PATENT OWNER’S
`DEMONSTRATIVES
`
`Liquidia Technologies, Inc. v. United Therapeutics Corp.
`
`IPR2020-00770 – U.S. Patent No. 9,604,901
`
`June 23, 2021
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`UT EX2037
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`DEMONSTRATIVES
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`Liquidia Technologies, Inc. v. United Therapeutics Corp.
`
`IPR2020-00770 – U.S. Patent No. 9,604,901
`
`June 23, 2021
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`CHALLENGED CLAIMS OF THE ’901 PATENT
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`2
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`EX1001 (901 Patent), 17:24-18:29; Paper 12 (POR), 1.
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`CHALLENGED CLAIMS 1-9
`
` Ground 1: Obviousness over Phares
`
` Ground 2: Obviousness over Moriarty in view of Phares
`
`3
`
`Paper 1 (Petition), 2-3, 25; id., 29-48 (Ground 1); id., 49-75 (Ground 2); EX1002 (Winkler), ¶¶62-141 (Ground 1); id., ¶¶142-
`238 (Ground 2); Paper 12 (POR), 1-2, 27-51 (Ground 1), 51-66 (Ground 2).
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`GROUNDS FOR INSTITUTION
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` Ground 1: Obviousness over Phares
`– Claims 1-9, no demonstration of reasonable likelihood of obviousness
`
` The “best course of action here is to permit the parties to fully develop the record
`during trial before resolving these disputes.”
` Ground 2: Obviousness over Moriarty in view of Phares
`– Claims 1-5 and 8-9
`
`– Claims 6-7, no demonstration of reasonable likelihood of obviousness
`
` “we are not persuaded”
`
`4
`
`Paper 7 (Institution Decision), 22-28 (Ground 2, claims 1-5 + 8-9), 28-29 (claims 6 + 7), 30-31 (Ground 1).
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`LIQUIDIA FAILED TO
`CARRY ITS
`BURDENS
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`5
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`LIQUIDIA HAS FAILED TO PROVE ITS PRIMA FACIE CASE
` Closed impurity claim limitations:
`– Neither Moriarty nor Phares teach an impurity profile.
` Salt Formation:
`– Moriarty does not teach contacting a solution of treprostinil with a base to form a salt of
`treprostinil.
`– Moriarty does not teach isolating a salt of treprostinil.
` Scale:
`– Phares does not teach a single reaction that yields even 1 gram of product after
`purification, let alone a reaction relevant to treprostinil diethanolamine.
` Storage:
`– Neither Moriarty nor Phares teach storage.
`– Phares suggests instability due to polymorphs and hygroscopicity, drastically complicating
`the manufacture, storage, and stability of pharmaceutical batches and products.
`Paper 12 (POR), 27-51 (Ground 1), 51-66 (Ground 2).
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`6
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`LIQUIDIA’S SLOPPINESS IS FATAL TO THEIR PETITION
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` Didn’t establish that a translation was correct
` Didn’t have sworn testimony from Dr. Winkler
` Provided unintelligible testimony from Dr. Hall-Ellis
` Didn’t establish that their art was actual prior art
`
`7
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`Paper 31 (MtE), 2-10; Paper 12 (POR), 17-22.
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`LIQUIDIA IMPROPERLY ATTEMPTS TO SHIFT BURDEN OF PROOF
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` Petitioner bears the burden for:
`– Unpatentability over printed publication
`prior art
`– Collateral estoppel
`
`“In an inter partes review
`instituted under this chapter,
`the petitioner shall have the
`burden of proving a
`proposition of unpatentability
`by a preponderance of the
`evidence.”
`
`-
`
`35 U.S.C. §316(e)
`
`8
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`Paper 6 (POPR), 7, 57; Paper 12 (POR), 28-29, 48, 63.
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`LEVEL OF
`ORDINARY SKILL IN
`THE ART
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`9
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`COMPARING THE PROFFERED POSA DEFINITIONS
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` Dr. Pinal: Consistent with claims, specification, and asserted art
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` Dr. Winkler: Self-serving and unsupported by evidence
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` Dr. Hall-Ellis: Bizarre
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`10
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`Paper 6 (POPR), 55-57; Paper 12 (POR), 1-2; Paper 25 (Sur-Reply), 13-16.
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`DR. PINAL ACTUALLY CONSIDERED BACKGROUNDS OF THOSE IN THE
`ASSERTED ART + REAL PROBLEMS IN THE FIELD
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`“[T]he POSA in the relevant field in December
`2007 would have been an experienced process
`chemist or chemical engineer. This individual
`must have had experience in the production
`and
`manufacture
`of
`pharmaceutical
`compositions and pharmaceutical products.”
