Petitioner’s Reply In Support of Petition
`IPR2020-00770
`U.S. Patent No. 9,604,901
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`LIQUIDIA TECHNOLOGIES, INC.,
`
`Petitioner
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`
`Patent Owner
`
`
`
`
`Inter Partes Review No. IPR2020-00770
`U.S. Patent No. 9,604,901
`
`
`PETITIONER’S REPLY
`
`
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`2.
`
`3.
`
`SUMMARY OF THE ARGUMENT ............................................................. 1 
`I.
`II. DR. PINAL’S OPINIONS ARE SELF-SERVING AND
`DISINGENUOUS ........................................................................................... 1 
`III. DR. WINKLER’S DECLARATION WAS PROPERLY
`CONSIDERED ............................................................................................... 1 
`IV. CLAIM CONSTRUCTION ........................................................................... 3 
`A.
`Pharmaceutical Batch ........................................................................... 4 
`B.
`Storing, Storage .................................................................................... 6 
`V. UTC IMPORTS OTHER NON-EXISTENT LIMITATIONS INTO
`THE CLAIMS ................................................................................................ 8 
`VI. UTC UNNECESSARILY ELEVATES THE LEVEL OF
`ORDINARY SKILL IN THE ART ................................................................ 9 
`VII. MORIARTY AND PHARES RENDER CLAIMS 1-9 OBVIOUS ............ 10 
`A. Motivation to Combine Moriarty with Phares with a
`Reasonable Expectation of Success ................................................... 10 
`1.
`UTC is Precluded from Disputing Motivation to
`Combine ................................................................................... 10 
`A POSA Would Have Been Motivated to Form the
`Treprostinil Diethanolamine Salt of Phares with a
`Reasonable Expectation of Success ......................................... 12 
`Elimination of the Intermediate Isolation and
`Crystallization Steps of Moriarty Would Have Been
`Obvious .................................................................................... 15 
`The Instituted Combination of Moriarty and Phares Would
`Necessarily Result in a Pharmaceutical Batch Having
`Impurities “Resulting From” the Claimed Steps ................................ 17 
`C. A POSA Would Have Had a Reasonable Expectation That
`Treprostinil Diethanolamine Salt Could Be Stored at Ambient
`Temperature ........................................................................................ 18 
`-i-
`
`
`B.
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`

`

`TABLE OF CONTENTS
`(continued)
`
`B.
`
`C.
`
`Page
`VIII. PHARES RENDERS CLAIMS 1-9 OBVIOUS .......................................... 21 
`A.
`Phares Does Not Require Isolation of Crude Treprostinil Prior
`to Salt Formation ................................................................................ 21 
`Phares’ Treprostinil Salt Necessarily Contains Impurities
`“Resulting From” the Claimed Steps ................................................. 22 
`Phares Teaches the Synthesis of Both Enantiomeric Treprostinil
`Forms .................................................................................................. 23 
`Scaling Up Phares Would Have Been Obvious ................................. 24 
`Phares Renders Claims 2-5 and 8-9 Obvious ..................................... 25 
`A POSA Would Have Had a Reasonable Expectation That
`Treprostinil Diethanolamine Salt Could Be Stored at Ambient
`Temperature ........................................................................................ 26 
`IX. UTC’S ALLEGED EVIDENCE OF SECONDARY
`CONSIDERATIONS IS UNAVAILING ..................................................... 26 
`A. No Unexpected Results in Storability at Ambient Temperature ....... 26 
`B.
`Board Already Rejected UTC’s Other Arguments ............................ 27 
`THIS PROCEEDING IS CONSTITUTIONAL ........................................... 28 
`X.
`XI. CONCLUSION ............................................................................................. 28 
`
`D.
`E.
`F.
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`-ii-
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`

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`EXHIBITS
`
`1009
`
`1010
`
`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 Derivatives 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
`1017 Reply Declaration of Jeffrey D. Winkler, Ph.D.
`1018 Deposition transcript of Rodolfo Pinal, dated February 10, 2021
`1019 Gao, K., “Synthesis of A-Galceramides, (-)-Treprostinil, and Design
`and Synthesis of Anti-Viral Agents,” Thesis submitted as partial
`-iii-
`
`
`1011
`
`1012
`
`
`
`
`
`

`

`EXHIBITS
`
`Exhibit
`No.
