Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`LIQUIDIA TECHNOLOGIES, INC.,
`
`Petitioner
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`
`Patent Owner
`
`
`
`U.S. Patent No. 9,593,066
`
`Issue Date: March 14, 2017
`
`
`
`Title: Process to Prepare Treprostinil, the Active Ingredient in Remodulin®
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. Patent No. 9,593,066
`
`

`

`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 ’066 PATENT ............................................................ 8
`A.
`Brief Description of the ’066 Patent .................................................... 8
`B.
`Summary of the Prosecution History of the ’066 Patent ................... 13
`CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) ................. 17
`V.
`VI. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST
`ONE CLAIM OF THE ’066 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
`
`

`

`Table of Contents
`
`2.
`
`3.
`
`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 .................................................. 23
`The Claimed Treprostinil and Treprostinil
`Diethanolamine Salt Disclosed in the ’066 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. GROUNDS 1 AND 2: CLAIMS 1-10 ARE ANTICIPATED BY OR
`RENDERED OBVIOUS OVER PHARES .................................................. 26
`A. Overview Of Phares ........................................................................... 26
`B.
`Ground 1: Phares Renders Obvious Claims 1–7 of the ’066
`Patent under 35 U.S.C. § 103 ............................................................. 30
`1.
`Independent Claim 1 ................................................................ 30
`2.
`Dependent Claim 2 .................................................................. 41
`3.
`Dependent Claims 3 and 4 ....................................................... 42
`4.
`Dependent Claim 5 .................................................................. 43
`5.
`Dependent Claim 6 .................................................................. 44
`6.
`Dependent Claim 7 .................................................................. 45
`Ground 2: Phares Anticipates Claims 8-10 of the ’066 Patent
`under 35 U.S.C. § 102(b) ................................................................... 45
`1.
`Independent Claim 8 ................................................................ 45
`2.
`Dependent Claim 9 .................................................................. 49
`3.
`Dependent Claim 10 ................................................................ 49
`
`C.
`
`
`
`ii
`
`

`

`Table of Contents
`
`X. GROUND 3: CLAIMS 1-10 ARE RENDERED OBVIOUS UNDER
`35 U.S.C. § 103(A) OVER MORIARTY IN COMBINATION WITH
`PHARES ....................................................................................................... 50
`A. Overview of Moriarty ......................................................................... 50
`B. Motivation to Combine Moriarty with Phares ................................... 52
`C. Moriarty in Combination with Phares Renders Obvious Claims
`1-10 of the ’066 Patent under 35 U.S.C. § 103 .................................. 54
`1.
`Independent Claim 1 ................................................................ 54
`2.
`Dependent Claim 2 .................................................................. 63
`3.
`Dependent Claims 3, 4 and 5 ................................................... 64
`4.
`Dependent Claim 6 .................................................................. 65
`5.
`Dependent Claim 7 .................................................................. 66
`6.
`Independent Claim 8 ................................................................ 67
`7.
`Dependent Claim 9 .................................................................. 70
`8.
`Dependent Claim 10 ................................................................ 70
`XI. NO SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS
`EXIST ........................................................................................................... 71
`XII. CONCLUSION ............................................................................................. 71
`
`
`
`
`iii
`
`