`- Dr. Pinal
`
`11
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`EX2002, ¶100; Paper 12 (POR), 22-27; Paper 25 (Sur-Reply), 13-16.
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`DR. PINAL’S OPINION IS SUPPORTED BY EVIDENCE
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`“[T]he majority of medicinal chemists working in
`the
`pharmaceutical
`industry
`are
`organic
`chemists whose main concern is to design and
`to synthesize novel compounds as future drug
`entities. While they focus on this challenging
`primary goal, salt formation is often restricted to a
`marginal activity with the short term aim of obtaining
`nicely crystalline material. Moreover, chemists are
`not explicitly trained in the various aspects of
`pharmaceutical
`salts
`and
`their
`inherent
`opportunities.”
`
`- Stahl
`
`12
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`EX2008 (Stahl), iv; Paper 12 (POR), 22-27; Paper 25 (Sur-Reply), 13-16; EX2002 (Pinal), ¶94.
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`DR. WINKLER’S SELF-SERVING POSA DEFINITION
`
`in the art
`“[A] person of ordinary skill
`(POSA) of chemistry at the time of the
`alleged invention would have a master’s
`degree or a Ph.D.
`in medicinal or
`organic chemistry, or a closely related
`field.”
`- Dr. Winkler
`
`13
`
`EX1002, ¶¶16-17; Paper 1 (Petition), 25; Paper 12 (POR), 1, 22-27; Paper 25 (Sur-Reply), 13-16.
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`DR. WINKLER’S SELF-SERVING POSA DEFINITION
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`“I have assessed the level of ordinary skill
`in the art based upon my review of the
`prior art, the patent, and my over thirty
`years of working in the field of organic
`chemistry.”
`- Dr. Winkler
`
`14
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`EX1002 (Winkler), ¶¶14-15; Paper 1 (Petition), 25; Paper 12 (POR), 1, 22-27; Paper 25 (Sur-Reply), 13-16.
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`DR. WINKLER ASSUMES WHAT HE WAS OFFERED TO PROVE
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`“In deciding what the level of skill of the
`POSA would be, I simply considered the
`kinds of problems that – the types of
`problems
`that
`are
`typically
`encountered in organic and medicinal
`chemistry.”
`- Dr. Winkler
`
`15
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`EX2026 (Winkler Depo #1), 41:10-23; Paper 1 (Petition), 25; Paper 12 (POR), 1, 22-27; Paper 25 (Sur-Reply), 13-16.
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`DR. WINKLER’S UNSUPPORTED POSA DEFINITION
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`“I have been advised to consider factors
`such as the educational level and years
`of experience not only of the person or
`persons who have developed the
`invention, but also others working in
`the pertinent art at
`the time of
`the
`invention…”
`- Dr. Winkler
`
`16
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`EX1002 (Winkler), ¶¶14-15; Paper 1 (Petition), 25; Paper 12 (POR), 1, 22-27; Paper 25 (Sur-Reply), 13-16.
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`PARTIES + BOARD AGREE POSA DEFINITION SHOULD BE
`CONSISTENT WITH PRIOR ART
`
`“[W]e find that the level of ordinary skill in the
`art is reflected by the prior art, including
`Phares and Moriarty.”
`- Institution Decision
`
`17
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`Paper 7 (Institution Decision), 22; Paper 12 (POR), 22-23; Paper 25 (Sur-Reply), 13-16.
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`LEVEL OF SKILL REFLECTED BY THE ART
`
`KEN PHARES
` Ph.D. Pharmaceutical
`Chemistry
` VP of Pharmaceutical
`Development for ~20 years
`‒ Managed process scale-up
`‒ Coordinated pharmaceutical
`development from API
`characterization to drug
`product development process
`scale-up.
`
`DAVID MOTTOLA
` Ph.D. Pharmacology
` Guided product development
`from startup
` R&D leadership, including
`quality and process
`improvement
`
`BOB MORIARTY
` President and founder of
`Steroids Limited, 1989-2014
`‒ Commercial organic
`synthesis
` Professor emeritus of University
`of Illinois, Chicago
`
`18
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`EX2029-31 (LinkedIns); EX2032 (Winkler Depo #2), 225:16-239:21; Paper 25 (Sur-Reply), 13-14.
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`DR. WINKLER DOESN’T KNOW WHAT HE DOESN’T KNOW
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`“…the types of problems encountered in
`the art…”
`- Dr. Winkler
`
`19
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`EX1002 (Winkler), ¶¶14-15; Paper 12 (POR), 24-26; Paper 25 (Sur-Reply), 13-16.
