 1–9 .............................. 29
`1.
`Independent Claim 1 ................................................................ 29
`2.
`Dependent Claim 2 .................................................................. 40
`3.
`Dependent Claims 3 and 4 ....................................................... 40
`4.
`Dependent Claim 5 .................................................................. 42
`5.
`Dependent Claim 6 .................................................................. 43
`6.
`Dependent Claim 7 .................................................................. 45
`7.
`Dependent Claim 8 .................................................................. 45
`8.
`Dependent Claim 9 .................................................................. 48
`X. GROUND 2: CLAIMS 1-9 ARE RENDERED OBVIOUS UNDER
`35 U.S.C. § 103(A) OVER MORIARTY IN COMBINATION WITH
`PHARES ....................................................................................................... 49
`A. Overview of Moriarty ......................................................................... 49
`B. Motivation to Combine Moriarty with Phares ................................... 51
`
`
`
`ii
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`

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`Table of Contents
`C. Moriarty in combination with Phares renders obvious each of
`claims 1-9 of the ’901 patent under 35 U.S.C. § 103. ........................ 53
`1.
`Independent Claim 1 ................................................................ 53
`2.
`Dependent Claim 2 .................................................................. 64
`3.
`Dependent Claims 3 and 4 ....................................................... 64
`4.
`Dependent Claim 5 .................................................................. 67
`5.
`Dependent Claim 6 .................................................................. 67
`6.
`Dependent Claim 7 .................................................................. 70
`7.
`Dependent Claim 8 .................................................................. 70
`8.
`Dependent Claim 9 .................................................................. 74
`XI. NO SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS
`EXIST ........................................................................................................... 75
`XII. CONCLUSION ............................................................................................. 75
`
`
`
`
`iii
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`

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`EXHIBITS
`
`Description of Document
`
`Exhibit
`No.
`1001 U.S. Patent No. 9,604,901 to Batra, et al. (the “’901 patent”)
`1002 Declaration of Jeffrey D. Winkler, Ph.D. (“Winkler Decl.”)
`1003 Curriculum Vitae of Dr. Jeffrey D. Winkler
`1004 U.S. Patent No. 8,497,393 to Batra, et al. (the “’393 patent”)
`SteadyMed Ltd. v. United Therapeutics Corp., IPR2016-00006,
`1005
`Paper 82 (PTAB March 31, 2017) (“IPR2016-00006”)
`1006
`Prosecution History of the ’901 patent
`1007 U.S. Patent No. 6,765,117 to Moriarty, et al. (the “’117 patent”)
`1008
`PCT Application No. WO 2005/007081 (“Phares”)
`Moriarty, R.M., et al., “The Intramolecular Asymmetric Pauson-
`Khand Cyclization as a Novel and General Stereoselective Route to
`Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil),” J.
`Org. Chem. Vol. 69, No. 6,1890-1902 (2004) (“Moriarty”)
`Wiberg, K., Laboratory Technique in Organic Chemistry (1960),
`p.112 (“Wiberg”)
`Schoffstall, A.M. et al., Microscale and Miniscale Organic
`Chemistry Laboratory Experiments, 2d ed. (2004) pp. 200-202
`(“Schoffstall”)
`Certified English translation of Japanese Patent App. No. 56-
`122328A to Kawakami, et al. (“Kawakami”)
`Ege, S., Organic Chemistry Second Edition, Ch. 14 Carboxylic Acids
`and Their Derivates I. Nucleophilic Substitution Reactions at the
`1013
`Carbonyl Group (1989) pp. 543-547 (“Ege”)
`1014 U.S. Patent No. 4,306,075 to Aristoff (the “’075 patent”)
`1015 Declaration of Sylvia Hall-Ellis, Ph.D.
`1016
`Prosecution History of the ’393 patent
`
`1009
`
`1010
`
`1011
`
`1012
`
`
`
`iv
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`This is a petition for Inter Partes Review of claims 1-9 of U.S. Patent No.
`
`9,604,901 (Ex. 1001) (the “’901 patent”).
`
`I. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(A)(1)
`
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`
`Liquidia Technologies, Inc. (“Petitioner”) is the real party-in-interest.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`
`Petitioner is not aware of any related matters involving the ’901 patent.