`

`EXHIBITS
`
`Description of Document
`
`Exhibit
`No.
`1001 U.S. Patent No. 9,593,066 to Batra, et al. (the “’066 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 ’066 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
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`
`
`This is a petition for Inter Partes Review of claims 1-10 of U.S. Patent No.
`
`9,593,066 (Ex. 1001) (the “’066 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 ’066 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)
`zLiquidiaIPR@cooley.com
`ielrifi@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. 42,887)
`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
`Patent No. 9,593,066 B2
`correspondence address for the ’066 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 1-10 of the ’066 patent (a total of 10
`
`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 ’066 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 1-10
`
`of the ’066 patent and requests that each claim be found invalid based on the
`2
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`following grounds:
`
`Ground
`1.
`2.
`3.
`
`’066 Claim(s)
`1–7
`8–10
`1–10
`
`Basis for Challenge
`Obvious over Phares under 35 U.S.C. § 103(a)
`Anticipated by Phares under 35 U.S.C. § 102(b)
`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
`
`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 1-10 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
`
`differences between the asserted art and the prior art involved during examination;
`3
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`(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
`
`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
`
`additional evidence and facts presented in the petition warrant reconsideration of the
`
`prior art or arguments. Trial Practice Guide Update (July 2019) at 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 ’066 patent 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 ’066 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 Notification
`
`for the claims of the ’066 patent on February 22, 2017 and roughly two weeks after
`
`4
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`the ’066 patent issued. (Ex. 1005; Ex. 1006 at 2-3.) The claims of the ’393 patent
`
`and the ’066 patent are substantively similar. (Winkler Decl., ¶ 37.)
`
`Importantly, the Examiner relied upon statements from the Patent Owner
`
`supported by documents submitted during the ’393 IPR as grounds for allowance of
`
`the ’066 patent claims. (Ex. 1006 at 63.) 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 at 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 Gerate GmbH,
`
`IPR2019-01469, Paper 6 at 8-9 (P.T.A.B. Feb. 13, 2020) (designated as precedential
`
`Mar. 24, 2020).
`
`For example, the Examiner found that based on the expert declarations from
`
`Dr. Williams and Dr. Ruffolo submitted during the ’393 IPR, and statements made
`
`by Patent Owner based on these declarations, Moriarty did not disclose the same
`
`treprostinil product as the ’066 patent because the product of Moriarty had a different
`
`impurity profile from the product of the ’066 patent. (Ex. 1006 at 65.) The Examiner
`
`was also convinced that because the treprostinil product in Moriarty was not the
`
`same as the treprostinil product in the ’066 patent, it would not have been obvious
`
`5
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`to use the salt formation step of Phares to decrease the amount of impurities of the
`
`treprostinil product. (Id.) Examiner therefore withdrew the § 103 rejection. (Id.)
`
`Conversely, relying on these same expert declarations, the PTAB found that
`
`Moriarty disclosed the identical treprostinil product as the ’393 patent (which is the
`
`same treprostinil disclosed in the ’066 patent), finding that the treprostinil purity
`
`reported by Moriarty exceeded each of the purity levels 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 at 16 (emphasis added).)
`
`In addition, the PTAB found the Patent Owner did not dispute that Phares
`
`discloses the identical chemical structure for the treprostinil diethanolamine salt
`
`product claimed in the ’393 patent (the same treprostinil salt product claimed in the
`
`’066 patent). (Id. at 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
`
`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 ’066 patent invalid for similar bases as those
`6
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`found to invalidate the ’393 patent under 35 U.S.C. §§ 102(b) and/or 103(a) as
`
`anticipated by or obvious in view of Phares and obvious in view of Moriarty in light
`
`of Phares. (Id. at 43-44; see also Sections IX and X 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 ’066 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 the fully reasoned Final Written
`
`Decision. Those arguments and analysis are presented in this Petition to support
`
`invalidation of the ’066 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, 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. § 103(a) as being unpatentable over Moriarty in view of Phares.
`
`(Ex. 1006 at 100.) Here, Petitioner also contends that claims 1-7 of the ’066 patent
`
`are invalid under 35 U.S.C. § 103(a) as obvious in light of Phares alone, and claims
`
`
`
`1 In fact, the same Examiner committed the same error in prosecution of both the
`’393 and ’066 patents. (Ex. 1016 at 42, 57-64, 68-73, 99-102; Ex. 1006 at 61-63
`(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 at 43-44, 67-68, 83-84.) The Board should do the same here.
`
`7
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`8-10 are invalid under § 102(b) as anticipated by Phares. (See Sections IX and X
`
`below.) Additionally, here different claim limitations of the ’066 patent are being
`
`addressed, not only the limitations regarding the impurities as considered by the
`
`Examiner during the ’066 patent prosecution history. (Ex. 1006 at 77-78.) In other
`
`words, in this Petition, the references are applied differently than 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.” § 325(d). In fact, while the prior art was presented to the
`
`Office, the arguments presented by the Patent Owner were contrary to those
`
`presented herein and, importantly, contrary to those found by the PTAB to invalidate
`
`substantially similar claims of the parent ’393 patent in the ’393 patent IPR.
`
`IV. SUMMARY OF THE ’066 PATENT
`
`A. Brief Description of the ’066 Patent
`
`The ’066 patent is entitled “Process to Prepare Treprostinil, the Active
`
`Ingredient in Remodulin®.” The claims of the ’066 patent are product-by-process
`
`claims. These claims include two independent (claims 1 and 8) and eight dependent
`
`claims.
`
`The ’066 patent discloses an “improved process” to prepare prostacyclin
`
`derivatives such as treprostinil. (Ex. 1001, Abstract.) Claim 1 is drawn to a
`
`8
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`pharmaceutical composition comprising
`
`treprostinil or a pharmaceutically
`
`acceptable salt thereof. Claim 8 is drawn to a process of preparing the same product
`
`from claim 1, comprising the steps of alkylation of an intermediate triol to form a
`
`treprostinil salt. (Id., claims 1 and 8.)
`
`Each of the independent claims include limitations that the claimed
`
`pharmaceutical composition is made by a process comprising: (a) providing a
`
`starting batch of treprostinil having one or more impurities resulting from prior
`
`alkylation and hydrolysis steps; (b) forming a treprostinil salt by adding a base; and
`
`(c) preparing a pharmaceutical composition comprising
`
`treprostinil or a
`
`pharmaceutically acceptable salt thereof from the isolated treprostinil salt.
`
`1[b]
`1[c]
`
`1[d]
`
`Claim Limitation
`
`1[a] A pharmaceutical composition comprising treprostinil or a
`pharmaceutically acceptable salt thereof,
`said composition prepared by a process comprising:
`providing a starting batch of treprostinil having one or more impurities
`resulting from prior alkylation and hydrolysis steps,
`forming a salt of treprostinil by combining the starting batch and a
`base,
`isolating the treprostinil salt, and
`preparing a pharmaceutical composition comprising treprostinil or a
`pharmaceutically acceptable salt thereof from the isolated treprostinil
`salt,
`1[g] whereby a level of one or more impurities found in the starting batch
`of treprostinil is lower in the pharmaceutical composition, and
`1[h] wherein said alkylation is alkylation of benzindene triol.
`
`1[e]
`1[f]
`
`9
`
`