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`PROBLEMS IN THE ART ARE NOT ONES ORGANIC + MEDICINAL
`CHEMISTS KNOW HOW TO SOLVE
`“Problems concerning the physical
`form of drug
`substances have been with us for nearly 10 years at
`the interface between the disciplines essential to
`the development of new drugs: chemical process
`development, analytical chemistry, pharmaceutical
`sciences, pharmacokinetic, toxicology, and clinical
`studies. These problems have for many years figured
`prominently in the nightmares of industrial chemists
`and pharmacists, not to mention those of their quality
`assurers, regulatory writers, and project managers.”
`- Stahl
`
`20
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`EX2008 (Stahl), iv; Paper 1 (Petition), 25; Paper 12 (POR), 24-26; Paper 25 (Sur-Reply), 13-16; EX2002 (Pinal), ¶94.
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`PROBLEMS HERE ARE NOT ONES ACADEMICS KNOW HOW TO SOLVE
`
`the specific
`“Academics … heard about
`problems related to pharmaceutical crystal and
`powder engineering fairly late from industrial
`colleagues who are often reticent to air their
`difficulties in public.”
`
`- Stahl
`
`21
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`EX2008 (Stahl), iv; Paper 12 (POR), 24-26; Paper 25 (Sur-Reply), 13-16; EX2002 (Pinal), ¶94.
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`RELEVANT EVIDENCE SUPPORTS DR. PINAL’S CONCLUSIONS…
`
`“[I]n my opinion, an organic or medicinal
`chemist is not an appropriate definition for
`the person of ordinary skill in the art. Neither
`is a sophomore organic chemistry student or an
`individual with a bachelors with five years’
`experience in organic chemistry.”
`
`- Dr. Pinal
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`22
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`EX2002 (Pinal), ¶100; Paper 12 (POR), 22-27; Paper 25 (Sur-Reply), 13-16.
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`…DR. WINKLER’S OPINION LACKS SUPPORT
`
` Dr. Winkler does not cite a single piece of
`evidence (except for his own CV) in rendering his
`opinion on the level of ordinary skill in the art.
`
` Instead, he makes references elsewhere to
`undergraduate textbooks on micro and miniscale
`laboratory experiments and dismisses the
`technology of the ’901 patent as “organic
`chemistry 101.”
`
`23
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`EX1002 (Winkler), ¶¶14-17 (POSA definition); id., ¶¶5, 47 (organic chemistry 101); Paper 6 (POPR), 56-57; Paper 12
`(POR), 22-27; EX2002 (Pinal), ¶¶21-27, 80, 84-85, 88, 90-101, 141, 202-07.
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`THE EXPERTS’ CONTRASTING EXPERIENCE
`
`Dr. Rodolfo Pinal
` Ph.D. in Pharmaceutical Sciences
` Associate Professor, Department of Industrial and
`Physical Pharmacy at Purdue University
` Director of Purdue’s Center for Pharmaceutical
`Processing Research
` 30+ years studying formulation science
` 13+ years in pharmaceutical industry
`‒ Research Associate + Senior Scientist in pre-
`formulation
`‒ Principal Scientist in sterile dosage forms
`‒ Principal Scientist + Research Leader in solid
`state pharmaceutics
`‒ Extensive work with process chemists in the
`chemical synthesis department’s Kilo Lab.
`
`Dr. Jeffrey Winkler
` Ph.D. in Chemistry
`‒ 35+ years of experience in academia
`‒ Focuses on development of new synthetic
`organic methodology and natural product
`synthesis
`‒ “an expert in the field of organic chemistry”
` Submitted unsworn “declaration” that merely
`copied the attorney argument in the Petition
`‒ Testimony riddled with scientific errors and
`inaccuracies
` Evasive and unresponsive at depositions
`
`24
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`Paper 12 (POR), 22-27; EX2002 (Pinal); EX2026 (Winkler Depo #1); 47:12-20; Paper 6 (POPR), 29-30.
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`DR. HALL-ELLIS’S BIZARRE POSA DEFINITION
`
`A POSA “would typically be someone who is a
`medical physicist with a Ph.D.
`(or similar
`physics, medical
`advanced
`degree)
`in
`physics, or a related field, and two or more
`years of experience in radiation oncology
`physics, treatment planning, treatment plan
`optimization related to radiation oncology
`applications, and computer programming
`associated with treatment plan optimization.”
`- Dr. Hall Ellis
`
`25
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`EX1015 (Hall-Ellis), ¶16; Paper 6 (POPR), 55; Paper 25 (Sur-Reply), 13-16.
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`CLAIM
`CONSTRUCTION
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`26
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`LIQUIDIA OFFERED NO CONSTRUCTIONS
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`“The petition must
`set forth: … (3) How
`the challenged
`claim is to be
`construed.”
`-
`37 C.F.R. §42.1-4(b)(3)
`
`“For purposes of
`resolving this IPR,
`Petitioner
`does
`not
`believe
`construction
`of
`claim terms
`is
`required.”