`
`C. Lead and Back-Up Counsel under 37 C.F.R. § 42.8(b)(3)
`
`Petitioner provides the following designation of counsel.
`
`LEAD COUNSEL
`Ivor R. Elrifi (Reg. No. 39,529)
`ielfifi@cooley.com
`COOLEY LLP
`ATTN: Patent Group
`1299 Pennsylvania Avenue NW,
`Suite 700
`Washington, DC 20004
`Tel: (212) 479-6840
`Fax: (212) 479-6275
`
`
`BACK-UP COUNSEL
`Erik B. Milch (Reg. No. 42887)
`emilch@cooley.com
`COOLEY LLP
`11951 Freedom Drive, 14th Floor
`Reston, VA 20190-5640
`Tel: (703) 456-8573
`Fax: (703) 456-8100
`
`Deepa Kannappan
`(pro hac vice to be filed)
`dkannappan@cooley.com
`COOLEY LLP
`3175 Hanover St.
`Palo Alto, CA 94304-1130
`Tel: (650) 843-5673
`Fax: (650) 849-7400
`
`D.
`
`Service Information
`
`The Petition is being served by FEDERAL EXPRESS to the current
`
`1
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`correspondence address for the ’901 patent, Foley & Lardner LLP, 3000 K Street
`
`N.W., Suite 600, Washington, DC 20007-5109. Petitioner may be served by e-mail
`
`at the addresses provided above for lead and back-up counsel.
`
`E.
`
`Power of Attorney
`
`Filed concurrently with this petition per 37 C.F.R. § 42.10(b).
`
`II.
`
`PAYMENT OF FEES - 37 C.F.R. § 42.103
`
`This Petition requests review of claims 1-9 of the ’901 patent (a total of 9
`
`claims) and is accompanied by a payment of $30,500. 37 C.F.R. § 42.15. This
`
`Petition meets the fee requirements of 35 U.S.C. § 312(a)(1). 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. 50-1283.
`
`III. REQUIREMENTS FOR INTER PARTES REVIEW UNDER 37 C.F.R. §§ 42.104 AND
`42.108
`
`A. Grounds for Standing Under 37 C.F.R. § 42.104(a)
`
`Petitioner certifies that the ’901 patent is eligible for inter partes review and
`
`further certifies that Petitioner is not barred or otherwise estopped from requesting
`
`inter partes review on the grounds identified in this Petition.
`
`B.
`
`Identification of Challenge Under 37 C.F.R. § 42.104(b) and
`Statement of Precise Relief Requested
`
`Petitioner requests that the Board institute inter partes review of claims 1-9
`
`2
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`of the ’901 patent and requests that each claim be found invalid based on the
`
`following grounds:
`
`Ground
`1.
`2.
`
`’901 Claim(s)
`1–9
`1–9
`
`Basis for Challenge
`Obvious over Phares under 35 U.S.C. § 103(a)
`Obvious over Moriarty in view of Phares under
`35 U.S.C. § 103(a)
`
`Part VIII of this Petition explains why the challenged claims are invalid. This
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`Petition is accompanied by the Declaration of Dr. Jeffrey D. Winkler (Ex. 1002,
`
`“Winkler Decl.”), a qualified expert in the field (Ex. 1003, Curriculum Vitae of Dr.
`
`Jeffrey D. Winkler), to further support its arguments.
`
`C. Threshold Requirement for Inter Partes Review 37 C.F.R. §
`42.108(c)
`Inter partes review of claims 1-9 should be instituted because this Petition
`
`establishes a reasonable likelihood that Petitioner will prevail with respect to each
`
`of the claims challenged. 35 U.S.C. § 314(a).
`
`D. Considerations under 35 U.S.C. § 325(d)
`
`This Petition does not present a scenario in which “the same or substantially
`
`the same prior art or arguments previously were presented to the Office.” 35 U.S.C.
`
`§ 325(d).