`

`3
`
`4
`
`5
`
`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`2
`The pharmaceutical composition of claim 1, wherein the salt is
`isolated in crystalline form.
`The pharmaceutical composition of claim 1, wherein the base is
`selected from the group consisting of sodium, ammonia, potassium,
`calcium, ethanolamine, diethanolamine, N-methylglucamine, and
`choline.
`The pharmaceutical composition of claim 3, wherein the base is
`diethanolamine.
`The pharmaceutical composition of claim 1, wherein the base is
`combined with treprostinil that has not been previously isolated.
`The pharmaceutical composition of claim 1, wherein the isolated salt
`is stored at ambient temperature.
`The pharmaceutical composition of claim 1, which is a pharmaceutical
`solution.
`8[a] A process of preparing a pharmaceutical product comprising
`treprostinil or a pharmaceutically acceptable salt thereof, comprising:
`alkylating a triol intermediate of the formula:
`
`6
`
`7
`
`8[b]
`
`
`
`8[c]
`8[d]
`8[e]
`8[f]
`
`
`hydrolyzing the resulting compound to form treprostinil,
`forming a salt of treprostinil stable at ambient temperature,
`storing the treprostinil salt at ambient temperature, and
`preparing a pharmaceutical product from the treprostinil salt after
`storage,
`8[g] wherein the pharmaceutical product comprises treprostinil or a
`pharmaceutically acceptable salt thereof.
`A pharmaceutical product prepared by the process of claim 8.
`The process as claimed in claim 8, wherein forming the salt of
`treprostinil stable at ambient temperature is performed by adding
`
`9
`10
`
`10
`
`