`- Liquidia
`
`27
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`Paper 1 (Petition), 18-19; Paper 6 (POPR), 7; Paper 12 (POR), 8.
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`LIQUIDIA’S EVER-CHANGING MOODS
`Claim Term
`Liquidia’s IPR Construction
` Pharmaceutical Batch
` No construction required
`(claims 1-4, 6, and 8)
`
` No construction required
`
` Contacting the solution
`comprising treprostinil
`from step (b) with a base
`to form a salt of
`treprostinil
`
` Ambient temperature
`(claim 6)
`
`Liquidia’s District Court Construction
` “Pharmaceutical batch made according to
`the process recited in steps (a) – (d) and
`optionally (e), wherein no purification
`steps appear between alkylation and salt
`formation”
`
` “contacting the solution comprising
`treprostinil from step (b) with a base to
`form a salt of treprostinil, wherein the salt
`is formed without isolation of treprostinil
`after alkylation and hydrolysis”
`
` No construction required
`
` “Room temperature or, on average 25˚ C”
`
` Storing/Storage (claim 6)
`
` No construction required
`
` Indefinite
`
`28
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`Paper 1 (Petition), 18-19; EX1053 (Markman Transcript); Paper 38 (Petitioner’s Motion to Submit Supplemental Evidence), 6-8.
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`THE BOARD FOLLOWED UT’S CONSTRUCTION FOR FOUR TERMS
`
` Pharmaceutical Batch
`
` Pharmaceutical Product
`
` Storing/Storage
`
` A Salt Treprostinil
`
`29
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`Paper 7 (Institution Decision), 15-17; Paper 6 (POPR), 6-11.
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`THE BOARD’S PHARMACEUTICAL BATCH CONSTRUCTION
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`“[A] specific quantity of treprostinil (or its salt)
`that is intended to have uniform character
`and quality, within specified limits, and is
`produced
`according
`to
`a
`single
`manufacturing order during the same cycle
`the uniform
`of manufacture, wherein
`character and quality is such that
`it still
`contains impurities resulting from the method
`by which it is produced.”
`
`- Institution Decision
`
`30
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`Paper 7 (Institution Decision), 15-16; Paper 12 (POR), 9-10; EX2025 (Pinal Response), ¶¶75-79.
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`THE BOARD’S PHARMACEUTICAL PRODUCT CONSTRUCTION
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`“[A] chemical composition manufactured for
`pharmaceutical use.”
`- Institution Decision
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`31
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`Paper 7 (Institution Decision), 15-16; Paper 6 (POPR), 9-10; Paper 12 (POR), 10-11; EX2025 (Pinal Response), ¶¶71-74.
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`THE BOARD’S A SALT TREPROSTINIL CONSTRUCTION
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`“[A] salt of treprostinil.”
`
`- Institution Decision
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`32
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`Paper 7 (Institution Decision), 15-16; Paper 12 (POR), 12; EX2025 (Pinal Response), ¶80.
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`THE BOARD’S STORING/STORAGE CONSTRUCTION
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`Requiring “stability of the material being stored
`in a batch quantity in the context of commercial
`pharmaceutical manufacturing” and “that
`the
`stored material possesses stability sufficient
`to allow manufacture and which maintains
`integrity for a sufficient period of time to be
`useful for the preparation of a pharmaceutical
`product.”
`- Institution Decision
`
`33
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`Paper 7 (Institution Decision), 16-17; Paper 12 (POR), 11-12; EX2025 (Pinal Response), ¶¶81-83.
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`RELEVANT EVIDENCE SUPPORTS UT’S POSITIONS
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`“Based on the current record, and for the
`purposes of
`this decision, we generally
`agree with Patent Owner’s
`proposed
`constructions of these terms because they
`are supported by relevant evidence.”
`- Institution Decision
`
`34
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`Paper 7 (Institution Decision), 15-16; Paper 12 (POR), 8-16; EX2025 (Pinal Response), ¶¶71-83.
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`UT’S CONSTRUCTIONS FOLLOW FROM THE SPECIFICATION
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`“[I]t is fundamental that
`claims are to be
`construed in the light of
`the specifications, and
`both are to be read with a
`view to ascertaining the
`invention.”
`- United States v. Adams,
`383 U.S. 39, 48-49 (1966).
`
`35
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`Paper 6 (POPR), 6-7; Paper 12 (POR), 8.
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`LIQUIDIA TAKES
`
`LIQUIDIA TAKES
`SHORTCUTS USING
`THE ’393 IPR
`
`SHORTCUTS USING
`
`THE ”393 IPR
`
`IEEEEEEEEEEEEEEEEEEEE - EEEEEEEEEEE
`36
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`LIQUIDIA DOES NOT ANALYZE THE CLAIMS AS A WHOLE
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` Liquidia and Dr. Winkler identified and then considered only two differences
`from the ’393 patent claims.