`
`The July 2019 Trial Practice Guide Update addressed the exercise of
`
`discretion under Section 325(d) and listed six, non-exclusive factors (the Becton
`
`factors) that are to be considered in this analysis: (1) the similarities and material
`
`3
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`differences between the asserted art and the prior art involved during examination;
`
`(2) the cumulative nature of the asserted art and the prior art evaluated during
`
`examination; (3) the extent to which the asserted art was evaluated during
`
`examination; (4) the extent of the overlap between the arguments made during
`
`examination and the manner in which a petitioner relies on the prior art or a patent
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`owner distinguishes the prior art; (5) whether a petitioner has pointed out sufficiently
`
`how the Office erred in evaluating the asserted prior art; and (6) the extent to which
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`additional evidence and facts presented in the petition warrant reconsideration of the
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`prior art or arguments. Trial Practice Guide Update (July 2019), 29-30 (citing
`
`Becton Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586, Paper 8 at 17–
`
`18 (P.T.A.B. Dec. 15, 2017) (informative).
`
`While the Examiner considered both Moriarty (Ex. 1009) and Phares (Ex.
`
`1008) and relied upon these two prior art references in issuing a rejection of all
`
`claims of the ’901 patent as either anticipated by Moriarty under 35 U.S.C. § 102(b)
`
`or obvious over Moriarty in view of Phares under 35 U.S.C. § 103(a), the Examiner
`
`did not have an accurate and complete picture of the prior art. As described in detail
`
`below in Section IV.B., at the time of examination of the ’901 patent, a parallel Inter
`
`Partes Review for parent patent No. 8,497,393 (the “’393 patent”) was underway.
`
`(Ex. 1005.) In fact, the ’393 IPR Final Written Decision (the “’393 IPR”) was
`
`entered on March 31, 2017, just over one month after the Examiner mailed an Issue
`
`4
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`Notification for the claims of the ’901 patent on February 14, 2017 and only two
`
`days after the ’901 patent issued. (Ex. 1005; Ex. 1006, 8-9.) The claims of the ’393
`
`patent and the ’901 patent are substantively similar.
`
`Importantly, the Examiner relied upon statements from the Patent Owner
`
`supported by documents submitted during the ’393 IPR as grounds for allowance of
`
`the ’901 patent claims. (Ex. 1006, 87.) These same documents were relied upon by
`
`the PTAB to support its declaration that all claims of the ’393 patent were invalid
`
`under both 35 U.S.C. §§ 102(b) and 103(a). (Ex. 1005, 43-44, 67-68, 83-84.) The
`
`Examiner therefore erred in discounting the arguments set forth by the petitioner and
`
`its expert in the ’393 IPR and by misapplying the references cited during prosecution
`
`of the ’066 patent, contradicting the PTAB’s Final Written Decision in the ’393 IPR.
`
`See Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte GmbH,
`
`IPR2019-01469, Paper 6 at 8-9 (P.T.A.B. Feb. 13, 2020) (designated Mar. 24, 2020).
`
`For example, the Examiner withdrew the §§ 102 and 103 rejections “in view
`
`of applicant’s arguments, amendments and the accompanying declarations”
`
`provided during the ’393 IPR, without further explanation. (Ex. 1006, 87.)
`
`Conversely, relying on these same expert declarations and arguments, the
`
`PTAB found that Moriarty disclosed the identical treprostinil product as the ’393
`
`patent (which is the same treprostinil disclosed in the ’901 patent), finding that the
`
`treprostinil purity reported by Moriarty exceeded each of the purity levels
`
`5
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`exemplified in the specification of the ’393 patent:
`
`“the evidence of record establishes that the variability in
`the impurity profile and overall purity level between
`individual batches of treprostinil produced according to
`the process steps recited in the challenged claims renders
`the claimed treprostinil structurally and functionally the
`same as treprostinil produced according to Moriarty.”
`
`(Ex. 1005, 16 (emphasis added).)
`
`In addition, the PTAB found the Patent Owner did not dispute that Phares
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`discloses the identical chemical structure for the treprostinil diethanolamine salt
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`product claimed in the ’393 patent (the same treprostinil salt product claimed in the
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`‘901 patent). (Id., 43 (“[W]e find that Phares treprostinil is at least as pure as
`
`treprostinil produced according to the process disclosed in the ’393 patent, and
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`therefore, Phares necessarily discloses treprostinil having a purity of 99.5% or
`
`higher.”).)