`
`1020
`
`1022
`
`Description of Document
`fulfillment of the requirements for the degree of Doctor Of
`Philosophy in Chemistry in the Graduate College of the University of
`Illinois at Chicago, 2006
`Parks, B.W., et al., “Convenient Synthesis of 6,6-Bicyclic
`Malonamides: A New Class of Conformationally Preorganized
`Ligands for f-Block Ion Binding,” J. Org. Chem., 71:9622-27 (2006)
`1021 Hanessian, S., et al., “Structure-Based Organic Synthesis of a
`Tricyclic N-Malayamycin Analogue,” J. Org. Chem., 71:9807-17
`(2006)
`Frost, J.M., et al., “Synthesis and Structure – Activity Relationships
`of 3,8-Diazabicyclo[4.2.0]octane Ligands, Potent Nicotinic
`Acetylcholine Receptor Agonists,” J. Med. Chem., 49:7843-53
`(2006)
`1023 Regan, J., et al., “Quinol-4-ones as Steroid A-Ring Mimetics in
`Nonsteroidal Dissociated Glucocorticoid Agonists,” J. Med. Chem.,
`49:7887-96 (2006)
`Paulekuhn, G.S., et al., “Trends in Active Pharmaceutical Ingredient
`Salt Selection based on Analysis of the Orange Book Database,” J.
`Med. Chem., 50:6665-72 (2007)
`1025 Mak, K.K.W., et al., “Mannich Reactions in Room Temperature
`Ionic Liquids (RTILs): An Advanced Undergraduate Project of
`Green Chemistry and Structural Elucidation,” J. Chem. Ed.,
`83(6):943-46 (2006)
`Supplemental Materials to Mak, K.K.W., et al., “Mannich Reactions
`in Room Temperature Ionic Liquids (RTILs): An Advanced
`Undergraduate Project of Green Chemistry and Structural
`Elucidation,” J. Chem. Ed., 83(6):943-46 (2006)
`1027 Baar, M.R., et al., “Enantiomeric Resolution of (±)-Mandelic Acid
`by (1R,2S)-(–)-Ephedrine,” J. Chem. Ed., 82(7):1040-42 (2005)
`Supplemental Materials for Baar, M.R., et al., “Enantiomeric
`Resolution of (±)-Mandelic Acid by (1R,2S)-(–)-Ephedrine,” J.
`Chem. Ed., 82(7):1040-42 (2005)
`1029 Brigandi, L.M., et al., “Synthesis and Analysis of Copper Hydroxy
`Double Salts,” J. Chem. Educ., 82(11):1662 (2005)
`-iv-
`
`
`1024
`
`1026
`
`1028
`
`
`
`
`
`

`

`EXHIBITS
`
`Exhibit
`No.
`1030
`
`Description of Document
`Supplemental Material for Online Publication for Brigandi, L.M., et
`al., “Synthesis and Analysis of Copper Hydroxy Double Salts,” J.
`Chem. Educ., 82(11):1662 (2005)
`1031 Hamilton, “Experiment #5: Resolution of (R,S)-1-Phenylethylamine
`via Diastereoisomer formation with (2R),(3R)-Tartaric Acid,”
`Laboratory Manual for Chemistry 202, Organic Chemistry
`Laboratory I at Mount Holyoke College (2006)
`1032 Yadav, J.S., et al., “A concise and stereoselective synthesis of both
`enantiomers of altholactone and isoaltholactone,” Tetrahedron
`Letters, 44:5831-33 (2003)
`Takadoi, M., et al., “Synthetic studies of himbacine, a potent
`antagonist of the muscarinic M2 subtype receptor 1. Stereoselective
`total synthesis and antagonistic activity of enantiomeric pairs of
`himbacine and (2’S,6’R)-diepihimbacine, 4-epihimbacine, and novel
`himbacine congeners,” Tetrahedron 58 (2002) 9903–23
`1034 Berge, S.M., et al., “Pharmaceutical Salts,” J. Pharm. Scis., 66(1):1-
`19 (1977)
`Excerpts from Loewenthal, H.J.E., et al., A Guide for the Perplexed
`Organic Experimentalist, Chapter 4: Running Small-scale Reactions
`in the Research Laboratory, pp. 87-119, 2d ed. (1990)
`1036 Heidelberger, M., An Advanced Laboratory Manual of Organize
`Chemistry (1928)
`Product Information for Remodulin (2006) (“Remodulin Label”)
`1037
`Excerpt from Hawley’s Condensed Chemical Dictionary, 15th ed.