`
` Liquidia and Dr. Winkler decided that those differences were “immaterial.”
`
` Therefore, they say, the ’393 patent IPR Final Written Decision controls.
`
`37
`
`Paper 25 (Sur-Reply), 4-5; see Paper 1 (Petition), 4-8, 19; EX1002 (Winkler), ¶¶36-37; Paper 15 (Reply), 1, 10-12;
`EX1017 (Winkler Reply), ¶¶24, 39-40, 64-73, 128.
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`LIQUIDIA + DR. WINKLER FOCUS ON “DIFFERENCES,” NOT EACH
`CLAIM AS A WHOLE
`
`“The only differences are bolded: the
`’901 patent’s independent claim 1
`includes an impurities limitation in
`the preamble and an amount of
`treprostinil limitation at the end of the
`claim.”
`- Dr. Winkler
`
`38
`
`EX1017 (Winkler Reply), ¶69; Paper 15 (Reply), 11-12; Paper 25 (Sur-Reply), 4-5.
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`LIQUIDIA + DR. WINKLER FOCUS ON “DIFFERENCES,” NOT EACH
`CLAIM AS A WHOLE
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`39
`
`Paper 25 (Sur-Reply), 4-5; see Paper 15 (Reply), 11-12; EX1017 (Winkler Reply), ¶¶68-69.
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`DR. WINKLER ONLY CONSIDERS TWO CLAIM LIMITATIONS
`
`I
`that
`differences
`only
`“The
`considered,
`the
`in
`other words,
`differences as a scientist that I felt were
`important here are the ones that I’m
`showing.”
`- Dr. Winkler
`
`40
`
`EX2032 (Winkler Depo #2), 194:20-198:4; Paper 25 (Sur-Reply), 4-5.
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`DR. WINKLER CONSIDERS EVEN THESE TWO LIMITATIONS “IMMATERIAL”
`
`“[T]hese differences are immaterial,
`because they are disclosed by the exact
`same combination of Moriarty and
`Phares that invalidated the ’393 patent.”
`- Dr. Winkler
`
`…but a closer look shows even
`these limitations are not taught by
`the asserted art.
`
`41
`
`EX1017 (Winkler Reply), ¶69; Paper 15 (Reply), 11-12; Paper 25 (Sur-Reply), 4-5.
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`LIQUIDIA’S COMPARISON WITH THE ’393 PATENT IS BOTH
`INACCURATE + MISLEADING
`
`42
`
`Paper 6 (POPR), 33-34, 43-50; Paper 12 (POR), 2-8, 14-16; EX2002 (Pinal), ¶¶72-83; EX2025 (Pinal Response), ¶43;
`see EX1017 (Winkler Reply), ¶¶68-69; Paper 15 (Reply), 11-12.
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`LIQUIDIA OVERLOOKS LACK OF OVERLAP OF DEPENDENT CLAIMS
`’393 Patent
`’901 Patent
` Missing
` 2. The pharmaceutical batch of claim 1, which has been dried under vacuum.
` Missing
` 3. A pharmaceutical product comprising a therapeutically effective amount of treprostinil from a
`pharmaceutical batch as claimed in claim 1.
`
` Missing
`
` Missing
`
` Missing
`
` 4. A pharmaceutical product comprising a therapeutically effective amount of a salt [of]
`treprostinil from a pharmaceutical batch as claimed in claim 1.
`
` 6. 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.
` 8. A method of preparing a pharmaceutical batch, as claimed in claim 1, 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.
`
`43
`
`EX2025 (Pinal Response), ¶43; Paper 6 (POPR), 43-50; Paper 12 (POR), 2-8, 14-16.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`GROUND 2:
`MORIARTY +
`PHARES
`
`44
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`LIQUIDIA FAILED TO
`ESTABLISH
`MOTIVATION TO
`COMBINE
`
`45
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`UT CAN ARGUE LACK OF MOTIVATION TO COMBINE
`
` The ’901 and ’393 patent are directed to different inventions:
`– Claim limitations are different
` Pharmaceutical batch, impurities resulting from steps (a)-(d), at least 2.9 g, etc.
`– Claim scope is different
`– Claim construction is different
`– Level of ordinary skill in the art is different
`– Relevant field is different
`
`46
`
`Paper 6 (POPR), 62-64; Paper 12 (POR), 52-54.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`UT CAN ARGUE LACK OF MOTIVATION TO COMBINE
`
` The Board must consider whether a POSA
`would have been motivated to combine the
`prior art in the way claimed in the claims at
`issue and had a reasonable expectation of
`success in doing so.