`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`diethanolamine to treprostinil.
`
`
`More specifically, the ’066 patent discloses a process for the preparation of a
`
`compound of Formula I (which includes treprostinil) shown below:
`
`
`
`(Ex. 1001 at col. 2:7-21.) Where: w = 1, 2, or 3; Y1 is trans-CH=CH-, cis-CH=CH
`
`, —CH2(CH2)m-, or
`
`; m is 1, 2, or 3; M1 is α-OH: β-R5 or α-R5: β-OH
`
`or α-OR2: β-R5 or α-R5: β-OR2, wherein R5 is hydrogen or methyl, R2 is an alcohol
`
`protecting group; L1 is α-R3: β-R4, α-R4: β-R3, or a mixture of α-R3: 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
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`are other than alkyl, with the proviso that R7, is phenoxy or substituted phenoxy,
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`only when R3 and R4 are hydrogen or methyl, being the same or different, (3) phenyl,
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`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by
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`one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy,
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`with the proviso that not more than two substituents are other than alkyl, (4) cis-
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`CH=CH—CH2—CH3, (5) —(CH2)2—CH(OH) —CH3, or (6) —(CH2)3—
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`CH=C(CH3)2; wherein —C(L1)-R72 taken together is: (1) (C4-C7)cycloalkyl
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`optionally substituted by 1 to 3 (C1-C5)alkyl; (2) 2-(2-furyl)ethyl; (3) 2-(3-
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`thienyl)ethoxy; or (4) 3-thienyloxymethyl. (Id. at cols. 2:46-3:15.)
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`
`
`The ’066 patent discloses alkylating the treprostinil with an alkylating agent
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`and then hydrolyzing with a base. (Id. at col. 2:7-3:17.) The ’066 patent further
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`discloses contacting the product from the alkylation and hydrolysis steps with a base
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`to form a salt (e.g. using the base diethanolamine to form treprostinil diethanolamine
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`salt) of Formula IS shown below:
`
`
`
`
`
`2 Though the patent recites —C(L1)-R2, a POSA would understand this to be a
`typo. It should be “—C(L1)-R7” because the patent teaches that L1 and R7 can be
`taken together to form a “cycloalkyl,” which a POSA would understand to be a
`ring. (Ex. 1001 at col. 3:2.)
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`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`(Id. at col. 3:19-30.) The treprostinil salt can then be reacted with an acid to form
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`the compound of Formula 1 (treprostinil). (Id. at col. 3:31-33.) Formula 1 is at least
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`90.0%, 95.0%, or 99.0% pure. (Id. at col. 9:22-23.)
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`
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`The ’066 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:
`
`
`
` (Id. at col. 3:52-66.)
`
`
`
`The ’066 patent discloses that these process steps can be conducted at ambient
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`temperature and the resulting treprostinil, or pharmaceutically acceptable salt
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`thereof, can be stored at ambient temperatures. (Id. at col. 17:32-36.)
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`B.
`
`Summary of the Prosecution History of the ’066 Patent
`
`The ’066 patent issued March 14, 2017 from application No. 14/849,981, filed
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`September 10, 2015. (Ex. 1001 at 1.) Application No. 14/849,981 is a divisional of
`
`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.
`
`No. 8,497,393, which is a continuation of Application No. 12/334,731, filed on
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`13
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`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`December 15, 2008, now Pat. No. 8,242,305. (Id.) The ’066 patent claims priority
`
`to provisional application No. 61/014,232, filed December 17, 2007. (Id.)
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`During prosecution, the Examiner rejected the pending claims (substantially
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`similar to issued claims 1-10 of the ’066 patent) under 35 U.S.C. § 103(a) as being
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`unpatentable over Moriarty (Ex. 1009) in view of Phares (Ex. 1008). (Ex. 1006 at
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`100.) The Examiner correctly noted that Moriarty discloses the synthesis of
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`treprostinil. (Ex. 1006 at 100.) These steps include: (a) alkylation of benzindene
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`triol and (b) hydrolysis of the product from step (a). (Id.) The Examiner noted that
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`the treprostinil (Compound 7) prepared has a purity of 99.7%. (Id.) The Examiner
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`further noted that Moriarty fails to teach preparation of a diethanolamine salt of
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`treprostinil and
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`the preparation of a pharmaceutical product comprising
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`diethanolamine salt. (Id.) However, the Examiner noted that Phares teaches the
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`preparation of treprostinil diethanolamine by dissolving treprostinil acid and treating
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`with diethanolamine and discloses two polymorphs of treprostinil diethanolamine.
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`(Id.; Ex. 1008 at 22.)
`
`Examiner stated 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 the treprostinil by the
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`method of Moriarty, especially since Moriarty discloses a method for preparing a
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`treprostinil acid which is the starting material for the process of Phares. (Ex. 1006
`
`at 101.) The Examiner further noted that since the ’066 patent is directed to the same
`
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`