`
`As such, Petitioner contends that Phares alone, or Phares in combination with
`
`Moriarty would render the claims of the ’901 patent invalid for the same bases as
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`those found to invalidate the ’393 patent under 35 U.S.C. § 103(a) as obvious over
`
`Phares or as obvious over Moriarty in view of Phares. (Id., 43-44; see also Section
`
`IX below for detailed grounds of invalidity). Since the Examiner did not have the
`
`’393 patent IPR Final Written Decision in hand at the time the ’901 patent claims
`
`were being considered by the Office, the Examiner was not able to weigh the full
`
`scope of evidence before the Board in the ’393 IPR and did not have the benefit of
`6
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`the fully reasoned Final Written Decision. Those arguments and analysis are
`
`presented in this Petition to support invalidation of the ’901 patent and thus, the full
`
`scope of the arguments and rationale associated with the prior art references as
`
`presented herein were not previously considered and/or misapplied by the
`
`Examiner.1
`
` In addition, prior art references Moriarty and Phares are being presented in a
`
`different light in the current Petition. During prosecution, the Examiner rejected the
`
`pending claims under 35 U.S.C. § 102(b) as anticipated by Moriarty and § 103(a) as
`
`being unpatentable over Moriarty in view of Phares. (Ex. 1006, 118-121.) Here,
`
`Petitioner contends that the claims of the ’901 patent are invalid under 35 U.S.C.
`
`§ 103(a) as obvious over Phares and as obvious over Moriarty in light of Phares.
`
`(See Sections IX and X below.) Additionally, here all claim limitations of the ’901
`
`patent are being addressed, not only the limitations regarding (1) the steps of
`
`alkylation and hydrolysis and (2) the impurities resulting from those steps, as
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`considered by the Examiner during the ‘901 patent prosecution history. (Ex. 1006,
`
`118-121.) In other words, in this Petition, the references are applied differently than
`
`
`
`1 In fact, the same Examiner committed the same error in prosecution of both the
`’393 and ’901 patents. (Ex. 1016, 42, 57-64, 68-73, 99-102; Ex. 1006, 86-87
`(Examiner Yevgeny Valenrod).) The Board corrected the Examiner’s error and
`applied Moriarty and Phares to invalidate all of the ’393 patent claims in IPR2016-
`00006. (Ex. 1005, 43-44, 67-68, 83-84.) The Board should do the same here.
`
`7
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`they were during prosecution.
`
`For all of the reasons presented herein, this Petition does not present a scenario
`
`in which “the same or substantially the same prior art or arguments previously were
`
`presented to the Office.” 35 U.S.C. § 325(d).
`
`IV. SUMMARY OF THE ’901 PATENT
`
`A. Brief Description of the ’901 Patent
`
`The ’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.
`
`
`
`8
`
`

`

`1[b]
`1[c]
`
`1[d]
`
`1[e]
`1[f]
`
`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`Claim Limitation
`
`1[a] A pharmaceutical batch consisting of treprostinil or a salt thereof and
`impurities resulting from:
`(a) alkylating a benzindene triol,
`(b) hydrolyzing the product of step (a) to form a solution comprising
`treprostinil,
`(c) contacting2 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.
`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,
`
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`2 Certificate of correction: “(c) containing the” should be –”(c) contacting the--.” (Ex. 1006, 2.)
`
`9
`
`

`

`8[b]
`8[c]
`
`8[d]
`
`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`comprising:
`(a) alkylating a benzindene triol,
`(b) hydrolyzing the product of step (a) to form a solution comprising
`treprostinil,
`(c) contacting 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.
`A method as claimed in claim 8, wherein the salt of treprostinil is a
`diethanolamine salt.
`
`8[e]
`8[f]
`
`9
`
`
`More specifically, the ’901 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.) 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: 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). (Id. at cols. 2:46-3:20; Winkler Decl., ¶27.)