`1038
`(2007)
`1039 Refiled Declaration of Jeffrey D. Winkler, Ph.D. (Ex. 1002)
`
`1033
`
`1035
`
`
`
`
`
`-v-
`
`
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`I.
`SUMMARY OF THE ARGUMENT
`
`Patent Owner’s (“UTC”) arguments are either tied to language not present in
`
`the claims or to motivation to combine arguments already rejected by the PTAB in
`
`IPR2016-00006 over the ’393 Patent, the ’901 Patent’s parent. The combination of
`
`Phares and Moriarty, or Phares alone, render each of the ’901 Patent claims obvious.
`
`II. DR. PINAL’S OPINIONS ARE SELF-SERVING AND DISINGENUOUS
`
`UTC’s expert, Dr. Pinal, attacks Dr. Winkler by misquoting,
`
`mischaracterizing, and worst, changing words in Dr. Winkler’s testimony to
`
`discredit him. Such actions by Dr. Pinal, and by extension UTC, evidence that their
`
`positions lack credibility. Examples of Dr. Pinal’s and UTC’s twisting of Dr.
`
`Winkler’s testimony are provided in Dr. Winkler’s Supplemental Declaration. See
`
`EX1017, Section VI (detailing the extent of Dr. Pinal’s errors).
`
`III. DR. WINKLER’S DECLARATION WAS PROPERLY CONSIDERED
`
`Petitioner properly relied upon the declaration of Dr. Jeffrey D. Winkler
`
`(EX1002) to establish the obviousness of the ’901 Patent.
`
`Any omissions in Dr. Winkler’s declaration with respect to the oath or perjury
`
`1
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`statement were harmless and have been cured.1 Dr. Winkler filed a modified
`
`declaration swearing to the truth of his statements therein (see EX1039, ¶241), and
`
`UTC has deposed him on the opinions he presented therein. See generally EX2026;
`
`see also Google v. CyWee Group, IPR2018-01257, Paper 69, 2-4 (P.T.A.B. Sept. 6,
`
`2019) (granting party authorization to correct unsworn declaration when opposing
`
`party cross-examined the expert); Fidelity Information Services v. Mirror Imaging,
`
`CBM2017-00064, Paper 54, 5-8 (P.T.A.B. Jan. 2, 2019) (same).
`
`Dr. Winkler’s opinions are supported by reasoned analysis and evidentiary
`
`support. UTC does not cite any particular paragraph(s) of Dr. Winkler’s declaration
`
`to support its argument to the contrary. See POR18 (citing EX2025). To the extent
`
`Dr. Winkler’s declaration does not provide a source for every opinion, Dr. Winkler
`
`relies on his experience, general knowledge, and understanding of a POSA in
`
`
`
`1 UTC’s waived its argument regarding Dr. Winkler’s declaration under 37 C.F.R. §
`
`42.63. UTC did not file a proper objection because it did not file a motion to exclude.
`
`See 37 C.F.R. § 42.64(c). To the extent it did, that objection was untimely because
`
`it was not raised within ten business days of institution. See id., § 42.64(b)(1) (“Any
`
`objection to evidence submitted during a preliminary proceeding must be filed
`
`within ten business days of the institution of the trial.”).
`
`2
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`December 2007. And UTC’s criticism of similarities between the Petition and Dr.
`
`Winkler’s declaration is meritless: Dr. Winkler testified that he drafted his
`
`declaration (EX2026, 18:11-13), and the Petition adopted his language for precision
`
`and scientific accuracy.
`
`UTC’s contention that Dr. Winkler, an organic chemist without a law degree,
`
`must understand the doctrine of inherent obviousness to opine on the teachings of
`
`the prior art is erroneous. POR21-22. Dr. Winkler’s testimony assists the Board in
`
`resolving the factual inquiries underlying the obviousness inquiry. See LG Chem v.