`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`sequence of steps the amount of impurities in the treprostinil diethanolamine is
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`inherently lower than it was in the starting batch of treprostinil. (Id.) Regarding
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`claim 8 of the ’066 patent, Examiner stated that Phares teaches a dosing solution
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`comprising treprostinil diethanolamine. (Id.)
`
`In addition, Examiner issued a Double Patenting rejection over U.S. Patent
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`No. 8,242,305. (Id. at 102.)
`
`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 at 76.) Patent Owner
`
`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.)
`
`Patent Owner, relying on the ’393 IPR documents and expert declarations
`
`contained therein, argued that the pharmaceutical batch produced according to a salt
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`formulation process as covered by claim 1 is different from the product produced by
`
`the process described in Moriarty. (Id.) Specifically, this was because the processes
`
`result in products having different impurity profiles, with the pharmaceutical
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`composition of claim 1 having a higher average purity. (Id.) Patent Owner claimed
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`that this difference was “critical to the successful manufacture of a clinical product.”
`
`(Id. at 77.)
`
`In response to Phares, Patent Owner claimed that due to the “differences in
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`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`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.) Therefore, one of
`
`ordinary skill in the art would have no reasonable expectation of success in removing
`
`any undesired treprostinil stereoisomer impurities by salt formation. (Id.) Patent
`
`Owner did not address the Double Patenting rejection. (Id.)
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`Examiner issued a Final Rejection on November 30, 2016. (Ex. 1006 at 61.)
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`Examiner withdrew the § 103 rejection in view of Patent Owner’s arguments. (Id.
`
`at 63.) The Examiner noted that Moriarty fails to teach the formation of the salt prior
`
`to purification, and that the sample in Moriarty does not contain the impurities from
`
`alkylation and hydrolysis because it is a “pure sample.” (Id.) Examiner further
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`relied on expert declarations from Dr. Williams and Dr. Ruffolo, who described that
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`the product of Moriarty had a different impurity profile from the product in the ’066
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`invention. (Id.)
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`The Double Patenting rejection was maintained and Applicants subsequently
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`filed a terminal disclaimer to the ’305 patent on November 30, 2016. (Ex. 1006 at
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`41.) Examiner issued a Notice of Allowance on January 30, 2017. (Id. at 3.) An
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`Issue Notification was sent on February 22, 2017, just over one month before the
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`’393 IPR Final Written Decision was entered on March 31, 2017. (Id. at 3; Ex.
`
`1005.)
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`Petition for Inter Partes Review of
`Patent No. 9,593,066 B2
`V. CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(b)(3)
`
`For petitions filed on or after November 13, 2018, a claim subject to inter
`
`partes review is given its “plain and ordinary meaning” as articulated in Phillips v.
`
`AWH Corp., 415 F.3d 1303, 1312-1313 (Fed. Cir. 2005) (the plain and ordinary
`
`meaning of a claim term is the meaning that term would have to a person of ordinary
`
`skill in the