`– PersonalWeb Techs. LLC v. Apple, Inc., 848 F.3d
`987, 991 (Fed. Cir. 2017)
`
` The issues decided in the 393 IPR are
`different and distinct from those at issue
`here.
`
`Issue preclusion requires that “an
`issue or fact or law is actually
`litigated and determined by a valid
`and final judgment, and the
`determination is essential to the
`judgment.”
`
`B & B Hardware, Inc. v. Hargis Indus., Inc.,
`-
`135 U.S. 1293, 1303 (2015) (quoting Restatement
`(Second) of Judgements §27).
`
`47
`
`Paper 6 (POPR), 62-64; Paper 12 (POR), 52-54; Paper 7 (Institution Decision), 25, n.7 (encouraging parties to discuss
`whether issue preclusion applies in this proceeding).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`LIQUIDIA’S MOTIVATION IMPROPERLY STARTS WITH THE ’901
`PATENT …
`
`“A POSA at the time of invention of the ’901
`patent would have had reason to combine,
`and a reasonable expectation of success in
`combining, Moriarty and Phares. The
`combination of Moriarty and Phares
`discloses the same process steps and
`the same treprostinil product of the ’901
`patent.”
`- Liquidia
`
`48
`
`Paper 6 (POPR), 62-64; see Paper 1 (Petition), 51 (citation omitted).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`…AND ENDS WITH THE ’901 PATENT
`
` Liquidia’s only other motivations—increasing
`synthetic efficiency and lowering production
`costs—come from the ’901 patent specification.
`
`invention provides advantages
`“[T]he present
`[including that] the required amount of flammable
`solvents and waste generated are greatly
`reduced…[T]he present invention provides for
`a process that is more economical, safer,
`faster, greener, easier
`to operate, and
`provides higher purity.”
`- The ’901 Patent
`
`49
`
`Paper 6 (POPR), 62-64; see Paper 1 (Petition), 51; EX1001 (901 Patent), 6:4-18.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`WHY CHANGE MORIARTY?
`
`50
`
`EX1009 (Moriarty), 13; Paper 6 (POPR), 62-64; EX2002 (Pinal), ¶¶294, 297-300; see Paper 1 (Petition), 52, 56
`(indicating the claimed invention may have worse purity than Moriarty); EX1002 (Winkler), ¶¶149, 151.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`WHY CHANGE MORIARTY?
`
` Liquidia asserts a POSA would have combined Moriarty with Phares to
`“eliminate the intermediate purification step taught by Moriarty, thereby
`increasing synthetic efficiency and lowering production costs for the synthesis
`of treprostinil diethanolamine salt.”
` Neither Moriarty nor Phares notes an existing problem with synthetic
`efficacy or production costs of the Moriarty process.
` Phares does not teach that salt production increases synthetic efficiency
`or lowers production costs.
`
`51
`
`Paper 6 (POPR), 62-64; EX2002 (Pinal), ¶¶294, 297-300; see EX1002 (Winkler), ¶¶149, 151; Paper 1 (Petition), 51-53.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`WHY CHANGE MORIARTY?
`
` Liquidia asserts a POSA would have combined Moriarty with Phares to
`“eliminate the intermediate purification step taught by Moriarty, thereby
`increasing synthetic efficiency and lowering production costs for the synthesis
`of treprostinil diethanolamine salt.”
` Adding Phares’s salt formation adds steps, forms a new chemical entity,
`adds to the number of synthetic steps, increases complexity, imparts
`concerns over stability.
`
`52
`
`Paper 6 (POPR), 62-64; EX2002 (Pinal), ¶¶294, 297-300; see EX1002 (Winkler), ¶¶149, 151; Paper 1 (Petition), 51-53.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`THE WORKING EXAMPLE IS MORE COMPLEX THAN MORIARTY
`
`53
`
`EX2025 (Pinal Response), ¶¶89-90 (annotating ’901 patent Example 6); Paper 6 (POPR), 61-62; Paper 12 (POR), 63-64;
`EX2002 (Pinal), ¶¶133-34.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`THE WORKING EXAMPLE IS MORE COMPLEX THAN MORIARTY
`
`54
`
`EX1001 (901 Patent), Example 6; Paper 6 (POPR), 61-62; EX2002 (Pinal), ¶¶133-34; Paper 12 (POR), 31-32; EX2025 (Pinal
`Response), ¶¶89-90.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`DR. WINKLER'S CHEMICAL IMPOSSIBILITY
`
`“Dr. Pinal argues that a POSA would not be motivated to
`eliminate the crude treprostinil isolation step because
`‘the POSA would have to first neutralize the KOH by
`means of an acid work-up to access neutral treprostinil
`free acid’...Moriarty discloses that KOH can be
`neutralized in the presence of methanol using HCl
`to
`access the neutral treprostinil free acid. See Ex. 1009 at 13
`(‘Then the reaction mixture was refluxed for 3 h and cooled
`at 0 ˚C, then 3 M aqueous HCl was added until pH 10-
`- Dr. Winkler
`12.’).”