`
`Celgard, IPR2014-00692, Paper 76, 46-48 (P.T.A.B. Oct. 5, 2015) (denying Patent
`
`Owner’s motion to exclude expert testimony for failing to apply the “correct legal
`
`standards for inherency”).
`
`IV. CLAIM CONSTRUCTION
`
`UTC’s constructions of “pharmaceutical batch” and “storing”/”storage” seek
`
`to improperly import several undefined limitations from FDA regulations, contrary
`
`to well-settled patent law.2 Helsinn Healthcare S.A. v. Teva Pharms. USA, 855 F.3d
`
`
`
`2 For purposes of this proceeding, Petitioner does not contest the Board’s
`
`construction of “pharmaceutical product” nor UTC’s construction of “[c]ontacting
`
`the solution comprising treprostinil from step (b) with a base to form a salt of
`
`
`
`3
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`1356, 1372 (Fed. Cir. 2017) (“Approval of a new drug by FDA…is a more
`
`demanding standard than that involved in the patents-in-suit.”); Scott v. Finney, 34
`
`F.3d 1058, 1063 (Fed. Cir. 1994) (“Testing for the full safety and effectiveness…is
`
`more properly left to the [FDA].”). For the reasons stated below, UTC’s
`
`unsupported constructions should be rejected.
`
`A.
`
`Pharmaceutical Batch
`
`As the Examiner noted during prosecution, the “[s]pecification fails to provide
`
`a limiting definition for the term ‘batch’ and as such meets [sic] and bounds of the
`
`said term are unclear.” EX1006, 175. UTC’s proposed construction of
`
`“pharmaceutical batch” pulls language directly from FDA regulations and uses the
`
`terms “uniform character and quality,” “single manufacturing order,” or “same cycle
`
`of manufacture.” POPR8-9 (citing 21 C.F.R. § 210.3). Neither these terms nor the
`
`now-relied upon FDA definition of “batch” appear anywhere in the ’901 Patent
`
`claims, specification, or file history. See generally EX1001; EX1006. UTC’s
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`construction thus “creates more ambiguity than clarity” by introducing terms that
`
`themselves would require construction. Merck Sharp & Dohme Corp. v. Actavis
`
`
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`treprostinil,” as Phares or Moriarty meet these limitations under the plain and
`
`ordinary meaning of these terms, and the Board’s constructions.
`
`4
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`Labs. FL, No. 15-cv-6075, 2017 WL 2784703, at *8-9 (D.N.J. June 27, 2017); E-
`
`Pass Techs. v. 3Com, 473 F.3d 1213, 1220 (Fed. Cir. 2007) (terms used “to enunciate
`
`the proper construction of a claim” should not “themselves [be] limitations that
`
`require interpretation”).
`
`Moreover, UTC’s construction ignores statements it made to overcome prior
`
`art, characterizing the “pharmaceutical batch” as being made without purification
`
`before salt formation. EX1001, 16:66-17:1 (“[t]he purification of benzindene nitrile
`
`by column chromatography is eliminated” from the prior art process); id., Example
`
`6 (Step 12); EX2007, 3928-929 (UTC’s ’393 POR distinguishing Moriarty based on
`
`the purification step)3; POPR56 (“no purification steps appear between alkylation
`
`and salt formation”); POR25 (“purification is excluded between alkylation and salt
`
`formation”); EX1018, 79:9-11 (“Q: [T]he present invention excludes column
`
`chromatography, correct? A: Yes.”).
`
` Thus, a POSA would understand
`
`“pharmaceutical batch” to mean one “made according to the process recited in steps
`
`(a)–(d) and optionally (e), wherein no purification steps appear between alkylation
`
`and salt formation.”
`
`
`
`3 Statements made during IPR proceedings are directly relevant to claim
`
`construction. Aylus Networks v. Apple, 856 F.3d 1353, 1361 (Fed. Cir. 2017).
`
`5
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`UTC’s construction also imports storage limitations into “pharmaceutical
`
`batch” (POR9), but the Board’s construction did not (Dec. at 15-16). Such
`
`importation renders the other claim terms “storing”/”storage” superfluous, violating
`
`the canon that “when a patent claim does not contain a certain limitation and another
`
`claim does,
`
`that
`
`limitation cannot be read
`
`into
`
`the former claim
`
`in
`
`determining…validity[.]” SRI Int’l v. Matsushita Elec., 775 F.2d 1107, 1122 (Fed.