`
`10
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`
`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., 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:
`
`11
`
`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`(Id. at cols. 9:33-45, 12:45-59, 14:35-47.) The treprostinil salt can then be isolated
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`and reacted with an acid to form treprostinil, as shown below:
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`(Id. at col. 14:30-15:24, Example 5.) As disclosed in one embodiment, the resulting
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`carboxylic acid, Formula IV, is at least 90.0%, 95.0%, 99.0%, or 99.5% pure. (Id.
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`at col. 9:49-50.)
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`
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`The ’901 patent further discloses alkylating a treprostinil triol intermediate
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`(Formula V, shown below) to form treprostinil or a pharmaceutically acceptable salt
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`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
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`least 2.9 g of treprostinil or its salt which has been dried under a vacuum. (Id., 15:8-
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`11.) The ’901 patent does not teach storing the resulting treprostinil salt at ambient
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`temperature; it only specifically discloses this for a “crude” salt. (Id. at col. 17:4-8.)
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`B.
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`Summary of the Prosecution History of the ’901 Patent
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`The ’901 patent issued March 28, 2017 from application No. 14/754,932, filed
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`June 30, 2015. (Ex. 1001, 1.) Application No. 14/754,932 is a continuation of
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`Application No. 13/933,623, filed on July 2, 2013, now Patent No. 9,156,786, which
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`is a continuation of Application No. 13/548,446, filed on July 13, 2012, now Pat.
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`No. 8,497,393, which is a continuation of Application No. 12/334,731, filed on
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`December 15, 2008, now Pat. No. 8,242,305. (Id.) The ’901 patent claims priority
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`to provisional application No. 61/014,232, filed December 17, 2007. (Id.)
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`During prosecution, the Examiner rejected pending claims 1, 2, 3, 6, 7 and 8
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`under 35 U.S.C. § 102(b) as being anticipated by Moriarty (Ex. 1009). (Ex. 1006,
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`176.) The Examiner correctly noted that Moriarty discloses compound 7, which has
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`the same structure as the ’901 patent and discloses a method of preparing compound
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`7. (Id.) In addition, Examiner issued a Double Patenting rejection over claims 9 and
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`15 of U.S. Patent No. 8,497,393. (Id., 177.)
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`In response, Patent Owner amended the claims to incorporate claim 4 (“the
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`high purity treprostinil batch of claim 1, which contains at least 2.9 g of
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`treprostinil”), which had not been rejected, into claim 1. (Id., 165, 227.) Patent
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`Owners also filed a terminal disclaimer over the ’393 patent to obviate the double
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`patenting rejection. (Id., 167.)
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`Examiner then issued a first Notice of Allowance on September 18, 2015.
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`(Id., 145.) However, Patent Owner filed a Request for Continued Examination
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`(“RCE”) on December 8, 2015, wherein the claims were amended to essentially the
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`present claims of the ’901 patent and new claims directed to treprostinil salt were
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`added. (Id., 137-38.) Patent Owners simultaneously filed an Information Disclosure
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`Statement (“IDS”), wherein the ’393 Petition for IPR (Ex. 1005) and references Ege
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`(Ex. 1013), Schoffstall (Ex. 1011), and Wiberg (Ex. 1010) cited therein were
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`disclosed. (Id., 127.)
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`Given the claim amendments and IDS, Examiner issued a second Non-Final
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`Office Action on February 11, 2016. (Id., 116-124.) Examiner rejected claims 1-3,
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`6, 8, and 9 under 35 U.S.C. § 102(b) as being anticipated by Moriarty. (Id., 118.)
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`Examiner again correctly noted that Moriarty disclosed a method for preparing
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`treprostinil, said method including the steps of: (a) alkylation of benzindene triol and
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`(b) hydrolysis of the product of step (a). (Id.) Examiner further noted that Moriarty
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`disclosed preparation of 441g of treprostinil (a therapeutically effective amount),
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`99.7% purity. (Id., 118-119.) Examiner stated that “[a]lthough the method of
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`Moriarty and the steps recited in the instant claims are not identical, the product
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`obtained is the same.” (Id.) If the product in the product-by-process claim is the
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`same or obvious from the product of the prior art, the claim is unpatentable even
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`though the prior art product was made by a different process. (Id.)