`
`55
`
`EX1017 (Winkler Reply), ¶103; EX2025 (Pinal Response), ¶¶158, 185, 232; Paper 31 (MtE), 5-8; Paper 12 (POR), 29-34.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`DR. WINKLER’S ARISTOFF HAIL MARY FAILS TO CONSIDER THE
`DIFFERENT PROCESSES
`
`“[T]he neutralization doesn’t occur at pH 10 to
`12...I looked at footnote 18(c), I saw the paper by
`Aristoff…in 1985. And so I looked at that paper to
`see whether
`the workup procedure for
`the
`formation of the treprostinil free acid, how that
`compared to what was described in Moriarty…”
`- Dr. Winkler
`
`56
`
`EX2032 (Winkler Depo #2), 168:1-177:12; Paper 31 (MtE), 5-8.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`WHAT HAPPENED TO DR. WINKLER’S RATIONALE?
`
`“[T]he neutralization doesn’t occur at pH 10 to
`12…[M]ost of the solvent was removed in vacuo.
`The resulting solution was diluted with water and
`extracted in ethyl acetate…The aqueous layer
`was acidified to pH 2 to 3 by addition of 3 molar
`HCl…and then extracted with ethyl acetate.
`- Dr. Winkler
` Dr. Winkler backtracks to agree Moriarty’s full
`work-up needs to be performed before salt
`form can be pursued.
`
`57
`
`EX2032 (Winkler Depo #2), 168:1-177:12; Paper 31 (MtE), 5-8; Paper 25 (Sur-Reply), 1-2, 20-24; Paper 12 (POR), 29-34; Paper 1 (Petition), 38 (asserting
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`a POSA could skip Moriarty’s isolation to be “faster, more efficient, and more economical”); EX2025 (Pinal Response), ¶¶158-63.
`
`UT EX2037
`
`
`
`DR. WINKLER’S BACKTRACK UNDERMINES ANY MOTIVATION
`
`58
`
`EX1008 (Phares), 22; Paper 6 (POPR), 51; EX2025 (Pinal Response), ¶¶158-63, 237; Paper 12 (POR), 30-32.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`WHY CHANGE MORIARTY?
`
`“Moriarty does not teach preparation
`of a diethanolamine salt of treprostinil
`or preparation of a pharmaceutical
`product comprising treprostinil salt.”
`- Dr. Winkler
`
`59
`
`EX1002 (Winkler), ¶149; Paper 6 (POPR), 62-64; EX2002 (Pinal), ¶¶294, 297-300; Paper 12 (POR), 60-62.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`WHY CHANGE MORIARTY?
`
`Q: “Does Moriarty teach converting the
`treprostinil back into a salt?”
`
`“Moriarty does not
`Dr. Winkler:
`explicitly teach that, no.”
`
`60
`
`EX2025 (Winkler Depo #1), 130:15-18; Paper 6 (POPR), 62-64; EX2002 (Pinal), ¶¶294, 297-300; Paper 12 (POR), 60-62.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`DR. WINKLER ADMITS MORIARTY DOES NOT TEACH AT LEAST:
`
`61
`
`EX1002 (Winkler), ¶149; EX2025 (Winkler Depo #1), 130:15-18; Paper 6 (POPR), 62-64; Paper 12 (POR), 60-62;
`EX1001 (901 Patent), 17:24-18:29.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`NO ESTABLISHED MOTIVATION TO COMBINE
`
` Moriarty and Phares teach different
`compounds and have different focuses
`and aims.
`
` The mere fact that a modification could
`be made falls well short of a motivation
`such that the POSA would have made
`the modification.
`
`“[I]t is not enough to show that ‘a
`skilled artisan, once presented with
`the two references, would have
`understood that they could be
`combined.’”
`
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`-
`IPR2018-00827, Paper 9, 10-11 (2018) (informative)
`(citing Personal Web Techs., LLC v. Apple, Inc., 848
`F.3d 987, 993 (Fed. Cir. 2017)).
`
`62
`
`Paper 6 (POPR), 64; Paper 12 (POR), 54-56; EX2025 (Pinal Response), ¶¶110-13, 161-62, 250, 260-64.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`MORIARTY + PHARES ARE DIRECTED TO DIFFERENT PROBLEMS
` Moriarty only addresses improving the synthesis of treprostinil.
`– Does not address or contemplate salts, prodrugs, or enantiomers thereof.
`– Does not identify anything wrong, inefficient, or undesirable about its synthesis or
`treprostinil product.
`– Teaches treprostinil for subcutaneous injection.