`
`Cir. 1985) (en banc).4
`
`Regardless, under either construction, Moriarty discloses a “pharmaceutical
`
`batch” of 500g. UTC’s expert testified that Moriarty is “almost identical” to the
`
`“Former Process” listed in Example 6 of the ’901 Patent, and that the term “batch”
`
`as used to describe the “Former Process” and “Process According to the Invention”
`
`in Example 6 means a “pharmaceutical batch” to a POSA. EX1018, 89:4-9, 90:14-
`
`92:9.
`
`B.
`
`Storing, Storage
`
`Similarly, the ’901 Patent provides no definition of “storing” or “storage.” Its
`
`disclosure is limited to a single use of the term: “Additional advantages of this
`
`
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`4 Even the FDA regulation imported into UTC’s construction does not include a
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`storage stability limitation. See EX2004.
`
`6
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`process are: (a) crude treprostinil salts can be stored as raw material at ambient
`
`temperature[.]” EX1001, 17:4-10. Otherwise, only claim 6 includes the terms.
`
`UTC’s proposed construction requiring (i) that the “stored material possesses
`
`stability sufficient to allow manufacture” and (ii) “maintains integrity for a sufficient
`
`period of time to be useful for preparing a pharmaceutical product” is flawed for
`
`three reasons. POR11-12.
`
`First, importing a stability limitation violates claim differentiation canon,
`
`because the term “stable” is separately defined in the ’901 specification (EX1001,
`
`5:4-10) and is recited along with the term “storing” in claim 8 of the related ’066
`
`Patent.5 EX2027, 18:38-61. UTC’s definition of “storing/storage” is essentially the
`
`definition of “stable,” and renders the terms redundant.
`
`Second, UTC’s construction is inconsistent with its construction of this same
`
`term during prosecution of the ʼ901 Patent’s parent, the ʼ786 Patent. Relying on the
`
`declaration of Dr. Liang Guo, UTC argued that “a person of ordinary skill in the art
`
`would recognize that the term ‘stored’…means stored for a period of at least three
`
`
`
`5 Omega Engineering v. Raytek Corp., 334 F.3d 1314, 1334 (Fed. Cir. 2003)
`
`(presumption that “the same claim term in the same patent or related patents carries
`
`the same construed meaning”).
`
`7
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`months.” EX2028, 193. Dr. Guo declared that a POSA reading the sentence “crude
`
`treprostinil salts can be stored as raw material at ambient temperature,” would
`
`“recognize that the term ‘stored’ in this statement means stored for a period of at
`
`least three months.” EX2028, 0198, ¶6. This same sentence appears in the ʼ901
`
`Patent. EX1001, 17:5-6.
`
`Third, UTC’s construction of “storing”/“storage” is inconsistent with the plain
`
`and ordinary meaning of the term. See EX1038, 4 (Hawley’s Definition of
`
`“Storage”) (“Any method of keeping raw materials, chemicals, food products, and
`
`energy while awaiting use, transportation, or consumption.”).
`
`V. UTC IMPORTS OTHER NON-EXISTENT LIMITATIONS INTO THE CLAIMS
`
`The Board should reject UTC attempts to import non-existent “ultra-pure” or
`
`“highly pure” and “commercial” or “industrial” scale limitations into the claims.
`
`POR6, 7, 23-24, 27, 47.
`
`No claim specifies the purity level of the claimed pharmaceutical batch or
`
`pharmaceutical product and the sole independent claim requires “pharmaceutical
`
`batch consisting of…impurities[.]” See EX1001, claim 1.6 And a section of UTC’s
`
`Response is titled, “[c]laim 1 requires a pharmaceutical batch consisting
`
`
`
`6 All emphasis is added unless otherwise noted.
`
`8
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`of…impurities.” POR35. Accordingly, importing non-existent and factually
`
`inaccurate purity limitations into the claims is improper.
`
`Nor is “at least 2.9 g” indicative of “commercial” scale. EX1017, ¶¶50-57.