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`In addition, Examiner rejected added claims 10-12 under 35 U.S.C. § 103(a)
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`as being obvious over Moriarty (Ex. 1009) in view of Phares (Ex. 1008). (Id., 119-
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`20.) Examiner noted that Moriarty disclosed a method for preparing treprostinil
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`(compound 7). (Id.) However, Moriarty failed to teach preparation of a
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`diethanolamine salt of treprostinil and the preparation of a pharmaceutical product
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`comprising diethanolamine salt. (Id.)
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`Examiner correctly noted that Phares teaches the preparation of treprostinil
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`diethanolamine by dissolving treprostinil acid and treating it with diethanolamine.
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`(Id., 121.) Examiner found that Phares further disclosed two polymorphs of
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`treprostinil diethanolamine and their stability. (Id.)
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`Examiner noted that one skilled in the art practicing the invention of Phares
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`would have found it obvious to prepare diethanolamine salt of treprostinil prepared
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`by the method of Moriarty because Moriarty discloses a method of preparing a
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`treprostinil acid which is needed starting material for the process of Phares. (Id.)
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`This resulting salt would meet the limitations directed to the pharmaceutical product
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`because treprostinil diethanolamine is the sole claimed component of the claimed
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`pharmaceutical product. (Id.) One skilled in the art would have also found it obvious
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`to prepare a pharmaceutical product from the treprostinil diethanolamine salt of
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`Phares prepared from the treprostinil free acid that has been obtained by the process
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`of Moriarty. (Id.)
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`In addition, Examiner issued a Double Patenting rejection of claims 13 and 14
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`over U.S. Patent No. 8,242,305. (Id., 123.)
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`In response, Patent Owner submitted a notification of related proceedings to
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`bring to the Examiner’s attention all documents from IPR2016-00006 (Ex. 1005),
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`which involves the parent ’393 patent (Ex. 1004). (Ex. 1006, 98.) Patent Owner
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`noted that “[d]ocuments provided in that notification include the Patent Owner’s
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`Response and expert declarations from Dr. Williams and Ruffolo.” (Id.)
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`Patent Owner, relying on the ’393 IPR documents and expert declarations
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`contained therein, argued that the pharmaceutical batch of claim 1 differs from the
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`product resulting from the synthesis disclosed in Moriarty. (Id., 99.) Specifically,
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`this was because the processes result in products having different impurity profiles,
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`with the pharmaceutical composition of claim 1 having a higher average purity. (Id.)
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`Patent Owner claimed that this difference was “critical to the successful manufacture
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`of a clinical product.” (Id.)
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`In response to Phares, Patent Owner claimed that due to the “differences in
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`the resulting products [compared to Moriarty] it would not have been obvious to use
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`the salt formation step of Phares to decrease amounts of stereoisomer impurities of
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`treprostinil, which are acidic rather than neutral or basic.” (Id., 99-100.) Therefore,
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`one of ordinary skill in the art would have no reasonable expectation of success in
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`removing any undesired treprostinil stereoisomer impurities by salt formation. (Id.,
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`100.) Patent Owner did not address the Double Patenting rejection. (Id.) However,
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`a POSA would understand that when one makes treprostinil salt and performs the
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`recrystallization steps, recrystallization does remove impurities, including non-
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`acidic or other salt impurities. (Winkler Decl., ¶¶47-49.)
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`Examiner issued a Final Rejection on October 19, 2016. (Ex. 1006, 85-90.)
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`Examiner withdrew the §§ 102 and 103 rejections “in view of applicants’ arguments,
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`amendments and the accompanying declarations.” (Id., 87.) Examiner did not
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`provide further analysis to support withdrawal of these rejections. (Id.)
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`The Double Patenting rejection was maintained and Applicants subsequently
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`filed a terminal disclaimer to the ’305 patent on October 21, 2016. (Ex. 1006, 72,
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`75.) Examiner issued a Notice of Allowance on November 9, 2016. (Id., 58.)
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`Patent Owners subsequently filed a second RCE on December 21, 2016,
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`wherein Patent Owners submitted an IDS disclosing that an invalidity contention
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`had been filed against the parent ‘393 patent. (Id., 36, 41-44.)
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`A final Notice of Allowance was sent on February 14, 2017, just over one
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`month be