`
` Phares contemplates chemical modifications to treprostinil, focusing on
`prodrugs and their enantiomers, to yield an oral, topical, or transdermal drug.
`– Teaches treprostinil’s absolute oral bioavailability is less than 10%.
`– Teaches treprostinil is irritating on skin contact, while prodrugs are not.
`– Does not teach scalability or purity.
`– Notes treprostinil diethanolamine is hygroscopic and polymorphic.
`
`63
`
`Paper 6 (POPR), 50-51, 64; Paper 12 (POR), 54-56; EX2025 (Pinal Response), ¶¶110-13, 161-62, 250, 260-64
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`
`
`LIQUIDIA’S
`
`BELATED
`
`LIQUIDIA’S
`BELATED
`MOTIVATION
`ARGUMENTS
`
`ARGUMENTS
`
`MOTIVATION
`
`IEEEEEEEEEEEEEEEEEEEE - EEEEEEEEEEE
`64
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`LIQUIDIA IMPROPERLY EXPANDS ON PETITION IN REPLY
`
` Argues new motivations to combine Moriarty with Phares
`including:
`– Crystal morphology
`– Safety
`– Improved bioavailability
`
`65
`
`Paper 25 (Sur-Reply), 1-2; see Paper 15 (Reply), 13-16; EX2032 (Winkler Depo #2), 287:6-296:19 (clinical safety),
`250:11-252:16 (bioavailability), 321:1-322:9 (crystal morphology).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`A PROPERLY CREDENTIALED POSA UNDERSTANDS THAT CRYSTAL
`MORPHOLOGY IS IMPORTANT
`“Crystal morphology is an important
`consideration when selecting a salt form.”
`
`- Stahl
`
`66
`
`EX2008 (Stahl), 62; Paper 6 (POPR), 66-67; EX2002 (Pinal), ¶258; Paper 12 (POR), 7, 32, 36-37; EX2025 (Pinal
`Response), ¶¶267-68.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`MORIARTY DISCLOSES NEEDLE-SHAPED CRYSTALS
`
`67
`
`EX1009 (Moriarty), 13; Paper 6 (POPR), 66-67; EX2002 (Pinal), ¶¶301-02; Paper 25 (Sur-Reply), 1-2; EX2025 (Pinal Response),
`¶¶267-68; see EX2026 (Winkler Depo #1), 134:22-135:17.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`LIQUIDIA OFFERS NO ARGUMENT + DR. WINKLER OFFERS NO
`OPINION ON CRYSTAL MORPHOLOGY
`Q: “Is a needle crystal morphology generally desirable
`in pharmaceutical production?”
`***
`Dr. Winkler: “I did not offer an opinion on that…I
`in the Pinal declaration there was
`know that
`discussion of needles being problematic, and
`taught against.”
`
`Q: “Do you have a basis for a contrary opinion?”
`
`Dr. Winkler: “Like I said, I offered no opinion on this
`question.”
`
`68
`
`EX2026 (Winkler Depo #1), 134:22-135:17; Paper 6 (POPR), 66-67; EX2002 (Pinal), ¶¶301-02; Paper 12 (POR), 38, 62;
`EX2025 (Pinal Response), ¶¶267-68.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`THE PRIOR ART CONFIRMS MORIARTY’S NEEDLES WOULD HAVE
`BEEN UNDESIRABLE
`“Generally, needle-shaped crystals are
`not desirable because of their poor flow
`properties.”
`
`- Stahl
`
`69
`
`EX2008 (Stahl), 62; ; Paper 6 (POPR), 66-67; EX2002 (Pinal), ¶¶301-02.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`…ONLY AT THE REPLY STAGE DID DR. WINKLER DEVELOP A
`THEORY BASED ON PINAL’S TESTIMONY
`“[A] POSA would have been motivated to
`eliminate the crystallization steps of
`Moriarty [to]…avoid formation of
`the
`‘white
`needles,’ which Dr. Pinal
`explains
`are
`associated
`with
`manufacturing difficulties…and directly
`form the treprostinil salt of Phares from
`the treprostinil solution of Moriarty.”
`- Dr. Winkler
`
`70
`
`EX1017 (Winkler Reply), ¶143; Paper 25 (Sur-Reply), 1; EX2025 (Pinal Response), ¶268.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`UT EX2037
`
`
`
`BUT EVEN DR. WINKLER AGREES MORPHOLOGY WOULD STILL BE
`UNPREDICTABLE
`the
`that
`is
`“My
`understanding
`morphology of
`the salt would not
`necessarily
`follow
`from
`the
`morphology of
`the free acid,
`that’s
`correct, if that’s what you’re asking.”
`- Dr. Winkler
`
`71
`
`EX2032 (Winkler Depo #2), 321:1-322:9; Paper 25 (Sur-Reply),
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