`
`Dr. Pinal agrees that no such terms appear in the claims. EX1018, 105:21-106:21,
`
`117:5-20. He also explained that the claims cover products prepared for non-
`
`commercial settings, such as clinical trials. Id. at 110:13-112:8. Additionally, UTC
`
`previously conceded, and the PTAB found, that Moriarty was the prior commercial
`
`process used to make treprostinil. IPR2020-00769, Paper 6, at 66 (P.T.A.B. July 14,
`
`2020) ( UTC admitting that the “Former Process” of Example 6 is “essentially the
`
`same” as the process disclosed in Moriarty, for U.S. Patent No. 9,593,066 with
`
`identical specification); EX1005, 17, 34, 38 (Board finding in ’393 IPR that the
`
`“Former Process” of Example 6 is the “process for preparing treprostinil according
`
`to Moriarty,” and that UTC used the Moriarty process to make commercial batches
`
`of treprostinil). Thus, there is no relevance of “commercial” versus “benchtop”
`
`synthesis with respect to the challenged claims. EX1017, ¶¶50-57.
`
`VI. UTC UNNECESSARILY ELEVATES THE LEVEL OF ORDINARY SKILL IN THE
`ART
`
`UTC’s attempt to inflate the level of ordinary skill is not supported by the
`
`claims or specification of the ʼ901 Patent. Cf. POR22-27; EX1017, ¶¶16-28. As
`
`stated above, a POSA need not have experience with “ultra-pure” pharmaceutical
`
`batches, with the heightened requirements for FDA approval of pharmaceutical salts,
`9
`
`

`

`IPR2020-00770
`U.S. Patent No. 9,604,901
`or the development of synthetic pathways for “commercial” scale pharmaceutical
`
`batches. See supra, p.9. Regardless, Dr. Winkler is a POSA even under UTC’s
`
`definition. EX1017, ¶¶7-14, 27; EX1003; EX2026, 24:13-25:18, 26:5-16, 27:5-21,
`
`29:23-30:21.
`
`VII. MORIARTY AND PHARES RENDER CLAIMS 1-9 OBVIOUS
`
`A. Motivation to Combine Moriarty with Phares with a Reasonable
`Expectation of Success
`
`1.
`
`UTC is Precluded from Disputing Motivation to Combine
`
`UTC’s argument concerning motivation to combine Moriarty with Phares is
`
`precluded because the issue was fully and fairly tried in a previous action involving
`
`substantially similar claims and was adversely resolved against UTC. For issue
`
`preclusion to apply, the unadjudicated and previously adjudicated claims need not
`
`be identical. Ohio Willow Wood v. Alps S., 735 F.3d 1333, 1342 (Fed. Cir. 2013)
`
`(applying issue preclusion to parent patent with substantially similar claim as
`
`invalidated child patent). Rather, “it is the identity of the issues that were litigated
`
`that determines whether [issue preclusion] applies.” Id. (emphasis in original). “If
`
`the differences between the unadjudicated patent claims and adjudicated patent
`
`claims do not materially alter the question of invalidity, [issue preclusion] applies.”
`
`Id.
`
`The issue of a motivation to combine Moriarty and Phares was already
`
`litigated and decided in the ’393 IPR and affirmed by the Federal Circuit. EX1005
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`U.S. Patent No. 9,604,901
`(aff’d, United Therapeutics v. SteadyMed, 702 F. App’x 990 (2017)); EX1017, ¶¶63-
`
`67. The’393 and ’901 Patent claims are substantially similar. EX1017, ¶68. Both
`
`patents require a process of (i) alkylating a benzindene triol; (ii) hydrolyzing the
`
`product of step (i); (iii) contacting the product of step (ii) with a base to form a
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`treprostinil salt; (iv) isolating the salt of treprostinil; and (v) optionally reacting the
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`treprostinil salt from step (iii) to form treprostinil. Id. (chart comparing claims).7
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`The only differences are that the ’901 Patent claims include an impurity limitation
`
`and amount of treprostinil. EX1017, ¶69. These differences are immaterial, because
`
`they are not excluded from the claims of the ʼ393 Patent and are nonetheless
`
`disclosed by the exact same combination of Moriarty and Phares that invalidated the
`
`’393 Patent. Id., ¶¶69-73.
`
`
`
`7 UTC is wrong that only the ’901 Patent prohibits isolation of the intermediate
`
`treprostinil acid before salt formation (POR53). The ’393 Patent claims a process
`
`step of “contacting the product of step ([b]) with a base B to form a salt.” EX1004,
`
`19:14, 20:27. The “product of step ([b]) in claim 1 of the ʼ393 Patent is a solution.
`
`Id., 12:34-39 (“A 50-L, cylindrical reactor . . . was charged with a solution of
`
`treprostinil in ethyl acetate (35-40 L from the previous step), anhydrous ethanol
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`(5.1L) and diethanolamine (435g).”); Example 6 (steps 30-31).
`
`
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`IPR2020-00770
`U.S. Patent No. 9,604,901
`Particularly for product-by-process claims, the product—not the process—
`
`controls. In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985); Amgen v. F. Hoffman-
`
`La Roche, 580 F.3d 1340, 1369 (Fed. Cir. 2009). UTC conceded that the ’393 and
`
`’901 Patents claim the same product. See EX1006, 98-99 (UTC citing certificates
`
`of analysis for the product claimed in the ʼ393 Patent, and relied upon by UTC’s
`
`experts, to argue that the “pharmaceutical batch” of the ʼ901 Patent “is different from
`
`the product produced by the process described in Moriarty 2004.”). Thus, the
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`storage issues claimed in the ’901 Patent claims 6 and 7 would be the same for both
`
`patents’ products.
`
`In sum, UTC has “not provided any explanation regarding how the
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`[additional] limitations” of the ’901 Patent are “patentably significant” to the
`
`motivation to combine Moriarty and Phares “in view of the obviousness
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`determination regarding the claims of the [’393] patent.” Ohio Willow Wood, 735
`
`F.3d at 1343 (emphasis in original). Thus, issue preclusion should apply.
`
`2.
`
`A POSA Would Have Been Motivated to Form the
`Treprostinil Diethanolamine Salt of Phares with a
`Reasonable Expectation of Success
`
`A POSA would be motivated to combine Phares and Moriarty because
`
`(1) Phares is directed to improving treprostinil, and the Moriarty process was a well-
`
`known way to make treprostinil and (2) eliminating the intermediate isolation and
`
`crystallization steps taught by Moriarty increases synthetic efficiency and lowers
`
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`IPR2020-00770
`U.S. Patent No. 9,604,901
`production costs for treprostinil diethanolamine salt. Pet., 52; EX1005, 50; EX1017,
`
`¶¶126-127.8 A POSA would have been further motivated to form the Phares salt
`
`from Moriarty’s free acid because:
`
` Bioavailability: As Dr. Pinal confirms, Moriarty’s treprostinil free acid
`
`has an “absolute oral bioavailability of less than 10%.” EX2025, ¶254
`
`(quoting EX1008, 4). Phares discloses, however, that treprostinil
`
`diethanolamine has an oral bioavailability of 21-25% when delivered in
`
`0.2-2.0 mg doses—a more than 100% increase. EX1008, 83. To improve
`
`bioavailability, a POSA would be motivated to form the treprostinil
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`diethanolamine salt of Phares. EX1017, ¶128, Section XI.C.1; see also
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`EX1018, 139:11-142:20.
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` Safety of Diethanolamine Salt: Phares discloses clinical studies in which
`
`humans received treprostinil diethanolamine, which exhibited a “safety
`
`profile…consistent with the reported safety profile and product labeling of
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`
`
`8 As of December 2007, “[s]alt formation [was] a well-known technique to modify
`
`and optimize the physical chemical properties of an ionizable research or
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`development compound.” EX1024, 1. By the end of 2006, over 50% of FDA-
`
`approved APIs were salts. Id., 2 (Table 1).
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`U.S. Patent No. 9,604,901
`[FDA-approved] Remodulin (treprostinil sodium) and other prostacyclin
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`analogs.” EX1008, 83. Because of the known safety of treprostinil
`
`diethanolamine, a POSA would have been motivated to form the
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`treprostinil diethanolamine of Phares. EX1017, ¶¶127-128, Section
`
`XI.C.2.
`
`Moriarty and Phares are not directed to different problems (cf. POR54-56)—
`
`both are directed to treprostinil. Even if they were, “[o]ne of ordinary skill in the art
`
`need not see the identical problem addressed in a prior art reference to be motivated
`
`to apply its teachings.” Cross Med. Prods. v. Medtronic Sofamor Danek, 424 F.3d
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`1293, 1323 (Fed. Cir. 2005).
`
`A POSA would have had a reasonable expectation of success in combining
`
`Moriarty with Phares, because, as Dr. Pinal explains, “[t]he end of Moriarty is the
`
`beginning of Phares” (EX1018, 135:6), formation of a salt by contacting a free acid
`
`with a base is basic chemistry (EX1017, ¶144, Section XI.E.2), “over 50% of all
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`APIs in the market today are produced as salts” (EX2025, ¶178), and Phares
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`discloses safely administering treprostinil diethanolamine (UT-15C) at “detectable
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`and potentially therapeutic” concentrations to clinical study patients (EX1018,
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`143:6-150:15). EX1017, ¶¶131-139; EX1008, 82 (Example 5).
`
`For these reasons, a POSA would be motivated to combine Moriarty with
`
`Phares with a reasonable expectation of success.
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`U.S. Patent No. 9,604,901
`3.
`and
`Isolation
`Intermediate
`the
`of
`Elimination
`Crystallization Steps of Moriarty Would Have Been
`Obvious
`
`UTC also argues that a POSA would not have been motivated to eliminate
`
`Moriarty’s isolation and crystallization steps9 before combining with Phares’ salt
`
`formation. POR29-34, 57-62. But UTC ignores that a POSA would be motivated
`
`to take the treprostinil free acid of Moriarty and convert it into a salt, as disclosed in
`
`Phares. A POSA would be further motivated to more efficiently perform these
`
`process steps. EX1017, ¶¶129-130. The Board already rejected UTC’s argument
`
`and accepted the efficiency motivation in the ’393 IPR. See EX1005, 47.
`
`As Dr. Winkler explains, a POSA looking to form a salt would eliminate the
`
`isolation step of Moriarty to more efficiently form a salt from a preexisting solution,
`
`without recourse to isolation of a solid, re-dissolving that solid, and then forming
`
`salt. EX1017, ¶¶140-144, Section XI.E.2. A POSA would have been motivated to
`
`eliminate the crystallization steps of Moriarty because (a) crystallization would not
`
`be needed if isolation of crude treprostinil is eliminated during the process of salt
`
`formation, and (b) eliminating crystallization would avoid formation of “white
`
`
`
`9 See EX1017, ¶141 (highlighting the eliminated isolation and crystallization steps
`
`of Moriarty in yellow and green, respectively).
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`U.S. Patent No. 9,604,901
`needles,” which Dr. Pinal explains may create manufacturing difficulties. See
`
`EX2025, ¶267 (quoting EX2008, 62) (“Generally, needle-shape crystals are not
`
`desirable because of their poor flow properties.”); EX1017, ¶143. Further, a POSA
`
`would have a reasonable expectation of success in eliminating these steps because
`
`the formation of a carboxylate salt by the addition of a base to a neutral carboxylic
`
`acid (i.e. treprostinil free acid) is a standard purification procedure. EX1017, ¶144,
`
`Section XI.E.2.
`
`UTC’s argument concerning “late-stage” or “large-scale” pharmaceutical
`
`manufacturing should be rejected. POR32, 34. The claims of the ’901 Patent do not
`
`include limitations requiring “late-stage” or “large-scale” manufacturing. See
`
`Sections IV-V, supra. Besides arguing that eliminating an isolation step can leave
`
`impurities in a final product (which is not an issue here as the ʼ901 Patent claims
`
`require the presence of impurities (POR35)), UTC provides no specific reason why
`
`a POSA would be motivated to perform the intermediate purification and isolation
`
`steps before forming the treprostinil diethanolamine salt. See POR29-34.
`
`Further, UTC mischaracterizes Dr. Winkler’s cross-examination testimony
`
`and overstates the standard for obviousness as to whether a POSA would “know,”
`
`versus have a “reasonable expectation of success.” POR33-34. Dr. Winkler was
`
`testifying only as to the potential for impurities to interact with reagents and not to
`
`the effect of eliminating the intermediate isolation step, as UTC contends. EX2026,
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`16
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`U.S. Patent No. 9,604,901
`111:16-112:15. Regardless, “[a] rea